Methods for direct alkene diamination, new & old

Abstract

The 1,2-diamine moiety is a ubiquitous structural motif present in a wealth of natural products, including non-proteinogenic amino acids and numerous alkaloids, as well as in pharmaceutical agents, chiral ligands and organic reagents. The biological activity associated with many of these systems and their chemical utility in general has ensured that the development of methods for their preparation is of critical importance. While a wide range of strategies for the preparation of 1,2-diamines have been established, the diamination of alkenes offers a particularly direct and efficient means of accessing these systems. The purpose of this review is to provide an overview of all methods of direct alkene diamination, metal-mediated or otherwise.

1. Introduction

The 1,2-diamine moiety is a ubiquitous structural motif found in a wealth of natural products, including non-proteinogenic amino acids and alkaloids, in pharmaceutical agents, chiral ligands and bases, and organic reagents.¹ The biological activity associated with many of these systems and their utility in general has ensured that the development of new methods for their preparation of is of critical importance. While a wide range of strategies for the preparation of 1,2-diamines have been established, the diamination of alkenes offers a particularly direct and efficient means of accessing these systems (Figure 1).

Figure 1.

General synthetic approaches to 1,2-diamines, including direct alkene difunctionalization.

Despite the importance of vicinal diamines, reviews concerning their preparation have, in the past, been rather infrequently published, in marked contrast to their 1,2-diol relatives.² However, that a recent resurgence of interest in the metal-mediated diamination of alkenes is apparent from the number of reviews dedicated to this specific topic which have appeared over the last decade.³ These articles notwithstanding, the purpose of the current review is to provide an overview of all methods of alkene diamination, metal-mediated or otherwise. In this context, the term “direct alkene diamination” encompasses reactions that lead to the formation of vicinal C_sp3-N bonds regardless of the substitution pattern or oxidation state of the nitrogen centers. Transformations in which carbon-nitrogen double bonds are formed, including the formation of α-amino-oximes during the photoaddition of N-nitroso compounds,⁴ will not be considered. Likewise, reactions in which 1,2-diamines are generated from alkenes with preexisting nitrogen-based substituents, e.g. the hydroamination of vinyl nitro compounds,⁵ will also not be discussed. Finally, since the hetero-Diels-Alder reaction of azo compounds has recently been reviewed in detail⁶ and involves 1,4- rather than 1,2-diamination of dienes, this subject will not be considered in the following article.

After an exposition of the occurrence and biological significance of 1,2-diamines, the review itself follows an essentially chronological path. Thus, the reaction of alkenes with binary nitrogen oxides and their surrogates is discussed first, followed by diamination processes that involve generation and addition of the azidyl radical. Methods employing haloamides, halogens, heavy metals and polyvalent iodine reagents then follow in sequence and finally, in the second half of the review, the metal-mediated diamination of alkenes under both stoichiometric and catalytic conditions will be discussed in depth.

2. Importance of 1,2-Diamines

2.1. Naturally Occurring 1,2-Diamines

1,2-Diamino carboxylic acids are widely distributed in the natural world, where they are found in an array of organisms in their both native state and as components of more complex natural products (Figure 2).⁷ Since they neither occur in proteins, or are coded for in the cellular genetic makeup, these amino acids are classified as non-proteinogenic.⁸ The simplest members of this group include 2,3-diaminopropionic (L-Dsp, 1) and 2,3-diaminobutanoic (Dap, 2) acid, which in addition to being found as components of non-ribosomal peptide antibiotics such as bleomycin⁹ and others,¹⁰ have also been isolated from an extraterrestrial source. Analysis of the Murchison meteorite has revealed the presence of a number of complex organic molecules, including 1 and 2, which may have participated in prebiotic polycondensation to form peptide nucleic acid material.¹¹

Figure 2.

Naturally occurring, non-proteinogenic 1,2-diamino acids and their derivatives.

Much of the interest in native 1,2-diamino acids and in particular heterocyclic β-substituted alanine derivatives stems from their role as excitatory amino acids (EAA). EAA receptors are widely distributed in the mammalian central nervous system (CNS) and play a role in a range of neural functions and abnormalities, having been implicated in such disorders as Alzheimer’s disease, epilepsy, Parkinsonism and AIDS-related dementia.¹² L-Quisqualic acid (3), isolated from the traditional Chinese medicine Shih-chun-tze, is a highly potent agonist of EAA receptors in both mammals and insects. Most recently, 3 was found as a component of the petals of zonal pelargoniums, and shown to act a potent antifeedant against the Japanese beetle, Popilla japonica.¹³ (-)-Dysibetaine (4), an unusual amino acid isolated from the marine sponge Dysidea herbacea, is also a neuroexcitotoxin, which may bind to the glutamate receptors present in the CNS of mice.¹⁴

As previously noted, 1,2-diamino acids are also found as components of non-ribosomal peptides. L-Capreomycidine (5), for example, is a key structural subunit of the tuberculostatic agent capreomycin 1B (6)¹⁵ while its β-epimer is found in the muraymycins, a family of uridylpeptide natural products that inhibit the peptidoglycan biosynthesis of Staphylococcus aureus.^16,17 Although the broad spectrum antibiotic strephothricin (7) does not contain a capreomycidine residue, this bis-diamine may be biogenetically related to this amino acid.¹⁸ Diamino carboxylic acids also play an important role in glycobiology. DiN-acetylated uronic acid residues, for example, are found in the B-band O-antigen of the lipopolysaccharide (LPS) of a number of respiratory pathogens, where they are believed to play an important role in host colonization and maintenance of infection. In this regard, nucleotide sugar UDP-2,3-diacetamido-2,3-dideoxy-D-mannuronic acid (8) is a key building block in the biosynthesis of the LPS of Pseudomonas aeruginosa, an opportunistic pathogen.¹⁹

Many alkaloid natural products conspicuously contain the vicinal diamine motif and its presence is often associated with significant biological activity (Figure 3). Structural complexity runs the gamut from relatively simple systems such as the pyrrolizidine alkaloid loline (9),²⁰ which despite it apparent simplicity presents a significant synthetic challenge,²¹ to the pentacycle citrinadin A (10)^22,23 and its structural relatives PF1270 A-C, a group of histamine H3 receptor agonists.²⁴ The 1,2-diamine functionality is also a unifying structural feature of the tetrahydroisoquinoline alkaloid family,²⁵ of which as illustrated by the antibiotic lemonomycin (11),^26,27 where it is embedded within the piperazine ring system at the core of all members of this large natural products class. In addition to terrestrial sources, marine organisms have also proven to be a rich source of biologically active 1,2-diamines, including the anti-tuberculosis agent manadomanzamine A (15),^28,29 the antineoplastic agent agelastatin A (12)³⁰ and eudistomin-K sulfoxide (13),³¹ a representative member of the eudistomin family that displays activity against both RNA and DNA viruses.³²

Figure 3.

A representative selection of naturally occurring alkaloids that encompass the 1,2-diamine framework.

While a number of the alkaloids represented in Figure 2 have succumbed to total synthesis, most recently pactamycin (14),^33,34 others including manadomanzamine A (15), remain unassailed and, a such, offer unique challenges for the development of new diamination methods. Despite the recent progress in diamination methodology, many of these targets present significant challenges to direct alkene amination methods and, as such, are an impetus to the continued investigation of diamine methods that offer enantiocontrol, differential N-protection and, importantly in the context of such complex targets, functional group compatibility.

2.2. 1,2-Diamine Pharmaceutical Agents

1,2-Diamines are found in wealth of non-natural, synthetic pharmacological tools and therapeutic agents, including several clinically approved drugs (Figure 4).³⁵ For example, the presence of a diamine-based substituent at the 7-position has proven critical in the clinical efficacy of a number of fluoroquinoline antibiotics,³⁶ including the fourth generation agent moxifloxacin (16) where this functionality is encompassed within a conformationally restricted 2,8-diazabicyclo[4.3.0]nonane ring system. Other notable anti-microbials bearing vicinal diamine moieties include the ethambutol analog SQ109 (17),³⁷ which possesses potent activity against multi-drug resistant tuberculosis, and the viral neuraminidase inhibitors oseltamivir (18)³⁸ and zanamivir (19),³⁹ which are employed for the treatment and prophylaxis of influenza virus A and B infections. In further reference to drug development, 1,2-diamines have proven to be valuable scaffolds from which to rapidly build compound libraries: notable discoveries made in this manner include SQ109 (17)³⁷ and stilbene diamine derivative 21, a potent inhibitor of hepatitis C virus RNA replication in the initial stage of infection.⁴⁰

Figure 4.

Pharmaceutically active, synthetic and semi-synthetic 1,2-diamines.

In addition to anti-infectives, 1,2-diamines are also found within a array of other pharmaceutical agents, including the antiproliferative agent nutlin-3 (22),⁴¹ the anti-emetic agent and NK₁-antagonist Sch 425078 (23),⁴² and the 2-substituted 6,8-diazabicyclo[3.2.2]nonane 20, which displays potent affinity for human σ- and δ-receptors, has a cytotoxic potency that exceeds cisplatin, and consequently has potential as an atypical anticancer agent.⁴³

With regard to semi-synthetic pharmaceutical agents, the incorporation of the non-natural vicinal diamine framework into sphingolipids and the associated change in charge of the polar head unit has proven to have a significant impact on the biological profile and metabolic stability of these molecules.⁴⁴ For example, α-galactosylceramide analog HS161 (24), which lacks a glycosidic linkage and bears an aminocyclitol as a carbohydrate surrogate, is a potent stimulator of invariant natural killer T cells,⁴⁵ while the 1-amino-1-deoxy sphingoid analog 25⁴⁶ is a specific inhibitor of human sphingosine kinase, an emerging target for cancer therapeutics.⁴⁷

2.3. 1,2-Diamines as Tools for Organic Synthesis

The importance of 1,2-diamines extends significantly beyond their role in natural products and pharmaceutical agents since they have also proven to be invaluable scaffolds for the construction of novel metal ligands,^48,49 including those that intercalate DNA,⁵⁰ radiopharmaceuticals and imaging agents.⁵¹ Diamines also serve as organocatalysts,⁵²⁵³ chiral reagents and chiral lithium amide bases⁵⁴ as well as organic receptors.⁵⁵ In particular, trans-1,2-diaminocyclohexane⁵⁶ and, to a lesser degree, it 5-membered congener⁵⁷ have proven to be privileged structures in this regard.

3. Binary Nitrogen Oxides & Related Reagents

3.1. Dinitrogen Tetroxide-Nitrogen Dioxide

The earliest known examples of direct alkene diamination involve the addition reaction of nitrogen dioxide, a process which has been studied for over a hundred years and has played a historically important role in the development of organic synthesis.^58,59 Among the various addition products formed in this process, including vicinal nitro-nitrato, nitro-nitrito and nitro-nitro compounds, it is the members of the latter group which are of interest since they are potential precursors of 1,2-diamines.

Longevity notwithstanding, the value of alkene dinitration has historically been limited by a number of practical difficulties, not least of which is the instability of the products formed in this process.⁶⁰ The reaction of nitrogen dioxide with alkenes is also made complex by virtue of the delicate equilibrium that exists between this compound, dinitrogen tetroxide (N₂O₄; 28)⁶¹ and its nitrite isomer 26 (Scheme 1).⁶² Furthermore, in polar media, both 26 and 28 can undergo heterolytic dissociation to form nitrosonium-nitrate (29) and nitronium-nitrite (30) ion pairs, which can also participate in the addition process.⁶³ As a consequence, reactions of N₂O₄-NO₂ with alkenes are often complex, display significant solvent effects and lead to the formation of numerous products, as exemplified by 2,3-dimethyl-2-butene (31) (Scheme 2).⁶⁴

Scheme 1.

Dyanamic equilibria of nitrogen dioxide.

Scheme 2.

Solvent dependancy in the reaction of nitrogen dioxide with 2,3-dimethyl-2-butene.

The mechanism of addition of N₂O₄-NO₂ with alkenes has been extensively examined, both kinetically⁶⁵ and spectroscopically (¹⁵N NMR),⁶⁶ and found to be highly dependent upon the concentration of N₂O₄-NO₂ as well as the nature of the reaction medium (Scheme 3).⁶⁷ These studies have largely confirmed Schechter’s original proposal of a radical mechanism,⁶⁸ in which NO₂ undergoes addition to the less substituted alkene position to form a β-nitroalkyl radical 37. Trapping of this intermediate with a second molecule of NO₂ then forms both dinitro 32 and nitro-nitronite 37 addition products. Oxidation of the latter species also gives rise to nitro-nitrate 34, which in common with 33 can undergo hydrolysis to form nitro alcohol 39. In more polar solvents, such as chloroform, addition can proceed through an ionic mechanism and, in this medium, formation of nitro-nitrato compound 34 becomes favored.

Scheme 3.

Mechanism of nitrogen dioxide-alkene addition.

At higher concentrations of NO₂, N₂O₅ may also participate in the initial rate determining step through direct alkene addition to form nitronite product 34 or addition to form β-nitroalkyl radical intermediate 37 and NO₂.⁶⁹ Given the electron deficient nature of NO₂ is it not surprising that the rate of addition of this radical is found to be highest with electron rich alkenes (Table 1).

Table 1.

Relative Rate of Reaction of Alkenes with N₂O₄-NO₂^a in Solution.^65b

Substrate	Relative Rateb
	0.1
	0.6
	1.0
	4.5
	16
	21.0

^aValues measured at ambient temperature in CCl₄ with a N₂O₄-NO₂ concentration of 0.1 M.

^bValues are reported relative to allylbenzene.

Although, in the case of non-symmetrically substituted alkenes, the regioselectivity of initial NO₂ alkene addition is high, non-selective trapping of the resulting β-nitroalkyl radical often leads to the formation of dinitro and β-hydroxy-nitro compounds, which, in the later case, arise from hydrolysis of the first-formed β-nitro-nitrito compounds (R = NO) (Scheme 4). The absence of skeletal rearrangement during the reaction of camphene (43) has been cited as evidence for a lack of an ionic pathway.^64b

Scheme 4.

Reaction of 1,2-disubstituted alkenes with N₂O₄.

From a practical standpoint, tetrasubstituted alkenes are the most suitable substrates for reaction with N₂O₄ since yields are generally high and bisnitration is the favored outcome. For example, reaction of Δ^9,10-octalin (46) gives rise to the formation of trans-fused decaline 47 (Scheme 5). Jacobsen has also gainfully employed the addition of N₂O₄ to cyclohexene 49 as a means to access C₂-symmetric trans-1,2-diamine 51.⁷⁰ Reaction of N₂O₄ in this case generated compound 50 as a single, trans-diastereomer, albeit in relative low yield. Hydrogenation of this vicinal dinitro compound, under medium pressure in the presence of Pd(OH)₂, proceeded in high yield to generate diamine 51, which was resolved by way of its mandelate salt. Jacobsen noted that slow addition of alkene to excess N₂O₄ was requisite for the success of this transformation since it served to avert polymerization between the tertiary radical intermediate and alkene. Müller-Bunz⁷¹ and Evans⁷² have reported closely related routes to diamine 51.

Scheme 5.

Reaction of cyclic tetrasubstituted alkenes with N₂O₄.

Other highly substituted cyclic alkene substrates which successfully undergo dinitration in the presence of N₂O₄, include 3-sulfolenes,⁷³ 3-phospholene oxides,⁷⁴ and siliacyclopent-3-enes (Figure 5).⁷⁵ In these cases, only the products of trans addition were observed.

Figure 5.

Dinitroalkane products resulting from the reaction of N₂O₄ with cyclic tetrasubstituted alkenes.

Electron deficient alkenes also undergo dinitration efficiently in the presence of nitrogen dioxide (Figure 6). Notable examples in this regard, include α,β-unsaturated nitriles⁷⁶ and perhaloalkenes.⁷⁷

Figure 6.

Dinitroalkane products resulting from the reaction of N₂O₄ with electron-deficient alkenes.

3.2. Nitric Oxide

Despite its possession of an unpaired single electron, nitric oxide (NO) in its pure state does not undergo addition to alkyl or aryl-substituted alkenes since this process is thermodynamically unfavorable. While this observation, first confirmed by Brown in 1957,⁷⁸ holds true for reactions conducted in the absence of higher nitrogen oxides, such as NO₂, this common impurity in NO catalyzes the addition process and leads to the formation of β-nitro-nitroso compounds (pseudonitrosites)⁷⁹ and/or their dimers.⁸⁰

Capitalizing on the fact that NO undergoes disproportionation to N₂O and NO₂ at high pressure, Wilkinson (Scheme 6)⁸¹ and others⁸² have successfully conducted the nitronitrosylation of a variety of alkene substrates under medium pressure, including perhaloalkenes.⁸³ In cases where the β-nitro-nitroso addition products are unstable, other secondary processes can take place, including elimination to form nitro alkenes (Scheme 7).⁸⁴

Scheme 6.

Addition of NO to alkenes is catalyzed by NO₂

Scheme 7.

Formation and decomposition of a β-nitro-nitroso-compound.

3.3. Dinitrogen Trioxide

Generated by the combination of NO₂ and NO at low temperature, through the aerial oxidation of NO, or by the treatment of metal nitrites with sulfuric acid, dinitrogen trioxide (N₂O₃) undergoes addition to alkenes to form β-nitro-nitroso compounds (pseudonitrosites) in high yield (Scheme 8).⁸⁵ From a mechanistic perspective, this transformation has been interpreted as involving a radical process in which NO₂ adds to the alkene to generate a β-nitro radical 63, which then traps NO. Despite some early confusion as to whether β-nitroso-nitrite products are also formed in this reaction, Pfab has unequivocally demonstrated that, in the case of 2-methylpropene (62), addition of N₂O₃ primarily generates 2-methyl-2-nitroso-1-nitropropane (64) and its trans-dimer 65.⁸⁶

Scheme 8.

Reaction of N₂O₃ with 2-methylpropene.

The reaction between alkenes and nitrogen trioxide has historically played an important role in the structural determination studies of terpene natural products since their pseudonitrosite derivatives are often highly crystalline and thus amenable to qualitative and quantitative analysis. Humulene (66), for example, undergoes reaction with N₂O₃ to yield a mixture of humulene nitrosite (67a), dinitrohumulene (67b) and nitronitratohumulene (67c) (Scheme 9).⁸⁷

Scheme 9.

Reaction of humulene with N₂O₃.

Extensive studies on the reaction of naturally-occurring propenylbenzenes, including asarone,⁸⁸ isosafrole,⁸⁹ cinnamyl acetate⁹⁰ and related substrates⁹¹ with N₂O₃ have been carried out by Bruckner and others (Scheme 10). In these cases, addition occurs efficiently with high regioselectively, although the products are often unstable and, in addition to undergoing dimerization, rapidly tautomerize to the more stable β-nitro-oxime derivatives. That the stereochemical course of this transformation has rarely been determined is a further indication of the reactivity of the primary addition products.

Scheme 10.

Reaction of N₂O₃ with propenylbenzenes.

The reaction of dinitrogen trioxide with a range of cyclic alkenes and dienes, including cyclopentadiene,⁹² cycloctadiene,^91,93 and indenes has also been reported (Figure 7).⁹⁴

Figure 7.

Products of the reaction of N₂O₃ with cyclic alkenes

That allyl and vinylsilanes 71 undergo addition, rather than substitution,⁹⁵ is indicative of a free radical mechanism (Scheme 11). A similar conclusion can be drawn from the regioselectivity observed during the addition of N₂O₃ to substituted chalcones 72.⁹⁶

Scheme 11.

Reactions of N₂O₃ with unsaturated silanes and chalcones.

Despite the extensive body of literature concerning the preparation of pseudonitrosites, conversion of these alkene addition products to the corresponding 1,2-diamines remains a challenging undertaking. In large part, this is due to the propensity with which these systems undergo competitive elimination; e.g. treatment of compound 75 with LiAlH₄ leads to the exclusive formation of monoamine 74 (Scheme 12).⁹³ Vicinal diamine 78 can be accessed from 74, albeit indirectly, through a sequence of Lewis acid-mediated isomerization to the corresponding α-nitro-oxime 76 and stepwise hydrogenation.

Scheme 12.

Conversion of pseudonitrosites to the corresponding diamines.

3.4. Silver Nitrate & Trimethylsilyl Chloride

Most recently, Demir and Findik have a reported a convenient method for the generation of dinitrogen trioxide, through the action of AgNO₃ on trimethylsilyl chloride (Scheme 13).⁹⁷ Treatment of alkenes, such as cyclohexene (55) with this reagent in THF or acetonitrile yielded the corresponding β-nitroso-nitrite compounds and their dimers.

Scheme 13.

In-situ generation of N₂O₃ with AgNO₃/TMSCl.

Since the focus of Demir’s study was the preparation of furoxanes (79), the initially formed addition products were directly treated with sulfuric acid to generate the desired heterocycles, presumably by way of the corresponding β-nitro-oximes. Nevertheless, the high yield of pseudonitrite (58a) and the furoxane products, indicate that the addition step in this case is efficient.

3.5. Nitrosyl Chloride & Dinitrogen Tetroxide

The reaction of nitrosyl chloride with alkenes has been extensively studied and almost exclusively leads to the formation of monomeric and dimeric β-nitroso chlorides. However, attempts by Adekenov and co-workers to nitrosochlorinate the guaianolide achillin (80a) led to the selective formation of cis-1,2-dinitro compound 81a (Scheme 14).⁹⁸ A similar result was subsequently noted for the closely related terpene grossmisin (80b).⁹⁹

Scheme 14.

Dinitration of unsaturated terpenes with the reagent combination NOCl/N₂O₄.

The unanticipated formation of compounds 81a and 81b was ascribed to the presence of N₂O₄ as an impurity in the NOCl employed in this transformation. N₂O₄ promotes a radical process and likely involves the formation of a β-nitroalkyl radical, which is trapped to form a nitrosonitrate, which undergoes oxidation ¹⁰⁰ to form the observed products. Indeed, reaction of 80a with NOCl spiked with N₂O₄ led to increased yield and rate over purified NOCl (37 vs. 80%), while treatment with N₂O₄ alone also generated 81a, albeit in lower yield.

3.6. Photolysis of N-Nitroso Compounds

N-Nitroso compounds undergo photolysis under acidic conditions to generate nitric oxide and the corresponding aminium radical (Scheme 15).⁴ In the case of N-nitrosopiperidine (NNP; 82) photolysis in acidic aqueous solution (pH 2) generates piperidinium radical 85, which originates from the lowest singlet excited state (84) of the NNP-acid complex 83.¹⁰¹

Scheme 15.

Photolysis of N-nitrosopiperidine (NNP) under acidic conditions.

Aminium radicals generated in this manner are electron deficient and undergo a range of chemical reactions, including addition to alkenes (Scheme 16). In the case of cyclohexene (55), photolysis in the presence of an equimolar quantity of N-nitrosodimethylamine generates trans-addition product 86 in high yield.¹⁰² Depending on the reaction conditions employed, this compound, to varying degrees, undergoes dimerization to yield 87, rearranges to α-amino-oxime 88, or takes part in a secondary process with the monomer of hyponitrous acid (HNO) to form N-nitrosohydroxylamine 89a. In light of these multiple pathways, yields of this type of process are often impractically low, although Chow has reported conditions, involving extended photolysis and the use of excess nitrosoamine, that favor the formation of N-nitrosohydroxylamines (89a-c).¹⁰³ In the case of cyclohexane derivative 86, reduction with LiAlH₄ generates the corresponding 1,2-diamine, which was acetylated to provide 90.

Scheme 16.

Photoaddition of N-nitrosodimethylamine with cyclohexene and other alkenes.

While irreversible tautomerization of the initially formed β-amino-nitroso monomers, such as 86, is observed for most substrates that bear a hydrogen atom at the position alpha to the nitroso group, those systems that lack this feature react to generate the N-nitroso products, as in the case of methylcyclohexene (91) (Scheme 17).¹⁰⁴ Unfortunately, while photoaddition with more substituted alkenes is highly regioselective, the addition products generated from these substrates are prone to fragmentation, as in the case of 92 which undergoes fragmentation and hydrolysis to form ketoaldehyde 94.

Scheme 17.

Formation and fragmentation of C-nitroso-β-amines.

3.7. Thermolysis of Tetramethyl-2-tetrazene-Lewis Acid Complexes

Prepared through the Hg(II)-mediated oxidation of 1,1-dimethylhydrazine,¹⁰⁵ tetramethyl-2-tetrazene (TMT) forms 1:1 complexes with a range of Lewis acids, including zinc halides (Scheme 18).¹⁰⁶ Taking advantage of the propensity of these compounds to readily undergo thermal decomposition to form dimethylamino radicals, Michejda and co-workers have developed a method for alkene diamination employing the zinc chloride complex 95.¹⁰⁷

Scheme 18.

Diamination of styrenes via the thermolysis of the tetramethyl-2-tetrazene-zinc chloride complex.

Heating 95 in the presence of excess ZnCl₂ and conjugated alkenes, such as indene (97) or α-methylstyrenes (100), leads to the formation of the corresponding bis(dimethylamino) adducts, albeit in low yield. That the reaction of 97 results in the exclusive formation of the trans addition product 99, was cited as evidence that addition of the two dimethylamino groups proceeds through a stepwise process rather than a concerted one. Detailed Hammett studies also suggest that the dimethylamino radical 96 generated upon the decomposition of 95 is intimately associated with zinc chloride.

3.8. Nitroamidation: Nitronium Salts & the Ritter Reaction

Alkenes undergo reaction with both nitrosonium and nitronium tetrafluoroborate in the presence of nitriles to generate carbocations 103 but whereas the former process leads to the formation N-hydroxyimidazolium salts,¹⁰⁸ the reaction of nitronium ions can be employed as a means of diamination. In the presence of nitrile solvents, these intermediates are trapped to form nitrilium ions 104, which undergo hydrolysis to form the products of nitroamidation (Scheme 19). The first report of this type of process was by Scheinbaum, who in 1971, reported that the reaction of simple alkenes 102 with nitronium tetrafluoroborate in acetonitrile generated α-nitro amides 105.^109,110

Scheme 19.

Nitroamidation alkenes with nitronium tetrafluoroborate in acetonitrile.

While Scheinbaum’s original report only encompassed three alkenes, Mellor and co-workers have subsequently studied this nitroamidation method in more detail, employing a wider range of substrates and found that, in the case of conjugated alkenes, higher yields can be obtained through use of CH₂Cl₂ as a co-solvent (Scheme 20).¹¹¹ In all cases, addition was found to be rapid, highly regioselective and favored the Markovnikov products. That trans-β-methylstyrene (106) undergoes cis addition was confirmed by conversion of 107a to imidazoline 108. Notably, 1-phenylcyclohexene underwent trans addition to yield 107e. Nitroacetamidation of less nucleophilic alkenes, including hex-1-ene, oct-1-ene, cyclohexene, and cyclopentene, was found to be considerably less efficient.

Scheme 20.

Reaction of alkenes with nitronium tetrafluoroborate.

In light of the expense of nitronium tetrafluoroborate and its high moisture sensitivity, Mellor has developed a method for its in-situ electrogeneration from nitrogen dioxide, through anodic oxidation (Scheme 21).¹¹² Yields, in most cases, are higher than those obtained with the non-electrogenerated reagent, an observation which was ascribed to the absence of acidic impurities present during electrolysis.

Scheme 21.

Nitroamidiation of conjugated alkenes with electrochemically generated nitronium tetrafluoroborate.

In this one-pot procedure, electrogeneration of the nitrogen electrophile must precede alkene addition since co-electrolysis failed to provide the nitroacetamide products.

3.9. Ceric Ammonium Nitrate-Sodium Nitrite-Acetonitrile

In an approach that avoids the use of nitronium salts, Vankar and co-workers have developed a nitroamidation method that entails the treatment of alkenes with ceric ammonium nitrate (CAN) and sodium nitrite in nitrile solvents (Scheme 22).¹¹³

Scheme 22.

Vankar’s alkene nitroamidation method.

Oxidation of nitrite under these conditions is proposed to generate nitrogen dioxide, which undergoes alkene addition to form a β-nitroalkyl radical 111. A second electron transfer to CAN then generates carbocation 112, which participates in a Ritter reaction to yield the observed products. Notably, use of benzonitrile and acrylonitrile offer access to benzamides (113b) and α,β-unsaturated amides (113e). That this process displays negligible diastereoselectivity in the substrates examined, reflects the intermediacy of the carbocation intermediate.

3.10. Acetyl Chloride-Silver Nitrate-Acetonitrile

Vankar has recently developed a reagent system comprising of acetyl chloride, silver nitrate and acetonitrile for the nitration and nitroamidation of glycals and simple alkenes (Scheme 23).¹¹⁴ The acetyl nitrate (115) generated under these conditions is posited to undergo reaction with the substrate to generate a β-nitro carbocationic intermediate 116 whose fate is highly dependent on both the reaction conditions employed and the nature of the substrate itself.¹¹⁵ In the case of tri-O-benzylated galactal 120, reaction at elevated temperature leads to proton loss from the intermediate glycosyl cation and formation of nitroglucal 119. Nitroamidation, on the other hand, is favored at lower temperatures and in the case of 120, leads to the formation of 121 with high diastereoselectivity. Routes to 2-nitro-1-acetamido sugars of this type are of importance in light of the biological significance of 2-amino-β-glycosylamines, which constitute the core structural motif of N-linked glycoproteins.

Scheme 23.

Vankar’s second-generation alkene nitroamidation method and its application to the preparation of 2-nitroglycals and 2-nitro-1-acetamido sugars.

A significant temperature dependence was also observed with E-stilbene (122), which underwent nitroamidation with complete cis selectivity (Scheme 24). Although cyclohexene and 1-methylcyclohexene undergo nitroamidation, the formation of 125a and 126a is accompanied by significant quantities of the elimination products 125b and 126b.

Scheme 24.

Nitroamidation of simple alkenes under Vankar’s conditions.

4. Alkene Bisazidonation via Redox

The azide anion (N₃⁻) has a relatively low E₀ (ca. −0.6 V)¹¹⁶ and consequently can be oxidized with a range of organic and metal-based oxidizing agents to the corresponding azidyl radical (N₃^·). This species is sufficiently electrophilic to undergo addition to a range of alkenes^117,118 and trapping of the resulting β-azidoalkyl radical with a suitable azide donor, offers a convenient means of alkene diazidonation under mild reaction conditions. This “redox-chain” approach to diamination was first reported by Minisci and co-workers who utilized the reaction between tert-butyl hydroperoxide or hydrogen peroxide, and ferrous sulfate to effect the transformation (Scheme 25).^119,120 From a mechanistic standpoint, Minisci has proposed that ferrous sulfate mediates the decomposition of hydroperoxide (1) and the resulting alkoxy radical interacts with an azido Fe(III) complex to generate the azidyl radical (2). Upon alkene addition, azide transfer between an iron(III) azide complex and the β-azido radical then generates the 1,2-diazide and completes the redox cycle.

Scheme 25.

Ferrous sulfate-mediated diazidonation of alkenes.

Minisci has also reported the use of a Fe(II)/Fe(III) system in the conjunction with a variety of oxidants, including hydrogen peroxide, permanganate,¹²¹ and Ce(IV) salts (Scheme 26).¹²²

Scheme 26.

Ferric-Ferrous sulfate-mediated diazidonation of alkenes.

As shown in Scheme 27, the combination of ammonium peroxydisulfate and the Fe(II)/Fe(III) system also been employed for the diazidonation of styrene (127) (Scheme 27).¹²³ In this case, the yield of diazide 128 is significantly improved over that obtained with hydrogen peroxide.

Scheme 27.

Ferric-Ferrous sulfate-mediated diazidonation of alkenes in the presence of ammonium peroxydisulfate.

Fristad has reported the use of Mn(III) acetate as a highly effective reagent for alkene diazidonation (Scheme 28).^124,125 In this case, treatment of alkenes with Mn(OAc)₃ and sodium azide in acetic acid at elevated temperatures leads to the formation of 1,2-diazides 133 in high yield. Efficiency not withstanding, this methodology necessitates a large excess of azide (15 equiv) in order to prevent the formation of monoazidination products, which presumably arise from hydrogen atom transfer to the β-azido radical intermediate. Although the mechanism of this transformation has yet to be fully delineated, the dramatic rate acceleration noted in the presence of alkenes was posited as evidence of a ligand-transfer oxidation, rather than the participation of the azide radical.

Scheme 28.

Mn(III)-mediated diazidonation of alkenes.

Snider has subsequently reported a modification of Fristad procedure in which replacement of acetic acid with a mixture of acetonitrile and trifluoroacetic acid as the reaction medium leads to significant improvements in yield (Scheme 29).¹²⁶ That acid sensitive substrates, such as tetrahydropyran (134), are tolerant of these conditions is likely a reflection of the fact that reactions proceed at temperatures as low as −20 °C. Recent application of this methodology include the preparation of 1,2-cyclohexanediamines for oxaliplatin-type complexes¹²⁷ and the synthesis of imine-based protein labels.¹²⁸

Scheme 29.

Snider’s Mn(III)-mediated diazidonation of alkenes.

Alkene diazidonation can also be accomplished through electrochemical generation of the azidyl radical. Schäfer has reported that co-electrolysis of solutions of sodium azide in glacial acetic acid and alkenes (1:3, v/v) leads to the formation of 1,2-diazides 136 (Scheme 30).¹²⁹

Scheme 30.

Alkene diazidonation via azide anion electrolysis.

While this method is reasonably efficient for electron-rich, styrene substrates, the yield for cyclic and acyclic alkenes is less satisfactory.

5. Heavy Metal-Mediated Bisazidonation

5.1. Lead(IV) Acetate-Trimethylsilyl Azide

Lead(IV) acetate azide [Pb(OAc)_4-n(N₃)_n] (137) is an effective azide transfer reagent, which is generated by the reaction of lead(IV) acetate and trimethylsilyl azide.¹³⁰ In light of its thermal instability (decomposition occurs rapidly above −20 °C), this reagent must be generated in situ.¹³¹ Zbiral has reported the reaction of this reagent with alkenes to form vic-diazides, albeit in a highly temperature and solvent dependent manner (Scheme 31). In the case of styrene (128), reaction of 137 in acetonitrile at −20 °C leads to the formation of phenacyl azide (138) while reaction at 20 °C generates vic-azide 139 in high yield. In dichloromethane, reaction of 137 and 128 leads to more complex mixtures of products whose composition is dependent on the order of reagent addition.

Scheme 31.

Generation of [Pb(OAc)_4-n(N₃)_n] and its temperature dependent reaction with styrene.

The formation of elimination (143) and rearrangement (145) products during the reaction of camphene (142) and other bridged alkenes with 137, has been cited by Zbiral as persuasive evidence of a “positive” azide-transfer, in which aziridinium ion 141 and carbocation intermediate 142 are involved (Scheme 32).¹³² Unfortunately, in most substrates, diazidonation is accompanied by the formation of vicinal acetoxy-azido products. Furthermore, acyclic alkenes, such as trans-stilbene (122), undergo diazidonation in a non-stereospecific manner as a result of the cationic intermediate.

Scheme 32.

Reaction of [Pb(OAc)_4-n(N₃)_n] with camphene and E-stilbene.

While the usefulness of Zbiral’s reagent with non-cyclic alkenes is limited by the intermediacy of cations, this is not the case with cyclic substrates. Draper has shown that steroidal 4,6-dien-3-ones 148 are suitable substrates for diamination and undergo reaction with 137 to form B-ring vic-diazides 150 with high stereoselectivity (Scheme 33).¹³³ In this case, it is suggested that the lead-mediated azide transfer proceeds through silyl dienol ether 149, which is formed by the Lewis acid-mediated 1,4-addition of trimethylsilyl azide to 148.

Scheme 33.

Reaction of [Pb(OAc)_4-n(N₃)_n] with steroidal 4,6-dien-3-ones.

The behavior of steroidal dienone substrates stands in contrast to that of the analogous trisubstituted Δ⁶-steroidal alkenes, which, depending on the reaction conditions employed, react with the lead tetraacetate-trimethylsilyl azide reagent to form allylic azides¹³⁴ or seco keto nitriles.¹³⁵

5.2. Thallium(III) Acetate-Trimethylsilyl Azide

Zbiral has also developed an analogous reagent to 137, generated from thallium(IV) acetate, which also mediates diazidonation, albeit in a less efficient manner (Scheme 34).¹³⁶ Treatment of thallium(III) acetate with trimethylsilyl azide generates [Tl(OAc)_3-n(N₃)_n] (151), which undergoes reaction with alkenes to generate the corresponding aziridinylazothallium compounds 152 and 154. While only putative intermediates in the analogous lead-mediated transformations, these organothallium compounds are sufficiently stable to permit isolation.

Scheme 34.

Reaction of [Tl(OAc)_4-n(N₃)_n] with cyclohexene and 4-allylanisole.

Thermolysis of 152 and 154 leads to the formation of 1,2-diazido compounds 153 and 156, although, in both cases, the predominant products are the parent alkenes, which were proposed to arise through a cheletropic fragmentation reaction.

6. Heavy Metal-Mediated Diamination

6.1. Thallium Acetate-Amines

Barluenga has reported a method for the preparation of diamines using thallium(III) acetate. Treatment of alkenes with aromatic amines in the presence of this heavy metal salt leads to the efficient formation of the corresponding diamines 158 (Scheme 35).¹³⁷ While primary and secondary aromatic amines participate in this process, primary aliphatic amines fail to react. This reaction is thought to proceed via aminothallation to generate an organothallium intermediate, 157, which subsequently undergoes substitution. Notably, 1,4-dienes, specifically 1,4-hexadiene and 1,4-cyclooctadiene, undergo double addition to form cyclic and bicyclic products 158f and 158g respectively. The relative stereochemistry of these products was not reported.

Scheme 35.

Addition of aromatic amines to alkenes in the presence of thallium(III) acetate.

6.2. Mercury Acetate-Amines

Barluenga and co-workers have demonstrated the ability of β-amino alkylmercury(II) salts, formed through alkene aminomercuration, to undergo substitution with a range of nucleophiles, including amines. Initial studies found that treatment of alkenes with the reagent generated from tetrafluoroboric acid and mercury(I) oxide and aromatic or primary amines led to the efficient formation of 1,2-diamines 160 and Hg(0) (Scheme 36).¹³⁸ The efficiency of this process is highly dependent on the degree to which the C-Hg bond is polarized. For example, the treatment of the β-amino alkylmercury salts of acetate and halides with amines leads only to retromercuration and formation of alkenes.

Scheme 36.

Addition of aromatic amines to alkenes in the presence of mercury(II) tetrafluoroborate.

In a more recent mechanistic study, Barluenga has investigated the aminomercuration of 1,4-cyclooctadiene (161) under these conditions as a means of accessing 2,6-disubstituted-9-azabicyclo[3.3.l]nonanes (Scheme 37).¹³⁹ Treatment of 161 with mercury(II) tetrafluoroborate in the presence of aniline leads directly to the formation of bicyclic triamine 163 as a single diastereomer. The reaction is thought to proceed via intermediate 162.¹⁴⁰ The aminomercurials 162 (X = Cl, OAc) generated from mercury(II) chloride or acetate, proved to be less prone to substitution and their transformation to 163 requires more forcing conditions. Reagent notwithstanding, the authors propose that the formation of the observed products proceeds via an aziridinium ion intermediate(s) generated by the internal displacement of the mercury centers in 162.

Scheme 37.

Mercury(II)-mediated bis-diamination of 1,4-cyclooctadiene.

Barluenga has found that (+)-limonene (164) displays unexpected behavior in its diamination reactions with mercury(II) tetrafluoroborate (Scheme 38).¹⁴¹ While reaction of this diene at low temperature proceeded as anticipated, with Markovnikov selectivity at the more accessible exocyclic alkene, heating the resulting aminomercurial (165) at 80 °C leads to the formation of trans-diamine 167 (Ar = Ph, p-ClPh, p-MePh). The formation of this product was attributed to mercurinium ion exchange whereby 165, unable to undergo displacement to form an aziridinium ion, undergoes β-elimination and ion transfer to generate intermediate 166. Stepwise substitution with two equivalents of arylamine then leads to the observed trans-1,2-diamine.

Scheme 38.

Diastereoselective mercury(II)-mediated diamination of (+)-limonene proceeds with unanticipated regioselectivity.

7. N,N-Dihaloarylsulfonamides & N-Haloarylsulfonamides

7.1. N,N-Dihaloarylsulfonamides-Acetonitrile

Although a stepwise approach to diamination and thus beyond the purview of this article, the aziridination of alkenes and use of the strained products as substrates for ring-opening via a Ritter reaction is an appealing strategy for the stereocontrolled introduction of vicinal nitrogen functionality.¹⁴² In this regard, Li and co-workers, in 2003, first reported a novel method for the indolizidination of α,β-unsaturated carbonyl compounds which is thought to proceed via the Ritter-type reaction of an aziridinium ion intermediate (Scheme 39).^143,144 Treatment of α,β-unsaturated ketones and esters, such as methyl cinnamate (168), with N,N-dichloro-p-toluenesulfonamide (TsNCl₂, 167), 4 Å molecular sieves, and the complex generated from Rh₂pfb₄ and Ph₃P in acetonitrile was found to generate trans-substituted 2-dichloromethyl-2-imidazolines 170 in moderate to high yield and with excellent diastereoselectivity. The formation of trans imidazolines in this case corresponds to a cis diamination process.

Scheme 39.

Direct imidazolination of α,β-unsaturated ketones and esters with the reagent combination TsNCl₂/MeCN/Rh₂pfb₄·PPh₃.

Li has also discovered a number of other catalysts that significantly accelerate the imidazolination process, including Rh₂TFA₄·PPh₃,¹⁴⁵ FeCl₃·PPh₃,¹⁴⁶ MnO₂,¹⁴⁷ and most recently, triphenylphosphine.¹⁴⁸ In the case of MnO₂ and Rh₂TFA₄·PPh₃, diamination proceeds to generate the trichloromethyl rather than dichloromethyl imidazolines. The copper-catalyzed (CuI·PPh₃) addition of N,N-bromo-p-toluenesulfonamide (TsNBr₂) to α,β-unsaturated ketones and esters has also been reported.¹⁴⁹ In this case, the formation of dichloromethyl imidazolines is favored.

On the basis of their work on the related alkene aminohalogenation reaction,¹⁵⁰ Li and co-workers have posited a general mechanistic interpretation of this remarkable transformation (Scheme 40). In a stereospecific process that is accelerated but not dependent upon catalyst additives (vide infra), diamination commences with the formation of N-sulfonyl-N-chloroaziridinium ion 172. In the presence of nitriles, participation of this intermediate in a Ritter-type reaction, involving nucleophilic ring opening at the more substituted or benzylic position, then generates 1N-(tosyl)imidazolium ion 174. Given the overall syn stereochemistry of the diamination process, Li has suggested that this process occurs via a [2+3] mechanism in which 174 is formed directly. Displacement of the 1N-chlorine group in this intermediate then gives rise to 3N-(tosyl)imidazolium ion 175, which undergoes proton loss and a second S_N2′-type displacement to form 2-chloromethyl imidazoline 177. 3N-Chlorination of 177 and a repetition of the deprotonation and displacement steps are then proposed to lead to the observed product 178.

Scheme 40.

Proposed mechanism for Li’s alkene syn-imidazolination process.

Intriguingly, subsequent studies by Li have revealed that during the addition of TsNCl₂ to α,β-unsaturated ketones the need for a catalyst can be obviated simply by raising the reaction temperature to 50 °C.¹⁵¹ Furthermore, in the case of the more reactive reagent N,N-dichloro-2-nitrobenzenesulfomamide (NsNCl₂, 180), imidazolination of enones 179 proceeds in the absence of catalyst at room temperature to generate the dichloromethyl adducts (Scheme 41).¹⁵² Interestingly, when conducted in the absence of molecular sieves, addition of 180 proceeds at 50 °C to the corresponding trichloromethyl imidazoline products 181.

Scheme 41.

Direct imidazolination of α,β-unsaturated ketones with the reagent combinations NsNCl₂/MeCN.

In order to avoid the inconvenience of handling N,N-dichlorosulfonamides 169 and 180, Li has a protocol for the in-situ generation of these unstable reagents. Treatment of enones and dienones with p-toluenesulfonamide (182) and N-chlorosuccinamide (NCS) at 50 °C generates the expected products in comparable yield to the parent reagent (Scheme 42).¹⁵³ Notably, other nitrile partners, including isobutyronitrile and benzonitrile can be employed and, in the case of benzylideneacetone, leads to the formation of 183f and 183g, respectively. NsCl₂ (180) can also be generated in this manner, although in the case of this more electrophilic reagent, esters as well as unsaturated ketones undergo imidazolination.¹⁵⁴

Scheme 42.

Direct imidazolination of α,β-unsaturated ketones with the reagent combination TsNCl₂/NCS/RCN.

Importantly, Li and co-workers have demonstrated that the imidazoline products 183 can be hydrolyzed to the corresponding open-chain diamines without epimerization at either chiral center (Scheme 43).¹⁵⁵ Exposure of these heterocycles to aqueous hydrochloric acid at 70 °C mediates rapid hydrolysis to the differentially protected syn-1,2-diamines 184 in excellent yield. Stannic chloride (SnCl₄/THF/H₂O) has also been utilized as an effective promoter of imidazoline hydrolysis.^149,148

Scheme 43.

Acidic hydrolysis of imidazolines to form differentially protected vicinal diamines.

7.2. N-Chlorosaccharin-Acetonitrile-KOEt

An elegant one-pot method for the cis-imidolizidination of alkenes has also been developed by Booker-Milburn and coworkers (Scheme 44).¹⁵⁶ In the presence of acetonitrile, alkenes undergo a Ritter-type reaction with the electrophilic chlorinating agent N-chlorosaccharin (NCSacc, 185) to generate a putative nitrilium ion intermediate 187. Capture of 187 by the saccharin anion gives rise to β-chlorosulfonylamidines 188. Treatment of these reactive intermediates with potassium ethoxide then mediates ring-opening of the benzothiazoletrione ring to form an amidine anion 189, which cyclizes to form the corresponding imidazoline systems 186 in low to moderate yield. When isolable, by-products of this process include aziridines and allylic chlorides, which arise from the first-formed chloronium ion intermediate through eliminative ring opening and capture by saccharide, respectively. In common with Li, Booker-Milburn has found that the ring opening of the imidazoline products to differentially protected diamines under acidic conditions presents no difficulties.

Scheme 44.

Imidazolination of alkenes with the reagent combination NCSacc/MeCN/KOEt.

7.3. Chloramine-T-Iodine-Acetonitrile

In 2006, Ramesh and Kumar reported the use of chloramine T in a remarkably straightforward, one-pot method for the diamination of glycals (Scheme 45).^157,158 Treatment of tri-O-acetyl-D-glucal (190) with 2.3 equivalents of chloramine T in the presence of a catalytic quantity of iodine (15 mol%) leads to the selective formation of β-D-gluco 1,2-disulfonamide 191a in good yield. This mild procedure is successful with a range of mono-, di- and trisaccharide glycals, is compatible with both O-acetate and O-benzyl protecting groups and, in most cases examined, proceeds with complete diastereoselectivity.

Scheme 45.

Iodine catalyzed one-pot diamination of glycals with chloramine-T.

On the basis of their own observations and studies by Komatsu on the iodine-catalyzed aziridination of alkenes using chloramine-T,¹⁵⁹ Ramesh and Kumar have proposed a mechanism for the diamination process (Scheme 46). Rapid reaction of chloramine-T (192) with iodine is thought to generate iodine-chloramine-T complex 193, which reacts from the β-face of glycal 190 to form iodonium ion 194. Diaxial ring opening of this species at the anomeric center by chloramine-T then leads to 195, which, with the aid of iodide, undergoes cleavage of the N-Cl bond and ring closure to form glycal aziridine 196 and iodine monochloride (ICl). Ring opening of 196 by a second molecule of chloramine-T then yields 1,2-disulfonamide 191a, after protonation. That stoichiometric quantities of iodine monochloride were found to mediate this transformation in place

Scheme 46.

Proposed mechanism of Ramesh’s one-pot glycal diamination method.

In light of the central structural role that 2-amino-β-glycosylamines play in N-linked glycoproteins, the development of synthetic routes to this glycodomain is a goal considerable importance. In this regard, Ramesh has exploited the differential reactivity of the anomeric and C-2 sulfonamide groups within the glycal addition products to develop a general route to glycosyl amino acids and peptides (Scheme 47). For instance, N-acetylation of 197 proceeds only at the more nucleophilic C-2 position to provide 198 in excellent yield. Conversion of this material to N-Ala-Asp linked glycopeptide 200 was accomplished through a four-step sequence involving protection of the anomeric nitrogen, didetosylation, removal of the Alloc group from 199 and peptide coupling of the liberated anomeric amine.

Scheme 47.

Synthesis of N-Ala-Asp linked glycopeptide X.

8. Iodine Azide & Surrogates

8.1. Iodine Azide

The first reports of pseudohalogen-mediated diazidonation were made by Hassner and involve the use of iodine azide (IN₃) prepared by the action of sodium azide on iodine monochloride (ICl) (Scheme 48).¹⁶⁰ Although explosive in its pure state, iodine azide can be handled as a 0.25 M solution in polar organic solvents.¹⁶¹ In most cases, reaction with alkenes generates the products of anti-iodo-azidination (2), which are proposed to arise from the ring opening of an iodonium intermediate. In the presence of excess azide anion and with extended reaction times, displacement of the iodide group can take place to yield cis-1,2-diazides (3).^162,163,164 In the absence of excess azide, diazides can also form since the iodide generated during displacement reacts with iodine azide to generate iodine and an azide anion (3).¹⁶⁵

Scheme 48.

Generation, reaction and iodide-mediated disproportionation of iodine azide.

While acyclic 1,2-diazides have a tendency to undergo spontaneous elimination to form vinyl azides,¹⁶⁶ Sasaki has demonstrated that medium-sized cyclic alkenes, including tropone ethyleneketal (201), 1-ethoxycarbonyl-1(1H)-azepine and cyclooctatetraene (205), undergo diazidonation successfully (Scheme 49).¹⁶² In light of the instability of these products, they were trapped as their respective 1,3-dipolar cycloadducts 204 and 208; treatment with dimethyl acetylenedicarboxylate (DAC) proceeded smoothly. In the case of 208, valence tautomerism of cyclooctatriene 206 generates bicyclo[4.2.0]octatriene 207 which undergoes cycloaddition.

Scheme 49.

Diazidonation of cyclic polyenes with iodine azide-sodium azide.

Tamura has also reported the reaction of benzo[b]furans and 1-acyl and 1-tosyl-indoles with IN₃ in the presence of sodium azide to generate the corresponding 2,3-diazido-2,3-dihydrobenzo[a]furans and 2,3-diazidoindolines 212 (Scheme 50).¹⁶⁷ In all cases, but compound 212d, mixtures of trans and cis stereoisomers were obtained reflecting the likely intermediacy of cationic intermediates, such as 211.¹⁶²

Scheme 50.

Diazidonation of benzo[b]furans and 1-acyl and 1-tosyl-indoles.

Employing a modification of Hassner’s original conditions,^161b Schönenberger has reported the preparation of 1,2-diaryl-1,2-diazidoethanes 213 through the addition of IN₃ to E-stilbenes (Scheme 51).¹⁶⁸ That in the case of 213c, anti rather syn addition occurs may indicate the intermediacy of a β-azidocarbocation, which would be trapped from the less hindered face.

Scheme 51.

Divergent reactions of 1,3-dienes with bromine and iodine azides.

Hassner has reported a single example of the 1,2-diazidonation of a 1,3-diene (Scheme 51).¹⁶⁹ In this case, the reaction of E,E-diphenylbutadiene (215) with IN₃ generates 1,2-diazide 216 while addition of BrN₃ leads only to bromoazide 214; this likely reflects the diminished nucleofugality of the bromide group in comparison with iodide. Exposure of 215 to sodium azide in DMF generates compound 216.

In view of the difficulties associated with the handling of iodine azide, Kirschning and co-workers have developed a stable polymer-bound form of this useful reagent (Scheme 52).¹⁷⁰ Sequential treatment of polymer-bound iodide 217 with (diacetoxyiodo)benzene (DIAB) and trimethylsilyl azide generates a resin formulated as bis(azido)iodate salt 219. While most substrates undergo only azido-iodination, prolonged reaction of electron-rich alkenes with this reagent leads to the formation of 1,2-diazides, albeit in low yield and without stereospecificity. In the case of 220, it seems probable that 222 arises from azido-iodide 221, through a non-concerted displacement process.

Scheme 52.

Preparation and reaction of polymer-bound iodine azide.

Generated by the reaction of DIAB (223) with Me₃SiN₃ and tetraethylammonium iodide, bis(azido)iodate salt 225 (Scheme 53),¹⁷¹ the solution phase variant of 219, has also been employed for alkene diazidonation, by Austin and co-workers in their synthesis of the marine natural product dibromophakellstatin (228).¹⁷²

Scheme 53.

Generation of a solution-phase bis(azido)iodate salt and its use in the synthesis of (±)-dibromophakellstatin.

The key step is this endeavor involves installation of the syn-1,2-diamine functionality present on the piperidinone ring of 228. Treatment of alkene 226 with 225 provided syn-diazide 227b as the major product, albeit in modest yield, while reaction with iodine azide led to the exclusive formation of anti addition product 227a. The authors propose that while both diazides isomers may arise from a common haloazide intermediate, the cis isomer does so via bimolecular nucleophilic displacement. The trans isomer, on the other hand, appears to arise from an azido-iminium ion that undergoes ring opening from the less hindered face.

9. Halogen-Mediated Diamination & Cycloguanidination

9.1. Vicinal Diamination of 1,4-Dihydropyridines

The use of intermolecular alkene aminohalogenation as a means to accomplish the direct diamination of carbon-carbon double bonds is relatively uncommon since the competitive oxidation of alkyl and aryl amines presents a significant setback.^173,174 However, in the case of highly reactive alkene partners, such as enamines, this undesirable process can be avoided. In this regard, Lavilla and co-workers have reported a highly effect method for the vicinal diamination of 1,4-dihydropyridines (Scheme 54).¹⁷⁵ Treatment of N-alkyl-1,4-dihydropyridine 229 with iodine (3.5 equiv) in the presence of a range of cyclic amines (25 equiv) leads to the formation of the corresponding trans-2,3-diaminotetrahydropyridines 231 in high yield. The stereoselective generation of these products was rationalized in terms of the regioselective formation and trapping of a 3-iodo-3,4-dihydropyridinium ion to form intermediate 230. Internal displacement of the iodide then generates an aziridinium ion which undergoes ring opening at the 1-position with a second equivalent of amine giving rises to the trans-substituted products.

Scheme 54.

Vicinal diamination of 1,4-dihydropyridines in the presence of iodine.

While simple primary amines fail to undergo this reaction, N,N′-dimethylethylenediamine reacts with compound 229 to generate the cis-bicyclic adduct 231d in high yield.

9.2. Halogen-Mediated Cycloguanidination & Related Processes

While the direct cycloguanidination of alkenes via transition metal catalysis has recently garnered considerable attention (vide infra), the use of halogens and their synthetic equivalents to effect this transformation with 1,2-dihydropyridines has also met with considerable success. The first reports of this form of alkene diamination were made by Al-Mourabit and co-workers as part of their on-going study of 2-aminoimidazole alkaloid synthesis (Scheme 55). Treatment of carbomethoxydihydropyridine (232) with bromine or NBS in the presence of 3–4 equivalents of Boc-guanidine generated bicycles 233a and 233b, which upon exposure to HCl, where converted to cyclic guanidine 234.¹⁷⁶ N-Protected tetrahydropyridines 235¹⁷⁷ and 1,2-dihydropyridine imidates¹⁷⁸ were also found to undergo this bromine-induced transformation. In both cases, the annulation process likely proceeds in stepwise fashion where bromoamination of the enamine precedes intramolecular ring closure through N-alkylation.

Scheme 55.

Bromine-mediated cycloguanidination of N-acylated dihydropyridines and tetrahydropyridines with Boc-guanidine.

Tepe and co-workers have gainfully employed a closely related aza-annulation in their recent synthesis of the oroidin-type alkaloid (±)-dibromophakellin (240) (Scheme 56).¹⁷⁹ Treatment of a mixture of dipyrrolopyrazinone 238 and Boc-guanidine with NBS gave rise to the Boc-protected natural product 239 in low yield.

Scheme 56.

Key alkene cycloguanidination step in Tepe’s synthesis of dibromophakellin.

Further studies by Al-Mourabit have revealed that 2-aminopyrimidine (242), which is a stronger nucleophile than Boc-guanidine, can be used in place of this reagent (Scheme 57). For example, treatment of N-acylpyrrole tetrahydropyridine 241 with N-iodosuccinimide (NIS) in the presence of 242 afforded adduct 244 with moderate efficiency.¹⁸⁰

Scheme 57.

NIS-mediated cycloguanidination of N-acylated dihydropyridines with 2-aminopyrimidine.

The aza-annulation of dipyrrolopyrazinone 245, albeit without the assistance of halogen reagents, has also been described by Lindel and co-workers in their synthesis of dibromophakellstatin (247) (Scheme 58).¹⁸¹ In this situation, the activated complex generated from ethyl-N-tosyloxycarbamate and calcium oxide is proposed to react with 247 to generate an acyliminium ion that traps excess ethyl-N-tosyloxycarbamate. Subsequent cyclization and loss of ethanol then generates the imidazolidinone ring of the natural product in a single step with reasonable yield.

Scheme 58.

Key alkene cycloguanidination step in Lindel’s synthesis of dibromophakellstatin.

Although the iodonium-induced cyclization of unsaturated carboxamides, sulfonamides and carbamates to form N-heterocycles is well documented,¹⁸² the participation of N-ω-alkenyl ureas in this type of cyclization, as exemplified by the conversion of 248 to 249,¹⁸³ is comparatively rare (Scheme 59). Notwithstanding question of N vs. O selectivity, this is somewhat surprising given that 5-exo-tet cyclization of the iodoamination products in this case potentially offers an entry point to imidazolidin-2-ones, the formal products of alkene diamination. In this regard, Muñiz and Barluenga have successfully employed the iodonium source bis(pyridine)iodonium tetrafluoroborate (IPy₂BF₄) as a mediator of the direct intramolecular oxidative diamination of δ-alkenyl ureas 250 (Scheme 60).¹⁸⁴

Scheme 59.

Illustrative example of the intramolecular iodoamidation of an N-δ-alkenyl urea.

Scheme 60.

Intramolecular oxidative diamination of alkenes with N-sulfonyl ureas in the presence of bis(pyridine)iodonium tetrafluoroborate.

Treatment of N-δ-alkenyl-N′-sulfonyl ureas 250 with IPy₂BF₄ in toluene at 120 °C was found to selectively generate, in the case of terminal and 1,1-disubstituted alkenes, bicyclic imidazolidin-2-ones 253 in consistently high yield (Scheme 60). A single N-alkyl-N′-sulfonyl guanidine derivative was also found to undergo cyclization to form compound 253g in near quantitative yield. Less successfully, the cyclization of internal alkene substrates, such as 250 (R = Me), gave rise to mixtures of diamination and oxamidation products 252. Notably, the formation of both bicyclic urea 253 (R = Me) and isourea 252 occur in a stereospecifically syn fashion with respect to alkene geometry.

From a mechanistic perspective, Muñiz and Barluenga have proposed that imidazolidinone formation occurs through a sequence of two anti C-N bond-forming steps: (a) formation and ring opening of an iodonium ion giving rise to intermediate 251 and, (b) selective S_N2 displacement of the iodide group by the second nitrogen atom to form the products of a cis-diamination. Support for this hypothesis was gained from the deuterium labeling study outlined in Scheme 61.

Scheme 61.

Stereochemical course of N-sulfonyl ureas-alkene diamination reaction.

Windenhoefer and Li have recently reported a milder method for the intramolecular oxidative diamination of N-δ-alkenyl-N′sulfonyl ureas (Scheme 62).^185, For example, treatment of 256 with iodosuccinimide (NIS; 2 equiv) and sodium bicarbonate (1 equiv) at room temperature gave rise to bicyclic imidiazolidin-2-one 258a in high yield. Notably, the formation of products 258f-h occurs with high diastereolselectivity. In contrast to the findings of Muñiz and Barluenga,¹⁸⁴ the NIS-mediated cyclization of internal alkene substrates generates only diamination products, e.g. 258h, although, as before, this transformation proceeds in a stereospecific, syn manner.

Scheme 62.

Intramolecular oxidative diamination of alkenes with N-sulfonyl ureas in the presence of N-iodosuccinimide.

The oxidative cyclization of unsaturated sulfonylureas 256 has also been studied by Michael and co-workers, who employ iodosylbenzene in the presence of Lewis and Brønsted acids to mediate this process.¹⁸⁶ Although alkene diamination was observed, the predominant outcome of these reactions proves to be the formation of cyclic isoureas through intramolecular oxamidation.

10. Hypervalent Iodine Reagents

In light of their ready availability, low toxicity and reduced environmental impact, hypervalent iodine reagents have largely replaced heavy metals, such as mercury, lead and thallium, as the reagents of choice for alkene diazidonation and diamination.¹⁸⁷

10.1. Aryl-λ³-iodanes

The reaction of alkenes with aryl-λ³-iodanes has proven to be a particular effective and versatile method for the co-introduction of vicinal heteroatoms. However, in the case of alkene diamination use of these reagents is made impractical by the ease with which they oxidize primary and secondary amines. This however is not the case with azide ligands and the use of aryl-λ³-iodanes to effect alkene diazidonation has been reported by a number of groups. In 1972, Zbiral and Ehrenfreund reported that treatment of unsaturated esters 259 with PhI(OAc)₂/TMSN₃ leads to the formation of vic-diazides 260, albeit in low yield and with very limited substrate scope. (Scheme 63).¹⁸⁸ Notably, electron-rich alkenes 261 display a different reactivity mode and are converted to α-azido ketones 262.¹⁸⁹

Scheme 63.

Diazidonation of α,β-unsaturated esters with Zbiral’s hypervalent iodine reagent.

Moriarty and Khosrowshahi have reported a related, but considerable more effective diazidonation reagent generated by the action of sodium azide on iodosylbenzene (Scheme 64).¹⁹⁰ A range of alkenes, including benzofuran and N-benzoylindole, undergo reaction to yield diazides 264 with variable diastereoselectivity. Although Moriarty proposed an ionic mechanism, involving the formation and displacement of an iodonium ion intermediate 263, subsequent studies by Magnus (vide infra) suggest that a radical pathway may also exist. That Δ^5,6-steroids react with (PhIO)_n/NaN₃ to form the corresponding 7α-azidosteroids, rather than undergo diazidonation is further evidence of the presence of azide radicals in these reactions.¹⁹¹

Scheme 64.

Synthesis of vicinal diazides using Moriarty’s hypervalent iodine reagent.

Armimoto and co-workers have reported the diazidonation of allylsilanes using a mixture of iodosylbenzene and trimethylsilyl azide (TMSA) (Scheme 65).¹⁹² In this case, treatment of (PhIO)_n with TMSA at −78 °C for 3 h generates a reagent formulated as 266 or (diazidoiodo)benzene (267). Reaction with allylsilanes then provides the corresponding vicinal diazides 268 in moderate to high yield. Although the diastereoselectivity of this process was not reported, the functional group tolerance is notable. Arimoto has proposed that diazide formation proceeds via a [2+3] cycloaddition to form a triazoline intermediate, which then undergoes ring opening with azide.

Scheme 65.

Diazidonation of allylsilanes with the reagent combination (PhIO)_n/TMSN₃.

While studying methods for the electrophilic amination of ketones and their derivatives,¹⁹³ Magnus and co-workers found that treatment of triisopropyl (TIPS) enol ethers, such as 269, with the reagent combination (PhIO)_n/TMSN₃ led to dramatically differing results depending on the reaction temperature employed (Scheme 66). Reaction of 269 at 0 °C rapidly leads to the formation of β-azidonation product 270, while reduction at −78 °C favors the formation of 271a, the product of α-bis-azidonation.¹⁹⁴ It was also found that addition of catalytic quantities of the stable radical TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) served to suppress the β-azidonation pathway in favor of α-bis-azidonation. The α-azidonation process has wide substrate scope and, in most cases, proceeds with high stereoselectivity (Scheme 67).

Scheme 66.

Temperature dependent reactivity of TIPS enol ethers with (PhIO)₂/Me₃SiN₃ and substrate scope of bis-azidonation.

Scheme 67.

Proposed mechanism of enol ether bis-azidonation.

The mechanisms of these divergent transformations have been studied in detail and while β-azidonation is thought to involve ionic dehydrogenation at the β-position and capture of the resulting enonium ion by azide, α-azidonation is an azide radical addition process (Scheme 67).¹⁹⁵ Magnus has proposed that at low temperature, reaction between 265 and trimethylsilyl azide generates aryl-λ³-iodane 266 which is captured by TEMPO to form iodine(VI) species 272. Homolytic cleavage of 272 generates an azidyl radical, which then participates in the addition process to yield 271a by way of radical intermediate 274.

Although unsuitable precursors for the preparation of free 1,2-diamines, the α-bis-azidonation products shown in Scheme 67 undergo, with the aid of aluminum-based Lewis acids, substitution with a range of carbon nucleophiles to provide O-protected 1,2-azidoalcohols 275a and 275b (Scheme 68). Trapping of the intermediate onium ion in the case of bis-azide 271a proceeds with excellent diastereoselectivity.

Scheme 68.

Lewis acid-mediated reaction of bis-azide 271a with carbon nucleophiles.

Magnus has also employed the PhIO/Me₃SiN₃ reagent combination for the preparation of diamino pyrans (Scheme 69).¹⁹⁶ For example, treatment of dihydropyran (276, R = H) provided trans-bis-azide 277a while bis-azidonation of unsaturated carbamate 276 (R = NHCO₂Ad) proceeded with complete diastereoselectivity to yield 1,2-diaxial bis-azide 277b.

Scheme 69.

Bis-azidonation of glycals using the reagent combination PhIO/Me₃SiN₃.

In 2011, Muñiz and co-workers reported a breakthrough method for the iodine(III)-mediated intermolecular enantioselective diamination of styrenes (Scheme 70).¹⁹⁷ This method is not only notable in that it is metal-free and practical, requiring only two components, but is the first example of intermolecular, enantioselective alkene diamination. Employing Ishihara’s C₂-symmetric chiral iodane 280 (Scheme 71)¹⁹⁸ and bismesylide (278) as the nitrogen source, alkenes underwent addition to form diamines 279 with good yields and high asymmetric induction. In all but a few cases, the crystallinity imparted by the bissulfonyl groups facilitates purification of these products to enantiomeric purity by a single recrystallization.

Scheme 70.

Enantioselective, intermolecular diamination of styrenes under metal-free conditions.

Scheme 71.

Structure of Ishihara’s C₂-symmetric chiral iodane 280 and proposed mechanism for the enantioselective alkene diamination mediated by this reagent.

Muñiz has proposed a tentative mechanistic rationale for this transformation, in which 279 undergoes ligand exchange with 280 to generate unstable aryl-λ³-iodane 281 (Scheme 71). Reaction between 281 and the alkene then generates anti addition product 283 by way of iodonium ion 282. Ionization and formation of aziridinium ion 284 then precedes ring opening at the benzylic position to yield the observed product. The intermediacy of an aziridinium ion was invoked in order to rationalize the formation of the anti diamine product in the case of trans-β-methylstyrene (106).

As shown in Scheme 72, this methodology has been successfully applied to the preparation of the immunomodulator and veterinary anthelmintic (S)-levamisole (289). Removal of the four methanesulfonyl groups from styrene adduct 286 was accomplished in a four step sequence involving hydride reduction to bis-mono protected 287, N-benzoylation, radical N-desulfonylation under Parson’s conditions¹⁹⁹ and acidic hydrolysis. After neutralization of salt 288, the free diamine was converted to target 289 by way of the corresponding mercaptoimidazoline.²⁰⁰

Scheme 72.

Muñiz’s enantioselective synthesis of the anthelmintic (S)-levamisole.

11. Transition Metal-Catalyzed Diamination

While non-radical, transition metal-mediated alkene diamination processes have been known since the early 1970s it is only in the last decade that the value of this approach has begun to be realized in earnest. Two general mechanistic pathways by which transition metal complexes can mediate alkene diamination can be envisioned (Scheme 73).²⁰¹

Scheme 73.

General mechanistic pathways leading to the transition metal-mediated diamination of alkenes.

In the more classical manner, formation of a metal-alkene π complex precedes insertion, which generates a metal-alkyl species. Reductive elimination of this intermediate or nucleophilic displacement of the metal center then gives rise to the diamination product (eq. 1). Alternatively, metal complexes can undergo a ligand-based cis-addition reaction in which both carbon-nitrogen bonds are simultaneously generated (eq. 2).²⁰² Although of this latter process also forms the basis of the catalytic, osmium(VIII)-mediated dihydroxylation and aminohydroxylation of alkenes and thus firmly established in the canon of organic synthesis,²⁰³ the preparation of diamines through this approach has proven to be considerably more challenging.

11.1. Metal Nitrosyl Complexes

Brunner and Loskot first reported the ligand-based reaction of cobalt nitrosyl complex 291 with bicyclo[2.2.1]hep-2-enes in 1971.²⁰⁴ Generated from the reaction of cyclopentadienylcobalt dicarbonyl (290) and nitric oxide (NO) in hexanes,²⁰⁵ air-stable 291 undergoes addition to strained alkenes to form dinitrosoalkane complexes 292 (Scheme 74). This process is both diastereoselective; only the exo complexes are formed; and regioselective; in the case of dienes, i.e. in the case of 292, addition takes place only at the electron-rich alkene partner. Detailed mechanistic studies conducted by Bergman have subsequently revealed that the addition process proceeds through the intermediacy of CpCo(NO)₂, which is generated by the reaction of NO with 291.²⁰⁶

Scheme 74.

Generation of cyclopentadienylnitrosylcobalt dimer and its reaction with strained alkenes.

Brunner’s early observations were subsequently developed by Bergman and co-workers, who employed this transformation as a method for the direct 1,2-diamination of alkenes (Scheme 75).²⁰⁷ In this case, in-situ reduction of the dinitrosoalkane ligands with LiAlH₄ generates the corresponding 1,2-diamines 294 in fair to excellent yield. Notably, Bergman found that the reaction of 291 is not restricted to norbornyl systems and indeed undergoes stereospecific addition to a range of di-, tri- and tetra-substituted aliphatic alkenes. Unfortunately, despite the stereospecificity of the initial addition step, epimerization occurs to varying degrees during ligand reduction and mixtures of diamine isomers are obtained.

Scheme 75.

Two-step, one-pot 1,2-diamination of alkenes using cyclopentadienylnitrosylcobalt dimer/NO/LiAlH₄.

Taking advantage of the ability of dinitrosyl cobalt complexes to undergo reversible exchange with alkenes and the reactivity of the dinitrosoalkane ligand system itself, Toste and Bergman have more recently employed cobalt nitrosoalkane adducts as vinyl anion equivalents for the C-H functionalization of alkenes²⁰⁸ and dienes.²⁰⁹ With regard to alkene diamination, a remarkable application of their strategy to the preparation of the polycyclic 1,2-diamine 300 is shown in Scheme 76.²¹⁰

Scheme 76.

Cobalt-mediated [3+2]-annulation of alkenes with α,β-unsaturated ketones.

Most recently, Bergman and Toste have reported the first example of ruthenium-mediated alkene bis-nitrosylation (Scheme 77).²¹¹ Efficiently generated by the action of nitric oxide on [RuCl₂(NO₂)₂(THF)₂] (302), dinitrosyl complex 303 was found to undergo reaction with strained and tetrasubstituted alkenes in the presence of chelating ligands to form six-coordinate dinitrosoalkane complexes 304.

Scheme 77.

Reaction of alkenes with the dinitrosyl complex [RuCl₂(NO)₂(THF)].

In the case of 1,1-disubstituted and 1,1,2-trisubstituted alkenes addition is accompanied by tautomerization and complexes containing a nitrosoalkane and oxime functional group were isolated. In the case of 1-methylcyclohexene, reaction with 303 leads to the formation of compound 304d.

11.2. Imido-osmium(VIII) Reagents

Although first prepared in 1959,²¹² that imidoosmium(VIII) complexes undergo reaction with alkenes to form 1,2-diamines was not reported until 1977.²¹³ These air and moisture-stable reagents are readily prepared by the condensation of amines, or their equivalents, with osmium tetroxide (305) (Scheme 78).²¹⁴ In the case of N-trimethylsilyl-tert-butylamine, condensation proceeds to generate a mixture of compounds 306–308, which can be chromatographically separated.

Scheme 78.

Preparation of imido-osmium(VIII) complexes from osmium tetroxide.

Sharpless and co-workers were first to report the reaction of bis(tert-butylimido)osmium (307) and tris(tert-butylimido)osmium (308) with terminal and trans-disubstituted alkenes (Scheme 79).²¹⁵ In all cases, addition took place in stereospecific and chemoselective fashion to form diimido complexes. In contrast to osmate(VI) esters, osmaimidazolidines display remarkable stability,²¹⁶ although can be reduced to the corresponding 1,2-di-tert-butylamines 311 with LiAlH₄. Regarding substrate reactivity, cis-disubstituted and trisubstituted alkenes react slowly with 307 and 308 while introduction of electron-withdrawing groups, as in the case of fumarate 309, increases the rate of addition. This reactivity reflects the increased nucleophilicity of the imido complexes in comparison with OsO₄.²¹⁷

Scheme 79.

Stoichiometric diamination of alkenes with oxotris(tert-butylimido)osmium(VIII)/LiAlH₄.

The stoichiometric reaction of trisimidoosmium complexes with alkenes has also been studied by Schrock and co-workers, who reported the reaction of aryl imido complex 312 with simple alkenes, including ethylene and norbornene (Scheme 80).²¹⁸ Despite substantial steric encumbrance at the metal center of 312, formation of the metallaimidazolidines 313 and 314 occurred smoothly at room temperature. To date, this chemistry has not been employed in the preparation of free 1,2-diamines.

Scheme 80.

Stoichiometric diamination of alkenes with a sterically encumbered oxotris(arylimido)osmium(VIII) complex.

During the past decade, Muñiz and co-workers have expanded the early studies of Sharpless and Schrock and extensively investigated various aspects of the osmium-mediated diamination reaction as well as optimized the yield of this process.^219,220 In common with Sharpless, Muñiz has found that electron-deficient alkenes are the most favored substrates for diamination, but has also demonstrated that in addition to acrylate and cinnamate esters 315, α,β-unsaturated ketones, aldehydes, amides 318, nitriles and even 3-pyridyl acrylates are suitable substrates (Scheme 81).²²¹ Liberation of the 1,2-diamines from their corresponding metallaimidazolidines can be accomplished through reduction with LiAlH₄ or NaBH₄.²¹⁹

Scheme 81.

Stoichiometric diamination of electron-deficient alkenes with alkenes with dioxobis(tert-butylimido)osmium(VIII).

Although, to date, the inherent stability of the osmaimidazolidines has hampered the development of a fully catalytic, enantioselective variant of the diamination reaction, Muñiz has successfully deployed a number of strategies to control the absolute facial selectivity of the stoichiometric process. While efforts to effect enantioselection through the addition of Cinchona-based chiral ligands have largely been unsuccessful, as a result of the inability of 307 to complex these Lewis bases, use of chiral auxiliaries has proven more forthcoming. For example, reaction of (-)-8-phenylmenthyl acrylate derivatives 319 with 307 proceeds from the Re-face with good to excellent levels of diastereoselectivity (Scheme 82).²¹⁹ An enantioselective catalytic variant has also been developed which employs a Ti-TADDOLate catalyst and 307 as the stoichiometric nitrogen source.²²² Under these conditions, diamination of crotonyl oxazolidinone 321 (R = Me) takes place on the Re,Si-face with excellent levels of enantioinduction. The success of this process appears to stem from the comparatively low reactivity of this substrate class, which, in the absence of Lewis acids, reacts with 307 18 times slower than methyl crotonate.

Scheme 82.

Diastereo- and enantioselective diamination of electron-deficient alkenes with alkenes with dioxobis(tert-butylimido)osmium(VIII).

With regard to the reaction of the more nucleophilic tris(imido) osmium(VIII) reagent 308, Muñiz has found that, in the case of non-symmetrical olefins, formation of a configurationally stable stereogenic center at the osmium atom occurs concomitantly with diamination (Scheme 83).²²³ Methyl methacrylate (323), for example, undergoes reaction with near complete diastereoselectivity to favor formation of the osmaimidazoline 324a in which the ester group and bulky imino moiety are in a syn relationship. Compounds of this type represent rare examples of chiral-at-metal complexes with tetrahedral coordination. Diastereoselectivity was also observed in cinnamate and crotonate systems, albeit to a lesser degree.

Scheme 83.

Formation of stereogenic osmium centers during the diamination of alkenes with oxotris(tert-butylimido)osmium(VIII).

11.3. Stoichiometric Palladium(II)-Mediated Alkene Diamination

The first report of palladium-assisted alkene diamination was made in 1977 by Bäckvall, who employed stoichiometric quantities of trans-bis(benzonitrile)dichloropalladium(II) and various oxidants, including mCPBA, to mediate this one pot, two step transformation (Scheme 84). Diamine formation in this case occurs through a sequence of trans-aminopalladation,²²⁴ oxidation of the resulting β-amino σ-alkylpalladium(II) species 326 to a palladium(IV) species and reductive displacement by dimethylamine.²²⁵ Under these conditions, simple primary and 1,2-disubstituted alkenes, such as 325, underwent diamination with complete syn-selectivity in moderate to high yield. Although a range of oxidants, including Br₂, Pb(OAc)₄ and NBS, mediated the transformation of 326 to 327, mCPBA was consistently found to provide the highest yields. This observation may be attributable to the comparatively low reactivity of this reagent with alkenes, which were used in two to four-fold excess.

Scheme 84.

Bäckvall’s stoichiometric Pd-mediated 1,2-diamination of alkenes.

Bäckvall subsequently reported the stoichiometric palladium-assisted syn-1,4-diamination of 1,3-dienes with dimethylamine. ²²⁶ In this case, 1,2-diamination was not observed and the process is believed to involve the formation of a 4-dimethylamino π-allyl palladium complex that upon activation with AgBF₄ or PPh₃ undergoes displacement with excess amine to form the observed products.

11.4. Group 10 Metal-Catalyzed Diamination of Alkenes and Dienes with Urea Derivatives

Despite the promise of Bäckvall’s seminal work, catalytic variants of this diamination process were unknown until 2005, when the groups of Booker-Milburn (Scheme 86)²²⁷ and Muñiz (Scheme 86)²²⁸ respectively reported catalytic, inter- and intramolecular versions of this transformation. Although likely proceeding via differing catalytic cycles (vide infra), success in each case, was achieved through a realization that in order to develop a transition metal catalyzed diamination process, three major obstacles necessarily must be overcome, namely the avoidance of catalyst-product complexation, the attenuation of β-hydride elimination from the intermediate σ-alkylpalladium species and, in the case of 1,3-dienes, the circumvention of the 1,4-diamination process noted by Bäckvall.²²⁶ In both studies, undesirable product-Pd(II) ligation was avoided through the use of ureas as a source for both transferred nitrogen atoms. In the case of Booker-Milburn’s work on 1,3-dienes, use of N,N′-dialkylureas as a tethered nitrogen source also served to prevent the formation of 1,4-diamination products.

Scheme 86.

Proposed mechanism of Booker-Milburn’s Pd(II)-catalyzed diene diamination.

Booker-Milburn and co-workers found that treatment of 1,3-dienes with N,N′-diethylurea (328) in the presence of catalytic bis(acetonitrile)palladium dichloride and benzoquinone (p-BQ), as a stoichiometric oxidant, led to the efficient formation of vinylic cyclic ureas 329 (Scheme 85).²²⁷ Although the diamination of isoprene proceeded with marginal regioselectivity, addition takes place exclusively at the less substituted alkenes of 1-alkyl and aryl-substituted dienes. Noting, among other observations, that a chloride-bearing Pd(II) precatalyst is a prerequisite for the success of this transformation, Booker-Milburn proffered the mechanistic interpretation outlined in Scheme 86. In this case, anti-aminopalladation of the diene 330 generates electrophilic η³-allyl intermediate 332 (or its π-allyl isomer) which in preference to β-hydride elimination undergoes intramolecular reductive displacement of Pd(II) to generate cyclic urea 329a and a Pd(0) species which is reoxidized by p-BQ in the presence of HX.

Scheme 85.

Booker-Milburn’s Pd(II)-catalyzed intermolecular 1,2-diamination of 1,3-dienes via a “diverted” Wacker process.

In 2005, Muñiz and co-workers reported the first example of Pd(II)-catalyzed intramolecular alkene diamination employing ω-alkenyl-substituted ureas 334 (Scheme 87).²²⁸ In the presence of catalytic palladium(II) acetate, stoichiometric quantities of the hypervalent iodine oxidant PhI(OAc)₂ and acetate as a base, these terminal alkenes underwent diamination to form cyclic ureas 335 with five-, six-, and seven-membered fused rings in excellent yield. Tricyclic systems, such as 335i, are also readily available under these remarkably mild conditions. This methodology is also notably robust: it can be conducted with a range of commercially available palladium catalysts and iodine(III) reagents; does not display significant solvent dependence; and proceeds under aerobic conditions.

Scheme 87.

Muñiz’s Pd(II)-catalyzed intramolecular 1,2-diamination of terminal alkenes.

Extensive kinetic, spectroscopic and labeling studies have led Muñiz to propose that diamination proceeds through a two-step mechanism whose catalytic cycle is outlined in Scheme 88. In this case, deprotonation and palladium coordination to the urea anio 337 is followed by syn-aminopalladation, which is found to be rate limiting. The resulting square-planar σ-alkylpalladium(II) complex 339 then undergoes oxidation with iodosobenzene diacetate to form cationic palladium(IV) intermediate 340.²²⁹ After dissociation of the urea from the octahedral palladium center, product formation takes place by way of an intramolecular S_N2-type displacement, which proceeds with inversion and regenerates Pd(II) catalyst.²³⁰ Key to the success of this overall transformation is the observation that while σ-alkylpalladium(II) species 339 is susceptible to iodine(III)-mediated oxidation, palladium(II) complex is not.

Scheme 88.

Proposed catalytic cycle for Muñiz’s Pd(II)-catalyzed intramolecular 1,2-diamination of terminal alkenes.

While ω-alkenyl-substituted ureas which encompass internal alkenes are not suitable substrates for diamination with the palladium acetate-PhI(OAc)₂ combination, Muñiz has shown that the transfer of two nitrogen atoms to homoallylic sulfonamide substrates such as 342 is not only feasible with these conditions but offers a convenient entry point to bisindolines (344a-c), bispyrrolidines (344d) and annulated indolines (344e) (Scheme 89).²³¹ In this case, endo-selective anti-aminopalladation, palladium oxidation and amide dissociation is followed by internal displacement to generate the products of syn-diamination.

Scheme 89.

Muñiz’s route to bisindolines via Pd(II)-catalyzed intramolecular 1,2-diamination of internal alkenes.

Muñiz and Barluenga have also established that copper(II) salts can be employed as terminal oxidants in place of PhI(OAc)₂ and that under these conditions, diamination of internal alkenes is feasible (Scheme 90).¹⁸⁴ Notably, the stereochemical course of diaminations conducted in the presence of copper(II) bromide displays a distinct substrate dependence, which arises from variations in the manner by which the final C-N bond is generated. For example, cyclization of E-styrene derivative 345 proceeds with overall retention of alkene stereochemistry, while reaction of E-acrylate 350 takes place with inversion to yield the cis-configuration 351.²³² In the former case, initial syn-aminopalladation is thought to be followed by anti-bromination/depalladation, giving rise to alkyl bromide 348. C-N bond formation then takes place through an intramolecular S_N2-type displacement to generate both the anti-configured urea 346a and isourea 346b. While acrylate 350 also undergoes initial syn-aminopalladation, formation of the second C-N bond is proposed to take place through amide dissociation and oxidatively-induced S_N2 ring closure of intermediate 354.

Scheme 90.

Stereochemically divergent diamination of non-terminal alkenes and its mechanistic origin.

The use of copper(II) salts as terminal oxidants has demonstrated excellent substrate generality and has also been employed in a remarkably straightforward construction of cyclic guanidines (Scheme 91).²³³ Cyclization of N-ω-alkenyl guanidines 355 generated a range of bicyclic products 356, including annulated piperidines, in excellent yield. That diamination in this case proceeds with overall syn-diastereoselectivity has been substantiated by deuterium labeling studies.

Scheme 91.

Direct synthesis of bicyclic guanidines via Pd(II)-catalyzed intramolecular cycloguanidination of terminal alkenes employing copper chloride as the terminal oxidant.

In a recent extension of their work on the diamination of tethered ureas, Muñiz and co-workers have developed an intermolecular variant of their methodology that features the regioselective transfer of nitrogen from two distinct sources, namely bistosylimide and saccharin, which exclusively takes part in the initial aminopalladation step (Scheme 92).²³⁴ Employing bis(benzonitrile)palladium dichloride as the precatalyst and iodosobenzene dipivalate as the terminal oxidant, a wide range of functionalized terminal alkenes 357 undergo addition to generate the corresponding diamines 358 with complete regioselectivity and in excellent yield. This methodology is not restricted to the use of bistosylimide and indeed diamination with bis(2-trimethylsilylethanesulfonyl)imide (SES₂NH)²³⁵ offers the advantage that the saccharide residue and one of the SES groups can be simultaneously removed through treatment with cesium fluoride. In 2011, Muñiz also reported the intermolecular diamination of allylic ethers employing saccharine and N-fluoro-bis(phenylsulfonyl)imide (NSFI), which acts as both the oxidant and nitrogen source for the second carbon-nitrogen bond forming step.²³⁶

Scheme 92.

Intermolecular Pd(II)-catalyzed diamination of terminal alkenes.

In a complementary approach to Muñiz’s methodology, Michael and co-workers have developed an approach to the intra/intermolecular diamination of N-ω-alkenyl amides, carbamates and ureas which employs N-fluoro-bis(phenylsulfonyl)imide (NSFI) as an external electrophilic aminating agent (Scheme 93).²³⁷ In the presence of NSFI, catalytic palladium(II) trifluoroacetate and a triethylammonium benzenesulfonimide additive, these substrates, as exemplified by 360, undergo cyclization to form 2-aminomethyl pyrrolidine derivatives 361, in which benzenesulfonimide from NSFI is incorporated. The addition of TEMPO in this case serves to prevent alkene isomerization mediated by palladium hydride species. Michael’s methodology is notable for its generality, functional/protecting group tolerance and, importantly, the fact that the products of diamination can be differentially deprotected under relatively mild conditions.

Scheme 93.

N-Fluorobenzenesulfonamide-promoted alkene intra/intermolecular diamination of terminal alkenes.

Detailed mechanistic studies by Michael have revealed that diamination in this case proceeds via overall syn addition of both nitrogen centers through the proposed catalytic cycle outlined in Scheme 94.^237b In this case, the initial step differs from the work of Muñiz in that it proceeds via an anti-aminopalladation step to form Pd(II)-alkyl complex 363. Oxidative addition of NFBS to 363 then generates highly reactive Pd(IV) species 364 from which benzenesulfonimide dissociates to form coordinatively unsaturated 365. Formation of the second C-N bond now occurs through intermolecular S_N2 displacement of the C-Pd bond to form 366 and regenerate Pd(II).

Scheme 94.

Proposed catalytic pathway for the N-fluorobenzenesulfonamide (NSFI) promoted intra/intermolecular alkene diamination reaction.

11.5. Nickel-Mediated Alkene Diamination

Muñiz and co-workers have also employed nickel(II) salts for the intramolecular diamination of N-γ-alkenyl sulfamides, ureas and guanidines 367 (Scheme 95).²³⁸ In addition to the obvious economic advantages over palladium(II) complexes, nickel catalysts in this case are notable for their longevity under the reaction conditions and their ability to successfully mediate sulfamide transfer.²³⁹ While deuterium labeling studies have revealed that diamination is a stereospecific process with respect to alkene geometry and proceeds with syn stereochemistry whether this arises through a syn/anti or anti/syn process remains to be established. Nonetheless, that these reactions proceed through an initial aminometallation step is apparent from the isolation of 368a, which likely arises from protonation of a C-Ni bond. In general, substrates encompassing internal alkenes fail to undergo diamination in the presence of nickel catalysts.

Scheme 95.

Nickel(II)-catalyzed intramolecular diamination of N-γ-alkenyl sulfamides, ureas and guanidines.

11.6. Copper(II) Carboxylate-Mediated Alkene Diamination

Chemler and co-workers have pioneered the use of copper(II) carboxylates for the mediation and catalysis of alkene carboamination, aminooxygenation and diamination.²⁴⁰ From a synthetic perspective, this methodology represents a uniquely powerful confluence of organometallic and radical chemistry that has been applied to the preparation of a diverse range of heterocycles.²⁴¹ In 2005, this group first reported the direct intramolecular diamination of γ-alkenyl and δ-alkenyl-substituted sulfamides, such as 369, which undergo cyclization in the presence of three equivalents of copper(II) acetate to form the corresponding five and six-membered sulfamides 370 (Scheme 96). In all cases examined, diamination proceeds with complete exo-regioselectively and, in the case of product 370e, with a high level of diastereoselectivity.

Scheme 96.

Copper(II) acetate-promoted intramolecular diamination of γ-alkenyl and δ-alkenyl-substituted sulfamides encompassing 1- and 1,2-substituted terminal alkenes.

From a mechanistic standpoint, Chemler has proposed that this diamination commences with base-assisted ligand exchange between unsaturated sulfamide 369 and copper(II) acetate to form intermediate 370 (Scheme 97). This species then undergoes rate-determining syn-aminocupration to form unstable alkylcopper(II) species 371 which subsequently suffers Cu-C bond homolysis giving rise to primary radical 372, whose existence is suggested by deuterium labeling studies. Interaction of this electron deficient intermediate with copper acetate would then form alkylcopper(III) complex 373 which, upon reductive elimination,²⁴² would give rise to cyclic sulfamide 370a through formation of the second C-N bond.

Scheme 97.

Proposed mechanism of the copper(II) carboxylate promoted intramolecular alkene diamination reaction.

As a result of methodological limitations imposed by the low solubility of copper(II) acetate, Chemler has introduced copper(II) neodecanoate [Cu(nd)₂] as a second-generation mediator of diamination (Scheme 98).²⁴³ Adoption of this organic soluble complex obviates the need for polar non-protic solvents such as DMSO and DMF and allows reactions to be conducted in 1,2-dichloroethane (DCE), albeit in a pressure tube since reaction temperatures are significantly higher than the boiling point (84 °C) of this solvent. Nonetheless, these conditions offer significantly higher yields and facilitate the generation of a broader range of bis(amino) products, including ureas (376f), bis(anilines) (376g) and α-amido-pyrroles (376h). Of particular note is the high selectivity for the formation of cis-2,5-disubstituted pyrrolidines observed during the cyclization of α-substituted pent-4-enyl sulfamides such as 376.

Scheme 98.

Copper(II) neodecanoate [Cu(nd)₂]-promoted intramolecular diamination of terminal alkenes.

In a valuable extension of their original diamination methodology, Chemler and co-workers have most recently reported an intra/intermolecular variant of this chemistry in which external N-nucleophiles, including azide, sulfonamides, benzamide and a wide range of anilines, participate in the second C-N bond-forming step (Scheme 99).²⁴⁴ For example, in the presence of copper(II) 2-ethylhexanoate [Cu(eh)₂] 2-substituted 1-allyl-1-benzyl ureas 378 undergo diamination with these external nucleophiles to form 4-substituted imidazolinones 379 in excellent yield. This strategy has also successfully been applied to the preparation of 2,5-disubstituted pyrrolidines such as 379e and 379f through the cyclization of N-γ-alkenyl sulfonamides.

Scheme 99.

Copper(II) 2-ethylhexanoate-promoted intra/intermolecular alkene diamination.

Through the use of the chiral bis(oxazoline) ligand (R,R)-Ph-box, Chemler has also successfully rendered the intermolecular diamination of N-mesyl-ortho-allylaniline (380) enantioselective (Scheme 100).²⁴⁴ While attempts to employ MnO₂ as a terminal oxidant with unsaturated sulfamide and urea substrates failed, the cyclization of this substrate in the presence of p-toluenesulfonamide proceeds to form 381 with promising enantioselectivity and is catalytic in copper(II) triflate.

Scheme 100.

Enantioselective copper-catalyzed intra/intermolecular diamination of N-mesyl-ortho-allylaniline.

11.7. Gold-Mediated Alkene Diamination

Despite the substantial progress made over the last decade in the use of gold catalysts for alkene hydroamination²⁴⁵ and more recently oxidative coupling reactions,²⁴⁶ the exploitation of this chemistry towards alkene diamination is relatively unexplored. In this context, Muñiz’s 2009 report detailing the use a Au(I)/Au(III) cycle to intercept the hydroamination pathway in favor of the oxidative diamination of N-γ-alkenyl ureas 382 is significant (Scheme 101).²⁴⁷ Of several gold complexes examined, triphenylphosphinegold(I) acetate proved to be the most effective catalyst and, in the presence of PhI(OAc)₂ and sodium acetate, mediates the conversion of these substrates to the corresponding imidazolinones 382 in excellent yield. In contrast to palladium catalysis, diamination under these conditions proceeds with overall syn-selectivity as revealed by the formation of tricycle 383h.

Scheme 101.

Gold-catalyzed intramolecular diamination of γ-alkenyl-substituted ureas encompassing 1-substituted and 1,2-disubstituted alkenes.

On the basis of a deuterium labeling study and investigation of the stoichiometric reactions of isolated model gold complexes, Muñiz has proposed the mechanism outlined in Scheme 102. Diamination is thought to commence with the formation of alkylgold(I) complex 385 through alkene anti-aminoauration. Oxidation of this intermediate then proceeds irreversibly giving rise to the corresponding gold(III) complex 386 which undergoes intramolecular displacement with inversion at the gold(III)-bearing carbon center to generate the reduced gold(I) complex and the observed product 388. In support of this proposal, Muñiz has demonstrated that while triphenylphosphinegold(I) acetate is inert to iodine(III)-mediated oxidation, a model alkylgold(I) complex is rapidly converted to the corresponding gold(III) species. Furthermore, it has been shown that this high-valent complex readily undergoes S_N2-like displacement with the anion of an N-tosyl urea to form a C-N bond and generate triphenylphosphinegold(I) acetate.

Scheme 102.

Proposed mechanism for the gold-catalyzed, iodine(III)-promoted intramolecular diamination of γ-alkenyl-substituted ureas.

Nevado and de Haro have also employed Au(I)/Au(III) catalysis to achieve the oxidative difunctionalization of alkenes including the intra/intermolecular aminoamidation of N-tosyl-4-pentenyl alkenes 389 (Scheme 103).²⁴⁸ Using the cationic complex [(Ph₃P)AuSbF₆] and Selectfluor (391) as a bystanding oxidant,²⁴⁹ these substrates undergo 6-endo-trig cyclization in nitrile solvents to generate N-piperidin-3-yl carboxamides 390 in high yield. Several nitriles, including acetonitrile, propionitrile and butyronitrile act as external nucleophiles in this reaction and while currently limited to terminal alkenes, this diamination method represents an important complement to related Pd(II)/Pd(IV)-catalyzed processes which proceed with 5-exo selectivity; cf. Scheme 90.

Scheme 103.

Gold-catalyzed, oxidative intra/intermolecular diamination of N-tosyl-4-pentenyl amines in the presence of nitrile nucleophiles.

Nevado has suggested that diamination in this case can potentially occur through a number of manifolds, as outlined in Scheme 104. In the predominate pathway, 389 undergoes gold(I)-mediated 6-endo trans-aminoauration to form 392 which is oxidized by Selectfluor to the corresponding alkyl-gold(III) species 392. Substitution of fluoride by acetonitrile, hydrolysis of this now activated ligand and subsequent reductive elimination would then give rise to the major aminoamidation product 394. The formation five-membered amines, such as 390g, can be ascribed to the analogous 5-exo pathway involving intermediates 395 and 396. Nevado has also noted that diamination may also proceed through an alternative mechanism, namely one in which the common bicyclic aziridinium ion 398,²⁵⁰ formed through the intramolecular reductive elimination of 392 and/or 396, participates in a Ritter reaction with the nitrile solvents to form the observed products.²⁵¹

Scheme 104.

Possible mechanistic pathways involved in the gold(III)-catalyzed intra/intermolecular alkene diamination reaction.

Although not strictly falling within the brief of this review as it involves alkene hydroamination rather diamination, Widenhoefer’s gold(I)-catalyzed cyclization of N-δ-allenyl ureas 399 is worthy of note since it offers diastereoselective access to bicyclic imidazolidinones 400 and related systems with high efficiency (Scheme 105).²⁵² Cyclization in this case is promoted by a catalytic mixture of the gold(I) N-heterocyclic carbene complex (401)AuCl and AgPF₆ at room temperature. In addition to displaying a tolerance for a range of urea N-substituents, incorporation of heteroatoms within the heptadienyl chain of 399 provides access to both morpholine (400b) and piperazine (400c) systems.

Scheme 105.

Preparation of bicyclic imidazolidin-2-ones through the gold(I)-catalyzed dihydroamination of N-δ-allenyl ureas.

11.8. Metal-Mediated Addition of Diaziridinones and Related Systems to Conjugated Alkenes

Arguably, the most well established and synthetically proven transition metal-mediated alkene diamination method is that developed Shi and co-workers, who have pioneered the use of strained diaziridinones and their analogs as unique and versatile nitrogen sources. In contrast to other metal-catalyzed diamination procedures reported to date, this approach to alkene oxidation is distinct in that catalytic turnover is mediated by the diaminating agent itself rather than an external oxidant. In this regard, Shi’s approach is conceptually related to the work of Donohue²⁵³ and Yoon²⁵⁴ who have respectively employed N-sulfonyloxycarbamates and N-sulfonyl oxaziridines as “preoxidized” nitrogen sources for the oxamination of alkenes. This general strategy holds a number of strategic advantages, not least of which are operational simplicity and the increased functional group tolerance associated with the absence of an external oxidizing agent.

In 2007, Shi first reported the use of di-tert-butyldiaziridinone (402)²⁵⁵ as a nitrogen source in the diamination of conjugated dienes (403) (Scheme 106).²⁵⁶ Employing 402 and Pd(PPh₃)₄ as a catalyst (10 mol%), a range of substrates, including acyclic and cyclic dienes, dienol ethers, dienoates and trienes, underwent diamination to form imidazolidinones 404 with high yield and excellent regioselectivity for the internal alkene. By adding diaziridinone 402 slowly in the absence of solvent, Shi has subsequently established that catalytic loading can be reduced to 1–2 mol%. That the regioselectivity observed by Shi is different from that previously found by Booker-Milburn and Lloyd-Jones²²⁷ is an indication that a different mechanism is involved in this case. Importantly from a practical perspective, removal both partial and complete, of the N-tert-butyl groups from the diamination products 404 can be accomplished cleanly through solvolysis with strong acids, such as TFA (vide infra). Alternatively, treatment with aqueous acid under forcing conditions (conc. HCl, reflux, 30 h) mediates complete deprotection to the corresponding 1,2-diamines.

Scheme 106.

Palladium(0)-catalyzed diamination of conjugated dienes and trienes using di-tert-butyldiaziridinone as the nitrogen source.

On the basis of detailed spectroscopic studies and accompanying kinetic data, Shi has proposed that diamination in this case proceeds through the mechanism outlined in Scheme 107. The reaction commences with the rate-determining oxidative insertion of a Pd(0) species, thought to be Pd(PPh₃)₂, into the N-N bond of 402 to form symmetrical four-membered Pd(II) complex 405. Reversible ligand exchange with the dienyl substrate 403 then gives rise to complex 406, which undergoes migratory insertion to form π-allyl species 407. In the final step of the cycle, reductive elimination of the product 408 regenerates the Pd(0) catalyst.

Scheme 107.

Proposed catalytic cycle for palladium(0)-catalyzed diamination of 1,3-dienes using di-tert-butyldiaziridinone.

With regard to asymmetric diamination, Shi and co-workers have successfully identified a number ligand types that effectively mediate this intermolecular process. To date, the most successful ligand identified has been the BINOL-based phosphorous amidite 410, which when employed in a 1:2.2 ratio with Pd₂(dba)₃ offers good yields and high enantioselectivity with a range of substrates (Scheme 108).²⁵⁷ Asymmetric internal diamination of 1,3-dienes has also been achieved with N-heterocyclic carbene-Pd(0) complexes, albeit with slightly lower enantioselectivity (62–78% ee) than that found with 410.²⁵⁸

Scheme 108.

Asymmetric palladium(0)-catalyzed diamination of conjugated dienes and trienes with di-tert-butyldiaziridinone.

In addition to dienes and trienes, Shi has also found that monosubstituted and 1,1-disubstituted olefins 411 undergo Pd(0)-catalyzed diamination at the allylic and homoallylic positions in the presence of excess di-tert-butyldiaziridinone (402) (Scheme 109). Under solvent free conditions, slow addition of 402 to these terminal alkenes leads to the formation of diamination products 412 in good yield and complete regio- and stereoselectivity. In addition to displaying good functional tolerance, this transformation is also successful with substrates that bear two terminal alkenes thus providing access to fully protected tetramines such as 412h.

Scheme 109.

Palladium-catalyzed dehydrogenative diamination of terminal alkenes at allylic and homoallylic positions: use of di-tert-butyldiaziridinone as the nitrogen source and terminal oxidant.

From a mechanistic standpoint, Shi has suggested that this remarkable transformation proceeds through a catalytic cycle in which diaziridinone 413 plays a dual role as both hydrogen acceptor in the oxidation of alkene 411 to 1,3-diene 417 and the nitrogen source for the diamination of this intermediate (Scheme 110). After formation via oxidative insertion of Pd(0) into the N-N bond of 402, Pd(II) species 414 complexes olefin 411 and mediates formation of π-allyl complex 416 through removal of the allylic hydrogen. β-Hydride elimination from 416 then regenerates the Pd(0) catalyst and gives rise to urea 418 and diene 417, which undergoes diamination through the mechanism previously discussed. Although proceeding through a different mechanism, diaziridinone 413 (R = t-Bu) has also been used as a dehydrogenating agent in its own right, under copper catalysis.²⁵⁹

Scheme 110.

Proposed catalytic cycle for palladium-catalyzed dehydrogenative diamination of terminal alkenes with di-tert-butyldiaziridinone.

Shi has also developed a catalytic asymmetric variant of the allylic/homoallylic diamination reaction that employs the chiral H₈-BINOL-derived phosphorus amidite 422 in combination with Pd₂(dba)₃ (Scheme 111).²⁶⁰ Success in this case was found to depend significantly upon the palladium/ligand ratio with a 1:2.2 mixture offering excellent levels of enantioselectivity with most substrates. In the case of bis-diamination (421e) and those substrates with existing stereogenic centers, the stereochemical outcome of diamination was found to be primarily controlled by the chiral catalyst.

Scheme 111.

Palladium-catalyzed asymmetric dehydrogenative diamination of terminal alkenes at allylic and homoallylic positions.

Having successfully established conditions for asymmetric alkene diamination, Shi and co-workers have subsequently demonstrated the value of this methodology in its application to the synthesis of (+)-CP-99,994 (427), a human neurokinin 1 (NK1) substance P receptor antagonist (Scheme 112).²⁶¹ Obtained through the diamination of 4-phenyl-1-butene, building block 423 was converted to ester 423 by way of a 3-step sequence featuring oxidative cleavage of the alkene, olefination of the resulting aldehyde and hydrogenation. Treatment of 423 with trifluoroacetic acid then effected selective mono-de-N-alkylation to provide compound 424 in excellent yield and suitably differentiated for introduction of the N-benzyl group found in target 427. After N-nosylation of 424, the remaining N-tert-butyl group was cleaved by treatment with methanesulfonic acid to yield 425. Saponification of this imidazolidinone and recyclization under acidic conditions then provided δ-lactam 426, which was converted to (+)-CP-99,994 (427) through a sequence of N-alkylation, with 2-methoxybenzyl chloride, removal of the N-nosyl group and lactam reduction.

Scheme 112.

Shi’s asymmetric synthesis of (+)-CP-99,994.

While thiadiaziridine 1,1-dioxide (428)²⁶² also participates in the palladium-catalyzed allylic/homoallylic diamination reaction, it does so with complementary regioselectivity to that displayed by diaziridinone 402 (Scheme 113).²⁶³ For example, alkenes 429 in the presence of 2 equivalents of 428 undergo dehydrogenative diamination at the termination position to form mono-substituted sulfamides 430 in moderate to good yield. The observation that 1,3-pentadiene undergoes diamination with 428 at the internal position has led Shi to propose that rather than involving the formation of a diene intermediate, diamination actually occurs through the Pd(II)-mediated formation and cyclization of an allylic sulfamide.

Scheme 113.

Palladium-catalyzed dehydrogenative diamination of terminal alkenes at allylic and homoallylic positions: use of N,N-di-tert-butylthiadiaziridine 1,1-dioxide as nitrogen source and oxidant.

The search of alternative diamination catalyst systems with increased substrate scope and complementary regioselectivity to that offered by palladium has lead Shi and co-workers to investigate the use of copper(I) salts.²⁶⁴ Among a various systems evaluated, a 1:1 combination of CuCl and triphenyl phosphite (P(OPh)₃) was found to effectively mediate the reaction of 402 with a wide range of conjugated dienes and trienes 403 at the terminal position (Scheme 114). Reactions in this case proceed at room temperature and do so with good to high yield.

Scheme 114.

Copper(I)-catalyzed terminal diamination of conjugated dienes and trienes with di-tert-butyldiaziridinone.

Despite the challenges presented by the involvement of radicals species in the copper-catalyzed, internal diamination reaction (vide infra), Shi has successfully developed an asymmetric variant of this process which employs a combination of CuCl and the bisphosphine ligand (R)-DTBM-SEGPHOS.^265,266 In this case, diamination of conjugated dienes and a triene with 402 proceeded in 59–93% yield and with enantioselectivities between 62 and 74%. Shi has also shown that copper(I) catalysts imbued with a chiral, BINOL-based phosphate ligand can also mediate asymmetric, external diamination, albeit with somewhat lower ee’s (49–61%).²⁶⁷

In more recent studies, Shi has found that, in the absence of phosphine ligands, copper(I) salts and in particular inexpensive CuBr promote diene diamination at the internal alkene position, in common with palladium-based catalysts (Scheme 115).²⁶⁸ Using di-tert-butyldiaziridinone (402) as the nitrogen source, a diverse range of substrates, including 1-substituted, 1,2-disubstitiuted, 1,3-disubstituted, cyclic and even 1,2,3-trisubstituted dienes undergo reaction to form imidazolidinones 421 in high yield and regioselectivity. Notably, diamination under these conditions can also be conducted on large scale; e.g. using 5 mol% CuBr, compound 421a was prepared on a 38 g scale.

Scheme 115.

Copper(I)-catalyzed internal diamination of conjugated dienes and trienes with di-tert-butyldiaziridinone.

The remarkable switch in selectivity for external and internal diamination observed with the use of CuCl-P(OPh)₃ and CuBr catalysts has been attributed, by Shi, to the existence of two competing reaction mechanisms respectively involving Cu(II) and Cu(III) species (Scheme 116). In both cases, diamination is proposed to commence with the Cu(I)-mediated reductive cleavage of diaziridinone 402 to form Cu(III) complex 433 and/or the corresponding open-chain Cu(II) amidyl radical 434. In the presence of phosphine ligands, generation of 434 appears to be favored and addition of this species for reasons of sterics and product stability takes place at the terminal position of diene 410 to generate allyl radical 436 and/or its organocopper(III) analog 47. Reductive elimination the generates the second C-N bond and gives rise to the terminal diamination product 431 and the Cu(I) catalyst. Internal diamination, on the other hand, is thought to involve the intermediacy of four-membered Cu(III) complex 433 that, in the absence of phosphine ligands, coordinates the diene to form 437. In an analogous fashion to the Pd-catalyzed process, migratory insertion of the nitrogen atom to the internal double bond of this system then gives rise to π-allyl species 438. Final reductive elimination then gives rise to internal diamination product 432 and returns the Cu(I) catalyst.

Scheme 116.

Proposed dual mechanisms for the copper(I)-catalyzed internal and external diamination of conjugated dienes.

With regard to the copper-catalyzed diamination of alkenes, Shi has found that, if activated by the presence of an aryl group, 1,1-disubstituted olefins 439 are suitable substrates for this process (Scheme 117).²⁶⁹ Using 5 mol% of a 1:1 combination of CuCl and PPh₃, a wide range of styrene and acrylate derivatives undergo diamination with di-tert-butyldiaziridinone (402) at 65 °C to form the corresponding imidazolidinones 440 in high yield. Of particular note has been Shi’s application of this methodology to synthesis of the potent NK₁ antagonist Sch 425078 (443) from allyl ether 421.²⁶⁹

Scheme 117.

Copper(I)-catalyzed diamination of disubstituted terminal alkenes; synthesis of Sch 425078.

While monosubstituted terminal alkenes fail to undergo diamination with di-tert-butyldiaziridinone (402) under palladium catalysis, N,N-di-tert-butylthiadiaziridine 1,1-dioxide (428) in the presence of CuCl-P(n-Bu)₃ undergoes addition to a range of activated systems, including styrenes, 3-vinylindoles, enynes and enol ethers to form cyclic sulfamides 446 (Scheme 118).²⁷⁰ Most recently, in 2011, Shi and co-workers has reported that while conjugated dienes also undergo terminal diamination with reagent 428 in the presence of CuCl-P(n-Bu)₃, the use of CuBr leads to a near complete change in regioselection for internal diamination.²⁷¹

Scheme 118.

Copper(I)-catalyzed intermolecular diamination of activated terminal alkenes with di-tert-butyldiaziridinone.

The common occurrence of cyclic guanidines in pyrrole-2-aminoimidazole alkaloids and the intense synthetic interest that this marine natural product family has evoked ensures that the development of methods to access this functional group is of considerable importance.²⁷² In this regard, the cycloguanidation of alkenes offers a particularly appealing approach for the late-stage introduction of these highly polar ring systems in fully protected form. Shi and co-workers have found that di-tert-butyl diaziridinimine 402 readily undergoes Cu(I)-catalyzed addition at the terminal positions of conjugated dienes, trienes, enynes and monosubstituted alkenes 447 to yield the cyclic N-cyano guanidines 448 in good to excellent yield (Scheme 119).²⁷³ Deprotection of these products is readily accomplished in high yield by solvolysis in acid and neutralization with NaOH.

Scheme 119.

Copper(I)-catalyzed cycloguanidation of alkenes, dienes and trienes using di-tert-butyldiaziridimine.

12. Diamination via Pericyclic Processes

12.1. Imido Selenium Compounds

While the use of pericyclic reactions is perhaps the least well developed approach to direct alkene 1,2-diamination, a select number of notable and compelling studies have been reported. Sharpless and Singer, for example, have employed the reaction of selenium dioxide bis(imide) 451 with 1,3-dienes to accomplish diamination with exclusive cis selectivity (Scheme 120).²⁷⁴ Generated in situ by the oxidation of selenium powder in the presence of p-toluenesulfonamide (449) and it sodium salt 450, compound 451 undergoes regioselective reaction with cyclic and acyclic 1,3-dienes to generate 1,2-diaminoalkanes 456 in moderate to low yield. In the case of 452, this transformation is believed to proceed through the intermediacy of [4+2] cycloadduct 453, which undergoes ring opening with p-toluenesulfonamide to form 453. [2,3]-Sigmatropic rearrangement of this intermediate then gives rise to the observed cis products, after desulfurization of the selenium(II) amide 455.

Scheme 120.

One-pot 1,2-diamination of 1,3-dienes with the selenium dioxide bis(imide) reagent 451.

In order to facilitate the deprotection of the diamine products, Sharpless has also developed reagent 459 where the tosyl groups are replaced by o-nitro benzenesulfonyl substituents (Scheme 121).²⁷⁵ Prepared under milder conditions, from the corresponding N,N′-dichlorosulfonamide 457 and sodium sulfonamide 458, this compound, with the notable exception of 1,3-cyclopentadiene, reacts less efficiency with 1,3-dienes than 451. Electron-withdrawing substituents were found to reduce substrate reactivity towards this highly electrophilic species: reaction of 1,3-cyclohexadiene carboxylate failed to yield diamine and provided only traces of 460d, the product of an apparent ene reaction.

Scheme 121.

1,2-Diamination of 1,3-dienes with the modified selenium dioxide bis(imide) reagent 459.

The primary advantage of reagent 459 is the degree to which N-nosyl groups facilitate the N-alkylation of the vicinal sulfonamides and the ease with which this protecting group can subsequently be cleaved (Scheme 122). For example, bis-N-alkylation of 460a and deprotection using Fukuyama’s conditions,²⁷⁶ provides a route to mono-N-alkylated diamines 461 with reasonable overall efficiency.

Scheme 122.

12.2. Imido Sulfur Compounds

Weinreb has reported a related, but stepwise method for the stereocontrolled 1,2-diamination of 1,3-dienes which employs sulfur dioxide bis(imides) 463a and 463b (Scheme 123).²⁷⁷ In comparison to their selenium congeners (i.e. 453), the 3,6-dihydrothiazin-imines resulting from the [4+2] cycloaddition of these reagents are less reactive. Consequently, conversion to the diamination products requires a distinct ring-opening step with an organometallic nucleophile to generate an allylic sulfilimine prior to its [2,3]-sigmatropic rearrangement. In the case of (E,E)-2,4-hexadiene (462), reaction with bis(sulfonamide) 463a gave rise to a separable 1:1 mixture of S-epimers 464a and 464b. Sequential treatment of cia-trans isomer 464b with phenylmagnesium bromide and trimethyl phosphite provided vicinal sulfonamide 466 in excellent yield. Although cis-cis adduct 464a failed to react with the Grignard reagent because of steric hindrance, its conversion to 466 was accomplished with methyllithium. Notably, simple heating cis-cis-thiazinimine 464a promotes [2,3]-sigmatropic rearrangement to thiadiazolidine 467, which can be reduced with NaBH₄ to the unsaturated disulfonamide 466.

Scheme 123.

Weinreb’s three-step, two-pot 1,2-diamination of 1,3-dienes with the sulfur dioxide bis(imides).

13. Diamination via Organocatalysis

Despite the volume of published work concerning organocatalysis and its use for both the α- and β-amination of saturated and unsaturated carbonyl compounds,⁵² there are relative few reports concerning the exploitation of this powerful synthetic strategy for the direct 1,2-diamination of alkenes. In 2007, Jørgensen and co-workers disclosed the first example of the organocatalyzed asymmetric diamination of α,β-unsaturated aldehydes (Scheme 124).²⁷⁸ Use of chiral secondary amine 471, in this case, promotes the regioselective and enantioselective addition of succinamide (468) to enals 469. Upon subsequent addition of diethyl azodicarboxylate (412), intermediate enamine 474 underwent amination giving rise to the syn-diamination products 470 with excellent enantiomeric excess, albeit in rather low conversion and moderate diastereoselectivity. Difficulties faced in the development of this process include the tendency of the electrophilic nitrogen-source to undergo decomposition in the presence of succinamide as well as its ability to act as a dienophile towards α,β-unsaturated aldehydes.

Scheme 124.

Jørgensen’s organocatalyzed asymmetric multicomponent syn-selective diamination of α,β-unsaturated aldehydes.

More recently, MacMillan and co-workers have successfully brought to bear their cycle-specific organocascade catalysis strategy to this problem and in doing so have accomplished the stepwise, one-pot diamination of crotonaldehyde (477) in high yield and near complete enantioselectivity (Scheme 125).²⁷⁹ In this case, while imidazolidinone 476 is employed as a LUMO-lowering iminium catalyst to promote the 1,4-addition of silyloxycarbamate 478, (R) or (S)-proline are used as catalysts for the subsequent enamine amination reaction with dibenzylazodicarboxylate (479). A strategic advantage of this approach is that through the appropriate choice of catalyst combination, both the absolute and relative stereochemistry of the addition process can be controlled. From a practical standpoint, diamination is conducted in a one-pot, stepwise manner where proline, 479 and water are introduced after the completion of the 1,4-addition and the resulting α-amino aldehydes are reduced to the corresponding primary alcohols 480 in situ.

Scheme 125.

Application of cycle-specific organocatalysis to the enantio- and diastereoselective diamination of crotonaldehyde.

14. Summary and Outlook

Although the direct diamination of alkenes has been known for more than a century, the last decade has heralded a renaissance of interest in this important yet traditionally problematic reaction. In large part, success in this area has stemmed from the development of new metal-catalyzed and iodine(III)-mediated processes. However, since no single method currently offers complete stereo- and/or regiocontrol for all systems, there remains much to be accomplished in this field. For example, despite the promise of diaminations that are reliant on binary nitrogen oxides, these methods are limited by the difficultly associated with handling these toxic reagents and complexity of the transformations they mediate. In this context, the development of catalytic metal-mediated dinitrosylation methods is clearly a goal of considerable importance. Despite the promising work of Muñiz in the area of osmium-mediated alkene diamination, a methodology gap remains between this stoichiometric chemistry and a practical, catalytic diamination variant of the Sharpless asymmetric dihydroxylation reaction. In this regard, the use of pre-oxidized nitrogen sources has proven to be a highly productive approach for Shi and co-workers and invites other developments of this elegant approach to alkene diamination. With regard to organocatalytic methods of diamination, although initial studies by Jørgensen and MacMillan have confirmed the feasibility of this approach, future developments in this area will likely be dependent on the identification of nucleophilic and electrophilic nitrogen species that are compatible with one another. Notwithstanding the notable examples noted in the current article, the application of metal-mediated diamination to the synthesis of complex targets and in particular natural products remains in its infancy. Undoubtedly, the deployment of new alkene diamination reactions in preparation of such complex substrates will not only clarify the scope and limitation of existing processes but also spur the development of new methodologies.

15. Note Added in Proof

While this paper was in review, Chiba and co-workers reported the development of a novel method for the synthesis of bi- and tricyclic amidines. This alkene diamination process proceeds through the intramolecular, copper-catalyzed aerobic [3+2]-annulation of N-alkenyl amidines. The resulting cyclic amidines are readily converted to the corresponding 1,2-diamines by reduction with alane (Wang, Y. F., Zhu, X., Chiba, S. J. Am. Chem. Soc. 2012, 134, 3679–3682).

Figure 8.

1,2-Diazides generated by the reaction of iodine azide with trans-stilbenes.