Synthesis of Cyclic Guanidines via Silver-Catalyzed Intramolecular Alkene Hydroamination Reactions of N-Allylguanidines

Abstract

The silver-catalyzed hydroamination of tosyl-protected N-allylguanidines is described. These reactions provide substituted cyclic guanidines in high yields. The reactions are amenable to the construction of quaternary stereocenters as well as both monocyclic and bicyclic guanidine products.

Graphical Abstract

Cyclic guanidines are an important class of compounds that exhibit highly interesting biological activities,¹ and they have also found applications as synthetically useful organocatalysts.² The preparation of cyclic guanidines has often been accomplished via ring-closing S_N2 reactions,³ haloamination of alkenes,⁴ or through guanylation of 1,2-diamine derivatives.^5,6 More recent approaches have involved metal-catalyzed transformations that typically allow for generation of cyclic guanidines in an efficient manner from simple precursors.^7,8

One powerful method for the metal-catalyzed synthesis of nitrogen heterocycles that has attracted considerable attention over the past 25 years is the intramolecular hydroamination of amines bearing pendant alkenes.⁹ However, despite the high level of activity in this field and the many advances that have resulted, intramolecular alkene hydroamination reactions of guanidine nucleophiles have not previously been described. Looper, Gin, and van der Eycken have independently conducted elegant work on metal-catalyzed alkyne hydroamination reactions of guanidines,¹⁰ but extension of these methods to analogous alkene hydroaminations has remained elusive.

We recently described a new approach to the synthesis of cyclic guanidines 2 via Pd-catalyzed alkene carboamination reactions between aryl bromides and N-allylguanidines bearing N-PMP protecting groups (1) (Scheme 1, eq 1).^11,12,13 These transformations provided the desired products in good chemical yield for a variety of different substrate combinations. However, removal of the PMP protecting groups proved to be quite challenging, and efforts to cleave both PMP groups from the product were not successful.

Scheme 1.

To overcome this limitation, we began to explore alternative N-protecting groups for the carboamination reactions, and initial studies on the use of substrates bearing a single N-tosyl protecting groups (e.g., 3a) provided promising preliminary results.¹² During efforts to optimize these reactions we examined the influence of silver salts on reactions of 3a, as other studies conducted in our lab suggested that formation of cationic intermediate palladium complexes may facilitate reactions of relatively electron-poor substrates.^12,14 Although these conditions failed to provide the desired alkene carboamination product 4 (Scheme 1, eq 2), we were intrigued to discover that the cyclic guanidine 5a derived from the hydroamination of the alkene was produced in 20% yield. A series of control reactions demonstrated that the palladium was not necessary for the transformation to occur, but the presence of silver acetate (1 equiv), and base was required for the reaction to occur.¹⁵

Given the significance of the guanidine products and the novelty of the hydroamination reaction, we set out to optimize the Ag-catalyzed conversion of 3a to 5a (Table 1). Since our preliminary result employed a stoichiometric amount of AgOAc, we began our optimization studies by modifying the conditions shown in Scheme 1, eq 2 by simply omitting the aryl bromide and the palladium catalyst, and decreasing the loading of silver acetate to 10 mol % (Table 1, entry 1). Unfortunately, these conditions failed to produce the desired product. However, use of AgOTf as catalyst and a higher reaction temperature (138 °C) did result in catalyst turnover, and provided the desired product in 40% yield (Table 1, entry 3). Omission of the phosphine ligand from the reaction mixture led to a slight improvement in yield (45%) (Table 1, entry 4). A brief survey of copper and gold catalysts did not provide satisfactory results.

Table 1.

Optimization Studies^a

entry	catalyst	solvent	t (°C)	atmosphere	yield (%)b
1	AgOAc	PhCH3	100	N2	<2c
2	AgOTf	PhCH3	100	N2	14c
3	AgOTf	Ph(CH3)2	138	N2	40c
4	AgOTf	Ph(CH3)2	138	N2	45
5	Ag2O	Ph(CH3)2	138	N2	15
6	Cu(OTf)2	Ph(CH3)2	138	N2	25
7	CuI	Ph(CH3)2	138	N2	18
8	AuPPh3OTf	Ph(CH3)2	138	N2	<2
9	AgOTf	Ph(CH3)2	138	O2	70
10	AgNO3	Ph(CH3)2	138	O2	99d
11	AgNO3	PhCH3	40	O2	<2d
12	AgNO3	PhCH3	80	O2	99d
13	AgNO3	PhCH3	80	air	85d
14	AgNO3	PhCl	80	air	99
15	AgNO3	PhCl	80	O2	99
16	AgNO3	PhCl	80	N2	60e,f
17	AgNO3	PhCl	80	N2	99e,g

^aConditions: 1.0 equiv 3a, 1.0 equiv t-BuONa, 10 mol % catalyst, solvent (0.1 M), 40–138 °C, 17–21 h. Reactions were conducted on a 0.075 to 0.25 mmol scale.

^bYields were determined by ¹H NMR analysis using phenanthrene as an internal standard.

^cThe reaction was conducted in the presence of the ligand Nixantphos (10 mol %).

^dThe reactions were conducted at 0.033 M concentration.

^eThe reaction was conducted in distilled and degassed chlorobenzene.

^fReaction progress stopped at 60% conversion (40% unreacted starting material)

^gThe reaction was conducted using 1 equiv AgNO₃.

During the course of these optimization studies we noticed that chemical yields were not satisfactorily reproducible, and we began to suspect that adventitious oxygen may play a role in these reactions. As such, we carried out the AgOTf-catalyzed hydroamination of 3a under an atmosphere of oxygen and were pleased to discover the desired product was formed in 70% yield (Table 1, entry 9). When silver nitrate was employed as catalyst and the concentration was decreased to 0.033 M the reaction provided 99% yield of 5a (Table 1, entry 10). Finally, the use of chlorobenzene as solvent allowed the reactions to be conducted at a higher, more synthetically useful concentration (0.1 M) at lower temperature (80 °C).

Further experimentation indicated the reaction could be conducted under an atmosphere of air rather than O₂ (Table 1, entries 13–14). However, reactions carried out under air proved to give inconsistent results that appeared to depend on the level of atmospheric humidity present on any given day. Control experiments were carried out under a nitrogen atmosphere to further examine the role of O₂ in these reactions. Treatment of 3a with 10 mol % AgNO₃ under N₂ in degassed chlorobenzene led to only 60% conversion of starting material to product (Table 1, entry 16). However, use of a full equivalent of AgNO₃ under these oxygen-free conditions gave results comparable to the use of 10 mol % AgNO₃ under an oxygen atmosphere (Table 1, entry 17).

Before further exploring the scope of these reactions, we quickly surveyed the influence of two other nitrogen protecting groups on reactivity. As shown in Scheme 2, eq 3, use of substrate 6 bearing a N-p-methoxyphenylsulfonyl group led to the formation of the desired product 7 in 96% yield. Unfortunately efforts to prepare the analogous p-nitrophenyl derivative have thus far been unsuccessful. In addition, the reaction of di-boc protected substrate 8 failed to produce the desired hydroamination product (Scheme 2, eq 4).

Scheme 2.

In order to examine the scope of the silver-catalyzed guanidine hydroamination reactions, several substrates with different substitution patterns were synthesized and subjected to the optimized reaction conditions. As shown in Table 2, substrates 3a–3d and 3g–3j bearing a variety of substituents on the non-cyclizing nitrogen atom were converted to the desired products in excellent yields (Table 2, entries 1–4 and 7–10). In addition, substitution on the internal alkene carbon was tolerated as substrates 3e and 3f were converted to cyclic guanidines 5e and 5f in high yield (Table 2, entries 5–6), although slightly higher reaction temperatures (100 °C) were required in these cases. Several functional groups including a cyclic acetal (Table 2, entry 8), an aryl ether (Table 2, entry 10), and a TBS-protected alcohol (Table 2, entry 9) were also tolerated, although approximately 20% of desilylated product was generated in this latter reaction. Although transformations of 1,1-disubstituted alkene substrates proceeded smoothly, efforts to carry out the Ag-catalyzed hydroamination of 1,2-disubstituted alkene substrates 9 or 10 (Scheme 3, eq 5) were unsuccessful. No desired products were obtained in these reactions even with increased catalyst loadings (40 mol % Ag) and temperatures (138 °C). In addition, preliminary studies on 6-membered ring formation from substrate 11 failed to produce the desired cyclic guanidine product.

Table 2.

Ag-Catalyzed Intramolecular Hydroamination Reactions^a

entry	substrate	R1	R2	product	yield (%)b
1	3a	Me	H	5a	95
2	3b	Bn	H	5b	98
3	3c	Allyl	H	5c	97
4	3d	PMP	H	5d	99
5c	3e	Bn	Me	5e	94
6c	3f	Et	Me	5f	96
7	3g	(CH2)2Ph	H	5g	97
8	3h		H	5h	89
9d	3i	(CH2)3OTBS	H	5i	72
10	3j	(CH2)2OPh	H	5j	88

^aConditions: 1.0 equiv substrate 3, 1.0 equiv t-BuONa, 15 mol % AgNO₃, chlorobenzene (0.1 M), O₂ balloon, 80 °C, 16–18 h. Reactions were conducted on a 0.25 mmol scale.

^bIsolated yield (average of two or more experiments).

^cThe reaction was conducted using 20 mol % AgNO₃ catalyst at 100 °C for 18 h.

^dApproximately 20% of the desilylated alcohol was also generated.

Scheme 3.

To explore the diastereoselectivity of these reactions, we sought to prepare substrates analogous to 3 but bearing a substituent (methyl or phenyl) at the allylic position. Unfortunately use of standard methods to generate these compounds has thus far been unsuccessful. Nonetheless, we were gratified to find the intramolecular alkene hydroamination reactions are amenable to the stereoselective construction of bicyclic guanidine derivatives. As shown in Scheme 4, eq 6, treatment of 12 with a AgNO₃ catalyst and t-BuONa under an oxygen atmosphere afforded bicyclic product 13 in 89% yield and 3:1 dr. The analogous hydroamination of 14 afforded bicycle 15 in 99% yield and >20:1 dr (Scheme 4, eq 7).

Scheme 4.

We briefly examined deprotection of the N-arylsulphonyl group to afford the corresponding NH guanidine product. We have previously illustrated that N-tosyl groups can be cleaved from 2-aminoimidazoles (aromatic guanidine derivatives) via reduction with Li/naphthalene. Unfortunately, our preliminary efforts to apply those conditions to the cyclic guanidine 5b gave unsatisfactory results. Analysis of the reaction mixture by NMR and ESI-MS indicated the N-tosyl group was cleaved, but competing cleavage of the N-benzyl group was also observed. In addition, it proved to be very difficult to recover the deprotected material after aqueous workup due to water solubility. However, deprotection of the corresponding N-4-methoxyphenylsulfonyl derivative 7 under acidic conditions afforded the desired guanidinium salt 16 in 60% yield (eq 8).

(8)

Currently the mechanism of the Ag-catalyzed alkene hydroamination reactions remains unclear. We have no evidence to suggest these transformations do not proceed in a manner analogous to other hydroamination reactions that employ electrophilic late-metal catalysts (alkene activation by the catalyst, attack of the pendant nucleophile, and protodemetallation).⁹ However, in contrast to typical late-metal catalyzed alkene hydroamination reactions, which are typically conducted under neutral or slightly acidic conditions, the strong base t-BuONa is essential for our transformations. Thus, it is possible these reactions proceed via an atypical pathway. The role of oxygen is also not entirely clear at this point. However, the observation that the hydroamination of 3a in degassed chlorobenzene solvent under a N₂ atmosphere proceeded to 60% conversion (Table 1, entry 16) with 10 mol % catalyst and full conversion (99% yield) with a full equivalent of AgNO₃ (Table 1, entry 17) indicates oxygen is not essential for reactivity or catalyst turnover. As such, it appears likely that oxygen plays a role in stabilizing (or preventing reduction of) the silver catalyst.

In conclusion, we have developed the first metal-catalyzed intramolecular alkene hydroamination reactions of guanidine nucleophiles. These transformations provide access to five-membered cyclic guanidines bearing methyl substituents adjacent to a ring nitrogen atom in excellent yield. Future studies will be directed towards expanding the scope of these transformations and developing enantioselective variants.