Cu-Catalyzed Three-Component Carbofunctionalization of 1,3-Dienes

Abstract

The carboamination of 1,3-dienes provides direct and efficient access to allylic amines in a step-economical fashion. Herein, we disclose a three-component 1,3-diene carboamination reaction that provides modular access to a multitude of allylic amines. A representative scope 1,3-dienes, activated alkyl halides, and amines are demonstrated to serve as components for this reaction with yields ranging from up to 96%. High regioisomeric ratios are observed with both substituted and unsubstituted diene derivatives for either 1,2- or 1,4-carboamination (≥12:1). Mechanistic investigations demonstrate that the reaction proceeds via atom transfer radical addition (ATRA) to the diene, affording an isolable allylic halide intermediate. The scope was expanded to a general carbofunctionalization, by adding an exogenous O, S, P, or C nucleophile and base, to the reaction upon formation of the allylic halide, in a two-step, one-pot process.

Graphical Abstract

INTRODUCTION

Allylic amines constitute an important class of compounds that exhibit unique pharmacological activities and are versatile synthetic intermediates.^1–4 As such, an array of methods have been devised to access this valuable structural motif.⁵ Generally, their synthesis relies on the privileged reactivity of a preinstalled allylic functional group⁶ through rearrangement,^7–9 reductive amination,¹⁰ substitution,^11–13 or the use of organomagnesium reagents,^14,15 and pre-formed imines.^16–18 These reactions face challenges including the use of toxic and/or pyrophoric reagents, poor functional group tolerance, and in the case of substitution, overalkylation. To overcome these challenges, a myriad of transition metal-catalyzed allylic functionalizations have been developed, for example the Tsuji-Trost-type allylic substitutions,^19–21 allylic C–H amination,^22–28 hydroamination of dienes,^29–38 or hydroaminomethylation of alkynes.^39–41

Multicomponent reactions allow for the synthesis of structurally diverse molecules with excellent step-economy.^42–45 Three or more reagents joined in a single step is highly desirable as these reactions allow for the rapid generation of related organic scaffolds for diversity-oriented synthesis and structure-activity-relationship studies.^46–48 One of the first examples of this approach for the synthesis of allylic amines was demonstrated by Heck in 1978, in which he utilized a palladium catalyst to join terminal alkenes, vinyl halides, and secondary amines.⁴⁹ More recently, an attractive alternative approach for multicomponent allylic amine synthesis has been developed—the transition metal-catalyzed carboamination of dienes (Figure 1).^50–57 These reactions generally employ Pd^{50,53,58–61} or Rh^62,54 catalysts to couple a commodity diene, e.g. butadiene, with an electrophilic alkyl fragment and a nucleophilic amine. While powerful, these methods rely on the use of expensive precious metal catalysts. As such, efforts have been made to identify methods that employ coinage metals for carbofunctionalization reactions.^51,63–77

Figure 1.

Catalytic difuctionalization of 1,3-dienes yields access to structurally diverse products.

There are a number of recent Cu-catalyzed diene difunctionalization reactions. In a recent example from Chemler, Cu-catalyzes the oxidative carboamination of substituted dienes with a β-aminoethyl–BF₃K salt for the synthesis of pyrrolidine derivatives.⁷⁸ In 2018, Zhang reported the multicomponent Cu-catalyzed carboazidation of dienes⁷⁹. A year later, Wang developed a Cu-catalyzed amino oxygenation of 1-substituted butadiene derivatives⁸⁰ More recently, Xing reported an asymmetric carbocyanation of 1,3-dienes.⁸¹ Despite these advances, a more general reaction platform that would enable the modular assembly of diverse allylic amines from three independent components remains a challenge. To maximize the versatility of the carboamination reaction for diversity-oriented synthesis, it would be beneficial to develop a multicomponent process that enables the direct coupling of radical precursors, dienes, and nucleophiles.

Our group has developed several Cu-catalyzed alkene carbofunctionalization reactions that combine diverse nucleophiles with α-halocarbonyl compounds⁸² to accomplish the fully intermolecular 1,2-difunctionalization of alkenes.^83–88 Investigation into the mechanism of the carboamination reaction revealed that the reaction was occurring though Cu-catalyzed atom transfer radical addition (ATRA) of the alkyl halide across the styrene, followed by Cu-catalyzed intramolecular S_N2 to generate a highly reactive, cyclic oxocarbenium intermediate suitable for capture by diverse nucleophiles.⁸⁹ We hypothesized that analogous allylic halides and/or allylic oxocarbenium intermediates, obtained from engaging conjugated π-systems, namely 1,3-dienes could potentially deliver an array of interesting allylic functionalities in a fully modular fashion. Such a reaction platform would not only directly address the challenge of modular allylic amine synthesis but would also take advantage of readily accessible (often commercially available) starting materials and employ an inexpensive, abundant catalyst. Herein, we report the development of the Cu-catalyzed carbofunctionalization of conjugated dienes via in situ-generation allylic halides.

METHODS

General Procedure for the Cu-catalyzed Carbofunctionalization of 1,3-Dienes.

In a nitrogen-filled glove box, a DCM stock solution containing CuBr (50 mM, 5.0 mol %) and tmphen (100 mM, 10. mol %) was prepared in a 4-mL vial. In the glove box, the vial was heated at 60 °C until complete dissolution of the catalyst was achieved (approximately 5 minutes). A 4-mL vial was charged with 400 µL of this stock solution, followed by DIPEA (38 µL, 0.22 mmol, 1.1 equiv), nucleophile (0.20 mmol, 1.0 equiv), alkyl halide (0.35 mmol, 1.8 equiv), and 1,3-diene (0.30 mmol, 1.5 equiv). A magnetic stir bar was added to the vial, which was then sealed with a Teflon-lined screw cap. The reaction was brought out of the glove box and stirred vigorously (800 RPM) at ambient temperature (25 ± 2 °C) for 24 hours, after which time the vial was diluted with ethyl acetate (2.0 mL). The crude mixture was adsorbed onto diatomaceous earth and purified by silica gel column chromatography (hexane/ethyl acetate) to afford the reported products. Isolated yields listed below are the average of two or more independent reactions.

RESULTS AND DISCUSSION

Initial investigations focused on developing the Cu-catalyzed carboamination of 1,3-butadiene an inexpensive and abundant commodity chemical. Optimization efforts employed a commercially available 2.0 M solution of 1,3-butadiene in THF, radical precursor ethyl α-bromoisobutyrate (1a), and N-methyl-toluidine (3a) as the nucleophilic amine. Under our previously optimized conditions for the carboamination of vinylarenes,⁸³ we observed a promising 57% isolated yield of 1,4-carboamination product 4 with 7.7:1 E/Z diastereoselectivity (Table 1, entry 1).

Table 1.

Select reaction optimization^a

entry	1a (x equiv)	2a (y equiv)	[Cu]	ligand (mol %)	base	solvent	T (°C)	yield (%)b	d.r. (E:Z)	r.r. (1,4:1,2)
1	2.0	1.0	Cu(OTf)2	bpy (5)	K3PO4c	DCE	80	57	7.7:1	>20:1
2	2.0	1.0	Cu(OTf)2	bpy (5)	K3PO4 c	DCE	25	42	17:1	>20:1
3	2.0	1.0	CuBr	bpy (5)	K3PO4 c	DCE	25	45	18:1	>20:1
4	2.0	1.0	CuBr	tmphen (5)	K3PO4 c	CH2Cl2	25	51	>20:1	>20:1
5	2.0	1.0	CuBr	tmphen (5)	DIPEA	CH2Cl2	25	60	>20:1	>20:1
6	1.8	1.5	CuBr	tmphen (5)	DIPEA	CH2Cl2	25	58	>20:1	>20:1
7d	1.8	1.5	CuBr	tmphen (10)	DIPEA	CH2Cl2	25	96(95e)	>20:1	>20:1
8	1.8	1.5	CuCl	tmphen (10)	DIPEA	CH2Cl2	25	93	18:1	>20:1
9	1.8	1.5	CuBr2	tmphen (10)	DIPEA	CH2Cl2	25	88	17:1	>20:1
10	1.8	1.5	CuBr	phen (10)	DIPEA	CH2Cl2	25	76	>20:1	>20:1
11	1.8	1.5	CuBr	bpy (10)	DIPEA	CH2Cl2	25	57	>20:1	>20:1
12	1.8	1.5	CuBr	PMDTA (10)	DIPEA	CH2Cl2	25	32	>20:1	>20:1
13	1.8	1.5	CuBr	tmphen (10)	K2CO3	CH2Cl2	25	86	>20:1	>20:1
14	1.8	1.5	CuBr	tmphen (10)	NaHCO3	CH2Cl2	25	94	>20:1	>20:1
15	1.8	1.5	CuBr	tmphen (10)	TEA	CH2Cl2	25	66	>20:1	>20:1
16	1.8	1.5	CuBr	tmphen (10)	DIPEA	DMSO	25	76	>20:1	>20:1
17	1.8	1.5	CuBr	tmphen (10)	DIPEA	DMA	25	80	>20:1	>20:1
18	1.8	1.5	CuBr	tmphen (10)	DIPEA	DCE	25	75	>20:1	>20:1
19	1.8	1.5	CuBr	tmphen (10)	DIPEA	MeCN	25	20.	>20:1	>20:1
20	1.8	1.5	CuBr	tmphen (10)	DIPEA	THF	25	< 1	>20:1	>20:1

^a1a (x equiv), 2a (y equiv), 3a (0.10 mmol), [Cu] (5.0 mol %), ligand (5.0–10.0 mol %), base (1.0 equiv), 0.20 mL solvent (0.50 M), 24 h; see SI for experimental details.

^bDetermined by GC analysis using 1-methylnaphthalene as an internal standard.

^c1.1 equiv.

^dTypically the reaction is set up under a N₂ atmosphere in the glovebox, if instead run under N₂ using Schlenk techniques 4 is obtained in 89%, under an air atmosphere reaction affords 4 in 2–5% yield.

^eIsolated yield (0.2 mmol scale), average of three runs.

Notably, the 1,2-regioisomer (4’) was not detected. Gratifyingly, reducing the reaction temperature to 25 °C significantly improves the selectivity to 17:1, albeit at the expense of yield (42%) (Table 1, entry 2). Employing a Cu(I) precatalyst, CuBr, and 3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) as the ligand restores the reactivity and further improves the diastereoselectivity when the reaction is run in methylene chloride (CH₂Cl₂) (Table 1, entry 4). We tentatively attribute the increased reactivity of the [(tmphen)CuBr] in CH₂Cl₂ to improved solubility of the catalyst. Further, utilization of a soluble organic base, diisopropylethylamine (DIPEA), moderately increased the yield to 60% (>20:1 d.r.). Finally, adjusting the relative stoichiometry of the reagents gives our final conditions (Table 1, entry 7, Tables S1-S11): 1a (1.75 equiv), 2a (1.5 equiv), 3a (1.0 equiv), CuBr (5.0 mol %), tmphen (10 mol %), DIPEA (1.0 equiv), in CH₂Cl₂ (0.5 M) for 24 h affords 4 in 96% in situ yield and 95% isolated yield with > 20:1 d.r. and > 20:1 r.r. Deviations from our optimized conditions confirm that tmphen is superior to bipyridine (bpy), 1,10-phenanthroline (phen) and N,N,N’,N’’,N’’-pentamethyldiethylenetriamine (PMDTA) (Table 1, entries 10–12). Several inexpensive heterogeneous bases also promote the desired reactivity (Table 1, entries 13–14); notably, NaHCO₃ affords 4 in 94% yield (>20:1 d.r. and r.r.). Homogenous base triethylamine (TEA), however, provides a diminished 66% yield of 4 (Table 1, entry 15). Other solvents, including DMSO, DMA, and DCE promote the reaction with only a moderate decrease in yield, while MeCN and THF dramatically reduce the desired reactivity (Table 1, entries 16–20).

With the optimized conditions in hand, we sought to explore the scope of the carboamination of 1,3-butadiene. Gratifyingly, the reaction tolerates a range of nitrogen-containing nucleophiles (Table 2). Both electron-rich and deficient arylamine derivatives are excellent substrates for the reaction and afford products 5–24 in 52–90% yield (average yield 71%) and >20:1 E/Z selectivity. Steric encumbrance proximal to the nucleophilic amine has little impact on the transformation: ortho-substituted N-methylanilines as well as N-alkylanilines (N-2-propyl and N-benzyl) afford 5–12 and 23–24 in 60–90% yield. 8-Aminoquinoline affords the desired compounds 25 in an excellent 90% yield. Further, benzophenone imine is an efficient substrate, giving masked primary amine 26 in 69% yield.

Table 2.

Amine Nucleophile Scope^a

^a1a (1.8 equiv), diene (1.5 equiv), amine (0.20 mmol, 1.0 equiv), DIPEA (1.0 equiv), CuBr (5 mol %), tmphen (10 mol %), CH₂Cl₂ (0.50 M), 25 °C, 24 h; unless otherwise stated, the d.r is >20:1 E/Z.

^b48 h.

^cWith 3.3 equiv of amine nucleophile, 2a (0.20 mmol, 1.0 equiv).

Unfortunately, under these conditions, aniline reacts to give the desired product 37 in only 28% yield due to the formation of double-allylation product 38 in 70% yield (relative to aniline as the limiting reagent) (Scheme 1). This over-allylation can be avoided by adjusting the stoichiometry of the reaction. Thus, the use of 3 equivalents of amine relative to 2a results in a 75% isolated yield of the desired mono-allylation adduct 37 (Scheme 1). Alternatively, double allylation product 38 can be formed selectively in the presence of 3.1 equivalents of 1a and 2.2 equivalents of 2a.

Scheme 1. Double-Allylation Product Conditions.

Next, we strove to expand our reaction to additional classes of amine nucleophiles. Primary amines, used in excess to avoid double-allylation products, proved to be excellent substrates with butylamine and benzylamine both participating to afford 28 and 29 in 95 and 89% yield, respectively. Allylamine shows excellent reactivity and chemoselectivity towards the formation of the carboamination product 30 in 87% yield, demonstrating the selectivity of the optimized reaction conditions for conjugated π-systems over alkenes.

Piperidines, morpholines, and piperazines are commonly found in small-molecule drugs^45,90. These secondary cyclic amine nucleophiles proved to be excellent substrates in this carboamination reaction: piperidone ketal 31, morpholine 32, thiomorpholine 33, and piperazines 34–36 are formed in very good to excellent yield (59–96%). Notably, several of these substrates require extended reaction times (48 h) to achieve full conversion, possibly due to inhibition of the catalyst by the strongly coordinating amine. Finally, we demonstrated the late-stage functionalization of complex molecules containing pharmaceutically relevant motifs: amoxapine, a second-generation antidepressant, provides corresponding allylic amine 35 in 96% yield. Similarly, xylazine, a non-opioid sedative, affords the corresponding carboamination product 27 in a 62% yield. Overall, this carboamination system demonstrates excellent functional group tolerance: halides (8–12, 17–21), ethers (6, 7, 13, 21), nitriles (14), ketones (15), esters (16), imines (26), acetals (31), as well as aromatic (25) and aliphatic heterocycles (31–36) are exemplified.

Tertiary bromides bearing electron-withdrawing groups (EWG) are ideal reaction partners (Table 3) as they stabilize the carbon-centered radical formed upon Cu-mediated reduction of the C–Br bond and direct coupling between the alkyl halide and amine, via S_N2, does not occur. The reaction tolerates a variety of different EWGs on the alkyl component, including esters (39–45), amides (50–52), nitriles (49), and halogens (43, 52). Secondary bromides also participate, as the corresponding allylic amines 44 and 45 are afforded 59 and 62% yield, respectively; unfortunately, 46, was barely detected. The observed reduction in the isolated yields with secondary alkyl halides is, in part, due to the observed competing direct alkylation of the nucleophile. This trend is exacerbated in the case of primary bromides, where the alkylated electrophiles are formed and the desired carboamination product 47 is not detected while 48 is scarcely observed (<3%). Steric hindrance proximal to the bromide does not significantly affect the reaction as 42, 45, and 49 are obtained in 74, 62, and 76% yield, respectively. Additional functional groups, including alkynes (39), electron-rich arenes (41), alkyl fluorides (43), alkyl chlorides (53), Weinreb amides (51), and oxazolidinones (52) are all tolerated.

Table 3.

Electrophile Scope^a

^aSee Table 2 for full reaction conditions, >20:1 E/Z crude ratio (determined by GC).

As seen in Table 2 and Table 3, 1,3-butadiene is an excellent substrate for the carboamination reaction. We sought to determine the impact of substituents on the diene on both the regio– and diastereoselectivity (Table 4). Internally substituted isoprene (2-methyl-1,3-butadiene) affords regioisomeric carboamination products 54a and 54b in 66% (>20:1 d.r.) and 25% (6.7:1 d.r.) isolated yield, respectively. The observed regioselectivity (3.4:1 in situ, 4.4:1 isolated) is due to radical addition preferentially occurring to form the more stable tertiary allylic radical intermediate. The major regioisomer 54a is formed as a >20:1 d.r., favoring the E-alkene; we attribute this excellent stereoselectivity to the ground state bias towards the s-trans conformer (see SI for more details). 2,3-Dimethylbutadiene affords 55 in 78% yield and 3.2:1 d.r. The low diastereoselectivity is consistent with the minimal steric differentiation between the s-cis and s-trans conformers.

Table 4.

1,3-Diene Scope^a

^aSee Table 2 for full reaction conditions, >20:1 E/Z isolated ratio.

^b40 °C instead of 25 °C.

^cNaHCO3 instead of DIPEA.

^dDMSO instead of CH₂Cl₂.

1-Substituted butadienes are highly selective for the 1,2-carboamination products. 56’ and 57’ are formed in good yields, 65% and 55%, respectively, as single regio- and diastereoisomers. This change in regioselectivity is likely due to functionalization occurring selectively at the less hindered allylic position. Acyclic 1,4-disubstituted butadiene derivatives do not participate at room temperature; increasing the temperature to 40 °C improves reactivity and affords 59 in 38% yield, albeit in a reduced 3:1 d.r. Notably, the 1,4-isomer is favored, as the less hindered C4 is selectively functionalized. Under the standard reaction conditions, 1,1- and 1,2-disubstituted butadiene derivatives generate elimination products selectively (see SI for more details).⁹¹ Gratifyingly, increasing the temperature at 40 °C and using the less soluble sodium bicarbonate as the base, with phenyl-2-methylbutadiene affords allylic amines 60 and 61 in 48% and 88% yield with N-methyl toluidine and toluidine, respectively. Unfortunately, alternative conditions to favor the carboamination reaction over the elimination side reaction with 1,1-disubstituted butadienes were not identified.

Cyclic 1,3-dienes proved to have distinct reactivity from their acyclic counterparts. Combining 1a with 4-methoxy-N-methylaniline and 1,3-cyclohexadiene does not afford 1,4-carboamination product 63 under the standard reaction conditions (see SI for more details). Substituting CH₂Cl₂ for DMSO, under otherwise identical reaction conditions, restores the reactivity of this cyclic 1,3-diene and affords access to 63–71. Notably, only the 1,4-regioisomer is observed, with a high diastereoselectivity (>20:1) favoring the trans product, as confirmed by XRD. Additional radical precursors are shown to participate (70-71) in good to very good yields. As with 1,3-butadiene, a variety of arylamines can be combined with 1,3-cyclohexadiene, though those bearing electron-withdrawing substituents tend to afford the desired products in reduced yields. Further, alkyl amines afford products in negligible yield, potentially due to inhibition by these strongly coordinating nucleophiles. Notably, the over-allylation of primary arylamines is not observed with these substrates. Unfortunately, other cyclic dienes do no show promising reactivity under our carboamination conditions; trace carboamination products were observed with cyclopentadiene and no reaction was observed with either cycloheptadiene or cyclooctadiene.

Inspired by the double-allylation reaction observed with primary arylamines (Scheme 1), we hypothesized that using two different dienes, 1,3-butadiene and 1,3-cyclohexadiene, would facilitate a double-carboamination and rapidly develop chemical complexity from simple starting materials. When both 1,3-butadiene and 1,3-cyclohexadiene are added simultaneously to the same pot, only double-allylated product 38 is detected. We credit this observation to the selectivity of 2a over the less reactive cyclic diene (see SI for more details) (Scheme 2). 1,3-Cyclohexadiene is not prone to over-allylation, as primary anilines and amines afford single allylation products 66–71. As such, we sought a telescoped process to achieve the double-carboamination adducts, where first 1,3-cyclohexadiene is combined with an amine and alkyl fragment and then 1,3-butadiene is later added to the same pot. Promisingly, under these conditions, 72 is observed, albeit in low yields (12% in situ yield). Alternatively, a two-step process is possible to access 72 in 39% isolated yield: the carboamination protocol is first executed on cyclohexadiene and, following an aqueous work-up to remove the DMSO, the crude product is subjected to a second carboamination reaction with the 1,3-butadiene.

Scheme 2. Telescoped Double-Allylation of Aniline.

With the scope in hand, we sought to attain an understanding of the mechanism of this carboamination reaction to rationalize the observed regiodivergence with different substituted conjugated dienes. While 2,3-dimethyl butadiene and isoprene exhibit analogous reactivity to butadiene, 1,2-carboamination is observed with 1-substituted 1,3-butadienes, and 1,3-cyclohexadiene requires DMSO as the solvent to achieve reactivity. We hypothesized that these dienes react through different mechanisms. Our Cu-catalyzed styrene carboamination reactions are proposed to involve an oxocarbenium intermediate that is subject to capture by a nucleophile.^83,85,87,92 As some of the alkyl halides exemplified in this work do not contain the requisite carbonyl for oxocarbenium formation, this stabilized carbocation intermediate cannot be required to facilitate incorporation of the nucleophile. Previously, we observed that reactions that proceed via oxocarbenium intermediates afford lactone products when tert-butyl α-bromoisobutyrate is employed as the alkyl halide.^83,87 Therefore, we subjected 1,3-butadiene, 1-cyclohexyl-1,3-butadiene, and 1,3-cyclohexadiene to the optimized conditions with tert-butyl α-bromoisobutyrate with and without 3a. With 1,3-butadiene, in the absence of 3a, ATRA adduct 73 is formed in near quantitative yield (99%) (Scheme 3A). This observation is consistent with related Cu-mediated ATRA of alkenes and alkynes.^93–97 Similarly, in the reaction between butadiene and tert-butyl α-bromoisobutyrate, lactone 74 is not detected; rather, allyl bromide 75 is formed in 89% yield (Scheme 3B). In addition, in the presence of 3a, we observe the selective formation of the carboamination product 76 in 80% yield (Scheme 3C). Finally, subjection of 75 and 3a to the reaction conditions leads to the formation of 76 in 72% yield (Scheme 3D). Combined, these results support that the 1,4-carboamination of butadiene is occurring via atom transfer radical addition and subsequent substitution by the amine nucleophile. Finally, a one-pot, two-step sequence was developed; upon completion of the ATRA reaction we added 3a and observe the selective formation of 4 in 90% isolated yield.

Scheme 3. Mechanistic Studies. (a) Isolation of the atom transfer adduct. (b and c) Investigating the intermediacy of an oxocarbenium ion intermediate. (d) Subjection of the ATRA adduct to the reaction conditions.

A mixture of ATRA adducts is formed in the reaction between 1a and 1-cyclohexylbutadiene in the presence of the copper catalyst. Under analogous conditions with tert-butyl α-bromoisobutyrate and without any nucleophilic amine, the exclusive formation of lactone 78 is observed (Scheme 4A). Intriguingly, the same lactone 78 is formed as the major product in the presence of 3a (Scheme 4B). The formation of this lactone indicates that oxocarbenium formation and fragmentation is competitive with nucleophilic capture with 1-substituted 1,3-butadienes. This observation may explain the regiodivergence with this class of 1,3-diene, as the oxocarbenium intermediate would be expected to increase the electrophilicity of C2 over C4. Similarly, this intermediate may further rationalize the excellent regioselectivity observed with 58’, where the 1,2-carboamination product forms despite the lack of significant steric or electronic differentiation of the corresponding allylic carbocation. Finally, with 1,3-cyclohexadiene lactone 81 forms in the absence of 3a (Scheme 4C) and carboamination product 82 forms exclusively in its presence (Scheme 4D), consistent with the formation of an oxocarbenium intermediate followed by S_N2'.

Scheme 4. Mechanistic Studies with Buta-1,3-dien-1-ylcyclohexane and Cyclohexadiene. (a and b) Formation of a lactone with a t-butyl ester with and without an amine nucleophile with 1-substituted dienes supporting an oxocarbenium intermediate. (c and d) Foramtion of a lactone in the absence of an amine nucleophile but not in its presence.

A proposed catalytic cycle is shown in Scheme 5. First, (i.) [Cu(I)] reduces the C–Br bond to generate [Cu(II)]–Br and alkyl radical I. (ii.) Radical addition to the 1,3-diene affords allylic radical II. The next step may depend upon the nature of the 1,3-diene. When 1,3-butadiene is used, (iii-a.) atom transfer occurs between the [Cu(II)]–Br to the allylic radical to generate allylic bromide III-A which undergoes subsequent (iv-a.) S_N2 with the nucleophile. With 1-substituted 1,3-dienes, (iii-b.) the allylic radical can be oxidized to the oxocarbenium intermediate III-B by the copper catalyst, which then (iv-b.) undergoes ring-opening by the amine.

Scheme 5.

Potential Mechanistic Pathways

There are limited reports of the ATRA between alkyl halides and dienes for the generation of allyl halides.^98–105 Reported transformations generally are limited to electron-deficient radical precursors^{100–102,105} and/or require visible light to promote the reduction of the alkyl halide.^102–104 We aimed to determine if our conditions would allow for the direct synthesis of allylic halides from 1,3-dienes and a range of alkyl halides. Indeed, in the absence of a nucleophilic amine, the ATRA reaction affords the desired products in good to excellent yields with a variety of radical precursors^106–108 (Table 5). Notably, with 88 and 89, a mixture of the Br and Cl products are observed; the extra Cl atom likely comes from the CH₂Cl₂ solvent.¹⁰⁹ Unsurprisingly, the products are highly reactive and prone to decomposition; for example, 84 cannot be isolated, despite the excellent 81% in situ yield.

Table 5.

Allylic Halide Scope^a

^aR–Br (1.2 equiv), diene (0.3 mmol, 1.0 equiv), DIPEA (0.66 equiv), CuBr (3.3 mol %), tmphen (6.6 mol %), CH₂Cl₂ (0.66 M), 25 °C, 24 h.

Next, we sought to leverage our mechanistic insights and knowledge of the ATRA intermediate to enhance the reactivity of several challenging substrate classes for this 1,4-carboamination reaction by developing a one-pot, two-step protocol. We hypothesized that first forming the ATRA intermediate and subsequent addition of nucleophiles that are problematic under our standard conditions may allow convenient access to additional 1,3-diene carbofunctionalization products (Table 6). Importantly, this approach does not require isolation of the unstable ATRA adducts, rather, it relies on the simple sequential addition of reagents. Indeed, 1-bromoacetonitrile, a primary electrophile prone to undergo S_N2 with the amines, now participates in the desired carboamination reaction to afford 90 in 58% yield. Likewise, additional functional groups are tolerated, for example, terminal alkyne 91 is formed in 43% yield.

Table 6.

Expansion of Scope to Other Nucleophiles^a

^aSee Table 2 for full reaction conditions.

^bK₃PO₄ instead of DIPEA.

Relatively acidic oxygen, sulfur, phosphorous, and carbon-based nucleophiles undergo carbofunctionalization with this modified reaction sequence in the presence of additional DIPEA. Diethyl-phosphite, benzoic acid, and thiophenol afford 92, 93, and 94 in 49%, 55%, 66% yield, respectively, demonstrating that this platform provides rapid access to C–P, C–O, and C–S bonds in addition to alkyl amination products. Further, malononitrile can be used to produce 95 in 63% yield. Less acidic diethylmalonate requires a stronger base, K₃PO₄, to give 96 in 37% yield. Finally, we demonstrated this strategy for the late-stage functionalization of bioactive molecules indomethacin, gemfibrozil and estrone, to form 97, 98, and 99 in synthetically useful yields.

CONCLUSION

We have developed a multicomponent carboamination reaction that joins readily available 1,3-conjugated dienes with alkyl bromides and a variety of nucleophiles. The scope of the reaction is broad with respect to all three components, generally affording the products in high regio- and diastereoselectivities. The >70 examples presented with yields ranging from 20–99% (68% average yield) attest to the excellent functional group tolerance of the transformation. With most dienes, 1,4-difunctionalization is favored; however, regiodivergence to the 1,2-difunctionalization product is observed with 1-substituted 1,3-diene derivatives. As with our previous carbofunctionalization reactions, 1-substituted and cyclic dienes likely proceed through oxocarbenium intermediates. With 1,3-butadiene, however, ATRA occurs to form the allylic bromide, which undergoes subsequent substitution with the nucleophile. This mechanistic insight facilitated the development of a telescoped process that expands our reaction to primary alkyl halides as well as oxygen, sulfur, phosphorous, and carbon-based nucleophiles. This report highlights the versatility and modularity of our Cu-catalyzed three-component carbofunctionalization platform.

Supplementary Material

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Supporting Information

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Representative optimization data

Additional experimental details, materials, and methods

Tabulated characterization data for all new compounds

DFT Calculations

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