Enantio- and Diastereoselective Synthesis of Homoallylic α‑Trifluoromethyl Amines by Catalytic Hydroalkylation of Dienes

Abstract

We describe a strategy for the enantio- and diastereoselective synthesis of homoallylic α-trifluoromethyl amines by the catalytic hydroalkylation of terminal dienes. Trifluoromethyl-substituted isatin-derived azadienolate nucleophiles undergo γ-selective alkylation with a Pd–DTBM-SEGPHOS catalyst, which additionally promotes regioselective addition to the diene and delivers products in up to 86% yield, 10:1 dr, and 97.5:2.5 er.

Graphical Abstract

Chiral amines bearing an α-trifluoromethyl group hold a significant place among classes of medicinally important N-containing molecules. The CF₃ group modulates a number of pharmacological parameters, alters the amine basicity and polarity significantly, and stands in as a non-hydrolyzable amide surrogate.¹ Despite the beneficial properties this motif might impart upon drug-like molecules, methods for the catalytic enantioselective synthesis of α-trifluoromethyl amines are fairly uncommon, with most approaches to these enantioenriched compounds relying on chiral auxiliary chemistry.²

A valuable subset of these compounds are α-trifluoromethyl homoallylic amines. Recently, a number of groups have investigated allylic substitution approaches to these molecules utilizing azaallyl anion building blocks.³ With an isatin⁴ activating group for the nucleophile (Scheme 1), an Ircatalyzed procedure gives rise to branch-selective coupling of the allylic carbonate exclusively at the azadienolate’s α-position; however, this product spontaneously undergoes aza-Cope rearrangement to deliver a net γ-allylation. As a result, the unsaturated amines bear only one stereogenic center.^4,5 The same class of nucleophiles have been utilized in a γ-selective allylation with Morita–Baylis–Hillman-type allylic carbonates by employing a chiral nucleophilic catalyst (Scheme 1).⁶ These coupling processes can yield homoallylic amines with vicinal syn stereogenic centers;^6a however, the product scope is limited to aryl-substituted allylic centers and carbonyl-containing alkenes.^7,8

Scheme 1.

Prior Catalytic Enantioselective α-CF ₃ Homoallylic Amine Synthesis and Proposed Strategy

Given our longstanding interests in both umpolung synthesis of amines⁹ and diene hydrofunctionalization reactions,¹⁰ we envisioned that the merger of these strategies would allow for the enantio-, diastereo-, and regioselective preparation of α-CF₃ homoallylic amines that bear vicinal stereogenic centers and internal alkenes,^10a potentially enabling the anti diastereomer to be accessed (Scheme 1). Several challenges had to be met and overcome for the successful realization of this idea. Primary among these was regioselectivity. In contrast to previous metal-catalyzed allylic substitution methods, our goal was to develop a kinetically γ-selective allylation of isatin azadienolates, obviating the aza-Cope rearrangement and thus giving rise to a fundamentally different product connectivity than would otherwise be available. Could a catalyst be found that is γ-selective, and would this process still be efficient? Would the same catalyst also provide regioselectivity with respect to the diene? Finally, would such a catalyst allow for control of the relative and absolute stereochemistry of the homoallylic amine products? Only recently has a diene hydroalkylation that sets two stereogenic centers in one bond-forming event been reported.¹¹ Herein, we illustrate that Pd–DTBM-SEGPHOS promotes the γ-selective coupling of azadienolates with the terminal olefin of dienes, generating the anti diastereomer of homoallylic α-CF₃ amines with excellent levels of stereocontrol.¹²

We initiated our investigations by exploring the coupling of N-trifluoroethyl imine 1 and phenylbutadiene 2a (Table 1).¹³ Whereas most ligands favor azadienolate α-alkylation product 3a′ under Pd catalysis, bis(phosphines) comprised of 3,5-di-tert-butyl-4-methoxy (DTBM) aryl groups at phosphorus exclusively deliver the desired γ-alkylation product 3a (compare entries 3 and 6 with entries 1–2 and 4–5).¹⁴ Notably, the diastereomeric ratio for 3a is also considerably higher with the more γ-selective catalysts, affording the anti diastereomer as the major isomer (entries 3 and 6). Use of DTBM-SEGPHOS provides the greatest conversion to 3a, which is isolated in 9:1 dr and 91.5:8.5 er (entry 6).¹⁵ We discovered that the enantioselectivity could be improved by the addition of 10 mol % NaBAr^F₄ (93:7 er, entry 7).¹⁶ By switching the solvent from diethyl ether to 1,4-dioxane, the γ-alkylation product 3a is isolated in 80% yield, 8:1 dr, and 95:5 er (entry 9).

Table 1.

Optimization for γ-Selective Addition of an Isatin-Derived Azadienolate to Phenylbutadiene^a

entry	L	NaBArF4 (Y/N)	3a:3a′ b	conv to 3a/3a′ b (%)	dr of 3ab	er of 3ac
1	BINAP	N	1:2.5	48	1:1	nd
2	MeO-BIPHEP	N	1:2.5	66	1.5:1	nd
3	DTBM-MeO-BIPHEP	N	>20:1	49	7:1	nd
4	SEGPHOS	N	1:1.1	30	3:1	nd
5	DM-SEGPHOS	N	1:1.5	38	3:1	nd
6	DTBM-SEGPHOS	N	>20:1	>98	9:1	91.5:8.5
7	DTBM-SEGPHOS	Y	>20:1	>98	9:1	93:7
8d	DTBM-SEGPHOS	N	>20:1	>98	8:1	94:6
9d,e	DTBM-SEGPHOS	Y	>20:1	97 (80)f	8:1	95:5

^aReactions run under N₂ with 0.15 mmol of diene 2a (0.75 M).

^bDetermined by 376 MHz ¹⁹F NMR spectroscopy of the unpurified mixture.

^cDetermined by HPLC analysis of purified 3a.

^d1,4-Dioxane as solvent.

^eReaction for 12 h.

^fIsolated yield of purified 3a. nd = not determined.

Taking the conditions in Table 1, entry 9, as optimal, we next explored the scope of aryl-substituted terminal dienes for coupling with 1 (Table 2). Both electron-rich (e.g., entries 1 and 6–7) and electron-poor (entries 2–3) dienes generate the homoallylic amine products with ≥87% conversion, ≥7:1 dr, and moderate to good enantioselectivity. Heterocycles are tolerated, with furyl-substituted 3i (entry 8) and pyridyl-containing 3j (entry 9) isolated in good yields and stereo-selectivities. The majority of dienes lead exclusively to the γ-alkylation product; however, an ortho substituent on the arene results in a more sluggish reaction (44% conversion in 12 h) that furnishes approximately 10% α-coupling of the azadienolate (entry 5). Improving reaction efficiency required the omission of NaBAr^F₄, and while diastereoselectivity was lower, enantioselectivity remained high (92.5:7.5 er). In all, aryl-substituted dienes readily participate in couplings with 1 at room temperature, affording homoallylic α-trifluoromethyl amines 3b−j in 59–86% yield.

Table 2.

Aryl Diene Scope in Azadienolate Coupling^a

entry	product (3); R1	conv to 3ab (%); yield of 3c (%)	dr of 3b	er of 3d
1	3b; 4-(MeO)(C6H4)	87; 68	10:1	94:6
2	3c; 4-CI(C6H4)	98; 75	7:1	90.5:9.5
3	3d; 4-(F3C)(C6H4)	94; 74	8:1	90:10
4	3e; 3-Me(C6H4)	89; 72	6:1	93:7
5e	3f; 2-Me(C6H4)	63; 59	2:1	92.5:7.5
6	3g; 2-naphthyl	94; 62	8:1	94:6
7	3h; 3,4-dioxolato(C6H3)	94; 86	10:1	91.5:8.5
8	3i; 2-furyl	69; 59	8:1	93:7
9	3j; 3-pyridyl	83; 82	7:1	94:6

^aReactions run under N₂ with 0.15 mmol of diene 2 (0.75 M).

^bDetermined by 376 MHz ¹⁹F NMR or 400 MHz ¹H NMR spectroscopy of the unpurified mixture.

^cIsolated yield of purified 3.

^dDetermined by HPLC analysis of purified 3.

^eReaction run without NaBAr^F₄; 9:1 3f:3f′.

Alkyl-substituted terminal dienes are also effective coupling partners; however, the Pd–DTBM-SEGPHOS-catalyzed processes with imine 1 require elevated temperature (50 °C) to proceed effectively (Table 3). Consequently, we also omitted the NaBAr^F₄ additive to enable the reaction to proceed at a higher rate. Both linear (entries 1–3) and α-branched (entries 4–5) dienes participate in the reactions, affording homoallylic amines 3k−o in 43–83% yield in up to 4:1 dr and 91:9 er. Products derived from isomerization of the diene along the alkyl chain (“chain walking”) prior to enolate addition could not be detected, including with phenethyl 2k or heptadienoate 2m. Alkyl dienes largely or solely lead to γ-alkylation of the azadienolate, although it is notable that piperidine 2o affords ca. 9% α product 3o′. We also observed roughly 8% of an additional γ-alkylation product 3k″ with phenethyl diene 2k. Homoallylic amine 3k″ bears a different connectivity with respect to the diene-derived fragment, and a series of experiments suggest that 3k″ is formed from the aza-Cope rearrangement of α-alkylation product 3k′.¹⁷

Table 3.

Azadienolate–Alkyl Diene Coupling Scope^a

entry	product (3); R1	conv to 3 (%);b yield of 3 (%)c	dr of 3b	er of 3d
1e	3k; Ph(CH2)2	82; 69	4:1	88:12
2	31; n-hexyl	65; 60	4:1	81.5:18.5
3	3m; EtO2C(CH2)2	84; 83	3:1	91:9
4	3n; Cy	61; 43	3:1	90:10
5f		83; 83	3:1	86.5:13.5

^aReactions run under N₂ with 0.15 mmol of diene 2 (0.75 M).

^bDetermined by 376 MHz ¹⁹F NMR or 400 MHz ¹H NMR spectroscopy of the unpurified mixture.

^cIsolated yield of purified 3.

^dDetermined by HPLC analysis of purified 3.

^eA 10:1 mixture of γ-alkylation products 3k and 3k″ was formed; see ref 17.

^f11:1 3o:3o′.

Intriguingly, in the course of our alkyl diene studies, we discovered that hexadienoate 2p (Scheme 2) undergoes diene isomerization into conjugation with the ester prior to its coupling with 1, furnishing the ethyl-substituted stereogenic center of homoallylic amine 3p. The process is reasonably efficient, with the α-CF₃ amine obtained in 48% yield, 12:1 dr, and 97.5:2.5 er. Comparatively, its internal diene analogue 4 also delivers acrylate 3p with similar levels of stereoselectivity but lower conversion.

Scheme 2.

Isomerization/Alkylation of 3,5-Hexadienoate and Comparison to Its Internal Diene Isomer

We have explored a number of additional reaction partners to expand the scope of the hydrofunctionalization (Figure 1). Imine 5 was tested in a coupling with diene 2a in order to access α-difluoromethyl amines, but unfortunately, the nucleophile undergoes complete decomposition without alkylation. Substituted imines, such as 6, would form products bearing tetrasubstituted stereogenic centers^5,6b,8 but were unreactive. Other dienes were also investigated. Alcohol- and silyl ether-containing alkyl dienes 2q and 2r lead to a complex mixture of products, which we surmise to be a combination of the desired γ-alkylation 3, the regiomeric α-alkylation 3′, and the aza-Cope rearrangement products 3″, all as a mixture of diastereomers, rather than products attributable to chain walking.

Figure 1.

Limitations in Reaction Partners.

The diene hydroalkylation with imine 1 can be performed on a 1.0 mmol scale to furnish the α-trifluoromethyl isatin-protected homoallylic amine 3a in 82% yield (Scheme 3). Additionally, hydrolysis of the isatin moiety under mildly acidic conditions delivers the free amine 7 in 77% yield.

Scheme 3.

Scale Up of Azadienolate Hydroalkylation and Product Imine Hydrolysis

Catalytic enantioselective diene hydrofunctionalization provides an enabling route toward highly valuable chemical building blocks that are not readily prepared by other methods. Here, in combination with imine umpolung,³ we have shown that important homoallylic α-trifluoromethyl amines bearing contiguous stereogenic centers and an internal olefin can be accessed for the first time. Utilizing an isatin auxiliary, we have discovered that, in contrast to other transition-metal-catalyzed processes, palladium ligated with DTBM-SEGPHOS allows for regioselective γ-alkylation of the derived azadienolate, generating the anti diastereomer of the homoallylic α-CF₃ amines with high levels of stereocontrol. This catalytic process should open up new chemical space for drug discovery.