Palladium-Catalyzed, Enantioselective Desymmetrization of N-Acylaziridines with Indoles

Abstract

Ring opening reactions of meso-aziridines generate chiral amine derivatives where the control of stereochemistry is possible through enantioselective catalysis. We report the use of a diphosphine–palladium(II) catalyst for the highly enantioselective desymmetrization of N-acylaziridines with indoles. The β-tryptamine products are isolated in moderate to high yield across a range of indole and aziridine substitution patterns. The synthetic utility of β-tryptamine products is demonstrated by conversion to the brominated pyrroloindoline derivative.

Graphical Abstract

Carbon–nitrogen bonds are prevalent in organic small molecules of interest to the chemical community. Many nitrogen-containing compounds are chiral, resulting in the extensive development of enantioselective methods for nitrogen installation.¹ Aziridines are classic synthetic intermediates that provide an opportunity to construct carbon–nitrogen bonds at chiral carbons with adjacent functional group complexity.² Rapid development of meso-aziridine desymmetrization in recent decades was possible for a wide variety of heteroatom nucleophiles and cyanide.³ More recent catalyst systems have facilitated the introduction of complex carbon nucleophiles⁴ including indoles.⁵ Aziridine opening with indole equivalents produces substituted tryptamines that are found in a range of biologically active natural products (Figure 1).⁶

Figure 1.

Natural products containing the tryptamine core.

Our interest in developing catalysts for aziridine desymmetrization began with the palladium-catalyzed rearrangement of N-acylaziridines to oxazolines.⁷ Previous success employing indoles as nucleophiles in the ring opening of N-acylaziridines⁸ compelled us to investigate the aziridine desymmetrization. Wang and co-workers reported the use of indoles to generate enantioenriched tryptamines under magnesium catalysis while our work was underway (Scheme 1).^5a In their method, indole substitution is limited to the benzene portion (sites 4–7), except for 3-substituted indoles that produce the pyrroloindoline product.^5b Herein, we report a complementary method for synthesizing tryptamines by a palladium-catalyzed aziridine desymmetrization. Our method functions under reduced catalyst loading, and substitution is tolerated at indole positions 1 and 2.

Scheme 1.

New Method for Aziridine Desymmetrization with Indoles

The investigation into the desymmetrization of isoxazole-based aziridine 5 began with catalyst conditions we previously developed for the Heine rearrangement.⁷ The palladium(II) catalyst derived from DTBM-SEGPHOS failed to generate tryptamine 6 in the presence of excess indole (entries 1 and 2, Table 1). A decrease in the size of the substituents on the ligand to DM-SEGPHOS led to the first indication of a product in high enantioselectivity (entries 3 and 4). Other noncoordinating counterions could be employed, but enantioselectivity decreased slightly (entries 5 and 6). A survey of alternative axially chiral diphosphine ligands did not improve the reaction outcome (entries 7–11). An alteration of the isoxazole 5-position to aziridine 7 gave an increase in yield but a slightly lower enantioselectivity (entry 12). Final optimized conditions were achieved by replacing the solvent with α,α,α-trifluorotoluene (TFT, entry 13).

Table 1.

Catalyst Optimization for the Synthesis of Enantioenriched Tryptamines^a

entry	R	ligandb	X	yield (%)c	ee (%)d
1	Me	DTBM-SEGPHOS	OTf	0
2	Me	DTBM-SEGPHOS	bf 4	0
3	Me	DM-SEGPHOS	OTf	0
4	Me	DM-SEGPHOS	bf 4	45	91
5	Me	DM-SEGPHOS	SbF6	58	86
6	Me	DM-SEGPHOS	PF6	43	87
7	Me	Tol-BINAP	bf 4	32	87
8	Me	DM-BINAP	bf 4	42	87
9	Me	DM-MeO-BIPHEP	bf 4	49	89
10	Me	Tol-GARPHOS	bf 4	41	88
11	Me	DM-GARPHOS	bf 4	39	89
12	t-Bu	DM-SEGPHOS	bf 4	58	89
13e	t-Bu	DM-SEGPHOS	bf 4	66	92

^aReaction conditions: aziridine 5 or 7 (0.1 mmol), 1H-indole (0.3 mmol), and 50 mg of 4 Å powdered molecular sieves were added to the preformed catalyst (0.01 mmol of metal–ligand complex and 0.018 mmol of silver salt) in 3:2 toluene/CH₂Cl₂ (0.2 M) and heated to 40 °C for 48 h.

^bThe DM prefix refers to 3,5-dimethylaryl substituents on phosphorus. All ligands screened were the R enantiomer with complete structures provided in the Supporting Information.

^cIsolated yield from a single run.

^dDetermined by HPLC.

^eReaction solvent was α,α,α-trifluorotoluene.

Optimized catalyst conditions were utilized to investigate the reaction substrate scope with respect to indole. The preformed [(R)-DM-SEGPHOS]Pd(BF₄)₂(H₂O)₂ catalyst (9) was determined to be the diaqua complex by X-ray crystallography with a structure similar to known diphosphine–palladium(II) diaqua complexes⁹ (Figure 2; see the Supporting Information). Reactions were conducted with 10 mol % 9 and excess indole to maximize the yield of tryptamine 10 (Table 2). 1H-Indole and 1-methylindole reacted at the C-3 position in moderate yield and high enantioselectivity (entries 1 and 2). A significant increase in yield occurred for related indoles when a 2-methyl substituent was added (entries 3 and 4). These results are best explained by the methyl group blocking the C-2 addition for entries 3 and 4 (when compared to entries 1 and 2).¹⁰ An ethyl group can be installed at C-2 (entry 5), but 2-phenylindole gave no product formation (data not shown). Methyl substituted indoles in positions 4–7 proceeded in varying yield but with high enantioselectivities (entries 6–9). Ether and fluoro substituents are tolerated on the indole with consistently high enantioselectivity, where the electron-deficient fluoro groups significantly reduce yield (entries 10–12). The addition of 2-methyl substituents was useful to increase both yield and enantioselectivities for several 5-substituted indoles (entries 13–15 versus entries 7, 10, and 11). The broad success of indole substitution patterns is complementary to previously reported enantioselective tryptamine synthesis by desymmetrization where 1- and 2-substituted indoles were unreactive.^5a

Figure 2.

[(R)-DM-SEGPHOS]Pd(H₂O)₂(BF₄)₂ crystal structure.

Table 2.

Indole Substrate Scope for Aziridine Desymmetrization^a

entry	R1	R2	R3	yield (%)b	ee (%)c
1	H	H	H	69	92
2	Me	H	H	49	95
3	H	Me	H	88	95
4	Me	Me	H	84	98
5	H	Et	H	78	97
6	H	H	4-Me	45	88
7	H	H	5-Me	66	93
8	H	H	6-Me	68	94
9	H	H	7-Me	59	94
10	H	H	5-OMe	65	93
11	H	H	5-F	32	92
12	H	H	6-F	29	94
13	H	Me	5-Me	86	97
14	H	Me	5-OMe	88	97
15	H	Me	5-F	59	97

^aReaction conditions: aziridine 7 (0.2 mmol), indole (0.8 mmol), catalyst 9 (0.02 mmol), and 100 mg of 4 Å powdered molecular sieves in α,α,α-trifluorotoluene (1 mL) were heated to 40 °C for 48 h.

^bIsolated yield from two or more runs.

^cDetermined by HPLC.

The aziridine backbone was modified to investigate the reaction scope with 2-methylindole (11, Table 3). Substituents containing functionalized 6-membered ring backbones (entries 1 and 2) also gave excellent results when compared to aziridine 7 (entry 3, Table 2). Ring size played a role in the reaction outcome with the smaller ring substrate (entry 3) slightly decreasing ee and the larger ring substrate (entry 4) decreasing yield. Two aziridines with acyclic substituents led to product in good yield and excellent ee as a single diastereomer (entries 5 and 6). The addition of ether substituents was possible but drastically reduced the reaction rate. A dioxepin substrate gave synthetically useful results over an extend reaction period (entry 7), while introduction of a tetrahydrofuran ring decrease yield and % ee (entry 8). The ether substituent may bind to palladium, but the reason for poor selectivity in entry 8 is unclear. We observed similar results with a related catalyst for aziridine rearrangement.⁷

Table 3.

Aziridine Substrate Scope for Tryptamine Synthesis^a

entry	aziridine	time (h)	yield (%)b	ee (%)c
1		48	88	97
2		72	81	98
3		48	79	94
4		72	62	97
5		48	73	95
6		48	64	93
7		120	53	91
8		168	25	53

^aReaction conditions: aziridine (0.2 mmol), 2-methylindole (0.8 mmol), catalyst 9 (0.02 mmol), and 100 mg of 4 Å powdered molecular sieves in α,α,α-trifluorotoluene (1 mL) were heated to 40 °C for the time indicated.

^bIsolated yield from two or more runs.

^cDetermined by HPLC.

Reaction conditions were modified for a gram scale experiment. We hoped to minimize the indole necessary while also reducing catalyst loading. The new reaction conditions include 5 mol % catalyst, standard organic solvents, and only two equivalents of indole. Despite the adjustments, tryptamine 13 could still be produced in good yield with high enantioselectivity (Scheme 2). The absolute configuration of 13 was determined by X-ray crystallography (see the Supporting Information).

Scheme 2.

Gram-Scale Reaction Conditions

The isoxazole amide directing group required for optimized catalyst conditions can be readily removed. Treatment of tryptamine 8 with excess Boc₂O leads to Boc protection at both N–H bonds (Scheme 3). The intermediate can be directly treated with a basic methanol solution to remove the acylisoxazole group in excellent yield over 2 steps. Boc-protected tryptamine 14 undergoes diastereoselective bromination to provide a 76% yield of pyrroloindoline 15,¹¹ which could be useful for further complex molecular synthesis.

Scheme 3. Tryptamine Deprotection and Functionalization.

^aReaction conditions: 1) Boc₂O, DMAP, THF, 60 °C, 6 h: 2) K₂CO₃, MeOH, 23 °C, 1 h, 88% over 2 steps. ^bNBS, PPTS CH₂Cl₂, −10 °C, 6 h, 76%, 5:1 dr.

The proposed catalytic cycle is depicted in Figure 3. Our previous work on related palladium catalysts in aziridine desymmetrization indirectly indicated isoxazole binding.⁷ The formation of complex 16 initially occurs with the displacement of water from precatalyst 9.¹² We have indicated bidentate coordination to the carbonyl oxygen but recognize N-acylaziridines are twisted amides that may bind via nitrogen. Enantioselective attack by 11 occurs to generate 17. After rearomatization with proton transfer, complex 18 will undergo ligand exchange with 3 to release the product (12) and turn over the catalyst. We view the role of molecular sieves as maintaining a dry solution to prevent catalyst decomposition during heating that may lead to a background reaction.

Figure 3.

Proposed catalytic cycle.

We have detailed a new palladium-catalyzed method for the desymmetrization of meso-aziridines in high enantioselectivity. The conditions are complementary to current literature, providing rapid access to tryptamines with various substitution patterns at low catalyst loading. The necessary isoxazole protecting group can be readily removed to generate a synthetically useful intermediate. Initial NMR experiments suggest a catalyst–aziridine complex along the catalytic cycle.