Catalytic, Enantioselective, Intramolecular Carbosulfenylation of Olefins

Abstract

The first catalytic, enantioselective carbosulfenylation of alkenes with an aromatic nucleophile is described, using a BINAM-based selenophosphoramide catalyst. E-Alkyl- and aryl-substituted alkenes afforded tetrahydronaphthalenes with complete diastereospecificity, and generally high enantiomeric ratios.

The reaction of sulfur(II) electrophiles with alkenes¹ to afford sulfenofunctionalized products has been thoroughly studied since the 1960’s primarily in the context of investigating the chemistry of thiiranium ions.² These reactive intermediates can be generated by a variety of different sulfenylating reagents (Scheme 1). In addition to the wide range of nucleophiles that have been employed in intermolecular sulfenofunctionalization reactions, the intramolecular capture (sulfenocyclization reactions) can be effected with sulfenylating agents to form carbocycles and heterocycles. Moreover, sulfenium initiated cyclizations have also been successful with polyolefins⁵ and electron rich arenes.⁶ Several examples of nucleophilic opening of chiral thiiranium ions are reported. However, these species are generated by anchimerically-assisted ionization of enantiomerically enriched hydroxy sulfides formed from asymmetric dihydroxylation of alkenes.⁷ These enantiomerically enriched thiiranium ions have been captured with various nucleophiles in inter- and intramolecular fashion.⁸ However, only two reports of direct, enantioselective methyl-sulfenylation reactions have been reported, both employing stoichiometric reagents.⁹

Scheme 1.

As part of a broadly based program to apply the concept of Lewis base activation of Lewis acids¹⁰ to the reactions of main group elements, we have investigated the chemistry of selenium (II)¹¹ and sulfur (II)¹² electrophiles. From extensive preparative and mechanistic studies, we have discovered that the functionalization of isolated alkenes with N-phenylsulfenylphthalimide, 1, is susceptible to catalysis by Lewis bases and the intermediate thiiranium ions are stable^12a and can be captured enantiospecifically with a variety of heteroatom nucleophiles. ^12b These insights led to the development of the first, catalytic, enantioselective sulfenoetherification of unactivated double bonds using 1, MsOH and a chiral selenophosphoramide as the Lewis base.^12c In continuation of these studies we sought to expand the scope of the asymmetric sulfenofunctionalization^13–15 to include carbocyclizations with aromatic nucleophiles. Although such transformations are known, no examples of catalytic, enantioselective cyclizations are on record.

In view of the conditions reported for the sulfenoetherification, the initial conditions for the sulfenocarbocyclization of alkene 2a employed 1 (1.0 equiv), MsOH (1.0 equiv), and Lewis base (10 mol %) in CDCl₃ at −20 °C. A number of chiral phosphoramides were tested to develop an asymmetric variant of the intramolecular sulfenocarbocyclization. The initial survey of Lewis bases was carried out with E/Z mixtures of the starting material 2a. The trans/cis ratio of the diastereomeric products 3a was determined by ¹H NMR spectroscopic analysis of the purified material and the enantiomeric composition of the products was determined by chiral stationary phase, supercritical fluid chromatographic (CSP-SFC) analysis (Table 1). The exclusive formation of trans- and cis-1,2-disubstituted-1,2,3,4-tetrahydronaphthalenes from E- and Z-olefins respectively is in accordance with the anticipated diastereospecificity characteristic of other seleno-¹¹ and thiofunctionalizations. ¹² Chiral Lewis base (R)-4a afforded cyclized products 3a with moderate enantioselectivity for the major product, trans-3a (Table 1, entry 1). However, the minor, cis-3a was produced in racemic form.

Table 1.

Survey of Chiral Lewis Bases to Sulfenocarbocyclization of 2a.^a

entry	E/Zb	acid (equiv)	cat	mol, %	X	trans/cisc	er,d trans	er,d cis
1e	62:38	MeSO3H (1.0)	(R)-4a	10		62:38	32:68	51:49
2e	96:4	MeSO3H (1.0)	(R)-4b	10		96:4	11:89	49:51
3e	94:6	MeSO3H (1.0)	(S)-4c	10		94:6	86:14	59:41
4e	94:6	MeSO3H (1.0)	(S)-4d	10	N(i-Pr)2	94:6	83:17	61:39
5e	96:4	MeSO3H (1.0)	(S)-4e	10	N(i-Bu)2	96:4	95:5	32:68
6e	95:5	MeSO3H (1.0)	(S)-4f	10	N(i-amyl)2	95:5	88:12	64:36
7e	62:38	MeSO3H (1.0)	(R)-4g	10	N(Et)2	62:38	15:85	47:53
8e	95:5	MeSO3H (1.0)	(S)-4h	10	N(n-Bu)2	95:5	92:8	66:34
9f	100:0	EtSO3H (0.75)	(S)-4e	10	N(i-Bu)2	100:0	96:4	-
10f	100:0	EtSO3H (0.75)	(S)-4e	5	N(i-Bu)2	100:0	71:29	-
11f	100:0	EtSO3H (0.75)	(S)-4e	2	N(i-Bu)2	100:0	67:33	-

^aReaction conditions: 2a (0.12 mmol), 1 (0.12 mmol), RSO₃H (0.12 mmol), CDCl₃ (0.2 M), −20 °C.

^bE/Z ratio of the starting material was determined by ¹H NMR spectroscopic analysis.

^cthe E/Z ratio and trans/cis ratio of the cyclization products was determined by ¹H NMR spectroscopic analysis.

^dthe enantiomeric ratio was determined by CSP-SFC analysis.

^eReactions were completed in 24 h.

^eReactions were completed in 48 h.

Increasing the size of the ring to the azepane catalyst (R)-4b led to higher enantioselectivity for trans-3a but gave cis-3a in racemic form (entry 2). A further increase in the size of the ring with azocane catalyst (R)-4c achieved slightly reduced enantioselectivity in the formation of trans-3a (entry 3). cis-3a was still obtained with moderate enantioselectivity. Use of acyclic, branched and secondary external amines with diisopropylamino substituted selenophosphoramide (R)-4d afforded reasonable enantioselectivity for trans-3a (entry 4). Evaluation of other catalysts prepared from branched secondary amines allowed the identification of the diisobutyl-derived catalyst (S)-4e, which afforded excellent enantioselectivity for trans-3a (entry 5). Further extension to the diisoamylamine derived catalyst (S)-4f afforded results similar to the azepane catalyst (R)-4b for trans-3a and a slight improvement for cis-3a (entry 6). The use selenophosphoramide catalyst (R)-4g and (S)-4h derived from linear dialkylamines afforded excellent enantioselectivities for trans-3a (entry 7 and 8) but with lower enantioselection than (S)-4e bearing a diisobutylamino group.

With a highly enantioselective Lewis base catalyst in hand, the exploration of the diversity of the substituent patterns on the alkene as well as the nucleophilicity of the aromatic residue needed for effective cyclization were investigated. Surprisingly, however, upon scaling the reactions to 1.0 mmol, the enantioselectivities decreased. Consequently, the critical reaction parameters had to be revaluated, in particular the acid source and loading.¹⁶ After extensive optimization it was found that EtSO₃H (0.75 equiv) served effectively and reproducibly as the Brønsted acid for cyclization. Using 10 mol % of catalyst (S)-4e, EtSO₃H (0.75 equiv) substrate (E)-2a substrate afforded excellent enantioselection of trans-3a (96:4) with high conversion (Table 1, entry 9). Lowering the loading of (S)-4e to 5 and 2 mol % afforded enantiomeric ratios of 71:29 and 67:33 respectively (entries 10 and 11).

At this point, the exploration of the generality of this transformation was investigated. Gratifyingly, application of the optimized conditions to a large variety of E-alkyl- and aryl-substituted alkenes afforded the cyclized products in moderate to excellent yields (50–92%) with good to excellent enantioselectivities and as single (trans) diastereomer (Table 2). For example, under these conditions E-methyl-substituted alkene (E)-2a formed trans-3a in excellent yield and enantioselectivity to furnish cyclized products trans-3b - trans-3d in moderate yields but very good enantiomeric ratios (entries 3–5). Unactivated E-alkenes bearing linear, β-branched, and alicyclic substituents afforded excellent levels of enantioselectivity and reacted with similar rates. The length of the alkyl chain on the alkene did not influence the rate or enantioselectivity of the reaction. However, the presence of a chlorine atom on the alkyl chain ((E)-2c) decreased the rate of the reaction while maintaining high level of enantioselectivity. Cyclopropyl substrate (E)-2e bearing branching at the allylic position led to a good yield and enantioselectivity (entry 6) whereas common cycloalkyls (5- and 6-membered) gave lower yields and enantioselectivities (entries 7–8). If the alkene contained a tert-butyl substituent, no cyclization occurred. Cyclization of substrates 2h and (E)-2i containing geminally-disubstituted alkenes allowed formation of quaternary carbon centers in good yields. Trisubstituted alkenes were more reactive than disubstituted E-alkenes, but the enantioselectivities were lower (entries 9 and 10). Interestingly, byproducts resulting from proton initiated cyclization reaction were formed in 2–8% yield with trisubstituted alkenes.¹⁸

Table 2.

Cyclization with Alkyl-substituted Alkenes.¹⁷

entry	substrate	R1	R2	product	time, d	temp, °C	era,b	yield, %c
1	(E)-2a	CH3	H	trans-3a	3	−20	97:3	92
2	(Z)-2a	H	CH3	cis-3a	1	0	52:48	91
3	(E)-2b	n-C5H11	H	trans-3b	3	−20	96:4	73
4	(E)-2c	(CH2)3Cl	H	trans-3c	6	20	94:6	63
5	(E)-2d	i-Bu	H	trans-3d	3	−20	96:4	77
6	(E)-2e	cyclopropyl	H	trans-3e	3	−20	95:5	88
7	(E)-2f	cyclopentyl	H	trans-3f	3	0	82:18	50d
8	(E)-2g	cyclohexyl	H	trans-3g	3	0	85:15	70e
9	2h	CH3	CH3	3h	1	−20	80:20	90f
10	(E)-2i	C6H5	CH3	trans-3i	2	−20	71:29	82g
11	(E)-2j	C6H5	H	trans-3j	2	−20	94:6	90
11	(E)-2k	4-CH3C6H4	H	trans-3k	2	−20	94:6	86
13	(E)-2l	4-CH3OC6H4	H	trans-3l	1	−20	92:8	86
14	(E)-2m	2-CH3C6H4	H	trans-3m	3.5	−20	92:8	82h
15	(E)-2n	2-naphthyl	H	trans-3n	2	−20	89:11	61i
16	(E)-2o	4-NC-C6H4	H	trans-3o	6	20	89:11	83
17	(E)-2p	4-CF3C6H4	H	trans-3p	3	20	92:8	85

^aThe enantiomeric ratio was determined by CSP-SFC analysis.

^bThe absolute configurations of the products were assigned by comparison of their CD spectra with trans-3b.

^cYields of analytically pure products.

^dUnreacted starting material was recovered (15%).

^eUnreacted starting material was recovered (16%).

^fAn 8% yield of protiocyclization product was isolated.

^gA 2% yield of protiocyclization product was was isolated.

^hUnreacted starting material was recovered (4%).

ⁱUnreacted starting material was recovered (36%).

The next stage of the investigation focused on the scope of (E)-aryl-substituted alkenes that could participate in the cyclization (Table 2). Substrates (E)-2j, (E)-2k, and (E)-2l bearing no substituents or electrondonating substituents afforded cyclization products in good yields and enantioselectivities (entries 11–13). As was observed with trisubstituted alkenes, increasing the electronic density of the double bond led to faster cyclization. However, substrate (E)-2m bearing a methyl group in the ortho position reacted slowly, but with good enantioselectivity (entry 14). Substrate (E)-2n bearing a 2-naphthyl substituent afforded good selectivity but in lower yield (entry 15). Finally, alkenes (E)-2o and (E)-2p bearing electron-deficient aromatic groups furnished nearly identical enantioselectivities in very slow reactions (entries 16 and 17). The very slow cyclization (even at room temperature) of E-styrenes bearing electron– withdrawing substituents could be ascribed to the electron-deficient nature of the alkene, which would slow the formation of the thiiranium species.

The final exploration of substrate scope was carried out with less monosubstituted aryl groups. Substrates bearing a methoxy group in the 3-position with respect to the tethered alkene afforded a mixture of cyclized products 6–9, with both n-pentyl ((E)-5b) and phenyl ((E)-5j) substituents (Scheme 2). With (E)-5b, a 3:1 ratio of 6/7 was produced in good yields and enantioselectivities (entry 1). However, substrate (E)-5j bearing a phenyl substituent afforded a 1:1 ratio of 8/9, but good enantioselectivity was still achieved for both constitutional isomers.

Scheme 2.

In conclusion, the first catalytic, asymmetric carbosulfenylation of olefins has been accomplished by using a cocatalytic system of a Brønsted acid (EtSO₃H) and a chiral Lewis base (S)-4e. This method enables efficient access to enantioenriched trans-tetrahydronaphthalenes with complete diastereospecificity, generally high enantiomeric ratios and a broad substrate scope with Eolefins. Formation of quaternary centers was achieved in moderate enantioselectivities. Further investigations