Stereoselective and Regioselective Intramolecular Friedel-Crafts Reaction of Aziridinium Ions for Synthesis of 4-Substituted Tetrahydroisoquinolines

Abstract

Optically active 4-substituted tetrahydroisoquinolines were synthesized via intramolecular Friedel-Crafts (FC) reactions of aziridinium ions in a highly regioselective and stereoselective manner. Control experiments suggest the formation and ring opening of aziridinium ions as the key intermediates in the Lewis acid catalyzed FC reactions.

Abstract Graphical

Aziridinium ions have been utilized as highly reactive intermediates in asymmetric synthesis of diverse small molecules and complex natural products.^1–3 Strained aziridinium ions have been limitedly isolated and characterized.^4–8 Nucleophilic ring opening of substituted aziridinium ions have been recognized as an efficient synthetic route to chiral precursor molecules including amines, amino nitriles, amino ethers, and aminoesters.^9–12 Despite synthetic versatility, ring opening reaction of aziridinium ions remains an underexplored area, while other three-membered congeners such as aziridines and epoxides have numerous applications in organic synthesis. Limited investigations on ring opening of the aziridinium ions in part stems from difficulty in isolation and characterization of the labile entities and the lack of general and efficient methods for synthesis of the aziridinium ions or their precursors with functionalities. Nucleophilic opening reactions of the aziridinium ions are expected to occur at the two electrophilic carbons (C₂ and C₃) under mild conditions. N-substituents, C-substitutents, or counter anions in the aziridinium ions are potential nucleophiles that can attack the electrophilic carbons in intramolecular nucleophilic reactions. With this potential diverse reactivity, we were interested in exploration of azirindium ions for intramolecular Friedel-Crafts (FC) reaction. FC reaction is one of the useful synthetic methods for carbon-carbon bond formation in organic synthesis.^13–14 We hypothesized that aziridinuim ions containing an aromatic N-substitutent will undergo intramolecular FC reactions to provide 4-substituted tetrahydroisoquinolines (THIQ) in high regio- and stereoselectivity. THIQ derivatives were reported to possess biological functions including anticancer, antibiotic, and dopamine inhibitory or stimulating activities.^15–17In particular, 4-substituted THIQs such as nomifensine and dichlofensine are known to display dopamine inhibitory or anti-depressant action.^16–17 However, straightforward and general synthetic methods for optically active 4-substituted THIQs are rarely reported.^18–19 Herein we report a new synthetic method for enantiomerically enriched 4-substituted THIQs based on the intramolecular FC reaction of aziridinium ions.Enantiomerically enriched β-haloamines 1-3 (Table 1) were prepared from β-amino alcohols with various functionalities and substituents and used as precursor molecules to generate aziridinium ions in situ for intramolecular FC reactions.

Table 1.

Synthesis of THIQ analogues (R)-5a and (R)-5b.

entry	substrate	R1	X	time	temp	yield (%)	ee (%)
1	(R)-1a	Ph	Br	1 min	0 oC	81	71
2	(R)-1a	Ph	Br	45 min	− 70 to − 20 oC	50	79
3	(R)-1a	Ph	Br	15 min	− 20 oC	55	70
4	(R)-2a	Ph	Cl	1 min	0 oC	75	63
5	(R)-3a	Ph	I	1 min	0 oC	72	61
6	(R)-1b	CH3	Br	4 h	0 oC	NR	-
7	(R)-1b	CH3	Br	4 h	reflux	90	97

β-bromoamines (R)-1a (R¹ = Ph) and (R)-1b (R¹ = Me) were used for our initial feasibility study on intramolecular FC reactions (Table 1). In the presence of AlCl₃, FC reaction of (R)-1a in toluene under mild condition (0 ^oC, 1 min) instantly provided (R)-5a (81% isolated yield, 71% ee) (Table 1, entry 1). The retained stereochemistry at the benzylic chiral center in (R)-5a suggests that the FC reaction involved formation of aziridinium ion (S)-4a as the key intermediate. Opening of aziridinium ion (S)-4a occurred at the stabilized benzylic position to furnish (R)-5a as the regiospecific isomer. The same reaction of (R)-1a at lower temperature (−20 ^oC or −70 ^oC) provided (R)-5a in similar stereoselectivity but lower isolated yield (Table 1, entries 2 and 3). (R)-1b (R¹ = Me) required longer reaction time and heating (0 ^oC to reflux, 4 h) due to inherent lower reactivity of a secondary alkyl substrate relative with a benzylic substrate towards substitution reactions. It is noteworthy that the FC reaction gave (R)-5b in excellent yield and stereoselectivity (90%, 97% ee) (Table 1, entry 7). Retained stereochemistry at the chiral center in (R)-5b also suggests formation and ring opening of aziridinium ion (S)-4b. Change of the leaving group (Cl or I) led to formation of (R)-5a in lower isolated yield and ee (Table 1, entries 4 and 5). This result suggests that a leaving group plays a role in formation of aziridinium ions and THIQs.

Lewis acid catalysts were screened for the formation of THIQs (R)-5a and (S)-5b (Table 2). Other catalysts weaker than AlCl₃ were surveyed for reaction of (R)-1a in toluene. FeBr₃ was the most effective catalyst producing (R)-5a in the highest stereoselectivity (83% ee) (Table 2, entry 2). The FC reaction using InCl₃ and TiCl₄ (Table 2, entries 3 and 4) was significantly slower compared to the reaction using FeBr₃ and provided (R)-5a in a slightly higher isolated yield and stereoselectivity (72–78%, 77–81% ee). SnCl₄ was significantly less efficient (29%) than other catalysts, although the reaction provided (R)-5a in high enantioselectivity (81% ee). (S)-1b required a stronger Lewis acid and provided (S)-5b from the reaction using FeBr₃ and InCl₃ in poor isolated yield (<25%) but good enantioselectivity ). No FC product was obtained from the reaction of (S)-1b with TiCl₄ and SnCl₄ under reflux.

Table 2.

Effect of catalyst on the formation of THIQ analogues (R)-5a and (S)-5b.

entry	substrate	catalyst	temp	time	yield (%)	ee (%)
1	(R)-1a	AlCl3	0 oC	1 min	81	71
2	(R)-1a	FeBr3	0 oC	1 min	59	83
3	(R)-1a	InCl3	rt	20 h	78	77
4	(R)-1a	TiCl4	rt	15 h	72	81
5	(R)-1a	SnCl4	rt	2.5 h	29	81
6	(S)-1b	AlCl3	reflux	4 h	93	97
7	(S)-1b	FeBr3	reflux	14 h	25	85
8	(S)-1b	InCl3	reflux	96 h	22	97

The reaction of (R)-1a or (S)-1b was carried out in different solvents (Table 3). Among the solvents screened for the reaction of (R)-1a, dichloroethane (DCE) gave the best result (95%, 78% ee) (Table 3, entry 4). A lower isolated yield observed with aromatic solvents (toluene, benzene, xylene, <81%) compared to halogenated solvents (DCE, CHCl₃, and CH₂Cl₂, >91%) is ascribed to the formation of intermolecular FC products from reaction of (R)-1a with the aromatic solvents. No product was formed from the reaction of (R)-1a in THF and hydrocarbon solvents, cyclohexane (Chx) and hexane (Table 3, entries 7–9). Less reactive (S)-1b was more selective in solvent. The FC reaction of (S)-1b proceeded only in the aromatic solvents producing (S)-5b in excellent ee, and no FC product was obtained from the reaction of (S)-1b in halogenated solvents (DCE, CH₂Cl₂, CHCl₃).

Table 3.

Effect of solvents on the formation of THIQ analogues (R)-5a and (S)-5b.

entry	substrate	solvent	time	temp	yield (%)	ee (%)
1	(R)-1a	Toluene	1 min	0 oC	81	71
2	(R)-1a	Benzene	1 min	0 oC	81	59
3	(R)-1a	xylene	1 min	0 oC	70	69
4	(R)-1a	(CH2Cl)2	1 min	0 oC	95	78
5	(R)-1a	CH2Cl2	1 min	0 oC	91	75
6	(R)-1a	CHCl3	1 min	0 oC	94	62
7	(R)-1a	Chx	48 h	0 oC	NR	-
8	(R)-1a	Hexane	48 h	0 oC	NR	-
9	(R)-1a	THF	48 h	0 oC	NR	-
10	(S)-1b	Toluene	4 h	reflux	93	97
11	(S)-1b	Benzene	4 h	reflux	87	>99
12	(S)-1b	Xylene	3 h	reflux	73	98
13	(S)-1b	(CH2Cl)2	48 h	reflux	NR	-

We also investigated scope of the substrates for intramolecular FC reactions using β-bromoamines 1a-g (Table 4). FC reactions of β-bromoamines 1a-g were screened for reactions using AlCl_3. The reaction of (R)-1a and (R)-1b provided (R)-5a and (R)-5b (71% ee and 97% ee), respectively (Table 4, entries 1 and 2). Replacement of C-substituent from methyl to n-propyl (1c) led to formation of (R)-5c in lower isolated yield but as a nearly exclusive enantiomer (79%, >99% ee) (Table 4, entry 3). The effect of N-substitution on the formation of THIQ analogues was studied. Intramolecular FC reaction was found to be quite sensitive to N-substitution. The reactions of β-bromoamine (R)-1d containing N-naphthyl groups provided (R)-5d in lower isolated yield (49%) but in excellent stereoselectivity (Table 4, entry 4). A significant drop of both isolated yield and ee of (R)-5e was observed from the reaction of (R)-1e having m-bromobenzyl group (54%, 78% ee) (Table 4, entry 5). In both of the substrates 1d and 1e, FC reactions occurred at the aromatic carbon ortho to N-methylene group with the exclusive regioselectivity. Change in N-substituent from benzyl (1a) to allyl group (1f) led to the formation of (R)-5f in poor isolated yield and stereoselectivity (41% yield and 19% ee) (Table 4, entry 6). FC Reaction of (S)-enantiomers of 1a-f provided (S)-5a-f in comparable yield and ee to the enantiomeric counterparts (Supporting Information). When N-Bn (1a) was replaced with N-CH₃ (1g), the chiral center in 5g was almost completely racemized (Table 4, entry 7). This result appears to imply that π-π stacking between the nucleophilic aromatic ring and the non-reactive N-aromatic ring or interaction between the aromatic π system and nitrogen cation in the aziridinium intermediate is essential for the formation of the FC products in high stereoselectivity.^12,20

Table 4.

Substrate scope for the synthesis of various THIQ analogues 5.

entry	substrate	temp	solvent	product	yield (%)	ee (%)
1	(R)-1a	0 oC	Toluene	(R)-5a	81	71
2	(R)-1b	reflux	Toluene	(R)-5b	90	97
3	(R)-1c	reflux	Toluene	(R)-5c	79	>99
4	(R)-1d	reflux	Toluene	(R)-5d	49	>99
5	(R)-1e	reflux	Toluene	(R)-5e	54	78
6	(R)-1f	-20 oC	DCE	(R)-5f	41	19
7	(R)-1g	-20 oC	DCE	(R)-5g	68	2

The stereochemistry in (R)-5a and (R)-5b was confirmed by preparing the known THIQ analogues (R)-7a²¹ and (R)-7b²² by N-debenzylation of (R)-5a and (R)-5b (Scheme 1). The formation and ring opening of aziridinium ions 4 was proposed as the basis for good to absolute control of stereochemistry in the synthesis of THIQs 5 as shown in Scheme 1. The retained stereochemistry at the chiral center in 5 can be explained by a mechansim wherein aziridinium ion 4 was first formed via intramolecular S_N2 reaction followed by subsequent cleavage of the loose N₁−C₂ bond in aziridinium ion 4 by the attack of the N-aromatic ring from the front side in a S_Ni pathway. This unusual nucleophilic reaction proceeding with retention at the chiral center appears to occur due to the nature of the strained aziridinium ring and the presence of the non-reacting N-aromatic group which can stabilize the postive charge in C₂ of the aziridinium ion 4 via cation-π interaction or interact with the attacking aromatic ring via π-π stacking. A similar mechanism was proposed for an acid-promoted intramolecular ring opening of aziridine proceeding with retained stereochemistry at the chrial center.^23–26 The observed high stereoselectivity in the reaction of (R)-5a-e rules out a classical S_N1 pathway of the FC reaction of (R)-1a-e. A direct S_N2 inversion at the chiral center from intramolecular FC reaction of (R)-1 by displacement of bromide by the aromatic ring was excluded as the obvious N-substitution effect was observed. As stated above, change of N-substituent from benzyl to allyl (1f) and methyl (1g) led to a significant or almost complete loss of stereoselectivity in the respective formation of (R)-5f and (R)-5g. The FC reaction of β-bromoamines 1f and 1g are reasonably speculated to proceed via a S_N1 pathway involving more dissociated carbocation that can be formed from aziridinium ion (Scheme 1).

Scheme 1.

Proposed mechanism of the intramolecular Friedel-Crafts reaction and confirmation of the stereochemistry in the THIQ analogues (5).

To further prove the hypothesis based on the formation of an aziridinium ion as the key reactive intermediate, control experiments were conducted. First, optically active aziridinium ions 9 were prepared (Scheme 2) and characterized by ¹H and ¹³C NMR and optical rotation. Bromination of β-amino alcohols 8 using NXS (X = Br, Cl, I) and PPh₃ provided β-haloamines 1 from the ring opening of aziridinium ions 4 by the halide counteranion. The intramolecular substitution reaction of β-bromoamines 1 proceeded in a S_N2 pathway to provide aziridinium ions 9 with inverted stereochemistry. The formation of aziridinium ion 9 was promoted by sequestration of the halide in 1 using AgClO₄ or AgBF₄. We then prepared β-bromoamine (S)-10 containing a tosyl (Ts) group to understand anchimeric participation of the neighboring nitrogen to form aziridinium ion (Scheme 3). No neighboring group participation and resultant formation of aziridinium ion was expected for (S)-10 substituted with the tosyl group. Reaction of (S)-10 provided only debenzylation product 11 in 97% yield, and no FC product 12 was formed. Finally, we investigated whether involvement of N-aromatic ring in the FC reaction was more favorable than that of the aromatic ring in a C-substituent (Scheme 4). The FC reaction of (±)-1h containing a phenylpropyl group gave only endo-THIQ 5h. No exocyclization products 13 and 14 were formed, and involvement of the phenyl ring linked to the propyl spacer in the FC reaction was found to be a disfavorable process. It should be noted that formation of 14 from a direct S_N2 displacement of bromide by the phenyl group linked via the propyl chain was not observed. The experimental results described above suggest that intramolecular FC reaction of β-haloamines 1 for stereoselective synthesis of THIQs 5 involves formation and opening of aziridinium ions 4, and direct conversion of β-haloamines 1 to THIIQs 5 in a S_N2 pathway is unlikely.

Scheme 2.

Synthesis and characterization of optically active β-haloamines 1 and aziridinium ions 9.

Scheme 3.

Lewis acid-promoted debenzylation of β-bromoamine 10.

Scheme 4.

Friedel-Crafts reaction of C-substituted aziridinium ion 5h.

In conclusion, we have shown that the reactive aziridinium ions can be utilized for the synthesis of 4-substituted THIQs in high yield and enantioselectivity. We have also carried out the control experiments and demonstrated that the intramolecular FC reactions proceed via stereoselective and regiospecific ring opening of the aziridinium ions to produce THIQs.