An unusual reactivity of BBr₃: Accessing tetrahydroisoquinoline units from N-phenethylimides

Abstract

Isoindoloisoquinalinone, pyrroloisoquinolinone and benzo[a]quinolizinone units are constructed via intramolecular cyclization of the methoxy substituted N-phenethylimides using BBr₃.

The heterocycles containing a tetrahydroisoquinoline unit constitute a major class in the pharmacologically active isoquinoline alkaloid family¹ and hence attracted the great attention of synthetic chemists.² Molecules containing tetrahydroisoquinoline skeleton have generally been constructed through the synthetic protocols such as Pictet–Spengler,³ Bischler–Napieralski,⁴ Pomeranz-Fritsch-Bobbitt,⁵ N-acyliminium ion cyclization,⁶ Parham type cyclization,⁷ base induced aryl mediated cyclization,⁸ and other sophisticated methods.⁹ These methods either involve the harsh condition or multiple steps to effect the cyclization.

During the course of our investigation on the preparation of resorcinol 1 from dimethoxyderivative 2a (Fig. 1) on treatment with boron tribromide, a reagent commonly used for the demethylation of aryl methyl ether,¹⁰ we have observed an unusual reactivity. The methyl group remained unaffected even with excess of BBr₃; instead, the reaction proceeded smoothly to afford the cyclized product, isoindoloisoquinolinone derivative, 3a.

Fig. 1.

This observation prompted us to investigate the feasibility of this unexpected reaction of BBr₃ with methoxy substituted phenethylimides and herein we report the first single step synthesis of tetrahydroisoquinoline derivatives such as isoindoloisoquinolinone, pyrroloisoquinolinone and benzo[a]-quinolizinone units using BBr₃. Preliminary experiments revealed that the cyclization reaction required two equivalents of BBr₃ with 2a, while the lesser equivalent led to incomplete reaction. To examine the efficacy of other Lewis acids to effect this cyclization process, the reactions were carried out with substrate 2a in presence of other Lewis acids (LA) such as BF₃·OEt₂, FeCl₃, TiCl₄, AlCl₃, ClTi(OⁱPr)₃, Ti(OⁱPr)₄, ZnCl₂, SnCl₄ and AlBr₃ (Scheme 1). The results are summarized in Table 1.

Scheme 1.

Screening of Lewis acids for cyclization.

Table 1.

Cyclization of 2a using common Lewis acids

Entry	Lewis Acid	Equiv.	Reaction time/h	3a (%)a
1	BF3·OEt2	2	96	58
2	FeCl3	2	6.5	53
3	TiCl4	2	12	72
4	AlCl3	2	8	75
5	AlBr3	2	4.5	83
6	BBr3	4	0.5	88
7	BBr3	2	0.5	91
8	BBr3	1	0.5	46

^aIsolated yield.

When 2a was treated with 2 equivalents of Lewis acids such as ClTi(OⁱPr)₃, Ti(OⁱPr)₄, ZnCl₂ and SnCl₄ the reactions failed to afford the cyclized product and revealed that the Lewis acidities of these reagents are not sufficient enough to facilitate the cyclization process. Whereas, the Lewis acids AlCl₃, AlBr₃, FeCl₃, TiCl₄ and BBr₃ were successfully afforded the cyclized product. Depending on the Lewis acids the time required for the completion of the reaction and yield varied. For example, the Lewis acids TiCl₄, AlCl₃, FeCl₃ and AlBr₃ required 12 h, 8 h, 6.5 h and 4.5 h for complete conversion of the starting material 2a to the cyclized product 3a in 72%, 75%, 53% and 83% yield respectively. The reaction was sluggish when BF₃·OEt₂ was used as a Lewis acid; the reaction was incomplete even after 3 days of stirring at room temperature (entry no. 1; Table no. 1). The cyclization of 2a using BBr₃ (in CH₂Cl₂ at −15 °C to room temperature) was fast, clean and gave the cyclized product within 30 min.

Further utility of BBr₃ for this cyclization reaction was examined by treating mono/di/tri methoxy substituted phenethylphthalimides and the results are summarized in Table 2 (Scheme 2). For example, the substrates 2b and 2e underwent regioselective cyclization at C-6 position which is para to the C-3 methoxy group to afford 3b and 3e respectively. The reaction of N-[2-(3,4-dimethoxyphenyl)ethyl]phthalimide 2b gave 72% of the cyclized product 3b along with a mixture of both mono and di demethylated products. Reaction temperature (−78 °C and 27 °C) as well as the quantity of BBr₃ did not alter the yields of both cyclized and demethylated product from 2b. Similarly, 2,3-dimethoxy and 3,4,5-trimethoxy derivatives furnished the corresponding cyclized products 3c and 3d in 37% and 42% yield respectively; along with demethylated products. Methylenedioxy phenethylphthalimide 2f underwent complete ether cleavage to the catechol derivative. The success of the cyclization depend on the relative position of the methoxy groups with respect to the phenyl ring carbon that participates in the cyclization; amethoxy groupmust be present at C-3/C-5 positions so that the phenyl carbons C-6/C-2 respectively participate in the C–C bond forming reaction (Scheme 2). When methoxy group was present at C-4 carbon, demethylation was a competing reaction (2b–d).

Table 2.

Cyclization of 2a–e using 2 equiv. of BBr₃

S. No.	Substitutions					3 (%)a
	Entry	R1	R2	R3	R4
1	2a	H	OMe	H	OMe	3a (91)
2	2b	H	OMe	OMe	H	3b (72)
3	2c	OMe	OMe	H	H	3c (37)
4	2d	H	OMe	OMe	OMe	3d (42)
5	2e	H	OMe	H	H	3e (81)
6	2f	H	–OCH2O–		H	—b
7	2g	H	H	H	H	N.R.c

^aIsolated yield.

^bOnly demethylenated product was obtained.

^cNo reaction.

Scheme 2.

Cyclization of 2a–e using BBr₃.

Unsubstituted phenethylphthalimide failed to give the cyclized product even after stirring 2g with BBr₃ for the extended period of time. These examples revealed that the sufficient mesomeric activation of the reacting nucleophilic carbon is important for a successful cyclization.

Preferential coordination of BBr₃ with imide carbonyl group over methoxy group was evidenced from the ¹H NMR studies¹¹ of the reaction mixture and the mixture of hydroxy lactam 3a and BBr₃ in CDCl₃ (Fig. 2). This complexation facilitated the electrophilic substitution at C-6 via nucleophilic addition on the imide carbonyl group to furnish the boron derivative of hydroxylactam Aprior to the N-acyliminium ion formation. With the expulsion of boron species (Br₂BO⁻) from A produced the stable intermediate I the N-acyliminium ion (Scheme 3). Further, this speculation was supported by the fact that the phenethylphthalimide 2g failed to give the cyclized product; the reactivity generally observed for the N-acyliminium ion cyclization.

Fig. 2.

¹H NMR spectra of a) 2a + BBr₃; b) 3a + BBr₃.

Scheme 3.

Proposed reaction mechanism.

Next we turned our attention to examine the applicability of this methodology to the methoxy substituted phenethyl aliphatic imides such as N-[2-(3,5-dimethoxyphenyl)-ethyl]succinimide 5a (Scheme 4). On treatment with BBr₃, 5a furnished the cyclized product 6a, which underwent dehydration readily to a very unstable compound 7a in 60% yield.^7a Hence the in situ generated intermediate II, N-acyliminium ion, was reduced with NaBH₄/CH₃OH instead of quenching with water in a one pot fashion to deliver the tricyclic lactam, pyrroloisoquinolinone 8a in 88% yield.¹² Similarly, the imide 5c gave 8c in 69% yield along with demethylated products. Glutarimides 5b and 5d gave the cyclized tricyclic lactams, tetrahydroisoquinoline core 8b and 8d, present in the α-glucosidase inhibitors schulzeine-A/B/C,¹³ in 89% and 71% yields respectively.

Scheme 4.

One pot conversion of aliphatic imides to lactam.

The formation of hydroxy lactam from phthalimides and lactam from aliphatic imides were unambiguously confirmed through spectral techniques as well as single crystal X-ray structural analysis of selected molecules (Fig. 3).¹⁴

Fig. 3.

ORTEP diagram of 3a and 8b (50% probability ellipsoids).

In conclusion we have documented a simple methodology to construct the tetrahydroisoquinoline containing skeleton, employing the boron tribromide as Lewis acid. Applicability of this reaction towards the synthesis of tetrahydroisoquinoline unit present in the alkaloid schulzeine-A/B/C was successfully carried out. Further investigations on extending the scope of this cyclization process as well as the modification of Lewis acids to facilitate cyclization reaction is in progress.