Stereospecific synthesis of highly functionalized benzo[3.1.0]bicycloalkanes via multistep cascade reactions

Abstract

A facile approach for the synthesis of benzo[3.1.0]bicycloalkanes via alkylation/cyclopropanation cascade reactions of benzyl bromide with triphenylphosphonium bromide has been developed. By elaborate designing of starting materials, this multistep cyclization proceeded smoothly with a wide range of substrates, providing the benzo[3.1.0]bicycloalkanes in 52–90% yields with exclusive diastereoselectivity.

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The benzo[3.1.0]carbobicycles are widely distributed as key skeletons in a variety of natural products and biologically active compounds,^1,2 as well as versatile building blocks in organic synthesis.³ Considerable efforts have been devoted to forge this core structure.⁴ Cyclopropanation of cyclic alkenes with metal carbenes is one of the most direct protocols and has been intensively studied.⁵ However, current limitations of this process include the difficulty associated with the cyclopropanation of trisubstituted olefins, alongside the paucity of stereocontrol of the cyclopropanation, probably because the metal carbene might be very sensitive to the steric hindrance of the alkene.⁶ An alternative strategy of tandem Michael addition/nucleophilic substitution of ylides, including sulfur, nitrogen and phosphorus, etc., to α,β-unsaturated compounds has been developed to produce cyclopropanes in impressive elegance.^7,8 In the construction of trisubstituted benzo[3.1.0]carbobicycles, intramolecular reactions of chalcone derived benzyl bromides in terms of sulfur ylide methods have presented powerful potential (53% yield, Scheme 1, eqn (1)).^8l However, in the cases of tetrasubstituted benzo[3.1.0]carbobicycles, relevant studies become difficult because the corresponding secondary benzyl bromides are unstable. Recently, we developed a cascade strategy and found that alkylation of phosphorus ylide provided a facile access to stereo hindered phosphonium salts,⁹ which could be easily deprotonated to in situ generate the corresponding phosphorus ylide. Followed by typical tandem Michael addition/nucleophilic substitution, a tetrasubstituted benzo[3.1.0]carbobicycle was constructed (Scheme 1, eqn (2)). Herein, we wish to report this reaction in detail.

Scheme 1 Ylide mediated cyclopropanation.

Initial studies focused upon synthesis of benzo[3.1.0]bicycloalkanes via alkylation/cyclopropanation cascade reactions of chalcone-derived benzyl bromide 1a and benzyltriphenylphosphonium bromide 2a (Table 1). Treatment of 2a with Cs₂CO₃ and 1a at 80 °C in DME (dimethyl ether) led to the alkylation of the in situ generated phosphorus ylide, with subsequent intramolecular cyclization giving 3a in 58% yield with an exclusive cis¹⁰ diastereoselectivity (entry 1). Using toluene and ethyl acetate as solvents, the reaction could also proceed in moderate yields (entries 2 and 3). The effect of using a protic solvent was explored, and 55% yield was obtained (entry 4). Both 1,2-dichloroethane and DMF could raise the yield to 70% (entries 5 and 6). When acetonitrile was employed as the solvent, an obvious acceleration of the reaction was observed, and the yield was increased to 82% after 13 hours (entry 7). Alternative inorganic bases such as Na₂CO₃, K₂CO₃, and NaOH were also examined, and typically a stronger base led to a higher reactivity (entries 8–10). However, when a much stronger base like t-BuOK was used, the reaction becomes complicated, only 6% of the desired product was obtained (entry 11). In addition, an organic base such as DBU resulted in rather low yield after 20 hours (4% yield, entry 12).

Table 1 Reaction optimization^a

Entry	Base	Solvent	t (h)	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), base (1.8 mmol), in solvent (4 mL). b Isolated yield.
1	Cs2CO3	DME	18	58
2	Cs2CO3	Toluene	14	58
3	Cs2CO3	EA	18	53
4	Cs2CO3	^tBuOH	23	55
5	Cs2CO3	DCE	14	70
6	Cs2CO3	DMF	17	70
7	Cs2CO3	CH3CN	13	82
8	Na2CO3	CH3CN	13	Trace
9	K2CO3	CH3CN	23	64
10	NaOH	CH3CN	13	78
11	t-BuOK	CH3CN	19	6
12	DBU	CH3CN	20	4

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With the optimized reaction conditions in hand, we next investigated the generality of this tandem cyclization reaction, as shown in Table 2. A range of chalcone derivatives 1a–h with different substituents on the benzoyl group, including 4-^tBu-, 4-F-, 3-Br, 2-Br, etc., were reacted with 2a smoothly to give the corresponding cyclopropanes 3a–h in good to high yields, and neither electronic changes nor substitution positions on the aryl ring had a significant effect on the reactivities (64–85% yields, entries 1–8). Heterocyclic substrates 1i and 1j, containing 2-furyl and 2-thienyl, both can be converted to the desired products in 70% and 81% yields, respectively (entries 9 and 10). Acetyl and pivaloyl products 3k and 3l could be accomplished facilely in good yields (71% and 83% yields, entries 11 and 12). When cinnamoyl substrate 1m was examined, the indanyl cyclopropane 3m was furnished in moderate yield (entry 13). Remarkably, the current catalytic system is also compatible with a series of phosphonium salts, bearing aryl, heteroaryl and fused-aryl groups. For example, in the case of 4-Br and 3-MeO substituted benzyltriphenylphosphoniums, the reactions showed good to high reactivity (entries 14 and 15). 2-Furyl and 2-thienyl phosphoniums were well tolerated in this tandem cyclization reaction at mild reaction temperatures (entries 16 and 17). With 2-naphthyl phosphonium salt, 3r was afforded in 81% yield after 13 hours (entry 18). Remarkably, in all cases, the diastereoselectivity of these reactions was excellent, only one diastereomer 3a–r was observed. The stereochemistry of 3a was identified by X-ray analysis. As shown in Fig. 1, the torsion angle of C(18)–C(8)–C(10)–C(11) in 3a is 8.2°, and the torsion angle of C(1)–C(9)–C(10)–C(11) in 3a is −124.5°, which indicate that the relative configuration of 3a is cis.¹¹

Fig. 1 X-Ray crystal structures of 3a.

Table 2 Reaction scope^a

Entry	R	Ar	Product	t (h)	Yield^b (%)
a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), Cs2CO3 (1.8 mmol), CH3CN (4 mL). b Isolated yield. c 20 °C. d 40 °C.
1	Ph	Ph	3a	14	82
2	4-^tBuC6H4	Ph	3b	16	78
3	4-MeOC6H4	Ph	3c	16	85
4	4-FC6H4	Ph	3d	12	82
5	4-ClC6H4	Ph	3e	14	65
6	4-BrC6H4	Ph	3f	12	65
7	3-BrC6H4	Ph	3g	16	64
8	2-BrC6H4	Ph	3h	16	73
9	2-Furyl	Ph	3i	10	70
10	2-Thienyl	Ph	3j	10	81
11	Me	Ph	3k	12	71
12	^tBu	Ph	3l	12	83
13	Styryl	Ph	3m	13	57
14	Ph	4-BrC6H4	3n	18	82
15	Ph	3-MeOC6H4	3o	18	90
16^c	Ph	2-Furyl	3p	20	75
17^d	Ph	2-Thienyl	3q	22	52
18	Ph	2-Naphthyl	3r	13	81

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A possible mechanism for the tandem cyclization reactions is proposed as shown in Scheme 2. The benzyltriphenylphosphonium bromide 2a was initially treated with Cs₂CO₃ to in situ generate phosphorus ylide, followed by alkylation with 1a to give the corresponding phosphonium salt. In the presence of Cs₂CO₃, the phosphonium salt II was deprotonated, followed by an intramolecular conjugate addition of ylide III and a S_N2 nucleophilic cyclopropanation, furnishing bicycloalkane 3a and releasing Ph₃P. The reaction is stereospecific in all cases that we have studied. It was proposed that the transition-state TS-2 might be more stable than the transition-state TS-1 due to the steric effects between the triphenylphosphine group and the benzoyl group in TS-2. Thus, the formation of an intermediate IV-2 is favored over that of an intermediate IV-1. Furthermore, because of the repulsion between the indanyl group and the benzoyl group, compound 3a was furnished as the major product.

Scheme 2 Mechanistic and stereochemical proposal.

Conclusions

In summary, we have developed a facile approach for the synthesis of benzo[3.1.0]bicycloalkanes via alkylation/cyclopropanation cascade reactions of benzyl bromides with triphenylphosphonium bromide. By elaborate designing of starting materials, this multistep cyclization proceeded smoothly with a wide range of substrate scopes, providing the benzo[3.1.0]bicycloalkanes in 52–90% yields with exclusive diastereoselectivity. Further investigations into this process are currently ongoing in our laboratory.

Acknowledgements

We are grateful for the financial support from the National Natural Sciences Foundation of China (Nos. 21121062 and 20932008), the Chinese Academy of Sciences. We thank Dr Xue-Bing Leng (SIOC) and Mr Jie Sun (SIOC) for X-ray crystal analysis. Dedicated to Professor Max Malacria on the occasion of his 65th birthday.

Notes and references

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10. The cis isomer is defined by the phenyl group and the benzoyl group substituted on cyclopropane, which are on the same side of the cyclopropane ring.
11. CCDC 962017 (3a) contains the supplementary crystallographic data for this paper.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and the characterization data of new compounds. CCDC 962017. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4qo00134f

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