Catalytic (3 + 2) annulation of donor–acceptor aminocyclopropane monoesters and indoles†

The efficient catalytic activation of donor–acceptor aminocyclopropanes lacking the commonly used diester acceptor is reported here in a (3 + 2) dearomative annulation with indoles. Bench-stable tosyl-protected aminocyclopropyl esters were converted into cycloadducts in 46–95% yields and up to 95 : 5 diastereomeric ratio using catalytic amounts of triethylsilyl triflimide. Tricyclic indoline frameworks containing four stereogenic centers including all-carbon quaternary centers were obtained.


Introduction
Vicinal donor-acceptor (D-A) cyclopropanes are useful threecarbon 1,3-zwitterion synthetic equivalents for the synthesis of carbocyclic scaffolds. 1 The electronic properties of the donor and acceptor groups are essential to obtain stable yet reactive enough push-pull systems. Dicarbonyl motifs are acceptors of choice for metal-catalyzed ring opening reactions. 1d Among the many possible transformations, (3 + 2) annulations giving access to ve-membered rings are especially useful and have been thoroughly investigated with several donor substituents, with a particular focus on aryl 2 and protected amines 3 (Scheme 1a). Enantioselective methods have also been reported. 4 In contrast, D-A cyclopropanes with a single carbonyl acceptor have been less studied (Scheme 1b). Such substrates lead to the formation of one more stereocenter and do not require a decarboxylation step to remove the diester group. 5 However, activation and control over diastereoselectivity is challenging for these less reactive cyclopropanes. Only rare examples of (3 + 2) annulations have been reported, and they are oen neither catalytic nor stereoselective. 1d,e Cyclopropanecarbaldehydes were mostly suitable in iminiumenamine catalysis for ring-opening reactions rather than annulations. 6 Annulation reactions of cyclopropyl ketones were performed using stoichiometric Lewis acids such as SnCl 4 , TiCl 4 , BF 3 $Et 2 O and Me 2 AlCl. 7 Reactions with less reactive cyclopropyl monoesters are limited to alkoxycyclopropanes using silyl triates or organoaluminium reagents as stoichiometric activators. 7a,8 Catalytic activation remains limited to ring expansion, intramolecular annulation and spirocyclic D-A cyclopropanes. 9 Only one catalytic intermolecular (3 + 2) annulation of 2-butoxycyclopropanecarboxylate with silyl enol ethers was described by Ihara and co-workers using bistri-imide, but no stereoselectivity was observed. 10 Furthermore, in contrast to the numerous reports for annulation of aminocyclopropane diesters, 3 there is currently no report on the use of aminocyclopropane monoesters in annulation reactions, despite the importance of nitrogen-containing building blocks in synthetic and medicinal chemistry. Phthalimide and succinimide have the appropriate electronic properties in the case of aminocyclopropane diesters, 3 but are not donating enough when a single ester group is present. With carbamate protecting groups, the ring-opening processes of aminocyclopropane monoesters are limited to hydrolysis and rearrangements. 11 A carbamate-protected aminocyclopropyl ketone was also showed by our group to react intramolecularly in a formal homo-Nazarov cyclization. 12 Annulations of D-A cyclopropanes with indole derivatives are particularly interesting, as they provide a quick access to polycyclic indoline scaffolds (Scheme 2). Aminocyclopropanes are especially attractive starting materials, as the obtained indoline-fused cyclopentylamines are present in the core of alkaloid natural products, such as vindolinine, pleiomutinine or huncaniterine A and B. 13 3-Methylindoles were used by Kerr and co-workers in a ytterbium triate catalyzed (3 + 2) annulation with cyclopropane diesters (Scheme 2a). 14 However, in the absence of substituent at the C-3 position, ring-opening products were obtained. Ring-opening was also observed with aminocyclopropanes by our group. 15 Ila and co-workers later showed that annulation products can be obtained not only with 3-alkylsubstituted, but also with unsubstituted indoles and arylcyclopropanes, but only using a stoichiometric amount of boron triuoride etherate as activator. 7d Recently, Tang and coworkers described the in situ formation of unstable tosylprotected aminocyclopropane diesters and their use in intramolecular annulation with indoles leading to tetracyclic indolines (Scheme 2b). 16 By comparison, arylcyclopropyl ketones 7d and alkoxycyclopropyl monoesters 8b gave annulation products in good yields, but these methods are not catalytic and are limited to the synthesis of tertiary stereocenters at the acceptor position (Scheme 2c). Low diastereoselectivities are obtained for several substitution patterns and in the case of alkoxycyclopropanes, annulation was successful only for C3unsubstituted indoles.

Scheme 2 Annulations of D-A cyclopropanes and indoles.
Scheme 3 Screening of several push-pull systems for the TMS triflimide-catalyzed (3 + 2) annulation of aminocyclopropanes 1a-f with 1-methylindole (2a). (Scheme 2d). With indoles 2 as partners, key for success was the use of a silyl bistriimide as catalyst, generated in situ from silyl ketene acetal 3 through protodesilylation. 17,18 In contrast to previous (3 + 2) annulations of cyclopropane monoesters that all required stoichiometric amounts of Lewis acid, 7d,8b full conversion could be achieved with only 2.5 mol% TESNTf 2 for several substrates. Furthermore, the method is unique for its tolerance towards substitution patterns, as it works for both C2-and C3substituted indoles and can be used for the rst time to introduce a non-symmetrical all carbon quaternary center at the acceptor position in good yield and high diastereoselectivity.

Screening of aminocyclopropanes and optimization
Our work started with identifying a suitable push-pull system (Scheme 3). Aminocyclopropanes 1a-f were used in the (3 + 2) annulation with 1-methylindole (2a) using Lewis acids as catalysts. Preliminary experiments using TMS triate led to no reaction (see ESI †), although such conditions have been successful for alkoxycyclopropanes. 8b Compared to silyl tri-ates, silyl triimides have shown superior catalytic activity. 17 TMS triimide was formed through the protodesilylation of trimethylsilyl ketene acetal 3a with bistriimide. 18 Although the aminocyclopropyl esters protected by a phthalimide (1a), an amide (1b) or a nosyl group (1c) were not reactive, the tosyl protecting group (1d) furnished the cycloadduct 4a in 85% yield and 91 : 9 dr. The introduction of an oxazolidinone (1e) or a ketone (1f) as the electron withdrawing group led to stability issues and decomposition in presence of TMS triimide.
With the optimal D-A aminocyclopropyl ester 1d, the inuence of the substituents on the silicon was examined starting from silyl ketene acetals 3a-f (Table 1). Using trimethylsilyl ketene acetal 3a (entry 1), the reaction was completed in less than 30 minutes leading to cycloadduct 4a in 85% yield and 91 : 9 dr. NOESY experiments allowed the determination of the relative conguration of both isomers (see ESI †). The TES group (3b) and other tri-n-alkyl silyl groups (3c and 3d) improved the dr to 93 : 7 (entries 2-4). Increasing the bulkiness of the silyl groups (TBS and TIPS, 3e and 3f) led to a decrease of the diastereoselectivity (entries 5 and 6). The yield was slightly improved by diminishing the catalyst loading to 2.5 mol% at 0.3 mmol scale without affecting the diastereoselectivity (entry 7). Finally, cycloadduct 4a was obtained in 87% yield and 92 : 8 dr when the reaction was performed at 0.3 M concentration (entry 8).

Scope of indole derivatives 19
The optimal conditions of entry 7 were then applied to different indole derivatives 2a-u (Scheme 4a). Indoles 2b-d protected by a TBS, a benzyl or a PMB group were converted to cycloadducts 4b-d in 78-92% yield and diastereoselectivities $91 : 9. A functionalized N-alkyl substituent led to the formation of compound 4e in similar yield and dr. Free indole gave no reaction. Indoles 2f-k substituted at the 2 and/or 3-position leading to sterically more encumbered products 4f-k were successful. For all substitution patterns, annulation products were obtained without ring-opening side reactions. Protected tryptophol and tryptamine gave the desired cycloadducts 4h and 4i with a quaternary carbon center in 84%/81% yield and 71 : 29/80 : 20 dr. Excellent yields and diastereoselectivities were obtained for alkyl substituents (4l and 4m), a methoxy (4n), a protected nitrogen (4o) and halogens (4p-s) on the aryl ring. Other functional groups such as pinacol borane and a tri-uoromethyl group were also tolerated (4t and 4u). More electron withdrawing substituents such as an ester or a nitrile gave no reaction. X-ray crystal structure analysis of 4o 20 conrmed the relative conguration of the cycloadducts. The all-cis substituted product was the major diastereoisomer in all cases. The diastereoselectivity decreased with increasing substitution at C2/C3 position (no substituent: 84 : 16-95 : 5, one substituent: 71 : 29-92 : 8, two substituents: 58 : 42-70 : 30).

Scope of aminocyclopropanes
The scope of aminocyclopropanes 1 was then examined (Scheme 4b). These substrates were easily obtained by copper-catalyzed cyclopropanation of the corresponding enamides and diazo compounds. 21 First, aminocyclopropane 1g bearing a tosyl and a benzyl on the nitrogen as orthogonal protecting groups afforded cycloadduct 5a in 89% yield and 80 : 20 dr. Replacement of the ethyl ester (E) by a triuoroethyl ester group was tolerated (5b). More substituted aminocyclopropanes 1i-n bearing quaternary stereocenters were then prepared. Bicyclo[4.1.0] aminocyclopropane 1i led to the formation of tetracyclic compound 5c in 75% yield and 67 : 33 dr. Aminocyclopropane 1j bearing a fully substituted center at the donor position showed some reactivity only at room temperature, leading to product 5d in 27% yield and >95 : 5 dr. Aminocyclopropanes fully substituted at the carbon center next to the ester group were more reactive. Alkyl, aryl and allyl substituents led to the formation of (3 + 2) cycloadducts 5e-g bearing a carbon quaternary center in 78-86% yield and 80 : 20-88 : 12 dr. 18 To the best of our knowledge, such indoline products bearing a quaternary stereocenter have never been accessed before via an annulation of D-A cyclopropanes. When an intramolecular reaction was performed with aminocyclopropane 1n, the desired product 5h was obtained in >95 : 5 dr, but with another relative conguration (supported by NOESY experiments, see ESI †), in agreement with the results reported by Tang and coworkers using aminocyclopropane diesters. 16 We further performed the reaction with 1 mmol of aminocyclopropane 1d with protected indoles 2b-d and obtained similar yields and dr (Scheme 5). With 2a, a further scale up to 1.00 g (3.36 mmol) was done, giving 4a in 90% yield and 93 : 7 dr. Aer reduction of the ester on 4c with DIBALH, the tosyl group was removed using reductive naphthalene/lithium conditions leading to amino alcohol 6. Due to the cis orientation of the nitrogen and the ester, a bridgehead lactam 7 was produced in 43% yield when tosyl removal was performed directly on 4c. Finally, the TBS protecting group was removed with TBAF producing free indole 8 in 82% yield. Unfortunately, attempts to epimerize the ester center through enolate formation followed by reprotonation were not successful.
We then attempted to gain information about the reaction mechanism by starting with enantiopure aminocyclopropane ent-1d (Scheme 6a, eqn (1)). 22 Racemic cycloadduct 4a was obtained in the TES triimide-catalyzed (3 + 2) annulation with 2a (eqn (1)). Moreover, using cis-substituted cyclopropane cis-1d led to the formation of 4a with the same diastereoselectivity as observed for trans-substituted cyclopropane 1d (eqn (2)). Considering these results, the formation of an open-chain reactive intermediate is probable (Scheme 6b). The protodesilylation of silyl ketene acetal 3b produces the active TES triimide catalyst, 17,18 which then activates aminocyclopropane 1d through silylation of the ester. Ring-opening leads to iminium I, which is attacked by indole 2a at the most nucleophilic position to give iminium II. A Mannich reaction closes then the ring delivering the (3 + 2) cycloadduct 4a. The diastereoselectivity is controlled by minimizing steric repulsions between the silyl enol ether and the indole ring (II vs. III).

Conclusion
In conclusion, a (3 + 2) annulation reaction of tosyl-protected aminocyclopropane monoesters with indoles catalyzed by triethylsilyl triimide was disclosed. The tricyclic indoline products were obtained in excellent yields, high degrees of stereoselectivity and short reaction times (less than 30 minutes) with the formation of four stereocenters in one operation, including quaternary centers. The method gives access to complex nitrogen-substituted polycyclic indoline scaffolds of high interest for synthetic and medicinal chemistry.

Author contributions
V. P. discovered and optimized the reaction, studied the scope, performed the functionalization of the products and the studies on the mechanism, prepared the experimental part and the rst dra of the manuscript. E. G. L. R. did the required revisions aer the departure of V. P. She performed the scale up of the transformation and further scope extension and functionalization attempts on the products and prepared the related experimental part. J. W. designed the overall research, supervised the work, nalized the manuscript, proofread the experimental part and coordinated the overall project.

Conflicts of interest
There are no conicts to declare.