DOI: 10.1002/chem.201402947

Communication

& Asymmetric Synthesis

One-Pot Asymmetric Synthesis of Quaternary Pyrroloindolones through a Multicatalytic N-Allylation/Hydroacylation Sequence Hong Lu, Jun-Bing Lin, Jin-Yu Liu, and Peng-Fei Xu*[a] and NHCs are both Lewis basic and compatible in the same reaction vessel,[7] we envisioned that the combination of tertiary amine catalysis and NHC catalysis would be feasible through sequential N-allylation/hydroacylation reaction (Scheme 1). Our

Abstract: An intramolecular, quaternary carbon center forming hydroacylation of a-substituted acrylates has been discovered. This interesting transformation can be readily incorporated into a multicatalytic tandem process enabled by a combination of nucleophilic tertiary amine and N-heterocyclic carbene catalysis. With no additional stoichiometric base required, this transformation affords the quaternary pyrroloindolones with high levels of enantioselectivity.

The Stetter reaction represents a versatile umpolung strategy toward forming valuable ketones directly from aldehydes and activated olefins and has found a broad range of applications in organic synthesis.[1] With more and more activated alkenes being exploited in catalytic Stetter reactions, Glorius and coworkers recently explored the use of unactivated olefins in Stetter reactions, which is complementary to traditional transition-metal-promoted hydroacylation processes.[2–3] Among the various types of Stetter reactions, organocatalytic hydroacylation reactions leading to the reaction of nucleophilic acyl anions at the a-positions of activated olefins has not been reported.[4] Furthermore, with a-substituted activated olefins, this class of transformation will lead to highly functional quaternary carbon stereocenters. Therefore, the development of such a catalytic hydroacylation reaction will significantly extend the scope of current N-heterocyclic carbene (NHC) catalyzed reactions and offer great potential for the synthesis of structurally diverse molecules. Owing to its high potential for extending substrate scope and achieving unprecedented transformations, multicatalysis[5] has emerged as a powerful strategy for the rapid generation of molecular complexity. To implement one-pot multicatalytic transformations, issues associated with incompatibility and selectivity must be addressed. Nucleophilic tertiary amine catalyzed asymmetric allylic alkylation of Morita–Baylis–Hillman (MBH) carbonates with various nucleophiles is well-established for the preparation of acrylates derivatives.[6] As tertiary amines

Scheme 1. Multicatalytic synthesis of pyrroloindolones containing a quaternary carbon center through an N-allyation/hydroacylation sequence.

research group is focused on the synthesis of various heterocyclic scaffolds through asymmetric catalysis.[8] We envisioned that by using chiral catalysts, the multicatalytic process would allow for the enantioselective synthesis of quaternary pyrroloindolones[9] , whose derivatives are ubiquitous and the ring system of which is common in a number of pharmaceutically important compounds and bioactive alkaloids (Figure 1).[10] Indole-2-carbaldehyde 1 a and MBH carbonate 2 a were chosen for initial optimization of the reaction parameters of

[a] H. Lu, Dr. J.-B. Lin, J.-Y. Liu, Prof. P.-F. Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University, Lanzhou 730000 (P. R. China) Fax: (+ 86) 931-8915557 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402947. Chem. Eur. J. 2014, 20, 11659 – 11663

Figure 1. Examples of biologically active natural products containing a pyrroloindolones-type moiety.

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Communication the N-allylation. It was found that when the reaction was conducted in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO; 20 mol %), in xylene at 50 8C for 0.5 h, expected N-allylation adduct 3 a was obtained in 90 % yield. Next, a series of chiral tertiary amines derived from cinchona alkaloids were screened to uncover asymmetric variants of this process. As anticipated, commercially available alkaloid hydroquinidine 1,4phthalazinediyl, (DHQD)2PHAL, gave satisfactory results at 50 8C after 36 h. Upon investigating solvents and temperature, the optimal conditions were found to be (DHQD)2PHAL (20 mol %) in xylene at 50 8C.[11] With the reaction conditions of N-allylation optimized, the hydroacylation of 3 a promoted by NHC was further explored. Upon completion of the N-allylation reaction, 6 a and 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) were added to the reaction mixture. To our delight, hydroacylation product 4 a was produced in 82 % yield after 6 h, with only a minor amount of product 5 a from the normal Stetter reaction detected. Similarly, NHC 6 b, an analogue of 6 a, gave comparable results after a reaction time of 12 h. When the catalyst was changed to thiazolium salt 6 c, which was previously used in the hydroacylation of unactivated olefins and arynes,[2a–c] the product 4 a was not formed; instead, undesired adduct 5 a was formed. Catalysts 6 d and 6 e were also examined, but the results were unsatisfactory. Interestingly, while screening different bases, it was found that additional base had little influence on the reaction. We wondered whether the tertiary amine catalyst for the N-allylation reaction could also serve as the base in the hydroacylation reaction. Surprisingly, the reaction went smoothly without any additional base added (Table 1, entry 10). Furthermore, the yield and enantioselectivity did not change when the catalyst loading was decreased (Table 1, entry 11). With the optimal reaction conditions established, the scope of the sequential reaction was explored by employing a variety of MBH carbonates. As show in Table 2, all the reactions afforded the corresponding pyrroloindolones containing a quaternary carbon center in high yields with good to excellent levels of enantioselectivity. The electronic and steric properties of the MBH carbonates had noticeable effect on the outcome of the reaction. Electron-withdrawing substituents at para position of the phenyl group gave higher levels of reactivity and enantioselectivity compared to those substrates with electron-donating substituents (Table 2, entries 2–6 versus entries 7–8). The electron-rich substrate required more catalyst and a longer reaction time (Table 2, entry 8). However, the electronic properties of substituents at the meta position of the phenyl group had minimal impact on the reaction (Table 2, entries 9–12). Notably, the presence of substituents at the ortho position of the phenyl group seem to have an unfavorable effect on reaction rate, the reactions requiring more catalyst (20 mol %) and a longer reaction time (Table 2, entries 13 and 14). Substrates with bulky substituents could also be transformed smoothly (Table 2, entries 15 and 16). MBH carbonates with heteroaromatic rings were also tolerated, affording the products with excellent yield and moderate levels of enantioselectivity (Table 2, entry 17). Furthermore, the reactions could be extended to an aliphatic MBH carbonate, the product being obtained in 52 % Chem. Eur. J. 2014, 20, 11659 – 11663

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Table 1. Optimization of hydroacylation.[a]

Entry

NHC

Base

t [h]

Yield [%][b]

d.r.[c]

ee [%][d]

1 2 3 4 5 6 7 8 9 10[e] 11[e,f]

6a 6b 6c 6d 6e 6a 6a 6a 6a 6a 6a

DBU DBU DBU DBU DBU NaOAc K2CO3 NEt3 DABCO – –

6 12 12 12 12 12 12 12 12 8 12

82 80 0 0 20 79 79 81 80 82 82

> 20:1 > 20:1 --> 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1

82 82 – – 82 81 81 82 82 82 82

[a] Unless otherwise specified, the reaction was carried out with 6 (20 mol %) and base (20 mol %) in xylene (1 mL) at 50 8C. [b] Yields of isolated product. [c] Determined by 1H NMR analysis of the crude products. [d] Determined by HPLC analysis using a chiral column. [e] Reaction run without additional base. [f] Reaction run with 10 mol % 6 a.

yield, 10:1 d.r., and 61 % ee (Table 2, entry 18). However, when the cinnamyl group was replaced with a cyclohexyl group, little product was detected, probably due to the low reactivity of the substrate (Table 2, entry 19). Indole-2-carbaldehydes with different substituents were also investigated. Although the substrates bearing electron-rich groups needed more catalyst (20 mol %) and additional base (DBU, 20 mol %), the levels of enantioselectivity were higher than those bearing electrondeficient groups (Table 2, entries 20–22). The structure and absolute configuration of the product was determined to be (2R, 3R) by using X-ray crystallographic analysis of 4 d (Figure 2).[12] To gain further mechanistic insights into the unprecedented hydroacylation reaction, a deuterium labeling experiment was carried out. When deuterated indole-2-carbaldehyde, [D1]1 a,[13] was used as the starting material, in combination with 2 d, as anticipated, the deuterium atom was incorporated exclusively at the methyl group to give product [D1]-4 d (Scheme 2).[14] Based on this deuterium labeling experiment, we propose the following mechanism. The initial nucleophilic reaction of the tertiary amine on the MBH carbonate affords intermediate I, with concurrent release of CO2. The tert-butoxide

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Communication Table 2. Scope of the synthesis of quaternary pyrroloindolone derivatives.[a]

Entry

R1

R2

t [h][b]

Yield [%][c]

d.r.[d]

ee [%][e]

1 2 3 4[f] 5 6 7 8[g] 9 10 11 12 13[g] 14[g] 15 16 17 18 19 20 21[g, h] 22[g, h]

H H H H H H H H H H H H H H H H H H H 5-Cl 5-MeO 4-MeO

Ph 4-FC6H4 4-ClC6H4 4-BrC6H4 4-CF3C6H4 4-CNC6H4 4-MeC6H4 4-MeOC6H4 3-FC6H4 3-ClC6H4 3-BrC6H4 3-MeC6H4 2-MeC6H4 2-ClC6H4 a-naphthyl b-naphthyl 2-thienyl cinnamyl cyclohexyl b-naphthyl b-naphthyl b-naphthyl

48 48 48 48 48 42 58 84 48 48 48 58 70 108 72 58 40 48 120 48 72 72

4 a, 82 4 b, 81 4 c, 81 4 d, 84 4 e, 80 4 f, 83 4 g, 77 4 h, 70 4 i, 83 4 j, 83 4 k, 79 4 l, 78 4 m, 75 4 n, 67 4 o, 81 4 p, 83 4 q, 91 4 r, 52 trace 4 s, 72 4 t, 63 4 u, 69

> 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 > 20:1 10:1 nd > 20:1 > 20:1 > 20:1

82 87 90 90 84 92 88 85 83 81 81 85 85 87 90 89 69 61 nd 83 90 87

Scheme 2. Deuterium labeling experiment.

[a] Unless otherwise specified, the reaction was carried out with aldehyde 1 (0.1 mmol), MBH carbonates 2 (0.2 mmol), amine (20 mol %), and 4  MS (50 mg) in xylene (1 mL) at 50 8C. After completion, salt 6 a (10 mol %) was added. [b] For both two steps. [c] Yield of isolated product for both steps. [d] Determined by 1H NMR analysis of the crude products. [e] Determined by HPLC analysis using a chiral column. [f] The absolute configuration of 4 d was determined by X-ray analysis; see the Supporting Information. [g] Reaction run with 20 mol % 6 a. [h] Reaction run with 20 mol % DBU.

anion thus generated then deprotonates indole-2-carbaldehyde 1, which undergoes an SN2’ reaction with I to yield product 3. In the hydroacylation process, the free NHC, generated in situ through deprotonation of NHC precursor 6 a by the tertiary amine, reacts with 3 to form intermediate II. The Breslow intermediate subsequently participates in an intramolecular cyclization to give intermediate IV, which affords the desired product 4 a and regenerates the catalyst (Scheme 3). In summary, we have discovered an unprecedented intramolecular hydroacylation of a-substituted acrylates enabled by a combination of nucleophilic tertiary amine and N-heterocyclic carbene (NHC) catalysis. Notably, no additional stoichiometric base was needed to generate the NHC catalyst in this process. This multicatalytic transformation offered a facile approach to quaternary pyrroloindolones with high yields and high levels of enantioselectivity through sequential N-allylation/hydroacylation. Further studies and applications of the novel hydroacylation are currently underway.

Experimental Section General procedure for the synthesis of pyrroloindolones To a flame-dried vessel were successively added indole-2-carbaldehyde 1 (14.5 mg, 0.1 mmol), MBH carbonate 2 (58.4 mg, 0.2 mmol), (DHQD)2PHAL (15.6 mg, 0.02 mmol), 4  Molecular sieves (50 mg), and finally xylene (1.0 mL). The reaction mixture was stirred at 50 8C for the specified reaction time. Then NHC (2.6 mg, 0.01 mmol) was added, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash column chromatography (petroleum ether/CH2Cl2/EtOAc) to give the corresponding pyrroloindolones 4.

Acknowledgements We are grateful for the NSFC (21032005, 21172097, 21372105), the International S&T Cooperation Program of China (2013DFR70580), the National Basic Research Program of China (2010CB833203), and the “111” program from MOE of P.R. China.

Figure 2. The X-ray crystal structure of compound 4 d. Chem. Eur. J. 2014, 20, 11659 – 11663

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Communication

Scheme 3. A proposed catalytic cycle.

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Received: April 4, 2014 Published online on July 30, 2014

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hydroacylation sequence.

An intramolecular, quaternary carbon center forming hydroacylation of α-substituted acrylates has been discovered. This interesting transformation can...
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