Cobalt-catalyzed hydrocyanation and hydroarylation of enamines

Tetrahedron Letters xxx (xxxx) xxx

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Cobalt-catalyzed hydrocyanation and hydroarylation of enamines Shigeru Arai a,b,⇑, Yuichi Sato a, Natsuki Ito a, Atsushi Nishida a,b a b

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, 260-8675 Chiba, Japan Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, 263-8522 Chiba, Japan

a r t i c l e

i n f o

Article history: Received 12 September 2019 Revised 18 October 2019 Accepted 23 October 2019 Available online xxxx Keywords: Hydrocyanation Hydroarylation Cobalt Enamine

a b s t r a c t A mild, general and efficient hydrocyanation and hydroarylation of enamines catalyzed by Co(salen) complexes are described. Both reactions include regioselective CAH bond formation of enamines, and the corresponding products are obtained in high yield. Hydroarylation critically discriminates the benzyl and benzoyl aromatic rings on nitrogen in cyclization step, and the corresponding isoindolinones including quaternary carbons are exclusively given. Ó 2019 Elsevier Ltd. All rights reserved.

Cobalt-catalyzed hydrogen atom transfer [1–3] has been one of the most practical synthetic tools due to the use of less-toxic radical initiators, less-expensive metal species, mild reaction condition, and functional group tolerance. Particularly, Co(salen) complexes with silanes have been potentially useful to install CN [4,5], oxime [6], aromatic [7,8], nitrogen [9–13], oxygen [14,15], sulfur [16], and halogen [17,18] functionalities into simple and unactivated olefins with highly regioselective manner. Further applications to prepare complex molecules have been demonstrated to prove their power as a synthetic methodology [3,19]. On the other hand, enamines have been typically used as nucleophiles however, their utilization in radical chemistry has been still limited [20–23]. Herein we report the synthetic transformations focused on hydrocyanation and hydroarylation that are triggered by cobalt-mediated regioselective hydrogen atom transfer processes (Scheme 1). First of all, we examined hydrocyanation using 1a (Scheme 2). The reaction completed under Carreira’s condition [3–5] using Co (salen) (cat. A, 2 mol%) with TsCN and PhSiH3) in EtOH at room temperature within 20 min, and 2a was obtained in 87% yield without any regioisomer (3a) nor hydrosilylation products such as 3b [24]. According to the report by Nemoto and co-workers, Ni-catalyzed hydrocyanation of 1a gives a mixture of 2a and 3a with the ratio of 1:3.4 [25]. Above exclusive formation of 2a under cobalt catalysis proves its potential synthetic utility using enamines and further investigations were continued. ⇑ Corresponding author at: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, 260-8675 Chiba, Japan. E-mail address: [email protected] (S. Arai).

First, we estimated the relative reactivity of enamine using 3a and 3c (1:1 M ratio). Both were reactive however the former was much more reactive to give 2a in 82% yield whereas 3d was resulted in 46% yield within 20 min (Scheme 3) [4]. This result suggests that the effect of nitrogen functionality on C@C bond gives a positive influence in rate enhancement. The substrate scope was next investigated (Table 1). When other substituted N-acyl enamines were examined, their reactivity was highly dependent on the nature of substituents. For example, a methyl group (1b) was suitable to give 2b in 73%, exclusively however, both phenyl and CO2Me groups (1c,d) completely prevented the reaction even after 25 h (entries 1–3). The N-formyl enamides which have N-Boc and -alloc groups were smoothly transformed to the corresponding carbonitriles (2e,f) in respective yields of 68% and 25% (entries 4, 5). In the case of N-benzoyl substituents, 2g-i were given in the range of 67–88% yields, suggesting that the electronic property of benzene rings does not influence seriously in the reaction efficiency (entries 6–8). The regioselectivity observed in 2a-i would be dependent on the predominant formation of nitrogen-stabilized carboradical intermediate (4), which smoothly reacts with TsCN to form a C-CN bond. N-mono-acyl group such as pyrrolidone derivatives were also suitable for this reaction and 2i,k were obtained in respective yields of 28% and 75% (entries 9, 10). In case of cyclic and NH free enamines containing a benzoyl group gave the corresponding adducts of 2l,m in 80% and 66% yield, respectively (entries 11, 12). N-phenyl and -benzyl oxazolidone derivatives were both applicable to be transformed to 2n,o in moderate yield within 30 min (entries 13, 14). During the above studies, we observed that the plausible radical intermediate such as 4 was reactive enough to promote cyclization

https://doi.org/10.1016/j.tetlet.2019.151314 0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi. org/10.1016/j.tetlet.2019.151314

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S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx Table 1 The substrate scope of hydrocyanation using 1b-o.

Scheme 1. Hydrocyanation and hydroarylation of enamines.

Scheme 2. Hydrocyanation of 1a under cobalt catalysis.

1

Five mol% cat. A was used.

Scheme 3. Competitive experiment using 1a and 3c.

with aromatic ring on nitrogen. For example, the reaction using 5a with cat. A (2 mol%) and PhSiH3 (1.2 eq) at room temperature promoted hydroarylation [7,8] to give 6a in 58% together with 8a in 15% yield, respectively (Scheme 4). The benzylic aromatic ring was less reactive, and the corresponding adduct such as 7a was not obtained at all. The structure of a former product (6a) is isoindolinone with a quaternary carbon and is a structural motif of cyclopramides and speradines [26,27]. This hydroarylative cyclization is a highly potential synthetic method to enable facile control of regiochemistry and discrimination of two inequivalent (red and blue) aromatic rings in 5a [28]. Above preliminary result prompted us to optimize the conditions (Table 2). A use of a larger amount of silane was not effective to increase the yield of 6a (entry 1). The use of iPrOH slightly increased the formation of 8a and t-BuOH decreased the reaction rate to give similar conversion (entry 2, 3). Next, we turned to examine Co(salen) B-D, that are used for hydroarylation of olefins [7,8]. They exhibited the similar catalytic activity to give 6a in high yields (entries 4–6), and sequential solvent effect revealed that ethanol is the best solvent of choice in both conversion to 6a and preventing hydrolysis of 5a (entries 6–10). Reducing amount of silane (0.1 eq) was enough to proceed the reaction and 6a was given in 90% yield after 2 h (entry 11). Finally, the reaction using 0.2 eq. of silane completed within 30 min in 86% yield of 5a (entry 12). A use of toluene instead was less effective in conversion even after 4 h (entry 13).

Scheme 4. Hydroarylative cyclization of 5a under cobalt catalysis.

Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi. org/10.1016/j.tetlet.2019.151314

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S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx Table 2 Optimization of hydroarylative cyclization of 5a. Entry

Catalyst1

PhSiH3 (eq)

Conditions

6a (%)

8a (%)

5a (%)

Yield %

Yield %

Yield %

1 2 3 4 5 6 7 8 9 10 11 12 13

A A A B C D D D D D D D D

2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 0.1 0.2 0.2

EtOH, 1 h iPrOH, 1 h t-BuOH, 12 h EtOH, 2 h EtOH, 2 h EtOH, 2 h Toluene, 2 h CH2Cl2, 5 h CH3CN, 6 h THF, 3 h EtOH, 2 h EtOH, 0.5 h Toluene, 4 h

45 61 64 84 85 85 93 68 90 88 90 86 71

12 24 12 3 0 0 5 10 0 9 2 3 5

0 0 0 0 0 0 0 0 0 0 0 0 18

0

72

72

89 88 95

89 88 95

89 88 95

1

Racemic complexes of B-D were used as a catalyst.

Table 3 The substrate scope of hydroarylative cyclization using 5b-k.

O

FG

N

N R1

1 2 3 4

6b-k

substrates FG

O

2

3 4

N 5

Bn

Me

5b: FG = 4-CF3 5c: FG = 2-Br 5d: FG = 3,5-Me2 5e: FG = 3,5-F2

8

time (h)

0.5 0.5 0.5 0.5

products O

FG

N Bn

Bn 5f: R2 = (CH2)2Ph 5g: R2 = CO2Me

2 5

N Bn

R2

H

R2

8b: 6%

6f: 68%2) 6g: 74%

8f: 8%

6h: 90% 6i: 41%2,3)

8h: 2%

O

O N

R1 5h: R = (CH ) Ph 1 2 2 5i: R1 = allyl

0.5 4

N R2

Me

3

9

H

Me O

Me

6b: 83% 6c: 73%1) 6d: 93% 6e: 94%

O N

7 8

H

Me

O 5 6

NHR1

+

H

R2

5b-k

O

FG

EtOH, rt

R2

entry

O

FG

cat. D (2 mol%) PhSiH3 (0.2 eq)

R1

N

0.5

Me

O

O

Bn

Me

N Bn

N Bn

H

H

Me Me

5j

6j-1: 64%

Me

8j: 5%

6j-2: 25% Me

O

O N

10 Me 5k

N

Bn N Bn

0.5 Me

H Bn O

H

6k-1: 36%

6k-2: 39%

CCDC: 1942426

1

PhSiH3 (0.4 eq) was used. PhSiH3 (3 eq) was used. Catalyst loading: 7 mol%.

2 3

Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi. org/10.1016/j.tetlet.2019.151314

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S. Arai et al. / Tetrahedron Letters xxx (xxxx) xxx

resulting residue was purified by column chromatography (hexane:AcOEt = 15:1) to give 6d (60.9 mg, 0.242 mmol, 93%) as brown solid. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgment This work was supported by the Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS) (Grant No. 17K08205). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tetlet.2019.151314. Scheme 5. Plausible reaction pathway.

References

Finally, the substrate scope of this hydroarylative cyclization was investigated (Table 3). Various aromatic rings involving CF3, Br, F and methyl groups were suitable to achieve up to 94% yield (entries 1–4). Substituent effect of R1 and R2 was next investigated. Longer alkyl and acyl groups such as 5f,g and N-alkyl groups (5h,i) were all applicable to give the corresponding adducts (6f–i) in the range of 41–90% yield (entries 5–8). In the case of 3-substituted substrate (5j), both cycloadducts such as 6j-1 and 6j-2 were obtained in respective yields of 64% and 25% (entry 9), and their structures were both determined by a previously reported 1H NMR spectra [29–31]. Naphthalene system gave both 5- and 6membered ring products of 6k-1 and 6k-2 without selectivity, and the structural determination of the former product was confirmed by X-ray crystallographic analysis [32] (entry 10). This cyclization reaction would be triggered by the regioselective hydrogen atom transfer to 5. The resulting nucleophilic radical (9) would favorably react with electron deficient aromatic rings to give 10, and the release of hydrogen radical gives the corresponding isoindolinones (6) to close the catalytic cycle. The regioisomeric products from 5j could be originated from two possible intermediates (10j-1,2). The stabilization effect by a methyl group in 10j-1 would be favored to proceed a predominant reaction pathway and 6j-1 was given as a major product (Scheme 5) [29–31]. In conclusion, we have established the cobalt-catalyzed cyano and aryl functionalizations using enamines in regioselective manner. These methods offer the functionalized nitrogen-containing compounds through facile creation of quaternary carbons under mild conditions, and we believe they have enough impacts in synthetic organic chemistry. Further investigation aiming new applications are currently underway. Experimental section Experimental procedure for Co-catalyzed hydroarylative cyclization, synthesis of 6d To a solution of 5d (64.3 mg, 0.26 mmol) and Co complex D (3.1 mg, 0.0052 mmol) in EtOH (1.3 mL, 0.2 M) was added PhSiH3 (6 lL, 0.052 mmol) at room temperature. After being stirred for 30 min, the solvent was removed under reduced pressure. The

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Please cite this article as: S. Arai, Y. Sato, N. Ito et al., Cobalt-catalyzed hydrocyanation and hydroarylation of enamines, Tetrahedron Letters, https://doi. org/10.1016/j.tetlet.2019.151314