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Synlett 2014; 25(14): 2072-2074
DOI: 10.1055/s-0034-1378496
letter
© Georg Thieme Verlag Stuttgart · New York

Proline-Catalyzed Dehydrogenative Cross-Coupling Reaction between Chromene and Aldehydes

Zi-Jun Wu
a   Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. of China
,
Jian Qian
b   Zhejiang Jianye Chemical Co. Ltd., Hangzhou, 311604, P. R. of China
,
Tian-Tian Wang
a   Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. of China
,
Zhi-Zhen Huang*
a   Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. of China
c   State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. of China   Fax: +86(571)88807077   Email: huangzhizhen@zju.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 30 April 2014

Accepted after revision: 14 June 2014

Publication Date:
16 July 2014 (online)

 
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Abstract

An unprecedented DCC reaction between chromene and aldehydes catalyzed by proline has been developed via direct C–H functionalization. A plausible mechanism using DDQ to activate α-C–H of chromene and proline to activate aldehyde is also proposed.


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Key words

C–H functionalization - DCC reaction - organocatalysis - oxidation - chromene

The dehydrogenative cross-coupling (DCC) reactions between two C–H bonds have been recognized as attractive and potent strategies for the formation of C–C bonds in the contemporary era.[1] Among them, the DCC reactions between benzylic sp 3 C–H bonds and α-C–H bonds of aldehydes or ketones have drawn much attention.[2] [3] [4] [5] For example, in 2011, Mancheño and co-workers developed DCC reactions of isochromans with aldehydes or ketones under the catalysis of Cu(OTf)2 and by using TEMPO-derived oxoammonium salt as an oxidant.[3a] Later, Lou’s group reported a DCC reaction of isochromans with ketones by using MnO2–MeSO3H as an oxidative system.[3b] In 2013, Liu et al. revealed an enantioselective DCC reaction of isochromans with aldehydes by using a MacMillan catalyst and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).[3c] Chromene unit exists widely in natural products and pharmaceutical molecules.[6] In 2012, Floreancig’s group disclosed a novel reaction of chromenes with allylic silanes and one example of an enolsilane using DDQ as an oxidant.[4] Recently, Rueping et al. found an enantioselective coupling reaction of 2-ethoxy-2H-chromenes with aldehydes under the catalysis of Yb(OTf)3 and a MacMillan catalyst.[5] However, to the best of our knowledge, the DCC reaction of chromenes with aldehydes via direct α-C–H functionalization remains unknown. Herein we wish to present our recent results on this DCC reaction catalyzed by l-proline using DDQ as an oxidant.

Initially, chromene (1) and butyraldehyde (2a) were chosen as model substrates to explore and optimize the DCC reaction. When pyrrolidine and DDQ were employed as an organocatalyst and an oxidant respectively, a trace amount of the desired product 3a was observed. When LiClO4 and 4 Å MS were added as additives,[7] we were pleased to find that under the catalysis of 20 mol% pyrrolidine, the desired product 3a was obtained in 40% yield using DDQ as an oxidant and MeCN as a solvent at room temperature after reduction with NaBH4 (entry 1, Table [1]).[8]

Table 1 Optimization of DCC Reaction between Chromene (1) and Aldehyde 2a a

Entry

Catalyst

Oxidant

Solvent

Yield (%)b

 1c

A

DDQ

MeCN

trace

 2

A

DDQ

MeCN

40

 3

B

DDQ

MeCN

trace

 4

C

DDQ

MeCN

56

 5

D

DDQ

MeCN

84

 6

D

TBHP

MeCN

 0

 7

D

O2

MeCN

 0

 8

D

DDQ

toluene

trace

 9

D

DDQ

THF

 0

10d

D

DDQ

MeCN

38

a Reaction conditions: 1 (0.3 mmol), LiClO4 (1.2 equiv), 4 Å MS (75 mg), and DDQ (0.36 mmol) in solvent (2 mL) under N2 at 0 °C; 2a (0.9 mmol), organocatalyst (20 mol%), r.t., 24 h; NaBH4 (1.0 mmol).

b Isolated yield.

c In the absence of LiClO4 and 4 Å MS.

d In air.

Then, other organocatalysts were examined, and l-proline proved to be best among these organocatalysts (compare entries 2–4 with entry 5, Table [1]; also see supporting information). Other oxidants, such as tert-butyl hydroperoxide (TBHP) and oxygen led to no 3a (entries 6 and 7, Table [1]). When the reaction was performed in air instead of under nitrogen, the yield of 3a was decreased (entry 10, Table [1]). It is noteworthy that without l-proline, no desired coupling reaction occurred.

After screening of reaction conditions, it can be concluded that the optimized reaction should be performed by using 20 mol% of l-proline, 1.2 equivalents of DDQ, 1.2 equivalents of LiClO4 and 4 Å MS in MeCN at room temperature.[9] Under the optimized conditions, we examined the scope of the l-proline-catalyzed DCC reaction. It was found that other straight-chain aldehydes 2b–g besides pentraldehyde (2a) also underwent the DCC reaction smoothly with chromene (1) via α-C–H activation to give the desired products 3b–g in 66–90% yields after reduction (entries 2–7, Table [2]). Although the α-carbon in isopentaldehyde (2h) is more hindered as compared to that in butyraldehyde (2a), 2h still reacted with chromene (1) smoothly to afford the desired product 3h in an excellent yield (entry 8, Table [2]). Replacing alkyl group in 2a–g with benzyl group in 2i led to an unfavorable effect on the DDC reaction to give 3i in a reduced yield (entry 9, Table [2]).

Table 2 DCC Reaction between Chromene (1) and Aldehydes 2a–i [10]

Entry

2 (R)

3

Yield (%)a

1

2a (Et)

3a

84

2

2b (Me)

3b

76

3

2c (n-Pr)

3c

66

4

2d (n-Bu)

3d

80

5

2e (n-pentyl)

3e

90

6

2f (n-hexyl)

3f

82

7

2g (n-heptyl)

3g

90

8b

2h (i-Pr)

3h

93

9b

2i (Bn)

3i

64

a The dr was ca. 1:1.

b Reaction time = 48 h.

A plausible mechanism for the DCC reaction is depicted in Scheme [1]. Initially, chromene is oxidized to generate oxocarbenium ion 4 by DDQ.[11] Then, the enamine 5 resulting from the reaction of aldehyde 2 with proline in situ attacks nucleophilically on oxocarbenium ion 4 to form ammonium 6. Hydrolysis and subsequent reduction gives the desired product 3.

Zoom Image
Scheme 1 Plausible mechanism for the DCC reaction between chromene (1) and aldehyde 2

In conclusion, we have developed a novel DCC reaction between chromene and aldehydes catalyzed by proline via direct C–H functionalization. Various aldehydes 2a–i were able to react smoothly with chromene (1) using DDQ as an oxidant, and LiClO4 and 4 Å MS as additives in MeCN at room temperature, affording the desired coupling products 3a–i in good yields. A plausible mechanism using DDQ to activate α-C–H of chromene (1) and proline to activate aldehyde 2 is also proposed. The studies of DCC reactions of other chromenes with aldehydes or ketones and their asymmetric reactions are currently underway.


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Acknowledgment

Financial supports from MOST of China (973 program 2011CB808600), the National Natural Science Foundation of China (No. 21072091 and 21372195) and The Low Carbon Fatty Amine Engineering Research Center of Zhejiang Province (2012E10033) are gratefully acknowledged.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information

  • References and Notes

  • 4 Clausen DJ, Floreancig PE. J. Org. Chem. 2012; 77: 6574
    CrossrefSearch in Google Scholar
  • 5 Rueping M, Volla CM. R, Atodiresei L. Org. Lett. 2012; 14: 4642
    CrossrefSearch in Google Scholar
  • 6 Sperry J, Wilson ZE, Rathwell DC. K, Brimble MA. Nat. Prod. Rep. 2010; 27: 1117
    CrossrefSearch in Google Scholar
  • 7 LiClO4 may promote the conversion of chromene to oxocarbenium ion pair and 4 Å MS may prevent the formation of ether dimers. For details, see ref. 4.
  • 8 2H-Chromenyl alcohols 3 are more stable than the products of the DCC reaction.
  • 9 Under the optimized conditions, the ee values of the two diastereomers of 3a are about 22%.
  • 10 General Procedure for the DCC Reaction of Chromene (1) with Aldehyde 2a–i, Followed by Reduction for 3a–i: Under nitrogen, the mixture of chromene (1; 39.6 mg, 0.3 mmol), LiClO4 (38.16 mg, 0.36 mmol), 4 Å MS (75 mg), DDQ (81.72 mg, 0.36 mmol) was stirred for 0.5 h in freshly distilled MeCN (2 mL) at 0 °C. Then aldehyde 2 (0.9 mmol) and l-proline (6.9 mg, 0.06 mmol) were added, and the reaction mixture was stirred for 24 h at r.t. (about 20 °C). After evaporation of the solvent under reduced pressure, NaBH4 (37.83 mg, 1.0 mmol) and EtOH (2 mL) were added to the mixture. The reaction mixture was stirred for 2 h at 0 °C. Then H2O (10 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (silica gel; PE–EtOAc, 1:10 or 1:20) to give the desired product 3.

  • References and Notes

  • 4 Clausen DJ, Floreancig PE. J. Org. Chem. 2012; 77: 6574
    CrossrefSearch in Google Scholar
  • 5 Rueping M, Volla CM. R, Atodiresei L. Org. Lett. 2012; 14: 4642
    CrossrefSearch in Google Scholar
  • 6 Sperry J, Wilson ZE, Rathwell DC. K, Brimble MA. Nat. Prod. Rep. 2010; 27: 1117
    CrossrefSearch in Google Scholar
  • 7 LiClO4 may promote the conversion of chromene to oxocarbenium ion pair and 4 Å MS may prevent the formation of ether dimers. For details, see ref. 4.
  • 8 2H-Chromenyl alcohols 3 are more stable than the products of the DCC reaction.
  • 9 Under the optimized conditions, the ee values of the two diastereomers of 3a are about 22%.
  • 10 General Procedure for the DCC Reaction of Chromene (1) with Aldehyde 2a–i, Followed by Reduction for 3a–i: Under nitrogen, the mixture of chromene (1; 39.6 mg, 0.3 mmol), LiClO4 (38.16 mg, 0.36 mmol), 4 Å MS (75 mg), DDQ (81.72 mg, 0.36 mmol) was stirred for 0.5 h in freshly distilled MeCN (2 mL) at 0 °C. Then aldehyde 2 (0.9 mmol) and l-proline (6.9 mg, 0.06 mmol) were added, and the reaction mixture was stirred for 24 h at r.t. (about 20 °C). After evaporation of the solvent under reduced pressure, NaBH4 (37.83 mg, 1.0 mmol) and EtOH (2 mL) were added to the mixture. The reaction mixture was stirred for 2 h at 0 °C. Then H2O (10 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (silica gel; PE–EtOAc, 1:10 or 1:20) to give the desired product 3.

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Zoom Image
Scheme 1 Plausible mechanism for the DCC reaction between chromene (1) and aldehyde 2