Highly stereoselective synthesis of 2-aminobenzylidene derivatives by a convergent 3-component approach

DOI: 10.1055/s-0034-1378906

Source and publish data:

Synlett p. 2913 - 2917 (2014)

Update date:2022-09-26

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Authors:

Xu, Zian

Ge, Jingying

Wang, Tianchi

Luo, Ting

Liu, Hongwei

Yu, Xinhong

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Article abstract of DOI:10.1055/s-0034-1378906

An one-pot stereoselective synthesis of 2-aminobenzylidene derivatives from readily available 5-nitro/cyano-activated 2-halobenzaldehydes (2-chloro-5-nitrobenzaldehyde, 2-bromo-5-nitrobenzaldehyde, 2-fluoro-5-nitrobenzaldehyde, 5-cyano-2-fluorobenzaldehyd

Full text of DOI:10.1055/s-0034-1378906

LETTER

▌2913

letter

Highly Stereoselective Synthesis of 2-Aminobenzylidene Derivatives by a

Convergent 3-Component Approach

Synthesis of 2-Aminobenzylidene Derivatives

Zian Xu, Jingying Ge, Tianchi Wang, Ting Luo, Hongwei Liu,* Xinhong Yu*

Shanghai Key Laboratory of New Drug Design and School of Pharmacy, East China University of Science & Technology, Shanghai 200237,

P. R. of China

E-mail: hwliu@ecust.edu.cn; E-mail: xhyu@ecust.edu.cn

Received: 30.08.2014; Accepted after revision: 02.10.2014

from simple readily available materials under mild condi-

Abstract: An one-pot stereoselective synthesis of 2-aminoben-

tions is particularly valuable for such a process. Herein we

zylidene derivatives from readily available 5-nitro/cyano-activated

report a three-component access to 2-amino-5-nitroben-

zylidene and 2-amino-5-cyanobenzylidene derivatives 4

2-halobenzaldehydes (2-chloro-5-nitrobenzaldehyde, 2-bromo-

5-nitrobenzaldehyde, 2-fluoro-5-nitrobenzaldehyde, 5-cyano-2-flu-

orobenzaldehyde), the active methylidene compounds (cyanoacet- from readily available 2-halo-5-nitrobenzaldehyde (1a–

amide and ethyl cyanoacetate), and secondary cycloamines via a

novel parallel convergent Knoevenagel–nucleophilic aromatic sub-

stitution and nucleophilic aromatic substitution–Knoevenagel con-

cloamines 3 via a novel parallel convergent Knoevena-

densation cascade approach under mild conditions has been

developed with high stereoselectivity and in 52–88% yields.

c), 5-cyano-2-fluorobenzaldehyde (1d), cyanoacetamide

(2a), and ethyl cyanoacetate (2b), and secondary cy-

gel–nucleophilic aromatic substitution and nucleophilic

aromatic substitution–Knoevenagel condensation cascade

Key words: convergent cascade, Knoevenagel–S_NAr reaction,

approach under mild conditions with high E selectivity

one-pot reaction, 2-halobenzaldehyde

and in 52–88% yields. To the best of our knowledge, this

is the first example of parallel convergent Knoevenagel–

nucleophilic aromatic substitution and nucleophilic aro-

The development of fast, highly efficient, and environ-

matic substitution–Knoevenagel condensation cascade

mentally benign synthetic protocol is of particular signif-

access to benzylidene-scaffold derivatives.

icance. The one-pot multicomponent reactions (MCR)

Our previous investigation of one-pot MCR and cascade

have prominent advantages over the classical multistep

reactions⁵has revealed the three-component Knoevena-

gel–nucleophilic aromatic substitution reactions and veri-

fied the first Knoevenagel condensation and subsequent

S_NAr process. 4-Fluorobenzaldehyde can participate in

such three-component reaction smoothly (Scheme 1, eq.

1).^5aHowever, when the substrate was replaced by 2-flu-

orobenzaldehyde, the expected S_NAr reaction hardly oc-

curred (Scheme 1, eq. 2).⁶In order to promote the

aforementioned reaction, an electron-withdrawing group

such as NO₂or CN was added to the benzene ring. By this,

the reaction goes as anticipated (Scheme 1, eq. 3).

syntheses in their higher synthetic efficiency.¹Therefore,

in the last decade research in academia and industry has

increasingly emphasized the application of MCR in indus-

trialization.^1,2

Compounds containing a benzylidene scaffold could co-

valently bond to the SH group of cysteine residue at the

ATP moiety of epidermal growth factor receptor (EGFR)

or other nucleophiles at different receptors by Michael ad-

dition.³Therefore, 2-amino-5-nitrobenzylidene and 2-

amino-5-cyanobenzylidene derivatives could be potential

intermediates of EGFR inhibitors (EGFRi, Figure 1).

To explore the feasibility of the newly proposed three-

component reaction, we carried out a model reaction be-

tween 2-chloro-5-nitrobenzaldehyde (1a), cyanoacet-

amide (2a), and piperidine (3a) in ethanol (Table 1, entry

1). As disclosed by researches on S_NAr reactions, the ma-

jor influencing factors in nucleophilic reactivity of amines

is their basicity and bulkiness, and cyclic secondary

amines were found to be the most reactive.^5a,7In S_NAr re-

actions, the amine plays the dual role of nucleophile and

base.⁸To neutralize the HX generated in reaction, an ex-

cess of amine or additional base is needed to facilitate the

reaction. Therefore, the feeding ratio of 1a (1 equiv), 2a

(1 equiv), and 3a (2.5 equiv) was selected as optimized re-

action conditions. It is noteworthy that in this procedure

solvents have meaningful impact on the yield of this pro-

cess. Although the reactions were not satisfying in H₂O

(Table 1, entries 2 and 3), it was found that the process

R³

R⁴

R¹

R²

R⁵

R⁶

Figure 1 Potential side chains on the scaffold of EGFR inhibitors

They were usually prepared by stepwise S_NAr⁴and subse-

quent Knoevenagel reaction. Developping highly effi-

cient facile one-pot, three-component synthetic methods

SYNLETT 2014, 25, 2913–2917

Advanced online publication: 05.11.2014

DOI: 10.1055/s-0034-1378906; Art ID: st-2014-u0729-l

2914

Z. Xu et al.

LETTER

previous work

n = 0–3

EtOH

n = 0–3

MW, 5–10 min

72–90%

(1)

CHO

(2.5 equiv)

CHONH₃

EtOH, MW

( 2)

CHO

160 °C, 20 min

CONH₂

this work

n = 0–3

CHO

DMF or EtOH

52–88%

n = 0–3

(3)

EWG

(2.5 equiv)

EWG

Scheme 1 A cascade three-component approach

performed in DMF generally afforded moderate to good As revealed in Table 2, the one-pot cascade protocol

yield (Table 1, entries 4–8).

serves as a general method for the preparation of 2-amino-

benzylidene-scaffold derivatives from 2-halo-5-nitro-

benzaldehyde (1a–c), or 5-cyano-2-fluorobenzaldehyde

(1d), cyanoacetamide (2a), or ethyl cyanoacetate (2b),

and secondary cycloamines 3.⁹Compared to 2-chloro-5-

nitrobenzaldehyde (Table 2, entry 15) and 2-bromo-5-ni-

trobenzaldehyde (Table 2, entry 16), the reactions of 2-

fluoro-5-nitrobenzaldehyde, active methylidene com-

pounds, and secondary cycloamines in ethanol afforded

higher isolated yields (Table 2, entries 17–21). Much to

our surprise, we observed that the reactions of 2-chloro-5-

nitrobenzaldehyde or 2-bromo-5-nitrobenzaldehyde with

active methylidene compounds and secondary cycloam-

ines got better yield in DMF (Table 2, entries 1–14) than

in ethanol (Table 2, entries 15 and 16). Among the used

secondary cycloamines, the reactions of heptamethylene-

imine with 5-nitro- or 5-cyano-activated 2-halobenzalde-

hydes 1 and active methylidene compounds 2 got the

lowest yield owing to its spatial hindrance, while the reac-

tions of 2-fluoro-5-nitrobenzaldehyde are faster than

those of 2-fluoro-5-cyanobenzaldehyde because the nitro

group has a stronger electron-withdrawing effect than the

cyano group does. The Knoevenagel condensation prod-

ucts and final products should have the same configura-

tion (E configuration¹⁰) for the carbon–carbon double

bonds that are stiff and nonrotatable.

Table 1 Optimization of Reaction Conditions^a

O₂N

CONH₂

O₂N

CHO

CONH₂

Entry

Solvent

Temp (°C)

Time (min) Yield (%)^b

EtOH

H₂O

72^c

69^d

H₂O

100

DMF

110

^aReaction conditions: Unless specified, a mixture of 1a (1.0 mmol,

1.0 equiv), 2a (1.0 mmol, 1.0 equiv), and 3a (2.5 mmol, 2.5 equiv) in

solvent (2 mL) was heated for a specified time.

^bIsolated yield.

In the course of the above cascade access to 4a, both in-

termediates 5a and 6a were detected and transferred to 4a,

respectively, by the fractional-step reactions. Remark-

ably, the above one-pot processes proceeded in a conver-

gent cascade manner (Scheme 2): first, 2-chloro-5-

^cReaction conditions: 1a (1.0 mmol, 1.0 equiv), 2a (1.0 mmol, 1.0

equiv), and 3a (2.0 mmol, 2.0 equiv).

^dReaction conditions: 1a (1.0 mmol, 1.0 equiv), 2a (1.0 mmol, 1.0

equiv), 3a (1.0 mmol, 1.0 equiv), and Et₃N (1.5 mmol, 1.5 equiv).

Synlett 2014, 25, 2913–2917

LETTER

Synthesis of 2-Aminobenzylidene Derivatives

2915

nitrobenzaldehyde (1a) reacted with piperidine (3a) and (2a) to yield ethyl (E)-2-cyano-3-(5-nitro-2-(piperidin-1-

followed by the S_NAr product 5-nitro-(piperidin-1- yl)phenyl)acrylate (4a). Alternatively, 1a condensed with

yl)benzaldehyde (5a) condensed with ethyl cyanoacetate 2a catalyzed by pyrrolidine, and then 3a reacted as nucle-

Table 2 Scope of Three-Component Knoevenagel–Nucleophilic Aromatic Substitution Reactions

n = 0–3

CHO

n = 0–3

EWG

Entry

EWG

Time

(min)

Temp

(°C)

Yield

(%)

NO₂

CONH₂

CO₂Et

CONH₂

CO₂Et

CONH₂

CO₂Et

CH₂

130

120

105

108

CH₂

NMe

CH₂CO₂Me

CH₂

NMe

CHCO₂Me

CH₂

NBn

CH₂

64^a

69^a

88^a

86^a

82^a

78^a

80^a

54^a

65^a

68^a

52^a

74^a

75^a

CH₂

NMe

CHCO₂Me

CH₂

NMe

CHCO₂Me

CH₂

^aReaction was carried out in EtOH and purified by recrystallization with EtOH.

Synlett 2014, 25, 2913–2917

2916

Z. Xu et al.

LETTER

COOEt

S_NAr

O₂N

CHO

Knoevenagel

O₂N

CHO

COOEt

S_NAr

Knoevenagel

O₂N

COOEt

Scheme 2 A convergent cascade mechanism

(f) Kumar, A.; Gupta, M. K.; Kumar, M. Green Chem. 2012,

14, 290. (g) Burchak, O. N.; Mugherli, L.; Ostuni, M.;

Lacapere, J. J.; Balakirev, M. Y. J. Am. Chem. Soc. 2011,

133, 10058. (h) Maeda, S.; Komagawa, S.; Uchiyama, M.;

Morokuma, K. Angew. Chem. Int. Ed. 2011, 50, 644.

(i) Znabet, A.; Ruijter, E.; de Kanter, F. J. J.; Koehler, V.;

Helliwell, M.; Turner, N. J.; Orru, R. V. A. Angew. Chem.

Int. Ed. 2010, 49, 5289. (j) Presset, M.; Coquerel, Y.;

Rodriguez, J. Org. Lett. 2009, 11, 5706. (k) Airiau, E.;

Girard, N.; Mann, A.; Salvadori, J.; Taddei, M. Org. Lett.

2009, 11, 5314.

ophilic reagent with the Knoevenagel product ethyl (E)-α-

cyano-3-(2-fluoro-5-nitro)acrylate (6a) to yield 4a.

In summary, we have developed a one-pot convergent

Knoevenagel–nucleophilic aromatic substitution reaction

to prepare 2-aminobenzylidene derivatives, which fea-

tures the domino formation of one carbon–carbon double

bond and one carbon–nitrogen bond. The process pro-

ceeds highly stereoselectively and in good yields. The fur-

ther transformations of these compounds are under way.

(3) Powers, J. C.; Asgian, J. L.; Ekici, Ö. D.; James, K. E. Chem.

Rev. 2002, 102, 4639.

Acknowledgment

(4) (a) Cao, J.; Feng, J. X.; Wu, Y. X.; Tuo, Y. Y. P. Chin.

Chem. Lett. 2010, 21, 935. (b) Medimagh, R.; Marque, S.;

Prim, D.; Chatti, S.; Zarrouk, H. J. Org. Chem. 2008, 73,

2191. (c) Sutharsan, J.; Lichlyter, D.; Wright, N. E.;

Dakanali, M.; Haidekker, M. A.; Theodorakis, E. A.

Tetrahedron 2010, 66, 2582.

We gratefully acknowledge financial support from the National

Science Foundation of China (20972051 and 21476078) and the

Shanghai Committee of Science and Technology (12431900902,

12431900900, 08431901800 and 08430703900).

(5) (a) Xu, H.; Yu, X.-H.; Sun, L.-Y.; Liu, J.; Fan, W.; Shen,

Y.-J.; Wang, W. Tetrahedron Lett. 2008, 49, 4687. (b) Zu,

L.-S.; Xie, H.-X.; Li, H.; Wang, J.; Yu, X.-H.; Wang, W.

Chem. Eur. J. 2008, 14, 6333. (c) Wang, J.; Zhang, M.-M.;

Zhang, S.-L.; Xu, Z.-A.; Li, H.; Yu, X.-H.; Wang, W. Synlett

2011, 473. (d) Zou, Z.-Q.; Deng, Z.-J.; Yu, X.-H.; Zhang,

M.-M.; Zhao, S.-H.; Luo, T.; Yin, X.; Xu, H.; Wang, W. Sci.

China Chem. 2012, 55, 43. (e) Xie, H.-X.; Zhang, S.-L.; Li,

H. X.-S.; Zhao, S.-H.; Xu, Z.-A.; Song, X.-X.; Yu, X.-H.;

Wang, W. Chem. Eur. J. 2012, 18, 2230. (f) Zhang, X.-S.;

Song, X.-X.; Li, H.; Zhang, S.-L.; Chen, X.-B.; Yu, X.-H.;

Wang, W. Angew. Chem. Int. Ed. 2012, 51, 7282.

(6) Nitsche, C.; Steuer, C.; Klein, C. D. Bioorg. Med. Chem.

2011, 19, 7318.

Supporting Information for this article is available online

http://www.thieme-connect.com/products/ejournals/journal/

10.1055/s-00000083.SunpfgIpi

References and Notes

(1) For selected recent reviews of MCR, see: (a) Brauch, S.; van

Berkel, S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42,

4948. (b) Dömling, A.; Wang, W.; Wang, K. Chem. Rev.

2012, 112, 3083. (c) de Graaff, C.; Ruijter, E.; Orru, R. V. A.

Chem. Soc. Rev. 2012, 41, 3969. (d) Ruijter, E.; Scheffelaar,

R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50, 6234.

(e) Estevez, V.; Villacampa, M.; Menendez, J. C. Chem.

Soc. Rev. 2010, 39, 4402. (f) Ganem, B. Acc. Chem. Res.

2009, 42, 463. (g) Hulme, C. Multicomponent Reactions;

Zhu, J.; Bienyamé, H., Eds.; Wiley-VCH: Weinheim, 2005,

311–341.

(7) Mečiarová, M.; Toma, S.; Podlesná, J.; Kiripolský, M.;

Císařová, I. Monatsh. Chem. 2003, 134, 37.

(8) Prim, D.; Kirsch, G. Tetrahedron 1999, 55, 6511.

(9) Typical Experimental Procedure

Cyclic secondary amine (2.5 equiv) was treated with 2-

halobenzaldehyde (1 mmol) and active methylidene

compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The

mixture was stirred and heated to reflux. After the reaction

was completed, the mixture was cooled down to r.t. and

poured into H₂O (10 mL). Crude products were filtered off

and purified by recrystallization in EtOH or by column

chromatography on silica gel; 52–88% yield.

(2) For selective recent examples of MCR, see: (a) Deng, X. X.;

Du, F. S.; Li, Z. C. ACS Macro Lett. 2014, 3, 667. (b) Liu, F.

L.; Chen, J. R.; Zou, Y. Q.; Wei, Q.; Xiao, W. J. Org. Lett.

2014, 16, 3768. (c) Powner, M. W.; Zheng, S. L.; Szostak, J.

W. J. Am. Chem. Soc. 2012, 134, 13889. (d) Chen, M. Z.;

Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 1352.

(e) Jiang, B.; Yi, M. S.; Shi, F.; Tu, S. J.; Pindi, S.;

McDowell, P.; Li, G. Chem. Commun. 2012, 48, 808.

Synlett 2014, 25, 2913–2917

LETTER

(E)-α-Cyano-3-[5-nitro-2-(piperidin-1-yl)phenyl]-

Synthesis of 2-Aminobenzylidene Derivatives

2917

2.4, 2.8 Hz), 8.13 (1 H, s), 7.99 (1 H, s), 7.86 (1 H, s), 7.32

(1 H, d, J = 9.2 Hz), 3.79 (4 H, m), 3.17 (4 H, m). ¹³C NMR

(101 MHz, DMSO-d₆): δ = 162.44, 157.87, 147.47, 140.87,

127.80, 125.51, 123.98, 119.26, 116.28, 109.05, 66.39,

52.66.

acrylamide (4a)

Yield 81%; yellow solid; 0.24 g. ¹H NMR (400 MHz,

DMSO-d₆): δ = 8.66 (1 H, d, J = 2.4 Hz), 8.36 (1 H, m, J =

2.4, 2.8 Hz), 8.08 (1 H, s), 7.96 (1 H, s), 7.84 (1 H, s), 7.24

(1 H, d, J = 9.2 Hz), 3.13 (4 H, s), 1.68 (4 H,s), 1.61 (2 H, s).

¹³C NMR (101 MHz, DMSO-d₆) δ = 162.58, 158.82, 147.99,

140.06, 127.74, 125.50, 123.44, 119.09, 116.37, 106.10,

53.54, 25.98, 23.82.

(E)-α-Cyano-3-[5-nitro-2-(4-methylpiperazin-1-

yl)phenyl]acrylamide(4d)

Yield 76%; yellow solid; 0.25g. ¹HNMR (400 MHz, DMSO-

d₆): δ = 8.66 (1 H, d, J = 2.4 Hz), 8.26 (1 H, m, J = 2.2, 9.0

Hz), 8.08 (1 H, s), 7.97 (1 H, s), 7.84 (1 H, s), 7.27 (1 H, d,

(E)-α-Cyano-3-[5-nitro-2-(pyrrolidin-1-yl)phenyl]-

acrylamide (4b)

J = 9.2 Hz), 3.16 (4 H, s), 2.51 (4 H, s), 2.25 (3 H, s). ¹³

Yield 72%; yellow solid; 0.24g. ¹H NMR (400 MHz,

DMSO-d₆) δ = 8.68 (1 H, d, J = 2.4 Hz), 8.31 (1 H, m, J =

2.4, 2.8 Hz), 8.13 (1 H, s), 7.99 (1 H, s), 7.85 (1 H, s), 7.31

(1 H, d, J = 8.8Hz), 3.78 (4 H, s), 3.16 (4 H, s). ¹³C NMR

(101 MHz, DMSO-d₆): δ = 162.45, 157.87, 147.47, 140.88,

127.82, 125.53, 123.97, 119.29, 116.28, 109.10, 66.39,

52.66.

NMR (101 MHz, DMSO-d₆): δ = 162.47, 158.04, 147.70,

140.56, 127.77, 125.48, 123.72, 119.28, 116.32, 108.64,

54.74, 52.28, 45.99.

(10) (a) Lee, J.; Gauthier, D.; Rivero, R. J. Org. Chem. 1999, 64,

3060. (b) Gazit, A.; Yaish, P.; Gilon, C.; Levitzki, A. J. Med.

Chem. 1989, 32, 2344. (c) Xu, H.; Yu, X.-H.; Sun, L.-Y.;

Liu, J.; Fan, W.; Shen, Y.-J.; Wang, W. Tetrahedron Lett.

2008, 49, 4687. (d) Sutharsan, J.; Lichlyter, D.; Wright, N.;

Dakanali, M.; Haidekker, M. A.; Theodorakis, E. A.

Tetrahedron 2010, 66, 2582. (e) Balalaie, S.; Bararjanian,

M.; Hekmat, S.; Salehi, P. Synth. Commun. 2006, 36, 3703.

(E)-α-Cyano-3-[5-nitro-2-(morpholin-1-yl)phenyl]-

acrylamide(4c)

Yield 88%; yellow solid; 0.25g. ¹H NMR (400 MHz,

DMSO-d₆): δ = 8.68 (1 H, d, J = 2.4 Hz), 8.31 (1 H, m, J =

Synlett 2014, 25, 2913–2917

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Article Doi

Highly stereoselective synthesis of 2-aminobenzylidene derivatives by a convergent 3-component approach

DOI: 10.1055/s-0034-1378906

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Article abstract of DOI:10.1055/s-0034-1378906

Full text of DOI:10.1055/s-0034-1378906

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