Organocatalytic conjugate addition of 2-arylacetates and 2-arylacetonitriles having an electron-withdrawing group to α,β- unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2011.02.073

A catalytic conjugate addition reaction of 2-arylacetates and 2-arylacetonitriles having an electron-withdrawing group to α,β- unsaturated ketones has been established using pyrrolidine as a catalyst. The reagents having NO2-, CO₂Me-, and CN-fu

Full text of DOI:10.1016/j.tetlet.2011.02.073

Tetrahedron Letters 52 (2011) 2353–2355
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Tetrahedron Letters
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Organocatalytic conjugate addition of 2-arylacetates and 2-arylacetonitriles
having an electron-withdrawing group to
a,b-unsaturated ketones
⇑
Jungho Do, Sung-Gon Kim
Department of Chemistry, Kyonggi University, San 94-6, Iui-dong, Yeongtong-gu, Suwon 443-760, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic conjugate addition reaction of 2-arylacetates and 2-arylacetonitriles having an electron-with-
Received 21 December 2010
Revised 16 February 2011
Accepted 18 February 2011
Available online 22 February 2011
drawing group to
reagents having NO2À, CO2Me-, and CN-functional groups on the aromatic ring can be used; the reaction
with various ,b-unsaturated ketones provided the Michael addition products in good yields.
a,b-unsaturated ketones has been established using pyrrolidine as a catalyst. The
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalyst
Conjugate addition
Michael reaction
a,b-Unsaturated ketone
The conjugate addition reaction of carbon nucleophiles to elec-
CN
NO2
tron-poor alkenes is a powerful tool for forming a carbon–carbon
bond formation in organic synthesis; consequently, it helps gener-
ate a diverse array of products.1 Versatile activated methylenes,
such as 1,3-diketones, 1,3-dinitriles, ketoesters, malonate esters,
and nitroesters are valuable nucleophiles for conjugate addition
to ,b-unsaturated nitriles and carbonyls. In particular, this reaction
has attracted attention in asymmetric organocatalytic reactions in
recent years.2 The adducts of conjugate addition provide syntheti-
cally useful blocks for the synthesis of biologically active natural
products and pharmaceutical compounds.3 However, despite
belonging to an important class of nucleophiles, simple less reac-
tive activated methylenes such as benzylesters are not employed
in asymmetric organocatalytic reactions since they do not easily
participate in conjugate addition of enones.4,5
NC
NC
p
p
K
a 16.0
p
K
a 12.3
O
SO2Ph
Ph
NC
NC
Ka 16.0
pKa 15.8
Figure 1. Benzylcyanide derivatives having an electron-withdrawing group.
Benzylcyanide (pKa 22) and benzylester (ethyl 2-phenylacetate,
pKa 23) are less acidic than malonate esters (diethyl malonate, pKa
16) and 1,3-dinitrile (malononitrile, pKa 11), making it difficult to
use them as nucleophiles in an organocatalytic conjugate addition
reaction. However, addition of an electron-withdrawing group to
the phenyl ring lowers the pKa values of benzylcyanide and benzy-
lester. The pKa values for 4-(cyanomethyl)-benzonitrile and 2-(4-
nitrophenyl)acetonitrile are 16 and 12, respectively (Fig. 1).10 Thus,
we envisioned that organocatalytic conjugate addition would be
possible if benzylester containing an electron-withdrawing group
was used instead of just benzylester. However, to the best of our
knowledge, the use of this compound as nucleophile in conjugate
addition reactions has never been reported.
A numerous natural products including rubioncolin B,6 flustr-
amine B,7 (À)-siccanin,8 and (À)-morphine9 have a chiral center
at the benzylic position. Many efforts have been made to introduce
a stereogenic center at the benzylic position. Therefore, less reac-
tive methylenes such as benzylesters to a,b-unsaturated carbonyls,
which enables the leading intermediates to be used in the synthe-
sis of natural products is of considerable importance. However,
developing these methylenes as nucleophiles in an asymmetric
organocatalytic reaction is still a challenging task. Herein, we re-
port the conjugate addition of 2-arylacetates and 2-arylacetonitr-
iles having an electron-withdrawing group to
ketones using an organocatalyst.
a,b-unsaturated
The conjugate addition reaction of methyl 2-(4-nitrophenyl)ace-
tate 2a to (E)-4-phenylbut-3-en-2-one 3a was selected as the model
reaction (Table 1). The pyrrolidinyl tetrazole catalyst 1a (Fig. 1) was
initially examined as an organocatalyst in this reaction since this
⇑
Corresponding author. Tel.: +82 31 249 9631; fax: +82 31 249 9639.
E-mail address: sgkim123@kgu.ac.kr (S.-G. Kim).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.073

2354
J. Do, S.-G. Kim / Tetrahedron Letters 52 (2011) 2353–2355
Table 1
Table 2
Organocatalytic conjugate addition of methyl 2-(4-nitrophenyl)acetate (2a) to (E)-4-
Organocatalytic conjugate addition of 2-arylacetate and 2-arylacetonitrile to (E)-4-
phenylbut-3-en-2-one (3a)a
phenylbut-3-en-2-one (3a)a
O2N
O2N
O
O
R2
R2
catalyst
(10 mol%)
additive
R1
pyrrolidine
(20 mol%)
R1
OMe
OMe
Me
2
2a
+
+
Ph
CH2Cl2, rt
Ph
O
CH2Cl2, rt
O
O
Me
drc
O
Ph
R1
Me
Ph
Me
3a
4
3a
4a
Entry
R2
Product
Time (h)
Yieldb (%)
Entry
Catalyst
Additive
Time (h)
Yieldb (%)
1
CO2Me
CO2Me
CO2Me
CN
CN
CN
CN
CN
CN
CN
p-NO2
o-NO2
p-CO2Me
p-NO2
o-NO2
p-CO2Me
o-CO2Me
p-CN
4a
4b
4c
4d
4e
4f
4g
4h
4i
24
48
48
24
24
40
48
24
40
24
95
64
54
99
71
77
65
90
53:47
60:40
54:46
64:36
53:47
60:40
52:48
64:36
51:49
1
1a
1a
1a
1a
1a
1a
1b
1b
—
—
24
24
36
56
12
36
12
32
24
24
No rxn
No rxn
76
72
89
85
91
84
76
2
2
Bn2NH (1 equiv)
K2CO3 (1 equiv)
3d
4
3c
4
Piperidine (1 equiv)
Pyrrolidine (1 equiv)
Pyrrolidine (10 mol %)
Pyrrolidine (1 equiv)
Pyrrolidine (10 mol %)
Pyrrolidine (1 equiv)
Pyrrolidine (10 mol %)
5
5
6
7
8
9
10
6
7d
8
9
10
o-CN
H
99
No rxn
4j
—
90
a
Unless otherwise specified, the reaction was carried out in CH2Cl2 (0.5 M) with
a
Unless otherwise specified, the reaction was carried out in CH2Cl2 (0.5 M) with
1.5 equiv of 2 relative to 3a in the presence of 20 mol % of pyrrolidine.
1.5 equiv of 2a relative to 3a in the presence of 10 mol % catalyst and additive.
b
Isolated yield after chromatographic purification.
b
Isolated yield after chromatographic purification.
Performed in DMF.
c
Determined by 1H NMR analysis.
c
d
1 equiv of pyrrolidine was added.
catalyst 1a has gave the product in good yield with high enantiose-
Table 3
lectivity for the conjugate addition reaction of malonate to
Organocatalytic conjugate addition of methyl 2-(4-nitrophenyl)acetate (2a) to
a,b-
,b-unsaturated enones.11 No reaction was observed in the absence
unsaturated ketonesa
a
of additive base and when dibenzylamine was used as a base after
24 h at room temperature (entries 1 and 2). The reaction proceeded
to furnish the corresponding product 4a in moderate yields using
K2CO3 and piperidine as the base (entries 3 and 4). The pyrrolidine
additive afforded the desired product 4a with good reactivity
(entries 5 and 6) even using of catalytic amount. Under these
O2N
O
O
pyrrolidine
(20 mol%)
p
-NO2Ph
R2
OMe
OMe
2a
+
CH2Cl2, rt
O
O
R1
R2
R1
R1
conditions, L-proline 1b readily catalyzed the conjugate addition
3
5
reaction of methyl 2-(4-nitrophenyl)acetate 2a to (E)-4-phenyl-
but-3-en-2-one 3a resulting in a good yield (entries 7 and 8).12
However, unfortunately, the pyrrolidinyl tetrazole catalyst 1a and
Entry
R2
Product
Time (h)
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
p-MePh
p-MeOPh
p-ClPh
5a
5b
5c
5d
5e
5f
5g
5h
5i
24
48
48
48
48
32
48
24
24
99
79
88
93
63
94
60
93
99
53:47
53:47
53:47
53:47
58:42
57:43
55:45
59:41
52:48
L-proline 1b did not provide the chiral product 4a in this reaction.
Additionally, we found that pyrrolidine alone could promote and
even more catalyze this reaction without 1a or 1b (entries 9 and
10).12
p-BrPh
p-NO2Ph
1-Naphthyl
2-Furyl
–(CH2)2–
–(CH2)3–
N
O
1b
1a
N
N
H
N
H
a
Unless otherwise specified, the reaction was carried out in CH2Cl2 (0.5 M) with
1.5 equiv of 2a relative to 3 in the presence of 20 mol % of pyrrolidine.
HN
N
OH
b
Isolated yield after chromatographic purification.
Although this conjugate addition reaction does not achieve
enantiocontrol, we decided to explore the scope of this new pro-
cess. Firstly, this reaction proved to be general for a variety of ben-
zylcyanides and benzylesters having an electron-withdrawing
group 2. As revealed in Table 2, the reactions proceeded in good
yields in the case of both 2-arylacetate and 2-arylacetonitrile. Re-
agents having a CO2Me-functional group on the aromatic ring
Determined by 1H NMR analysis
c
the substituents on the aromatic ring, where electron-donating
(entries 1 and 2) and electron-withdrawing groups (entries 3–5)
are presented. Furthermore, conjugate aromatic and heteroaro-
À
showed relatively lower reactivities than those having NO2 and
matic a,b-unsaturated methyl ketones can participate in the
CN-functional groups (entries 3, 6 and 7). As expected, the conju-
gate addition reaction of 2-phenylacetonitrile (benzylcyanide) to
(E)-4-phenylbut-3-en-2-one 3a did not occur (entry 10).
processes as well (entries 6 and 7). Finally, we confirmed that
2-cyclopenten-1-one and 2-cyclohexen-1-one were suitable for
use in this reaction (entries 8 and 9).
The addition of methyl 2-(4-nitrophenyl)acetate 2a to various
We are also developing an asymmetric variant of this reaction.
For example, the reaction of methyl 2-(4-nitrophenyl)acetate 2a to
(E)-4-phenylbut-3-en-2-one 3a in the presence of catalyst 1c
furnished the corresponding product 4a in good yields and with
moderate enantioselectivities (Scheme 1).
a
,b-unsaturated ketones 3 was also evaluated and some represen-
tative results are shown in Table 3. The conjugate addition of 2-(4-
nitrophenyl)acetate 2a to aromatic ,b-unsaturated methyl
ketones exhibited good results. Significant structural variation in
aromatic ,b-unsaturated methyl ketones was tolerated in this
reaction, which occurred efficiently, independent of the nature of
a
a
In summary, we described organocatalytic conjugate addition
reaction of 2-arylacetates and 2-arylacetonitriles having an

J. Do, S.-G. Kim / Tetrahedron Letters 52 (2011) 2353–2355
2355
4. For palladium-catalyzed asymmetric reaction of ketone enolate, see: (a) Trost,
B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759; (b) You, S.-L.; Hou, X.-
L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett. 2001, 3, 149; (c) Trost, B. M.; Tang, W. J. Am.
Chem. Soc. 2003, 125, 8744.
5. For asymmetric reaction of ketone enolate using phasetransfer catalysts, see:
(a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446;
(b) Bhattacharya, A.; Dolling, U.-H.; Grabowski, E. J. J.; Karady, S.; Ryan, K. M.;
Weinstock, L. Angew. Chem., Int. Ed. 1986, 25, 476.
6. (a) Lumb, J.-P.; Choong, K. C.; Trauner, D. J. Am. Chem. Soc. 2008, 130, 9230; (b)
Singh, R.; Geetanjali, S.; Chauhan, M. S. Chem, Biodiversity 2004, 1, 1241; (c)
Itokawa, H.; Ibraheim, Z. Z.; Qiao, Y. F.; Takeya, K. Chem. Pharm. Bull. 1993, 41,
1869.
7. (a) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc.
Natl. Acad. Sci. 2004, 101, 5482; (b) Peters, L.; Konig, G. M.; Terlau, H.;
Wright, A. D. J. Nat. Prod. 2002, 65, 1633; (c) Carle, J. S.; Chrisophersen, C. J.
Org. Chem. 1981, 46, 3440; (d) Carle, J. S.; Christophersen, C. J. Am. Chem. Soc.
1979, 101, 4012.
O
NH2
O2N
p
-NO2Ph
O
*
OMe
Me
N
OMe
H
N
Ph
*
2a
(20 mol%)
1c
+
O
O
p
-NO2PhCO2H
(40 mol%)
4a
Ph
Me
DMF, rt, 18h
3a
86% yield, 65 :35 dr
major 77 : 23 er
minor 73: 27 er
Scheme 1. Asymmetric organocatalytic conjugate addition of methyl 2-(4-nitro-
phenyl)acetate (2a) to (E)-4-phenylbut-3-en-2-one (3a).
8. (a) Trost, B. M.; Shen, H. C.; Surivet, J.-P. J. Am. Chem. Soc. 2004, 126, 12565; (b)
Belloti, M. G.; Riviera, L. Chemioterapia 1985, 4, 431; (c) Ishibashi, K. J. J. Antibiot.
Ser. A 1962, 15, 161.
9. (a) Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem.
2000, 4, 343; (b) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Stabile, M.
R. Stud. Nat. Prod. Chem. 1996, 18, 43.
10. Bordwell, F. G.; Cheng, J.-P.; Bausch, M. J.; Bares, J. E. J. Phys. Org. Chem. 1988, 1,
209.
11. (a) Wascholowski, V.; Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Eur. J.
2008, 14, 6155; (b) Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Commun.
2006, 7, 66.
electron-withdrawing group to
rolidine as a catalyst.
a,b-unsaturated ketones using pyr-
The reagents having NO2À, CO2Me-, and CN-functional group on
the aromatic ring can be used and the reaction with various
unsaturated ketones provided the Michael addition products in
good yields. Current work focuses on expanding the scope of this
reaction to other substrates such as
a,b-
a,b-unsaturated aldehydes
and ,b-unsaturated nitriles, and on developing an efficient cata-
a
lytic asymmetric variant.
12. General procedure for the synthesis of 4 and 5. To a solution of a,b-unsaturated
ketones 3 (0.30 mmol) in CH2Cl2 (0.6 mL) at room temperature was added
pyrrolidine (0.060 mmol) followed by addition of 2-arylacetate or 2-
arylacetonitrile 2 (0.45 mmol). The resulting solution was stirred at room
Acknowledgments
temperature until complete consumption of
a,b-unsaturated ketones 3 was
observed as determined by TLC. The resulting mixture was direct purified by
silica gel chromatography to afford desired compounds 4 and 5.
methyl 2-(4-nitrophenyl)-5-oxo-3-phenylhexanoate (4a). Prepared by the
general procedure from (E)-4-phenylbut-3-en-2-one 3a (44 mg, 0.30 mmol),
methyl 2-(4-nitrophenyl)acetate 2a (88 mg, 0.45 mmol) and pyrrolidine
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2010-
0004139).
(52 lL, 0.060 mmol) in CH2Cl2 (0.6 mL) for 12 h to provide the desired
compound as an white solid (major: 51 mg, 50% yield, Rf = 0.32 (EtOAc/
hexanes = 1/3, v/v), minor: 46 mg, 45% yield, Rf = 0.22 (EtOAc/hexanes = 1/3, v/
v)) after silica gel chromatography in 30% EtOAc/hexanes.
References and notes
Major: mp 162–163 °C; 1H NMR (400 MHz, CDCl3) d 8.23 (d, J = 8.8 Hz, 2H),
7.66 (d, J = 8.8 Hz, 2H), 7.24–7.35 (m, 5H), 4.06 (d, J = 11.2 Hz, 1H), 3.96 (ddd,
J = 3.6, 9.6, 11.2 Hz, 1H), 3.42 (s, 3H), 2.71 (dd, J = 9.6, 16.8 Hz, 1H), 2.41 (dd,
J = 3.6, 16.8 Hz, 1H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3) d 206.1, 171.6,
147.7, 144.0, 140.7, 129.8, 128.7, 128.0, 127.4, 124.0, 57.3, 52.2, 46.8, 44.4,
30.7; MS m/z (%) 341 (M+, 10), 309 (13), 283 (17), 237 (21), 195 (50), 147 (65),
43 (100); Anal. Calcd for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 66.93;
H, 5.47; N, 4.01.
1. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon:
Oxford, 1992; (b) Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171; (c)
Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169; (d) Ballini, R.; Bosica, G.;
Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933.
2. (a) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: From Biomimetic
Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim,
Germany, 2005; (b) Dalko, P. I. Enantioselective Organocatalysis: Reactions and
Experimental Procedures; Wiley-VCH: Weinheim, Germany, 2007; (c) Almaßsi,
D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299.
3. (a) Barnes, D. M.; Ji, J. G.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H.
E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am.
Chem. Soc. 2002, 124, 13097; (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, N.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119; (c) Wang, Y.; Liu, X.; Deng, L. J.
Am. Chem. Soc. 2006, 128, 3928; (d) Brandau, S.; Landa, A.; Franzén, J.; Marigo,
M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 4305.
Minor: mp 132–133 °C; 1H NMR (400 MHz, CDCl3) d 8.00 (d, J = 8.8 Hz, 2H),
7.31 (d, J = 8.8 Hz, 2H), 6.98–7.15 (m, 5H), 3.90–4.00 (m, 2H), 3.73 (s, 3H), 3.00
(dd, J = 8.4, 16.4 Hz, 1H), 2.87 (dd, J = 4.0, 16.4 Hz, 1H), 2.03 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 206.0, 172.3, 147.0, 144.1, 139.8, 129.6, 128.5, 128.0, 127.1,
123.4, 57.1, 52.6, 48.2, 44.7, 30.5; MS m/z (%) 341 (M+, 11), 310 (15), 282 (13),
237 (22), 195 (48), 147 (64), 43 (100); Anal. Calcd for C19H19NO5: C, 66.85; H,
5.61; N, 4.10. Found: C, 66.80; H, 5.78; N, 3.72.