Hydrogen-bond-promoted C-C bond-forming reaction: Catalyst-free Michael addition reactions in ethanol

Article abstract of DOI:10.1055/s-2007-992377

A practical protocol for catalyst-free Michael addition reactions in ethanol was developed. The reaction was promoted efficiently in alcohol without any additives, and the importance of hydrogen-bonding activation was suggested. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-2007-992377

3160
LETTER
Hydrogen-Bond-Promoted C–C Bond-Forming Reaction:
Catalyst-Free Michael Addition Reactions in Ethanol
Catalyst-Free
e
iditionsji Shirakawa,* Shoichi Shimizu
Department of Applied Molecular Chemistry and High Technology Research Center, College of Industrial Technology, Nihon University,
Narashino, Chiba, 275-8575, Japan
Fax +81(47)4742579; E-mail: s5siraka@cit.nihon-u.ac.jp
Received 20 September 2007
ganic substrates are soluble in ethanol. In addition, reac-
Abstract: A practical protocol for catalyst-free Michael addition
tions in alcohol may offer different reactivity and
reactions in ethanol was developed. The reaction was promoted ef-
selectivity compared with other organic solvents, due to
ficiently in alcohol without any additives, and the importance of hy-
the effect of hydrogen-bonding interactions.2 Recently,
drogen-bonding activation was suggested.
Rawal et al. reported hydrogen-bond-promoted hetero-
Key words: alcohols, green chemistry, Michael additions, solvent
Diels–Alder reactions of ketones in alcohol without any
acid or base catalyst.3,4 In their study, dramatic solvent ef-
fects on the reaction rate were observed, and the impor-
tance of hydrogen-bonding activation of ketones by
alcohol to promote the reaction was mentioned.
effects, enols
Reducing the use of hazardous solvents and reagents is
one of the most important challenges in the effort to min-
imize pollution and risks associated with the production of
chemicals. Accordingly, the use of water as a reaction me-
dium alternative to toxic organic solvents has received
considerable attention in organic synthesis.1 However, be-
cause of the low solubility of many organic substrates in
water, additives such as surfactants are often needed to
promote reactions in water.
In this context, our group is interested in the development
of environmentally benign catalyst-free organic reactions
in ethanol. This report documents catalyst-free Michael
addition reactions of active methylene compounds with
various Michael acceptors in ethanol.5,6 In the present
study, interesting solvent effects were observed and the
reaction was promoted efficiently only in alcohol, a hy-
drogen-bonding solvent.
On the other hand, ethanol is an attractive reaction solvent
due to availability, low toxicity, and the fact that many or-
Table 1 Solvent Effect of Michael Addition Reaction
O
O
COOMe
O
COOMe
+
r.t., 12 h
(1.5 equiv)
1a
O
Entry
Solvent
Yield (%)a
1
Benzene
CHCl3
7
4
2
3
MeCN
2
4
THF
9
5
THF–H2O (9:1)
H2O
34
39
99
99
99
6
7
EtOH
8
1-PrOH
diethylene glycol
9
a Determined by GC.
SYNLETT 2007, No. 20, pp 3160–3164
x
x
.x
x
.2
0
0
7
Advanced online publication: 21.11.2007
DOI: 10.1055/s-2007-992377; Art ID: U8707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalyst-Free Michael Additions
3161
As a starting point for the investigation, our group tested
solvent effects in the Michael addition reaction of 1-oxo-
indan-2-carboxylic acid methyl ester to methyl vinyl ke-
tone (Table 1 and Figure 1). The reactions in benzene and
chloroform proceeded very slowly and produced the prod-
uct only in 7% and 4% yields, respectively (entries 1 and
2). Also, aprotic polar solvents such as acetonitrile and
THF were employed for the reaction and gave poor results
(entries 3 and 4). On the other hand, the ethanol solvent
promoted the reaction smoothly and produced the Micha-
el adduct 1a in quantitative yield after 12 hours (entry 7).
Other alcohols also promoted the reaction efficiently (en-
tries 8 and 9). It is noteworthy that reactions in aqueous
media also moderately promoted the reaction, and ob-
tained the product in 34–39% yields (entries 5 and 6).7,8
These results suggested the hydrogen-bonding activation
of the substrate by the solvent was important for efficient
promotion of the reaction.9
Figure 1 Reaction rate of Michael addition in different solvents
in good yields (entries 1 and 2). Also, when vinyl com-
pounds containing another electron-withdrawing group
(EWG) were used as the acceptor, the corresponding
After these interesting observations, the substrate general- products 1c–e were obtained in moderate to good yields
ity of catalyst-free Michael addition reactions in alcohol (entries 3–5). Furthermore, when the present reaction sys-
was investigated. Initially, the generality of Michael ac- tem was applied to the C–N bond-forming reaction by us-
ceptors was examined (Table 2). Michael addition reac- ing azodicarboxylate as a Michael acceptor, the desired
tions using vinyl ketones proceeded smoothly at ambient amination product 1f was obtained in excellent yield (en-
temperature and produced the Michael adducts 1a and 1b try 6).10
Table 2 Michael Addition Reactions of b-Ketoester with Various Michael Acceptors in Alcohol
O
O
COOMe
COOMe
EWG
(1.5 equiv)
+
R
EtOH
R
EWG
1
Entry
1
Michael acceptor
Conditionsa
r.t., 12 h
Yield (%)b
99 (1a)c
O
2
r.t., 24 h
72 (1b)
71 (1c)
O
O
3d,e
90 °C, 24 h
OMe
CN
4d,e
5d,f
6
70 °C, 48 h
90 °C, 24 h
r.t., 2 h
52 (1d)
80 (1e)g
99 (1f)h
NO2
Ph
N
Cbz
Cbz
N
a Reaction was carried out in a screw-capped flask heated at given temperature.
b Isolated yield.
c Determined by GC.
d Reaction in MeOH.
e Michael acceptor (5 equiv).
f Michael acceptor (3 equiv).
g Diastereomeric ratio ca. 1:1.
h Product 1f:
O
COOMe
N
NH
Cbz
Cbz
Synlett 2007, No. 20, 3160–3164 © Thieme Stuttgart · New York

3162
S. Shirakawa, S. Shimizu
LETTER
Next, substrate generality with respect to the Michael do- that is, it may work as a Brønsted acid. Also, the oxygen
nor was examined, and a variety of active methylene com- in ethanol may coordinate with the hydrogen in enol, and
pounds were subjected to Michael addition reactions of as a result, function as a Brønsted base. This dual activa-
methyl vinyl ketone (Table 3). When substrates contain- tion mode12,13 by ethanol may be important in promoting
ing 1,3-dicarbonyls, sulfonyl-, cyano-, and nitro-groups Michael addition reactions efficiently under catalyst-free
were employed as Michael donors the desired Michael ad- conditions.
dition products 2a–g were obtained in moderate to good
In summary, our group has developed catalyst-free
yields. In the case of benzoylacetonitrile as a Michael do-
Michael addition reactions in ethanol. It is noteworthy
nor, the bis-alkylated product 2e was selectively obtained
that the present reactions proceeded without the addition
of any acid or base catalyst, and that a variety of Michael
(entry 5).
The present catalyst-free Michael addition reactions in adducts were obtained. This remarkably simple and envi-
ethanol were easily practicable on a larger scale; the reac- ronmentally benign reaction system offers a practical C–
tion of 1-oxoindan-2-carboxylic acid methyl ester and C bond-forming method.
methyl vinyl ketone (1.2 equiv) was carried out on a 10
mmol scale (Scheme 1). After reaction for 24 hours at am-
bient temperature, the reaction mixture was evaporated to
remove the ethanol and excess methyl vinyl ketone, and
dried in vacuo to obtain the desired product 1a in quanti-
tative yield. It is noteworthy that the present method was
very simple and that the Michael addition product was
easily obtained without tedious workup procedures.
Measurements of Reaction Rates in Michael Addition Reaction
(Table 1 and Figure 1)
Methyl vinyl ketone (0.75 mmol) was added to a stirring solution of
1-oxoindan-2-carboxylic acid methyl ester (0.50 mmol) and di-
phenyl ether (0.50 mmol) as an internal standard in solvent (1.0 mL)
at r.t. At appropriate intervals, the reaction solution (20 mL) was
transferred to a microtube containing Et2O (0.50 mL) as diluent, and
The utility and applicability of the present reaction system then subjected to a GC analysis to determine the yield of product.
was extended to hydroxymethylation using aqueous form-
aldehyde (Scheme 2).11 The reaction of 1-oxoindan-2-car-
boxylic acid methyl ester with aqueous formaldehyde in
ethanol occured cleanly and afforded the desired hy-
droxymethylation product 3 in quantitative yield.
General Experimental Procedure for Michael Addition Reac-
tions in EtOH (Tables 2 and 3)
Michael acceptor (1.5–5.0 equiv) was added to a stirring solution of
Michael donor (0.50 mmol) in EtOH (1.0 mL),14 and the reaction
mixture was stirred in given conditions. After the evaporation of
EtOH, the resulting crude product was purified by flash chromatog-
raphy (neutral silica gel), and yielded a Michael addition product.
The proposed hydrogen-bonding interactions of ethanol
with the Michael donor and acceptor are shown in
Scheme 3. The hydrogen in ethanol may interact with car-
bonyl oxygen of the vinyl ketone via a hydrogen bond,
O
O
COOMe
O
COOMe
+
EtOH
r.t., 24 h
1a
O
(12 mmol)
(10 mmol)
2.60 g, 99% yield
Scheme 1 Larger-scale synthesis
O
O
COOMe
COOMe
+
aq HCHO
(1.5 equiv)
EtOH
r.t., 4 h
OH
3
99% yield
Scheme 2 Hydroxymethylation with aqueous formaldehyde
Et
EtOH
O
H
Et
O
H
O
H
H
O
O
O
O
R3
R3
R1
O
O
R3
R1
O
R2
R1
R2
O
R2
Scheme 3 Proposed hydrogen-bonding activation mode
Synlett 2007, No. 20, 3160–3164 © Thieme Stuttgart · New York

LETTER
Catalyst-Free Michael Additions
3163
References and Notes
Table 3 Michael Addition Reactions of Various Michael Donors
with Methyl Vinyl Ketone in Alcohol
(1) For reviews, see: (a) Li, C.-J.; Chan, T.-H. Organic
O
Reactions in Aqueous Media; Wiley: New York, 1997.
(b) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998. (c) Li, C.-J.
Chem. Rev. 1993, 93, 2023. (d) Li, C.-J. Chem. Rev. 2005,
105, 3095.
EWG
EWG
O
EWG
+
EtOH
R
R
EWG
(5 equiv)
2
(2) (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120.
(b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289.
(c) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 1520.
Entry Michael donor
Conditionsa
70 °C, 48 h
Yield (%)b
1c
90 (2a)
O
COOMe
(3) (a) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124,
9662. For theoretical studies, see: (b) Domingo, L. R.;
Andrés, J. J. Org. Chem. 2003, 68, 8662. (c) Gordillo, R.;
Dudding, T.; Anderson, C. D.; Houk, K. N. Org. Lett. 2007,
9, 501.
(4) This reaction system was elegantly applied to asymmetric
synthesis, see: (a) Huang, Y.; Unni, A. K.; Thadani, A. N.;
Rawal, V. H. Nature (London) 2003, 424, 146. (b) Thadani,
A. N.; Stankovic, A. R.; Rawal, V. H. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5846. (c) Unni, A. K.; Takenaka, N.;
Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127,
1336. (d) Zhang, X.; Du, H.; Wang, Z.; Wu, Y.-D.; Ding, K.
J. Org. Chem. 2006, 71, 2862.
2
90 °C, 24 h
81 (2b)
O
O
Ph
Ph
Ph
Ph
3
4
5
90 °C, 24 h
90 °C, 24 h
70 °C, 48 h
82 (2c)
83 (2d)
85 (2e)d
O
O
O
SO2Ph
CN
O
Ph
(5) For an example of Brønsted acid catalyzed Michael addition
reactions, see: Kotsuki, H.; Arimura, K.; Ohishi, T.;
Maruzasa, R. J. Org. Chem. 1999, 64, 3770.
6
7
90 °C, 48 h
90 °C, 24 h
52 (2f)
70 (2g)
O2N
COOEt
COOEt
COOEt
EtOOC
(6) Recent examples of chiral organocatalyst-promoted Michael
addition reactions, see: (a) Li, H.; Wang, Y.; Tang, L.;
Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (b) Okino, T.;
Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119. (c) Wang, J.; Li, H.; Duan, W.;
Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713. (d) Ye, J.;
Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
(7) For a catalyst-free Michael addition reaction of a-nitro-
cycloalkanones in water, see: Miranda, S.; López-Alvarado,
P.; Giorgi, G.; Rodriguez, J.; Avendaño, C.; Menéndez, J. C.
Synlett 2003, 2159.
a Reaction was carried out in a screw-capped flask heated at given
temperature.
b Isolated yield.
c Reaction in MeOH.
d Product was dialkylated product 2e:
O
CN
Ph
(8) For recent examples of metal- or base-catalyzed Michael
addition reactions in water, see: (a) Keller, E.; Feringa, B. L.
Tetrahedron Lett. 1996, 37, 1879. (b) Mori, Y.; Kakumoto,
K.; Manabe, K.; Kobayashi, S. Tetrahedron Lett. 2000, 41,
3107. (c) Shibatomi, K.; Nakahashi, T.; Uozumi, Y. Synlett
2000, 1643. (d) Bensa, D.; Brunel, J.-M.; Buono, G.;
Rodriguez, J. Synlett 2001, 715. (e) Shirakawa, S.;
Kobayashi, S. Synlett 2006, 1410. (f) Aplander, K.; Ding,
R.; Lindström, U. M.; Wennerberg, J.; Schultz, S. Angew.
Chem. Int. Ed. 2007, 46, 4543.
(9) Hydrogen-bonding activation by water in Diels–Alder
reaction, see: (a) Blake, J. F.; Jorgensen, W. L. J. Am. Chem.
Soc. 1991, 113, 7430. (b) Blake, J. F.; Lim, D.; Jorgensen,
W. L. J. Org. Chem. 1994, 59, 803.
(10) Pihko et al. also reported about progress of the reaction
between b-ketoester and azodicarboxylate without catalyst
in alcohol, see: Pihko, P. M.; Pohjakallio, A. Synlett 2004,
2115.
(11) For recent examples of metal-catalyzed hydroxymethylation
of active methylene compounds, see: (a) Ogawa, C.;
Kobayashi, S. Chem. Lett. 2007, 36, 56. (b) Fukuchi, I.;
Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2007, 349,
509. (c) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun.
1998, 71.
O
O
Larger-Scale Synthesis (Scheme 1)
Methyl vinyl ketone (12 mmol) was added to a stirring solution of
1-oxoindan-2-carboxylic acid methyl ester (10 mmol) in EtOH (20
mL), and the reaction mixture was stirred for 24 h at r.t. The reaction
mixture was evaporated to remove EtOH and excess methyl vinyl
ketone, and dried in vacuo to obtain Michael adduct 1a as a white
solid.
Compound 1a:15 1H NMR (400 MHz, CDCl3): d = 7.78 (d, J = 7.7
Hz, 1 H), 7.64 (dt, J = 1.1, 7.5 Hz, 1 H), 7.48 (d, J = 7.7 Hz, 1 H),
7.42 (t, J = 7.5 Hz, 1 H), 3.70 (s, 3 H), 3.68 (d, J = 17.3 Hz, 1 H),
3.05 (d, J = 17.3 Hz, 1 H), 2.48–2.68 (m, 2 H), 2.18–2.28 (m, 2 H),
2.13 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): d = 207.5, 202.3,
171.6, 152.5, 135.6, 135.0, 128.0, 126.4, 124.9, 59.1, 52.8, 38.8,
37.8, 30.0, 28.6 ppm. IR: 2953, 1743, 1713, 1607, 1434, 1277,
1251, 1210, 1195, 1176, 756 cm–1. MS (EI): m/z = 260 [M+], 228,
190, 157, 130.
Acknowledgment
(12) For reviews for dual activation, see: (a) Ma, J.-A.; Cahard,
D. Angew. Chem. Int. Ed. 2004, 43, 4566. (b) Shibasaki,
M.; Kanai, M.; Matsunaga, S. Aldrichimica Acta 2006, 39,
31.
We thank Kentaro Sasaki and Asuka Usui for their assistance in this
study.
Synlett 2007, No. 20, 3160–3164 © Thieme Stuttgart · New York

3164
S. Shirakawa, S. Shimizu
LETTER
(13) (a) Cokley, T. M.; Harvey, P. J.; Marshall, R. L.;
McCluskey, A.; Young, D. J. J. Org. Chem. 1997, 62, 1961.
(b) Asao, N.; Abe, N.; Tan, Z.; Maruoka, K. Synlett 1998,
377. (c) Vilotijevic, I.; Jamison, T. F. Science 2007, 317,
1189.
(14) Amount of EtOH could be reduced to 0.10 mL without loss
of reactivity.
(15) Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura,
S.; Hashimoto, S. Tetrahedron 2003, 59, 7307.
Synlett 2007, No. 20, 3160–3164 © Thieme Stuttgart · New York

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