Solvent-free Horner-Wadsworth-Emmons reaction using DBU

Article abstract of DOI:10.1016/j.tetlet.2010.04.072

The solvent-free Horner-Wadsworth-Emmons reaction with a variety of aldehydes using 1.5 equiv of DBU gave E-α,β-unsaturated esters and ketones in high yields. The E-selectivity was high and the used DBU was recovered.

Full text of DOI:10.1016/j.tetlet.2010.04.072

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Tetrahedron Letters 51 (2010) 3297–3299
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Solvent-free Horner–Wadsworth–Emmons reaction using DBU
*
Kaori Ando , Kyohei Yamada
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The solvent-free Horner–Wadsworth–Emmons reaction with a variety of aldehydes using 1.5 equiv of
Received 28 March 2010
Revised 10 April 2010
Accepted 19 April 2010
Available online 22 April 2010
DBU gave E-
DBU was recovered.
a,b-unsaturated esters and ketones in high yields. The E-selectivity was high and the used
Ó 2010 Elsevier Ltd. All rights reserved.
The Horner–Wadsworth–Emmons modification of the Wittig
reaction is a widely used method for the preparation of ,b-unsat-
ceeded rapidly without silica gel. Furthermore, the reaction of 1
with a variety of aldehydes proceeded in the absence of silica gel
a
urated esters.1 The phosphonate anions are strongly nucleophilic
and react readily with carbonyl compounds under mild conditions
to form olefins in good yields. Because of environmental concerns,
safety consideration, reduction of the costs, and simplicity of the
process, the solvent-free reaction has drawn great attention in re-
cent years.2 Furthermore, an increased reactivity is expected due to
the intimacy of the reagents. A limited number of reports have ap-
peared on the solvent-free Wittig olefination of phosphorus ylides
with carbonyl compounds.3 In these reactions, a mixture of car-
bonyl compounds and phosphorus ylides or phosphonium salts
with a base was milled in a dry mortar or heated under microwave
irradiation. As far as we know, only two reports described solvent-
free Horner–Wadsworth–Emmons (HWE) reactions.4 One is the so-
to give E-a,b-unsaturated esters highly selectively using DBU.
Herein, we would like to report a solvent-free HWE reaction by just
using phosphonate reagents, aldehydes, and DBU or tetramethyl-
guanidine (TMG) (Scheme 1).
The solvent-free HWE reaction of 1 with benzaldehyde was car-
ried out using several amines. As shown in Table 1, DBU and TMG6
were found to be the most effective and the reaction gave E-4a in
96% and 90% yields, respectively, and 99:1 E-selectivity (entries 1
and 2). Trialkylamines, Et3N, Bu3N, and i-Pr2NEt, were much less
effective (entries 3–5).
We examined the solvent-free HWE reaction of 1 with a variety
of aldehydes using DBU. The results are summarized in Table 2.7,9
The reaction with benzaldehyde using 1.1 equiv of DBU gave E-4a
in 92% yield after 1 h, and the reaction proceeded within 0.5 h
using 1.5 equiv of DBU to give 96% yield (entries 1 and 2). The reac-
tion of 1 with p-chloro- and p-methoxybenzaldehyde, furfural, and
4-(1H-imidazo-l-yl)benzaldehyde using 1.5 equiv of DBU also gave
E-olefins in 95–98% yields with 98:2–99:1 E-selectivity (entries 3–
6). The reaction with E-cinnamaldehyde gave 4f in 86% yield with
slightly lower 96:4 selectivity. The reaction with n-octanal gave 4g
in 85% yield with 98:2 selectivity. TMG gave a slightly higher 87%
yield (entry 9). For the most of the reaction described in Table 2,
TMG can replace DBU as a base. Generally, slightly lower yields
were obtained except for the reaction with n-octanal. We also per-
formed the reaction in THF (0.5 mol/L), which gave much lower
lid phase reaction by milling a highly p-conjugated solid aldehyde
with p-Ar-benzylphosphonates using t-BuOK4a and the other is the
silica gel-catalyzed reaction using 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as a base reported by Inanaga and co-workers.4b In the
latter, the E-a,b-unsaturated esters were obtained with high selec-
tivity when a mixture of triethyl phosphonoacetate 1, aldehyde,
and silica gel-dispersed DBU was stirred. During the course of
our study on the Z-selective HWE reagents, ethyl (diarylphospho-
no)acetates 2,5 we were interested in their solvent-free HWE reac-
tion. When we applied their procedure to our HWE reagent
(PhO)2P(O)CH2CO2Et 2a, that is, a mixture of 2a, PhCHO, and DBU
(1:1:1) was stirred with silica gel (0.6 g/mmol) for 10 h, ethyl cin-
namate was obtained in 70% yield. Disappointingly, the E-isomer
was mainly obtained with 71:29 selectivity. The moderate yield
seemed to be mainly due to the inefficient mixing because of the
troublesome cases using the heterogenous silica gel. When the
reaction of 2a with PhCHO using DBU was performed in the ab-
sence of silica gel, the reaction smoothly proceeded to give ethyl
cinnamate in 97% yield within 30 min. Although we could not get
the Z-isomer selectively, we found that the HWE reaction pro-
64% yield after 4 h (entry 10). The reaction of
a-branched alde-
hydes, cyclohexancarboxaldehyde, and 2-ethylhexanal also gave
E-olefins in higher 99:1 selectivity in 90–92% yields (entries 11
and 12). Although the reaction of bulkier pivalaldehyde proceeded
slowly, E-4j was obtained in 91% yield with >99:1 selectivity
DBU
CO2Et
(EtO)2P(O)CH2CO2Et + RCHO
no solvent
1
3
R
E-4
* Corresponding author. Tel./fax: +81 58 293 2674.
E-mail address: ando@gifu-u.ac.jp (K. Ando).
(o-R'C6H4O)2P(O)CH2CO2Et
2 R'=H, Cl, Me, i-Pr
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.072
Scheme 1.

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3298
K. Ando, K. Yamada / Tetrahedron Letters 51 (2010) 3297–3299
Table 1
The solvent-free HWE reactions of the a-Me-substituted phos-
Effect of a base on the solvent-free HWE reaction of 1 with benzaldehydea
phonate reagent 6 with aldehydes were also performed using
1.5 equiv of DBU (Table 3). The reaction of 6 with benzaldehyde
proceeded smoothly at room temperature to give E-7a in 96% yield
with 87:13 selectivity (entry 1). Change of the reaction tempera-
ture from room temperature to 120 °C has almost no effect on
the stereochemical outcomes (entries 1–3). The reaction of 6 with
n-octanal proceeded slowly at room temperature to give E-7b in
73% yield after 24 h with 67:33 selectivity together with the recov-
ered 6 (22%) (entry 4). When the reaction was performed at 70 °C,
7b was obtained in 77% yield with 75:25 E-selectivity together
with the recovered 6 (17%). Furthermore, 92:8 selectivity was ob-
tained at 120 °C in 31% yield (entry 6). Although the E-selectivity of
the reaction with n-octanal increased at higher temperature, the
reaction was not much accelerated and slow decomposition of 6
and/or 7b occurred at 120 °C. When 7b (E/Z = 17:83)12 was heated
at 70 °C for 6 h, neither the isomerization nor the decomposition
was observed. However, the isomerization did occur in the pres-
ence of DBU at 70 °C to give E/Z = 50:50 and 60:40 mixture after
6 h and 9 h later, respectively. Thus slow isomerization occurred
at 70 °C, but noticeable decomposition was not detected. At higher
temperature, the volatile aldehyde evaporated and stuck to the
upper wall of the reaction flask, therefore the reaction did not pro-
CO2Et
E-4a
base
RT
no solvent
(EtO)2P(O)CH2CO2Et
+ PhCHO
Ph
1
3a
Entry
Base (equiv)
Time (h)
Yield%
E:Z
1
2
3
4
5
DBU (1.5)
0.5
2
30
32
24
96
90
5
10
15
99:1
99:1
99:1
>99:1
97:3
TMG (1.5)
Et3N (1.5)
Bu3N (1.5)
i-Pr2NEt (1.5)
Table 2
The solvent-free HWE reaction of 1 with various aldehydes using DBUa
DBU
(1.5 equiv)
CO2Et
(EtO) P(O)CH CO Et
+
RCHO
2
2
2
RT
no solvent
R
1
3
E-4
Entry
R
Time (h)
Product
Yield%
E:Z
1
2
3
4
5
6
7
8
Ph
Ph
p-ClC6H4
p-MeOC6H4
Furfural
1
0.5
2
2
3
3
3
4
4
4
3
7
24
3
4a
4a
4b
4c
4d
4e
4f
4g
4g
4g
4h
4i
92
96
98
95
97
98
86
85
87
64
90
92
91
91
99:1
99:1
98:2
98:2
98:2
99:1
96:4
98:2
97:3
98:2
99:1
99:1
>99:1
97:3
ceed well. The reaction of 6 with a-branched aldehyde, cyclohex-
ancarboxaldehyde also proceeded slowly at room temperature to
give E-7c in 64% yield with 73:27 selectivity after 4 days. Although
the reactions with aliphatic aldehydes were slow, the present pro-
tocol can be applied for the synthesis of trisubstituted olefins espe-
cially from aromatic aldehydes.
The solvent-free HWE reaction using DBU was also applied for
the ethyl ketone-type reagent 8.13 The results are summarized in
Table 4. The reaction of 8 with benzaldehyde using 1.5 equiv of
DBU gave E-9a in 91% yield with 99:1 selectivity. The reaction with
n-octanal is also highly selective and gave E-9b in 78% yield with
p-Imid-C6H4
E-PhCH@CH
n-C7H15
n-C7H15
n-C7H15
c-C6H11
2-EtPentyl
t-Bu
9b
10c
11
12
13
14
4j
4k
BnOCHMe
a
>99:1 selectivity. The reaction with
hexanal gave E-9c in 89% yield with >99:1 selectivity. Thus the syn-
thesis of E- ,b-unsaturated ketones was performed using solvent-
a-branched aldehyde, 2-ethyl-
1.0 mmol of 1 and 1.1 mmol of 3 were used except for entry 1, where 1.0 mmol
of 1, 1.0 mmol of 3, and 1.1 mmol of DBU were used.
b
TMG (1.5 equiv) was used instead of DBU.
The reaction was performed in THF (0.5 mol/L).
a
c
free condition very efficiently.
O
(entry 13). The reaction of 2-benzyloxypropanal gave E-4k in 91%
yield with 97:3 selectivity. The same reaction in DME using BuLi
as a base gave E/Z = 90:10 selectivity.5b The E-selectivity of the
1
CO2Et
no solvent
5
HWE reaction with aldehydes having
a-oxygen functional group
DBU (3 equiv), RT, 45 h
TMG (1.5 equiv), RT, 75 h
20% yield
43% yield
is generally not high and the HWE reaction with those aldehydes
occasionally gave Z-olefins selectively.10 These solvent-free HWE
reactions gave E-a,b-unsaturated esters just by stirring 1, alde-
Scheme 2.
hyde, and DBU, and almost pure products were obtained by aque-
ous work-up using a small quantity of organic solvent or direct
flash chromatography after the reaction was completed. In addi-
tion, the E-selectivity is very high. Although 1.1 equiv of aldehydes
was used for most of the reactions in this study, excess quantity of
aldehydes was not needed. Actually, the main impurities after the
work-up are the excess amount of aldehydes and trace amount of
phosphonate reagent 1.
The recovery of the used DBU was next examined. The reaction
of 1, benzaldehyde, and DBU (1:1:1.5) was performed in a 10 mmol
scale and the mixture was stirred for 3 h and then E-4a was iso-
lated by flash chromatography (E/Z = 99:1, 93% yield). The eluate
with methanol was treated with 8 mol/L NaOH to give the recov-
ered DBU in 90% yield.11
Table 3
The solvent-free HWE reaction of the
DBU
a
-Me reagent 6 with various aldehydes using
DBU
(1.5 equiv)
CO2Et
Me
(
i
-PrO)2P(O)CHMeCO2Et
+
RCHO
no solvent
R
6
3
E
-7
Entry
R
Conditionsa
Yield%b
E:Z
1
2
3
4
5
6
7
Ph
Ph
Ph
RT, 3 h
7a
7a
7a
7b
7b
7b
7c
96
92
99
73(22)
77(17)
31(38)
64(34)
87:13
70 °C, 2 h
120 °C, 2 h
RT, 24 h
70 °C, 11 h
120 °C, 6 h
RT, 4 d
87:13
87:13
67:33
75:25
92:8
n-C7H15
n-C7H15
n-C7H15
c-C6H11
We further tried to apply this solvent-free HWE reaction to ke-
tones. Unfortunately, ketones reacted very slowly under the iden-
tical mild conditions with 1. For example, the reaction of 1 with
cyclohexanone gave 5 in 20% yield after 45 h using DBU and in
43% yield after 75 h using TMG (Scheme 2).
73:27
a
0.5 mmol of 6 and 0.55 mmol of 3 were used.
The number in parentheses is the recovered yield of 6 (%).
b

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K. Ando, K. Yamada / Tetrahedron Letters 51 (2010) 3297–3299
3299
Table 4
3. (a) Xu, C.; Chen, G.; Fu, C.; Huang, X. Synth. Commun. 1995, 25, 2229–2233; (b)
Spinella, A.; Fortunati, T.; Soriente, A. Synlett 1997, 93–94; (c) Liu, W.; Xu, Q.;
Ma, Y.; Liang, Y.; Dong, N.; Guan, D. J. Organomet. Chem. 2001, 625, 128–131; (d)
Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem. Soc. 2002,
124, 6244–6245; (e) Thiemann, T.; Watanabe, M.; Tanaka, Y.; Mataka, S. New. J.
Chem. 2004, 28, 578–584.
4. (a) Yang, J.; Tao, X.; Yuan, C. X.; Yan, Y. X.; Wang, L.; Liu, Z.; Ren, Y.; Jiang, M. H.
J. Am. Chem. Soc. 2005, 127, 3278–3279; (b) Jin, Y. Z.; Yasuda, N.; Inanaga, J.
Green Chem. 2002, 4, 498–500.
The solvent-free HWE reaction of the ketone reagent 8 with various aldehydes using
DBUa
Et
DBU
O
(1.5 equiv)
(MeO) P(O)CH COEt
+
RCHO
3
2
2
RT
no solvent
R
8
E-9
5. (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105–4108; (b) Ando, K. J. Org. Chem.
1997, 62, 1934–1939; (c) Ando, K. J. Org. Chem. 1998, 63, 8411–8416; (d) Ando,
K. J. Org. Chem. 1999, 64, 8406–8408; (e) Ando, K.; Oishi, T.; Hirama, M.; Ohno,
H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745–4749; (f) Ando, K. J. Synth. Org. Chem.
Jpn. 2000, 58, 869–876; (g) Ando, K.; Narumiya, K.; Takada, H.; Teruya, T. Org.
Lett. 2010, 12, 1460–1463.
Entry
R
Time (h)
Product
Yield%
E:Z
1
2
3
Ph
n-C7H15
2-EtPentyl
3
6
8
9a
9b
9c
91
78
89
99:1
>99:1
>99:1
6. The use of TMG as a base for the HWE reaction in THF at reflux for 24 h was
reported: Simoni, D.; Rossi, M.; Rondanin, R.; Mazzali, A.; Baruchello, R.;
Malagutti, C.; Roberti, M.; Invidiata, F. P. Org. Lett. 2000, 2, 3765–3768.
7. The E:Z ratios were determined by integration of the vinyl proton signals in
400 MHz 1H NMR spectra of the crude reaction mixture. All the HWE products
were known compounds. 1H NMR spectra are identical to the reported values:
both E- and Z-4a, 4g, 4h, 4i, 4k,5b E-4b, both E- and Z-4c, 4f, and 5,8a E-4d,8b
both E- and Z-4j,8c both E- and Z-7a, 7b, 7c,5c both E- and Z-8a,8d E-8b,8e Z-4b
and Z-4d.8f
8. (a) Miura, K.; Ebine, M.; Ootsuka, K.; Ichikawa, J.; Hosomi, A. Chem. Lett. 2009,
38, 832–833; (b) Cristau, H. J.; Taillefer, M. Tetrahedron 1998, 54, 1507–1522;
(c) Miura, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1993, 66, 2356–2364;
(d) Coveney, D. J.; Patel, V. F.; Pattenden, G.; Thompson, D. M. J. Chem. Soc.,
Perkin Trans. 1 1990, 2721–2728; (e) Gandon, V.; Bertus, P.; Szymoniak, J. Eur. J.
Org. Chem. 2000, 3713–3719; (f) Ando, K.; Suzuki, Y. Tetrahedron Lett. 2010, 51,
2323–2325.
9. A typical procedure of the solvent-free HWE reaction: (entry 12 in Table 2): To
a mixture of 1 (0.224 g, 1.0 mmol) and 2-ethyl hexanal (0.172 mL, 1.1 mmol)
was added DBU (0.223 mL, 1.5 mmol), and the resulting mixture was stirred for
7 h at room temperature under Ar atmosphere. The reaction was quenched
with water (5 mL) and the reaction mixture was extracted with AcOEt (5 mL).
The extract was washed with brine, dried (MgSO4), and concentrated to give 4i
in >90% purity. The product was isolated by flash chromatography (hexane/
AcOEt = 30:1) as colorless oil (0.183 g, 92% yield).
a
0.5 mmol of 8 and 0.55 mmol of 3 were used.
In summary, we showed that a solvent-free HWE reaction of 1
with a variety of aldehydes can be performed by just using
1.5 equiv of DBU as a base to give the E-olefins in high yields with
96:4 to >99:1 selectivity. The reaction of the ethyl ketone-type re-
agent 8 with aldehydes is also highly E selective to give a,b-unsat-
urated ketones in high yields. Furthermore, the used DBU can be
recovered easily in a high yield. This method also can be applied
to the synthesis of trisubstituted olefins especially from aromatic
aldehydes. This method is simple, environmentally friendly, and
safe, and it does not require any expensive catalysts or bases.
The additional advantages of workup simplicity and high E-selec-
tivity make this methodology a serious candidate for not only lab-
oratory use but also widespread industrial applications.
Acknowledgments
10. (a) Trost, B. M.; Mignani, S. M.; Nanninga, T. N. J. Am. Chem. Soc. 1988, 110,
1602–1608; (b) Bowden, M. C.; Pattenden, G. Tetrahedron Lett. 1988, 29, 711–
714.
We thank Mr. Yusaku Suzuki for his contribution to this work in
the early stage. This work was supported by Grants-in-Aid for Sci-
entific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
11. Recovery of DBU: After a mixture of 1 (2.242 g, 10.0 mmol), benzaldehyde
(1.01 mL, 10.0 mmol), and DBU (2.30 mL, 15.0 mmol) was stirred for 3 h, 4a
was isolated by flash chromatography (silica gel 10 g) as a colorless oil (E/
Z = 99:1, 93% yield). The eluate with MeOH was treated with 8 mol/L NaOH
(2 mL) and extracted with CH2Cl2 (3 mL Â 2). The organic phase was dried
(MgSO4) and concentrated to give the recovered DBU in 90% yield.
12. Compound 7b (E/Z = 17:83) was prepared from (PhO)2P(O)CHMeCO2Et.5c
13. Coppola, G. M. Synthesis 1988, 81–84.
References and notes
1. For a review: Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
2. (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–1074; (b) Martins, M. A. P.;
Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem. Rev. 2009, 109, 4140–
4182.