K. Ando et al. / Tetrahedron Letters 50 (2009) 5689–5691
5691
Table 3
formable to ketones and aldehydes with ease. In fact, cis-
unsaturated N-methoxy-N-methylamides were efficiently trans-
a,b-
The HWE reaction of 7 with aldehydes
formed to cis-a,b-unsaturated ketones by using organocerium re-
agents.5b Since it is easy to make the HWE reagents containing
other amide moieties, this method should give a variety of cis-
t-Bu
O
1) base, THF
2) RCHO
Me
Me
O
P(O)CH2C-N
R
C-N
O
a,b-unsaturated amides with high selectivity. We have already
2
OMe
OMe
7
9
made both the dimethylamide reagent and the reagent bearing a
methyl glycinate. Both can serve as reagents for the synthesis of
bioactive natural products. The results will be reported in the near
future.
Entry
RCHO
Base
Temperature
Yield (%)
cis:trans
1
2
3
4
5
6
7
8
9
PhCHO
PhCHO
t-BuOK
t-BuOKb
t-BuOK
t-BuOK
t-BuONa
t-BuOK
t-BuONa
t-BuOK
t-BuONa
t-BuOK
t-BuONa
t-BuOKb
ꢀ78 °C, 4 ha
ꢀ78 °C, 4 ha
ꢀ78 °C, 2 h
ꢀ78 to 0 °C
ꢀ78 to 0 °C
ꢀ78 to 0 °C
ꢀ78 to 0 °C
ꢀ78 to 0 °C
ꢀ78 to 0 °C
ꢀ40 to 25 °C
ꢀ78 to 0 °C
ꢀ78 to 0 °C
94
97
95
92
95
95
91
96
96:4
98:2
97:3
90:10
92:8
89:119
91:9
94:6
93:7
95:5
92:8
89:11
p-ClPhCHO
n-Octanal
n-Octanal
c-HexylCHO
c-HexylCHO
2-Et-hexanal
2-Et-hexanal
t-BuCHO
Acknowledgment
This work was supported by Grants-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
89(11)c
91
10
11
12
t-BuCHO
2E-Hexenal
86
References and notes
75(16)c
1. (a) Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Czaicki, N. L.; Koide, K. J. Am.
Chem. Soc. 2007, 129, 2648–2659; (b) Petri, A. F.; Sasse, F.; Maier, M. E. Eur. J.
Org. Chem. 2005, 1865–1875; (c) Chakraborty, T. K.; Laxman, P. Tetrahedron Lett.
2003, 44, 4989–4992.
a
After the specified time, the reaction mixture was gradually warmed to 0 °C.
18-crown-6 (1 equiv).
The number in parentheses is the recovered yield of 7 (%).
b
c
2. (a) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D.
J. J. Am. Chem. Soc. 1998, 120, 6488–6499; (b) Davis, F. A.; Qi, H.; Sundarababu,
G. Tetrahedron 2000, 56, 5303–5310; (c) Carey, J. S. J. Org. Chem. 2001, 66, 2526–
2529.
from bromoacetyl bromide and N,O-dimethylhydroxylamine
hydrochloride in the presence of triethylamine in 81% yield. The
o-t-BuPh reagent 7 was prepared by heating (2-t-BuPhO)2POEt
and 8 in 56% yield.14
The results of the HWE reaction of 7 are summarized in Table
3.15 The o-t-BuPh reagent 7 was treated with t-BuOK at ꢀ78 °C
for 15 min and reacted with benzaldehyde. Since a trace of the re-
agent 7 was left after 4 h, the mixture was allowed to warm up to
3. Ando, K. Synlett 2001, 1272–1274.
4. Fortin, S.; Dupont, F.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5437–5439.
5. (a) Kojima, S.; Hidaka, T.; Ohba, Y.; Ohkata, K. Phosphorus, Sulfur and Silicon
2002, 177, 729–732; (b) Kojima, S.; Hidaka, T.; Yamakawa, A. Chem. Lett. 2005,
34, 470–471.
6. Peterson reaction: Kojima, S.; Inai, H.; Hidaka, T.; Ohkata, K. Chem. Commun.
2000, 1795–1796.
7. (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.
0 °C. The a,b-unsaturated amide 9 was obtained with 96% cis selec-
tivity in 94% yield (entry 1). Adding 1 equiv of 18-crown-6 im-
proved the selectivity to 98% (entry 2). p-Chlorobenzaldehyde is
more reactive than benzaldehyde and the reaction took only two
hours at ꢀ78 °C to complete. 97% cis selectivity was obtained in
95% yield (entry 3). For the aliphatic aldehydes, the reaction also
hardly proceeded at ꢀ78 °C, thus the reaction mixture was gradu-
ally warmed to 0 °C over about 2 h after the addition of the alde-
hydes. The reaction with n-octanal gave 9 in 90% selectivity
using t-BuOK. This selectivity was improved to 92% by using t-BuO-
Na as in the case of the morpholine amide reagent 4d (entries 4
and 5). Also, t-BuONa gave a higher selectivity for the reaction with
cyclohexanecarboxaldehyde (entries 6 and 7). However, t-BuOK
gave higher 95 and 94% selectivity for the reactions with 2-ethyl-
hexanal and pivalaldehyde (entries 8–11). The reaction with 2-
trans-hexenal also gave 9 selectively (entry 12). These results can
be favorably compared with the results of the phenyl reagent 2c.3
The methods described here provide simple routes to a wide
8. Touchard, F. P.; Capelle, N.; Mercier, M. Adv. Synth. Catal. 2005, 347, 707–711.
9. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
10. (a) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc.
1990, 112, 7001–7031; (b) Nuzillard, J.; Boumendjel, A.; Massiot, G. Tetrahedron
Lett. 1989, 30, 3779–3780; (c) Netz, D. F.; Seidel, J. L. Tetrahedron Lett. 1992, 33,
1957–1958.
11. (a) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett 1997, 1414–1415;
(b) Kurosu, M.; Kishi, Y. Tetrahedron Lett. 1998, 39, 4793–4796.
12. All the HWE products and the reagents described in this Letter were
characterized by 400 MHz 1H NMR spectra and mass spectroscopy. The
cis:trans ratios were determined by integration of the vinyl proton signals.
13. Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 4339–4342.
14. Preparation of 7: A mixture of (o-t-BuPhO)2POEt (6.890 g, 18.4 mmol) and 8
(3.351 g, 18.4 mmol) was heated at 150 °C under Ar atmosphere for 8 h.
Column chromatography (silica gel/33% AcOEt in hexane) gave 7 (4.573 g, 56%)
as a colorless powder (mp 62.7–63.5 °C). The reagents 4b–d were prepared in
the same way.
15. A typical procedure of the HWE reaction of 7 with p-ClPhCHO (entry 3 in Table
3):
A solution of 7 (0.30 mmol) in THF (6 mL) was treated with t-BuOK
(0.39 mmol) at ꢀ78 °C for 15 min. Then, p-ClPhCHO (0.32 mmol) was added.
After 2 h, the reaction was quenched with aqueous NH4Cl, extracted with
AcOEt, washed with brine, dried (MgSO4), and concentrated. The residue was
purified by flash chromatography (50% AcOEt in hexane) to give amide 9
(0.0729 g, 96%) as a colorless oil.
range of cis-a,b-unsaturated morpholine and Weinreb amides in
almost quantitative yields. These amides are believed to be trans-