Highly E-selective synthesis of α,β-unsaturated amides from N-2- methoxyphenyl aldimines via lithium ynolates

Article abstract of DOI:10.1016/S0040-4039(00)00986-2

Lithium ynolates reacted with N-2-methoxyphenyl (OMP) aldimines to afford α,β-unsaturated amides in excellent E-selectivity via a retro- Mannich reaction of the 2:1 adducts (β-lactams), followed by cleavage of the β-lactam enolates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00986-2

Tetrahedron Letters 41 (2000) 5947±5950
Highly E-selective synthesis of a,b-unsaturated amides from
N-2-methoxyphenyl aldimines via lithium ynolates
Mitsuru Shindo,* Soichiro Oya, Ryoko Murakami, Yusuke Sato and Kozo Shishido
Institute for Medicinal Resources, University of Tokushima, Sho-machi 1, Tokushima 770-8505, Japan
Received 17 May 2000; revised 7 June 2000; accepted 9 June 2000
Abstract
Lithium ynolates reacted with N-2-methoxyphenyl (OMP) aldimines to a€ord a,b-unsaturated amides in
excellent E-selectivity via a retro-Mannich reaction of the 2:1 adducts (b-lactams), followed by cleavage of
the b-lactam enolates. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: ynolates; imines; ole®nation; amides.
Kowalski1 and our group2 have reported that ynolate anions 13 react with aldehydes to give
a,b-unsaturated carboxylates at room temperature with high E-selectivity via ring opening of the
intermediate b-lactone enolates 2 (Scheme 1). Similarly, aldimines would be expected to react
with ynolate anions to a€ord a,b-unsaturated amides.4 Murai and co-workers reported one
example of a b-lactam enolate 4 generated by the reaction of the trimethylsilyl-substituted lithium
ynolate 1 (R=TMS) with the N-tosyl imine 3 to give the a,b-unsaturated amide 5 (Scheme 2),5
but there have been no reports of alkyl-substituted ynolate reactions.
Scheme 1.
Scheme 2.
* Corresponding author. Fax: +81-88-633-7294; e-mail: shindo@ph2.tokushima-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00986-2

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In the preceding paper, we showed that unactivated aldimines having an N-2-methoxyphenyl
substituent reacted with ynolates to provide b-lactams (2:1 adducts).6 We report, herein, the reaction
of alkyl-substituted ynolates with the unactivated imines to give the desired a,b-unsaturated
amides with excellent E-selectivity via a retro-Mannich reaction of the corresponding 2:1 adducts,
followed by cleavage of the b-lactam enolates.
We ®rst attempted the reaction of butyl-substituted lithium ynolate with the N-tosyl aldimine
3. As we reported previously,7 the ynolate reacted with 3 to give the b-lactam enolate 4 (R=Bu)
at ^78ꢀC, after which the reaction mixture was warmed to room temperature. However, it gave a
complex mixture of products, in contrast to Murai's successful results (Scheme 2).5 Next, the less
electrophilic N-4-methoxyphenyl (PMP) aldimine 6, which would furnish more basic (or nucleo-
philic) b-lactam enolates, was used, since stabilization of the b-lactam enolate by the tosyl group
might inhibit the ecient ring opening.
As expected, the desired a,b-unsaturated amide 7 was generated, but in only 16% yield after 12
h at room temperature, due to the slow cycloaddition step (Scheme 3). Thus, N-2-methoxyphenyl
(OMP) aldimines, which are much better electrophiles for lithium ynolates due to chelation,6,8
were examined (Scheme 4). To a THF solution (8 ml) of the lithium ynolate 1b, generated by the
reaction of the a,a-dibromoester (1.2 mmol) and tert-BuLi (4.8 mmol),9 was added the aldimine 8
(1.0 mmol) at room temperature. TLC showed that the 2:1 adducts 9 were immediately generated
then slowly converted into other compounds. After 1 h, the a,b-unsaturated amide 12 was
obtained in 96% yield in an E:Z ratio of 94:6. This product is thought to arise from the retro-
Mannich reaction, which is the rate-determining step, followed by ring opening of the resulting
b-lactam enolate 10.
Scheme 3.
Scheme 4.
The generality of this reaction was examined as shown in Table 1. Aryl aldimines gave the
desired amides in good yields with excellent E-selectivity. It is noteworthy that, although the
retro-Mannich reaction was quite slow, even a small ynolate (R=Me) provided the amides in
excellent yields (entries 1±3), while the ole®nation of aldehydes with the same ynolate resulted in
poorer yields.2a The aldimine of pivalaldehyde, which did not react with the ynolate at ^78ꢀC,
also a€orded the desired amide with excellent E-selectivity (entry 4). In the case of entry 5, only
products of decomposition were generated, even at ^78ꢀC, followed by gradually warming to

5949
room temperature. The reactions of butyl- and cyclohexyl-substituted ynolates proceeded rapidly
to give ole®ns in good yields (entries 6±9).
Table 1
Ole®nation of N-2-methoxyphenyl imines with lithium ynolates to give a,b-unsaturated amidesa
The a,b-unsaturated amides were converted into a,b-unsaturated carboxylic acids quantitatively
by acidic hydrolysis (Scheme 5).
Scheme 5.
In conclusion, we have found that N-2-methoxyphenyl aldimines react with alkyl-substituted
ynolates at room temperature to give a,b-unsaturated amides in good yields with good E-selectivity.
Acknowledgements
This work was supported by Grants-in-Aid for Scienti®c Research on Priority Areas (No. 283,
`Innovative Synthetic Reactions') from the Ministry of Education, Science, Sports and Culture,
Government of Japan, and the Eisai Award in Synthetic Organic Chemistry, Japan.

5950
References
1. Kowalski, C. J.; Fields, K. W. J. Am. Chem. Soc. 1982, 104, 321±323.
2. (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998, 39, 4857±4860. (b) Shindo, M.; Sato, Y.; Shishido,
K., J. Org. Chem. in press.
3. For a review, see: Shindo, M. Chem. Soc. Rev. 1998, 27, 367±374.
4. A lanthanaid tri¯ate-catalyzed reaction of a silyl ynol ether with N-4-methoxyphenyl aldimines giving a,b-
unsaturated amides has been reported: Shindo, M.; Oya, S.; Sato, Y.; Shishido, K. Heterocycles 2000, 52, 545±
548. Also see: Ishitani, H.; Nagayama, S.; Kobayashi, S. J. Org. Chem. 1996, 61, 1902±1903 and references cited
therein.
5. Kai, H.; Iwamoto, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 1996, 118, 7634±7635.
6. Shindo, M.; Oya, S.; Murakami, R.; Sato, Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 5943±5946.
7. Shindo, M.; Oya, S.; Sato, Y.; Shishido, K. Heterocycles 1998, 49, 113±116.
8. (a) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762±766. (b)
Kobayashi, S.; Nagayama, S. J. Org. Chem. 1997, 62, 232±233. (c) Kobayashi, S.; Nagayama, S. J. Am. Chem.
Soc. 1997, 119, 10049±10053 and references therein.
9. (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433±4436. (b) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron 1998,
54, 2411±2422.
10. General procedure for the synthesis of amides: To a solution of 2,2-dibromoester (1.2 mmol) in THF (6 ml) was
added tert-BuLi (4.8 mmol in pentane) at ^78ꢀC. After 3 h, the mixture was stirred at 0ꢀC for 0.5 min. A solution
of imine (1.0 mmol) in THF (2 ml) was then added to the ynolate solution at room temperature. The resulting
mixture was quenched with satd NaHCO3 aq. and extracted with ethyl acetate. The organic layer was washed with
brine and dried over Na2SO4. After evaporation, the amides were isolated by SiO2 column chromatography.