Synthesis of cis-3,4-diaryl α-methylene-γ-butyrolactams via sonochemical Barbier-type reaction

Article abstract of DOI:10.1016/j.tetlet.2010.05.057

A series of cis-3,4-diaryl a-methylene-c-butyrolactams were synthesized by the addition reaction of 3-phenylallyl bromide with N-tosyl aldimine via sonochemical Barbier-type reaction condition and then followed by the in situ intramolecular amidation. The cis-3,4-diaryl α-methylene-β- butyrolactam was obtained as the sole regio-and stereoisomeric product when N-tosyl aldimine was used as the substrate whereas the monoaryl α-methylene-β-butyrolactam was also generated when N-phenyl aldimine was used.

Full text of DOI:10.1016/j.tetlet.2010.05.057

Tetrahedron Letters 51 (2010) 3800–3802
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Synthesis of cis-3,4-diaryl a-methylene-c-butyrolactams via sonochemical
Barbier-type reaction
*
Adam Shih-Yuan Lee , Yu-Ting Chang
Department of Chemistry, Tamkang University, Taipei 251, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of cis-3,4-diaryl
a-methylene-c-butyrolactams were synthesized by the addition reaction of 3-
Received 24 March 2010
Revised 11 May 2010
Accepted 14 May 2010
Available online 25 May 2010
phenylallyl bromide with N-tosyl aldimine via sonochemical Barbier-type reaction condition and then
followed by the in situ intramolecular amidation. The cis-3,4-diaryl -methylene- -butyrolactam was
obtained as the sole regio- and stereoisomeric product when N-tosyl aldimine was used as the substrate
a
c
whereas the monoaryl
used.
a
-methylene-
c-butyrolactam was also generated when N-phenyl aldimine was
Ó 2010 Elsevier Ltd. All rights reserved.
a
-Methylene-
from a biological point of view because they exhibit less cytotoxic
activity than the corresponding -methylene- -butyrolactones,
c
-butyrolactams1–3 are interesting compounds
lyl bromide to N-tosyl aldimine via sonochemical Barbier-type
reaction condition.26–28
The first feasibility of our approach was first tested by adding a
mixture of zinc (5.0 mmol) and 1,2-diiodoethane (1.0 mmol) to a
THF solution of 3-phenylallyl bromide (1.2 mmol) and N-benzyl
aldimine (1.0 mmol) and then the reaction mixture was sonicated
a
c
making them display a variety of biological activities such as anti-
bacterial,4 anticancer,5 antivirus,6 kinase regulator7, and inhibitor
of proteasome.8,9 Compared to
a-methylene-c
-buryrolactones,10
the preparation of the corresponding nitrogenated derivatives is
the subject of a few reports in the literature. Allylation (Zn,11–17
In18) and metal-promoted cyclization (Pd,19 Rh,20 B,21) as well as
for 3 h (Table 1). The expected product 3,4-diphenyl-
a
-methylene-
-butyrolactam was only obtained with 4% and monoaryl
-butyrolactam ( -adduct) was produced as the major product
-methylene- -butyro-
-butyrolactam was determined and com-
c
c
a
anionic22–24 methodologies have been used to prepare
a
-methy-
(15%). The stereochemistry of 3,4-diaryl-
a
c
lene-c-butyrolactams: one disadvantage of many of these
lactam and monoaryl
c
procedures is that together with the expected compound the cor-
responding endocyclic unsaturated lactam is also generated,
resulting from an undesired isomerization. Among them, the
nucleophilic addition reaction of allylmetal with aldimine and then
followed by intramolecular cyclization is the most direct method
pared by 1H-NMR spectra of the reported compounds.11,22,24 The
choice of N-substituent for aldimine may exhibit impact regiose-
lectivity under allylation reaction. Thus, we investigated other aldi-
mines such as N-p-methoxy and N-tosyl aldimines under this
Barbier-type reaction conditions. The monoaryl
product was not observed when N-tosyl aldimine was introduced
and the yield of 3,4-diphenyl- -methylene- -butyrolactam in-
c-butyrolactam
for the synthesis of 3,4-disubstituted
a-methylene-c-butyrolac-
tam. However, 3,4-diaryl -methylene-
a
c-butyrolactams cannot
a
c
be produced easily by these methodologies due to the conjugation
stability of 3-phenylallyl bromide in the allylation reaction25
(Scheme 1). The addition of 3-substituted allylmetal to aldimine
followed by intramolecular amidation may produce two types of
creased dramatically to 72% (Table 1, entry 4). It is also worthy
to know that only cis-stereoisomer was observed by comparison
with the authentic compound. Previous studies showed that
a-methylene-c-lactams were produced by the allylation addition
a
-methylene-
and
-adduct (diaryl, SN20 pathway). Our laboratory previously
developed a simple and an efficient method for the synthesis of
3,4-disubstituted -methylene-
-butyrolactone10 and we further
employed this method for the preparation of -methylene-
butyrolactam by the reaction of allylic bromide with aldimine.
Herewith, we wish to report the synthesis of cis-3,4-diaryl-
methylene- -butyrolactam by the addition reaction of 3-phenylal-
c
-butyrolactams,
a
-adduct (monoaryl, SN2 pathway)
and then followed by amidation reaction which was afforded by
introduction of a coupling reagent such as DCC (dicyclohexylcarbo-
diimide).18 Our experimental results showed that regioselective
and stereoselective allylation and consequently intramolecular
amidation were all completed under the reaction condition with-
out further introducing amidating agent. Our previous investiga-
tions showed that the reaction mixture of Zn and ICH2CH2I in
THF became acidic solution (pH ꢀ2) under sonication which may
promote the following amidation reaction.10,29
c
a
c
a
c-
a
-
c
To understand and expand the scope for the synthesis of 3,4-
diaryl a-methylene-c-butyrolactams by this Barbier-type reaction,
* Corresponding author. Tel.: +886 2 26215656/2543; fax: +886 2 26223830.
E-mail address: adamlee@mail.tku.edu.tw (A.S.-Y. Lee).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.057

A.S.-Y. Lee, Y.-T. Chang / Tetrahedron Letters 51 (2010) 3800–3802
3801
a series of N-tosyl aldimines was investigated and the results are
shown in Table 2. The 3,4-diaryl -methylene- -butyrolactams
were obtained in all investigated cases and no -adduct (monoaryl
(20 mL), dried with MgSO4, filtered, and then the organic solvent
was removed under reduced pressure. Further purification was
achieved on a flash chromatograph with silica gel and ethyl ace-
tate/hexane as eluant.
a
c
a
product) was observed under the reaction condition. The cis-dia-
stereoselectivity is achieved and the stereochemistry was charac-
terized by spectral analysis.
The experimental results showed that the formation yields of
cis-3,4-diaryl
a-methylene-
c-butyrolactams are moderate to high.
A representative procedure30 for the synthesis of a cis-3,4-dia-
All the cis-3,4-diaryl
a-methylene-c-butyrolactams were charac-
ryl-
a
-methylene-
c
-butyrolactam is as follows: a solution of N-to-
terized by NMR and HRMS spectral analysis. The cis-diastereose-
syl aldimine (1.0 mmol) and 3-phenylallyl bromide (1.2 mmol) in
anhydrous THF (1.0 mL) was added by cannula to a reaction mix-
ture of zinc (5.0 mmol) and 1,2-diiodoethane31 (1.0 mmol) in anhy-
drous THF (5 mL). The reaction mixture was sonicated in a
commercial ultrasonic cleaning bath32 (Elma-T490DH, 50 kHz)
for 3 h at around 43 °C. After the sonication, an aqueous 5% NH4Cl
(8.0 mL) was added and the filtrate was extracted with ether
(20 mL ꢁ 3). The combined organic layer was washed with brine
lectivity is achieved in all investigated cases.
As a conclusion, we demonstrate here an efficient method for
the synthesis of cis-3,4-diaryl-
starting from easily preparable aldimines via sonochemical Barbi-
er-type reaction condition. The 3,4-diaryl- -methylene- -butyro-
a-methylene-c-butyrolactam
a
c
lactams were successfully synthesized by the regioselective
allylation of 3-phenylallyl bromide with N-tosyl aldimine and only
cis-stereoisomer was obtained under the reaction condition.
O
P
M
P
N
CO2Me
SN2'
N
P
N
CO2Me
Ar
Ph
Ar
Ph
+
Ph
Ar
H
Metal
γ -Adduct
Br
O
SN2
Dimerization
Ph
P
M
P
N
CO2Me
Ph
N
Ph
CO2Me
Ph
Ar
Ar
α-Adduct
CO2Me
Scheme 1. Allylation reaction of 3-phenalallyl bromide to lime.
Table 1
Optimization of imine under Barbier-type reaction
O
Zn / ICH2CH2I (5/1),
THF ,
, 3h ;
P
H
CO2Me
Br
Ts
Ar
N
Ph
+
N
Ar
sat'd. NH4Cl
1.2eq.
1.0eq.
Ph
Entry
1
Imine
c
-Lactam
Yield (%)
4 + 15
Bn
O
O
N
N
Bn
Bn
N
N
+
H
Ph
Ph
O
PMP
H
PMP
N
2
3
4
35
32 + 2
72
Ph
O
O
PMP
N
PMP
PMP
N
N
+
O
O
O
O
O
O
Ph
H
Ph
Ts
H
O
N
Ts
N
Ph
PMP = p-methoxyphenyl, Bn = benzyl, Ts = tosyl.

3802
A.S.-Y. Lee, Y.-T. Chang / Tetrahedron Letters 51 (2010) 3800–3802
Table 2
Synthesis of diaryl
Acknowledgments
a
-methylene-
c
-butyrolactams
-Lactam
Entry
Imine
c
Yielda (%)
We thank the National Science Council of Taiwan (NSC 95-2113-
M-032-003-MY3) and Tamkang University for the financial support.
Ts
H
O
N
Ts
N
Supplementary data
1
72
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.057.
Ph
N
Ts
H
O
N
References and notes
Ts
O
O
2
73
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Ph
O
N
Ts
H
N
N
Ts
N
N
6
7
81
66
O
Ph
O
Ts
H
Ts
S
S
Ph
Ts
O
N
Ts
N
H
8
9
52
41
Ph
O
Ts
H
N
Ts
N
31. The ZnI2 and ethene were generated form Zn powder and 1,2-diiodoethane
under sonication.
32. The bath should be filled with water containing some 3–5% detergent. In our
laboratory, we used Decon 90 which permits much more even cavitation in
bath water.
N
Ph
N
Ts
Ts
a
The yields were determined after chromatography purification.