Highly regio- and stereocontrolled synthesis of β-substituted α-tributylstannyl enamides

Article abstract of DOI:10.1016/j.tetlet.2006.02.141

The regio- and stereocontrolled synthesis of β-substituted α-stannyl enamides is reported starting from internal ynamides. The synthesis of new ynamides as well as bis-ynamides is also described. Finally first examples of successful cross-coupling to afford α/β-disubstituted enamides are also reported.

Full text of DOI:10.1016/j.tetlet.2006.02.141

Tetrahedron Letters 47 (2006) 3139–3143
Highly regio- and stereocontrolled synthesis of b-substituted
a-tributylstannyl enamides
David Buissonneaud and Jean-Christophe Cintrat*
CEA Saclay, DSV/DBJC, Service de Marquage Mole´culaire et de Chimie Bioorganique, F-91191 Gif Sur Yvette, France
Received 8 December 2005; revised 14 February 2006; accepted 24 February 2006
Available online 13 March 2006
Abstract—The regio- and stereocontrolled synthesis of b-substituted a-stannyl enamides is reported starting from internal ynamides.
The synthesis of new ynamides as well as bis-ynamides is also described. Finally first examples of successful cross-coupling to afford
a/b-disubstituted enamides are also reported.
Ó 2006 Elsevier Ltd. All rights reserved.
One of the main challenges in the synthesis of a,b-disub-
stituted enamides is the stereocontrol of the double
bond. Coupling of alkenes1, halogeno-alkenes2 or enol
sulfonates3 with amines usually gives excellent stereo-
control and yields but this approach is mostly limited
to specific alkenes. We have recently described the ste-
reocontrolled synthesis of a,b-stannyl and a-stannyl
b-silyl enamides.4 A stepwise coupling of these two
carbon-metal bonds should in principle yield stereo-
defined a,b-substituted enamides (Scheme 1). Unfortu-
nately, despite numerous efforts in this area, no
satisfactory results have been obtained.5
EWG
EWG
EWG
R2
N
Bu3SnH
Bu3Sn
R1
N
H
N
R2
+
R2
?
Bu3Sn
R1
R1
R1 = H
Scheme 2. Synthesis of stannylated enamides.
The first step of our approach was therefore the synthe-
sis of various 3-substituted ynamides. Coupling of
bromo-alkynes with amides following the Hsung
procedure easily affords the expected starting ynamides
(Scheme 3).6
EWG
EWG
EWG
1) R2X/"Pd"
2) R3X/"Pd"
Bu3Sn
M
N
R2
R3
N
R3
R2
N
R1
R1
R1
or
R2
R3
N
K3PO4
R2
R3
R1
N
H
+
Br
CuSO4
1,10-phenanthroline
M = SnBu3 or SiMe3
Scheme 1. Attempted couplings of bis-metallated enamides.
R1
Scheme 3. Synthesis of 3-substituted ynamides using the Hsung
protocol.
Therefore, we decided to turn our attention to a slightly
different approach in which the substituent at the b-car-
bon is introduced at a very early stage of the synthesis.
This means that we have to start from 2-substituted yn-
amides and then introduce a trialkylstannyl group at Ca
(Scheme 2). In this letter, we will describe the prepara-
tion of various a-tributylstannyl b-substituted enamides
and preliminary results of subsequent cross-coupling.
All products obtained using this procedure are displayed
in Table 1.
As reported in Table 1, numerous ynamides can be
obtained with modest to good yields. Different amides
can be engaged in such reactions including sulfonamides
(entries 1, 9, 14 and 21), oxazolidinones (entries 2–5,
10–11 and 15–18) or even imidazolidinones (entries 7,
12–13, 19–20 and 24) and pyrrolidinone (entry 8). The
bromo-alkynes used in the coupling can also range from
*
Corresponding author. Tel.: +33 (0)1 69 08 25 70; fax: +33 (0)1 69 08
79 91; e-mail: jean-christophe.cintrat@cea.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.141

3140
D. Buissonneaud, J.-C. Cintrat / Tetrahedron Letters 47 (2006) 3139–3143
Table 1. Synthesis of 3-substituted ynamides
Entry Amide
Bromo-alkyne
Product
Yield (%)
99
Ts
Bn
1
2
N-Benzyltoluenesulfonamide
Ph
Br
Ph
N
O
Oxazolidinone
62
35
O
O
Ph
Ph
N
O
3
4
5
(S)-(À)-4-Benzyl-oxazolidinone
(R)-(À)-4-Phenyl-oxazolidinone
(S)-(À)-4-Isopropyl-oxazolidinone
N
Bn
O
O
O
75
68
Ph
N
Ph
O
Ph
Ph
N
i
-Pr
O
Me
N
N
6
7
(4R,5S)-(À)-1,5-Dimethyl-4-phenylimidazolidinone
82
40
Ph
Me
O
Ph
Ph
Imidazolidinone
N
N
O
8
Pyrrolidinone
38
80
58
Ph
Bn
N
Ts
Bn
9
N-Benzyltoluenesulfonamide
Oxazolidinone
Bn
Br
N
O
10
O
O
Bn
N
O
11
(S)-(À)-4-Benzyl-oxazolidinone
33
Bn
Bn
N
Bn
O
Me
N
N
12
13
(4R,5S)-(À)-1,5-Dimethyl-4-phenylimidazolidinone
78
30
Ph
Me
O
Bn
Bn
Imidazolidinone
N
N
Ts
14
15
N-Benzyltoluenesulfonamide
n
n
-Hex
-Hex
53
65
N
n
-Hex
Br
Bn
O
Oxazolidinone
O
N

D. Buissonneaud, J.-C. Cintrat / Tetrahedron Letters 47 (2006) 3139–3143
3141
Table 1 (continued)
Entry Amide
Bromo-alkyne
Product
Yield (%)
O
16
(S)-(À)-4-Benzyl-oxazolidinone
46
O
n
-Hex
N
Bn
O
O
O
17
18
19
20
(R)-(À)-4-Phenyl-oxazolidinone
(S)-(À)-4-Isopropyl-oxazolidinone
(4R,5S)-(À)-1,5-Dimethyl-4-phenylimidazolidinone
Imidazolidinone
52
40
55
26
n
n
-Hex
-Hex
N
Ph
O
N
i
-Pr
O
n-Hex
Me
N
N
Ph
Me
O
n
-Hex
n-Hex
N
N
Ts
21
22
N-Benzyltoluenesulfonamide
72
59
TBDMSO(CH2)2
Br
TBDMSO(CH2)2
N
Bn
O
Oxazolidinone
O
TBDMSO(CH2)2
TBDMSO(CH2)2
N
O
O
23
24
(S)-(À)-4-Benzyl-oxazolidinone
23
85
N
Bn
O
TBDMSO(CH2)2
Me
N
N
(4R,5S)-(À)-1,5-Dimethyl-4-phenylimidazolidinone
Ph
Me
aliphatic (entries 14–24) to aromatic (entries 1–8) moie-
ties including benzylic derivatives (entries 9–13). Then,
with these ynamides in hand, the next step was the synthe-
sis of the desired stannylated product. As previously de-
scribed,4 a mixture of ynamide, Bu3SnH and Pd(PPh3)4
was stirred in THF at 60 °C under nitrogen until com-
plete disappearance of the starting ynamide as checked
by TLC (usually overnight). The crude mixture was then
evaporated to dryness and the ratio of E/Z compounds
The results are summarized in Table 2.
It is worth noting that most of the previously synthe-
sized ynamides can be subjected to palladium-catalyzed
hydrostannation. This reaction usually proceeds with
fair regioselectivities. The lowest regioselectivities are
usually obtained with phenyl substituted ynamides (en-
tries 1, 9 and 13). It also appears that the acyclic sulfon-
amides give a larger amount of b-stannylated enamides
(entries 1–4) when compared to carbamates or ureas.
The best ratios were obtained with cyclic amides, in this
case an intermolecular chelation of the carbonyl oxygen
atom to the tin atom could favour the formation of the
a-isomer. We should add that, in most cases, no trans
addition product could be detected by NMR except
for the silylated protected alcohol (entries 4, 8 and 11).
Finally, a double hydrostannylation of imidazolidinones
bearing two alkyne moieties on the N1 and N3 nitrogen
atoms was successful (entries 18–19). This should pave
1
was directly assigned by H NMR (Scheme 4).
Bu3SnH
Pd(PPh3)4
EWG
R2
EWG
EWG
N
H
N
Bu3Sn
H
N
R2
R2
+
Bu3Sn
R1
THF, 60
˚
C
R1
R1
Major
Scheme 4. Hydrostannation of 3-substituted ynamides.
Minor

3142
D. Buissonneaud, J.-C. Cintrat / Tetrahedron Letters 47 (2006) 3139–3143
Table 2. Synthesis of b-substituted a-tributylstannyl enamides
Table 2 (continued)
Entry b-Substituted a-stannyl enamides Yield (%) (a/b)a
Entry b-Substituted a-stannyl enamides Yield (%) (a/b)a
Bn
O
O
Tos
N
Ph
H
1
2
53
34
60/40
80/20
N
Hex
H
14
15
16
17
18
19
65
47
60
24
51
80
>95/5
>95/5
>95/5
91/9
iso-Pr
Bu3Sn
Bu3Sn
Bn
O
N
Tos
N
Hex
H
O
Bn
H
Bu3Sn
iso-Pr
Bu3Sn
Bn
Bn
Tos
N
Bn
H
O
3
4
23
22
87/13
O
Bu3Sn
N
Ph
H
Ph
Bu3Sn
Tos
N
74/26b
OTBDMS
O
N
O
Bu3Sn
O
H
Hex
H
Ph
O
Bu3Sn
N
Ph
H
5
6
70
39
>95/5
>95/5
>95/5
O
Bu3Sn
Bu3Sn
SnBu3
H
96/4
N
N
N
N
H
O
N
O
Ph
Ph
Hex
H
O
Bu3Sn
Bu3Sn
H
SnBu3
H
91/9
O
N
O
O
Hex
Hex
Bn
H
7
8
58
39
a Assigned by 1H NMR of the crude mixture.
b About 20% of a-trans compound was also observed.
c Not determined.
Bu3Sn
O
d Traces of a-trans compound were also observed (<5%).
c
N
—
OTBDMS
Bu3Sn
O
H
the way for the synthesis of a new class of acyclic or cyc-
lic polyureas. We are currently focussing our efforts on
the synthesis of these polymers, which could have poten-
tial applications for coatings, lubricants or supramole-
cular architectures. Finally in order to check that these
enamides could be involved in cross-coupling reactions
to furnish a,b-disubstituted enamides, a mixture of
a- and b-tributylstannyl b-phenyl N-tosyl N-benzyl
ynamide was subjected to our previously described con-
ditions7 (Scheme 5). The reaction proceeded smoothly
over 72 hours to afford the expected cross-coupling
products with in each reaction 10/15% of the hydrolyzed
compound (R = H in Scheme 5). The ratio of a- and
b-isomer obtained was consistent with the isomers ratio
of the starting material.
O
O
O
N
Ph
H
9
66
47
86
88/12
>95/5
93/7d
Bn
Bu3Sn
O
N
Hex
H
10
11
Bn
Bu3Sn
O
N
Bn
OTBDMS
Bu3Sn
H
O
Me
N
Me
12
13
56
62
>95/5
66/34
N
Hex
Ts
N
Ts
N
Ph
Bu3Sn
Pd2dba3 (8 mol %)
AsPh3 (14 mol %)
H
Bn
Bn
Bu3Sn
+ RX (1.3 eq.)
R
CuCl (5 eq)
THF, rfx
O
Ph
Ph
O
N
Ph
RX = PhI 47%
RX = BnBr 58%
α/β = 60/40
iso-Pr
Bu3Sn
H
Scheme 5. Cross-coupling of a b-phenyl stannylated enamide.

D. Buissonneaud, J.-C. Cintrat / Tetrahedron Letters 47 (2006) 3139–3143
3143
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Further experiments are now in progress to expand the
scope of this reaction and our results in this field will
be reported in due course.
In summary, we report here the first synthesis of
b-substituted a-stannyl enamides. Our approach fur-
nishes the expected regioisomer with, in most cases,
complete control of the double bond stereochemistry.
Finally, first attempts of cross-coupling reaction with
one of these stannyl enamides successfully afforded the
expected product. This work should compliment the
previously described carbometallation of ynamides
where trisubstituted or b-disubstituted enamides are
obtained.8
`
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References and notes
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