Synthesis of Linear α,β-Unsaturated Amides from Isocyanates and Alkenylaluminum Reagents

Article abstract of DOI:10.1055/s-0037-1610753

A new approach has been developed for the synthesis of linear α,β-unsaturated amides by the direct coupling of isocyanates with alkenylaluminum reagents. At room temperature, the desired α,β-unsaturated amides were isolated in good to excellent yields with good functional-group tolerance in the absence of any catalyst or additive.

Full text of DOI:10.1055/s-0037-1610753

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
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B. Chen, X.-F. Wu
Letter
Synlett
Synthesis of Linear ,-Unsaturated Amides from Isocyanates and
Alkenylaluminum Reagents
Bo Chena,b
Xiao-Feng Wu*a,b
H
R2
THF
N
C
O
R2
N
R1
R1
Al(i-Bu)2
+
0 °C to RT
16 h
O
•No metal catalyst
•No ligand
•30 examples
•Up to 88% yield
a Department of Chemistry, Zhejiang Sci-Tech University,
Xiasha Campus, Hangzhou 310018, P. R. of China
b Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Albert-Einstein-Straße 29a 18059 Rostock, Germany
Xiao-feng.wu@catalysis.de
Received: 07.01.2020
Accepted after revision: 02.02.2020
Published online: 19.02.2020
droamidation of alkynes with isocyanates by using nickel
hydrides generated in situ as catalysts (Scheme 1e). The
method turns parasitic -hydride elimination into a strate-
gic advantage, rapidly affording desired acrylamides in
good yields.10 Inspired by these achievements, we become
interested in developing a new synthetic protocol for the
synthesis of linear ,-unsaturated amides from isocya-
nates.
DOI: 10.1055/s-0037-1610753; Art ID: st-2020-k0008-l
Abstract A new approach has been developed for the synthesis of lin-
ear ,-unsaturated amides by the direct coupling of isocyanates with
alkenylaluminum reagents. At room temperature, the desired ,-un-
saturated amides were isolated in good to excellent yields with good
functional-group tolerance in the absence of any catalyst or additive.
Key words enamides, alkenylaluminum reagents, isocyanates, cou-
pling reaction, catalyst-free
a. Amides synthesis from acids and amines
O
O
R2
R2
activating reagent
+
OH
R1
N
R1
H2N
H
Linear ,-unsaturated amides are important structural
motifs in organic chemistry, functionalized materials, bio-
logically active compounds, and pharmaceuticals.1–4 Owing
to the important applications of these compounds in syn-
thetic chemistry and pharmaceuticals, the development of
new and efficient synthetic pathways for their preparation
has attracted continuous interest from organic chemists
(Scheme 1).5 Conventionally, ,-unsaturated amides are
prepared by nucleophilic substitution of the corresponding
activated carboxylic acid derivatives with amines (Scheme
1a).6 Alternatively, transition-metal-catalyzed carbonyla-
tions of alkenes or alkynes with amines or nitro compounds
have also been developed (Schemes 1b–d).7 However, these
methods are limited by their use of carbon monoxide gas,
which is highly toxic, odorless, and flammable, and requires
high-pressure equipment. Additionally, isocyanates have
also been explored as interesting amide precursors.8 ,-
Unsaturated amides can be relatively easily prepared by
lithiation of alkenyl halides and subsequent reaction with
isocyanates. Nickel-catalyzed procedures for the synthesis
of ,-unsaturated amides from terminal alkenes and ali-
phatic isocyanates have also been reported.9 More recently,
Martin and co-workers developed a conceptually new hy-
b. Hydroaminocarbonylation of alkynes
O
R3
[Catal] or radical
CO
R3
R1
R2
+
R1
N
H2N
H
R2
c. Aminocarbonylation of alkenes with tertiary amines
O
[Pd]/[Cu]
R'
+
NR'3
R
R
N
CO/O2
R'
d. Aminocarbonylation of alkenes with nitroarenes
O
[Pd]
Ar2
O2N Ar2
Ar1
+
Ar1
N
Mo(CO)6
H
e. Unsaturated amides from isocyanates and alkynes
Ar
H
[Ni], Mn
R2
R1 NCO
N
R2
Ar
+
R1
iPrBr, NMR, RT
O
f. Unsaturated amides from isocyanates (this work)
H
Catalyst-free
Al(i-Bu)2
R1 NCO
N
R2
+
R2
R1
THF, 0 °C to RT
16 h
O
30 examples
up to 88% yield
Scheme 1 Syntheses of linear ,-unsaturated amides
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B. Chen, X.-F. Wu
Letter
Synlett
Here, we report a new method for the synthesis of linear
,-unsaturated amides (Scheme 1f). Our initial investiga-
tions were carried out by using phenyl isocyanate and di-
isobutyl[(1E)-oct-1-en-1-yl]aluminum as model substrates.
The later was readily prepared from oct-1-yne and diisobu-
tylaluminum hydride (DIBAL-H). We dropped the alkenylal-
uminum solution into a solution of phenyl isocyanate in
THF at 0 °C, and then let the solution slowly warm up to
room temperature (25 °C) and continued to stir the mixture
until the reaction was complete. The whole process took 16
hours. To our delight, the desired product (E)-N-phenylnon-
2-enamide (3aa) was successfully obtained in 72% isolated
yield (Table 1, entry 1).11 Considering the easy manipula-
tions and practical advantages of the reaction conditions,
we were eager to examine the generality of this procedure.
As a first step, we tested various substituted aryl isocya-
nates (entries 2–9). Both electron-donating and electron-
withdrawing substituents on the aromatic ring were well
tolerated, and the desired products 3aa–ia were obtained in
moderate to good yields. With regard to the influence of the
position of the substituents on the yields of 3ba, 3ca, and
3da (entries 2–4), we found that the ortho-group reduced
the yield of the reaction because of its steric hindrance. Ac-
cording to the literature, nitro-substituted substrates are
generally incompatible with alkenylaluminum reagents. To
our delight however, 4-nitrophenyl isocyanate reacted
smoothly to give a 56% yield of amide 3ia (entry 9). Gratify-
ingly, aliphatic isocyanates were also well tolerated in this
transformation and delivered the corresponding ,-unsat-
urated amides 3ja and 3ka in yields of 81 and 68%, respec-
tively (entries 10 and 11). However, the desired products
were not detected when diisocyanate substrates were test-
ed (see Supporting Information).
Subsequently, we tested various alkenylaluminum re-
agents under our reaction conditions (Table 2). Aliphatic
alkenylaluminums, prepared from the corresponding
alkynes, were successfully transformed into the desired
products 3ab–ag in moderate to good yields (Table 2, en-
tries 1–6). Interestingly, a dienyl aluminum compound was
also tolerated in this reaction and gave the target products
3ah in 69% yield (entry 7). Moreover, aromatic alkenylalu-
minums were also tolerated, giving moderate yields of the
corresponding products 3ai–am (entries 8–12).
Next, we tested the reactions of 1-isocyanatobutane
with various alkenylaluminum reagents under our standard
conditions, and we obtained moderate to good yields of the
target products 3jn–jj (Table 3). It is also worth mentioning
that the reaction of phenyl isothiocyanate with diisobu-
tyl[(E)-oct-1-en-1-yl]aluminum was tested under our stan-
dard conditions, but none of the desired product was de-
tected.
Table 1 Synthesis of ,-Unsaturated Amides from Various Isocyanatesa
H
Al(i-Bu)2
N
n-Hex
R
NCO
+
n-Hex
R
THF, 0 °C to RT
16 h
O
1
2a 1.2 equiv
3
Entry
Isocyanate
Product
Yieldb
(%)
H
N
n-Hex
n-Hex
NCO
1
2
3
4
72
57
77
73
O
3aa
H
N
NCO
O
3ba
H
N
n-Hex
NCO
O
3ca
H
N
n-Hex
n-Hex
NCO
NCO
NCO
O
3da
H
N
5
6
7
75
70
70
O
F
F
3ea
H
N
n-Hex
O
Cl
Cl
3fa
H
N
n-Hex
NCO
O
MeO
MeO
3ga
H
N
n-Hex
n-Hex
NCO
NCO
8
78
56
81
68
O
MeS
O2N
MeS
O2N
3ha
H
N
9
O
3ia
H
N
n-Hex
NCO
10
11
O
3ja
H
N
n-Hex
NCO
O
3ka
a Reaction scale: 0.50 mmol.
b Yield of the isolated product.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
B. Chen, X.-F. Wu
Letter
Synlett
Table 2 (continued)
Table 2 Synthesis of ,-Unsaturated Amides from Alkenylaluminum
Reagentsa
Entry
Alkenylaluminum
Product
Yieldb (%)
56
H
Br
N
R
Al(i-Bu)2
2 1.2 equiv
Ph NCO
Ph
H
R
Br
THF, 0 °C to RT
16 h
N
O
12
1a
3
O
Al(i-Bu)2
3am
Entry
1
Alkenylaluminum
Product
Yieldb (%)
79
a Reaction scale: 0.50 mmol.
b Yield of the isolated product.
H
N
n-Pr
n-Pr
Al(i-Bu)2
O
Table 3 Synthesis of ,-Unsaturated Amides from 1-Isocyanatobutanea
3ab
H
N
H
n-Bu
N
R
Al(i-Bu)2
2 1.2 equiv
Bu NCO
Bu
n-Bu
R
2
3
82
77
Al(i-Bu)2
O
THF, 0 °C to RT
16 h
O
3
1j
3ac
H
N
Entry
1
Alkenylaluminum
Product
Yieldb (%)
61
n-Oct
n-Oct
O
O
Al(i-Bu)2
O
Bu
Bu
Cl
Cl
Al(i-Bu)2
3ad
N
H
3jn
H
N
4
75
2
3
4
83
88
82
N
H
O
Al(i-Bu)2
Al(i-Bu)2
3je
3ae
O
H
N
Bu
Bu
N
H
Al(i-Bu)2
Al(i-Bu)2
Al(i-Bu)2
5
6
65
71
O
Al(i-Bu)2
3jf
3af
O
H
N
N
H
3jh
Al(i-Bu)2
O
3ag
O
Bu
N
H
5
52
H
N
7
8
9
69
56
53
3ji
Al(i-Bu)2
Al(i-Bu)2
O
3ah
O
Cl
Bu
Bu
6
7
N
H
51
62
H
N
Al(i-Bu)2
3jl
Cl
O
O
O
3ai
N
H
Al(i-Bu)2
3jj
H
N
a Reaction scale: 0.50 mmol.
b Yield of the isolated product.
Al(i-Bu)2
3aj
F
On the basis of our results and a report in the literature,8
a plausible reaction pathway is proposed (Scheme 2). As
aluminum is a strong Lewis acid, the isocyanate coordinates
to the metal center through its nitrogen atom to forms
complex A. Next, addition of the alkenylaluminum reagent
to the isocyanate occurs to form intermediate B, which then
delivers the target product 3. The hydrogen in the amide
product might come from the THF solvent or from the
isobutyl group.
H
N
10
11
57
54
F
Al(i-Bu)2
O
3ak
Cl
Cl
H
N
Al(i-Bu)2
O
3al
Thieme. All rights reserved. Synlett 2020, 31, A–E

D
B. Chen, X.-F. Wu
Letter
Synlett
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R
N
C O
R
NCO
n-Hex
Al(i-Bu)2
n-Hex
i-Bu
Al
A
i-Bu
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H
i-Bu
i-Bu
N
n-Hex
R
Al
N
O
O
R
C
n-Hex
3
B
Scheme 2 Proposed reaction pathway
In summary, we have identified a convenient approach
to the synthesis of linear ,-unsaturated amides by the di-
rect coupling of isocyanates with alkenylaluminum re-
agents at room temperature. The desired ,-unsaturated
amides were isolated in good to excellent yields with good
functional-group tolerance. Considering the easy availabili-
ty of the starting materials and the convenient reaction
conditions, we believe this is a promising approach for the
synthesis of linear ,-unsaturated amides.
Funding Information
C.B. thanks the China Scholarship Council (CSC) for financial support.
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Acknowledgment
The analytical support of Dr W. Baumann, Dr C. Fisher, S. Buchholz,
and S. Schareina is gratefully acknowledged (all in LIKAT).
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Chem. 2016, 81, 2122. (e) Caulfield, M. J.; Qiao, G. G.; Solomon,
D. H. Chem. Rev. 2002, 102, 3067. (f) Buchanan, M. S.; Carroll, A.
R.; Addepalli, R.; Avery, V. M.; Hooper, J. N. A.; Quinn, R. J. J. Nat.
Prod. 2007, 70, 1827. (g) Fu, P.; Johnson, M.; Chen, H.; Posner, B.
A.; MacMillan, J. B. J. Nat. Prod. 2014, 77, 1245. (h) Putt, K. S.;
Nesterenko, V.; Dothager, R. S.; Hergenrother, P. J. ChemBio-
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(11) Amides 3; General Procedure
Under argon, a solution of the appropriate alkenylaluminum
(0.6 mmol) in hexane (0.6 mL) was added dropwise to a fresh
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

E
B. Chen, X.-F. Wu
Letter
Synlett
solution of the appropriate isocyanate (0.5 mmol) in THF (1 mL)
at 0 °C. The mixture was then warmed slowly to r.t. (25 °C) and
stirred until the reaction was complete (16 h). After removal of
solvent under reduced pressure, the pure product was obtained by
column chromatography [silica gel, heptane–ethyl acetate (5:1)].
(2E)-N-Phenylnon-2-enamide (3aa)
7.02 (t, J = 7.4 Hz, 1 H), 6.90 (dt, J = 15.1, 7.0 Hz, 1 H), 5.89 (dt, J =
15.3, 1.6 Hz, 1 H), 2.11 (qd, J = 7.1, 1.5 Hz, 2 H), 1.41–1.32 (m, 2
H), 1.21 (dddt, J = 14.6, 9.2, 6.6, 3.5 Hz, 6 H), 0.82 (t, J = 6.9 Hz, 3
H). 13C NMR (126 MHz, CDCl3):  = 164.4, 146.6, 138.2, 129.1,
129.0, 124.2, 120.0, 32.2, 31.6, 28.9, 28.2, 22.6, 14.1. HRMS
(ESI): m/z [M + H]+ calcd for C15H22NO: 232.1701; found:
232.1702.
Colorless oil; yield: 83 mg (72%). 1H NMR (500 MHz, CDCl3):
 = 7.64 (s, 1 H), 7.51 (d, J = 8.1 Hz, 2 H), 7.22 (t, J = 7.8 Hz, 2 H),
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E