Stereoselective formal hydroamidation of si-substituted arylacetylenes with DIBAL-H and isocyanates: Synthesis of (E)- And (Z)-α-Silyl-α,β-unsaturated amides

Article abstract of DOI:10.1021/acs.joc.0c01903

An efficient and stereoselective method for the synthesis of (E)- and (Z)-α-silyl-α,β-unsaturated amides and its synthetic applications are presented herein. The solvent-controlled hydroaluminations of Si-substituted alkynes with DIBAL-H generate diastereomerically enriched alkenylaluminum reagents that are directly reacted with isocyanates at ambient temperature to afford α-silyl-α,β-unsaturated amides in high yields with retained stereoselectivity. In particular, this process enables the synthesis of a broad range of (E)-α-silyl-α,β- unsaturated amides, which are the less studied isomers. The synthetic utility of this method is highlighted by its short reaction time, ease of purification, easily accessible substrates and reagents, gram-scale synthesis, and the further transformations of C-Si bonds into C-H, C-X, and C-C bonds.

Full text of DOI:10.1021/acs.joc.0c01903

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Featured Article
Stereoselective Formal Hydroamidation of Si-Substituted
Arylacetylenes with DIBAL–H and Isocyanates:
Synthesis of (E)- and (Z)-#-Silyl-#,#-unsaturated Amides
Hanseul Lee, Soohong Cho, Yunmi Lee, and Byunghyuck Jung
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01903 • Publication Date (Web): 10 Sep 2020
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Stereoselective Formal Hydroamidation of Si-Substituted
Arylacetylenes with DIBAL–H and Isocyanates: Synthesis of (E)-
and (Z)-α-Silyl-α,β-unsaturated Amides
Hanseul Lee,† Soohong Cho,† Yunmi Lee,†* and Byunghyuck Jung‡*
†
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Department of Chemistry, Kwangwoon University, Seoul 01897, Republic of Korea
Email: ymlee@kw.ac.kr
‡
Department of Emerging Materials Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu
42988, Republic of Korea
Email: byunghyuck.jung@dgist.ac.kr
[Table of Contents/Abstract Graphic]
Ar
O
R
hexanes
RNCO
22 °C, 1 h
H
N
55 °C, 2 h
H
SiMe3
R=alkyl, aryl
Ar=aryl, heteroaryl
62-98% yields
up to >98% E
Ar
SiMe3
H
+
(iBu)2Al
H
O
hexanes/THF=5/1
55 °C, 2 h
RNCO
R
Ar
N
22 °C, 1 h
H
SiMe3
77-98% yields
up to >98% Z
 Easily accessible reagents
 Ease of gram-scale synthesis
(No column chromatography)
 Efficient and stereoselective
 Functionalization of C-Si bond
[ABSTRACT]
An efficient and stereoselective method for the synthesis of (E)- and (Z)-α-silyl-α,β-unsaturated amides and its
synthetic applications are presented herein. The solvent-controlled hydroaluminations of Si-substituted alkynes
with DIBAL–H generate diastereomerically enriched alkenylaluminum reagents, which are directly reacted with
isocyanates at ambient temperature to afford α-silyl-α,β-unsaturated amides in high yields with retained
stereoselectivity. In particular, this process enables the synthesis of a broad range of (E)-α-silyl-α,β-unsaturated
amides, which are the less-studied isomers. The synthetic utility of this method is highlighted by its short reaction
time, ease of purification, easily accessible substrates and reagents, gram-scale synthesis, and the further
transformations of C–Si bonds into C–H, C–X, and C–C bonds.
and dienophiles in Diels–Alder reactions.4 Due to their
INTRODUCTION
significance and synthetic utility, various methods for
the construction of α,β-unsaturated amides have been
α,β-Unsaturated amides have attracted significant developed.5 A conventional strategy for preparing
amounts of attention as they are versatile building unsaturated amides involves the nucleophilic addition-
blocks for functional materials, potential drugs, and elimination reactions of amines with α,β-unsaturated
organic synthesis.1 For instance, polymers with carboxylic acids and coupling reagents.6 However, the
conjugated amides turn out to be excellent donor- lack of control over the regio- and stereoselectivity of
acceptor polymers and have been used in organic acrylamides prepared by conventional methods has led
electronics, including bulk heterojunction solar cells to the development of alternative protocols using
and organic field effect transistors.2 Natural products alkynes. The hydrometalation of an alkyne has been
containing acrylamide moieties exhibit a variety of widely used to generate an alkenylmetallic reagent,
bioactivities, including anti-inflammatory, antioxidant, and the successive functionalization of the C–M bond
and antiitch properties.3 Due to its intrinsic reactivity, to form the C–CONHR moiety results in the formation
the α,β-unsaturated amide structural motif has also of the α,β-unsaturated amide (Scheme 1).7 Nakao,
been used in various organic transformations, Hiyama, Tsuji, and coworkers described the use of Pd
including with nucleophiles in 1,4-addition reactions or Ni catalyst for the hydroamidation of alkynes with
1
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formamides, which serve as hydride sources to form coworkers demonstrated several examples of
alkenylmetal intermediates and the –CONR2 moiety enantioselective carbon–carbon bond forming
(Scheme 1-a).8 Martin and coworkers reported the Ni- reactions using E- or Z-pure alkenylaluminum reagents
catalyzed hydroamidations of alkynes with isocyanates generated in-situ from the solvent-controlled
in the presence of Mn and i-PrBr as the hydride source, hydroalumination of a Si-substituted acetylene with
which occurs through a β-hydride elimination (Scheme diisobutylaluminum hydride (DIBAL-H) (Scheme 1-
1-b).9 Ti-mediated alkyne-isocyanate coupling using i- g).14 Inspired by these studies, we assumed that treating
PrMgCl as a reductant provided (E)-tri- or tetra- E- or Z-pure Si-substituted alkenylaluminums with
substituted acrylamides via a titanacyclopropene isocyanates would lead to the construction of the
intermediate (Scheme 1-c).10 During our studies, Wu corresponding E or Z-α-silyl-α,β-unsaturated amides
and a coworker reported the synthesis of (E)- with high stereospecificities. In particular, synthetic
disubstituted acrylamides by treating isocyanates with approaches to the E-isomers of α,β-unsaturated amides
alkenylaluminum reagents (Scheme 1-d).11 Despite its have rarely been reported.5a Herein we describe the
practicality, there are compelling issues that need to be efficient and selective formal hydroamidations of silyl-
solved, including the substrate scope, which is limited substituted arylacetylenes. The silyl group plays a
to terminal alkynes, relatively long reaction times, and crucial role in controlling the regio- and
moderate yields. In addition, CO gas has been used in stereoselectivity, as well as subsequent synthetic
the hydroamidation of alkynes with amines promoted applications. The transformations of C–Si bonds into
by a Co2Rh2, Sn, Pd, or Fe catalyst to afford C–H, C–X, and C–C bonds generate variously
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acrylamides
with
outstanding
regio-
and functionalized analogs of acrylamides.
stereoselectivities (Scheme 1-e).12 Recently, the
synthesis of α,β-unsaturated amides with CO over a
palladium catalyst has been developed using
alkenylaluminum reagents and azides (Scheme 1-f).13
RESULTS AND DISCUSSION
We began our investigation by examining the
reactivity of phenyl isocyanate (3a) toward Si-
substituted vinylaluminum reagents, which were
generated from the regio- and stereoselective
hydroaluminations of Si-substituted phenylacetylenes
1 and 2a with DIBAL-H under the conditions
described previously by Hoveyda and coworkers,14 the
results of which are summarized in Table 1. The
addition of phenyl isocyanate to the (Z)-
vinylaluminum directly derived from the reaction of
Scheme 1. Methods for the formation of α,β-
unsaturated amides.
 Carbonyl from Formamides
a)
R
H
O
O
Ni or Pd
+
catalyst
R''
R''
R'
+
R
N
N
H
H
R'
R''
 Carbonyl from Isocyanates
N
C O
b)
R
R''
dimethylsilyl-substituted phenylacetylene
1
with
Ni catalyst
& Mn
Br
R'
+
+
DIBAL-H in a mixture of hexanes/THF (5/1) provided
only a trace of the desired amide product (entry 1).
However, when the trimethylsilyl-substituted (TMS-
substituted) phenylacetylene 2a was used under the
reaction conditions of entry 1, the nucleophilic
addition of the corresponding vinylaluminum to 3a
successfully proceeded to afford the desired (Z)-α,β-
unsaturated amide 4aa in >98% yield with >98% Z-
selectivity (entry 2). According to solvent-screening at
the vinylaluminum addition step, hexanes, toluene,
diethyl ether, or dichloromethane provided the desired
product 4aa in >95% yield with excellent
stereoselectivity in all cases. However, the use of THF
solely deteriorated the efficiency severely to generate
a trace of the amide 4aa. Hexanes were also used at
hydroalumination step of alkynes, so we chose hexanes
as the optimal solvent for nucleophilic addition
reaction. The concentrated reaction environment (0.5
M vs. 0.1 M) diminished the efficiency of the desired
transformation, but this did not affect the
stereoselectivity (entry 3). When the reaction with
isocyanate 3a was carried out for 10 min, the amide
product 4aa was obtained in 70% yield, and a duration
of 1 h was required for complete reaction (entries 4-5).
As highlighted in entry 6 (Table 1), (E)-selective
syntheses were also achieved using hexanes as the
solvent under the optimized reaction conditions, which
H
c)
R
d)
R
Ti(Oi-Pr)4
& i-PrMgCl
N
C
O
O
R'
H
+
+
+
+
R''
N
C
DIBAL-H
R''
 Carbonyl from CO (g)
e)
Co2Rh2, Fe, Pd,
R'' NH2
R'' N3
CO (g)
R
R'
R'
+
+
+
+
or Sn catalyst
f)
Pd catalyst
CO (g)
R
+
+
DIBAL-H
This work
R
R
O
N
hexanes
g)
R'NCO
Al(i-Bu)2
R'
H
H
55 °C, 2 h
H
TMS
>98% E
TMS
>98% E
R
TMS
Solvent-controlled
stereoselective
hydroalumination
Stereospecific
addition to
isocyanates
+
DIBAL-H
H
H
O
Hx/THF (5/1)
R'NCO
Al(i-Bu)2
R'
R
R
N
55 °C, 2 h
H
TMS
TMS
>98% Z
>98% Z
Despite the observed regioselective control and their
broad applicability, to the best of our knowledge, no
examples of E- or Z-controllable hydroamidation
reactions of alkynes have been reported. Hoveyda and
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provided the desired α,β-unsaturated amide 5a as a 3i–k bearing methyl or methoxy moieties at the meta-
single (E)-isomer in >98% yield.
or ortho-positions of their benzene rings proceeded
well to afford the desired amides 5i–kj with high
efficiency. A sterically demanding naphthyl isocyanate
3l and aliphatic isocyanates 3m–q, with benzyl,
cyclohexyl, tert-butyl, and furfuryl groups, were also
suitable for this transformation, and delivered versatile
functionalized amides 5l–q in yields of up to >98%. It
was noted that the chloroethyl and 2-chloropropyl
moiety on isocyanates were well tolerated, furnishing
the desired products 5p and 5r, which can be used in
further synthetic applications.
Table 1. Optimizing the reaction conditions.a
H
(i-Bu)2Al- (x equiv)
H
O
Ph
O
solvent, 55 °C, 2 h;
Ph
SiMe2R
(x equiv)
+
NHPh
Ph
H
NHPh
PhNCO 3a
hexanes, 22 °C, time
SiMe2R
SiMe2R
1
, R = H
2a
4aa
5a
, R = Me
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x
conc
(M)
time
(h)
4aa:5a
(%)b
entry
R
solvent
(equiv.)
hexanes:
THF (5:1)
hexanes:
THF (5:1)
hexanes:
THF (5:1)
hexanes:
THF (5:1)
1
2
3
4
5
6
H
3.0
3.0
1.5
1.5
1.5
1.5
0.1
0.1
0.5
0.1
0.1
0.1
3
trace
>98:<2
75:<2
Scheme 3. (E)-Selective hydroamidations with various
TMS-substituted alkynes.
Me
Me
Me
Me
Me
3
1
H
(i-Bu)2Al-
hexanes, 55 °C, 2 h;
Ar
O
10 min
70:<2
Ar
TMS
H
NHt-Bu
3o
t-BuNCO
TMS
2b-n
hexanes, 22 °C, 1 h
hexanes:
THF (5:1)
6
1
1
>98:<2
<2:>98
R
R
O
hexanes
NH
O
aReaction conditions: alkyne (0.75–1.50 mmol), DIBAL-H
(0.75–1.50 mmol), PhNCO (3a, 0.5 mmol), solvent (0.1–0.5
M) under N2. bDetermined by 1H NMR spectroscopy using
1,3,5-trimethoxybenzene as an internal standard.
NH
TMS
TMS
6ho
6io
6jo
, R = Me, >98%
, R = F, >98%
, R = Cl, 98%
6bo
6co
6do
6eo
6fo
, R = OMe, 90% (E/Z=87/13)
, R = Me, 98%
, R = F, >98%
O
, R = Cl, >98%
NH
Scheme 2. (E)-Selective formal hydroamidations using
various isocyanates.
, R = Br, 97%
Cl
6go
, R = CF3,70% E (E/Z=85:15)
TMS
6ko
, 97%
O
H
(i-Bu)2Al-
hexanes, 55 °C, 2 h;
Ph
O
S
O
O
O
NH
TMS
NH
NH
TMS
Ph
TMS
H
NHR
3
RNCO
TMS
5
TMS
6no
, 98%
2a
hexanes, 22 °C, 1 h
6lo
6mo
, 91%
, 95%
5a
, R = H, >98%
, R = OMe, >98%
, R = Me, 96%
, R = Cl, 93%
, R = Br, 91%
, R = I, 88%
Reaction conditions: alkyne (2, 0.45 mmol), DIBAL-H (0.45
mmol), t-BuNCO (3o, 0.3 mmol), hexanes (0.1 M) under N2.
Ph
O
5b
5c
5d
5e
5f
5g
5h
X
Ph
O
N
H
TMS
X
N
H
TMS
This method was applicable to various TMS-
substituted acetylenes, as shown in Scheme 3. The
hydroalumination/amidation reactions of isocyanate
3o with alkyne substrates 2b–k, with methoxy, methyl,
fluoro, chloro, bromo, and trifluoromethyl groups at
the ortho-, meta-, or para-positions of the benzene
rings, afforded the corresponding amides 6bo–ko in
high yields. We noted that most hydroamidations with
TMS-substituted arylacetylenes resulted in complete
5i
5j
, R = OMe, >98%
, R = Me, 94%
, R = CF3, 93%
, R = CN, 83%
Me
5m
, R = Bn, 90%
, R = Cy, 94%
, R = t-Bu, >98%
, R = CH2CH2Cl, 82%
5n
5o
5p
Ph
O
Ph
O
Ph
O
N
NHR
N
H
O
H
TMS
TMS
5q
TMS
, R =
, 89%
5l
, >98%
5k
, >98%
5r
, R = CH2CHClCH3, 62%
Reaction conditions: alkyne (2a, 0.45 mmol), DIBAL-H
(0.45 mmol), RNCO (3, 0.3 mmol), hexanes (0.1 M) under
E-selectivity;
however,
reactions
with
N2.
phenylacetylenes 2b and 2g, including para-methoxy
and para-trifluoromethyl substituents, resulted in
lower stereoselectivities (E/Z = 87/13 or 85:15). Based
on previous suggestions by Hoveyda and coworkers
With the determined optimized reaction conditions,
the isocyanates scope was investigated, as shown in
Scheme 2. All transformations were carried out on
hexanes to afford the (E)-isomers of the α,β-
unsaturated amides with stereoselectivities greater than
98%. The electronic nature of the aryl isocyanate did
not affect the efficiency and selectivity of the
nucleophilic addition of the TMS-substituted
vinylaluminum reagent obtained from the reaction of
2a with DIBAL-H. Aryl isocyanates 3a–h bearing
methoxy, methyl, halogen, trifluoromethyl, and cyano
groups at their para-positions were smoothly
converted into the corresponding (E)-amides 5a–h in
high yields (83 to >98%). Reactions with isocyanates
for the isomerization of
a
Si-substituted
alkenylaluminum intermediate (Scheme 4),14a we
assumed that an electron-donating para-methoxy
group stabilizes intermediate II through strong
resonance, which increases the value of k-2, while an
electron-withdrawing para-trifluoromethyl group
destabilizes intermediate II through strong induction,
which decreases the value of k1. While the E/Z mixture
of 6bo was not separable by silica gel column
chromatography, the 6go mixture was separated to
provide a 70% yield of the (E)-isomer. Acetylenes 2l–
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n substituted by furyl, thienyl, and naphthyl groups Silyl-substituted unsaturated amides are useful
also underwent amidation well to afford the desired synthetic intermediates that can be further
amides 6lo–no in yields of 91–98% with >98% E- functionalized by the stereospecific conversions of C–
selectivity. However, selective hydroalumination with Si bonds to C–H, C–X, and C–C bonds. We first
phenethyl-substituted trimethylsilylacetylene was demonstrated the protodesilylations of (E)- or (Z)-
inefficient under the established reaction conditions, silyl-substituted amides (Scheme 6). Protodesilylation
affording only a trace amount of the desired (E)-amide of (Z)-Si-alkene 4aa in the presence of
product. The dimerized side product was mainly observed.
tetrabutylammonium
fluoride
(TBAF)
or
trifluoroacetic acid (TFA) proceeded stereospecifically
Scheme 4. Isomerization of the Si-substituted to form the desired alkene 7a in high yields and with
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vinylaluminum intermediate.
more than 93% E-selectivity. However, the TBAF- or
TFA-mediated desilylation of (E)-Si-alkene 5a
produced a 1:1 mixture of (E)- and (Z)-alkene 8a.
When the fluoride source was replaced with AgF in the
presence of acetic acid under protic-solvent conditions,
the desired (Z)-alkene 8a was obtained in 95% yield
with complete Z-selectivity.15 It was presumably
because nucleophilic attack of F– at Si generates the
allenoate intermediate, which provides a 1:1 mixture of
the (E) and (Z) isomers when quenched with proton
source. The use of a protic solvent under acidic
conditions may facilitate rapid protonation prior to
allenoate isomerization, resulting in excellent
stereospecificity. Functional groups such as aryl,
heteroaryl, and N-alkyl moieties on the Si-substituted
amides did not affect the efficiency and
stereospecificity of the protodesilylation process, to
afford the corresponding alkene products 8b–d in 72–
88% yield with >98% Z-selectivity.
TMS
H
TMS
H
H
Al(iBu)2
Ar
Al(iBu)2 k1
k2
H
2
Ar
Al(iBu)2
Ar
Al(iBu)2
III
intermedate
TMS
k-2
k-1
II
intermedate
Our synthetic method can be also used to prepare
(Z)-selective α-silyl-substituted α,β-unsaturated
amides. As shown in Scheme 5, the reactions of
phenylacetylene 2a with a variety of aryl- and alkyl-
substituted isocyanates in a 5:1 mixture of hexanes and
tetrahydrofuran as the solvent successfully proceeded
to provide the corresponding amides 4aa–aq in 77–
98% yields with >98% Z-selectivity.
Scheme 5. (Z)-Selective hydroamidations with various
isocyanates.
H
O
H
(i-Bu)2Al-
Hx/THF (5/1), 55 °C, 2 h;
Ph
NHR
Ph
TMS
3
RNCO
TMS
hexanes, 22 °C, 1 h
2a
Scheme 7. Synthetic applications.
4
OMe
O
Br
Ph
O
O
O
a) Halogenation/Suzuki-coupling
O
O
Ph
NHPh Ph
N
Ph
N
H
N
H
O
15 mol % PPh3
20 mol %Pd2(dba)3
H
Ph
NHPh
TMS
TMS
TMS
TMS
OMe
NBS
Ph
Ph
NHPh
Ph
NHPh
4aa
4ab
4ae
4ai
, 98%
, 98%
, 92%
, 96%
CH3CN
100 °C, 1 h
>98% Z
Ar
B(OH)2, K3PO4
toluene
TMS
Br
9a
O
O
O
4aa
, 91%
100 °C, 12 h
Cl
O
Ph
N
H
Ph
N
H
Ph
N
X
>98% Z
O
H
O
TMS
4ao
TMS
4ap
TMS
4aq
NIS
9b
9c
, X = H, 82%
, X = OMe, 75%
NHPh
, >98%
, 95%
, 77%
Ph
NHPh
CH3CN
22 °C,5 h
>98% Z
TMS
I
Reaction conditions: alkyne (2a, 0.45 mmol), DIBAL-H
(0.45 mmol), RNCO (3, 0.3 mmol), hexanes/THF (0.1 M)
under N2.
9d
4aa
, 95%
b) Synthesis of oxazoline
Ph
O
Ph
O
DBU
CH2Cl2, 60 °C, 24 h
Cl
N
N
H
TMS
TMS
5p
10
, 89%, >98% E
Scheme 6. Stereospecific protodesilylations.
c) Synthesis of tertiary amide
(i-Bu)2Al-H
O
O
O
AgF, AcOH
Hx/THF (5/1), 55 °C, 2 h;
reaction conditions
Ph
TMS
Ph
Ph
NHPh
Ph
NHPh
Ph
NPh
Boc
THF/MeOH/H2O
22 °C, 24 h
3a
PhNCO
1) TBAF in THF: 98%, E/Z=93/7
2) TFA in CHCl3: 95%, >98% E
2a
TMS
TMS
H
hexanes, 22 °C, 1 h
then Boc2O
11
, 95%, >98% Z
4aa
7a
, >98% Z
H
N
O
O
3
o Amide
>98% E


O
Ph
O
Ph
N
Ph
NPh
Boc
reaction conditions
CH3CN, 60 °C, 15 h
NHPh
NHPh
13
12
, 91%
, 89%
1) TBAF in THF: 94%, E/Z=50/50
2) TFA in CHCl3: 92%, E/Z=50/50
TMS
5a
H
d) Gram-scale synthesis
8a
, >98% E
3) AgF, AcOH, THF/MeOH/H2O (2:2:1):
(i-Bu)2Al-H
hexanes, 55 °C, 2 h;
Ph
O
95%, >98% Z
Ph
TMS
98% (1.23 g)
>98% E
NHPh
3a
PhNCO
hexanes, 22 °C, 1 h
no SiO2 chromatography
(4 mmol)
2a
(6 mmol, 1.04 g)
TMS
S
H
O
Ph
O
Ph
O
5a
NHtBu
N
N
Ph
H
H
H
OMe
H
The usefulness of our method was demonstrated by
the synthesis of diarylsubstituted α,β-unsaturated
amides 9b–c through facile bromination and Suzuki-
8b
8c
8d
, 72%, >98% Z
, 88%, >98% Z
, 79%, >98% Z
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coupling sequences (Scheme 7a).16 Bromodesilylation We developed an efficient and straightforward method
of 4aa with N-bromosuccinimide (NBS) was easily for the synthesis of a broad range of new versatile α-
accomplished to give (Z)-bromoalkene 9a in 91% silyl-substituted-α,β-unsaturated amides through the
yield,9,17 which was then used in Pd-catalyzed coupling solvent-controlled
stereoselective
formal
reactions with arylboronic acids to afford the desired hydroamidation of TMS-substituted arylacetylenes
diarylsubstituted alkenes 9b–c in yields of 75-82% with readily available isocyanates and DIBAL-H under
without any detrimental effect on stereoselectivity. mild reaction conditions. This method has practical
Iodonation of 4aa with NIS also proceeded well to merits, including short reaction times and high yields,
provide (Z)-iodoalkene 9d in 95% yield. In addition, does not require column chromatography, and is easily
chloroethyl-substituted amide 5p was smoothly performed on the gram scale. Synthetic applications
transformed into the oxazoline 10 using DBU in 89% were demonstrated by the conversions of C–Si bonds
yield with >98% E-selectivity (Scheme 7b). Tertiary into C–H, C–X, and C–C bonds, with retained
amide as well as secondary amide could be synthesized stereochemistries. Further works of formal
with our protocol (Scheme 7c). (Z)-Selective hydroamidation with other types of alkynes are
hydroamidation of 2a with phenyl isocyanate (3a), ongoing.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
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60
followed by quenching with Boc anhydride produced
N-Boc-activated amide 11 in 95% yield with >98% Z-
selectivity. Protodesilylation of 11 with AgF in a protic
EXPERIMENTAL SECTION
solvent and metal-free transamidation of 12 with
General Information. Infrared (IR) spectra were recorded
on a ABB MB3000 FT-IR spectrophotometer, max in cm-1.
Bands are characterized as strong (s), medium (m), and weak
pyrrolidine afforded the desired tertiary amide 13 in
81% overall yield without any E/Z-isomerization.18 A
gram-scale synthesis was performed using more than 1
g of Si-substituted phenylacetylene 2a and 4 mmol of
3a, which delivered 5a in 98% yield (1.23 g) with
>98% E-selectivity (Scheme 7d). It is noteworthy that
the reactions of the vinylaluminum with 3a was
complete within 1 h at ambient temperature. In
addition, the product was purified by trituration with
hexanes, with no chromatographic purification
required. This gram-scale synthesis highlights the
superior practicality of our method.
Finally, we applied our synthetic method to the
concise synthesis of (E)-N-cinnamoyltyramine 16,
which is a component of the extracts from the dried
aerial part of P. taiwanense (Scheme 8).19 In particular,
16 exhibits remarkable free-radical scavenging activity,
with an IC0.200 value of 8.5 ± 0.8 M in the
diphenylpicrylhydrazyl radical decoloration assay.20
The synthesis of (E)-N-cinnamoyltyramine 16 was
achieved in two steps from 2a. When the reaction was
carried out with isocyanate 14 in CH2Cl2, owing to its
poor solubility in hexanes, (Z)-amide 15 was obtained
in 73% yield without any (E)-isomer observed.
Subsequent mild AgF-mediated protodesilylation of 15
provided the target product 16 in 50% overall yield
from 2a.
1
(w). H NMR spectra were recorded a JEOL JNM-AL400
(400 MHz) spectrometer. Chemical shifts are reported in
ppm from tetramethylsilane, with the solvent resonance as
the internal standard (CDCl3: δ 7.27 ppm and DMSO-d6:
2.50 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, m = multiplet), coupling constants (Hz), and
integration. 13C NMR spectra were recorded on a JEOL
JNM-AL400 (100 MHz) spectrometer with complete proton
decoupling. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal
standard (CDCl3: δ 77.00 ppm and DMSO-d6: 39.51). High-
resolution mass spectra (HRMS) were performed at the
Korea Basic Science Institute for technical assistance using
an electron ionization (EI) or an electrospray ionization
(ESI) time-of-flight mass spectrometer. Unless otherwise
noted, all reactions were carried out with distilled solvents
under an atmosphere of dry N2 in oven-dried (130 °C)
glassware. Hexane was purified by distillation from CaH2
immediately prior to use. Tetrahydrofuran was purified by
distillation from sodium benzophenone immediately prior to
use. DIBAL-H was purchased from Sigma-Aldrich
Corporation and used as received. A variety of isocyanate
were purchased from TCI, Alfa Aesar, Sigma-Aldrich
Corporation
and
used
as
received.
(Trimethylsilyl)Acetylene was purchased from TCI
Corporation and used as received. All work-up and
purification procedures were carried out with reagent grade
solvents in air. A variety of alkyne substrates were prepared
according to reported experimental procedures.21
Scheme 8. Syntheses of biologically active molecule
16.
Representative Experimental Procedure for the
Synthesis of (E)-α-Silyl-α,β-unsaturated Amides
(i-Bu)2Al-H
Hx/THF (5/1)
55 °C, 2 h;
OH
O
AgF, AcOH
Ph
TMS
(E)-N,3-Diphenyl-2-(trimethylsilyl)acrylamide
(5a).
Ph
N
THF/MeOH/H2O
22 °C, 24 h
NCO
H
2a
Hexanes (1.25 mL), DIBAL-H (0.356 mL, 2.00 mmol) and
trimethyl(phenylethynyl)silane (2a, 0.393 mL, 2.00 mmol)
were added to a vial (8 mL) under N2. The mixture was
heated to 55 ℃ and stirred for 2 h to afford the Si-substituted
vinylaluminum reagent (~1.0 M in hexanes), which was
directly used without purification. The vinylaluminum
solution (~1.0 M in hexanes, 0.450 mL, 0.450 mmol) and
hexane (2.55 mL) was then added into a vial (8 mL) under
N2, after which phenyl isocyanate (3a, 32.6 μL, 0.300 mmol)
was added dropwise. The reaction mixture was stirred at
room temperature for 1 h, after which the solution was
TMS
15
, 73%, >98% Z
HO
14
OH
CH2Cl2, 22 °C, 1 h
O
Ph
N
H
16
, 69%
CONCLUSION
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quenched by the addition of 1 N aqueous HCl (1 mL) and 135.8, 131.9, 128.7, 128.7, 128.4, 121.5, 116.9. -1.6; HRMS
water (2 mL). The mixture was extracted with EtOAc (5 x 3 (ESI) m/z: [M+H]+ Calcd for C18H21BrNOSi 374.0576,
mL). The organic layers were combined, dried over MgSO4, Found 374.0577.
filtered and concentrated. The crude product was purified
using silica gel column chromatography (EtOAc:hexanes =
1:4) to provide the 5a (87.9 mg, 0.298 mmol, >98% yield)
as a white solid. This compound has been previously
reported and spectra data match described.5a 1H NMR
(CDCl3, 400 MHz): δ 7.47-7.45 (m, 2H), 7.38-7.36 (m, 2H),
7.33-7.25 (m, 5H), 7.12-7.08 (m, 1H), 6.93 (br s, 1H), 6.86
(s, 1H), 0.31 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ
170.5, 142.9, 139.7, 137.8, 136.0, 128.9, 128.6, 128.5, 124.3,
120.1, -1.6. Anal. Calcd for C18H21NOSi: C, 73.17; H, 7.16;
N, 4.74; O, 5.42; Si, 9.51. Found: C, 72.93; H, 7.11; N, 4.57.
(E)-N-(4-Iodophenyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (5f). Compound 5f was
synthesized from 4-iodophenyl isocyanate (3f, 73.5 mg,
0.300 mmol) in 88% yield (111 mg, 0.264 mmol) as a white
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 208-209 °C;
IR (neat): 3302 (w), 2924 (w), 1643 (m), 1589 (m), 1497 (s),
1242 (m), 1188 (m), 1157 (m), 1003 (m), 895 (m), 833 (s)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
cm-1; H NMR (CDCl3, 400 MHz): δ 7.59 (dt, J = 8.7, 2.4
Hz, 2H), 7.41 (dd, J = 7.8, 1.4 Hz, 2H), 7.33-7.28 (m, 3H),
7.15 (dt, J = 9.2, 2.5 Hz, 2H), 6.90 (br s, 1H), 6.88 (s, 1H),
0.30 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 170.5,
(E)-N-(4-Methoxyphenyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (5b). Compound 5b was 142.7, 140.1, 137.9, 137.6, 135.8, 128.8, 128.7, 128.4, 121.8,
synthesized from 4-methoxyphenyl isocyanate (3b, 39.0 μL, 87.5. -1.6; HRMS (ESI) m/z: [M+H]+ Calcd for
0.300 mmol) in >98% yield (97.6 mg, 0.300 mmol) as a C18H21INOSi 422.0437, Found 422.0438.
white solid. The crude product was purified using silica gel
column chromatography (EtOAc:hexanes = 1:4). mp 159-
(E)-3-Phenyl-N-(4-(trifluoromethyl)phenyl)-2-
160 °C; IR (neat): 3280 (w), 1628 (m), 1597 (m), 1512 (s),
(trimethylsilyl)acrylamide (5g). Compound 5g was
synthesized from 4-(trifluoromethyl)phenyl isocyanate (3g,
43.0 μL, 0.300 mmol) in 93% yield (102 mg, 0.280 mmol)
as a white solid. The crude product was purified using silica
gel column chromatography (EtOAc:hexanes = 1:4). mp
202-203 °C; IR (neat): 3240 (w), 1651 (m), 1597 (m), 1535
(m), 1404 (m), 1319 (s), 1250 (m), 1088 (w), 1119 (s), 1065
(m), 1011 (w), 895 (m), 841 (s) cm-1; 1H NMR (CDCl3, 400
MHz): δ 7.54 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H),
7.42 (dd, J = 6.0, 1.6 Hz, 2H), 7.32-7.27 (m, 3H), 7.07 (s,
1412 (m), 1234 (s), 1041 (m), 1011 (m), 895 (m), 833 (s)
1
cm-1; H NMR (CDCl3, 400 MHz): δ 7.47 (d, J = 6.9 Hz,
2H), 7.33-7.25 (m, 5H), 6.86-6.83 (m, 4H), 3.78 (s, 3H),
0.31 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 170.4,
156.5, 142.9, 139.6, 136.0, 130.8, 128.6, 128.6, 128.5, 122.1,
114.1, 55.5, -1.6; HRMS (ESI) m/z: [M+H]+ Calcd for
C19H24NO2Si 326.1576, Found 326.1577.
(E)-3-Phenyl-N-(p-tolyl)-2-(trimethylsilyl)acrylamide
(5c). Compound 5c was synthesized was synthesized from 1H), 6.91 (s, 1H) 0.31 (s, 9H); 13C{1H} NMR (CDCl3, 100
p-tolyl isocyanate (3c, 38.0 μL, 0.300 mmol) in 96% yield MHz): δ 170.8, 142.5, 140.9, 140.4, 135.8, 128.9, 128.7,
(89.3 mg, 0.288 mmol) as a white solid. The crude product 128.4, 126.2 (q, JC-F = 3.9 Hz), 126.0 (q, JC-F = 32.8 Hz),
was purified using silica gel column chromatography 124.0 (q, JC-F = 271.2 Hz), 119.4, -1.6; HRMS (ESI) m/z:
(EtOAc:hexanes = 1:4). mp 195-196 °C; IR (neat) : 3286 [M+H]+ Calcd for C19H21F3NOSi 364.1345, Found 364.1345.
(w), 1636 (m), 1597 (m), 1512 (s), 1404 (w), 1319 (m), 1250
(s), 1018 (m), 895 (w), 833 (s) cm-1; 1H NMR (CDCl3, 400
(E)-N-(4-Cyanophenyl)-3-phenyl-2-
MHz): δ 7.46 (d, J = 7.3 Hz, 2H), 7.32-7.28 (m, 2H), 7.26-
7.24 (m, 3H), 7.10 (d, J = 8.7 Hz, 2H), 6.91 (br s, 1H), 6.85
(s, 1H), 2.31 (s, 3H), 0.30 (s, 9H); 13C{1H} NMR (CDCl3,
100 MHz): δ 170.4, 142.9, 139.5, 136.0, 135.2, 133.9, 129.4,
128.6, 128.5, 128.4, 120.2, 20.8, -1.6; HRMS (ESI) m/z:
[M+H]+ Calcd for C19H24NOSi 310.1627, Found 310.1628.
(trimethylsilyl)acrylamide (5h). Compound 5h was
synthesized from 4-cyanophenyl isocyanate (3h, 43.2 mg,
0.300 mmol) in 83% yield (79.8 mg, 0.249 mmol) as a white
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 221-222 °C;
IR (neat): 3256 (w), 3094 (w), 2222 (m), 1651 (m), 1589 (s),
1520 (s), 1404 (m), 1319 (m), 1250 (m), 1180 (w), 903 (m),
833 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.53-7.48 (m,
(E)-N-(4-Chlorophenyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (5d). Compound 5d was 4H), 7.40-7.37 (m, 3H), 7.28-7.27 (m, 3H), 6.90 (s, 1H),
synthesized from 4-chlorophenyl isocyanate (3d, 46.1 mg, 0.29 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 171.0,
0.300 mmol) in 93% yield (92.4 mg, 0.280 mmol) as a white 142.2, 142.0, 140.6, 135.7, 133.1, 128.8, 128.7, 128.3, 119.5,
solid. The crude product was purified using silica gel column 118.8, 106.8, -1.7; HRMS (ESI) m/z: [M+H]+ Calcd for
chromatography (EtOAc:hexanes = 1:4). mp 203-204 °C; C19H21N2OSi 321.1423, Found 321.1424.
IR (neat): 3302 (m), 3240 (m), 1913 (m), 1844 (m), 1774
(w), 1643 (m), 1520 (s), 1474 (w), 1396 (w), 1265 (w), 1134
(E)-N-(2-Methoxyphenyl)-3-phenyl-2-
(w), 926 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.40 (dd,
(trimethylsilyl)acrylamide (5i). Compound 5i was
J = 8.0, 1.6 Hz, 2H), 7.30-7.21 (m, 7H), 6.90 (br s, 1H), 6.86
(s, 1H), 0.28 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ
170.5, 142.7, 140.1, 136.4, 135.9, 129.3, 129.0, 128.8, 128.7,
128.4, 121.2, -1.6; HRMS (ESI) m/z: [M+H]+ Calcd for
C18H21ClNOSi 330.1081, Found 330.1082.
synthesized was synthesized from 2-methoxyphenyl
isocyanate (3i, 40.0 μL, 0.300 mmol) in >98% yield (97.6
mg, 0.300 mmol) as a light yellow solid. The crude product
was purified using silica gel column chromatography
(EtOAc:hexanes = 1:4). mp 105-106 °C; IR (neat): 3418 (m),
2924 (m), 1651 (s), 1597 (m), 1512 (s), 1458 (m), 1242 (s),
1180 (m), 1018 (m), 841 (s) cm-1; 1H NMR (CDCl3, 400
(E)-N-(4-Bromophenyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (5e). Compound 5e was MHz): δ 8.43 (dd, J = 7.5, 2.1 Hz, 1H), 7.62 (br s, 1H), 7.48
synthesized from 4-bromophenyl isocyanate (3e, 59.4 mg, (d, J = 7.3 Hz, 2H), 7.31-7.22 (m, 3H), 7.06-6.97 (m, 2H),
0.300 mmol) in 91% yield (102 mg, 0.274 mmol) as a white 6.86 (br s, 1H), 6.81 (dd, J = 7.5, 2.1 Hz, 1H), 3.65 (s, 3H),
solid. The crude product was purified using silica gel column 0.32 (s, 9H); 113C{1H} NMR (CDCl3, 100 MHz): δ 170.2,
chromatography (EtOAc:hexanes = 1:4). mp 210-211 °C; 148.0, 142.9, 139.7, 136.1, 128.4, 128.4, 128.3, 127.7, 123.6,
IR (neat): 3294 (w), 1643 (m), 1528 (m), 1304 (m), 1250 121.0, 120.0, 110.1, 55.6 -1.7; HRMS (ESI) m/z: [M+H]+
(m), 1173 (m), 1126 (m), 1003 (m), 887 (w), 825 (s) cm-1; Calcd for C19H24NO2Si 326.1576, Found 326.1575.
1H NMR (CDCl3, 400 MHz): δ 7.41-7.35 (m, 4H), 7.31-7.22
(m, 5H), 6.92 (br s, 1H), 6.86 (s, 1H), 0.28 (s, 9H); 13C{1H}
NMR (CDCl3, 100 MHz): δ 170.5, 142.6, 140.1, 136.9,
(E)-3-Phenyl-N-(o-tolyl)-2-(trimethylsilyl)acrylamide
(5j). Compound 5j was synthesized from o-tolyl isocyanate
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(3j, 37.0 μL, 0.300 mmol) in 94% yield (87.2 mg, 0.282 1H), 3.89-3.79 (m, 1H), 1.82 (dd, J = 12.8, 4.1 Hz, 2H), 1.65-
mmol) as a white solid. The crude product was purified 1.55 (m, 3H), 1.39-1.28 (m, 2H), 1.13-1.02 (m, 1H), 1.00-
using silica gel column chromatography (EtOAc:hexanes = 0.90 (m, 2H), 0.24 (s, 9H); 13C{1H} NMR (CDCl3, 100
1:4). mp 154-155 °C; IR (neat): 3240 (w), 1636 (s), 1582 MHz): δ 171.0, 143.3, 138.5, 136.2, 128.5, 128.3, 128.2,
(m), 1520 (s), 1450 (s), 1296 (m), 1250 (s), 1011 (m), 895 47.7, 32.8, 25.4, 24.8, -1.7; HRMS (ESI) m/z: [M+H]+ Calcd
(m), 841 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J for C18H28NOSi 302.1940, Found 302.1941.
= 8.2 Hz, 1H), 7.49-7.47 (m, 2H), 7.35-7.28 (m, 3H), 7.24-
7.20 (m, 1H), 7.11-7.09 (m, 1H), 7.06-7.02 (m, 1H), 6.91 (s,
(E)-N-(tert-Butyl)-3-phenyl-2-(trimethylsilyl)acrylamide
1H), 6.73 (br s, 1H), 1.86 (s, 3H), 0.33 (s, 9H); 13C{1H}
(5o). Compound 5o was synthesized from tert-butyl
NMR (CDCl3, 100 MHz): δ 170.3, 143.5, 139.7, 136.2,
135.6, 130.4, 128.6, 128.5, 128.4, 126.7, 124.8, 122.5, 17.1,
-1.5; HRMS (ESI) m/z: [M+H]+ Calcd for C19H24NOSi
310.1627, Found 310.1628.
isocyanate (3o, 34.0 μL, 0.300 mmol) in 99% yield (81.5 mg,
0.296 mmol) as a white solid. The crude product was
purified using silica gel column chromatography
(EtOAc:hexanes = 1:4). mp 133-134 °C; IR (neat): 3294 (m),
2962 (w), 1620 (s), 1535 (s), 1450 (w), 1250 (m), 1026 (m),
879 (m), 833 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.47-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-3-Phenyl-N-(m-tolyl)-2-(trimethylsilyl)acrylamide
(5k). Compound 5k was synthesized from m-tolyl 7.44 (m, 2H), 7.33-7.24 (m, 3H), 6.68 (s, 1H), 5.04 (br s, 1H),
isocyanate (3k, 39.0 μL, 0.300 mmol) in >98% yield (92.8 1.28 (s, 9H), 0.24 (s, 9H); 13C{1H} NMR (CDCl3,100 MHz):
mg, 0.300 mmol) as a white solid. The crude product was δ 171.3, 144.1, 138.1, 136.4, 128.5, 128.2, 128.2, 51.2, 28.5,
purified using silica gel column chromatography -1.7; HRMS (ESI) m/z: [M+H]+ Calcd for C16H26NOSi
(EtOAc:hexanes = 1:4). mp 199-200 °C; IR (neat) : 3294 276.1784, Found 276.1782.
(w), 1636 (m), 1605 (m), 1551 (s), 1489 (s), 1412 (w) , 1311
(m), 1250 (m), 1034 (w), 895 (m), 841 (s) cm-1; 1H NMR
(E)-N-(2-Chloroethyl)-3-phenyl-2-
(CDCl3, 400 MHz): δ 7.48-7.45 (m, 2H), 7.34-7.25 (m, 4H),
7.18 (t, J = 7.8 Hz, 1H), 7.12-7.09 (m, 1H), 6.93-6.91 (m,
2H), 6.85 (s, 1H), 2.33 (s, 3H), 0.31 (s, 9H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 170.4, 142.9, 139.6, 138.9, 137.7,
135.9, 128.8, 128.7, 128.6, 128.5, 125.1, 120.7, 117.1, 21.5,
-1.6; HRMS (ESI) m/z: [M+H]+ Calcd for C19H24NOSi
310.1627, Found 310.1628.
(trimethylsilyl)acrylamide (5p). Compound 5p was
synthesized from 2-chloroethyl isocyanate (3p, 26.0 μL,
0.300 mmol) in 82% yield (69.7 mg, 0.246 mmol) as a white
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 98-99 °C; IR
(neat): 3279 (m), 2924 (w), 1620 (s), 1543 (s), 1250 (s), 957
(w), 841 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.39-7.36
(m, 2H), 7.32-7.25 (m, 3H), 6.76 (s, 1H), 5.66 (br s, 1H),
3.57-3.49 (m, 4H), 0.24 (s, 9H); 13C{1H} NMR (CDCl3, 100
(E)-N-(Naphthalen-1-yl)-3-phenyl-2-
(trimethylsilyl)acrylamide (5l). Compound 5l was MHz): δ 172.4, 142.6, 139.6, 136.2, 128.4, 128.3, 43.6, 41.0,
synthesized from 1-naphthyl isocyanate (3l, 43.0 μL, 0.300 -1.7; HRMS (ESI) m/z: [M+H]+ Calcd for C14H21ClNOSi
mmol) in >98% yield (103 mg, 0.298 mmol) as a white solid. 282.1081, Found 282.1082.
The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 174-175 °C;
IR (neat): 3240 (w), 1636 (m), 1528 (m), 1497 (m), 1396
(w), 1250 (m), 995 (m), 833 (s) cm-1; 1H NMR (CDCl3, 400
MHz): δ 7.96 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H),
7.67 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 7.4 Hz, 2H), 7.49 (t, J
= 7.8, 1H), 7.45-7.41 (m, 1H), 7.34-7.27 (m, 5H), 7.12 (d, J
= 8.7 Hz, 1H), 7.01 (s, 1H), 0.39 (s, 9H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 170.8, 143.7, 140.0, 136.4, 134.0,
132.0, 128.7, 128.6, 128.6, 128.5, 127.0, 126.0, 125.8, 125.7,
125.4, 120.4, 120.2, -1.5; HRMS (ESI) m/z: [M+H]+ Calcd
for C22H24NOSi 346.1627, Found 346.1629.
(E)-N-(Furan-2-ylmethyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (5q). Compound 5q was
synthesized from furfuryl isocyanate (3q, 32.0 μL, 0.300
mmol) in 89% yield (80.2 mg, 0.268 mmol) as a white solid.
The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 106-107 °C;
IR (neat): 3271 (w), 1620 (m), 1535(m), 1250 (m), 1142 (m),
1
1003 (m), 949 (w), 841 (s) cm-1; H NMR (CDCl3, 400
MHz): δ 7.32-7.30 (m, 2H), 7.25-7.24 (m, 1H), 7.21-7.20 (m,
3H), 6.71 (s, 1H), 6.25 (dd, J = 3.0, 2.1 Hz, 1H), 6.11 (d, J =
3.2 Hz, 1H), 5.63 (s, 1H), 4.39 (d, J = 5.5 Hz, 2H), 0.21 (s,
9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 171.8, 151.0,
142.3, 141.8, 139.2, 135.9, 128.3, 128.2, 128.2, 110.2, 107.4,
(E)-N-Benzyl-3-phenyl-2-(trimethylsilyl)acrylamide
(5m). Compound 5m was synthesized from benzyl 36.1, -1.8; HRMS (ESI) m/z: [M+H]+ Calcd for
isocyanate (3m, 37.0 μL, 0.300 mmol) in 90% yield (83.9 C17H22NO2Si 300.1420, Found 300.1421.
mg, 0.271 mmol) as a white solid. The crude product was
purified using silica gel column chromatography
(EtOAc:hexanes = 1:4). mp 120-121 °C; IR (neat): 3279 (w),
3022 (w), 2955 (w), 1612 (m), 1535(m), 1443 (w), 1250 (m),
949 (w), 841 (s), 748 (s) cm-1; 1H NMR (CDCl3, 400 MHz):
δ 7.35-7.34 (m, 2H), 7.27-7.22 (m, 6H), 7.11-7.09 (m, 2H),
6.75 (s, 1H), 5.52 (s, 1H) 4.40 (d, J = 5.5 Hz, 2H), 0.24 (s,
9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 172.0, 142.9,
139.3, 137.8, 136.2, 128.5, 128.4, 128.3, 128.2, 128.0, 127.3,
43.6, -1.6; HRMS (ESI) m/z: [M+H]+ Calcd for C19H24NOSi
310.1627, Found 310.1628.
(E)-N-(2-Chloropropyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (5r). Compound 5r was
synthesized from 2-chloropropyl isocyanate (3r, 36.0 μL,
0.300 mmol) in 62% yield (55.0 mg, 0.186 mmol) as a white
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 108-109 °C;
IR (neat): 3259 (m), 1627 (s), 1597 (m), 1516 (s), 1496 (m),
1242 (s), 1172 (w), 875 (m), 837 (s), 752 (s) cm-1; 1H NMR
(CDCl3, 400 MHz): δ 7.41-7.39 (m, 2H), 7.34-7.29 (m, 3H),
6.79 (s, 1H), 5.68 (br s, 1H), 4.09-4.02 (m, 1H), 3.75 (ddd, J
= 14.2, 7.1, 3.8 Hz, 1H), 3.71 (ddd, J = 14.0, 8.5, 5.1 Hz,
1H), 1.43 (d, J = 6.7 Hz, 3H), 0.26 (s, 9H); 13C{1H} NMR
(E)-N-Cyclohexyl-3-phenyl-2-(trimethylsilyl)acrylamide
(5n). Compound 5n was synthesized from cyclohexyl (CDCl3, 100 MHz): δ 172.4, 142.7, 139.6, 136.3, 128.5,
isocyanate (3n, 38.0 μL, 0.300 mmol) in 94% yield (85.3 mg, 128.4, 128.3, 57.4, 46.9, 22.5, -1.6; HRMS (FAB) m/z:
0.283 mmol) as a white solid. The crude product was [M+H]+ Calcd for C15H23ClNOSi 296.1237, Found
purified using silica gel column chromatography 296.1234.
(EtOAc:hexanes = 1:4). mp 157-158 °C; IR (neat): 3263 (m),
2932 (m), 2854 (w), 1620 (s), 1535 (s), 1250 (s), 1018 (m),
833 (s) cm-1;1H NMR (CDCl3, 400 MHz): δ 7.42 (d, J = 7.3
Hz, 2H), 7.32-7.23 (m, 3H), 6.71 (s, 1H), 5.13 (d, J = 8.2 Hz,
(E)-N-(tert-Butyl)-3-(4-methoxyphenyl)-2-
(trimethylsilyl)acrylamide (6bo). Compound 6bo was
synthesized
from
((4-
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methoxyphenyl)ethynyl)trimethylsilane (2b, 92.0mg, 0.450 (2f, 114 mg, 0.450 mmol) and tert-butyl isocyanate (3o, 34.0
mmol) and tert-butyl isocyanate (3o, 34.0 μL, 0.300 mmol) μL, 0.300 mmol) in 97% yield (103 mg, 0.291 mmol) as a
in 90% yield (a 87:13 mixture of E and Z isomers, 83.1 mg, white solid. The crude product was purified using silica gel
0.272 mmol) as a white solid. The crude product was column chromatography (EtOAc:hexanes = 1:4). mp 127-
purified using silica gel column chromatography 128 °C; IR (neat): 3294 (w), 2970 (w), 2962 (w), 1620 (m),
(EtOAc:hexanes = 1:4). mp 80-81 °C; IR (neat): 3302 (m), 1535(m), 1481 (w), 1450 (w), 1242 (w), 1011 (m), 887 (w),
2962 (m), 1612 (s), 1512 (s), 1458 (m), 1304 (m), 1250 (s), 833 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.42 (dt, J =
1180 (m), 1026 (m), 887 (s) cm-1; 1H NMR (CDCl3, 400 8.7, 2.1 Hz, 2H), 7.32 (dt, J = 8.7, 2.1 Hz, 2H), 6.57 (s, 1H),
MHz), a 87:13 mixture of E and Z isomers: δ 7.41 (dd, J = 5.06 (br s, 1H), 1.29 (s, 9H), 0.22 (s, 9H); 13C{1H} NMR
8.7, 2.7 Hz, 2H), 7.40 (s, 0.15H), 7.20 (d, J = 8.7 Hz, 0.3 H), (CDCl3, 100 MHz): δ 171.0, 145.0, 136.5, 135.1, 131.3,
6.86 (d, J = 8.7 Hz, 0.3 H), 6.83 (d, J = 8.7 Hz, 2H), 6.59 (s, 130.1, 122.2, 51.2, 28.4, -1.8; HRMS (ESI) m/z: [M+H]+
1H), 5.48 (br s, 0.15H), 5.11 (br s, 1H), 3.82 (s, 0.45H), 3.81 Calcd for C16H25BrNOSi 354.0889, Found 354.0890.
(s, 3H), 1.42 (s, 1.35H), 1.31 (s, 9H), 0.22 (s, 9H), 0.10 (s,
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1.35H); 13C{1H} NMR (CDCl3, 100 MHz) of E isomer: δ
(E)-N-(tert-Butyl)-3-(4-(trifluoromethyl)phenyl)-2-
171.7, 159.6, 141.5, 137.6, 130.1, 129.1, 113.5, 55.2, 51.2,
28.6, -1.6; HRMS (ESI) m/z: [M+H]+ Calcd for
C17H28NO2Si 306.1889, Found 306.1889.
(trimethylsilyl)acrylamide (6go). Compound 6go was
synthesized from trimethyl((4-
(trifluoromethyl)phenyl)ethynyl)silane (2g, 109 mg, 0.450
mmol) and tert-butyl isocyanate (3o, 34.0 μL, 0.300 mmol)
in 70% yield (72.5 mg, 0.211 mmol) as a white solid. The
(E)-N-(tert-Butyl)-3-(p-tolyl)-2-
(trimethylsilyl)acrylamide (6co). Compound 6co was crude product was purified using silica gel column
synthesized from trimethyl(p-tolylethynyl)silane (2c, chromatography (EtOAc:hexanes = 1:4). mp 120-121 °C;
84.8mg, 0.450 mmol) and tert-butyl isocyanate (3o, 34.0 μL, IR (neat): 3294 (m), 1620 (s), 1535 (s), 1319 (s), 1250 (w),
0.300 mmol) in 98% yield (85.4 mg, 0.295 mmol) as a white 1126 (s), 1072 (m), 1018 (w), 887 (s) cm-1;1H NMR (CDCl3,
solid. The crude product was purified using silica gel column 400 MHz): δ 7.57 (br s, 4H), 6.68 (s, 1H), 5.03 (br s, 1H),
chromatography (EtOAc:hexanes = 1:4). mp 108-109 °C; 1.29 (s, 9H), 0.26 (s, 9H); 13C{1H} NMR (CDCl3,100 MHz):
IR (neat): 3286 (m), 2962 (m), 1620 (s), 1535 (s), 1450 (w), δ 170.8, 147.0, 139.8, 136.3, 130.0 (JC-F = 32.4 Hz), 128.7,
1242 (m), 1026 (m), 887 (m), 833 (s) cm-1;1H NMR (CDCl3, 125.1 (JC-F = 3.8 Hz), 124.0 (JC-F = 272.0 Hz), 51.4, 28.5, -
400 MHz): δ 7.35 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1.8; HRMS (ESI) m/z: [M+H]+ Calcd for C17H25F3NOSi
2H), 6.63 (s, 1H), 5.08 (br s, 1H), 2.34 (s, 3H), 1.30 (s, 9H), 344.1658, Found 344.1659.
0.23 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 171.5,
142.8, 138.1, 138.0, 133.4, 128.9, 128.6, 51.1, 28.5, 21.2, -
1.7; HRMS (ESI) m/z: [M+H]+ Calcd for C17H28NOSi
290.1940, Found 290.1938.
(E)-N-(tert-Butyl)-3-(m-tolyl)-2-
(trimethylsilyl)acrylamide (6ho). Compound 6ho was
synthesized from trimethyl(m-tolylethynyl)silane (2h, 84.8
mg, 0.450 mmol) and tert-butyl isocyanate (3o, 34.0μL,
0.300 mmol) in >98% yield (86.7 mg, 0.300 mmol) as a
(E)-N-(tert-Butyl)-3-(4-fluorophenyl)-2-
(trimethylsilyl)acrylamide (6do). Compound 6do was white solid. The crude product was purified using silica gel
synthesized from ((4-fluorophenyl)ethynyl)trimethylsilane column chromatography (EtOAc:hexanes = 1:4). mp 95-
(2d, 86.5 mg, 0.450 mmol) and tert-butyl isocyanate (3o, 96 °C; IR (neat): 3202 (m), 2962 (m), 1620 (s), 1528 (s),
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34.0 μL, 0.300 mmol) in >98% yield (87.4 mg, 0.298 mmol) 1450 (m), 1242 (m), 1026 (m), 833 (s) cm-1; H NMR
as a white solid. The crude product was purified using silica (CDCl3, 400 MHz): δ 7.32 (s, 1H), 7.23-7.18 (m, 2H), 7.09-
gel column chromatography (EtOAc:hexanes = 1:4). mp 7.07 (m, 1H), 6.66 (s, 1H), 5.05 (br s, 1H), 2.32 (s, 3H), 1.28
109-110 °C; IR (neat): 3302 (w), 2970 (w), 2924 (w), 1620 (s, 9H), 0.23 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ
(m), 1528(m), 1234 (m), 1018 (m), 879 (m), 825 (s) cm-1;1H 171.4, 143.7, 138.2, 137.7, 136.2, 129.0, 128.9, 128.1, 125.6,
NMR (CDCl3, 400 MHz): δ 7.41 (dd, J = 8.9, 5.3 Hz, 2H), 51.1, 28.5, 21.3, -1.7; HRMS (ESI) m/z: [M+H]+ Calcd for
6.95 (t, J = 8.7 Hz, 2H), 6.58 (s, 1H), 5.06 (s, 1H), 1.26 (s, C17H28NOSi 290.1940, Found 290.1941
9H), 0.20 (s, 9H); 13C{1H} NMR (CDCl3,100 MHz): δ 171.1,
162.4 (d, JC-F = 248.6 Hz), 143.8, 136.6, 132.5 (d, JC-F = 3.8
Hz), 130.2 (d, JC-F = 7.7 Hz), 115.0 (d, JC-F = 22.2 Hz), 51.1,
28.4, -1.8; HRMS (ESI) m/z: [M+H]+ Calcd for
C16H25FNOSi 294.1689, Found 294.1688.
(E)-N-(tert-Butyl)-3-(3-fluorophenyl)-2-
(trimethylsilyl)acrylamide (6io). Compound 6io was
synthesized from ((3-fluorophenyl)ethynyl)trimethylsilane
(2i, 86.5mg, 0.450 mmol) and tert-butyl isocyanate (3o, 34.0
μL, 0.300 mmol) in >98% yield (88.0 mg, 0.300 mmol) as a
white solid. The crude product was purified using silica gel
(E)-N-(tert-Butyl)-3-(4-chlorophenyl)-2-
(trimethylsilyl)acrylamide (6eo). Compound 6eo was column chromatography (EtOAc:hexanes = 1:4). mp 104-
synthesized from ((4-chlorophenyl)ethynyl)trimethylsilane 105 °C; IR (neat): 3202 (m), 2970 (m), 1620 (s), 1535 (s),
(2e, 93.9 mg, 0.450 mmol) and tert-butyl isocyanate (3o, 1450 (m), 1250 (s), 1142 (m), 1026 (m), 833 (s) cm-1; 1H
34.0 μL, 0.300 mmol) in >98% yield (92.7 mg, 0.299 mmol) NMR (CDCl3, 400 MHz): δ 7.30-7.19 (m, 3H), 6.99-6.93
as a white solid. The crude product was purified using silica (m, 1H), 6.61 (s, 1H), 5.06 (br s, 1H), 1.30 (s, 9H), 0.23 (s,
gel column chromatography (EtOAc:hexanes = 1:4). mp 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 170.9, 162.6 (d,
117-118 °C; IR (neat): 3302 (w), 2970 (w), 2924 (w), 1620 JC-F = 245.7 Hz), 145.6, 138.5 (d, JC-F = 7.7 Hz), 136.6 (d,
(m), 1528(m), 1489 (w), 1450 (w), 1250 (m), 1095 (m), 1018 JC-F = 1.9 Hz), 129.7 (d, JC-F = 8.6 Hz), 124.4 (JC-F = 2.9 Hz),
(m), 887(m), 833 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 115.1, 114.9, 51.3, 28.5, -1.8; HRMS (ESI) m/z: [M+H]+
7.39 (dt, J = 8.7, 2.3 Hz, 2H), 7.26 (dt, J = 8.7, 2.3 Hz, 2H), Calcd for C16H25FNOSi 294.1689, Found 294.1688.
6.58 (s, 1H), 5.06 (br s, 1H), 1.28 (s, 9H), 0.22 (s, 9H);
13C{1H} NMR (CDCl3, 100 MHz): δ 171.0, 144.8, 136.4,
(E)-N-(tert-Butyl)-3-(3-chlorophenyl)-2-
134.7, 133.8, 129.8, 128.3, 51.2, 28.4, -1.8; HRMS (ESI)
(trimethylsilyl)acrylamide (6jo). Compound 6jo was
m/z: [M+H]+ Calcd for C16H25ClNOSi 310.1394, Found
synthesized from ((3-chlorophenyl)ethynyl)trimethylsilane
310.1396.
(2j, 93.9 mg, 0.450 mmol) and tert-butyl isocyanate (3o,
34.0 μL, 0.300 mmol) in 98% yield (91.4 mg, 0.295 mmol)
as a white solid. The crude product was purified using silica
(E)-3-(4-Bromophenyl)-N-(tert-butyl)-2-
(trimethylsilyl)acrylamide (6fo). Compound 6fo was gel column chromatography (EtOAc:hexanes = 1:4). mp
synthesized from ((4-bromophenyl)ethynyl)trimethylsilane 120-121 °C; IR (neat): 3294 (m), 2970 (m), 1744 (s), 1620
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(s), 1535 (s), 1450 (w), 1358 (m), 1219 (s), 1026 (m), 833 123.8, 50.7, 28.1, -1.5; HRMS (ESI) m/z: [M+H]+ Calcd for
(s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.49 (s, 1H), 7.32- C20H28NOSi 326.1940, Found 326.1942.
7.29 (m, 1H), 7.25-7.24 (m, 2H), 6.60 (s, 1H), 5.05 (br s, 1H),
1.30 (s, 9H), 0.24 (s, 9H); 13C{1H} NMR (CDCl3,100 MHz):
Representative Experimental Procedure for the
δ 170.9, 145.8, 138.0, 136.4, 134.2, 129.5, 128.3, 128.2,
126.8, 51.4, 28.5, -1.8; HRMS (ESI) m/z: [M+H]+ Calcd for
C16H25ClNOSi 310.1394, Found 310.1394.
Synthesis of (Z)-α-Silyl-α,β-unsaturated Amides
(Z)-N,3-Diphenyl-2-(trimethylsilyl)acrylamide
(4aa).
Hexanes and THF (1.25 mL, 5:1, v/v), DIBAL-H (0.356 mL,
2.00 mmol) and trimethyl(phenylethynyl)silane (2a, 0.393
mL, 2.00 mmol) were added to a vial (8 mL) under N2. The
mixture was heated to 55 ℃ (heating block) and stirred for 2
h to afford the Si-substituted vinylaluminum reagent (~1.0
M in hexanes/THF=5:1), which was directly used without
purification. The vinylaluminum solution (~1.0 M in
hexanes/THF=5:1, 0.450 mL, 0.45 mmol) and hexane (2.55
mL) was then added into a vial (8 mL) under N2, after which
phenyl isocyanate (3a, 32.6 μL, 0.300 mmol) was added
dropwise. The reaction mixture was stirred at room
temperature for 1 h, after which the solution was quenched
by the addition of 1 N aqueous HCl (1 mL) and water (2 mL).
The mixture was extracted with EtOAc (5 x 3 mL). The
organic layers were combined, dried over MgSO4, filtered
and concentrated. The crude product was purified using
silica gel column chromatography (EtOAc:hexanes = 1:4) to
produce the desired acrylamide product 4aa in >98% yield
(E)-N-(tert-Butyl)-3-(2-chlorophenyl)-2-
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(trimethylsilyl)acrylamide (6ko). Compound 6ko was
synthesized from ((2-chlorophenyl)ethynyl)trimethylsilane
(2k, 93.9 mg, 0.450 mmol) and tert-butyl isocyanate (3o,
34.0 μL, 0.300 mmol) in 97% yield (90.4 mg, 0.292 mmol)
as an ivory solid. The crude product was purified using silica
gel column chromatography (EtOAc:hexanes = 1:4). mp 71-
72 °C; IR (neat): 3317 (m), 2962 (m), 1620 (s), 1520 (s),
1450 (w), 1366 (w), 1250 (s), 1049 (m), 841 (s) cm-1; 1H
NMR (CDCl3, 400 MHz): δ 7.57 (dd, J = 7.1, 2.5 Hz, 1H),
7.36-7.34 (m, 1H), 7.23-7.16 (m, 2H), 6.93 (s, 1H), 4.94 (br
s, 1H), 1.17 (s, 9H), 0.25 (s, 9H); 13C{1H} NMR (CDCl3,
100 MHz): δ 170.7, 146.6, 135.1, 135.0, 132.9, 130.3, 129.2,
129.1, 126.6, 51.1, 28.4, -1.7; HRMS (ESI) m/z: [M+H]+
Calcd for C16H25ClNOSi 310.1394, Found 310.1393.
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(E)-N-(tert-Butyl)-3-(furan-3-yl)-2-
(trimethylsilyl)acrylamide (6lo). Compound 6lo was (88.3 mg, 0.299 mmol) as a white solid. This compound has
synthesized from furan-3-ylethynyltrimethylsilane (2l, 82.0 been previously reported and spectra data match described.10
μL, 0.450 mmol) and tert-butyl isocyanate (3o, 34.0 μL, 1H NMR (DMSO-d6, 400 MHz): δ 10.01 (s, 1H), 7.69 (d, J
0.300 mmol) in 91% yield (72.7 mg, 0.274 mmol) as a = 7.3 Hz, 2H), 7.56 (s, 1H), 7.45-7.41 (m, 2H), 7.37-7.29 (m,
yellow solid. The crude product was purified using silica gel 5H), 7.05 (t, J = 7.3 Hz, 1H), 0.05 (s, 9H); 13C{1H} NMR
column chromatography (EtOAc:hexanes = 1:4). mp 93- (DMSO-d6, 100 MHz): δ 171.6, 144.3, 142.6, 139.5, 137.7,
94 °C; IR (neat): 3317 (m), 2962 (m), 1628 (s), 1528 (s), 128.6, 128.3, 128.1, 128.1, 123.2, 119.6, 0.1.
1450 (w), 1250 (m), 1026 (s), 833 (s) cm-1;1H NMR (CDCl3,
400 MHz): δ 7.55 (d, J = 0.9 Hz, 1H), 7.34 (d, J = 0.9 Hz,
(Z)-N-(4-Methoxyphenyl)-3-phenyl-2-
1H), 6.65 (s, 1H), 6.46 (s, 1H), 5.19 (br s, 1H), 1.39 (s, 9H),
0.20 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 171.5,
143.1, 142.7, 141.6, 128.1, 122.9, 109.8, 51.3, 28.7, -1.7;
HRMS (ESI) m/z: [M+H]+ Calcd for C14H24NO2Si 266.1576,
Found 266.1579.
(trimethylsilyl)acrylamide (4ab). Compound 4ab was
synthesized from 4-methoxyphenyl isocyanate (3b, 39.0 μL,
0.300 mmol) in 98% yield (95.8 mg, 0.294 mmol) as a white
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 144-145 °C;
IR (neat): 3286 (w), 1628 (m), 1597 (w), 1535 (m), 1512
(m), 1412 (w), 1242 (s), 1180 (w), 1041 (w), 895 (m), 833
(E)-N-(tert-Butyl)-3-(thiophen-3-yl)-2-
(trimethylsilyl)acrylamide (6mo). Compound 6mo was (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.65 (s, 1H), 7.60
synthesized from trimethyl(thiophen-2-ylethynyl)silane (2m, (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.34-7.24 (m, 5H), 6.85 (dt,
81.1 mg, 0.450 mmol) and tert-butyl isocyanate (3o, 34.0 μL, J = 9.1, 2.3 Hz, 2H), 3.76 (s, 3H), 0.10 (s, 9H); 13C{1H}
0.300 mmol) in 95% yield (80.6 mg, 0.286 mmol) as a white NMR (CDCl3, 100 MHz): δ 171.8, 156.3, 144.9, 144.1,
solid. The crude product was purified using silica gel column 137.6, 131.2, 128.3, 128.0, 128.0, 121.9, 114.1, 55.4, 0.1;
chromatography (EtOAc:hexanes = 1:4). mp 109-110 °C; HRMS (ESI) m/z: [M+Na]+ Calcd for C19H23NNaO2Si
IR (neat): 3302 (w), 2955 (w), 1620 (m), 1520 (m), 1250 348.1396, Found 348.1396.
(m), 1011 (w), 879 (w), 833 (s) cm-1; 1H NMR (CDCl3, 400
MHz): δ 7.27 (d, J = 4.6 Hz, 1H), 7.19 (d, J = 3.7 Hz, 1H),
6.98 (dd, J = 5.3, 3.9 Hz, 1H), 6.70 (s, 1H), 5.28 (br s, 1H),
1.41 (s, 9H), 0.22 (s, 9H); 13C{1H} NMR (CDCl3,100 MHz):
δ 170.7, 140.7, 139.8, 130.0, 128.7, 127.0, 126.9, 51.4, 28.7,
-1.7; HRMS (ESI) m/z: [M+H]+ Calcd for C14H24NOSSi
282.1348, Found 282.1349.
(Z)-N-(4-Bromophenyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (4ae). Compound 4ae was
synthesized from 4-bromophenyl isocyanate (3e, 59.4 mg,
0.300 mmol) in 92% yield (103 mg, 0.275 mmol) as a white
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 177-178 °C;
IR (neat): 3286 (w), 2924 (w), 1636 (m), 1589 (m), 1528
(m), 1489 (m), 1389 (m), 1311 (m), 1250 (m), 1011 (w), 895
(E)-N-(tert-Butyl)-3-(naphthalen-1-yl)-2-
(trimethylsilyl)acrylamide (6no). Compound 6no was (w), 833 (s) cm-1; 1H NMR (DMSO-d6, 400 MHz): δ 10.16
synthesized from trimethyl(naphthalen-1-ylethynyl)silane (br s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.57 (s, 1H), 7.50 (dt, J
(2n, 101 mg, 0.450 mmol) and tert-butyl isocyanate (3o, = 9.3, 2.5 Hz, 2H), 7.45-7.41 (m, 2H), 7.38 (m, 3H), 0.04 (s,
34.0 μL, 0.300 mmol) in 98% yield (96.0 mg, 0.295 mmol) 9H); 13C{1H} NMR (DMSO-d6, 100 MHz): δ 171.6, 144.7,
as a white solid. The crude product was purified using silica 142.4, 138.9, 137.6, 131.4, 128.3, 128.2, 128.2, 121.5, 114.8,
gel column chromatography (EtOAc:hexanes = 1:4). mp 99- 0.1; HRMS (ESI) m/z: [M+Na]+ Calcd for C18H20BrNNaOSi
100 °C; IR (neat): 3340 (w), 2962 (w), 1620 (m), 1520(m), 396.0395, Found 396.0397.
1450 (w), 1242 (m), 1018 (w), 979 (w), 841 (s) cm-1; 1H
NMR (CDCl3, 400 MHz): δ 7.97 (d, J = 7.8 Hz, 1H), 7.86
(Z)-N-(2-Methoxyphenyl)-3-phenyl-2-
(d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 6.9
Hz, 1H), 7.52 (quint, J = 7.8 Hz, 2H), 7.42 (d, J = 7.8 Hz,
1H), 7.39 (s, 1H), 4.76 (br s, 1H), 0.96 (s, 9H), 0.34 (s, 9H);
13C{1H} NMR (CDCl3, 100 MHz): δ 170.8, 147.3, 136.9,
134.1, 133.3, 131.0, 128.5, 128.2, 126.3, 126.3, 125.8, 125.4,
(trimethylsilyl)acrylamide (4ai). Compound 4ai was
synthesized from 2-methoxyphenyl isocyanate (3i, 44.7 mg,
0.300 mmol) in 96% yield (93.7 mg, 0.288 mmol) as a
colorless oil. The crude product was purified using silica gel
column chromatography (EtOAc:hexanes = 1:4). IR (neat):
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2958 (w), 1658 (m), 1601 (m), 1516 (s), 1458 (m), 1431 (m), 100 MHz): δ 164.4, 142.2, 138.1, 134.5, 129.8, 129.0, 128.8,
1249 (s), 1222 (m), 1026 (m), 841 (s) cm-1; 1H NMR (CDCl3, 127.9, 124.4, 121.0, 120.2.
400 MHz): δ 8.45 (d, J = 8.1 Hz, 1H), 7.95 (br s, 1H), 7.74
(s, 1H), 7.39-7.32 (m, 5H), 7.08 (td, J = 7.6, 1.7 Hz, 1H),
7.00 (td, J = 7.6, 1.4 Hz, 1H), 6.92 (dd, J = 8.1, 1.5 Hz, 1H),
3.94 (s, 3H), 0.13 (s, 9H); 13C{1H} NMR (CDCl3,100 MHz):
δ 171.5, 145.7, 144.3, 137.8, 128.5, 128.1, 128.0, 127.9,
123.6, 121.2, 119.8, 109.9, 55.7, 0.1; HRMS (EI) m/z: [M]+
Calcd for C19H23NO2Si 325.1498, Found 325.1498.
Representative Experimental Procedure for the
protodesilylation of (Z)-Amides
(Z)-N,3-diphenylacrylamide (8a). Glacial AcOH (80.0 μL,
1.38 mmol) was diluted with distilled water (500 μL) and the
resulting solution was added to a solution of (E)-N,3-
diphenyl-2-(trimethylsilyl)acrylamide (5a, 59.1 mg, 0.200
mmol) and AgF (148mg, 1.20 mmol) in a 1:1 mixture of
THF and MeOH (2 mL, 1:1, v/v). The resulting mixture was
stirred at ambient temperature for 24 h in the dark. The milky
solution was filtered through a pad of Celite® and the filtrate
was concentrated. The residue was dissolved in CH2Cl2 and
the solution washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by silica gel
column chromatography (EtOAc:hexanes = 1:5) to afford 8a
in 95% yield (42.4 mg, 0.190 mmol) as a white solid. This
compound has been previously reported and spectra data
match described.22 1H NMR (CDCl3, 400 MHz): δ 7.59 (br
s, 1H), 7.53-7.50 (m, 2H), 7.40-7.33 (m, 5H), 7.32-7.26 (m,
2H), 7.10 (tt, J = 7.3, 1.1 Hz, 1H), 6.88 (d, J = 12.5 Hz, 1H),
6.10 (d, J = 12.5 Hz, 1H); 13C{1H} NMR (CDCl3,100 MHz):
δ 164.8, 137.5, 134.6, 129.0, 128.9, 128.6, 125.0, 124.4,
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(Z)-N-(tert-Butyl)-3-phenyl-2-(trimethylsilyl)acrylamide
(4ao). Compound 4ao was synthesized from tert-butyl
isocyanate (3o, 34.0 μL, 0.300 mmol) in >98% yield (82.6
mg, 0.300 mmol) as a white solid. The crude product was
purified using silica gel column chromatography
(EtOAc:hexanes = 1:4). mp 117-118 °C; IR (neat): 3317 (m),
2962 (w), 1620 (s), 1528 (s), 1450 (w), 1296 (s), 1250 (s),
841 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 7.46 (s, 1H),
7.35-7.29 (m, 3H), 7.27-7.24 (m, 2H), 5.51 (br s, 1H), 1.43
(s, 9H), 0.07 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ
173.7, 145.2, 143.8, 138.1, 128.4, 128.1, 128.0, 51.5, 29.0,
0.2; HRMS (ESI) m/z: [M+Na]+ Calcd for C16H25NNaOSi
298.1603, Found 298.1605.
(Z)-N-(2-Chloroethyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (4ap). Compound 4ap was 119.9.
synthesized from 2-chloroethyl isocyanate (3p, 26.0 μL,
0.300 mmol) in 95% yield (80.0 mg, 0.284 mmol) as a white
(Z)-3-(2-Methoxyphenyl)-N-phenylacrylamide
(8b).
Compound 8b was synthesized from (E)-N-(2-
methoxyphenyl)-3-phenyl-2-(trimethylsilyl)acrylamide (5i,
65.1 mg, 0.200 mmol) in 88% yield (44.6 mg, 0.180 mmol)
as a yellowish solid. The crude product was purified using
silica gel column chromatography (EtOAc:hexanes = 1:5).
mp 59 °C; IR (neat): 2341 (s), 1670 (m), 1597 (m), 1519 (s),
1458 (s), 1431 (m), 1330 (w), 1288 (m), 1249 (s), 1172 (s),
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 74-75 °C; IR
(neat): 3279 (m), 2955 (w), 1620 (s), 1528 (s), 1443 (w),
1229 (m), 1250 (s), 1180 (w), 841 (s) cm-1;1H NMR (CDCl3,
400 MHz): δ 7.54 (s, 1H), 7.33-7.28 (m, 3H), 7.24-7.22 (m,
2H), 6.17 (br s, 1H), 3.68-3.61 (m, 4H), 0.04 (s, 9H);
13C{1H} NMR (CDCl3, 100 MHz): δ 173.9, 145.1, 143.5,
137.7, 128.2, 128.0, 128.0, 44.0, 41.3, 0.1; HRMS (ESI)
m/z: [M+Na]+ Calcd for C14H20ClNNaOSi 304.0900, Found
304.0900.
1
1114 (m), 1026 (s), 748 (s) cm-1; H NMR (CDCl3, 400
MHz): δ 8.46 (dd, J = 8.1, 1.7 Hz, 1H), 7.91 (br s, 1H), 7.55-
7.52 (m, 2H), 7.38-7.32 (m, 3H), 7.03 (td, J = 7.6, 1.7 Hz,
1H), 6.97 (td, J = 7.6, 1.4 Hz, 1H), 6.91 (d, J = 12.5 Hz, 1H),
6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.14 (d, J = 12.5 Hz, 1H), 3.64
(Z)-N-(Furan-2-ylmethyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (4aq). Compound 4aq was (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ 164.4, 147.8,
synthesized from furfuryl isocyanate (3q, 32.0 μL, 0.300 137.7, 134.7, 129.1, 128.6, 128.3, 127.4, 125.1, 123.7, 120.9,
+
mmol) in 77% yield (69.4 mg, 0.232 mmol) as a white solid. 119.7, 109.8, 55.4.; HRMS (EI) m/z: [M] Calcd for
The crude product was purified using silica gel column C16H15NO2 253.1103, Found 253.1100.
chromatography (EtOAc:hexanes = 1:4). mp 103-104 °C;
IR (neat): 3271 (w), 2361 (w), 1605 (s), 1535 (s), 1420 (m),
1296 (s), 1142 (m), 1003 (m), 903 (s), 849 (s) cm-1;1H NMR
(CDCl3, 400 MHz): δ 7.54 (s, 1H), 7.38 (d, J = 1.8 Hz, 1H),
7.36-7.30 (m, 3H), 7.26-7.23 (m, 2H), 6.35 (dd, J = 3.0, 2.1
Hz, 1H), 6.29 (dd, J = 3.2, 0.9 Hz, 1H), 5.96 (br s, 1H), 4.52
(d, J = 5.5 Hz, 2H), 0.05 (s, 9H); 13C{1H} NMR (CDCl3,100
MHz): δ 173.4, 151.5, 144.9, 143.7, 142.2, 137.8, 128.3,
128.0, 111.5, 107.5, 36.6, 0.0; HRMS (ESI) m/z: [M+Na]+
Calcd for C17H21NNaO2Si 322.1239, Found 322.1238.
(Z)-N-(Benzyl)-3-phenylacrylamide (8c). Compound 8c
was synthesized from (E)-N-benzyl-3-phenyl-2-
(trimethylsilyl)acrylamide (5m, 92.8 mg, 0.300 mmol) in
79% yield (55.9 mg, 0.236 mmol) as colorless liquid. The
crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). This compound
has been previously reported and spectra data match
described.23 1H NMR (CDCl3, 400 MHz): δ 7.43-7.41 (m,
2H), 7.31-7.26 (m, 6H), 7.16 (dd, J = 7.3, 2.3 Hz, 2H), 6.77
(d, J = 12.4 Hz, 1H), 6.01 (d, J = 12.4 Hz, 1H), 5.97 (br s,
N-Phenylcinnamaide (7a). A 10 mL round-bottom flask 1H), 4.41 (d, J = 5.9 Hz, 2H); 13C{1H} NMR (CDCl3, 100
equipped with a stirrer bar was charged with 4aa (60.0 mg, MHz): δ 166.9, 137.6, 136.4, 134.8, 128.8, 128.5, 128.4,
0.200 mmol), chloroform (3 mL), and trifluoroacetic acid (3 128.3, 127.9, 127.4, 124.6, 43.5.
mL) under N2. The resulting solution was stirred at 22 ℃ for
1 d. The mixture was diluted with ethyl acetate and carefully
(Z)-N-(tert-Butyl)-3-(thiophen-2-yl)acrylamide
(8d).
neutralized with saturated aqueous NaHCO3, after which it
was extracted with ethyl acetate (3 x 3 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified using silica gel
chromatography (EtOAc:hexanes = 1:3 with CH2Cl2) to
afford 7a in 95% yield (42.3 mg, 0.189 mmol) as a colorless
oil. This compound has been previously reported and spectra
data match described.11c 1H NMR (CDCl3, 400 MHz): δ 8.26
(br s, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.60 (d, J = 7.6 Hz,
2H), 7.44-7.42 (m, 2H), 7.36-7.28 (m, 5H), 7.12 (t, J = 7.5
Hz, 1H), 6.68 (d, J = 15.7 Hz, 1H); 13C{1H} NMR (CDCl3,
Compound 8d was synthesized from (E)-N-(tert-butyl)-3-
(thiophen-2-yl)-2-(trimethylsilyl)acrylamide (6mo, 84.4 mg,
0.300 mmol) in 72% yield (45.2 mg, 0.216 mmol) as a white
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:4). mp 100-101 °C;
IR (neat): 3279 (w), 2970 (w), 1643 (m), 1605 (w), 1551 (s),
1
1265 (m), 1219 (m), 1057 (w), 964 (w) cm-1; H NMR
(CDCl3, 400 MHz): δ 7.38 (d, J = 5.0 Hz, 1H), 7.29 (d, J =
3.7 Hz, 1H), 6.99 (dd, J = 5.0, 3.7 Hz, 1H), 6.78 (d, J = 12.4
Hz, 1H), 5.65 (d, J = 12.8 Hz, 1H), 5.56 (s, 1H), 1.40 (s, 9H);
13C{1H} NMR (CDCl3, 100 MHz): δ 165.7, 137.7, 132.9,
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130.4, 130.0, 126.4, 119.9, 51.3, 28.7; HRMS (ESI) m/z: HRMS (ESI) m/z: [M+H]+ Calcd for C22H20NO2 330.1494,
[M+H]+ Calcd for C11H16NOS 210.0953, Found 210.0952.
Found 330.1496.
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(Z)-2-Bromo-N,3-diphenylacrylamide (9a). (Z)-N,3- (Z)-2-Iodo-N,3-diphenylacrylamide
(9d).
(Z)-N,3-
Diphenyl-2-(trimethylsilyl)acrylamide (4aa, 59.1 mg, 0.200 diphenyl-2-(trimethylsilyl)acrylamide (4aa, 59.1 mg, 0.200
mmol) and N-bromosuccinimide (33.8 mg, 0.190 mmol) mmol) and N-iodosuccinimide (90.0 mg, 0.400 mmol) were
were added to a vial (8 mL), after which CH3CN (4 mL) was added to a vial (8 mL), after which CH3CN (4 mL) was
added. The reaction mixture was heated to 100 ℃ (heating added. The reaction mixture was stirred at 22 ℃ and stirred
block) and stirred for 1 h in the dark, after which the volatiles for 5 h in the dark. After the reaction time, the reaction
were removed under reduced pressure and the crude product solution was quenched by the addition of 10% aqueous
was purified by flash silica gel column chromatography Na2O3S2 (2 mL) and extracted with EtOAc (3 x 2 mL). The
(EtOAc:hexanes = 1:4) to obtain 9a in 91% yield (52.0 mg, organic layers were combined, dried over MgSO4, filtered
0.172 mmol) as a white solid. mp 77-78 °C; IR (neat): 3286 and concentrated. The crude product was purified using
(m), 2924 (w), 1643 (s), 1605 (s), 1512 (s), 1443 (m), 1311 flash silica gel column chromatography (EtOAc:hexanes =
(m), 1250 (m), 1188 (m), 1080 (w), 1018 (s), 918 (m) cm-1; 1:4) to obtain 9d in 95% yield (66.6 mg, 0.191 mmol) as an
1H NMR (CDCl3, 400 MHz): δ 8.58 (br s, 1H), 8.44 (s, 1H), ivory solid. mp 97-98 °C; IR (neat): 3348 (w), 1643 (s),
7.80 (dd, J = 7.5, 2.1 Hz, 2H), 7.65 (dd, J = 8.4, 1.2 Hz, 2H), 1597 (w), 1528 (s), 1443 (m), 1319 (m), 1250 (m), 1203 (w),
7.48-7.38 (m, 5H), 7.20 (t, J = 7.3 Hz, 1H); 13C{1H} NMR 1072 (w), 995 (m), 910 (s), 872 (s) cm-1; 1H NMR (CDCl3,
(CDCl3, 100 MHz): δ 160.0, 138.8, 137.3, 134.0, 130.0, 400 MHz): δ 8.41 (br s, 1H), 8.37 (s, 1H), 7.69-7.67 (m, 2H),
129.9, 129.1, 128.5, 125.1, 120.2, 114.7; HRMS (ESI) m/z: 7.63 (dd, J = 8.7, 0.9 Hz, 2H), 7.48-7.38 (m, 5H), 7.19 (t, J
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[M+H]+ Calcd for C15H13BrNO 302.0181, Found 302.0181.
= 7.3 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): δ 161.0,
145.7, 137.5, 136.2, 129.6, 129.0, 128.3, 125.0, 120.1, 93.8;
HRMS (ESI) m/z: [M+Na]+ Calcd for C15H12INNaO
371.9861, Found 371.9863.
(E)-N,2,3-Triphenylacrylamide (9b). In a glove box, (Z)-
2-bromo-N,3-diphenylacrylamide (9a, 30.2 mg, 0.100
mmol), phenylboronic acid (14.0 mg, 0.115 mmol),
Pd2(dba)3 (1.83 mg, 2.00 x 10-3 mmol), triphenylphosphine (E)-2-(2-Phenyl-1-(trimethylsilyl)vinyl)-4,5-
(3.93 mg, 0.0150 mmol), and K3PO4 (53.1 mg, 0.250 mmol) dihydrooxazole (10). A 10 mL round-bottom flask
were added to an 8 mL vial charged with a magnetic stirring equipped with a magnetic stirring bar was charged with 5p
bar. The vial was sealed with a cap (phenolic open-top cap (56.2 mg, 0.200 mmol) and CH2Cl2 (2.0 mL) under N2. DBU
with gray PTFE/silicone) and was removed from the glove (60.0 μL, 0.400 mmol) was added and the resulting solution
box. After purging with N2 gas for 5 min, toluene was added was allowed to warm to 60 ℃ (heating block) and stirred for
to the vial under N2. The solution was heated at 100 ℃ 24 h. The mixture was quenched by adding saturated
(heating block) and stirred for 12 h. The resulting mixture aqueous NH4Cl and extracted ethyl acetate (3 x 3 mL), dried
was cooled to room temperature, filtered through a plug of over MgSO4, filtered, and concentrated under reduced
Celite® (eluted with diethyl ether) and concentrated under pressure. The crude was purified using silica gel
reduced pressure. The crude product was purified by silica chromatography (EtOAc:hexanes = 1:4 with CH2Cl2) to
gel column chromatography (EtOAc:hexanes = 1:4) to afford 10 in 89% yield (43.6 mg, 0.178 mmol) as a yellowish
provide 9b in 82% yield (24.7 mg, 0.0825 mmol) as a white oil. IR (neat): 1651 (s), 1608 (m), 1492 (m), 1450 (w), 1361
solid. This compound has been previously reported and (m), 1249 (s), 1184 (m), 1157 (w), 991 (m), 960 (s), 921 (m)
1
spectra data match described.10 1H NMR (CDCl3, 400 cm-1; H NMR (CDCl3, 400 MHz): δ 7.41-7.38 (m, 2H),
MHz): δ 7.99 (s, 1H), 7.55-7.50 (m, 3H), 7.47-7.42 (m, 2H), 7.34-7.29 (m, 3H), 6.99 (s, 1H), 4.22 (t, J = 9.4 Hz, 2H), 3.95
7.38-7.36 (m, 2H), 7.31 (t, J = 7.8 Hz, 2H), 7.22-7.15 (m, (t, J = 9.4 Hz, 2H), 0.27 (s, 9H); 13C{1H} NMR (CDCl3, 100
4H), 7.10 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 6.9 Hz, 2H); MHz): δ 145.7, 137.8, 128.5, 128.1, 128.0, 123.6, 121.2,
13C{1H} NMR (CDCl3, 100 MHz): δ 164.9, 138.2, 137.8, 109.9, 55.7, 0.1; HRMS (EI) m/z: [M]+ Calcd for
135.8, 134.8, 134.6, 130.4, 130.0, 129.9, 128.9, 128.9, 128.8, C14H19NOSi 245.1236, Found 245.1231.
128.2, 124.4, 119.9.
Experimental Procedures for the Synthesis of 13
(E)-2-(4-Methoxyphenyl)-N,3-diphenylacrylamide (9c).
In a glove box, (Z)-2-bromo-N,3-diphenylacrylamide (9a,
30.2 mg, 0.100 mmol), (4-methoxyphenyl)boronic acid
(17.5 mg, 0.115 mmol), Pd2(dba)3 (1.83 mg, 2.00 x 10-3
mmol), triphenylphosphine (3.93 mg, 0.0150 mmol), and
K3PO4 (53.1 mg, 0.250 mmol) were added to an 8 mL vial
charged with a magnetic stirring bar. The vial was sealed
with a cap (phenolic open-top cap with gray PTFE/silicone)
and was removed from the glove box. After purging with N2
gas for 5 min, toluene was added to the vial under N2. The
solution was heated at 100 ℃ (heating block) and stirred for
12 h. The resulting mixture was cooled to room temperature,
filtered through a plug of Celite® (eluted with diethyl ether)
and concentrated under reduced pressure. The crude product
was purified using silica gel column chromatography
(EtOAc:hexanes = 1:4). mp 110-111 °C; IR (neat): 3387 (m),
2932 (m), 1666 (s), 1612 (s), 1512 (s), 1435 (s), 1311 (m),
tert-Butyl
(Z)-phenyl(3-phenyl-2-
(trimethylsilyl)acryloyl)carbamate (11). A 10 mL round-
bottom flask fitted with a reflux condenser was equipped
with a stirrer bar and charged with hexanes (0.35 mL), THF
(70 μL), DIBAL-H (80.0 μL mL, 0.450 mmol), and 2a (87.0
μL, 0.450 mmol) under N2. The mixture was warmed to
55 ℃ (oil bath) and stirred for 2 h, after which it was allowed
to cool to 22 ℃. Hexanes (2.5 mL) and isocyanate 3a (33.0
μL, 0.300 mmol) were then added under N2. After stirring at
22 ℃ for 1 h, Boc2O (98.0 mg, 0.450 mmol) was added to
the mixture, which was then stirred for an additional 1 h. The
mixture was quenched with saturated aqueous potassium
sodium tartrate and extracted with ethyl acetate (3 x 5 mL),
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified using silica gel
chromatography (EtOAc:hexanes = 1:20 to 1:10) to afford
11 in 95% yield (113 mg, 0.286 mmol) as a white solid. mp
80-81 °C; IR (neat): 2078 (w), 1753 (s), 1678 (m), 1369 (w),
1303 (w), 1253 (s), 1211 (m), 1149 (m), 1103 (m), 1072 (m),
1
1242 (s), 1180 (m), 1034 (m), 933 (w), 833 (m) cm-1; H
NMR (CDCl3, 400 MHz): δ 7.95 (s, 1H), 7.48 (dd, J = 8.7,
1.4 Hz, 2H), 7.33-7.26 (m, 5H), 7.22-7.17 (m, 3H), 7.12-
7.03 (m, 5H), 3.91 (s, 3H); 13C{1H} NMR (CDCl3, 100
MHz): δ 165.4, 159.9, 138.1, 137.9, 135.0, 134.2, 131.3,
130.4, 128.7, 128.7, 128.2, 127.5, 124.3, 119.8, 115.3, 55.3;
840 (s) cm-1; H NMR (CDCl3, 400 MHz): δ 7.53 (s, 1H),
7.43 (tt, J = 7.5, 1.6 Hz, 2H), 7.37-7.31 (m, 6H), 7.20 (dt, J
= 7.3, 1.4 Hz, 2H), 1.45 (s, 9H), 0.15 (s, 9H); 13C{1H} NMR
(CDCl3, 100 MHz): δ 175.9, 153.0, 144.1, 143.4, 138.9,
1
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137.9, 128.9, 128.4, 128.0, 127.6, 83.0, 27.9, 0.2; HRMS mL), DIBAL-H (0.133 mL, 0.750 mmol), and 2a (0.145 mL,
(EI) m/z: [M]+ Calcd for C23H29NO3Si 395.1917, Found 0.750 mmol) under N2. The mixture was warmed to 55 ℃
395.1920.
(oil bath) and stirred for 2 h, after which it was allowed to
cool to 22 ℃. CH2Cl2 (2.5 mL) and isocyanate 1424 (49.0
mg, 0.300 mmol) were then added to the mixture, which was
stirred at 22 ℃ for 1 h. The mixture was quenched by adding
1 N aqueous HCl (3 mL) and extracted with CH2Cl2 (3 x 5
mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified using
silica gel chromatography (CH2Cl2:acetone = 20:1 to 10:1)
to afford 15 in 73% yield (72.3 mg, 0.212 mmol) as a white
solid. mp 137 °C; IR (neat): 3128 (w), 1585 (m), 1516 (s),
1446 (m), 1357 (w), 1246 (s), 837 (s), 763 (w), 694 (s) cm-
1; 1H NMR (CDCl3, 400 MHz): δ 7.44 (s, 1H), 7.32-7.30 (m,
3H), 7.21-7.19 (m, 2H), 7.07 (dt, J = 9.3, 2.4 Hz, 2H), 6.98
(br s, 1H), 6.85 (dt, J = 9.3, 2.4 Hz, 2H), 5.76 (t, J = 5.6 Hz,
1H), 3.57 (q, J = 6.8 Hz, 2H), 2.81 (t, J = 6.8 Hz, 2H), 0.04
(s, 9H); 13C{1H} NMR (CDCl3, 100 MHz): δ 174.5, 155.2,
145.1, 143.6, 137.7, 129.9, 129.7, 128.3, 128.0, 128.0, 115.7,
41.1, 34.9, 0.0; HRMS (EI) m/z: [M]+ Calcd for
C20H25NO2Si 339.1655, Found 339.1656.
tert-Butyl (Z)-phenyl(3-phenylacryloyl)carbamate (12).
Glacial AcOH (80.0 μL, 1.38 mmol) was diluted with
distilled water (500 μL) and the resulting solution was added
to
a
solution
of
(Z)-phenyl(3-phenyl-2-
(trimethylsilyl)acryloyl)carbamate (11, 79.0 mg, 0.200
mmol) and AgF (148mg, 1.20 mmol) in a 1:1 mixture of
THF and MeOH (2 mL, 1:1, v/v). The resulting mixture was
stirred at ambient temperature for 24 h in the dark. The milky
solution was filtered through a pad of Celite® and the filtrate
was concentrated. The residue was dissolved in CH2Cl2 and
the solution washed with brine, dried over MgSO4, and
concentrated. The crude product was purified using silica gel
column chromatography (EtOAc:hexanes = 1:10) to afford
12 in 91% yield (58.8 mg, 0.182 mmol) as a white solid. This
compound has been previously reported and spectra data
match described.18 1H NMR (CDCl3, 400 MHz): δ 7.77 (d,
J = 15.7 Hz, 1H), 7.58-7.55 (m, 2H), 7.45-7.36 (m, 7H),
7.19-7.17 (m, 2H), 1.44 (s, 9H); 13C{1H} NMR (CDCl3, 100
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz): δ 168.1, 152.9, 144.2, 139.0, 135.0, 130.1, 129.0, N-(4-Hydroxyphenethyl)cinnamamide (16). A 4mL vial
128.8, 128.2, 127.8, 120.7, 83.2, 27.9.
equipped with a stirrer bar was charged with 15 (34.0 mg,
0.100 mmol), THF (0.5 mL), and MeOH (0.5 mL). Glacial
AcOH (40.0 μL, 0.690 mmol) was diluted with H2O (0.25
mL) and the resulting solution was added to the reaction vial.
AgF (72.0 mg, 0.600 mmol) was added and the resulting
solution was stirred at 22 ℃ for 24 h in the dark. The solution
was filtered through a pad of Celite® and the filtrate was
concentrated under reduced pressure. The crude product was
purified using silica gel chromatography (CH2Cl2:acetone =
10:1) to afford 16 in 69% yield (18.4 mg, 0.069 mmol) as a
white solid. This compound has been previously reported
and spectra data match described.20 1H NMR (CD3OD, 400
MHz): δ 7.55-7.50 (m, 3H), 7.38-7.36 (m, 3H), 7.06 (d, J =
8.8 Hz, 2H), 6.72 (d, J = 8.5Hz, 2H), 6.57 (d, J = 15.7 Hz,
1H), 3.48 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H);
13C{1H} NMR (CD3OD, 100 MHz): δ 168.6, 157.0, 141.6,
136.3, 131.3, 130.8, 130.7, 129.9, 128.8, 121.9, 116.3, 42.6,
35.8.
(E)-phenyl(3-phenyl-2-
(trimethylsilyl)acryloyl)carbamate (13). A vial (4 mL)
equipped with a stirrer bar was charged with 12 (48.0 mg,
0.150 mmol), CH3CN (0.15 mL), and pyrrolidine (15.0 μL).
The resulting solution was stirred at 60 ℃ (oil bath) for 15 h
and then diluted with ethyl acetate (1 mL). The mixture was
quenched with 1 N aqueous HCl (1 mL) and extracted with
ethyl acetate (3 x 1 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
purified using silica gel chromatography (hexanes:EtOAc =
1:2) to afford 13 in 89% yield (26.8 mg, 0.134 mmol) as a
white solid. This compound has been previously reported
and spectra data match described.20 1H NMR (CDCl3, 400
MHz): δ 7.71 (d, J = 15.7 Hz, 1H), 7.54 (dd, J = 7.6, 1.5 Hz,
2H), 7.40-7.34 (m, 3H), 6.74 (d, J = 15.7 Hz, 1H), 3.61 (dt,
J = 14.1, 6.9 Hz, 4H), 2.01 (quint, J = 6.8 Hz, 2H), 1.91
(quint, J = 6.8 Hz, 2H); 13C{1H} NMR (CDCl3, 100 MHz):
δ 164.7, 141.7, 135.3, 129.5, 128.7, 127.8, 118.9, 46.6, 46.0,
26.1, 24.3.
ASSOCIATED CONTENT
Experimental Procedure for the Gram-scale Synthesis of
5a
Supporting Information.
The supporting information
includes solvent screening for vinylaluminum addition to phenyl
isocyanate 3a and 1H NMR and 13C NMR spectra for all
compounds involving 2D-NOESY proton NMR spectra of
compound 5a, 4aa, and 10. This material is available free of charge
at https://pubs.acs.org/doi/10.1021/acs.joc.#######.
A 25 mL two-neck round-bottom flask fitted with a reflux
condenser was equipped with a magnetic stirring bar and
was charged with hexanes (5 mL), DIBAL-H (1.07 mL, 6.00
mmol), and (trimethylsilyl)acetylene (2a, 1.05 g, 6.0 mmol)
under N2 atmosphere. The mixture was heated to 55 ℃ (oil
bath) and stirred for 2 h. The resulting vinylaluminum
solution and hexane (34 mL) were then added into a 50 mL
round-bottom flask under N2, after which phenyl isocyanate
(3a, 0.440 mL, 4.00 mmol) was added dropwise. The
reaction mixture was stirred at room temperature for 1 h,
after which the solution was quenched by the addition of 1
N aqueous HCl (10 mL) and water (20 mL), filtered and
rinsed with H2O and hexanes. The solid was triturated with
AUTHOR INFORMATION
Corresponding Authors
Yunmi Lee – email: ymlee@kw.ac.kr
Byunghyuck Jung – email: byunghyuck.jung@dgist.ac.kr
ORCID
Yunmi Lee – 0000-0003-1315-4001
CH2Cl2 and hexanes to afford the desired product 5a in 98% Byunghyuck Jung – 0000-0002-8582-082X
yield (1.23 g, 4.0 mmol) as a white powdered solid.
Notes
Experimental Procedures for the Synthesis of 16
The authors declare no competing financial interest.
(Z)-N-(4-Hydroxyphenethyl)-3-phenyl-2-
(trimethylsilyl)acrylamide (15). A 10 mL round-bottom
flask fitted with a reflux condenser was equipped with a
stirrer bar and was charged with hexanes (0.5 mL), THF (0.1
ACKNOWLEDGMENTS
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This research was supported by the Basic Science Research
Fluconazole-Resistant Candida albicans to Fluconazole.
Bioorg. Med. Chem. Lett. 2015, 25, 34-37.
Program through the National Research Foundation of Korea
(NRF) (2020R1G1A1004460 and 2020R1A2C1005817). This work
was also partially supported by
Kwangwoon University in 2019.
a Research Grant from
[4] a) Waldmann, H. (S)-Proline Benzyl Ester as Chiral
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Toward the Development of a General Chiral Auxiliary.
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