Synthesis of 1-haloethenamides from ynamide through halotrimethylsilane- mediated hydrohalogenation

Article abstract of DOI:10.1016/j.tetlet.2013.11.091

A convenient synthesis of 1-haloethenamides has been achieved by utilizing halotrimethylsilane (TMSX, X = Cl, Br, I) and water. Halotrimethylsilane in 1 M CH₂Cl₂ solution functions as a halogen source of the in situ generated HX, and the HX added to the terminal triple bonds of ynamides in Markovnikov fashion.

Full text of DOI:10.1016/j.tetlet.2013.11.091

Tetrahedron Letters 55 (2014) 632–635
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Synthesis of 1-haloethenamides from ynamide through
halotrimethylsilane-mediated hydrohalogenation
⇑
Kazuhiro Ohashi, Shigenori Mihara, Akihiro H. Sato, Masataka Ide, Tetsuo Iwasawa
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2153, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of 1-haloethenamides has been achieved by utilizing halotrimethylsilane (TMSX,
X = Cl, Br, I) and water. Halotrimethylsilane in 1 M CH2Cl2 solution functions as a halogen source of the
in situ generated HX, and the HX added to the terminal triple bonds of ynamides in Markovnikov fashion.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 9 September 2013
Revised 12 November 2013
Accepted 19 November 2013
Available online 28 November 2013
Keywords:
1-Haloethenamide
exo-Methylene
Vinyl halide
Hydrohalogenation
Vinyl halides are clearly an important structure in organic syn-
thesis,1 because of their ability to serve as building blocks in a wide
variety of functional group transformations.2,3 The weakly bonded
halogens are highly reactive and incredibly useful toward con-
struction of complex molecules.4,5 They are readily converted into
various functional groups by halogen-metal exchange and are sig-
nificant for carbon–carbon bond forming reactions by way of tran-
sition-metal catalyzed cross-coupling reactions.6,7 From the
synthetic point of view, haloenamides8 are versatile variants of vi-
nyl halides.9 They are found in natural products,10 and their intrin-
sic electron-rich olefin has emerged as a new type of nucleophiles
in stereoselective C–C and C–N bond forming reactions.11 Haloena-
mide in exo-methylene fashion, namely 1-haloethenamide in
Scheme 1, is especially useful: the sterically unhindered moiety
and N-substituted halovinyl is potentially effective for synthesiz-
ing nitrogen-containing complex molecules. Despite the intriguing
utility of 1-haloethenamide, their synthetic availability still re-
mains a challenge, because of the inherent difficulty in hydrohalo-
genation.12 The stoichiometric addition of hydrogen halide (HX) to
terminal alkyne of ynamide is one way to prepare 1-haloethena-
mides; however, the generation and transfer of hygroscopic and
gaseous HX are inconvenient and difficult to perform,13–15 and
the problem associated with this type of reactions lies in the diffi-
culty of the formation of a mixture of stereoisomers and side-prod-
ucts caused by excess of HX.16 Although an alternative
hydrometalation exists, it requires several reaction steps and extra
operations.17
The pioneering work for efficient synthesis of haloenamides
from ynamides via addition of HX was reported by Hsung and
co-workers in 2003:18 the in situ generation of HX from MgX2
and H2O afforded
a-haloenamides with good selectivities of E/Z
ratios.19 The outcome of stereoselective addition is dictated by
the polarization of the triple bond caused by nitrogen.20 According
to the keteniminium resonance form, the halogen automatically
unites with a
-carbon;21 however, any trail for synthesizing 1-halo-
ethenamides was not documented.
On the other hand, we recently reported successful syntheses of
a-haloenamides as a single isomer in gram-scale using in situ gen-
erated HX.22 The in situ HX (X = I, Br) was generated from mixing of
1 M halotrimethylsilane (TMSX) in CH2Cl2 and 20 equiv of water,
and added to ynamide in nearly quantitative yields with perfect re-
gio- and stereoselectivity. The method completes the reaction
within 1 h under routine conditions, and showed extensive
substrate compatibility, giving novel compounds of not only
(1-iodoviny)arenes but also 1-(1-halovinyl)-1H-indoles and var-
iedly N-protected a-haloenamides.
In this Letter, we present a synthesis of 1-haloethenamides
from ynamides using in situ generated HX (Scheme 1). The
⇑
Corresponding author.
E-mail address: iwasawa@rins.ryukoku.ac.jp (T. Iwasawa).
Scheme 1. Syntheses of 1-haloethenamides 2, 3, and 4 via hydrohalogenation of 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.091

K. Ohashi et al. / Tetrahedron Letters 55 (2014) 632–635
633
Table 2
in situ HX was generated from 1 M TMSX (X = Cl, Br, I) and 20 equiv
Hydrochlorination and hydroiodation of 1 conducted via Scheme 1a
of H2O, and cleanly added to terminal alkyne of ynamide 1 in high
yields under a variety of routine reaction conditions. The resultant
products were applicable to transition-metal catalyzed reaction.18c
To the best of our knowledge, so far such a straightforward synthe-
sis of 1-haloenethenamide has not been reported. Thus, it provides
simple access to 1-haloethenamide moieties.
Initially, we commenced our investigations with the reaction
conditions previously reported for the TMSBr-mediated hydrobro-
mination (Scheme 1).22 The mixture of 123 and TMSBr24a was stir-
red at À78 °C for 10 min, and water was added, and the reaction
was allowed to warm to ambient temperature. After workup, the
product 2 was isolated with silica gel column chromatography
with typical coupling constant J = 1.2 Hz for exo-methylene
form.24b
Entry
Product
Solvent
Temp (°C)
Yield (%)
1
3
3
3
3
4
4
4
4
Cyclopentyl methyl ether
Cyclopentyl methyl ether
THF
THF
Cyclopentyl methyl ether
Cyclopentyl methyl ether
THF
THF
À78
0
92
94
90
95
89
88
90
18
2
3b
4
À78
0
5
6
À78
0
7
À78
8c
0
a
Reaction conditions: 1 (0.5 mmol), solvent (4 mL), 1 M (CH3)3SiX in CH2Cl2, H2O
(10 mmol).
6% of unreacted 1 was observed.
b
c
54% of unreacted 1 was observed.
As summarized in Table 1, the reactivity of 1 conducted via
Scheme 1 was evaluated. An appropriate amount of TMSBr proved
to be 1.2 equiv for completion at À78 °C (entries 1–3). For entries 4
and 5, ethereal solvents performed better than CH2Cl2; highest
yielding transformation in entry 5 was achieved under cyclopentyl
methyl ether (CPME), and the reaction at 0 °C gave comparable
yield with À78 °C (entry 6). For entry 7, acetone also carried out
the clean hydrobromination at 0 °C. For entry 8, the reaction under
acetonitrile endured to give 93% yield. For entry 9, the yield under
toluene was acceptable. It is worth noting that good yields were
achieved through the addition of TMSBr prior to water. For entries
1 and 2, the addition of water in advance did not improve the yield
very well; that is, the complexation of ynamide and TMSBr would
be important for the reaction mechanism. This phenomenon was
also observed in the previous report,22c and is agreeable with the
activation of TMSCl in Table 2.
To further clarify the reactivity of 1 with the in situ HX, chloro-
trimethylsilane (TMSCl) and iodotrimethylsilane (TMSI) were
tested as halogen sources (Table 2). The reactions with TMSCl un-
der CPME (entries 1 and 2) and THF (entries 3 and 4) smoothly pro-
ceeded to give the vinyl chloride 3 in more than 90% yields.25 For
entries 5–7 on hydroiodation with TMSI, high yielding transforma-
tions to the vinyl iodide 4 were also achieved in up to 90% yield
although the reaction at entry 8 did not work well. To our surprise,
the obstinate TMSCl quickly reacted with 1 although it did not re-
act with internal alkynes in the previous report.22b As depicted in
Table 1, the reaction mechanism emphasizes the importance of
complexation between ynamide and TMSX; thus, the sterically
unhindered alkyne of 1 tightly coordinates to TMSCl, and readily
activates the Si–Cl bond.22c
unfortunately, these gradually decayed to unclear impurities and
turned into dark colored stuff even though they were conserved
under argon atmosphere at low temperature. Actually, the iodide
4 was quite labile to totally decompose in ca. 2 days along with
turning to dark brown solid materials, and the bromide 2 in
10 days after purification was observed to totally decay. Chloride
3 holds against decay, and 70% of the whole did not change into
impurities in 1 week.
Preliminary mechanistic investigations were performed
through deuteration experiments; H2O in Scheme 1 was replaced
by D2O, and in situ DBr added to the triple bond of 1 (Table 3).
For entries 1 and 2, deuteriobromination under CPME and THF gen-
erated (E)-2-d1- without (Z)-2-d1 in high yields, and the addition
mode of DBr was precisely controlled with complete trans-selectiv-
ity. On the other hand, utilizing diethyl ether, acetone, dichloro-
methane, and acetonitrile as solvents gave non-negligible
amounts of (Z)-2-d1 (entries 3–6), and for entry 8 the reaction in
acetone at 0 °C underwent hydrobromination strangely in 35%
yield of 2 nevertheless dry solvent was used.26 Thus, we envisaged
that the kinetic significance of the protonation step would be
probed by the following experiment (entry 9). A blend of D2O
(10 equiv) and H2O (10 equiv) was used instead of H2O under
Table 3
Deuteriobromination of 1a
Thus, 1-haloethenamides 2, 3, and 4 seemed to be stable during
workup and silica gel column chromatography, and were obtained
as white solid materials right after purification; however,
Table 1
Screening of reaction conditions for hydrobromination of 1 conducted via Scheme 1a
Entry
Solvent
Temp (°C)
Yieldb (%)
Entry TMSBr (equiv) Solvent
Temp (°C) Yieldb (%)
(E)-2-d1
(Z)-2-d1
2
1
2c
3
4
5
2.0
2.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
CH2Cl2
CH2Cl2/H2O (4% v/v)
CH2Cl2
THF
À78
À78
À78
À78
56
64
89
91
95
93
89
93
86
1
2
3
4
5
Cyclopentyl methyl ether
THF
Diethyl ether
Acetone
CH2Cl2
CH3CN
Cyclopentyl methyl ether
Acetone
Cyclopentyl methyl ether
À78
À78
À78
À78
À78
À20
0
85
92
72
65
26
64
85
51
21
0
0
9
4
18
14
24
14
4
14
8
14
16
9
Cyclopentyl methyl ether À78
6
7
Cyclopentyl methyl ether
Acetone
0
0
6
7
8
CH3CN
Toluene
À20
9d
0
8
0
À78
7
0
35
79
9c
a
Reaction conditions: 1 (0.5 mmol), solvent (4 mL), 1 M (CH3)3SiBr in CH2Cl2,
H2O (10 mmol).
Isolated yields after short-plug column chromatography.
20 equiv of H2O was blended in advance with 4 mL of CH2Cl2.
6% of unreacted 1 was observed.
a
Reaction conditions: 1 (0.5 mmol), solvent (4 mL), 1 M (CH3)3SiBr in CH2Cl2,
D2O (10 mmol).
b
c
Determined by 1H NMR.
b
c
d
Instead of D2O, a blend of D2O (10 equiv) and H2O (10 equiv) was used.

634
K. Ohashi et al. / Tetrahedron Letters 55 (2014) 632–635
Table 4
CPME solvent in Scheme 1, which produced 2 as a dominant prod-
uct (79%) and (E)-2-d1 as a minor product (21%). Obviously, the
product distribution of 2 and (E)-2-d1 was affected by the rate dif-
ference of the C–H and C–D formations, indicating that the proton-
ation is the product-determining step.
Syntheses of 1-chloroethenamides 5 and 6
Whereas 20 equiv of water served as a proton source, methanol
mysteriously did not work (Scheme 2). To the mixture of 1 and
TMSBr was added 20 equiv of methanol: the target 2 was not ob-
served, and 84% of 4-methyl-N-pheynylbenzenesulfonamide was
isolated instead. Although the mechanism for dissociating C–N
bond of 1 with utilizing methanol is not yet fully known, the
molecular water in this reaction system proved to be indispensable
for exactly forming 1-haloethenamides.
R
Product
Yielda (%)
CH2CH@CH2
4-CH3Ph
5
6
95
98
a
With a viable route to the 1-haloethenamides in hand, we then
worked on applying the hydrochlorination to starting N-ethynyl
tosylamides bearing allyl and p-tolyl groups (Table 4). The reac-
tions smoothly proceeded to give the corresponding vinyl chlo-
ride 5 and 6 in 95% and 98% yields, respectively. The difference
in reactivity between allyl and p-tolyl groups was not observed;
each smoothly yielded the corresponding product. The products
5 and 6 were isolated as white solid materials that withstood
aqueous workup procedures and chromatographic purification
on silica gel. As for the stability of 5 and 6, the allyl 5 was stored
at room temperature for 1 week with no appreciable decomposi-
tion: however, unfortunately, the chloride 6 began to decay right
after isolation, and exhaustive decomposition was observed in ca.
4 h. Although we tried to explore substrate scope for synthesizing
other 1-haloethenamides, they were too labile to isolate. The
structural motif in 1-haloethenamide, in which exo-methylene
incorporated into alpha-haloenamide, would be originally quite
fragile.
In view of the situation, we attempted to certify the utility of
such an extremely fragile 1-haloethenamide. As shown in Table 5,
the synthetic potential was successfully performed by employ-
ment of the freshly prepared 1-haloetheneamides. The vinyl ha-
lide group is an excellent candidate for use in transition metal
mediated reactions such as Sonogashira coupling.16b Freshly pre-
pared bromide 2 and iodide 4 underwent the cross-coupling
with trimethylsilyl acetylene to yield enyne 7 in 60% and 66%
yields, respectively. For entries 3 and 4, each reaction with aryl-
acetylene also proceeded in 74% and 75% yields, respectively.
Note that the enyne 7, 8, and 9 were stable although the halide
2 and 4 were fragile27: thus, the employment of those halides
right after isolation was proved to be practicable for Sonogashira
reaction.
Isolated yields after short-plug column chromatography.
Table 5
Employment of 2 and 4 for synthesizing enynes 7, 8, and 9
Entry
Substrate
R
Product
Yielda (%)
1
2
3
4
2
4
2
2
(CH3)3Si
(CH3)3Si
Ph
7
7
8
9
60
66
74
75
3-ClPh
a
Isolated yields after short-plug column chromatography.
Acknowledgments
We are pleased to thank Dr. Toshiyuki Iwai at OMTRI for gentle
assistance with HRMS. We are very grateful to Professor Michael P.
Schramm at California State University of Long Beach for helpful
discussion.
Supplementary data
In conclusion, we have developed a simple procedure for the
synthesis of 1-haloethenamides from ynamides employing halotri-
methylsilane and water. This reaction is initiated by generation of
in situ HX from halotrimethylsilane and water in a wide variety of
reaction conditions, and the HX adds to terminal alkynes of yna-
mides in Markovnikov manner, resulting in regio- and stereoselec-
tive installation of H and X atoms. Although the products of
1-haloethenamides were easily broken into impurities, those
freshly prepared were fit for use to synthesize the corresponding
Sonogashira-coupling adducts of enynes. We hope this protocol
serves as a tool for the efficient synthesis of complex amine-
substituted molecules.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
11.091.
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Representative procedure for synthesizing 2 (Table 1, entry 4): To a solution of
1 (0.5 mmol) in anhydrous CH2Cl2 (4 mL) at À78 °C was added TMSBr (1 M in
CH2Cl2) dropwise over 5 min, and the mixture was stirred for 10 min. Then,
H2O (10 mmol) was added, and the cooling-bath was removed to warm to
room temperature. After additional stirring for 50 min, the reaction was
quenched at 0 °C with saturated aqueous sodium thiosulfate, and stirred for
30 min, and allowed to warm to ambient temperature. To the mixture was
added CH2Cl2, and organic phases were washed with brine, and then dried over
Na2SO4, and concentrated to give a crude product. Purification by silica gel
column chromatography (eluent; hexane/EtOAc = 4/1) afforded 2 in 89% yield
(157 mg) as white solid materials. 1H NMR (400 MHz, CDCl3)
d 7.71 (d,
12. (a) Stone, H.; Schecher, H. Org. Synth., Coll. 1963, 4, 543; (b) Stewart, L. J.; Gray,
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Reddy, Ch. K.; Periasamy, M. Tetrahedron Lett. 1990, 31, 1919–1920.
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877–882; (b) Griesbaum, K.; El-Abed, M. Chem. Ber. 1973, 106, 2001–2008; (c)
Fahey, R. C.; Lee, D.-J. J. Am. Chem. Soc. 1968, 90, 2124–2131; (d) Stacey, F. W.;
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E. J. Am. Chem. Soc. 1940, 62, 1367–1368.
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Wiemer, D. F. Tetrahedron Lett. 1993, 34, 2433–2436; (c) Furrow, M. E.; Myers,
A. G. J. Am. Chem. Soc. 2004, 126, 5436–5445; (d) Krafft, M. E.; Cran, J. W. Synlett
2005, 1263–1266; (e) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. J.
Org. Chem. 2007, 72, 2216–2219.
J = 8.3 Hz, 2H), 7.38–7.28 (m, 7H), 5.98 (d, J = 1.9 Hz, 1H), 5.68 (d, J = 1.9 Hz,
1H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.8, 138.6, 136.3, 129.9, 129.5,
129.0, 128.62, 128.57, 126.0, 122.8, 21.9. MS (DI) m/z: 351 (MH+), 272 ([MH-
Br]+). IR (neat): 3117 (C@C), 3032, 1344 (NSO2), 1233, 1162 cmÀ1. HRMS (DI)
calcd for C15H14(79)BrNO2S 350.9929, found 350.9913.
25. The difference in reactivity between TMSCl, TMSBr, and TMSI was not
observed. Each reagent quickly reacted with 1.
26. There is likelihood that Lewis acidic TMSBr assisted H-D exchange between
acetone and D2O to give HDO and H2O, and consequently the yield of 2
increased.
27. Enynes
8 and 9 were obtained in pure form right after column
chromatography: their purities decreased to ca. 85% in 1 h although the
further decomposition was not observed.