Regio-, and stereoselective iodobromination of ynamides for synthesis of (E)-1-bromo-2-iodoenamides

Article abstract of DOI:10.1002/ejoc.201402057

One-step synthesis of vicinal bromoiodoenamides from ynamides through IBr addition is described. Two types of IBr were used: commercially available IBr, and in situ generated IBr. This simple protocol enables highly efficient regio- and stereoselective iodobromination of the triple bond on a gram scale in anti-mode, and provides a potentially diverse scaffold for preparation of tetrasubstituted olefins. Copyright

Full text of DOI:10.1002/ejoc.201402057

FULL PAPER
DOI: 10.1002/ejoc.201402057
Regio-, and Stereoselective Iodobromination of Ynamides for Synthesis of
(E)-1-Bromo-2-iodoenamides
Masataka Ide,[a] Yuta Yauchi,[a] and Tetsuo Iwasawa*[a]
Keywords: Synthetic methods / Regioselectivity / Alkynes
One-step synthesis of vicinal bromoiodoenamides from
ynamides through IBr addition is described. Two types of IBr
were used: commercially available IBr, and in situ generated
IBr. This simple protocol enables highly efficient regio- and
stereoselective iodobromination of the triple bond on a gram
scale in anti-mode, and provides a potentially diverse scaf-
fold for preparation of tetrasubstituted olefins.
stoichiometric addition of iodobromine to alkyne is one
way to prepare a vicinal dihaloalkene; however IBr is incon-
venient, hygroscopic and hazardous, and this method often
results in poor regio- and stereochemical control.[11,12]
Herein we report the first example of a facile one-step
synthesis[13] of vicinal bromoiodoenamides from ynamides
in a highly regio- and stereoselective manner (Scheme 2).
Commercially available IBr and/or in situ generated IBr ac-
complished the reaction. Commercially available IBr
worked very well when used in diethyl ether solution. In situ
IBr was successfully generated from bromotrimethylsilane
(TMSBr) and N-iodosuccinimide (NIS). Thus, the methods
provide simple general entry to (E)-1-bromo-2-iodoenamide
substructures.
Introduction
Enamides are valuable intermediates in organic synthe-
sis,[1–3] because of their ability to serve as building blocks
in a wide variety of functional group transformations.[4]
They have also been found as substructures in bioactive nat-
ural products and pharmaceutically interesting com-
pounds.[5] Moreover, they recently have emerged as a type
of useful nucleophile in stereoselective C–C and C–N bond-
forming reactions.[6] From a synthetic point of view, vicinal
dihaloenamides are versatile variants of enamides. The re-
active bonds between sp2 carbon and halogen are advan-
tageous to chemical transformation, and this beneficial
point would expand the possibilities and importance of en-
amide structures. Bromoiodoenamides are especially useful,
because they could be converted into various functional
groups by halogen-metal exchange and be significant for
carbon–carbon bond-forming reactions by way of transi-
tion-metal catalyzed cross-coupling reactions.[7–9] Thus,
weakly bonded iodine/bromine and electron-rich olefins are
highly reactive and potentially functional toward synthe-
sized nitrogen-containing complex molecules.[10] Despite
the utility of vicinal dihaloalkenes, their synthetic availabil-
ity remains a challenge, because of the inherent difficulty in
regio- and stereoselective iodobromination (Scheme 1). The
Scheme 2. Regio- and stereoselective iodobromination of 1 to syn-
thesize 2.
Scheme 1. Iodobromination of alkynes for synthesis of vicinal
bromoiodoalkenes.
[a] Department of Materials Chemistry, Faculty of Science and
Technology, Ryukoku University,
Seta, Otsu, 520-2194, Japan
E-mail: iwasawa@rins.ryukoku.ac.jp
Results and Discussion
http://www.chem.ryukoku.ac.jp/iwasawa/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402057.
We started investigations with the reaction of 1 under-
taken as shown in Scheme 2: three methods were used. For
3262
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3262–3267

Regio-, and Stereoselective Iodobromination of Ynamides
method A, a mixture of 1 and IBr (0.5 m) in diethyl ether fragile in the solution state: a colorless solution of 2 in sev-
was stirred at –78 °C, and the reaction was warmed to am- eral solvents gradually turned colored and gave several
bient temperature. The IBr is commercially available;[14] spots by TLC monitoring.
however, it is occasionally unpleasant to work with. Thus,
Table 1. Screening of reaction conditions for method B.[a]
it is worthwhile developing an alternative way to generate
IBr in situ, such as for methods B and C. For method B, a
mixture of 1 and TMSBr (1 m) in dichloromethane was
stirred at –78 °C, then NIS (0.5 m) in acetonitrile was
added, and the reaction was conducted at room tempera-
ture. For method C, a mixture of NIS and TMSBr solution
was stirred at –78 °C, and then the appropriate amount of
1 in toluene was added. Luckily, for the crude mixture, both
1H NMR and 13C NMR spectroscopic analyses revealed a
97:3 isomeric ratio for method B and about 100:0 for meth-
ods A and C. Workup and purification with column
chromatography gave corresponding IBr adduct 2 in 71, 83,
and 90%, respectively, for methods A, B and C. Concerning
iodobromination of 1, the in situ version of methods B and
C was better than method A. The molecular structure of
2 was determined by crystallographic analysis as shown in
Figure 1, disclosing its stereochemistry as (E) fashion.[15]
Entry
Solvent
Temp. [°C]
Yield [%][b]
2
1-HBr
1
2
3
4
5
6
7
toluene
toluene
toluene
toluene
CH2Cl2
CH3CN
THF
–78
–45
–20
0
–78
–20
–78
–78
–78
83
87
77
80
70
65
36
72
90
3
5
2
8
5
1
7
11
0
8
CPME
toluene
9[c]
[a] Reaction conditions: 1 (126 mg, 0.50 mmol), solvent (2 mL),
TMSBr (1 m) in dichloromethane, NIS (0.5 m) in acetonitrile.
[b] Isolated yields for 2, and yield calculated by NMR spectroscopy
for 1-HBr in the crude state, see ref.[17]. [c] Performed by method
C.
With a workable protocol in hand, we studied the sub-
strate scope for methods A, B and C (Table 2). The synthe-
sis of 2 by method C and 3 by method B were readily ame-
nable to the gram scale. Evans auxiliary 4 in methods A–C
was afforded in about 75%, and there was no difference
in procedure. As for 5, unfortunately, the reaction showed
multiple spots by TLC monitoring for all methods, and
complex column chromatography was needed to isolate 5
from byproducts in 51–62% yield. For 6 and 7, the in situ
version of method B was effective in isolating the isomer as
cleanly as possible with only a slight amount of by-product;
however, methods A and C were unsuitable for the prepara-
tion of 6 and 7 because considerable amounts of the isomer
and by-product were formed. For indole 8, comparable
yields for methods A–C were obtained. The products of 6–
Figure 1. ORTEP drawing of 2 with thermal ellipsoids at the 50%
probability level. Hydrogen atoms are omitted for clarity. Selected
bond lengths [Å]: N(1)–C(1) = 1.417, C(1)–Br(1) = 1.934, C(2)–
I(1) = 2.114, C(1)–C(2) = 1.304.
As summarized in Table 1, screening of reaction condi- 8, unlike 2–5, dissolved very sparingly in the solvent used
tions for method B was conducted with 1. For Table 1, En- for column chromatography, and precipitation and/or
tries 1–4, appropriate temperatures were surveyed, and low recrystallization were used to isolate the product.[18,19] Ind-
temperatures were needed to give 2 in good yield. Unfortu- ole 9, which has an acetyl group at the 3-position was read-
nately, purification of 2 suffered from small amounts of by- ily soluble in organic solvents, unlike 8, and facile column
product, which was the hydrobromination adduct of (E)- chromatography resulted in 70% yield for method B and
methyl-1-bromo-2-phenylvinyl(phenyl)carbamate, namely 75% for method C; however, commercial IBr unworkable
1-HBr.[16,17] For Table 1, Entries 5–8, yields in dichloro- and resulted in isomeric mixtures. For viscous material 10,
methane, acetonitrile, tetrahydrofuran (THF), and cy- method A unexpectedly gave high yields for the transforma-
clopentyl methyl ether (CPME) were 70, 65, 36, and 72%, tion relative to methods B and C.[20] Although 2 for method
respectively; they were not higher than 83% in Table 1, En- C, 3 for method B, and 9 for methods B and C were ob-
try 1. For Table 1, Entry 9, method C accomplished clean tained as nearly single isomers, other reactions were slightly
iodobromination in a high 90% yield without producing contaminated, in the crude state, with isomers or hydro-
byproduct 1-HBr. However, these studies proved 2 to be halogenated byproducts. Thus, the different vicinal iodo-
Eur. J. Org. Chem. 2014, 3262–3267
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Ide, Y. Yauchi, T. Iwasawa
FULL PAPER
Table 2. Substrate scope.[a,b]
[a] Reactions were conducted on a 1 mmol scale of the ynamide, and yields are for isolated compounds as single isomers of 100% purity,
unless otherwise noted. [b] Method A, to the ynamide in a flask commercial IBr (1.5 equiv.) in Et2O was added; Method B, to the
ynamide in a flask TMSBr (1.5 equiv.) in CH2Cl2 was initially loaded, then NIS (1.5 equiv.) in CH3CN was added; Method C, to the
flask charged with NIS (1.5 equiv.) in toluene TMSBr (1.5 equiv.) in CH2Cl2 was initially loaded, then the ynamide in CH2Cl2 was added.
[c] A 61% yield calculated by NMR spectroscopy, 6/isomer = 80:20. [d] Many by-products in the crude state. [e] 47% yield calculated by
NMR spectroscopy, 7/isomer = 81:19. [f] Messy NMR spectrum in the crude state. [g] 56% yield calculated by NMR spectroscopy, 9/
isomer = 83:17.
bromoenamides differ in method, solubility, stability, and
purification.
Table 3. Evaluation of the reactivity of 1 under conditions shown
in Scheme 3.[a]
Different patterns of N-halosuccinimide/halotrimethylsil-
ane were tested, and the results are summarized in Table 3.
Interestingly, Table 3, Entry 4 shows a 63% yield of 2,
which is identical to the product resulting from methods A–
C in Scheme 2. This means both combinations of TMSI/
NBS and TMSBr/NIS generate in situ IBr which differ in
degree but not in kind, and each in situ IBr has intrinsically
similar reactivity to commercial IBr used in method A. The
use of TMSCl (Table 3, Entries 3, 6, and 9) showed no reac-
tion. Even the use of NCS (Table 3, Entries 7 and 8) did
not consume all of starting 1, and gave 48 and 33% yield
for 11 and 12, respectively, in which the chloride atom was
not installed as shown in Figure 2. In contrast, the combi-
nations of halogens, except for chloride, (Table 3, Entries 1,
2, 4, and 5) gave better yields and afforded the desired prod-
ucts. Thus, the product distribution was affected by the dif-
ference of the easily cleavable N–X and Si–X bonds. In fact,
the N–I bond in NIS generally possesses a lower bond-
dissociation energy than the N–Br bond for NBS and N–
Cl bond for NCS, reflecting the high yielding conversion of
1. The bond energies of Si–Cl, Si–Br, and Si–I are 113, 96,
and 77 kcal/mol, respectively:[21] the Si–Cl bond would be
difficult to activate. Thus, as shown in Scheme 3, these ob-
servations are consistent with the plausible reaction mecha-
nism that is composed of two stages. Initially, TMSBr reacts
with NIS to give in situ IBr and N-trimethylsilylsuc-
Entry
X
XЈ
Product
Yield
[%][b]
Recovered 1
[%][b]
1
2
3
4
5
6
7
8
9
I
I
I
Br
Br
Br
Cl
Cl
Cl
I
11
2
–
76
90
0
63
61
0
48
33
0
0
0
Br
Cl
I
Br
Cl
I
≈ 100
0
10
≈ 100
16
25
≈ 100
2
12
–
11
12
–
Br
Cl
[a] Reaction conditions: 1 (126 mg, 0.50 mmol), toluene (2 mL),
NXS (0.5 m) in acetonitrile, TMSXЈ (1 m) in dichloromethane.
[b] Isolated yields.
cinimide.[22,23] The complexation of starting ynamide and Figure 2. Iodide 11 and bromide 12.
3264 Eur. J. Org. Chem. 2014, 3262–3267
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Regio-, and Stereoselective Iodobromination of Ynamides
sidual solvent signals [1H NMR: CHCl3 (7.26 ppm). 13C NMR:
CDCl3 (77.0 ppm)]. Signal patterns are indicated as s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br., broad.
TMSX does not seem to be important.[16] Then, IBr that is
charged with cationic iodide and anionic bromide[17] and
undergoes an addition reaction to a ynamide substructure
in anti-mode,[10–12] to give a single isomer. The ynamide
moiety contains a keteniminium resonance form by polar-
ization of the triple bond of the nitrogen atom, and the
resultant charged α-carbon is more electrophilic than the β-
carbon that is negatively charged. This is supported by the
chemical shifts observed by 13C NMR spectroscopy that
showed the α-carbon downfield around 80 ppm, and the β-
carbon upfield around 70 ppm (e.g. for ynamide 1, signals
appear at 83.1 ppm and 70.3 ppm).
Representative Procedure by Method A for Preparation of Methyl
(E)-1-Bromo-2-iodo-2-phenylvinyl(phenyl)carbamate
(2):
(see
Scheme 2). Under an argon atmosphere, to a solution of 1 (281 mg,
1.1 mmol) in toluene (4.5 mL) at –78 °C was added IBr (348 mg,
1.7 mmol) in diethyl ether (3.4 mL) dropwise over 5 min, and the
mixture was warmed to room temperature. After stirring for 1 h,
the reaction was quenched at 0 °C with saturated aqueous sodium
thiosulfate, and stirred for 10 min, and warmed to ambient tem-
perature. The aqueous phase was extracted with toluene (10 mL
ϫ3), and the combined organic phases were washed with brine
(20 mL), and then dried with sodium sulfate, and concentrated to
give 524 mg of crude products. Purification by short-plug column
chromatography (eluent; dichloromethane) and precipitation from
dichloromethane/hexane afforded 361 mg of 2 in 71% yield as a
white solid. Analytical data are listed in the section below.
Representative Procedure by Method B for Preparation of Methyl
(E)-1-Bromo-2-cyclohexyl-2-iodovinyl(phenyl)carbamate (3): (see
Table 2). Under an argon atmosphere, to a solution of starting yna-
mide,
methyl
cyclohexylethynyl(phenyl)carbamate
(1.00 g,
3.9 mmol), in anhydrous toluene (16 mL) at –78 °C was added
TMSBr (5.9 mL of 1 m in dichloromethane) dropwise over 8 min,
and the mixture was stirred for 3 min. Then, NIS (1.33 g, 5.9 mmol)
in acetonitrile (12 mL) was slowly added over 5 min, and the cool-
ing-bath was removed to warm to room temperature. After ad-
ditional stirring for 1 h, the reaction was quenched at 0 °C with
saturated aqueous sodium thiosulfate, and stirred for 10 min, and
warmed to ambient temperature. The aqueous phase was extracted
with toluene (15 mL ϫ3), and the combined organic phases were
washed with brine (30 mL), and then dried with sodium sulfate,
and concentrated to give 1.94 g of crude products. Purification by
silica gel column chromatography (eluent; toluene) afforded 1.66 g
of 3 in 92% yield as a yellow viscous oil. Analytical data are listed
in the section below.
Scheme 3. Plausible reaction mechanism.
Conclusions
In conclusion, highly regio-, and stereoselective iodobro-
mination of ynamides was achieved by using commercially
available IBr and/or in situ generated IBr. The resultant sin-
gle isomer formed (E)-2-bromo-1-iodoenamides. In cases
for which commercial IBr did not work well, in situ gener-
ated IBr proved an effective reagent. In situ IBr could be
generated by reaction of TMSBr with NIS, which then
added to the ynamide according to the nature of the keten-
iminium resonance form. Application of this methodology
to simple alkynes is ongoing for the synthesis of tetra-sub-
stituted olefins bearing four different carbon-linked groups.
Representative Procedure by Method C for Preparation of Methyl
(E)-1-Bromo-2-iodo-2-phenylvinyl(phenyl)carbamate
(2):
(see
Table 2). Under an argon atmosphere, to a solution of NIS (1.35 g,
6.0 mmol) in anhydrous toluene (16 mL) at –78 °C was added
TMSBr (6.0 mL of 1 m in dichloromethane) dropwise over 7 min,
and the mixture was stirred for 5 min. Then, ynamide 1 (1.00 g,
4.0 mmol) in toluene (12 mL) was slowly added over 5 min, and
the cooling-bath was removed to warm to room temperature. After
additional stirring for 1 h, the reaction was quenched at 0 °C with
saturated aqueous sodium thiosulfate, and stirred for 10 min, and
warmed to ambient temperature. The aqueous phase was extracted
with toluene (15 mL ϫ3), and the combined organic phases were
washed with brine (30 mL), and then dried with sodium sulfate,
and concentrated to give 1.86 g of crude products. Purification by
silica gel column chromatography (eluent; hexane/dichloromethane
= 2:1) afforded 1.74 g of 2 in 95% yield as a yellowish solid. Analyt-
ical data are listed in the section below.
Experimental Section
General Methods: All reactions sensitive to air or moisture were
carried out under an argon atmosphere and anhydrous conditions
unless otherwise noted. Dry solvents were purchased and used
without further purification and dehydration. All reagents were
purchased and used without further purification. Analytical thin
layer chromatography was carried out on Merck silica 60 F254. Col-
umn chromatography was carried out with silica gel 60 n (Kanto
Chemical Co.). HRMS were reported on the basis of TOF (time
Preparation of 1
M Halotrimethylsilane (TMSX) Stock Solution in
Dichloromethane: TMSBr (3.5 g) was added to dry dichlorometh-
ane (20 mL), TMSI (5 g) was added to dry dichloromethane
(25 mL), and TMSCl (2.6 g) was added to dry dichloromethane
(21 mL); each was used as a 1 m TMSX solution for our experimen-
tal usage. The reactivity of the freshly prepared TMSX solution
was maintained at least for two weeks. However, in the case of 1 m
toluene solution of TMSX, unfortunately, complete decomposition
of flight), and EB (double-focusing) techniques. H and 13C NMR
spectra were recorded with a 5 mm QNP probe at 400 MHz and
100 MHz, respectively. Chemical shifts are reported relative to re-
1
1
by H NMR spectroscopy was observed only in 24 h.
Eur. J. Org. Chem. 2014, 3262–3267
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3265

M. Ide, Y. Yauchi, T. Iwasawa
FULL PAPER
Methyl (E)-1-Bromo-2-iodo-2-phenylvinyl(phenyl)carbamate (2): A), 57% yield, 148 mg (Method B) as a white solid (recrystalli-
1
71% yield, 361 mg (Method A), 82% yield, 199 mg (Method B), zation from methanol). H NMR (400 MHz, CDCl3): δ = 7.87 (d,
and 90% yield, 208 mg (Method C) as a yellowish white solid J = 7.9 Hz, 2 H), 7.39–7.29 (m, 7 H), 2.96 (s, 3 H), 2.45 (s, 3
1
(recrystallization from methanol). H NMR (400 MHz, CDCl3): δ H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.9, 142.4, 134.5,
= 7.58 (dd, J = 7.5, 1.3 Hz, 2 H), 7.46–7.31 (m, 8 H), 3.94 (s, 3 129.8, 129.3, 129.2, 128.7, 128.6, 120.1, 101.5, 36.2, 22.0 ppm. MS
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.2, 142.5, 138.8, (FAB): m/z = 492 [MH]+. IR (neat): ν = 2922, 1595, 1440, 1354,
˜
129.3, 129.2, 128.8, 128.7, 127.4, 125.5, 119.5, 99.3, 54.4 ppm. MS 1260, 1163, 1086, 982 cm–1. C16H15BrINO2S (492.17): calcd. C
(FAB): m/z = 458 [MH]+, 330 [M – I]+. IR (neat): ν = 2962, 1724, 39.05, H 3.07, N 2.85; found C 39.06, H 3.09, N 2.82.
˜
1627, 1492, 1435, 1311, 1265, 1218 cm–1. C16H13BrINO2 (458.09):
calcd. C 41.95, H 2.86, N 3.06; found C 41.83, H 2.87, N 2.71.
Ethyl (E)-1-(1-Bromo-2-iodo-2-phenylvinyl)-1H-indole-2-carboxyl-
ate (8): 61 % yield, 153 mg (Method A), 50 % yield, 249 mg
Methyl (E)-(1-Bromo-2-cyclohexyl-2-iodovinyl)(phenyl)carbamate
(3): 96% yield, 235 mg (Method A), 83% yield, 387 mg (Method
B), 71% yield, 329 mg (Method C) as a yellow viscous oil. 1H
NMR (400 MHz, CDCl3): δ = 7.46–7.43 (m, 2 H), 7.39–7.35 (m, 2
H), 7.28–7.25 (m, 1 H), 3.84 (s, 3 H), 2.36–2.29 (m, 1 H), 1.81–1.79
(m, 2 H), 1.74–1.70 (m, 2 H), 1.61–1.59 (m, 1 H), 1.48–1.36 (m, 4
H), 1.26–1.19 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
153.3, 138.8, 129.1, 126.9, 124.9, 117.5, 54.2, 47.4, 33.0, 32.8, 25.8,
(Method B), 60% yield, 300 mg (Method C) as a white solid (pre-
cipitation from dichloromethane/hexane for Method A and B;
recrystallization from ethanol for Method C). 1H NMR (400 MHz,
CDCl3): δ = 7.75 (d, J = 7.8 Hz, 1 H), 7.62–7.59 (m, 2 H), 7.53–
7.44 (m, 5 H), 7.41–7.37 (m, 1 H), 7.33–7.29 (m, 1 H), 4.47 (q, J
= 7.1 Hz, 2 H), 1.46 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 160.6, 142.3, 137.4, 129.4, 129.0, 128.9, 127.9, 127.2,
126.9, 123.3, 123.0, 114.3, 114.1, 112.0, 99.5, 61.4, 14.8 ppm. MS
25.7 ppm. MS (FAB): m/z = 464 [MH]+, 336 [M – I]+. IR (neat): ν
(FAB): m/z = 496 [MH]+, 368, ([M – I]+). IR (neat): ν = 1708, 1534,
˜
˜
2923, 2849, 1735, 1593, 1489, 1442, 1298, 1231 cm–1.
1474, 1442, 1396, 1380, 1325, 1261, 1200, 1144 cm– 1
.
=
C16H19BrINO2 (464.14): calcd. C 41.40, H 4.13, N 3.02; found C
41.42, H 4.01, N 2.82.
C19H15BrINO2 (496.14): calcd. C 46.00, H 3.05, N 2.82; found C
45.75, H 3.02, N 2.59.
(S,E)-3-(1-Bromo-2-iodo-2-phenylvinyl)-4-phenyloxazolidin-2-one
(4): Dichloromethane was used as solvent instead of toluene that
sparingly dissolved 4. 77% yield, 180 mg (Method A), 74% yield,
349 mg (Method B), 75% yield, 353 mg (Method C) of a yellowish
solid (recrystallization from dichloromethane/methanol). 1H NMR
(400 MHz, CDCl3): δ = 7.63–7.21 (m, 8 H), 7.15 (dd, J = 7.6,
2.3 Hz, 2 H), 5.25 (dd, J = 9.2, 9.2 Hz, 1 H), 4.74 (dd, J = 9.2,
9.2 Hz, 1 H), 4.44 (dd, J = 9.2, 9.2 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.0, 142.3, 134.2, 130.0, 129.2, 129.1,
129.0, 128.8, 128.5, 114.9, 99.2, 70.1, 62.3 ppm. MS (FAB): m/z =
(E)-1-[1-(1-Bromo-2-iodo-2-phenylvinyl)-1H-indol-3-yl]ethan-1-one
(9): 56% yield as calculated by NMR spectroscopy (Method A),
70% yield, 327 mg (Method B), 75% yield, 350 mg (Method C) as
a white solid (recrystallization from acetonitrile). 1H NMR
(400 MHz, CDCl3): δ = 8.84 (dd, J = 8.4, 1.6 Hz, 1 H), 7.89 (s, 1
H), 7.55–7.52 (m, 2 H), 7.50–7.39 (m, 6 H), 2.61 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 193.6, 141.8, 135.6, 133.9, 129.8,
129.0, 128.9, 126.4, 125.0, 124.2, 123.4, 120.8, 112.6, 111.6, 99.8,
28.1 ppm. MS (FAB): m/z = 466 [MH]+, 386, [M – Br]+. IR (neat):
ν = 1660, 1527, 1475, 1448, 1346, 1302, 1221 cm–1. C H BrINO
˜
18 13
469 [MH]+. IR (neat): ν = 2922, 1455, 1440, 1338, 1207, 1165, 1100,
˜
(466.12): calcd. C 46.38, H 2.81, N 3.01; found C 46.26, H 2.78, N
2.72.
1061, 1018 cm–1. C17H13BrINO2 (470.10): calcd. C 43.43, H 2.79,
N 2.98; found C 43.31, H 2.78, N 2.75.
Methyl (E)-[1-Bromo-2-iodo-2-(4-methoxyphenyl)vinyl](phenyl)-
carbamate (10): 80% yield, 206 mg (Method A), 62% yield, 249 mg
(Method B), 31% yield, 300 mg (Method C) as a white solid. 1H
NMR (400 MHz, CDCl3): δ = 7.57, (d, J = 8.2 Hz, 2 H), 7.43 (d,
J = 8.2 Hz, 2 H), 7.36–7.31 (m, 3 H), 6.87 (d, J = 8.7 Hz, 2 H),
3.93 (s, 3 H), 3.83 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]acetone):
δ = 160.8, 153.3, 139.5, 135.4, 130.9 (two peaks overlapped), 129.7,
127.5, 125.5, 114.6, 100.8, 55.7, 54.3 ppm. MS (FAB): m/z = 487
[M]+. HRMS: calcd. for C17H15BrINO3 [M+] 486.9280; found
486,9255.
(E)-N-Benzyl-N-(1-bromo-2-iodo-2-phenylvinyl)-4-methylbenzene-
sulfonamide (5): 62% yield, 195 mg (Method A), 59% yield, 336 mg
(Method B), 51 % yield, 228 mg (Method C) as a white solid
(recrystallization from benzene). 1H NMR (400 MHz, CDCl3): δ =
7.94 (d, J = 8.3 Hz, 2 H), 7.50–7.48 (m, 2 H), 7.38–7.22 (m, 8 H),
7.02 (dd, J = 8.1, 1.7 Hz, 2 H), 4.83 (d, J = 12.8 Hz, 1 H), 4.00 (d,
J = 12.8 Hz, 1 H), 2.47 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 145.1, 143.4, 135.0, 132.9, 131.2, 123.0, 129.4, 129.0, 128.9,
128.6, 128.5, 128.1, 118.9, 104.5, 53.3, 22.0 ppm. MS (MALDI-
TOF): m/z = 567 [MH]+. IR (neat): ν = 2921, 1594, 1456, 1347,
˜
1165 cm–1. C22H19BrINO2S (568.27): calcd. C 46.50, H 3.37, N
2.46; found C 46.49, H 3.29, N 2.37.
Methyl (E)-(1,2-Diiodo-2-phenylvinyl)(phenyl)carbamate (11): 76%
1
yield, 192 mg as a yellow solid. H NMR (400 MHz, CDCl3): δ =
7.56 (dd, J = 8.5, 1.5 Hz, 2 H), 7.46–7.33 (m, 8 H), 3.94 (s, 3
H) ppm. 13C NMR (100 MHz, CD3CN): δ = 153.4, 146.0, 139.6,
130.1 (two peaks overlapped), 129.7, 129.3, 127.9, 125.9, 102.5,
98.5, 54.7 ppm. MS (FAB): m/z = 506 [MH]+, 378 [M – I]+. IR
(E)-N-Benzyl-N-[1-bromo-2-(4-cyanophenyl)-2-iodovinyl]-4-methyl-
benzenesulfonamide (6): 61 % yield as calculated by NMR spec-
troscopy (Method A), 78% yield, 462 mg (Method B) as a whitish
yellow solid (recrystallization from acetonitrile). 1H NMR
(400 MHz, CDCl3): δ = 7.92 (d, J = 8.2 Hz, 2 H), 7.58 (d, J =
8.5 Hz, 2 H), 7.48–7.46 (m, 2 H), 7.39–7.38 (m, 5 H), 7.09 (d, J =
8.2 Hz, 2 H), 4.84 (d, J = 12.9 Hz, 1 H), 3.96 (d, J = 12.9 Hz, 1
H), 2.48 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.8,
145.4, 134.7, 132.7, 132.6, 131.2, 130.1, 129.3, 129.2, 129.1, 128.6,
120.5, 118.6, 112.6, 101.4, 53.4, 22.1 ppm. MS (MALDI-TOF): m/z
(neat): ν = 3054, 2969, 2930, 2871, 1593, 1487, 1455, 1441 cm–1.
˜
C16H13I2NO2 (505.09): calcd. C 38.05, H 2.59, N 2.77; found C
37.91, H 2.64, N 2.70.
Methyl (E)-(1,2-Dibromo-2-phenylvinyl)(phenyl)carbamate (12):
1
61% yield, 250 mg as a white solid. H NMR (400 MHz, CDCl3):
δ = 7.34–7.16 (m, 8 H), 6.92 (d, J = 7.9 Hz, 2 H), 3.80 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 154.3, 140.2, 138.1, 130.4, 129.6,
129.0, 128.8, 128.0, 127.2, 125.2, 123.3, 54.2 ppm. MS (FAB): m/z
= 592 [M]+. IR (neat): ν = 2222, 1594, 1495, 1456, 1346, 1164 cm–1.
˜
C23H18BrIN2O2S (593.28): calcd. C 46.56, H 3.06, N 4.72; found
C 46.56, H 3.07, N 4.57.
= 412 [MH]+, 330 [M – Br]+. IR (neat): ν = 1724, 1490, 1435, 1321,
˜
(E)-N-(1-Bromo-2-iodo-2-phenylvinyl)-N,4-dimethylbenzenesulfon- 1254, 1223, 1195, 1161, 1059 cm–1. C16H13Br2NO2 (411.09): calcd.
amide (7): 47% yield as calculated by NMR spectroscopy (Method C 46.75, H 3.19, N 3.41; found C 46.59, H 3.24, N 3.13.
3266
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Eur. J. Org. Chem. 2014, 3262–3267

Regio-, and Stereoselective Iodobromination of Ynamides
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Supporting Information (see footnote on the first page of this arti-
1
cle): The H NMR and 13C NMR spectra of all new compounds.
Acknowledgments
The authors thank Professor Ken-ichi Yamada and Professor
Yosuke Yamaoka at Kyoto University for assistance with measure-
ment of X-ray diffraction and scattering. Dr. Fukashi Matsumoto
and Dr. Toshiyuki Iwai at OMTRI are gratefully thanked for assist-
ance with HRMS and Professor Michael P. Schramm at CSULB
for helpful discussion.
[12] M. L. Ho, A. B. Flynn, W. W. Ogilvie, J. Org. Chem. 2007, 72,
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[13] Z. Chen, H. Jiang, Y. Li, C. Qi, Chem. Commun. 2010, 46,
8049–8051.
[14] Commercial IBr (25 g) enclosed in an ample was purchased
from Nacalai Tesque, Inc., and its purity is higher than 95%
(catalog number 19222-62, CAS 7789-33-5). Freshly prepared
and opened IBr was employed for all experiments.
[15] Crystal data of 2: orthorhombic, space group Pca21, colorless,
a = 12.272(3) Å, b = 11.030(7) Å, c = 11.831(1) Å, α = β = γ =
90°, V = 1601.6 Å3, Z = 4, T = 93 K, dcalcd. = 1.900 gcm–3,
μ(Mo-Kα) = 4.505 mm–1, R1 = 0.0648, wR2 = 0.1639, GOF =
1.070.
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Received: February 12, 2014
Published Online: April 9, 2014
Eur. J. Org. Chem. 2014, 3262–3267
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3267