Regio- and stereoselective synthesis of (E)-1-bromo-2-iodoalkenes through iodobromination of internal alkynes

Article abstract of DOI:10.1016/j.tet.2014.09.075

One-step synthesis of (E)-1-bromo-2-iodoalkenes from internal alkynes through IBr addition is described. The IBr was generated in situ from commercially available TMSBr and NIS. This simple protocol enables highly efficient regio- and stereoselective iodo

Full text of DOI:10.1016/j.tet.2014.09.075

Tetrahedron 70 (2014) 8532e8538
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regio- and stereoselective synthesis of (E)-1-bromo-2-iodoalkenes
through iodobromination of internal alkynes
*
Masataka Ide, Yuta Yauchi, Ryo Shiogai, Tetsuo Iwasawa
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2014
Received in revised form 20 September 2014
Accepted 22 September 2014
Available online 4 October 2014
One-step synthesis of (E)-1-bromo-2-iodoalkenes from internal alkynes through IBr addition is de-
scribed. The IBr was generated in situ from commercially available TMSBr and NIS. 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 differentially all-carbon tetra-
substituted olefins.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Alkene geometry
Stereoselectivity
Tetrasubstituted olefin
Iodobromination
Internal alkynes
1. Introduction
Given these limitations of typical procedures, methods
employing differentially substituted olefin templates have turned
Tetrasubstituted olefins bearing four different carbon-linked
groups have played an important role in organic chemistry,1 be-
cause of their ability to serve as pharmaceuticals,2 bioactive mol-
ecules,3 and potentially therapeutic compounds.4 They have also
been found as substructure in organic material science, for exam-
ple, molecular switches,5 optical devices,6 and macromolecular
architecture.7 Moreover, the olefins have been employed as key
building blocks for producing adjacent chiral-carbon centers
through face-selective addition reactions.8 Despite the utility of the
differentially all-carbon tetrasubstituted alkenes, their synthetic
availability remains a challenge owing to difficulty in geometrically
defined olefin synthesis. The endocyclic version having distinct
geometry are somewhat achievable by way of several protocols, for
example, carbonyl olefination,9 elimination reaction,10 olefin me-
tathesis,11 and cycloaddition.12 However, for the single formation of
acyclic version, those protocols encounter problem of low stereo-
chemical control. Even the carbometallation, a most widely used
for preparation of polysubstituted alkenes,13 requires a directing
group to control the stereoselectivity, which has limited utilities for
unsymmetrically internal alkyne substrates. This drawback causes
poor generality concerning substrate tolerance, metal option, and
a diversity of products on the reaction.14
out to be potent strategy for synthesis of tetrasubstituted olefins
bearing four different carbon-linked groups.1 Two outstanding
achievements were reported by Ferreira in 201315 and Ogilvie in
200616 (Scheme 1). Ferreira group developed trans-selective hal-
osilylation of unsymmetrical alkynes, and the halosilylated tem-
plate was transformed into the acyclic olefins. Ogilvie group found
the trans-selective iodochlorination, and the resultant template
was derived to the cross-coupling adducts. Noteworthy is that both
strategies adopt simple metal-free access to the templates and the
single isomeric templates warrant the geometry of the tetrasub-
stituted olefins. As other template approaches, carbolithiation of
trifluoromethyl enolethers,17 and successive cross-coupling of vi-
nyl-2-pyrimidilsulfide precursors,18 copper-catalyzed carbotri-
flation of unsymmetrical alkynes,19 were performed. However, one
of the most straightforward ways shown in Scheme 2 is still diffi-
cult: an addition reaction of molecular hetero-dihalogen such as IBr
to the alkynes gives four possible iodobrominated templates, and
lack of the auxiliary groups for stereo-control results in formidable
mixtures of products and low yields.20a,b Moreover, iodination is
frequently more difficult than bromination and chlorination, be-
cause the reaction proceeds slowly and is often reversible under
standard conditions.20c,d,e Actually, even metal-assisted and ionic
liquid-promoted iodination-protocols were limited to narrow
scope of substrate generality and reaction efficacy.20f,g,h
On the other hand, we recently reported regio- and stereo-
selective iodobromination of ynamides for synthesis of (E)-1-
* Corresponding author. Tel.: þ81 77 543 7461; fax: þ81 77 543 7483; e-mail
address: iwasawa@rins.ryukoku.ac.jp (T. Iwasawa).
http://dx.doi.org/10.1016/j.tet.2014.09.075
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

M. Ide et al. / Tetrahedron 70 (2014) 8532e8538
8533
Scheme 3. Regio- and stereoselective iodobromination of 1 to synthesize 2.
column chromatography gave corresponding IBr adduct 2 of
443 mg in 77% yields with the almost same 94:6 ratio. The mo-
lecular structure of 2 was determined by crystallographic analysis
as shown in Fig. 1,23 disclosing its stereochemistry as a (E)-1-
bromo-2-iodovinyl adduct.
Scheme 1. Differentially substituted olefin template strategy.
Fig. 1. ORTEP drawing of 2 with thermal ellipsoids at the 50% probability level. Hy-
ꢀ
drogen atoms are omitted for clarity. Selected bond lengths (A): C(2)eC(3)¼1.507,
Scheme 2. Iodobromination of internal alkynes for dihalogen templates, and the ac-
cess to tetrasubstituted olefins bearing four different carbon-linked groups.
C(3)eI(1)¼2.168, C(3)eC(4)¼1.267, C(4)eBr(1)¼1.905, C(4)eC(5)¼1.501.
bromo-2-iodo-enamides in gram-scale using in situ generated
To clarify the reactivity of triple bonds with IBr, a simple of 1-
phenyl-1-butyne 3 was tested (Scheme 4). For a, the in situ IBr
successfully completed the addition reaction, providing 2.45 g of 4
in 81% yield with a 98:2 isomeric ratio. On the other hand, for b,
commercially available IBr (neat sample)24 resulted in a 74:21:5
isomeric ratio through possible three reaction path. For c, IBr in
diethyl ether improved the ratio and lowered the yield compared
with those of b. For d, when IBr in diethyl ether acted at room
temperature, tremendous amounts of unreacted 3 were observed.
Unfortunately, for bed, Rf values of 3 and 4 on TLC analyzing were
too close to separate them in pure forms. Thus, the in situ IBr
proved to be more practical than the bulk: 4 with a 98:2 ratio has
the potential to assemble different carbon-linked groups into the
double bond accurately.
As summarized in Scheme 5, screening of substituents bonded to
the triple bond was conducted on the in situ IBr-mediated iodo-
bromination. For a, a symmetrical alkyne of 4-octyne undertook
smooth halogenation to yield5 in 78% as a single isomer; however, for
b,unsymmetrical3-octyneresultedin mixtureswith a50:50 isomeric
ratio. For c,25 7 was successfully isolated in 34% yield with a 91:9
isomeric ratio although unreacted methyl 3-phenylpropiolate was
recovered in 66%.26 Ford, mysteriously,1,2-di-p-tolylethyne ended up
in complicated mixtures including 41% of unreacted starting alkyne
and no desired adduct: neither did 1,2-diphenylethyne.27 These mean
alkyl substituents is necessary for completing the reaction and 1-aryl-
2-alkylethyne is relatively good substrate for outputting high
regioselectivity.
IBr.21 The IBr was generated from mixing of
1 M bromo-
trimethylsilane (TMSBr) in CH2Cl2 and 0.5 M N-iodosuccinimide
(NIS) in acetonitrile, and added to ynamides with high regio- and
stereoselectivity: the single isomeric adducts were formed as good
candidates for multi-substituted olefins.
In this paper, we present a synthesis of vicinal bromoio-
doalkenes from internal alkynes in a highly regio- and stereo-
selective manner, which would favor one of four possible pathways
in Scheme 2. The in situ generated IBr underwent the addition
reaction to conventional aliphatic alkynes having no heteroatoms
for control, although commercially available IBr didn’t work well
even when used in diethyl ether solution.21 The reaction completed
in 1 h under mild condition, and was readily amenable to gram-
scale. Thus, the method provides a general entry for (E)-1-bromo-
2-iodoalkenes that can be a diverse scaffold for differentially all-
carbon tetrasubstituted olefins.
2. Results and discussion
Initially, we commenced our investigations with the reactions
previously reported for the TMSBr/NIS combination-mediated
iodobromination (Scheme 3).21 The mixture of 1 and TMSBr (1 M)
in CH2Cl2 was stirred at ꢀ78 ꢁC for 5 min,22 then NIS (0.5 M) in
acetonitrile was added, and the reaction was conducted at room
temperature. The starting 1 disappeared right after addition of NIS,
and virtually single spot was observed on TLC monitoring. Fortu-
nately, for the crude mixture, 1H NMR spectroscopic analysis
revealed a 94:6 isomeric ratio. Workup and purification with
With a workable protocol in hand, we studied the substrate
scope for the iodobromination of 1-aryl-2-alkylethyne (Table 1).

8534
M. Ide et al. / Tetrahedron 70 (2014) 8532e8538
Table 1
Substrate scopea
Scheme 4. Iodobromination of 1-phenyl-1-butyne with the in situ and commercially
available IBr.
Different patterns of N-halosuccinimide/halotrimethylsilane
were tested on 1-phenyl-1-butyne, and the results are summarized
in Table 2. Interestingly, entry 2 shows a 76% yield and an 87:13
ratio of 4, which is similar to the record resulting from entry 4 of an
81% yield and a 98:2 ratio. This means both combination 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 Scheme bed. The generative efficiency of
Scheme 5. Screening of substituents bonded to the triple bonds.
The long C6H13-chained 8 was given with a high 98:2 isomeric ratio
in 81% yield. The sterically encumbered 9 with ortho-tolyl group
and 10 with 9-anthryl group was smoothly yielded in 97% with
a 97:3 isomeric ratio and 70% as a single isomer, respectively. For 11,
the attachment of the electron-donating methoxy group was no
problem for obtaining the well-defined alkene geometry. On the
other hand, unfortunately, syntheses of nitrile 12 and 13, and nitro
14 and 15 were accompanied by numerous amounts of the starting
alkynes. Laborious purification by silica-gel column chromatogra-
phy isolated the IBr adducts from the starting alkynes in 37e59%
yields. Interestingly, there was difference in isomeric ratios be-
tween the cyclohexyl and normal-hexyl compounds: 97:3 of 13 and
95:5 of 15 were achieved as more effective ratios compared to 87:13
of 12 and 76:24 of 14. This indicates that anionic Br would recognize
the difference of bulkiness between the cyclohexyl and normal
hexyl group, and the following addition of Br to the triple bonds
preferentially occurred at the carbon bonded to aromatic rings.
Thus, minor isomers in this reaction system would be (E)-form of
regio-isomers, in which the position of Br interchanges with that of
I on major products.
IBr charged with d d
þ of I and ꢀ of Br was better compatibility with
entry 4 than entry 2. The use of TMSI and NIS at entry 1 didn’t
consume all the starting 3, and afforded 16 in 26% yield as a single
isomer. For entries 3 and 7, TMSI/NCS and TMSCl/NIS gave only 16 in
low yields, in which the chloride atom was not installed. For entries
5, 6, 8, and 9, the starting 3 disappeared on TLC monitoring; how-
ever, the resultant crude products formed from messy unknown
side-products. Thus, practically,
a
worthwhile selective-
halogenation is observed only in the combination of TMSBr/NIS.
The product distribution seems to be affected by the polarized io-
dide, that is, readily produced by NIS compared to TMSI. The po-
larized I with dþ would activate the alkyne to form triangle
iodonium cation, and the triangle cation undertook an addition
reaction of anionic bromide at the benzylic carbon in anti-mode.
For NBS and NCS, the alkyne activation by cationic bromide and
chloride is more difficult than NIS, and the reagents didn’t have
control of the halogenation reaction.
To establish the utility of the vicinal iodobrominated adduct as
a differentially substituted olefin template, the IBr-adduct 4 was
subjected to conventional transformations using palladium-

M. Ide et al. / Tetrahedron 70 (2014) 8532e8538
8535
Table 2
3. Conclusion
Screening of halogen sourcesa
In summary, a convenient and practical route to (E)-1-bromo-
2-iodoalkenes from the simple internal alkynes in remarkable
yields with notable regio- and stereoselectivity was described.
The significant key was an exact addition of the in situ generated
IBr to the triple bond: the IBr produced from TMSBr and NIS was
more effective than commercially bulk IBr. Attempts at employing
nine combinations of TMSX/NX0S revealed the eight entries ex-
cept TMSBr/NIS were substantially unworkable: the underlying
clue would be attributable to a well-matching pair of anionic Br
from TMSBr and cationic iodide from NIS. Although the C]C
double bond appended to iodide and bromide is an excellent
candidate as a differentially substituted olefin template, we don’t
yet find a procedure for preparation of all-carbon tetrasubstituted
alkenes. Application of this iodobromination-methodology to
synthesizing differentially all-carbon tetrasubstituted olefins such
as (Z)-tamoxifen analogues is ongoing and will be reported in due
course.
Entry
X/X0
Product
Yield [%]b
26 (40c)
76
24
81
d
Isomeric ratio
Recovered 3 [%]
1
2
3
4
I/I
I/Br
I/Cl
Br/I
Br/Br
Br/Cl
Cl/I
Cl/Br
Cl/Cl
16
4
16
4
d
d
16
d
d
w100:0
87:13
w100:0
98:2
d
60
19c
32c
0
5d
6d
7
0
0
d
d
30c
d
w100:0
d
11c
0
8d
9d
d
d
0
4. Experimental section
4.1. General
a
Reaction conditions: 3 (130 mg, 1 mmol), toluene (4 mL), TMSX (1 M) in
dichloromethane, NX0S (0.5 M) in acetonitrile.
b
Isolated yields.
NMR yields.
c
d
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 pu-
rification and dehydration. All reagents were purchased and used
without further purification. Analytical thin layer chromatography
was carried out on Merck silica 60F254. Column chromatography
was carried out with silica gel 60N (Kanto Chemical Co.). HRMS
were reported on the basis of TOF (time of flight)-MS, and EB
(double-focusing)-MS. 1H 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 residual solvent signals [1H
NMR: CHCl3 (7.26 ppm); 13C NMR: CDCl3 (77.0 ppm)]. Signal pat-
terns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad.
Although the starting 3 disappeared on TLC, complex mixtures were produced
in the crude state.
catalyzed cross-coupling28 and lithiumehalogen exchange re-
actions29 (Scheme 6). Straightforwardly, the iodine-selective con-
version was aimed; however, unfortunately, trials were
unworkable. Although the consumption of the starting 4 was ob-
served on palladium-mediated reaction conditions, many unknown
by-products were generated along with 1-phenyl-1-butyne. In
particular, for Scheme 6a, Sonogashira reaction strangely put back 4
to numerous 57% of 1-phenyl-1-butyne.30,31 For Scheme 6b, the
employment of tert-BuLi also resulted in 80% conversion of 4 into 1-
phenyl-1-butyne. The Ferreira’s template of (E)-1-silyl-2-
iodoalkenes, and the Ogilvie’s template of (E)-1-chloro-2-
iodoalkenes, they have big difference in reactivity between Si and
I, or Cl and I, and so would be successfully lead to the cross-coupling
adducts. In our case, the reactivity between Br and I has close
analogy, and the palladium catalyzed-protocols are as yet un-
workable on the selective approach. In addition, the weak bonding
of CeI and CeBr in (E)-1-bromo-2-iodoalkenes seems to be readily
cleavable, giving the corresponding alkyne. Thus, a general method
for utilizing the (E)-1-bromo-2-iodoalkenes as a differentially
substituted olefin template is strongly desired, and development of
the method is focused in our group. On the other hand, from the
viewpoint of vinyl halides, halo-olefins have been found as sub-
structures in bioactive natural products and pharmaceutically in-
teresting compounds.32 So, the bis-halogenated olefins in this
paper might be worth constructing bioactive compounds and po-
tential therapeutics.
4.2. Preparation of 1 M halotrimethylsilane (TMSX) stock
solution in dichloromethane
TMSBr (3.5 g) was added to dry dichloromethane (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 experimental 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, un-
fortunately, complete decomposition by 1H NMR was spectroscopy
was observed only in 24 h.
4.3. General procedure of (E)-3-(1-bromo-2-iodobut-1-en-1-
yl)-1,6-dibutylpyrene 2, for Scheme 3
Under an argon atmosphere, to a solution of 1 (366 mg,
1.0 mmol) in anhydrous toluene (4 mL) at ꢀ78 ꢁC was added TMSBr
(1.5 mL of 1 M in dichloromethane) dropwise over 5 min, and the
mixture was stirred for 5 min. Then, NIS (337 mg, 1.5 mmol) in
acetonitrile 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 mLꢂ3), and the combined organic phases were washed with
brine (30 mL), and then dried with sodium sulfate, and concen-
trated to give 589 mg of crude products. Purification by silica gel
Scheme 6. Attempt at reacting on iodide-site of 4.

8536
M. Ide et al. / Tetrahedron 70 (2014) 8532e8538
column chromatography (eluent: hexane) afforded 443 mg of 2 in
77% yield as a yellow solid material. Analytical data are listed in the
section below.
1204 cmꢀ1; HRMS (DI) calcd for C10H8BrIO2: 365.8752, found
365.8779.
4.3.7. (E)-1-(1-Bromo-2-iodooct-1-en-1-yl)-4-methylbenzene
(8). 98% yield (w100:0, 200 mg); a pale yellow oil; 1H NMR
(400 MHz, CDCl3) 7.22 (d, J¼8.6 Hz, 2H), 7.17 (d, J¼8.6 Hz, 2H), 2.83
(t, J¼7.4 Hz, 2H), 2.36 (s, 3H), 1.65 (tt, J¼7.4, 7.4 Hz, 2H), 1.44e1.34
(m, 6H), 0.92 (t, J¼7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
141.5, 138.8, 129.34, 129.30, 117.9, 102.5, 45.6, 32.0, 28.6, 28.4, 21.7,
14.4 ppm; MS (EI) m/z: 406 (Mþ); IR (neat): 2923, 1606, 1505, 1454,
1180, 1110 cmꢀ1; HRMS (DI) calcd for C15H20BrI: 405.9793, found
405.9779.
4.3.1. 3-(But-1-yn-1-yl)-1,6-dibutylpyrene
(1).33,34 68%
yield
(730 mg); a yellow solid; mp: 94.5e95.2 ꢁC; 1H NMR (400 MHz,
CDCl3) 8.57 (d, J¼9.4 Hz, 1H), 8.29 (d, J¼9.4 Hz, 1H), 8.17 (d,
J¼9.2 Hz, 1H), 8.07 (d, J¼9.2 Hz, 1H), 8.03 (d, J¼9.4 Hz, 1H), 7.95 (s,
1H), 7.85 (d, J¼9.4 Hz, 1H), 3.34 (t, J¼7.8 Hz, 2H), 3.28 (t, J¼7.8 Hz,
2H), 2.67 (q, J¼7.5 Hz, 2H), 1.88e1.79 (m, 4H), 1.54e1.48 (m, 4H),
1.42 (t, J¼7.5 Hz, 3H),1.00 (t, J¼7.4 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3) 137.7, 136.6, 130.9, 130.6, 129.9, 129.1, 129.0, 127.9, 127.6,
125.7 (two peaks are overlapped), 125.5, 125.1, 123.4, 122.6, 118.3,
97.3, 79.6, 34.3, 34.1, 33.7, 33.5, 23.2, 23.1, 14.6, 14.4 (two peaks are
overlapped), 14.0 ppm; MS (FAB) m/z: 366 (Mþ); IR (neat): 3043,
2954, 2926, 2854, 2219, 1602, 1498, 1462 cmꢀ1; Anal. Calcd for
4.3.8. (E)-1-(1-Bromo-2-iodooct-1-en-1-yl)-2-methylbenzene
(9). 97% yield (97:3, 395 mg); a colorless oil; 1H NMR (400 MHz,
CDCl3) 7.28e7.20 (m, 3H), 7.11 (d, J¼7.7 Hz, 1H), 2.89 (dt, J¼7.5,
7.5 Hz, 1H), 2.76 (dt, J¼7.5, 7.5 Hz, 1H), 2.27 (s, 3H), 1.67 (tt, J¼7.5,
7.5 Hz, 2H), 1.45e1.35 (m, 6H), 0.93 (t, J¼10.9 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) 143.8, 135.6, 130.7, 129.2, 129.1, 126.5, 117.8, 104.4,
44.5, 32.0, 28.7, 28.4, 23.0, 19.6, 14.5 ppm; MS (FAB) m/z: 406 (Mþ);
C
28H30: C, 91.75; H, 8.25. Found: C, 91.74; H, 8.32.
4.3.2. (E)-3-(1-Bromo-2-iodobut-1-en-1-yl)-1,6-dibutylpyrene
(2). 77% yield (94:6, 215 mg); a yellow solid; mp: 109.7e110.6 ꢁC;
1H NMR (400 MHz, CDCl3) 8.34 (d, J¼9.4 Hz, 1H), 8.21 (d, J¼9.2 Hz,
1H), 8.12e8.07 (m, 3H), 7.86 (d, J¼9.4 Hz, 1H), 7.72 (s, 1H),
3.41e3.26 (m, 4H), 3.14 (dq, J¼7.3, 7.3 Hz, 1H), 3.02 (dq, J¼7.3,
7.3 Hz, 1H), 1.85 (tt, J¼7.6, 7.6 Hz, 2H), 1.84 (tt, J¼7.6, 7.6 Hz, 2H),
1.56e1.46 (m, 4H), 1.37 (t, J¼7.3 Hz, 3H), 1.01 (t, J¼7.3 Hz, 3H), 1.00
(t, J¼7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) 138.1, 137.7,
137.3, 129.9 (two peaks are overlapped), 129.1, 128.3, 128.1, 127.9,
126.1, 126.0, 125.9, 125.4, 124.2, 123.9, 122.7, 116.8, 107.1, 39.3, 34.4,
34.0, 33.8, 33.7, 23.3, 23.1, 14.4, 14.3, 13.6 ppm; MS (FAB) m/z: 572
(Mþ); IR (neat): 3044, 2948, 2925, 2852, 1603, 1499, 1463,
1368 cmꢀ1; Anal. Calcd for C28H30BrI: C, 58.66; H, 5.27. Found: C,
58.53; H, 5.40.
IR (neat): 3065, 3023, 2952, 2924, 2855, 1599, 1455, 1377 cmꢀ1
Anal. Calcd for C15H20BrI: C, 44.25; H, 4.95. Found: C, 44.49; H, 4.76.
;
4.3.9. (E)-9-(1-Bromo-2-iodooct-1-en-1-yl)anthracene
(10). 70%
yield (w100:0, 346 mg); yellow needles; mp: 128.9e129.7 ꢁC; 1H
NMR (400 MHz, CDCl3) 8.55 (s, 1H), 8.06e8.04 (m, 2H), 7.62e7.48
(m, 4H), 3.11 (t, J¼7.4 Hz, 2H), 1.91e1.84 (m, 2H), 1.65e1.41 (m, 6H),
1.00 (t, J¼7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) 136.9, 132.0,
129.1, 128.6, 128.1, 127.0, 126.0, 125.5, 115.5, 108.3, 44.9, 32.0, 29.1,
28.8, 23.0, 14.5 ppm; IR (neat): 3057, 2925, 2854, 1621, 1519, 1466,
1440 cmꢀ1; MS (FAB) m/z: 493 (Mþ); Anal. Calcd for C22H22BrI: C,
53.57; H, 4.50. Found: C, 53.41; H, 4.31.
4.3.3. (E)-(1-Bromo-2-iodobut-1-en-1-yl)benzene (4). 81% yield
(98:2, 2.45 g); a pale red oil; 1H NMR (400 MHz, CDCl3) 7.39e7.29
(m, 5H), 2.87 (q, J¼7.4 Hz, 2H), 1.19 (t, J¼7.4 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) 144.1, 129.4, 128.9, 128.6, 117.1, 103.9, 39.6,
13.3 ppm; MS (EI) m/z: 336 (Mþ), 257 ([MꢀBr]þ); IR (neat): 3054,
2969, 2930, 2871, 1593, 1487, 1455, 1441 cmꢀ1; Anal. Calcd for
4.3.10. (E)-1-(1-Bromo-2-iodooct-1-en-1-yl)-4-methoxybenzene
(11). 99% yield (>99:1, 420 mg); a yellow oil; 1H NMR (400 MHz,
CDCl3) 7.24 (d, J¼8.8 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 3.83 (s, 3H),
2.82 (t, J¼7.4 Hz, 2H), 1.65 (tt, J¼7.4, 7.4 Hz, 2H), 1.44e1.33 (m, 6H),
0.92 (t, J¼6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) 159.8, 136.7,
130.9, 117.9, 113.9, 102.6, 55.5, 45.6, 31.9, 28.6, 28.4, 22.9, 14.4 ppm;
MS (FAB) m/z: 422 (MHþ); IR (neat): 2952, 2924, 2854, 1602, 1505,
1462, 1291, 1247 cmꢀ1; Anal. Calcd for C15H20BrIO: C, 42.58; H, 4.76.
Found: C, 42.68; H, 4.60.
C
10H10BrI: C, 35.64; H, 2.99. Found: C, 35.66; H, 2.79; HRMS (DI)
calcd for C10H10BrI: 335.9011, found 335.9029.
4.3.4. (E)-4-Bromo-5-iodooct-4-ene (5). 78% yield (w100:0,
246 mg); a pale yellow oil; 1H NMR (400 MHz, CDCl3) 2.07 (t,
J¼7.3 Hz, 2H), 2.68 (t, J¼7.3 Hz, 2H), 1.63 (tq, J¼7.3, 7.3 Hz, 2H), 1.58
(tq, J¼7.3, 7.3 Hz, 2H), 0.96 (t, J¼7.3 Hz, 3H), 0.94 (t, J¼7.3 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) 130.0, 100.2, 47.8, 47.2, 22.0, 21.3,
13.3, 13.2 ppm; IR (neat): 2959, 2928, 2871, 1620, 1456, 1379, 1340,
862, 773, 742 cmꢀ1; MS (EI) m/z: 316 (Mþ); Anal. Calcd for C8H14BrI:
C, 30.31; H, 4.45. Found: C, 30.31; H, 4.35; HRMS (DI) Calcd for
C8H14BrI: 315.9324, found 315.9336.
4.3.11. (E)-4-(1-Bromo-2-iodooct-1-en-1-yl)benzonitrile (12). 52%
yield (87:13, 216 mg); a yellow oil; 1H NMR (400 MHz, CDCl3) 7.67
(d, J¼8.5 Hz, 2H), 7.40 (d, J¼8.5 Hz, 2H), 2.84 (t, J¼7.6 Hz, 2H), 1.65
(tt, J¼7.6, 7.6 Hz, 2H), 1.44e1.35 (m, 6H), 0.92 (t, J¼7.1 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) 148.3, 132.5, 130.3, 118.5, 114.9, 112.6,
104.4, 45.3, 31.8, 28.5, 28.3, 22.8, 14.4 ppm; MS (FAB) m/z: 418
([MH]þ); IR (neat): 2925, 2854, 2228, 1601, 1496, 1455, 1402, 1107,
831 cmꢀ1; Anal. Calcd for C15H17BrIN: C, 43.09; H, 4.10; N, 3.35.
Found: C, 43.11; H, 4.15; N, 3.28.
4.3.5. (E)-4-Bromo-3-iodooct-3-ene, and (E)-3-bromo-4-iodooct-3-
ene (6). 75% yield (50:50, 238 mg); a colorless oil; 1H NMR
(400 MHz, CDCl3) 2.76e2.64 (m, 4H), 1.60e1.48 (m, 2H), 1.41e1.30
(m, 2H), 1.12e1.04 (m, 3H), 0.96e0.92 (m, 3H) ppm; 13C NMR
(100 MHz, CDCl3) 124.1, 122.4, 101.3, 99.3, 45.8, 45.1, 40.2, 39.7, 30.7,
30.0, 22.0, 21.9, 14.4, 13.1, 12.5 ppm; MS (EI) m/z: 316 (Mþ); IR
(neat): 2956, 2927, 2871, 1622, 1455, 1431, 1080 cmꢀ1; HRMS (DI)
calcd for C8H14BrI: 315.9324, found 315.9325.
4.3.12. (E)-4-(1-Bromo-2-cyclohexyl-2-iodovinyl)benzonitrile
(13). 59% yield (97:3, 78 mg); a white solid; mp: 138.4e140.7 ꢁC; 1H
NMR (400 MHz, CDCl3) 7.67 (d, J¼8.6 Hz, 2H), 7.36 (d, J¼8.6 Hz, 2H),
2.53e2.47 (m, 1H), 1.87e1.67 (m, 5H), 1.52e1.39 (m, 4H), 1.27e1.18
(m, 1H) ppm; 13C NMR (100 MHz, CDCl3) 148.7, 132.7, 130.5, 118.7,
115.1, 112.6, 112.5, 48.4, 33.1, 25.8, 25.8 ppm; MS (FAB) m/z: 416
([MH]þ); IR (neat): 2924, 2849, 2230, 1598, 1496, 1448, 1268,
1207 cmꢀ1; Anal. Calcd for C15H15BrIN: C, 43.30; H, 3.63; N, 3.37.
Found: C, 43.23; H, 3.58; N, 3.36.
4.3.6. Methyl (E)-3-bromo-2-iodo-3-phenylacrylate (7). 57% yield
(90:10, 234 mg); a yellow oil; 1H NMR (400 MHz, CDCl3) 7.44e7.38
(m, 5H), 3.96 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) 166.4, 140.8,
130.0, 128.9, 128.8, 123.4, 81.9, 53.7 ppm; MS (EI) m/z: 366 ([MH]þ),
287 ([MHꢀBr]þ); IR (neat): 2950, 1725, 1590, 1442, 1432, 1240,
4.3.13. (E)-1-(1-Bromo-2-iodooct-1-en-1-yl)-4-nitrobenzene
(14). 55% yield (76:24, 245 mg); a yellow oil; 1H NMR (400 MHz,
CDCl3) 8.24 (d, J¼8.8 Hz, 2H), 7.46 (d, J¼8.8 Hz, 2H), 2.85 (t, J¼7.5 Hz,

M. Ide et al. / Tetrahedron 70 (2014) 8532e8538
8537
9. (a) Jenny, L.; Borschberg, H.-J. Helv. Chim. Acta 1995, 78, 715e731; (b) Mandai,
T.; Kaihara, Y.; Tsuji, J. J. Org. Chem. 1994, 59, 5847e5849; (c) Julia, M. Pure Appl.
Chem. 1985, 57, 763; (d) Kocienski, P. Phosphorus Sulfur 1985, 24, 97e127.
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2543e2552; (b) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. Tetrahedron Lett. 1997,
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2H), 1.67 (tt, J¼7.5, 7.5 Hz, 2H), 1.45e1.34 (m, 6H), 0.93 (t, J¼7.0 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) 150.2, 147.7, 130.7, 124.3,114.5,
104.8, 45.3, 31.9, 28.6, 28.4, 22.9,14.4 ppm; MS (FAB) m/z: 437 (Mþ);
IR (neat): 3108, 3077, 2925, 2854,1601,1519,1488,1456,1342 cmꢀ1
;
Anal. Calcd for C14H17BrINO2: C, 38.38; H, 3.91; N, 3.20. Found: C,
38.26; H, 3.91; N, 3.20.
11. (a) Conrad, J. C.; Parnass, H. H.; Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2005,
127, 11882e11883; (b) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao,
H. J. Am. Chem. Soc. 2004, 126, 10210e10211.
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Can. J. Chem. 2004, 82, 227e239; (c) Laurent, A.; Villalva-Serrvin, N. P.; For-
gione, P.; Wilson, P. D.; Smil, D. V.; Fallis, A. G. Can. J. Chem. 2004, 82, 215e226;
(d) Villalva-Serrvin, P.; Laurent, A.; Yap, G.; Fallis, A. G. Synlett 2003,
1263e1266; (e) Trost, B. M.; Macpherson, D. T. J. Am. Chem. Soc. 1987, 109,
3483e3484.
4.3.14. (E)-1-(1-Bromo-2-cyclohexyl-2-iodovinyl)-4-nitrobenzene
(15). 37% yield (95:5, 161 mg); yellowish white needles; mp:
119.5e120.4 ꢁC; 1H NMR (400 MHz, CDCl3) 8.22 (d, J¼8.8 Hz, 2H),
7.42 (d, J¼8.8 Hz, 2H), 2.54e2.48 (m, 1H), 1.86e1.83 (m, 2H),
1.75e1.68 (m, 3H), 1.54e1.39 (m, 4H), 1.27e1.20 (m, 1H) ppm; 13C
NMR (100 MHz, CDCl3) 150.5, 147.6, 130.8, 124.2, 115.3, 112.1, 48.4,
33.1, 25.8, 25.7 ppm; MS (FAB) m/z: 435 (Mþ); IR (neat) 2925, 2850,
1600, 1517, 1442, 1341 cmꢀ1; Anal. Calcd for C14H15BrINO2: C, 38.56;
H, 3.47; N, 3.21. Found: C, 38.64; H, 3.34; N, 3.14.
13. For reviews of alkyne carbometalation, see: (a) Normant, J. F.; Alexakis, A.
Synthesis 1981, 841e870; (b) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57,
5899e5913; (c) Negishi, E.-i.; Wang, G.; Rao, H.; Xu, Z. J. Org. Chem. 2010, 75,
3151e3182.
14. (a) Suginome, M.; Yamamoto, A.; Murakami, M. Angew. Chem., Int. Ed. 2005, 44,
2380e2382; (b) Zhou, C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765e3777; (c)
Shimizu, K.; Takimoto, M.; Mori, M. Org. Lett. 2005, 7, 195e197; (d) Konno, T.;
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2188e2190; (e) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42,
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2003, 125, 6358e6359; (g) Ma, S.; Jiao, N.; Ye, L. Chem.dEur. J. 2003, 9,
6049e6056; (h) Shirakawa, E.; Yamasaki, K.; Yoshida, H.; Hiyama, T. J. Am.
Chem. Soc. 1999, 121, 10221e10222; (i) Hojo, M.; Murakami, Y.; Aihara, H.; Sa-
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40, 715e731; (k) Mornet, R.; Gouin, L. Tetrahedron Lett. 1977, 18, 167e168.
15. Barczak, N. T.; Rooke, D. A.; Menard, Z. A.; Ferreira, E. M. Angew. Chem., Int. Ed.
2013, 52, 7579e7582.
4.3.15. (E)-(1,2-Diiodobut-1-en-1-yl)benzene
(16). 26%
yield
(w100:0, 305 mg); a whitish orange solid; mp: 49.0e50.2 ꢁC; 1H
NMR (400 MHz, CDCl3) 7.37e7.33 (m, 2H), 7.30e7.26 (m, 1H),
7.22e7.20 (m, 2H), 2.88 (q, J¼7.4 Hz, 2H), 1.18 (t, J¼7.4 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) 148.3, 128.8, 128.7, 128.5, 106.9, 94.0,
45.2, 13.3 ppm; MS (FAB) m/z: 384 (Mþ); IR (neat): 3050, 2963,
2925, 1572, 1485, 1451, 1437, 1368 cmꢀ1; Anal. Calcd for C10H10I2: C,
31.28; H, 2.62. Found: C, 31.50; H, 2.66.
Acknowledgements
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The authors thank Professor Kiyosei Takasu, and Professor Ken-
ichi Yamada and Professor Yosuke Yamaoka at Kyoto University for
assistance with measurement of X-ray diffraction and scattering,
and for employment of melting-point apparatus. Dr. Toshiyuki Iwai
and Dr. Takatoshi Ito at OMTRI are gratefully thanked for assistance
with HRMS, and Professor Michael P. Schramm at CSULB for helpful
discussion.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.09.075.
References and notes
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23. Crystal data of 2, numbered with CCDC (Cambridge Crystallographic Data
ꢀ
Centre) 1014387: triclinic, space group P-1, colorless, a¼7.1633(3) A, b¼11.
ꢀ
ꢀ
a
5854(5) A, c¼15.0892(6) A,
¼92ꢁ,
b
¼99ꢁ,
g
¼103ꢁ, V¼1199.7 A3, Z¼2, T¼93 K,
dcalcd¼1.587 g cmꢀ3
,
m
(Mo, K
a
)¼3.018 mmꢀ1, R1¼0.0646, wR2¼0.1776, GOF¼1.
067.
24. Commercial IBr (25 g) enclosed in an ample was purchased from Nacalai Tes-
que, 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.
25. The experiment by inverse addition was also performed: to the flask charged
with NIS in toluene TMSBr in CH2Cl2 was initially loaded, then methyl 3-
phenylpropiolate in toluene was added. The chemical yield was given in 46%
along with a 78:9:13 isomeric ratio, and 54% of unreacted alkyne remained
intact.
7. Marchand, A. P.; Zope, A.; Zaragoza, F.; Bott, S. G.; Ammon, H. L.; Du, Z. Tetra-
hedron 1994, 50, 1687e1698.
26. The employment of TMSBr and NIS in each 3 equiv increased the yield to 57%
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along with
a
90:10 isomeric ratio, although unreacted methyl 3-
phenylpropiolate was recovered in 43%.
27. The current method is not suitable for constructing tetraarylethene moieties
that recently attract much attention in material chemistry. The platform pro-
tocol reported by Itami and Yoshida enables to prepare the substructure, see:
Itami, K.; Yoshida, J. Bull. Chem. Soc. Jpn. 2006, 79, 811e824 and references
therein.

8538
M. Ide et al. / Tetrahedron 70 (2014) 8532e8538
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the reaction, the substrate seemed to be smoothly transformed into the cor-
responding IBr-adduct of (E)-3-(1-bromo-2-iodooct-1-en-1-yl)pyridine; how-
ever, right after workup operation, the pale yellow-colored reaction mixtures
turned to dark brown-colored oil along with production of the starting 3-(oct-
1-yn-1-yl)pyridine. These indicate the iodobromination could be reversible
reaction: the iodobromination for 7 at Scheme 5, 12e15 at Table 1 might reach
to equilibrium.
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