Elucidation of reaction process through β-halogen elimination in CuCN-mediated cyanation of (E)-1-bromo-2-iodoalkene

Article abstract of DOI:10.1016/j.tetlet.2015.12.063

The previously unknown reaction process involved with metal-mediated β-halogen elimination is described, including a description of a vinylic Rosenmund-von Braun reaction of (E)-(1-bromo-2-iodobut-1-en-1-yl)benzene. We investigated the product structures on the basis of crystallographic analyses and revealed that copper cyanide would form bifurcated paths to deliver the isomeric mixtures.

Full text of DOI:10.1016/j.tetlet.2015.12.063

Tetrahedron Letters 57 (2016) 483–486
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Elucidation of reaction process through b-halogen elimination
in CuCN-mediated cyanation of (E)-1-bromo-2-iodoalkene
⇑
Naoki Endo, Mao Kanaura, 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:
The previously unknown reaction process involved with metal-mediated b-halogen elimination is
described, including a description of a vinylic Rosenmund–von Braun reaction of (E)-(1-bromo-2-iodo-
but-1-en-1-yl)benzene. We investigated the product structures on the basis of crystallographic analyses
and revealed that copper cyanide would form bifurcated paths to deliver the isomeric mixtures.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 23 November 2015
Revised 11 December 2015
Accepted 15 December 2015
Available online 17 December 2015
Keywords:
Alkene geometry
Reaction mechanism
Stereoselectivity
Tetrasubstituted olefin
b-Halogen elimination
The efficient regio- and stereoselective synthesis of differen-
1
tially all-carbon tetrasubstituted olefins remains a challenge,
although the significance of such olefins lies in medicinal chem-
istry, material science, and synthetic chemistry.6 Particularly,
formation of the aliphatic and acyclic olefins bearing four different
carbon-linked groups often faces selectivity problems, giving iso-
meric mixtures. Even monumental protocols for forming a car-
2
,3
4,5
7
bonAcarbon double bond, such as carbometalation of alkynes,
carbonyl olefination, elimination reaction,9 olefin metathesis,
8
10
1
1
and cycloaddition, are powerless to produce such an aliphatic
and acyclic olefin as a single isomer, because they encounter trou-
bles of low stereochemical control and have limited utilities. These
limitations have created the expectation of synthesizing single iso-
12
mers on differentially substituted olefin templates and continu-
1
3
ous efforts have aimed to refine the diverse scaffold strategy.
Recently, we have reported regio- and stereoselective
iodobromination of unsymmetrically internal alkynes; for exam-
ple, as illustrated in Scheme 1a, 1-phenyl-1-butyne reacted with
Scheme 1. (a) Regio- and stereoselective iodobromination of 1-phenyl-1-butyne,
and the following attempt at reacting on iodide-site of 1; (b) Rathore’s report in
2002.
1
4
in situ generated IBr to yield anti-IBr adduct 1 predominantly.
To establish 1 as a stereo-defined alkenyl template for the synthe-
sis of tetrasubstituted olefins, 1 was subjected to conventional
transformations using palladium-catalyzed reactions; however,
the reaction put back 1 to 1-phenyl-1-butyne and didn’t afford
any desired product. Actually, similar observation on (E)-3,4-dibro-
mohex-3-ene was reported by the Rathore group in 2002
Scheme 1b):15 oxidative addition of palladium into the first car-
(
bonAbromine bond would form the organopalladium intermediate
that could then undergo subsequent b-halogen elimination to pro-
16
duce 3-hexyne. In both Scheme 1a and b, the eliminations were
too fast to pursue the process with NMR technique; thus, the
mechanistic aspect is not yet fully understood. Hence we chemists
don’t make good use of these vicinal dihaloalkenes for the synthe-
sis of tetrasubstituted olefins.
⇑
Corresponding author. Tel.: +81 77 543 7461; fax: +81 77 543 7483.
E-mail address: iwasawa@rins.ryukoku.ac.jp (T. Iwasawa).
http://dx.doi.org/10.1016/j.tetlet.2015.12.063
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

4
84
N. Endo et al. / Tetrahedron Letters 57 (2016) 483–486
Scheme 4. Stereo-retained synthesis of 8 and 10 from (E)-2, and 9 and 11 from (E)-
. Reaction conditions for 8 and 9, ethynylbenzene, 10 mol % PdCl (PPh , 20 mol %
PPh , 20 mol % CuI, toluene, Et N, 70 °C, 2 h; for 10 and 11, p-tolylboronic acid,
0 mol % Pd(PPh , 2 equiv K CO , DMF, 90 °C, 22 h.
3
2
3 2
)
Scheme 2. Vinylic Rosenmund–von Braun reactions of 1.
3
3
1
)
3 4
2
3
of vinyl bromides 2 (48% NMR yield) and 3 (9% NMR yield), and
bis-nitriles 4, and 1-phenyl-1-butyne 5. Further investigations
1
7
3
were demonstrated, and the system of Ph P@O/CuCN in toluene
at 130 °C formed 3 predominantly (49% NMR yield). Employment
of a large amount of silica gel gave separate fractions of single iso-
mers of 2 and 3 in 27% and 36% yield, respectively.
The stereochemistry of 2 and 3 was concluded from crystallo-
graphic analyses of 6 and 7 that are derived from palladium-cat-
alyzed transformation of 2 and 3 (Scheme 3, and Fig. 1). As
depicted in Scheme 3, cross-coupling on 2 and 3 yielded differen-
tially all-carbon tetrasubstituted acrylonitriles 6 in 88% and 7 in
2
0
5
8%, respectively. Crystallographic analyses of 6 and 7 deter-
mined the molecular structure as shown in Figure 1, which dis-
1
8,19
closed 6 as (E) and 7 as (E) stereochemistry.
Thus, we
Scheme 3. Pd-catalyzed synthesis of (E)-6 from 2, and (E)-7 from 3.
rationally described 2 as (E)- and 3 as (E)-form, and illustrated both
vinyl bromides with the array of four substituents attached to a
double bond as shown in the Scheme 2. Actually, to our surprise,
the structure of (E)-3 was beyond what we expected. The bromine
It appeared to us that understanding this intrinsic problem
would expand the importance and possibility of a vicinal diha-
loalkene as a diverse scaffold for tetrasubstituted olefin synthesis.
Herein we report previously unexplained reaction-paths involved
with b-halogen elimination on the basis of a vinylic Rosenmund–
von Braun reaction of (E)-(1-bromo-2-iodobut-1-en-1-yl)benzene.
Cyanation gave some products, and the structural identification
of them revealed that bifurcation from (E)-vinyl copper species
causes one route to undergo desired reductive-elimination and
another unpleasant b-halogen elimination.
2
atom of 1 finally migrated from the original sp -carbon to the adja-
2
cent sp -carbon, giving another (E)-isomer.
Both structures of (E)-2 and (E)-3 were unveiled, and some syn-
theses of differentially all-carbon tetra-substituted acrylonitrile
were performed through conventional palladium-catalyzed cross-
coupling techniques (Scheme 4). The protocols readily accom-
plished stereo-defined preparation of olefins 8–11. The important
thing here is that (E)-2 or (E)-3 never isomerize to another during
2
1
The reaction of 1 with CuCN under DMF solvent at 70 °C was
performed to give mixtures of four compounds (Scheme 2). The
analytical data of NMR and MS suggested they consisted of a set
the metal-catalyzed reactions. Thus, the unpleasant isomeriza-
tion reaction would be just triggered in the cyanation step of 1
with CuCN.
Figure 1. ORTEP drawings of 6 and 7 with thermal ellipsoids at the 30% probability level. Hydrogen atoms are omitted for clarity. Selected bond lengths [Å] for (E)-6 (a):
C1AC2 1.348, C1AC3 1.484, C1AC9 1.496, C2AC25 1.515, C2AC27 1.450; for (E)-7 (b): C1AC2 1.348, C1AC9 1.494, C1AC25 1.508, C2AC3 1.486, C2AC27 1.443.

N. Endo et al. / Tetrahedron Letters 57 (2016) 483–486
485
What kind of reaction process causes isomerization of the
Table 2
a
Evaluation of reactivities of (E)-2 and (E)-3 on cyanation
stereo-defined 1 to give two isomers of (E)-2 and (E)-3? Does heat-
ing make them tautomerize? Experiments with just heating in sol-
vents were tested on 1, (E)-2, and (E)-3 (Scheme 5). For 1, three
conditions of toluene/110 °C, DMF/70 °C, and DMF/130 °C didn’t
affect the tautomerization while DMF/130 °C slightly put 1 back
to 1-phenyl-1-butyne 5 (Scheme 5a, run 3). On the other hand,
Entry
Substrate
Temp (°C)
Time (h)
% yield
(
E)-2 and (E)-3 remained intact even in the harsh condition of
DMF/130 °C (Scheme 5b and c). This result suggests that tautomer-
ization by heating is unlikely.
4
Recovered (E)-2 or (E)-3
1
2
3
4
5
6
(E)-2
(E)-2
(E)-2
(E)-3
(E)-3
(E)-3
70
2
4
16
2
8
0
ꢀ100
Taking into account that a tautomerization occurs, we evalu-
ated the reactivity of 1 as reaction temperature rising (Table 1).
The cyanation at room temperature and 50 °C sparingly proceeded,
and most of the starting 1 remained intact but (E)-2 and alkyne 5
were formed (entries 1 and 2). At 70 °C overnight reaction con-
sumed all the starting 1 to afford (E)-2 as a main product (entry
120
120
70
120
120
64
19
a
a
0
0
0
ꢀ100
45
34
a
a
16
0
0
a
E)-2 and (E)-3 and 4 were totally decomposed, and 1H NMR of crude states
(
were messy.
3
). When the temperature went up to higher 90 °C and 130 °C
(
entries 4 and 5), the cyanation of 1 occurred faster; both decrease
in (E)-2 and increase in (E)-3 were observed. This clearly shows
that CuCN mediates the isomerization paths, and that heating
accelerates the stream from 1 to (E)-3. In addition, we set the
CuCN-mediated cyanation of (E)-2 and (E)-3 under DMF solvent,
respectively (Table 2). No reactions at 70 °C were observed (entries
1
and 3), while the reactions at 120 °C proceeded to yield single
2
2
product of 4 in 64% from (E)-2 and 45% from (E)-3 (entries 2
and 4). Thus, interestingly, the bis-nitrile 4 was formed at 70 °C
in Table 1, but not in Table 2.23 Any inter-conversion between
(E)-2 and (E)-3 was not observed.
Scheme 6. Plausible reaction paths.
From a view of these situations, we might draw plausible reac-
tion paths as depicted in the Scheme 6. First, the CuCN activated a
2
4
bond of carbonAiodine selectively. Then, the resultant (E)-vinyl
copper would bifurcate to afford (E)-2 by reductive elimination
and the alkyne 5 by b-halogen elimination: finally, 5 formally
reacted with the concomitant IBr to give 1 and iso-1,25 and iso-1
provoked the following cyanation to give (E)-3. Seemingly, from
Table 1, the rise in reaction-temperature presses to form 5 and
2
6
(E)-3.
In summary, crystallographic analysis revealed the stereochem-
istry of (E)-2 and (E)-3, and several experiments found which step
triggers product isomerization. These results give a suggestion of
reaction paths previously unexploited: the oxidative addition of
CuCN to 1 generated the (E)-vinyl copper, then it would be disas-
sembled into reductive elimination and b-halogen elimination,
and the former affords desired (E)-2 and the later unpleasant 5.
The alkyne 5 would be converted to (E)-3 through second oxidative
addition of CuCN to iso-1. Further synthetic development of the
Scheme 5. No tautomerization of 1, (E)-2, and (E)-3 by heating conditions.
Table 1
a
Temperature-dependent reactivity of 1 under the CuCN/DMF condition
(E)-1-bromo-2-iodoalkene on the basis of these reaction routes is
ongoing and will be reported in due course.
Acknowledgments
Entry
Temp (°C)
Time (h)
NMR yield (%)
1
(E)-2
(E)-3
4
5
Japan Society for the Promotion of Science Grant-in-Aid for
Scientific Research (C), Grant Number 24550066, supported this
work. The authors thank Dr. Seiji Watase, Dr. Toshiyuki Iwai and
Dr. Takatoshi Ito at OMTRI for assistance with measurement of
X-ray diffraction and scattering and HRMS. Prof. Dr. Kingo Uchida
at RU is gratefully thanked for help with measurement of UV–vis
absorption.
1
2
3
4
5
rt
74
22
22
5
82
74
0
0
0
2
9
48
40
32
0
0
9
18
26
0
0
24
26
24
2
7
15
16
5
50
70
90
130
1
a
All reactions were performed on 0.5 mmol of 1.

4
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N. Endo et al. / Tetrahedron Letters 57 (2016) 483–486
1
3
26, 11778; c) Lemay, A. B.; Vulic, K. S.; Ogilvie, W. W. J. Org. Chem. 2006, 71,
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1
3. a) Barczak, N. T.; Rooke, D. A.; Menard, Z. A.; Ferreira, E. M. Angew. Chem., Int.
Ed. 2013, 52, 7579; b) Suero, M. G.; Bayle, E. D.; Collins, B. S. L.; Gaunt, M. J. J.
Am. Chem. Soc. 2013, 135, 5332.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.12.
14. Ide, M.; Yauchi, Y.; Shiogai, R.; Iwasawa, T. Tetrahedron 2014, 70, 8532.
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63.
References and notes
1
2
.
.
Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
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1
1
7. Many experiments were tested under varied conditions for producing 2 (or 3)
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given as pesky mixtures. These results were summarized as Table 1S in
Supporting Information. In addition, we examined many vicinal-dihaloalkenes
on this cyanation, and almost all the substrates formed messy mixtures. For
example, the reactivity and selectivity of (E)-(1-bromo-2-iodobut-1-en-1-yl)
pyrene were similar to those of 1.
8. CCDC-1430461 (for (E)-6) contains the supplementary crystallographic data
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Monoclinic, space group P 21/c, colorless, a = 15.0762(5) Å, b = 8.0948(3) Å,
4
.
.
3
c = 16.5104(6) Å,
a
= 90°, b = 105°,
c
= 90°, V = 1950.28(12) Å , Z = 4, T = 296 K,
À3
À1
d
calcd
=
1.217 g cm
,
l(Mo-K
a) = 0.070 mm
,
R
1
= 0.0542, wR
2
= 0.2069,
5
a) Vicario, J.; Walko, M.; Meetsma, A.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128,
GOF = 1.074.
5
127; b) Jager, W. F.; de Jong, J. C.; de Lange, B.; Huck, N. P. M.; Meetsma, A.;
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c = 17.7179(6) Å,
a
= 90°, b = 109°,
c
= 90°, V = 1926.61(10) Å , Z = 4, T = 296 K,
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À1
dcalcd = 1.232 g cm
,
l(Mo-K
a
) = 0.071 mm
,
1 2
R = 0.0470, wR = 0.1352,
GOF = 1.043.
2
0. With viable pyrene-derivatives in hand, UV–vis absorption of (E)-6 and (E)-7
were checked; however, any significant difference between them was not
observed (Fig. 1S in Supporting Information).
1. The usage of (E)-3 in the cross-coupling reactions tends to decrease the
chemical yields compared to that of (E)-2, presumably due to difference in
steric congestion toward reactive CABr sites between ethyl of (E)-2 and phenyl
of (E)-3.
2
395; e) de Meijere, A.; Kozhushkov, S. I. Eur. J. Org. Chem. 2000, 3809.
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8.
9.
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2
6. Not only temperature-up but also external ligands would enhance the halogen
elimination. For example, the highest NMR yield of (E)-3 was given in 53%
under the condition of toluene (solvent), 110 °C, DMF (11 equiv), and CuCN
(
1.1 equiv), (see, entry 8 in Table 1S).
1
2. a) Begue, J.-P.; Bonnet-Delpon, D.; Bouvet, D.; Rock, M. H. J. Org. Chem. 1996, 61,
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