Effect of functional groups in organic chlorides on radical reduction with hydrostannane under microwave irradiation

Article abstract of DOI:10.1246/cl.170413

The effect of functional groups on the activation of molecules by microwave irradiation in the reduction of organic chlorides by Bu₃SnH was investigated. The reactivity of a substrate with a hydroxy group increased under microwave heating conditions in comparison with conventional heating.

Full text of DOI:10.1246/cl.170413

Advance Publication Cover Page
Effect of Functional Groups in Organic Chlorides on Radical Reduction with
Hydrostannane under Microwave Irradiation
Yoshihiro Nishimoto,* Satoshi Yazawa, Kensuke Kiyokawa, Takahito Kajiki, Yasunori Tsukahara,
Tomohisa Yamauchi, Yuji Wada, Akio Baba, and Makoto Yasuda*
Advance Publication on the web May 16, 2017
doi:10.1246/cl.170413
© 2017 The Chemical Society of Japan
Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire
manuscripts and a portion of the graphical abstract can be released on the web as soon as the submission is accepted. Note that the
Chemical Society of Japan bears no responsibility for issues resulting from the use of information taken from unedited, Advance
Publication manuscripts.

1
Effect of Functional Groups in Organic Chlorides on Radical Reduction with Hydrostannane
under Microwave Irradiation
Yoshihiro Nishimoto,*1 Satoshi Yazawa,2 Kensuke Kiyokawa,2 Takahito Kajiki,2 Yasunori Tsukahara,3 Tomohisa Yamauchi,3 Yuji
Wada,4 Akio Baba,2 and Makoto Yasuda*2
1Frontier Research Base for Global Young Researchers, Center for Open Innovation Research and Education(COiRE), Graduate School
of Engineering, Osaka University 2-1 Yamadaoka, Suita, Osaka 565-0871
2Department of Applied Chemistry, Graduate School of Engineering, Osaka University 2-1 Yamadaoka, Suita, Osaka 565-0871
3Microwave Chemical Co., Ltd. Techno Alliance 3F 2-8 Yamadaoka, Suita, Osaka 565-0871
4Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology,
Meguro-ku, Tokyo 152-8550
E-mail: nishimoto@chem.eng.osaka-u.ac.jp; yasuda@chem.eng.osaka-u.ac.jp
The effect of functional groups on the activation of
molecules by microwave irradiation in the reduction of
organic chlorides by Bu3SnH was invetigated. The reactivity
chloride 1 was reduced by Bu3SnH in the presence of AIBN
under both conventional heating (oil bath, 100 ºC) and
microwave irradiation conditions (CEM Discover microwave,
100 ºC). A higher yield was observed under the microwave
irradiation conditions. Other chlorinated substrates 3 and 5
bearing ester and hydroxy moieties, respectively, were also
examined and gave the same results wherein the microwave
irradiation system afforded higher yields.
of
a substrate with hydroxy group increased under
microwave heating conditions in comparison with
conventional heating.
Organic synthesis using microwave irradiation is now
being widely studied and numerous reactions are being
described.1,2 In most reactions with microwaves, polar
solvents that have a high dielectric loss are used, such as
H2O and dimethylsulfoxide, and the high temperature that is
generated leads to high efficiency of the reaction.3 On the
other hand, Kappe reported the use of silicon carbide as an
acceptor for irradiation even in non-polar solvent.4 Recent
reports have described a microwave-specific effect that is
caused by the absorption of microwave energy by a substrate
and/or reagent molecules rather than by a solvent. Yamada
reported that some enantioselective reactions such as
methanolysis and reduction of biaryl lactones as well as
Claisen rearrangement of an alkenyl allyl ether bearing a
phosphonate moiety were accelerated by microwave
irradiation without a loss of enantioselectivity at the same
internal reaction temperature that is used for conventional
heating.5 Some groups have described a reaction system that
is accelerated by the selective microwave heating of
substrates.6 Especially, Dudley has studied the microwave-
specific extra-temperature thermal effect that is caused by
microwave-absorbing substrates in a Friedel-Crafts reaction.7
In a previous study, our group reported the coupling reaction
between alcohols and active methylenes using a non-polar
solvent under microwave heating conditions,8 in which
microwaves are directly absorbed by the reaction substrates
to generate thermal energy related to the loss tangent of the
substrates and the locally generated thermal energy
accelerates the radical reaction of the molecule absorbing
micro wave.9 In this context, we investigated the functional
groups of substrates to establish the dependence these can
exert on selective microwave heating.
Scheme 1. Microwave promoted radical reduction of organic chlorides.
Reaction conditions: organic chloride 1, 3, or 5 (6.0 mmol), Bu3SnH (6.0
mmol), and AIBN (0.6 mmol), toluene (10 mL). Microwave irradiation
by Biotage Initiator (The internal temperature was measured by a built-
in IR sensor.). The yields were determined by GC.
We were interested in the influence that produced the
reaction rate of the functional groups in alkyl chlorides, but it
was difficult to compare the yields with a separate batch
reaction system, as shown in Scheme 1, because each system
requires
a radical initiator with different timing and
temperature profiles were slightly different for each of the
reaction systems under microwave conditions. Therefore, a
system containing a mixture of three alkyl chlorides, 1, 3,
and 5, was examined under conventional and microwave
reactions. The ratios of the produced compounds, 2, 4, and 6,
were compared and clearly showed the reactivities under
each of the conditions. This method is operationally simple
and quite reliable for the comparison of relative reaction
rates. As shown in Scheme 2, conventional heating
conditions (oil bath, 100 ºC) gave the products in the order
ester 4 > alkane 2 > alcohol 6. By contrast, microwave
irradiation (CEM Discover microwave, 100 ºC) resulted in
To investigate the effect that functional groups could
exert on microwave irradiation, we chose a radical reduction
of alkyl chlorides bearing different functional groups by
using Bu3SnH because the influence of polar functional
groups to the radical reaction under the conventional heating
conditions might be small (Scheme 1).10,11 The simple alkyl

2
Table 1 Microwave promoted radical reduction of three types of organic
the order ester 4 > alcohol 6 > alkane 2. In particular, the
production ratio of alkane 2 to alcohol 6 was reversed by
changing the heating conditions (MW or oil bath).
Microwave irradiation conditions gave alcohol 6 prior to
alkane 2 in contrast to the conventional heating conditions,
which indicated that the alcohol substrate 5 was more
sensitive to microwave heating than simple alkyl chloride 1.
chloridesa,b
50
40
30
20
10
0
50
40
30
20
10
0
aReaction conditions:
(0.4 mmol), toluene (20 mL). Mirowave irradiated by CEM Discover
(The internal temperature was measured by a fiber-optic sensor.).
bThe yields were determined by GC.
1 (4 mmol), 3 (4 mmol), 5 (4 mmol), AIBN
4
5
6
7
8
9
10
3
4
5
6
7
Next, the effect of microwave irradiation on
intramolecular selectivity was investigated by using substrate
7, which has two alkyl chloride moiety types (Scheme 3).
One (ClB) of the two alkyl chloride moieties in substrate 7 is
closer to the hydroxy group; the other (ClA) is a normal
chloroalkane type. The reactions of substrate 7 with Bu3SnH
in the presence of AIBN were carried out under both
conventional heating and microwave irradiation conditions.
Interestingly, reductions under both heating conditions
showed an equal selectivity of alkylchloride moieties
(reduction ratio of ClB in Scheme 3).12 These results
indicated that the microwave irradiation affected the
functionalized molecule rather than the functional group. In
other words, the whole of molecule 7 was activated by
microwave irradiation so that both ClA and ClB moieties were
activated in a similar manner.
Scheme 2. Microwave promoted radical reduction of organic chlorides.
Reaction conditions: 1 (4 mmol), 3 (4 mmol), 5 (4 mmol), Bu3SnH (4
mmol), AIBN (0.4 mmol), toluene (20 mL). Microwave irradiated by
CEM Discover (The internal temperature was measured by a fiber-optic
sensor.).
The effect of microwave power on the product ratio was
investigated (Table 1). For microwave power settings of 100,
150, and 200 W, the production ratios (4/2) of ester 4 to
alkane 2 were 1.58, 1.64, and 1.62, respectively (Table 1,
entries 2, 3, and 4). The ratio (6/2) of alcohol 6 to alkane 2
and that (6/4) of alcohol 6 to ester 4 did not change when
microwave power was increased (Table 1, entries 1, 2, and 3).
Therefore, the product ratio was only moderately affected by
microwave power.
Next, we compared microwave
irradiation conditions with conventional heating conditions
and the effect on the product ratio. Entry 4 in Table 1 shows
the results of conventional heating. The ratios of each
microwave conditions (100, 150, and 200 W) and
conventional heating conditions for a product ratio of 4/2
were 1.02, 1.05, and 1.04, respectively (Table 1, entries 1, 2,
and 3, MW/oil bath (4/2)). Therefore, the acceleration effects
of microwave heating on the reduction of 1 approximated
those of 3. On the other hand, the ratios of alkane 2 to
alcohol 6 and that of ester 4 to alcohol 6 under microwave
conditions were about 1.2-fold greater than those under
conventional heating (Table 1, entries 1, 2, and 3, MW/oil
bath (6/2) and (6/4)). Therefore, the reactivity of hydroxy-
substituted alkyl chloride
5 was most enhanced by
microwave irradiation among the three types of substrates.

3
Scheme 3. Investigation of intramolecular selectivity of reduction of
substrate 7 with two types of alkylchloride moieties. 7 (2 mmol),
Bu3SnH (2 mmol), and AIBN (0.2 mmol) in toluene-d8 (10 mL).
Microwave irradiation by Biotage Initiator (The internal temperature
was measured by a built-in IR sensor.). The ratio of reduced site was
determined by 1H NMR.
conditions compared with conventional heating conditions.
In addition, intermolecular competitive reduction using alkyl
chlorides bearing a hydroxy group at different positions
showed that the degree of activation by microwave
irradiation is affected even by small structural differences.
An investigation of this phenomenon is in progress.
This work was supported by JSPS KAKENHI Grants
Number JP15H05848 in Middle Molecular Strategy and
JP16K05719. Part of the work was supported by the
Sumitomo Electric Industries Group CSR Foundation to M.Y.
Y.N. acknowledges support from the Frontier Research Base
for Global Young Researchers, Osaka University, of the
MEXT program. Thanks are due to the Analytical
Instrumentation Facility, Graduate School of Engineering,
Osaka University, for assistance in obtaining the MS spectra.
Finally, intermolecular competitive reduction was
investigated using three types of alkyl chlorides, 11, 13, and
15, with hydroxy groups at different positions (Table 2).
With reduction under microwave irradiation, the production
ratio of 12 was higher than that under conventional heating
(12/14 and 12/16, Table 2), which suggested that the
activation of 11 by microwave irradiation was the highest
among these alkyl chlorides. In addition, the ratios of 14 and
16 for microwave and conventional conditions were 1.07 and
0.98, respectively, which showed that the reduction
selectivities of 13 and 15 were inversed by the change in
heating conditions. Therefore, the reduction in 14 compared
with that in 16 was clearly accelerated by microwave
irradiation. These results suggested that such a small
structural difference affects the degree of substrate activation.
Generally, the ability of a molecule to absorb energy from
microwave irradiation is related to the loss tangent of the
molecule, and this parameter strongly depends on molecular
structure.9 The differences in the loss tangent at 2.45 GHz
might have contributed to the differences in the degrees of
activation by microwave irradiation, which depended not
only on functional groups but also on the small differences in
the carbon-chain that were found in the present study.
Supporting
Information
is
available
on
http://dx.doi.org/10.1246/cl.******.
References and Notes
1
For first reports using microwaves, see: a) R. Gedye, F. Smith, K.
Westaway, H. Ali, L. Baldisera, L. Laberge, J. Rousell,
Tetrahedron Lett. 1986, 27, 279. b) R. J. Giguere, T. L. Bray, S.
M. Duncan, G. Majetich, Tetrahedron Lett. 1986, 27, 4945.
Selected reviews; a) C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43,
6250. b) A. Loupy, Microwaves in Organic Synthesis, Wiley-
VCH, Weinheim, 2006. c) C. O. Kappe, A. Stadler, Microwaves
in Organic and Medicinal Chemistry, Wiley-VCH, Weinheim,
2005. d) A. de la Hoz, Á. Díaz-Ortiz, A. Moreno, Chem. Soc. Rev.
2005, 34, 164. e) S. Caddick, R. Fitzmaurice, Tetrahedron 2009,
65, 3325. f) M. B. Gawande, S. N. Shelke, R. Zboril, R. S. Varma,
Acc. Chem. Res. 2014, 47, 1338.
2
3
4
5
N. E. Leadbeater, M. J. Marco, M. J. J. Org. Chem. 2003, 68, 888
J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2006, 71, 4651.
a) S. Kikuchi, T. Tsubo, T. Ashizawa, T. Yamada, Chem. Lett.
2010, 39, 574. b) K. Nushiro, S. Kikuchi, T. Yamada, Chem. Lett.
2013, 42, 165. c) K. Nushiro, S. Kikuchi, T. Yamada, Chem.
Commun. 2013, 49, 8371. d) S. Tashima, T. Sawada, K. Saito, T.
Yamada, Chem. Lett. 2016, 45, 649. e) S. Tashima, K. Nushiro, K.
Saito, T. Yamada, Bull. Chem. Soc. Jpn. 2016, 89, 833.
a) N. K. Kaiser, U. Bremberg, M. Larhed, C. Moberg, A. Hallberg,
Angew. Chem. Int. Ed. 2000, 39, 3596. b) A. Steinreiber, A.
Stadler, S. F. Mayer, K. Faber, C. O. Kappe, Tetrahedron Lett.
2001, 42, 6283. c) T. Durand-Reville, L. B. Gobbi, B. L. Gray, S.
V. Ley, J. S. Scott, Org. Lett. 2002, 4, 3847. d) J. A. Teske, A.
Deiters, J. Org. Chem. 2008, 73, 342. e) P.-K. Chen, M. R.
Rosana, G. B. Dudley, A. E. Stiegman, J. Org. Chem. 2014, 79,
7425.
Table 2. Investigation of intermolecular competitive reduction using
three types of alkylchlorides 11, 13, and 15a,b
6
7
M. R. Rosana, J. Hunt, A. Ferrari, T. A. Southworth, Y. Tao, A. E.
Stiegman, G. B. Dudley, J. Org. Chem. 2014, 79, 7437.
S. A. Babu, M. Yasuda, Y. Tsukahara, T. Yamauchi, Y. Wada, A.
Baba, Synthesis 2008, 1717.
8
9
C. Gabriel, S. Gabriel, E. H. Grant, B. S. J. Halsteadb, D. M. P.
Mingosb, Chem. Soc. Rev. 1998, 27, 213.
10
a) H. G. Kuivila, L. W. Menapace, J. Org. Chem. 1963, 28, 2165.
b) L. W. Menapace, H. G. Kuivila, J. Am. Chem. Soc. 1964, 86,
3047. (c) M. L. Poutsma, P. A. Ibarbia, Tetrahedron Lett. 1972,
13, 3309.
aReaction conditions: 11 (1 mmol), 13 (1 mmol), 15 (1 mmol), Bu3SnH
(1 mmol), AIBN (0.1 mmol), toluene (5 mL). Mirowave irradiated by
CEM Discover (The internal temperature was measured by a fiber-
optic sensor.). The yields were determined by GC.
11
12
The radical reduction of organic halides with fluorous stannane
under microwave heating is reported as a high-speed reaction
system. K. Olofsson, S.-Y. Kim, M. Larhed, D. P. Curran, A.
Hallberg, J. Org. Chem. 1999, 64, 4539.
The yields of each 9 and 10 are not determined because of
obscured NMR signals by overlapping. However, sum of the
yields of 9 and 10 can be determined. Therefore, the reduction
ratio o ClB is estimated by (9 + 10)/(8 + 9 + 10 + recovery of 7)
as shown in Scheme 3.
We investigated hydroxy and ester groups for their
effect on the activation of molecules by microwave
irradiation during the reduction of organic chlorides by
Bu3SnH, and found that hydroxy-substituted alkylchloride
was effectively activated under microwave irradiation