A practical screening strategy of arsenic ligands for a transition-metal-catalyzed reaction

Article abstract of DOI:10.1246/cl.170163

Organoarsenic ligands were synthesized via a safe and easy procedure, superior to the conventional synthetic methodologies. Diiodophenylarsine was prepared in situ, and was readily converted to diarylphenylarsines. Pd-catalyzed Mizoroki-Heck reaction was investigated using the obtained arsenic ligands. It was found that bulky and electron-donating ligands were effective for the reaction, meaning that the success in the screening of arsenic ligand structures was based on the present facile strategy.

Full text of DOI:10.1246/cl.170163

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A Practical Screening Strategy of Arsenic Ligands for a Transition Metal-Catalyzed Reaction
Hiroaki Imoto, Chieko Yamazawa, Susumu Tanaka, Takuji Kato, and Kensuke Naka*
Advance Publication on the web March 15, 2017
doi:10.1246/cl.170163
© 2017 The Chemical Society of Japan
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1
APractical Screening Strategy of Arsenic Ligands for a Transition Metal-Catalyzed Reaction
Hiroaki Imoto, Chieko Yamazawa, Susumu Tanaka, Takuji Kato and Kensuke Naka*
Faculty of Molecular Chemistry and Engineering, Graduate School of Science and Technology, Kyoto Institute of Technology,
Goshokaido-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
(E-mail: kenaka@kit.ac.jp)
Organoarsenic ligands were synthesized via a safe and
Cyclooligoarsines such as cyclo-(AsMe)5 and cyclo-
(AsPh)6 are synthesized from nonvolatile arsenics,
methylarsonic acid9a and phenylarsonic acid,9b respectively.
Recently, we have working on developing practical synthetic
routes for As−C bond formation using these cyclooligoarsines
as precursors.10 In the series of these studies, it has been found
that cyclooligoarsines are readily converted to diiodoarsines
by addition of iodine,10,11 and subsequent substitution reaction
with nucleophiles can lead to various kinds of arsenic
compounds (Scheme 1). As a result, we have succeeded in the
experimental studies on functional organoarsenic compounds
such as arsafluorene, arsole, and dithienoarsoles, and
disclosed the intriguing nature of an arsenic atom.10,12
Therefore, we assumed that this synthetic protocol can be
applied to the development of arsenic ligands for transition
metal-catalyzed reactions. In this work, strategy for the
construction of arsenic ligand library is proposed in order to
enable systematic studies on structure-activity relationship.
Mizoroki-Heck reaction13 was herein chosen for the structural
screening of the arsenic ligands, and the obtained arsenic
ligands were tested. In addition, oxidative resistance was
investigated to demonstrate the advantage of the arsenic
ligands over a phosphorus analogue, triphenylphosphine
(PPh3).
easy procedure, superior to the conventional synthetic
methodologies. Diiodophenylarsine was prepared in-situ, and
readily converted to diarylphenylarsines. Pd-catalyzed
Mizoroki-Heck reaction was investigated using the obtained
arsenic ligands. It was found that bulky and electron-donating
ligands were effective for the reaction, meaning the success in
screening of arsenic ligand structures based on the present
facile strategy.
Transition metal-catalyzed coupling reactions are,
needless to say, absolutely essential tools in the field of
organic synthesis. Accompanied with the growing demand for
the development of catalytic systems, ligand structure has
been varied and polished. Among various kinds of ligands,
trivalent phosphorus compounds have been extensively
studied.1,2 Structural effects of phosphorus ligands on catalytic
activity have been fully investigated to date, and the
widespread knowledge has been accumulated. Obviously,
challenging matters in organic reactions still remain, and
further variation of ligands is required. To embark on a new
stage of catalytic chemistry, the incorporation of other basic
building blocks should be effective.
An arsenic atom acts as a poorer -donor and -acceptor,
and has larger steric hindrance compared to a phosphorus
atom.3 It is reported that arsenic ligands accelerate reaction
rate4 and improve selectivity5 in some cases. Copper-free
Sonogashira-Hagihara coupling reaction needs triphenylarsine
(AsPh3) as a ligand.6 Moreover, a trivalent arsenic atom is
much more stable in the air than phosphorus atom. While
phosphorus ligands are often subjected to oxidation during
reaction and storage, arsenic analogues could be treated under
the ambient air. Because of these potential functions and
advantages, organoarsenic compounds are promising
candidates as a novel class of ligands for transition metal-
catalysts.
Scheme 1. Syntheses of functional arsenic compounds via in-
situ generation of diiodoarsines.10,12
Diarylphenylarsines PhR2As (3a-e) were synthesized as
However, structure-activity relationship of arsenic
ligands has been rarely investigated in researches on organic
reactions. This is because there is concern to the toxicity and
volatility of arsenic intermediates, e.g., arsenic chlorides and
hydrides, which are typically exploited in conventional
synthetic procedures for arsenic ligands.7 Actually, some of
these low molecular weight arsenic compounds were
tragically abused in World War I. The practical utilities of the
reported As−C bond formation reactions without volatile
arsenic intermediates are still limited; narrow applicable
ranges and/or severe reaction conditions.8 Synthetic barrier of
arsenic compounds should be overcome for further
advancement of transition metal-catalyst.
described in Table 1. A solution of iodine was added to a
dispersion of hexaphenylhexaarsine
1 for the in-situ
preparation of diiodophenylarsine 2, and subsequently the
solution of 2 was added to solutions of nucleophiles without
isolation. Organolithium or Grignard reagents were used as a
nucleophile,
and
column
chromatography
and
recrystallization gave arsenic compounds 3a-e in moderate
isolated yields (41-89%).14 The newly synthesized compounds
1
3a-d were characterized with H and 13C NMR spectra and
mass analysis.
For the observation of the structural features of the
ligands, the X-ray diffraction data of their palladium
complexes ([PdCl2(ligand)2]) were collected.15 The single
crystals suitable for the X-ray analysis were successfully

2
Tolman’s method.16 The cone angles of 3a-c and 3e are
182°, 191°, 203°, and 139°, respectively. The ligands 3a-c
have much larger values in comparison with the reported data
of PPh3 (145°),16 while 3e has smaller steric hindrance. It has
been shown that wide variety of steric hindrance was induced
into the prepared arsenic ligands. Pd-catalyzed Mizoroki-
Heck reaction was investigated to determine the effect of the
arsenic ligands. In addition to 3a-e, PPh3, and AsPh3 were
examined as commercially available ligands. For the
evaluation of the catalytic activity, the relatively challenging
Mizoroki-Heck reaction of p-bromotoluene and styrene was
selected (Scheme 2) in reference to the previous literature.8c
These substrates are not activated for Mizoroki-Heck reaction,
and suitable for comparing the catalytic activity. Palladium
catalyst was loaded as the mixture of [PdCl2(PhCN)2)] and
ligand. For the confirmation of the repeatability, each ligand
was examined several times, and the results were summarized
in Figure 1. The o-isopropoxy-substituted ligand 3c showed
the highest activity (43%), while in the case of 3e, the yield
(22%) was significantly lower than those of others (30-43%).
These results suggest that sterically hindered structures, which
were confirmed by the X-ray diffraction, are advantageous in
the reaction. From the view point of electron-donation ability,
the activities of the alkoxy-substituted ligands 3b and 3c were
relatively high (38% and 43%, respectively), meaning that the
more electron-donating the ligand, the higher the catalytic
activity. Reductive elimination and oxidative addition steps
are promoted by steric hindrance and electron-donation,
respectively. This is well corresponding to general phosphine
ligand systems.17 Especially, in the case of 3c, the yield (43%)
is compatible to that of the reported arsenic ligand (44%),8c
whose structure is optimized based on Buchwald-type
biphenyl backbone. It has been demonstrated that the
systematic study on arsenic ligand structures can be carried
out based on the facile synthetic strategy.
Table 1. Syntheses of arsenic ligands.
Yielda
[%]
Run
1
Nucleophile
Product
41
70
72
55
89
3a
3b
2
3
3c
3d
3e
4
5b
aIsolated yield. bReported in the reference 10.
obtained in the cases of 3a-c and 3e. The palladium dichloride
complexes [PdCl2(ligand)2] were synthesized as follows. cis-
Bis(benzonitrile)palladium(II) dichloride ([PdCl2(PhCN)2)])
and a ligand were reacted in chlorobenzene under reflux
condition overnight. The slow diffusion of dichloromethane
solutions of the complex to methanol gave the single crystals
of [PdCl2(ligand)2] (ligand = 3a-c and 3e). The isolated
complexes adopt trans configuration in the crystalline state.
Thus, to work as a catalyst, trans-cis isomerization and/or
transformation to mono-arsine state should occur. The As−Pd
bond lengths are approximately the same (2.40-2.43 Å) as
shown in Table 2. The cone angles are estimated based on the
Scheme 2. Mizoroki-Heck reaction.
Table 2. X−Pd (X = As or P) bond length and cone angle
of [PdCl2(ligand)2]
X−Pd (X = As or P) bond length
Cone anglea
[°]
Ligand
[Å]
2.430(2)
2.404(3)
2.432(4)
2.4172(9)
-
3a
3b
3c
3e
182
191
203
139
Figure 1. Yields of the Mizoroki-Heck reaction. The yields
were estimated by the 1H NMR spectra (Figure S13 in
Supporting Information18).
b
PPh3
145
aEstimated by Tolman’s method.16 bCited from reference 16.

3
Acknowledgement
The Mizoroki-Heck reaction was performed under an
open-air atmosphere to show oxidative resistance of the
arsenic ligand system. PPh3, AsPh3, and 3c were employed for
the reaction of Scheme 2 with adopting an open-air condition
(Figure S14 in Supporting Information18). It is worth nothing
that AsPh3 and 3c showed no significant difference; under N2,
30% (AsPh3) and 43% (3c), and under the open-air
atmosphere, 32% (AsPh3) and 41% (3c). In contrast, PPh3
may be oxidized during the reaction under the open-air
atmosphere, and the yield was lowered from 31% (N2) to 23%
(open-air). Then, we performed an oxidative resistance test;
chloroform solutions of PPh3, AsPh3, and 3c were subjected to
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “New Polymeric Materials
Based on Element-Blocks (No.2401)” (JSPS KAKENHI
Grant Number JP24102003) of The Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
References and Notes
1
W. Levason, G. Reid, Comprehensive Coordination Chemistry II; J.
A. McCleverty, T. J. Meyer, Eds.; Elsevier Science: Amsterdam,
The Netherlands, 2004; Vol. 1, Chapter 1.12, pp 253.
2
For recent reviews, see: a) J. R. Khusnutdinova, D. Milstein,
Angew. Chem. Int. Ed., 2015, 54, 12236. b) P. Chen, Acc. Chem.
Res. 2016, 49, 1052. c) A. C. Sather and S. L. Buchwald, Acc.
Chem. Res. 2016, 49, 2146.
1
dry air-bubbling for 8 h at room temperature. In the H NMR
spectra of AsPh3 and 3c, the oxidation was not observed.
However, approximately 5% amounts of PPh3 were oxidized
to triphenylphosphine oxide. This implies that catalytic
systems using the arsenic ligands are highly tolerant to air
oxidation. This is great advantage of the arsenic ligands over
phosphorus analogues in practical use.
Finally, the activity of 3c, which showed the highest
yield in Scheme 2, was evaluated in the Mizoroki-Heck
reaction using traditional substrates. The results are posted in
Table 3. Halobenzenes having electron-donating and
withdrawing groups were applied to the coupling reaction
with styrene, and n-butyl acrylate was used as a substrate. The
isolated yields were high (79-96%),19 suggesting that 3c
works as an active ligand for Mizoroki-Heck reaction.
Notably, even under an open-air condition, the catalytic
activity was never suffered (Run 1).
3
4
5
W. Levason, G. Reid, Comprehensive Coordination Chemistry II; J.
A. McCleverty, T. J. Meyer, Eds.; Elsevier Science: Amsterdam,
The Netherlands, 2004; Vol. 1, Chapter 1.16, pp 377.
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Uberman, S. E. Martín, Eur. J. Org. Chem. 2015, 2698.
Table 3. Scope of substrates for ligand 3c.
9
a) P. S. Elmes, S. Middleton, B. O. West, Aust. J. Chem. 1970, 23,
1559. b) J. W. B. Reesor, G. F. Wright, J. Org. Chem. 1957, 22,
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10
11
T. Kato, S. Tanaka, K. Naka, Chem. Lett. 2015, 44, 1476.
S. Tanaka, H. Imoto, T. Kato, K. Naka, Dalton Trans. 2016, 45,
7937.
4
t
Yielda
[%]
Run
5
R1
CN
X
Br
I
[h]
2
24
2.5
2.5
Styrene
Styrene
n-Butyl acrylate
95 (99)b
12
a) M. Ishidoshiro, Y. Matsumura, H. Imoto, T. Irie, T. Kato, S.
Watase, K. Matsukawa, S. Inagi, I. Tomita, K. Naka, Org. Lett.
2015, 17, 4854. b) M. Ishidoshiro, H. Imoto, S. Tanaka, K. Naka,
Dalton Trans. 2016, 45, 8717. c) T. Kato, H. Imoto, S. Tanaka, M.
Ishidoshiro, K. Naka, Dalton Trans. 2016, 45, 11338. d) Y.
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The isolated yields of 3a and 3d were relatively low. The 1H-NMR
spectrum of 3a in the crude state indicated that the reaction
proceeded quantitatively. Thus, recrystallization process should
lower the isolated yield of 3a due to its low crystallinity. On the
other hand, the 1H-NMR spectrum of 3d in the crude state showed
that the mono-substituted by-product may be contained.
Crystallographic data reported in this manuscript have been
deposited with Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-1525695-1525698. Copies
of the data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge, CB2
1EZ, UK; fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
C. A. Tolman, Chem. Rev. 1977, 77, 313.
1
2
3
4
OCH3
COCH3
COCH3
86
79
96
Br
Br
Styrene
aIsolated yields. bResult of the reaction under an open-air atmosphere is
in bracket.
13
14
In conclusion, we have demonstrated the structural
variation of organoarsenic ligands based on a practical
synthetic strategy. Diiodophenylarsine, which was safely and
easily prepared in-situ from the nonvolatile precursors, was
employed to obtain various arsenic ligands. The activity for
the Pd-catalyzed Mizoroki-Heck reaction was improved by
electron-donating and sterically hindered structure,
corresponding to the phosphorus chemistry.17 In spite of the
simple structure of 3c, the reaction yield was compatible to
the Buchwald-type arsenic ligands.8c Notably, the arsenic
ligands were highly tolerant to oxidation under an open-air
atmosphere, compared with a phosphorus analogue, PPh3.
This is the first report on the systematic study of arsenic
ligand structure based on a practical synthetic strategy.
Further development of arsenic ligands and more widely
applicable synthetic route are under investigation.
15
16
17
18
J.-P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651.
Supporting Information is also available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
The isolated yields in run 2 and 3 were relatively low (86% and
79%, respectively) probably because the products were lost during
the isolation process. Actually, in their 1H-NMR spectra in the
crude states, no signals derived from the substrates 4 were
19

4
observed, and only small amounts of unidentified impurities were
included.