Deoxygenation of sulfoxide and aza-aromatic N-oxide using a protocol of indium and acyl chloride

Article abstract of DOI:10.1055/s-2005-918492

Sulfoxides and aza-aromatic N-oxides were deoxygenated using a system of indium and pivaloyl chloride at room temperature to give the corresponding sulfides and aza-aromatics in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918492

SHORT PAPER
3499
Deoxygenation of Sulfoxide and Aza-aromatic N-Oxide Using a Protocol of
Indium and Acyl Chloride
a
a
a
b
c
D
E
eoxygenation
u
of
S
ulfoxide
n
and
A
za-aromatic
S
N
-Oxide oo Park, Seung Hwan Lee, Ji Hee Lee, Hak June Rhee, Cheol Min Yoon*
a
b
c
Graduate School of Biotechnology, Korea University, Sungbuk-ku Anamdong 5, 1 ga, 136-701 Seoul, South Korea
College of Science and Technology, Hanyang University, Sangnok-ku Sa-1 dong 1271, 425-791 Kyeonggi-do, South Korea
Department of Advanced Material Chemistry, Korea University, Jochiwon, 339-800 Choongnam, South Korea
Fax +82(2)32903433; E-mail: cmyoon@korea.ac.kr
Received 17 February 2005; revised 30 June 2005
Abstract: Sulfoxides and aza-aromatic N-oxides were deoxygenat-
ed using a system of indium and pivaloyl chloride at room temper-
ature to give the corresponding sulfides and aza-aromatics in high
yields.
Piv
O
S
O
S
+
Cl
S
Sulfoxide
or
PivCl
or
O
or
N
Key words: deoxygenation, sulfoxide, aza-aromatic N-oxides, in-
dium, sulfide
Indium
O
N
Piv
Cl
+
N
N-Oxide
Sulfoxides have become an increasingly important func- Scheme 1
tional group in organic synthesis, particularly in asymmet-
1
ric synthesis. Considerable effort has been contributed to
The deoxygenation of dibenzylsulfoxide serves as diag-
nostic measure of the utility of the reaction, since most
methods either fail completely with this substrate or only
provide poor yields of dibenzylsulfide.10 The deoxygen-
ation of benzyl sulfoxide was examined using several acid
chlorides (3 equiv) as an activating group in various protic
solvents using indium (1.5 equiv) at room temperature
and the results are listed in Table 1. The best result was
obtained in 96% yield when the reaction was conducted
using pivaloyl chloride as an activator and i-PrOH as a
solvent at room temperature (entry 3). The reaction of the
control test showed that the deoxygenation of sulfoxide
did not proceed at all without pivaloyl chloride or in the
presence of HCl. HCl which might be generated by alco-
holysis of pivaloyl chloride under our reaction condition
has been known to activate the indium metal and acceler-
the development of efficient methods for the deoxygen-
2
ation of sulfoxides to sulfides. However, many of these
transformations require prolonged reaction times, harsh
conditions, or reagents that are not readily available.3
Many other reported methods, even if they do proceed un-
der mild conditions with fair yields, have been explored
4
only on a limited number of simple substrates. Indium or
indium chloride mediated deoxygenations are known, but
the reactions require anhydrous conditions and reflux
5
temperatures. Deoxygenation of aza-aromatic N-oxide is
an important transformation in the synthesis of aza-aro-
matics such as quinolines, isoquinolines and pyridines.
Deoxygenations of aza-aromatic N-oxides with dehydrat-
ing reagents such as PCl , POCl , SO Cl and SOCl suf-
5
3
2
2
3
fer serious drawbacks such as chlorination of aza-
6
aromatic nucleus. Several other indium-mediated proto-
11
7
ate the reaction. On the basis of the experimental result,
we propose the reactive intermediate in the reaction is
acyl sulfinium ion, which has been known to be interme-
cols such as In/NH Cl and In/Cp TiCl -bimetallic
4
2
2
8
system are known to be effective for the deoxygenation
of N-oxide. However, they need heating and pre-heating.
12
diate in the Pummerer rearrangement. Pivaloyl chloride
has dual roles which are the activation of sulfoxide
through the formation of acetyl sulfinium ion and activa-
tion of indium metal by HCl generated in situ from alco-
holysis of pivaloyl chloride.
The observation of deoxygenation of isoquinoline N-ox-
ide during indium mediated allylation study of quinoline
N-oxide and quinoline activated by ethyl chloroformate9
encouraged us to explore the deoxygenation process of
sulfoxide and N-oxide using a protocol of indium and acid
halide. Herein we wish to report the deoxygenation of
sulfoxides and aza-aromatic N-oxides using a protocol of
indium and pivaloyl chloride (PivCl) at room temperature
A wide range of diaryl, aryl-alkyl, and dialkyl sulfoxides
under the reaction conditions were reduced to give the
corresponding sulfides in good to excellent yields at room
temperature as shown in Table 2. Both bromo and chloro
functional groups remained intact despite the possibility
(
Scheme 1). Pivaloyl chloride in the reaction seemed to
contribute as an activator by the polarization of N–O or S–
O bond through the formation of reactive intermediates.
13
14
of homocoupling or dehalogenation by indium (entries
6
and 7). For sulfoxide, the only difficulty encountered
was with the electronically poor sulfoxides such as phenyl
sulfoxide. However, quantitative yield of bis(4-chlo-
rophenyl) sulfide was obtained after the treatment of
bis(4-chlorophenyl) sulfoxide with an excess of indium
SYNTHESIS 2005, No. 20, pp 3499–3501
x
x.
x
x
.
2
0
0
5
Advanced online publication: 24.11.2005
DOI: 10.1055/s-2005-918492; Art ID: F03405SS
Georg Thieme Verlag Stuttgart · New York
©

3
500
E. S. Park et al.
SHORT PAPER
Table 1 Deoxygenation of Dibenzyl Sulfoxide Using Indiuma
The indium and pivaloyl chloride protocol was applied to
quinoline N-oxide as a model of N-oxides in various sol-
vent systems including protic solvents and the choice of
Entry Acid chloride
Solvent
i-PrOH
i-PrOH
i-PrOH
EtOH
Time (h) Yield (%)b
solvent was identified to be CH Cl . Quinoline N-oxide
1
2
3
4
5
6
Acetyl chloride
4
4
52
20
96
83
37
41
2
2
was readily reduced upon exposure to a system of indium
and pivaloyl chloride in CH Cl at room temperature to
Ethyl chloroformate
Pivaloyl chloride
Pivaloyl chloride
Pivaloyl chloride
Pivaloyl chloride
2
2
give quinoline in 94% yield (entry 1, Table 3). The deox-
ygenation of various aza-aromatic N-oxides was investi-
gated and the results are listed in Table 3. Some control
experiments revealed that N-oxides could not be deoxy-
genated by indium or pivaloyl chloride alone. The reac-
tions were very simple, good- to high-yielding and
complete within one hour. The reaction conditions are
compatible with other functional groups such as chloride,
phenyl and methoxy functional groups.
2
4
MeOH
t-BuOH
4
21
a
Indium (1.5 equiv) and pivaloyl chloride (3 equiv) at r.t.
Isolated yields.
b
In conclusion, sulfoxides and aza-aromatic N-oxides were
deoxygenated using a system of indium and pivaloyl chlo-
ride in i-PrOH or CH Cl , respectively to give the corre-
sponding sulfides and aza-aromatics in high yields. Our
method might be a mild and a nice simple alternative for
the other deoxygenation methods of sulfoxides and aza-
aromatics.
and pivaloyl chloride in THF at room temperature (entry
). Moreover, deoxygenation of relatively electron-rich
8
2
2
diphenyl sulfoxide (entry 4) seemed to be more effective
than that of bis(4-chlorophenyl) sulfoxide due to the sta-
bilization of transition state although it needed relatively
long reaction time depending on the electronic and steric
1
5
characteristics of the sulfoxide. Attempted reduction of
diphenyl sulfone (entry 9) resulted in only the recovery of
starting material, suggesting that the polarized nature of
Table 3 Deoxygenation of N-Oxide Using Indium and Pivaloyl
a
Chloride in CH Cl
2
2
1
0
sulfoxides is critical for reactivity.
Entry
1
N-Oxide
Time (min)
60
Yieldb,c (%)
94
Table 2 Deoxygenation of Sulfoxide Using Indium and Pivaloyl
Chloride in i-PrOH
N
O
Entry Sulfoxide
Indium
equiv)
PivCl
(equiv)
Time
(h)
Yielda,b
(%)
(
2
3
30
10
83
88
1
2
3
4
5
6
1.5
3
3
3
3
3
3
2
96
88
95
93
88
85
O
S
Me
Me
N
O
Ph
Ph
Ph
Ph
2
2
O
S
N
O
1.5
2
0.2
16
1
O
S
4
Me
30
97
Ph Me
O
N
O
S
Ph Ph
5
6
30
10
69
80
2
O
S
Cl
N
O
n-Bu
n-Bu
2
1.5
O
S
Ph
Me
Br
N
O
7
4
4
6
6
2
1
85
97
O
S
7
8
10
10
98
77
Ph
Cl
N
8c
O
O
S
MeO
Cl
Cl
N
O
9
O
O
3
6
12
N. R.
S
Ph Ph
a
Indium (1.1 equiv) and pivaloyl chloride (2 equiv) in CH Cl (0.3 M)
2
2
at r.t.
a
Isolated yields.
b
Isolated yields.
b
c
Data of products are consistent with reported values.16
c
17
Data of products are consistent with reported values.
THF as a solvent.
Synthesis 2005, No. 20, 3499–3501 © Thieme Stuttgart · New York

SHORT PAPER
Deoxygenation of Sulfoxide and Aza-aromatic N-Oxide
3501
Sulfoxides and aza-aromatic N-oxide were purchased from Aldrich
or Across Organics and used without purification. Functionalized
sulfoxides18 and aza-aromatic N-oxides were prepared according
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Int. 1977, 9, 63.
19
1
13
to the established procedures. H NMR and C NMR spectra were
recorded on a Varian 300 MHz spectrometer in CDCl as the sol-
(5) (a) Podlech, J.; Maier, T. C. Synthesis 2003, 633. (b) Pitts,
M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin
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3
vent and TMS as internal standard. All of the products are known
and the isolated products gave IR spectra in agreement with their
structures. IR spectra were measured on an Analet FT-IR(MAP-60).
11149. (e) Loh, T. P.; Hu, Q. Y.; Vittal, J. J. Synlett 2000,
Deoxygenation of Sulfoxide; Typical Procedure
To a solution of benzyl sulfoxide (81.0 mg, 0.352 mmol) in i-PrOH
523. (f) Loh, T. P.; Zhou, J. R.; Li, X. R. Tetrahedron Lett.
1999, 40, 9333.
(
1.8 mL) were added indium (60.6 mg, 0.528 mmol) and pivaloyl
(6) (a) Abrovitch, R. A.; Saha, J. G. Adv. Heterocycl. Chem.
1966, 6, 229. (b) Grimmett, M. R. Adv. Heterocycl. Chem.
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chloride (127.2 mg, 1.055 mmol) at r.t. The mixture was stirred at
r.t. until the reaction was complete (monitored by TLC). The reac-
tion was then quenched by addition of Na CO (200 mg), filtered
through Celite bed, concentrated and chromatographed on silica gel
column using a solution of EtOAc and hexane (1:10) as eluent to
give phenyl sulfide (96%) that was identical with a commercially
available authentic compound.
2
3
(7) Yadav, J. S.; Subba Reddy, B. V.; Muralidhar Reddy, M.
Tetrahedron Lett. 2000, 41, 2663.
(8) Yoo, B. W.; Choi, J. W.; Kim, D. Y.; Hwang, S. K.; Choi, K.
Deoxygenation of Aromatic N-Oxide; Typical Procedure
To a solution of isoquinoline N-oxide (81.8 mg, 0.564 mmol) in
CH Cl (2.8 mL) were added indium (71.2 mg, 0.620 mmol) and
I.; Kim, J. H. Bull. Korean Chem. Soc. 2002, 23, 797.
(9) Lee, S. H.; Park, Y. S.; Nam, M. H.; Yoon, C. M. Org.
Biomol. Chem. 2004, 2, 2170.
2
2
pivaloyl chloride (135.9 mg, 1.127 mmol) and the resulting mixture
was stirred at r.t. until the reaction was complete (monitored by
TLC). The reaction mixture was filtered through Celite bed and
Na CO (200 mg) was added to filtrate. After stirring for a while,
(10) Nicolaou, K. C.; Koumbis, A. E. Angew. Chem. Int. Ed.
2000, 39, 2529.
(11) Yadav, J. S.; Reddy, B. V. S.; Reddy, G. S. K. K. New J.
Chem. 2000, 24, 571.
2
3
the solution was filtered, concentrated and chromatographed on
short pad of silica gel using a 2% MeOH in CH Cl solution to give
isoquinoline (98%) that was identical with a commercially available
authentic sample.
(12) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401.
(13) Ranu, B. C.; Dutta, P.; Sarkar, A. Tetrahedron Lett. 1998,
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(14) Oxygenation of sulfoxides to sulfides: Ranu, B. C.; Dutta,
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2
2
(
15) Sanz, R.; Escribano, J.; Aguado, R.; Pedrosa, M. R.; Arnáiz,
F. J. Synthesis 2004, 1629.
Acknowledgment
(
16) (a) Nasser, I.; Habib, F.; Hamid, R. S. J. Org. Chem. 2002,
The authors wish to acknowledge the financial support of the Korea
Research Foundation (KRF-C00122) made in the program year
67, 2826. (b) Marques, A.; Marin, M.; Ruasse, M.-F. J. Org.
Chem. 2001, 66, 7588. (c) Kim, S. S.; Rajagopal, G.
Synthesis 2003, 2461.
2
005.
(
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Synthesis 2005, No. 20, 3499–3501 © Thieme Stuttgart · New York