Suggestion of unexpected sulfur dioxide mechanism for deoxygenations of pyridine N-oxides with alkanesulfonyl chlorides and triethylamine

Article abstract of DOI:10.3987/COM-00-8900

The reaction mechanism for unusual deoxygenations of pyridine N-oxides with alkanesulfonyl chlorides and triethylamine was explored. Some experimental facts suggested that sulfur dioxide generated in the reaction system might be responsible for the deoxygenations without chlorinations of the pyridine nucleus.

Full text of DOI:10.3987/COM-00-8900

HETEROCYCLES, Vol. 53, No. 7, 2000, pp. 1471 - 1474, Received, 15th March, 2000
SUGGESTION OF UNEXPECTED SULFUR DIOXIDE MECHANISM FOR
DEOXYGENATIONS OF PYRIDINE N-OXIDES WITH ALKANESULFONYL
CHLORIDES AND TRIETHYLAMINE
Yoshiki Morimoto,* Hajime Kurihara, Takamasa Shoji, and Takamasa Kinoshita
Department of Chemistry, Graduate School of Science, Osaka City University,
Sumiyoshiku, Osaka 558–8585, Japan
Abstract- The reaction mechanism for unusual deoxygenations of pyridine N-
oxides with alkanesulfonyl chlorides and triethylamine was explored. Some
experimental facts suggested that sulfur dioxide generated in the reaction system
might be responsible for the deoxygenations without chlorinations of the pyridine
nucleus.
Methanesulfonyl chloride (MsCl) is one of the usual reagents most frequently used in organic synthesis. It
is principally employed for the conversion of a hydroxyl group into a methylsulfonyloxy group, which is
highly reactive as a leaving group in nucleophilic substitution and elimination reactions to be removed as
methanesulfonate anion.1 It is also useful for protection of hydroxyl and amino groups, though to a smaller
extent.2 The utilization of MsCl appears to be practically restricted to these two objects to the best of our
knowledge. In the course of our synthetic studies of a marine macrocyclic alkaloid haliclamine,3 we found
that MsCl in the presence of triethylamine (Et3N) is a novel deoxygenation system of pyridine N-oxides (eq
1).4 The reaction mechanism of the deoxygenations, however, remains to be solved.
3
3
R
R
2
1
2
1
R
R
MsCl, Et N
3
(1)
4
4
N
R
R
+
–
R
N
R
CH Cl
2
2
0 °C – rt, 1–18 h
O
1
2
10–95%
It is well known that reactions of pyridine N-oxides with chlorinating agents such as PCl5, POCl3, SO2Cl2,
SOCl2, etc. produce a - or g-chloropyridines accompanied by the deoxygenation of the N-oxide function
through the reaction pathway shown by the reaction with SOCl2 in Scheme 1.5 On the contrary, the
deoxygenation by MsCl and Et3N proceeds without such chlorination of the pyridine nucleus. Thus, the
unusual behavior of familiar MsCl encouraged us to elucidate the reaction mechanism of this
deoxygenation. In this communication, we report sulfur dioxide generated in the reaction system might be
the real active species responsible for the unusual deoxygenation of pyridine N-oxides.

Scheme 1
Cl
N
SOCl
ref 6
MsCl, Et N
2
3
+
N
O
+
–
N
Cl
N
H
Cl
–
Cl
H
N
O
N
O
+
N
O
+
?
Cl
Cl
Cl
Cl
S
S
S
O
O
O
Firstly, some preliminary studies were carried out in order to explore the essential features of this novel
reaction (Table 1). Treatment of 3-methylpyridine N-oxide (3) with MsCl or (phenylmethane)sulfonyl
chloride in the presence of excess Et3N afforded the deoxygenation product, 3-methylpyridine (4), in 84 or
59% yield, respectively (entries 1 and 2). On the other hand, treatment with the same alkanesulfonyl
chlorides in the absence of Et3N resulted in recovery of the starting material (3) (entries 3 and 4). From the
reaction with p-toluenesulfonyl chloride and Et3N 4 could not be obtained, although 3 was consumed under
the conditions giving a complicated mixture (entry 5). These results show that the sulfonyl chloride
possessing an a -hydrogen and Et3N are essential for the deoxygenation of 3. This suggests the possibility
that sulfenes are implicated as intermediates in this deoxygenation process, because the easy generation of
sulfenes from alkanesulfonyl chlorides possessing an a -hydrogen and Et3N is a well-established process in
sulfene chemistry.7
Table 1. Deoxygenations of 3-Methylpyridine N-Oxide (3) with Alkanesulfonyl Chlorides under
Various Conditions
Me
Me
O
O
alkanesulfonyl chloride
CH Cl
RR'C S
N
O
3
+
–
N
2
2
0 °C – rt, 1–5 h
4
sulfene
product (yield%)a
entry alkanesulfonyl chloride (equiv.) base (equiv.)
1
2
3
4
5
MeSO2Cl (9)
PhCH2SO2Cl (5)
MeSO2Cl (9)
PhCH2SO2Cl (5)
p-TsCl (5)
Et3N (12)
Et3N (8)
4 (84)
4 (59)b
3 (91)
3 (94)
c
—
—
c
d
Et3N (8)
—
a Isolated yield. b 1,2-Diphenylethene (trans:cis = 65:35) was isolated in 32%
yield as a by-product. c Without base. d Complex mixture.
Furthermore, we isolated 1,2-diphenylethene (trans:cis = 65:35) in 32% yield as a by-product in addition to
4 in the reaction with (phenylmethane)sulfonyl chloride and Et3N (entry 2); this finding appears to be very
informative for the reaction mechanism. It is known that trans- and cis-1,2-diphenylethenes are produced

from (phenylmethane)sulfonyl chloride and Et3N through sulfene (5) (R = Ph), zwitterions (6 and 7), and
episulfone (8) accompanying extrusion of sulfur dioxide (Scheme 2).8 The same reaction sequence via 5 (R
= H), 6, and 7 is also invoked to explain some oligomeric products from MsCl and Et3N.9 Moreover, the
redox exchange between N-oxide (1) and sulfur dioxide has already been described.10 Thus, we assumed
that in the above-mentioned deoxygenation of pyridine N-oxides the nascent sulfur dioxide generated in the
reaction system might act as the reactive species in the presence of Et3N (Scheme 2).
Scheme 2. Plausible Mechanism for the Deoxygenations of Pyridine N-Oxides with Alkanesulfonyl
Chlorides and Triethylamine
–
+
Et N
3
RCH S NEt
RCH SO
3
2
RCH SO Cl
Et N
3
Et N·HCl
3
+
+
2
2
O
2
5
6
RCH SO
+
2
O
S
R
2
R = Ph
– SO , Et N
RCH CHR
CH S NEt
RCH SO
3
–
O
9
RHC CHR
2
– SO
2
7
2
2
3
8
3
R
R = H
oligomeric products
3
R
2
R
2
R
SO
2
+ SO
3
4
1
Et N
3
R
N
R
+
–
4
1
R
N
R
O
2
1
Table 2. Comparison of Our Deoxygenations with the Known Sulfur Dioxide Methods
3
R
(a) MsCl (9 equiv.), Et N (12 equiv.)
3
3
R
2
or
R
R
2
1
PhCH CHPh
R
(b) PhCH SO Cl (5 equiv.), Et N (8 equiv.)
2
2
3
+
25–35%
trans:cis = 3:2–2:1
1
4
N
R
+
–
solvent, 0 °C – rt
4
R
N
R
O
1
2
yield% of 2a
reagents (a)
dioxane, refluxc dioxane CH2Cl2 dioxane CH2Cl
1
SO2·NEt3 (2 equiv.) atmospheric SO2
reagents (b)
dioxane, refluxb
2
R1 = Me, R2 = R3 = R4 = H
R2 = Me, R1 = R3 = R4 = H
R3 = Me, R1 = R2 = R4 = H
R1 = R4 = Me, R2 = R3 =H
78
76
75
83
34
59
87
48
87
89
84
59
89
64
50
55
57
79
59
53
24e
d
—
31
67
a Isolated yield. b Cited from ref 10 (a). c Cited from ref 10 (b). d Not tested. e N-Oxide (1) (R1 = R4 =
Me, R2 = R3 = H) was recovered in 57% yield.
For comparison with the previous results using sulfur dioxide as reducing agent, several pyridine N-oxides
(1) were subjected to our deoxygenation procedure, and the satisfactory results were obtained, no formation
of chloropyridines being noticed (Table 2). In reagent system (b), 1,2-diphenylethene (trans:cis = 3:2–2:1)

was always isolated in 25–35% yields along with 2. Although there are a few differences in yields between
the previous procedures10 and ours, probably because of different reaction conditions, it appears that these
results support the sulfur dioxide mechanism for the deoxygenations of pyridine N-oxides with
alkanesulfonyl chlorides and Et3N (Scheme 2). Thus, the reason why our deoxygenations do not experience
chlorinations of the pyridine nucleus may be due to the sulfur dioxide mechanism different from the
conventional pathway shown in Scheme 1.
This mild deoxygenation procedure of pyridine N-oxides using the inexpensive and accessible MsCl and
Et3N is apparently more favorable than that using commercially unavailable sulfur dioxide-triethylamine
complex10a and that using intractable gaseous sulfur dioxide.10b The more detailed reaction mechanism is
under investigation.
ACKNOWLEDGMENTS
H. K. thanks the Suntory Institute for Bioorganic Research for the SUNBOR Scholarship. This work was
partially supported by the Saneyoshi Scholarship Foundation and a Grant-in Aid for Encouragement of
Young Scientists from the Japan Society for the Promotion of Science.
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1.
2.
3.
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