646
Chemistry Letters Vol.37, No.6 (2008)
Copper-catalyzed Oxidative Desulfurization-promoted Intramolecular Cyclization
of Thioamides Using Molecular Oxygen as an Oxidant:
An Efficient Route to Five- to Seven-membered Nitrogen-containing Heterocycles
Fumitoshi Shibahara,ꢀ Atsunori Yoshida, and Toshiaki Muraiꢀ
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193
(Received March 12, 2008; CL-080275; E-mail: fshiba@gifu-u.ac.jp, mtoshi@gifu-u.ac.jp)
Table 1. Copper-catalyzed oxidative desulfurization–cycliza-
tion of N-thioacyl-1,3-amino alcoholsa
Copper-catalyzed oxidative desulfurization-promoted intra-
molecular cyclization reactions of thioamides take place under
neutral and mild conditions by using molecular oxygen as an
oxidant. The process yields a wide variety of nitrogen-contain-
ing heterocycles with high efficiency.
R'
CuCl (20 mol%)
2
S
Ph OH
R'
O
Ph OH
R'
O
O
(balloon)
+
R
N
H
DMSO, 60 °C
R
N
H
R
N
2
Ph
1
3
Yieldb/%
Time
/h
Run
Substrate
The generation of an electrophilic species via the oxidative
activation of organosulfur compounds is of great interest.1
Thiocarbonyl compounds, such as dithioic acid esters and thio-
amides, readily participate in these types of oxidant-initiated
reactions.1b,2c Oxidants used for this purpose thus far include
halonium species, such as NIS, NBS, and I2. In these cases,
the reactions are often accompanied by halogenation of aromatic
moieties in the substrates and they produce hazardous by-prod-
ucts. Therefore, the development of environmentally benign
oxidants that promote these processes under mild conditions is
a worthy goal. On the other hand, we previously reported an
alkylation-promoted desulfurization–cyclization of N-thioacyl-
1,3-amino alcohols, but the reaction could be applied to limited
substrates due to the low desulfurization activity.2b Therefore,
we continuously investigated a widely applicable alternative de-
sulfurization procedure. Below, we report the results of an inves-
tigation of a new copper-catalyzed oxidative desulfurization-
promoted cyclization reaction of thioamides that uses molecular
oxygen as a stoichiometric oxidant and that is widely applicable
to the synthesis of nitrogen-containing heterocycles.
During recent studies,2 we observed that simple thioamides
readily yield the corresponding amides when treated with a
copper catalyst under an oxygen atmosphere.2d We expected that
this catalytic process, which takes place via oxidative activation
of the C=S group, could be utilized for oxidative desulfuriza-
tion-promoted substitution reactions. Initial experiments de-
signed to probe this proposal were carried out using the cycliza-
tion of 1a.2b Reaction of anti-1a with a catalytic amount of cop-
per(I) chloride (20 mol %) at 60 ꢁC in DMSO under an oxygen
atmosphere leads to formation of dihydro-1,3-oxazine cis-2a in
quantitative yield (Table 1, Run 1).3–6 Fortunately, the syn dia-
stereomer 1a also undergoes efficient cyclization when treated
under the same conditions (Run 2).7 In each case, stereochemis-
try of the amino alcohol moiety is retained, indicating that the
reaction formally proceeds via intramolecular nucleophilic addi-
tion of the hydroxy group to the activated thiocarbonyl without
epimerization.6 Importantly, the cyclization reaction occurs at
room temperature (anti-1a: 93% NMR yield for 24 h, syn-1a:
84% NMR yield for 24 h) and it can be applied to gram-scale
synthesis without loss of efficiency.6 In addition, the cyclization
reactions do not take place in the absence of either oxygen or
CuCl, and they afford elemental sulfur as the sole co-pro-
duct.2d,5,6 These results clearly show that CuCl serves as a cata-
2
3
1
2
3
4
5
6
7
8
9
1a R = Ph, R0 = Me
anti
syn
4
3
71 (>99)
—
—
71 (92)
1b R = Ph, R0 = t-Bu
1c R = Ph, R0 = CH2Cl
syn 2.5 67 (81) 18 (19)
syn
3
53 (70) — (30)
43 (59) 20 (16)
anti
1d R = 4-MeOC6H4-, R0 = Me syn
4
4
76 (98)
76 (99)
trace
trace
anti
1e R = 2-MeOC6H4-, R0 = Me syn
anti
2
7
61 (93) — (6)
63 (88) — (6)
66 (84) — (3)
9
10 1f R = t-Bu, R0 = Me
syn 24
anti 22
11
12 1g R = i-Pr, R0 = Me
— (13)
44 (84) — (7)
— (35)
—
syn
3
13
anti
7
—
aReactions were performed in DMSO at 60 ꢁC in the presence of
CuCl (20 mol %) under oxygen atmosphere with vigorous stirring.
bThe isolated yields. NMR yields are shown in parentheses.
lyst for the process and that oxygen is the stoichiometric oxidant.
Exploration of the scope of the reaction reveals that cyclization
of syn-1b, which contains a bulky t-butyl group ꢀ to the hydroxy
nucleophile, takes place to give 2b in high yield (Run 3). The
chlorine atom-containing substrate 1c also participates in this
process with chlorine remaining intact under the reaction condi-
tions (Runs 4 and 5). Also, 1d and 1e, in which the electrophilic-
ity of the thiocarbonyl carbon is reduced by the presence of elec-
tron-donating groups, undergo cyclization without appreciable
loss of efficiency (Runs 6–9). In contrast to reactions of the al-
kyl-substituted thioamides anti-1f and anti-1g that lead to forma-
tion of complex mixtures (Runs 11 and 13), the diastereomeric
substrates syn-1f and syn-1g afford the respective products 2f
and 2g in good yields (Runs 10 and 12). It may be partly due
to the different stability of the diastereomers of 2-alkyldihydro-
1,3-oxazines. Lastly, the tetrasubstituted dihydro-1,3-oxazines 5
can be prepared starting with the thioacyl amino alcohols 4
(Scheme 1) by using this methodology. Each of the stereoisom-
ers 4a–4d undergoes smooth cyclization to produce the corre-
sponding dihydro-1,3-oxazines 5a–5d in excellent yields.
The versatility of the oxidative desulfurization–cyclization
procedure was demonstrated by its application to the synthesis
of a variety of five- to seven-membered nitrogen-containing het-
erocycles (Scheme 2). The reactions of N-thioacyl-1,2- or 1,4-
Copyright Ó 2008 The Chemical Society of Japan
Shibahara, Fumitoshi
