Regioselective monohalogenation of 3,3-disubstituted bornane-2-thiones via thione-dihalogen complexes

Article abstract of DOI:10.1016/S0040-4039(01)01235-7

Reaction of 3,3-disubstituted bornane-2-thiones with Br₂, ICl, or Cl₂ afforded the corresponding 10-bromobornane-2-thiones, 10-iodobornane-2-thiones, or the products originated from skeletal rearrangement of 10-chlorobornane-2-thiones, respectively.

Full text of DOI:10.1016/S0040-4039(01)01235-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6167–6169
Regioselective monohalogenation of 3,3-disubstituted
bornane-2-thiones via thione–dihalogen complexes
Kazuaki Shimada,a,* Takashi Nanae,a Shigenobu Aoyagi,a Yuji Takikawaa and Chizuko Kabutob
aDepartment of Chemical Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate 020-8551, Japan
bInstrumental Analysis Center for Chemistry, Graduate School of Science, Tohoku University, Sendai, Miyagi 980-8578, Japan
Received 18 April 2001; revised 20 June 2001; accepted 6 July 2001
Abstract—Reaction of 3,3-disubstituted bornane-2-thiones with Br2, ICl, or Cl2 afforded the corresponding 10-bromobornane-2-
thiones, 10-iodobornane-2-thiones, or the products originated from skeletal rearrangement of 10-chlorobornane-2-thiones,
respectively. © 2001 Elsevier Science Ltd. All rights reserved.
d-Camphor and their derivatives have been widely used
as chiral auxiliaries and synthons for organic syntheses.
However, few practical methods for functionalization
of the bornane skeleton have been reported except for
the preparation of endo-3-bromocamphor, d-camphor-
10-sulfonic acid, and their derivatives. It is well known
that chalcogenoxo functionalities have a general poten-
tiality to immobilize dihalogen molecules through com-
plexation,1 and it was naturally expected that
dihalosulfurane-type complexes B, assumed to be
formed by the reaction of thiones (A) with an equimo-
lar amount of dihalogen, would result in regioselective
monohalogenation at the C-H group closed to the
halogen atom of B. In line with such expectation, we
attempted the treatment of bornane-2-thiones (2) with
various dihalogens or halogenating agents. In this
paper, we describe a novel regioselective monohalo-
genation of the C-10 position of 2 by treating with Br2
or ICl.
3,3-Disubstituted ketones 1a–b were prepared from d-
camphor (1c) according to the reported methods,2 and,
subsequently, ketones 1a–d were converted into thiones
2a–d (Table 1) by treating with Lawesson’s reagent.3
When a CH2Cl2 or a CDCl3 solution of 2a–b was
treated with Br2 (1.1 mol amt.) at rt, 2a or 2b was
converted into the corresponding 10-bromo derivative
(3a–b, X=Br) in high yields, and no benzylic bromina-
tion products were obtained in the case starting from
1
2b. The H NMR monitoring of the reaction in CDCl3
at 25°C also showed that 2a–b were completely con-
verted into 3a–b (X=Br) as soon as Br2 was added to
the solution of 2. The structure of 3b (X=Br) was
finally confirmed by X-ray crystallographic analysis,4
and the ORTEP drawing is shown in Fig. 1. However,
a similar treatment of thiofenchone (2d) with Br2 gave
3d (X=Br) in lower yield along with the formation of
unidentified products, and attempted bromination of
thiocamphor (2c) under similar conditions only gave a
R2
R2
R1
1 (Ch=O)
2 (Ch=S)
X
S
X H
S
X
S
H
R1
3
X2
2
R
H3C10
R
R
Ch
a: R1-R1=-(CH2)4-, R2=CH3
R'
R'
R'
b: R1-R1=-CH2(o-C6H4)CH2-, R2=CH3
c: R1=H, R2=CH3
B
C
A
d: R1=CH3, R2=H
Keywords: bornane-2-thione; halogenation; 10-halobornane-2-thione; dihalosulfurane; thione–I2 CT complex.
* Corresponding author. Tel.: +81-19-621-6324; fax: +81-19-621-6347; e-mail: shimada@iwate-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01235-7

6168
K. Shimada et al. / Tetrahedron Letters 42 (2001) 6167–6169
Table 1. Reaction of thiones 2 with a halogenating agent
R1
R1
R1
R1
R1
R1
R1
X2
R1
+
+
H3C
X
S
S
X
X
S
2
2
3
4 (X=Cl)
5 (X=Br)
6
Substrate 2
Reagent (mol amt.)
Solvent
Temp.
Time
Yield (%)a
4, 5
3
6
2a
2b
2b
2c
2d
2a
2b
2a
2a
2b
2a
Br2 (1.1)
Br2 (1.1)
Br2 (2.2)
Br2 (1.1)
Br2 (1.1)
I2 (1.1)
CH2Cl2
CH2Cl2
CDCl3
CH2Cl2
CH2Cl2
CDCl3
CDCl3
CH2Cl2
CH2Cl2
CH2Cl2
CDCl3
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
5 min
5 min
24 h
5 min
5 min
24 h
87 (3a, X=Br)
70 (3b, X=Br)
0
0
0
0
0
0
0
19 (75,b 5b)
Complex mixture
Complex mixture
0
0
46 (3d, X=Br)
0c
0
0
I2 (1.1)
24 h
0c
ICl (1.1)
Cl2 (excess)
Cl2 (excess)
t-BuOCl (1.1)
60 min
60 min
60 min
60 min
14 (3a, X=I)d,e
0
4 (6a)
0
0
0
0
0
36 (60,b 4a)
17 (50,b 4b)
0
85 (6a)
a Isolated yield.
b Estimated by integration of the 1H NMR spectrum of the crude reaction mixture.
c Starting material 2 was quantitatively recovered.
d The 10-chloro derivative 3a (X=Cl) was not found at all in the crude reaction mixture.
e 2a was recovered in 56% yield.
respectively.1 The formation of 10-iodo derivative 3a
(X=I) by treating 2a with ICl, in contrast with the
cases of the reactions of 2a–b with I2, also suggested the
formation of chloroiodosulfurane F (X, Y=Cl, I). Our
results strongly suggested that the regioselective halo-
genation of 2 would proceed stepwise including the
formation of intermediary dihalosulfuranes F (X, Y=
Cl, Br, I), intramolecular dehydrohalogenation of F,
and intramolecular halogen transfer from the sulfur
atom to the C-10 carbon atom in G. The t-BuOCl-
induced skeletal rearrangement of 2 was also suggested
to occur only from chlorosulfonium ions E (X=Cl).
Further treatment of 3a–b with Br2 (1.1 mol amt.) at rt
for 5 min only gave a recovery of 3a–b, and the
reaction of 3b with Br2 in CDCl3 in an NMR tube for
72 h gave dibromide 5b as a major component in the
reaction mixture. However, 5b was gradually decom-
posed and was isolated only in 19% yield along with
unidentified products after the usual workup and purifi-
cation. It is noteworthy that the further bromination of
complex mixture. A comparative treatment of ketones
1a–b with Br2 or a reaction of 2a with anhydrous HBr
at rt for 10 min also resulted in the recovery of 1a–b or
2a, respectively. So, it was clear that the complexation
of the thione moiety of 2 with Br2 was an essential step
for the regioselective bromination and that the steric
bulkiness around the thione moiety of 2 lacking an
a-methylene group was most effective for the reaction
in the light of the stabilization of the intermediary
complexes. However, a similar treatment of 2a–b with
I2 (1.1 mol amt.) only resulted in the recovery of 2a–b
in all cases, even though a CT band (u=320 nm) was
observed in the UV–vis spectrum of a mixture solution
of an equimolar amount of 2a and I2.1 A similar
treatment of 2a with ICl (1.1 mol amt.) gave 10-iodo
derivative 3a (X=I, 14%) and 6a (14%) along with the
recovery of 2a (56%). In contrast, treatment of 2a with
t-BuOCl (1.1 mol amt.) at rt gave only 6a in 85% yield.
The NMR monitoring of the reaction of 2a with Br2
(1.1 mol amt.) in CD2Cl2 at −70°C only showed an
approximate 10 ppm up-field shift of the thiocarbonyl
carbon signal in the 13C NMR spectrum along with a
slight down-field shift of two methyl and one methylene
1
signals of 2a in the H NMR spectrum, and the NMR
spectrum at −20°C only showed the signals of 3a (X=
Br). These results indicated that linear 1:1 complexes of
2-dihalogen were formed at the primary stage and
would undergo a facile conversion into 3 at higher
temperature. It is well known that the reaction of
electronically-stabilized thiones with Br2 or I2 afforded
T-shaped dibromosulfuranes or linear CT complexes,
Figure 1. ORTEP drawing of 3b (X=Br).

K. Shimada et al. / Tetrahedron Letters 42 (2001) 6167–6169
6169
R1
R1
R1
R1
X-Y
∆
R1
2
R1
X
- Y-
+ Y-
H2C
H Y
X
H3C
H3C
S
S
X
S
Y
E
D
F
- HY
R1
R1
R1
R1
X-Y
4, 5
R1
X
R1
- [ S ]
H2C
H2C
S
S
H2C
X
S
X
X
G
H
3
Scheme 1. Plausible reaction path for the formation of 3, 4, and 5.
3b was sluggish, and no gem-dibromo product was
obtained. Treatment of 2a–b with Cl2 (gas, excess) also
gave dichlorides 4a–b in low yields along with uniden-
tified products, and the structure of 4a was determined
by X-ray crystallographic analysis.5 The similarity in
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1
the H NMR and 13C NMR spectral patterns of 4a to
those of 5a indicated that 5 possessed the same skeleton
with the same halogenation pattern as those of 4, and
these results clearly showed that the skeletal rearrange-
ment would proceed exclusively by the further reaction
of 3 with halogens. It was assumed that an intramolec-
ular attractive interaction between the halogen atom at
the C-10 position and the cationic sulfur center of H
would prevent the formation of T-shaped dihalosul-
furanes like F6 (Scheme 1).
In conclusion, we have achieved a convenient and
regioselective monohalogenation of 3,3-disubstituted
bornane-2-thiones 2 by treating with 1 molar amount of
Br2 or ICl. Further attempts for detection of intermedi-
ary dihalosulfuranes F as well as novel synthetic exten-
sion of 10-halobornane derivatives 3 as chiral synthons
or chiral auxiliaries are in progress in our laboratory.
2. (a) Krapcho, A. Synthesis 1974, 383–419 and references
cited therein; (b) Helmchen, G.; Selim, A.; Dorsch, D.;
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3. Shimada, K.; Kodaki, K.; Aoyagi, S.; Takikawa, Y.;
Kauto, C. Chem. Lett. 1999, 695–696.
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