Resolution of racemic aryl dichloromethyl sulfoxides with (-)-menthone

Article abstract of DOI:10.1016/j.tetasy.2009.08.031

The addition reaction of the sodium α-sulfinyl carbanion of a racemic aryl dichloromethyl sulfoxide to (-)-menthone in the presence of boron trifluoride diethyl etherate gave an adduct as a mixture of two easily separable diastereomers. After separation of the diastereomers, they were each treated with sodium hydride to afford enantiomerically pure aryl dichloromethyl sulfoxides and (-)-menthone both in high yields. This procedure provides a simple and efficient method for the resolution of racemic aryl dichloromethyl sulfoxides.

Full text of DOI:10.1016/j.tetasy.2009.08.031

Tetrahedron: Asymmetry 20 (2009) 2073–2076
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Resolution of racemic aryl dichloromethyl sulfoxides with (ꢀ)-menthone
*
Takafumi Noguchi, Toshifumi Miyagawa, Tsuyoshi Satoh
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2009
Accepted 25 August 2009
Available online 26 September 2009
The addition reaction of the sodium
a-sulfinyl carbanion of a racemic aryl dichloromethyl sulfoxide to
(ꢀ)-menthone in the presence of boron trifluoride diethyl etherate gave an adduct as a mixture of two
easily separable diastereomers. After separation of the diastereomers, they were each treated with
sodium hydride to afford enantiomerically pure aryl dichloromethyl sulfoxides and (ꢀ)-menthone both
in high yields. This procedure provides a simple and efficient method for the resolution of racemic aryl
dichloromethyl sulfoxides.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Herein, we report a new method for the preparation of chiral aryl
dichloromethyl sulfoxides (S)-2 and (R)-2 by the resolution of their
Chiral sulfoxides are one of the most widely used chiral auxilia-
ries in asymmetric synthesis. In view of their importance in organic
synthesis, their synthesis, chemistry, and synthetic uses have long
been investigated and reviewed.1 Previously, we studied the prep-
aration of chiral chloromethyl p-tolyl sulfoxide 1 and 1-chloroalkyl
p-tolyl sulfoxides,2 and their uses in new asymmetric syntheses.3
In continuation of our interest in aryl 1-halogenated-alkyl sulfox-
ides in organic synthesis, we recently started to investigate the
use of aryl dichloromethyl sulfoxide and some new synthetic
methods have appeared (Fig. 1).4
racemates with (ꢀ)-menthone.
2. Results and discussion
A representative example is reported for the resolution of race-
mic dichloromethyl p-tolyl sulfoxide 2a as shown in Scheme 1. At
first, racemic dichloromethyl p-tolyl sulfoxide 2a was synthesized
from methyl p-tolyl sulfoxide with NCS in THF in high yield.4a
A
solution of sodium hexamethyldisilazide (NaHMDS; 1.9 mol/L
solution in THF; 1.26 mL, 2.4 mmol) was added dropwise to a solu-
tion of racemic 2a (446 mg; 2.0 mmol), (ꢀ)-menthone (0.52 mL;
3.0 mmol), and BF3–OEt2 (0.39 mL; 3.0 mmol) in 20 mL of dry
THF at ꢀ78 °C. The reaction mixture was stirred at ꢀ78 °C for
10 min and the reaction was quenched by adding satd aq NH4Cl.
The addition reaction proceeded from the equatorial side of the
ketone group in menthone6, and adduct 3a was obtained as a mix-
ture of two diastereomers with respect to the sulfur stereogenic
center. Starting material 2a was recovered in 9% yield from this
reaction. It is also noteworthy that when this reaction was con-
ducted without the Lewis acid, only a complex mixture was ob-
tained. Fortunately, the diastereomers were found to be easily
separable on silica gel column chromatography to give the more
polar adduct 3a-P (Rf value 0.25; Merck Silica Gel TLC plate
60F254 (hexane–AcOEt = 5:1); 335 mg; 44%) and the less polar ad-
duct 3a-L (Rf value 0.48; 305 mg; 40%) both as amorphous solids.
The structure of adducts 3a was not clear at this stage; however,
later, the whole structures of 3a-P and 3a-L were determined as
shown in Scheme 1.
O
S
O
S
O
S
:
CHCl2
:
Ar
Ar
CH2Cl
CHCl2
H3C
(R)-2
1
(S)-2a Ar = 4-Methylphenyl
b
c
d
e
f
Ar = Phenyl
Ar = 2-Naphthyl
Ar = 4-Methoxyphenyl
Ar = 4-Chlorophenyl
Ar = 4-Nitrophenyl
Figure 1.
In our aforementioned new synthetic methods using aryl
dichloromethyl sulfoxide, in some cases, it was anticipated that
when optically active aryl dichloromethyl sulfoxide was used, a
new asymmetric synthesis could be performed.4b,c However, to
the best of our knowledge, only one report has been published
for the preparation of chiral aryl dichloromethyl sulfoxides 2.5
Next, NaH (1.8 mmol) was added to a solution of the main
product 3a-P (335 mg; 0.89 mmol) in 10 mL of THF at 0 °C and
the reaction mixture was stirred for 10 min. By this treatment, a
retro-aldol-type reaction took place to give enantiomerically pure
* Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
dichloromethyl p-tolyl sulfoxide (+)-2a ([a]D = +172.3, acetone;
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.031

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T. Noguchi et al. / Tetrahedron: Asymmetry 20 (2009) 2073–2076
O
S
O
S
CHCl2
CHCl2
H3C
O
2a (racemic)
H3C
(+)-(S)-2a
(-)-Menthone
(1.5 eq)
O
NaHMDS (1.2 eq),
BF3-OEt2 (1.5 eq),
THF, -78 °C, 10 min
S
NaH (2 eq)
THF, 0 °C, 10 min
:
CHCl2
H3C
(-)-(R)-2a
O
Separation of
diastereomers
OH
CCl2-S
CH3
3a (a mixture of two diastereomers)
O
O
CH3
OH
OH
S
R
S
S
S
S
Cl Cl
Cl Cl
CH3
3a-L
3a-P
O
O
S
Bu3SnH (3 eq)
AIBN (0.3 eq)
S
CH3
CHCl2
H3C
H3C
Benzene, reflux,
30 min, 95%
(S)-2a
(+)-(R)-methyl p-tolyl sulfoxide
Scheme 1. Resolution of racemic dichloromethyl p-tolyl sulfoxide 2a with (ꢀ)-menthone.
Table 1
Addition reaction of sodium
a-sulfinyl carbanion of aryl dichloromethyl sulfoxide 2 to (ꢀ)-menthone
O
S
O
NaHMDS (1.2 eq)
BF3-OEt2 (1.5 eq)
O
OH
OH
R
S
Ar
+
S
+
S
Ar
CHCl2
S
O
S
THF, -78 °C, 10 min
Ar
Cl
Cl
Cl Cl
2
3-L
3-P
Entry
2
Yield (%)
Ar
3-P
3-L
2a
1
2
3
4
2b
2c
2d
38
39
30
41
43
34
13
9
19
MeO
2e
2f
36
31
35
34
11
17
Cl
5
O2N
a
The yield for the recovered starting aryl dichloromethyl sulfoxide 2.

T. Noguchi et al. / Tetrahedron: Asymmetry 20 (2009) 2073–2076
2075
Table 2
The retro-aldol-type reaction of adducts 3-P and 3-L with NaH to afford (S)-2 and (R)-2, respectively
O
S
O
O
NaH (2.0 eq)
OH
S
:
S
∗
CHCl2
Ar
Ar
Ar
THF, 0 ºC, 10 min
CHCl2
Cl Cl
(S)-2
(R)-2
3-P or 3-L
Entry
(S)-2
(R)-2
b
b
Ar
Yield (%)
eea (%)
[a
]
D
Yield (%)
90
eea (%)
[a]
D
1
2
3
4
5
88
91
88
90
93
98
99
98
99
99
+152.3
+182.8
+152.8
+160.6
+153.6
97
99
99
99
99
ꢀ150.7
ꢀ179.7
ꢀ145.3
ꢀ158.0
ꢀ159.6
94
91
90
85
MeO
Cl
O2N
a
The enantiomeric purity was determined by HPLC with chiral stationary column, CHIRALCEL OD.
All specific rotations were measured in acetone at room temperature.
b
183 mg; 92%) as colorless crystals. The enantiomerical purity of the
product was easily determined to be over 99% by HPLC with chiral
stationary column, CHIRALCEL OD. In this reaction, at the same
time, (ꢀ)-menthone was obtained in 93% yield. The chlorine atoms
in the dichloromethyl p-tolyl sulfoxide (+)-2a produced were re-
duced with Bu3SnH under radical conditions7 to give (+)-(R)-
methyl p-tolyl sulfoxide8 in 95% yield. The absolute configuration
of the dichloromethyl p-tolyl sulfoxide (+)-2a produced was deter-
mined to be (S) from the results of this reduction. The same treat-
ment of adduct 3a-L gave (ꢀ)-(R)-dichloromethyl p-tolyl sulfoxide
yields and in about 99% enantiomeric purity. Data for the produced
enantiomerically pure aryl dichloromethyl sulfoxides are reported
in the Ref. 9.
3. Conclusion
In conclusion, a simple, efficient, and reliable procedure for the
resolution of racemic aryl dichloromethyl sulfoxides was achieved
by using (ꢀ)-menthone as the chiral auxiliary in two steps. More-
over, the (ꢀ)-menthone used is recovered in almost quantitative
yield and can be reused without special purification. The procedure
presented herein should contribute greatly to the synthesis of
enantiomerically pure aryl dichloromethyl sulfoxides and to asym-
metric synthesis using chiral sulfoxides.
(R)-2a ([
a
]
D = ꢀ174.4, acetone) in 90% yield with (ꢀ)-menthone
(90%).
The whole procedure can be expressed as a cycle shown in
Scheme 1. Thus, the reaction of (ꢀ)-menthone with racemic 2a
gives an adduct as an about 1:1 mixture of two diastereomers
3a. These diastereomers are easily separated by a silica gel column
chromatography to give 3a-P and 3a-L. A retro-aldol-type reaction
takes place when adducts 3a-P and 3a-L are treated separately
with NaH to give enantiomerically pure (+)-(S)-2a and (ꢀ)-(R)-2a,
respectively, with (ꢀ)-menthone, both in high yields. Needless to
say, the recovered (ꢀ)-menthone can be used in the next experi-
ment without further purification.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and by a TUS Grant for Re-
search Promotion from Tokyo University of Science, which are
gratefully acknowledged.
The generality of this procedure was investigated with racemic
dichloromethyl phenyl sulfoxide 2b, dichloromethyl 2-naphthyl
sulfoxide 2c, dichloromethyl4-methoxyphenyl sulfoxide2d, dichlo-
romethyl 4-chlorophenyl sulfoxide 2e, and dichloromethyl 4-nitro-
phenyl sulfoxide 2f. The results for the addition reaction of the
References
1. (a) Some selected recent books and reviews concerning chemistry, synthesis,
and synthetic uses of optically active sulfoxides: The Chemistry of Sulphones and
Sulphoxides; Patai, S., Rappoport, Z., Eds.; John Wiley and Sons: Chichester, 1988;
(b) The Syntheses of Sulphones, Sulphoxides, and Cyclic Sulphides; Patai, S.,
Rappoport, Z., Eds.; John Wiley and Sons: Chichester, 1994; (c) Carreno, M. C.
Chem. Rev. 1995, 95, 1717; (d) Mikolajczk, M.; Drabowicz, J.; Kielbasinski, P.
Chiral Sulfur Reagents; Applications in Asymmetric and Stereoselective Synthesis;
CRC Press: Boca Raton, 1997; (e) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P. Tetrahedron: Asymmetry 1997, 8, 1339; (f) Fernandez, I.; Khiar, N.
Chem. Rev. 2003, 103, 3651; (g) Pellissier, H. Tetrahedron 2006, 62, 5559;
(h) Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm, C., Eds.;
Wiley-VCH: Weinheim, 2008.
sodium a-sulfinyl carbanion of racemic aryl dichloromethyl sulfox-
ides 2 with (ꢀ)-menthone are summarized in Table 1. As shown in
Table 1, all the reactions gave an almost 1:1 mixture of adducts 3-
P and 3-L in up to 82% yields with 9–19% yields of recovered starting
material 2. The separation of the two diastereomers by silica gel col-
umn chromatography proved to be a straightforward task.
The removal of the chiral auxiliary, (ꢀ)-menthone, from adducts
3-P and 3-L proceeded smoothly with NaH in THF at 0 °C and the
results are summarized in Table 2. All the reactions gave optically
active aryl dichloromethyl sulfoxides in between 85% and 94%
2. (a) Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. Tetrahedron Lett. 1988, 29, 313;
(b) Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. J. Org. Chem. 1989, 54, 3130.
3. Some of our papers selected for asymmetric syntheses using optically active
chloromethyl p-tolyl sulfoxide and 1-chloroalkyl p-tolyl sulfoxides: (a) Satoh, T.;

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Motohashi, S.; Kimura, S.; Tokutake, N.; Yamakawa, K. Tetrahedron Lett. 1993, 34,
4823; (b) Satoh, T.; Kobayashi, S.; Nakanishi, S.; Horiguchi, K.; Irisa, S.
(ꢀ)-(R)-Dichloromethyl phenyl sulfoxide (R)-2b: Colorless oil. ½a D29
¼ ꢀ150:7
ꢁ
(c 0.50, acetone).
Tetrahedron 1999, 55, 2515; (c) Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S.
Tetrahedron 2001, 57, 3891; (d) Satoh, T.; Yoshida, M.; Takahashi, Y.; Ota, H.
Tetrahedron: Asymmetry 2003, 14, 281; (e) Satoh, T.; Fukuda, Y. Tetrahedron
2003, 59, 9803; (f) Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245; (g)
Sugiyama, S.; Satoh, T. Tetrahedron: Asymmetry 2005, 16, 665; (h) Satoh, T.;
Hirano, M.; Kuroiwa, A.; Kaneko, Y. Tetrahedron 2006, 62, 9268; (i) Kido, M.;
Sugiyama, S.; Satoh, T. Tetrahedron: Asymmetry 1934, 2007, 18; (j) Sugiyama, S.;
Nakaya, N.; Satoh, T. Tetrahedron: Asymmetry 2008, 19, 401; (k) Nakaya, N.;
Sugiyama, S.; Satoh, T. Tetrahedron Lett. 2009, 50, 4212.
(+)-(S)-Dichloromethyl 2-naphthyl sulfoxide (S)-2c: Colorless crystals; mp 95.5–
96 °C (AcOEt–hexane); IR (KBr) 2954, 1585, 1348, 1183, 1073, 1053, 817, 784,
739, 477 cmꢀ1 1H NMR d 6.25 (1H, s), 7.59–7.69 (2H, m), 7.79 (1H, dd, J = 1.74,
;
8.62 Hz), 8.00 (1H, s), 7.93–8.03 (2H, m), 8.33 (1H, s). MS m/z (%) 258 (10), 175
(100), 147 (18), 127 (23), 115 (8). Calcd for C11H8Cl2OS: M, 257.9673. Found: m/z
257.9675. ½a 2D8
¼ þ182:8 (c 0.30, acetone).
ꢁ
(ꢀ)-(R)-Dichloromethyl 2-naphthyl sulfoxide (R)-2c: Colorless crystals; mp
95.5–96 °C (AcOEt–hexane); ½a D28
¼ ꢀ179:7 (c 0.31, acetone).
ꢁ
(+)-(S)-Dichloromethyl 4-methoxyphenyl sulfoxide (S)-2d: Colorless oil; IR
4. (a) Miyagawa, T.; Satoh, T. Tetrahedron Lett. 2007, 48, 4849; (b) Miyagawa, T.;
Tatenuma, T.; Tadokoro, M.; Satoh, T. Tetrahedron 2008, 64, 5279; (c) Satoh, T.;
Noguchi, T.; Miyagawa, T. Tetrahedron Lett. 2008, 49, 5689.
5. Rao, K. R.; Sattur, P. B. J. Chem. Soc., Chem. Commun. 1989, 342.
6. Dillen, J. L. M.; Meth-Cohn, O.; Moore, C.; van Rooyen, P. H. Tetrahedron 1988, 44,
3127.
7. Satoh, T.; Sato, T.; Oohara, T.; Yamakawa, K. J. Org. Chem. 1989, 54, 3973.
8. Solladie, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
9. Data for enantiomerically pure aryl dichloromethyl sulfoxides 2a–2f are as
follows.
(neat) 2963, 1593, 1497, 1259, 1066, 832, 786, 529 cmꢀ1 1H NMR d 3.89 (3H,
;
s), 6.14 (1H, s), 7.04–7.09 (2H, m), 7.70–7.75 (2H, m). MS m/z (%) 238 (4), 155
(100), 139 (5), 123 (4), 92 (5), 77 (5), 64 (3), 28 (10). Calcd for C8H8Cl2O2S: M,
237.9622. Found: m/z 237.9620. ½a D28
¼ þ152:8 (c 0.30, acetone).
ꢁ
(ꢀ)-(R)-Dichloromethyl 4-methoxyphenyl sulfoxide (R)-2d: Colorless oil.
½ ꢁ ¼ ꢀ145:3 (c 0.50, acetone).
a 2D8
(+)-(S)-Dichloromethyl 4-chlorophenyl sulfoxide (S)-2e: Colorless crystals; mp
57.5–58 °C (AcOEt–hexane); IR (KBr) 2963, 1568, 1471, 1387, 1088, 1061, 785,
741, 505 cmꢀ1 1H NMR d 6.18 (1H, s), 7.54–7.59 (2H, m), 7.72–7.77 (2H, m). MS
;
m/z (%) 242 (9), 161 (45), 159 (100), 131 (13), 111 (12), 75 (12), 28 (16). Calcd for
(+)-(S)-Dichloromethyl p-tolyl sulfoxide (S)-2a: Colorless crystals; mp 49.5–
50 °C (AcOEt–hexane); IR (KBr) 2965, 1593, 1490, 1165, 1086, 1063, 1014, 809,
C7H5Cl3OS: M, 241.9127. Found: m/z 241.9123. ½a D28
¼ þ160:6 (c 0.25, acetone).
ꢁ
(ꢀ)-(R)-Dichloromethyl 4-chlorophenyl sulfoxide (R)-2e: Colorless crystals; mp
787, 648, 511 cmꢀ1
;
1H NMR d 2.45 (3H, s), 6.15 (1H, s), 7.35–7.40 (2H, m), 7.66–
57.5–58 °C (AcOEt–hexane); ½a D28
¼ ꢀ158:0 (c 0.18, acetone).
ꢁ
7.70 (2H, m). MS m/z (%) 222 (8), 139 (100), 91 (12), 77 (6), 55 (7). Calcd for
(+)-(S)-Dichloromethyl 4-nitrophenyl sulfoxide (S)-2f: Colorless crystals; mp
83.5–84 °C (AcOEt–hexane); IR (KBr) 2986, 1606, 1533, 1343, 1087, 1063, 852,
C8H8Cl2OS: M, 221.9673. Found: m/z 221.9675. ½a D28
¼ þ172:3 (c 0.36, acetone).
ꢁ
(ꢀ)-(R)-Dichloromethyl p-tolyl sulfoxide (R)-2a: Colorless crystals; mp 49.5–
791, 752, 680, 535 cmꢀ1 1H NMR d 6.29 (1H, s), 8.00–8.03 (2H, m), 8.42–8.45
;
50 °C (AcOEt–hexane); ½a D28
ꢁ
¼ ꢀ174:4 (c 1.0, acetone).
(2H, m). MS m/z (%) 253 (22), 170 (52), 154 (11), 124 (17), 96 (12), 83 (100), 76
(20), 70 (10), 50 (18), 28 (20). Calcd for C7H5Cl2NO3S: M, 252.9367. Found: m/z
(+)-(S)-Dichloromethyl phenyl sulfoxide (S)-2b: Colorless oil; IR (neat) 3060,
2960, 1445, 1060, 782, 688, 515 cmꢀ1
;
1H NMR d 6.17 (1H, s), 7.54–7.67 (3H, m),
252.9365. ½a 2D8
¼ þ153:6 (c 0.30, acetone).
ꢁ
7.78–7.82 (2H, m). MS m/z (%) 208 (7), 125 (100), 97 (20), 77 (22), 51 (12), 28
(ꢀ)-(R)-Dichloromethyl 4-nitrophenyl sulfoxide (R)-2f: Colorless crystals; mp
(16). Calcd for C7H6Cl2OS: M, 207.9516. Found: m/z 207.9513. ½a D29
ꢁ
¼ þ152:3
83.5–84 °C (AcOEt–hexane); ½a D28
¼ ꢀ159:6 (c 0.19, acetone).
ꢁ
(c 0.50, acetone).