Preparation of tert-Alkyl aryl sulfides from tert-alcohols via quinone-mediated oxidation-reduction condensation between tert-Alkyl diphenylphosphinites and 2-sulfanyl-1,3-benzothiazole

Article abstract of DOI:10.1246/cl.2005.638

A convenient two-step procedure for the construction of sulfur-containing quaternary centers from tert-alcohols involving chiral ones is established. tert-Alkyl diphenylphosphinites 1 were easily prepared in excellent yields from tert-alcohols and ClPPh

Full text of DOI:10.1246/cl.2005.638

638
Chemistry Letters Vol.34, No.5 (2005)
Preparation of tert-Alkyl Aryl Sulfides from tert-Alcohols via Quinone-mediated
Oxidation–Reduction Condensation between tert-Alkyl Diphenylphosphinites
and 2-Sulfanyl-1,3-benzothiazole
Kazuhiro Ikegai,y;yy Wanchai Pluempanupat,y;yy;yyy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
Kitasato Institute for Life Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641
yy
yyyDepartment of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
(Received January 13, 2005; CL-050063)
A convenient two-step procedure for the construction of sul-
Table 1. Optimization of quinone derivatives
fur-containing quaternary centers from tert-alcohols involving
chiral ones is established. tert-Alkyl diphenylphosphinites 1
were easily prepared in excellent yields from tert-alcohols and
ClPPh2 by the combined use of Et3N and a catalytic amount
of DMAP. Subsequent condensation of 1 with thiol 3 smoothly
proceeded in the presence of quinone 2d to afford the corre-
sponding tert-alkyl sulfides 4 in good to high yields via SN2 dis-
placement. Removal of benzothiazol-2-yl group of (R)-4j was
achieved with LiAlH4 to afford the desired chiral thiol (R)-5 in
high yield.
N
Quinone 2a−2h
(2.0 equiv.)
S
HS
3 (1.0 equiv.)
Me
N
Me Me
Me
S
CHCl3 (1.0 M)
Ph2PO CO2Me
1a (2.0 equiv.)
MeO2C
S
4a
rt, 12 h
Entry
1
Quinone
Yield/ %
Entry
5
Quinone
OMe
O
Yield/ %
91
2a
2b
2c
34
51
84
2e
O
O
O
O
O
O
O
OMe
OBn
t
Bu
2
3
4
2f
91
O
O
6
Nucleophilic substitution at quaternary carbon centers via
SN2-type displacement has been regarded as one of the most
challenging topics in current organic synthesis, however, only
a few successful examples have been reported.1,2 Recently, it
was shown from our laboratory that a new-type of oxidation–
reduction condensation of tert-alkyl diphenylphosphinites 1,
prepared from n-BuLi-treated tert-alcohols and chlorodiphenyl-
phosphine (ClPPh2), with heteroaryl thiols proceeded smoothly
by the promotion of 2,6-dimethyl-1,4-benzoquinone (DMBQ;
2c) under neutral and mild conditions to afford various tert-alkyl
aryl sulfides in moderate to good yields.2a In a similar fashion,
preparation of chiral tertiary alkyl sulfides was also achieved
using chiral benzylic tert-alkyl phophinite via SN2 displacement.
In order to establish a practical and convenient method of
forming sulfur-containing quaternary centers, a condensation
of tert-alkyl phosphinites 1 with 2-sulfanyl-1,3-benzothiazole
(3) and a development of a preparative method of the phosphin-
ite 1 under mild condensations were investigated in detail. Now,
we would like here to describe an effective method for the syn-
thesis of tert-alkyl benzothiazol-2-yl sulfides 4 from tert-alco-
hols by the oxidation–reduction condensation of 1 with thiol 3
using 2,6-di-tert-butyl-1,4-benzoquinone (DBBQ; 2d) as an
oxidant.
OBn
Cl
Me
O
2g
2h
6
O
O
O
7
8
Cl
F
Me
t
F
F
Bu
N.D.
O
2d quant.
O
F
t
Bu
amino)pyridine (DMAP) as shown in Scheme 1.3,4 The reactions
completed within 2 h at room temperature and pure phosphinites
were obtained just by filtration through a pad of alumina using an
eluent of hexane/ethyl acetate (v/v ¼ 9=1) under the conditions
resisting to air-oxidation of phosphinites. It should be noted that
the above conditions are obviously milder than those of the pre-
viously reported procedure of using a strong base as n-BuLi5
which afforded 1j in only 8% yield.
Since sufficient amounts of phosphinites are available by the
above procedure, the screening of 1,4-benzoquinone derivatives
was tried in order to choose an excellent one for the condensa-
tion of phosphinite 1a with thiol 3 (Table 1). It was considered
that 1a is one of most suitable substrates for SN2 substitution be-
cause the reaction center of 1a is activated by the ꢀ-carboxylic
ester group.1a–1d,6 The reaction was tried first by using simple
1,4-benzoquinone (2a) which was successfully employed in
our previous papers,2b–2c but the desired sulfide 4a was obtained
in only 34% yield (Entry 1). The use of 2-tert-butyl-1,4-benzo-
quinone (2b) or DMBQ 2c,2 on the other hand, dramatically im-
proved the yield of 4a up to 84% (Entries 2, 3). This suggests
that substituents at 2- and 6-positions of 2a effectively suppress
the undesired competitive E2 elimination1b caused by the phe-
nolic anion generated from 1,4-benzoquinone.2e Further experi-
ments concerning the above substituent effects finally led to the
use of bulky DBBQ 2d7 and it afforded 4a in a quantitative yield
Phosphinites 1a–1k were easily prepared from the corre-
sponding tert-alcohols in excellent yields (95%-quant.) by sim-
ply adding chlorodiphenylphosphine (ClPPh2) in the presence
of triethylamine (Et3N) and a catalytic amount of 4-(dimethyl-
ClPPh2 (1.1 equiv.)
Et3N (1.2 equiv.)
DMAP (0.3 equiv.)
R2
R1
HO R3
R2
R1
Ph2PO R3
THF (0.5 M)
1a−1k
rt, 2h, 95%−quant.
Scheme 1. Preparation of tert-alkyl diphenylphosphinites.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.5 (2005)
639
Table 2. DBBQ-mediated condensation of 1 with 3a
via inversion of configuration by SN2 displacement. Subsequent
removal of benzothiazol-2-yl group of thus formed 4 provides a
new and convenient route to the synthesis of chiral tert-thiols
from chiral tert-alcohols.
3 (1.0 equiv.)
R1 R2
Ph2PO R3
R1 R2
N
DBBQ 2d (2.0 equiv.)
R3
S
S
CHCl3 (1.0 M)
rt, 12 h
1 (2.0 equiv.)
4
This study was supported in part by the Grant of the 21st
Century COE Program from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
% eeb
Yield
/%
% eec
Phosphinite
R1
R2
R3
Product
(config.)
(config.)
1b
1c
1d
1e
1f
Me Me CO2Bn
Me Me CO2tBn
Me Me COPh
—
—
—
—
—
—
4b
4c
4d
4e
4f
87 (78d)
90 (66d)
52 (22d)
90 (78d)
53 (48d,e
34 (35d,e
—
—
—
—
—
—
References and Notes
1
see: a) A. Avenoza, J. H. Busto, F. Corzana, G. J. Oses, and J. M.
For SN2 reactions from tert-alcohols with various nucleophiles,
´
Me Me
Me –(CH2)4–
Me Me (CH2)2Ph
Et
CH2Ph Me CO2Et
Ph
)
)
Peregrina, Chem. Commun., 2004, 980. b) Y.-J. Shi, D. L.
Hughes, and J. M. McNamara, Tetrahedron Lett., 44, 3609
(2003). c) N. D. Smith and M. Goodman, Org. Lett., 5, 1035
(2003). d) F. Effenberger and S. Gaupp, Tetrahedron:
1g
4g
1h
1i
Me CO2Bn >99 (S)
78 (S)
Me CO2Me >99 (S)
Me Ph 97 (S)
4h
4i
73
61
73
76
>99 (R)
76 (R)
99 (R)
86f (R)
1j
Ph
Et
4j
Asymmetry, 10, 1765 (1999). e) J. Wachtmeister, A. Muhlman,
¨
1k
4k
B. Classon, and B. Samuelsson, Tetrahedron, 55, 10761 (1999).
a) T. Mukaiyama and K. Ikegai, Chem. Lett., 33, 1522 (2004).
b) T. Shintou, K. Fukumoto, and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 77, 1569 (2004). c) T. Shintou and T. Mukaiyama,
Chem. Lett., 32, 1100 (2003). d) T. Mukaiyama, T. Shintou,
and K. Fukumoto, J. Am. Chem. Soc., 125, 10538 (2003). e)
T. Shintou and T. Mukaiyama, J. Am. Chem. Soc., 126, 7359
(2004).
A general procedure is as follows; to a stirred solution of alcohol
(10 mmol) and DMAP (3 mmol) in dry THF (20 mL) were added
Et3N (12 mmol) followed by ClPPh2 (11 mmol) under Ar
atmosphere. After stirring at rt for 2 h, TLC showed complete
consumption of the alcohol, and the resulted white slurry was
concentrated by a rotary evaporator. After the dilution of the
residue with hexane/EtOAc (v/v ¼ 9=1, 100 mL), the mixture
was filtered through a pad of alumina (activated, 300 mesh;
purchased from Wako Pure Chemical Industries, Ltd.) and
Celite. The filtrate was concentrated under reduced pressure to
give the desired phosphinites in >95% yields. Since tert-alkyl
phosphinites were moderately sensitive to air and moisture, they
should be stored at <10 ꢄC under dry Ar atmosphere.
G. Jones and C. J. Richards, Tetrahedron: Asymmetry, 15, 653
(2004).
aReactions were carried out on a 0.5 mmol scale. bEe of alcohols. cDetermined
by HPLC using commercially available chiral columns. dDMBQ 2c was used
instead of DBBQ 2d. eData cited from Ref. 2a. f4k was obtained with 65% ee
by DMBQ (See Ref. 2a).
2
3
(Entry 4). Interestingly, dialkoxy derivatives 2e and 2f8 were al-
so found to be effective oxidants and 4a was obtained in 91%
yield in both cases (Entries 5, 6). In contrast, the use of elec-
tron-deficient dichloro derivative 2g or fluoranil 2h2e,9 gave
the desired products in quite low yields (Entries 7, 8).
After reaction conditions of using DBBQ 2d were opti-
mized,10 the generality of this reaction was examined by using
various tert-alkyl phosphinites (see Table 2). Phosphinites 1b–
1e bearing ester, ketone, or phenyl group at the quaternary cen-
ters were smoothly transformed into the corresponding sulfides
4b–4e in good to high yields (52–90%). It is noted that the use
of 2d instead of 2c fairly improved the yields in the coexistence
of such reactive phosphinites 1b–1e while good results were not
obtained when phosphinites 1f–1g were used. Chiral phosphin-
ites 1h–1j were also successfully employed in this reaction,
and the enantiomerically enriched tert-alkyl sulfides 4h–4j were
afforded in good yields with either perfect or nearly complete in-
version at the quaternary centers. Condensation of benzylic tert-
alkyl phosphinite 1k, which was considered to proceed via SN1
reaction, also gave the inverted sulfide 4k in 76% yield with high
ee (86% ee).
4
5
a) T. Shintou, W. Kikuchi, and T. Mukaiyama, Bull. Chem. Soc.
Jpn., 76, 1645 (2003). b) T. Mukaiyama, W. Kikuchi, and
T. Shintou, Chem. Lett., 32, 300 (2003). c) D. A. Evans, K. R.
´
Campos, J. S. Tedrow, F. E. Michael, and M. R. Gangne,
J. Am. Chem. Soc., 122, 7905 (2000).
F. G. Bordwell and W. T. Brannen, Jr., J. Am. Chem. Soc., 5,
4645 (1964).
6
The absolute stereochemistry of 4j was determined after re-
ductive cleavage of the benzothiazol-2-yl group as described in
Scheme 2; that is, treatment of (R)-4j (99% ee) with lithium alu-
minum hydride11 in refluxing diethyl ether for 4 h gave (R)-512 in
7
8
T. Mukaiyama and H. Aoki, Chem. Lett., 34, 142 (2005).
a) N. Morita, Chem. Pharm. Bull., 8, 66 (1960). b) E. J. Tisdale,
B. G. Vong, H. Li, S. H. Kim, C. Chowdhury, and E. A.
Theodorakis, Tetrahedron, 59, 6873 (2003).
23
95% yield. The optical rotation of (R)-5 ½ꢀꢁD ꢂ32:6 (c 0.41,
9
T. Shintou and T. Mukaiyama, Chem. Lett., 32, 984 (2003).
CH2Cl2) is in good agreement with that of the literature value12
10 A general procedure is as follows; to a stirred solution of phos-
phinite (1.0 mmol) in dry CHCl3 (0.5 mL) were successively
added thiol 3 (0.5 mmol) and DBBQ (1.0 mmol) at rt under Ar
atmosphere. After 12 h, the crude product was purified using
preparative TLC to afford the corresponding sulfide.
20
½ꢀꢁD ꢂ31:8 (c 0.36, CH2Cl2, ꢃ99% ee).13 Thus, the first exam-
ple of synthesis of chiral tert-thiol from chiral tert-alcohol via
SN2 substitution was established.
It is important to note that construction of sulfur-containing
chiral quaternary centers from chiral tert-alcohols was achieved
11 For deprotection of benzothiazol-2-yl group using alkyl
`
metals, see: a) V. Calo, F. Scordari, A. Nacci, E. Schingaro,
L. D’Accolti, and A. Monopoli, J. Org. Chem., 68, 4406
(2003). b) A. R. Katritzky, W. Kuzmierkiewicz, and J. M.
Aurrecoechea, J. Org. Chem., 52, 844 (1987).
LiAlH4
(4 equiv.)
Me
Ph
N
Me
S
Ph
MeO2C
HO
SH
Et2O
reflux, 4 h
95%
S
12 O. Stratmann, B. Kaiser, R. Frohlich, O. Meyer, and D. Hoppe,
¨
Chem.—Eur. J., 7, 423 (2001).
13 The absolute configurations of 4h, 4i, and 4k were deduced from
the stereochemical outcome of the reaction of (S)-1j to (R)-4j.
(R)-5
(R)-4j
Scheme 2. Deprotection of benzothiazol-2-yl group.
Published on the web (Advance View) March 26, 2005; DOI 10.1246/cl.2005.638