Asymmetric synthesis of α-fluoro-α-sulfenyl-β-ketoesters using DBFOX-Ph/Ni(II) complex

Article abstract of DOI:10.1016/j.jfluchem.2009.08.004

Enantioselective α-sulfenylation of α-fluoro-β-ketoesters 4 with phenylsulfenyl chloride catalyzed by DBFOX-Ph/Ni(II) complex afforded the corresponding α-fluoro-α-sulfenyl-β-ketoesters 2 in moderate to good yields with excellent enantiomeric excesses up

Full text of DOI:10.1016/j.jfluchem.2009.08.004

Journal of Fluorine Chemistry 130 (2009) 1049–1053
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
Asymmetric synthesis of
Ni(II) complex
a-fluoro-a-sulfenyl-b-ketoesters using DBFOX–Ph/
*
Takehisa Ishimaru, Shinichi Ogawa, Etsuko Tokunaga, Shuichi Nakamura, Norio Shibata
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
A R T I C L E I N F O
A B S T R A C T
Enantioselective
Article history:
a
-sulfenylation of
a
-fluoro-
b
-ketoesters 4 with phenylsulfenyl chloride catalyzed by
Received 3 August 2009
DBFOX–Ph/Ni(II) complex afforded the corresponding
to good yields with excellent enantiomeric excesses up to 93% ee.
be effectively converted to tri-fluorinated -sulfenylcarboxylates by the use of DAST, which should be
useful intermediates for the synthesis of non-racemized fluorinated isosteres of pharmaceutically
attractive SM32. The enantioselective -phenylsulfenylation as well as -pentafluoro-phenylsulfenyla-
tion of non-fluorinated -ketoesters 5 were also carried out under the same catalyst conditions affording
up to 95% ee of the products 6–8.
a
-fluoro-
a
-sulfenyl-
b
-ketoesters 2 in moderate
Received in revised form 19 August 2009
Accepted 20 August 2009
Available online 26 August 2009
a
-Fluoro-
a
-sulfenyl- -ketoesters can
b
a
a
a
Keywords:
b
Sulfenylation
Fluorination
ß 2009 Elsevier B.V. All rights reserved.
b-Ketoesters
Chiral catalysis
Enantioselective
1. Introduction
disclosed the enantioselective a-sulfenylation of b-ketoesters
using chiral Ti(TADDOLato) complexes [4e–4g]. Although these
methodologies are efficient, clearly more efficient catalysts are
required to attain sufficient reactivity, selectivity and versatility.
Incidentally, fluorine-containing organic compounds have
attracted much attention because of their utility in the field of
pharmaceuticals, agrochemicals and material sciences [5]. Chiral
organofluorine compounds containing a fluorine atom bonded
directly to a stereogenic center have been utilized in the
pharmaceutical chemistry and in materials science [6]. As part
of our studies on the design and synthesis of biologically active
Chiral organosulfur-containing compounds are synthetic
targets attracting much recent interest in view of both their
ambiguous synthetic utilities as chiral building blocks and chiral
ligands, as well as unique biological activities [1]. a-Sulfenylated
carbonyl compounds are particularly attractive synthetic inter-
mediates since they have been used for a variety of organic
transformations [2]. Among various strategies that have been
available for this purpose, enantioselective electrophilic sulfe-
nylation of carbonyl compounds, including aldehydes, ketones,
1,3-dicarbonyl compounds or their equivalents with various
electrophilic sulfenylating reagents, which allows the direct
organofluorine compounds [7,8], we required chiral
a-fluoro-a-
sulphenyl- -ketoesters 2 as synthetic intermediates for non-
b
conversion of racemic or achiral carbonyl compounds to chiral
a
-
racemized fluoro-isosteric analogue of SM32 which has potent
sulfenyl carbonyl compounds in single operation, is an
a
biological activity (Fig. 1) [9].
important process in organic synthesis [3,4]. Despite the
undoubted utility of this process, however, there had been
relatively few successful reports of catalytic electrophilic
enantioselective sulfenylation until recent years [4]. Wang
A series of a-fluoro-a-sulfenyl-b-ketoesters 2 should also be
used as versatile building templates to prepare other pharmaceu-
tically attractive molecules. Two general strategies were devised
for this purpose. One of these involves the enantioselective
et al. described for the first time the
a
-sulfenylation of aldehydes
fluorination of
second strategy uses an enantioselective installation of the
sulfenyl group to -fluoro- -ketoesters 4 (Fig. 1). In this paper,
we examined both strategies and found that the enantioselective
sulfenylation of -fluorinated -ketoesters catalyzed by DBFOX–
Ph/Ni(II) catalyst is effective for the synthesis of chiral, non-
racemic -fluoro- -sulfenyl- -ketoesters 2 in high enantioselec-
tivities with up to 93% ee. Non-fluorinated -ketoesters 5 were also
a-sulfenyl-b-ketoesters 3 to compounds 2. The
and ketones in the presence of chiral pyrrolidine trifluoro-
methane-sulfonimide [4a]. Subsequently, Jørgensen and co-
workers reported an elegant catalytic enantioselective sulfeny-
lation of aldehydes using prolinol organocatalysts in high yields
and excellent enantioselectivities [4b–d]. Togni et al. also
a
b
a
b
a
a
b
b
nicely sulfenylated under the same catalytic conditions to provide
* Corresponding author.
E-mail address: nozshiba@nitech.ac.jp (N. Shibata).
the sulfenylated compounds 6–8 with up to 95% ee.
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.08.004

1050
T. Ishimaru et al. / Journal of Fluorine Chemistry 130 (2009) 1049–1053
Fig. 1. Two general strategies for the synthesis of fluoro-SM32 via chiral, non-
racemic -fluoro- -sulfenyl- -ketoesters 2.
Scheme 1. DBFOX–Ph/Ni(II) catalyzed enantioselective fluorination of
-ketoester 1b.
a-sulfenyl-
a
a
b
b
2. Results and discussion
Recently, we reported the catalytic enantioselective fluorina-
tion of b-ketoesters, oxindoles, malonates and oxa-thiazolidinones
by DBFOX–Ph/metal complexes to furnish corresponding fluori-
nated compounds in high yields with excellent enantioselectivities
up to 99% ee [10]. Two-point binding is explained as being
indispensable to achieve high enantioselectivity [10–12]. We
Scheme 2. Synthesis of tri-fluorinated carboxylate 1b from 2b by DAST.
therefore first attempted the fluorination of
a-sulfenylated b-
ketoester 3b with N-fluorobenzenesulfonimide (NFSI) under our
previously reported conditions; namely, in the presence of
Ni(ClO4)2Á6H2O (10 mol%), DBFOX–Ph (11 mol%) in CH2Cl2. How-
ever, the level of enantioselectivity in this reaction was dis-
appointingly low even for substrates capable of chelation to the
metal center (Scheme 1, 46% yield, 20% ee) [13].
[4e]. a-Sulfenylation of a-fluorinated b-ketoester 4a was exam-
ined with phenylsulfenyl chloride (PhSCl) as an electrophilic agent
in the presence of a catalytic amount of Ni(ClO4)2Á6H2O (10 mol%),
and DBFOX–Ph (11 mol%) in CH2Cl2, at room temperature.
Corresponding
a-sulfenylated a-fluoro-b-ketoester 2a was
obtained in moderate yield with high enantioselectivity
(Table 1, entry 1, 93% ee) [13]. Neither chemical yield nor
enantioselectivity was improved in different solvent systems like
THF and toluene (runs 2 and 3). It is interesting to note that the
This unsuccessful result prompted us to explore an alternative
strategy, i.e., enantioselective
ketoesters 4 instead of enantioselective
sulfenyl- -ketoesters. Asymmetric -functionalization of
a
-sulfenylation of
a
-fluorinated
b-
a-
a-
a
-fluorination of
˚
b
a
addition of a molecular sieve (MS-4 A) was essential for this
fluorinated carbonyl compounds and their equivalents is an
important topic in recent years in the field of organic chemistry
[14,15], however, there is only one example available for the
reaction (run 4). A stoichiometric amount of organic base such as
diisopropylethylamine and proton sponge was not an effective
additive in this reaction (runs 5 and 6), but the addition of an
inorganic base such as potassium carbonate improved the
asymmetric sulfenylation of
a-fluorinated carbonyl compounds
Table 1
Enantioselective
a-sulfenylation of a-fluorinated-b-ketoesters 4a–c with PhSCl catalyzed by DBFOX–Ph/Ni(II).
.
Runa
4
Additive
Time (h)
2
Yield (%)
ee (%)b
˚
1
2c
3d
4
5e
6e
7e
8f
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
MS-4 A
17
84
84
12
24
24
27
96
18
17
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
48 (80)c
35
93
82
80
–
˚
MS-4 A
˚
MS-4 A
7
None
NR
˚
MS-4 A + DIEA
48
17
54
87
–
˚
MS-4 A + PS
8
˚
MS-4 A + K2CO3
65
˚
MS-4 A
Trace
53 (70)c
62 (80)c
˚
9
MS-4 A
86
87
˚
10
MS-4 A
a
˚
The reaction of 4 with PhSCl (1.2 equiv.) was carried out in the presence of Ni(ClO4)2Á6H2O (10 mol%), (R,R)-DBFOX–Ph (11 mol%), MS-4 A in CH2Cl2 at room temperature.
b
c
d
e
f
ee was determined by HPLC analysis using CHIRALPAK AD-H.
THF was used as solvent.
Toluene was used as solvent.
Diisopropylethylamine (1.0 equiv.), proton sponge (PS) or K2CO3 (1.0 equiv.) was added.
Zn(OAc)2 was used instead of Ni(ClO4)2Á6H2O.

T. Ishimaru et al. / Journal of Fluorine Chemistry 130 (2009) 1049–1053
1051
Table 2
Scope of the asymmetric
a-sulfenylation of non-fluorinated
b
-ketoesters 5 to 6.
.
Entrya
5
R1
R2
Time (h)
6
Yield (%)
ee (%)b
1
2
5a
5b
5c
5d
5e
5e
5f
Me
Me
Et
tBu
tAm
tBu
tBu
17
18
17
19
23
30
0.5
6a
6b
6c
6d
6e
6e
6f
76 (96)c
61 (84)c
43 (88)c
49 (95)c
78
88
90
88
95
45
59
25
3
4
Ph
5
6d
7
61
57
a
˚
The reaction of 5 with PhSCl (1.2 equiv.) was carried out in the presence of Ni(ClO4)2Á6H2O (10 mol%), (R,R)-DBFOX–Ph (11 mol%), MS-4 A in CH2Cl2 at room temperature.
b
c
ee was determined by HPLC analysis.
Based upon recovered starting material.
THF was used as solvent.
d
Scheme 3. Pentafluorosulfenylation of 5 by the use of C6F5SCl.
Fig. 2. Proposed transition state structure.
ketoesters 5e and f shows a somewhat low enantioselectivity of 59
ee and 25% ee, respectively (entries 5–7), which is a limitation of
conversion of this reaction without a major loss of enantiopurity
the present method (Table 2).
(run 7). When changing the Lewis acid from Ni(ClO4)2Á6H2O to
Zn(OAc)2, only a trace amount of the product was obtained even
after a longer reaction time (run 8). Therefore, we concluded that
the best condition for this reaction was the one mentioned in run 1.
On the basis of the reported X-ray structure of the (R,R)-DBFOX–
Ph/Ni(II) complex [10], we assumed octahedral complexes
coordinated with a water molecule for DBFOX–Ph/Ni(II)/5 as
shown in Fig. 2. In the complex, the Re face of 5 is shielded by one of
the phenyl groups of DBFOX–Ph so that PhSCl approaches from the
Si face of the substrates (Fig. 2).
Finally, pentafluorosulfenylation of 5a, c was instead examined
by the use of C6F5SCl as an electrophile. The reaction was
completed rapidly and gave both high yields and high enantios-
electivities of 7 and 8 (Scheme 3) [13].
Next, to examine the generality of this catalytic enantioselective
sulfenylation of -fluoro- -ketoesters by DBFOX–Ph/Ni(II)
complexes, we studied the sulfenylation of other -ketoesters
4b and 4c. As can be seen from the results summarized in Table 1,
the corresponding -fluoro- -sulfenylated -ketoesters 2b and 2c
a-
a
b
4
b
a
a
b
were obtained in moderate yields with high enantioselectivities
(runs 9 and 10) [13]. The molecular sieves play an important role in
the reaction (run 4 vs. others), but the exact mechanisms are not
clear. It is highly likely that it should activate the Ni(ClO4)2Á6H2O
by the coordination as one of the ligands.
3. Conclusion
In conclusion, we have synthesized chiral, non-racemic
fluoro- -sulfenyl- -ketoesters 2 by the enantioselective electro-
philic sulfenylation of -fluoro- -ketoesters 4 in the presence of a
catalytic amount of DBFOX–Ph/Ni(II) complex. The methodology
can be applicable for the enantioselective -phenylsulfenylation as
well as -pentafluoro-phenylsulfenylation of non-fluorinated b-
a-
Resulting
a
-fluoro-
a
-sulfenyl-
b
-ketoester 2b was nicely trans-
a
b
formed to tri-fluorinated
a
-sulfenyl carboxylate 1b by DAST in
a
b
89%, which should be a useful intermediate for the synthesis of
fluoro-SM32 (Scheme 2).
a
To explore the scope of the reaction, non-fluorinated
b
-
a
ketoesters were next used as substrates for the enantioselective
sulfenylation reaction. As expected, the DBFOX–Ph/Ni(II) complex
is a general catalyst for the enantioselective sulfenylation of acyclic
ketoesters 5. Although DBFOX–Ph–metal(II) complexes have been
actively used for asymmetric reactions including halogenation,
hydroxylation, Michael addition and Diels–Alder reactions, this
sequence serves as the first example of sulfenylation using DBFOX–
Ph/metal(II) complex. Total synthesis of the fluoro-SM32 is now
being developed.
b
-ketoesters to afford corresponding non-fluorinated
lated -ketoesters in good yields with high enantioselectivities up
to 95% ee [13]. On the other hand, sulfenylation of cyclic
a-sulfeny-
b
b
-

1052
T. Ishimaru et al. / Journal of Fluorine Chemistry 130 (2009) 1049–1053
4. Experimental
No. 21390030 (JSPS). We thank Kishida Chemical Ltd. for the
generous gift of DBFOX–Ph.
4.1. General procedure for the enantioselective catalytic sulfenylation
reaction
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2a: Colorless oil; 1H NMR (CDCl3, 200 MHz): 1.40 (s, 9H), 2.20 (d,
J = 3.2 Hz, 3H), 7.30–7.40 (m, 3H), 7.54–7.58 (m, 2H); 19F NMR
(CDCl3, 188 MHz): À132.6 (d, J = 2.6 Hz); 13C NMR (CDCl3,
50.3 MHz): 196.1 (d, J = 28.3 Hz), 161.8 (d, J = 27.9 Hz), 135.5 (d,
J = 1.6 Hz), 129.7, 128.9, 127.2, 105.0 (d, J = 242.6 Hz) 85.2, 27.7,
26.1; IR (neat): 3061, 2981, 2929, 1732, 1474, 1441, 1395, 1371,
1279, 1153, 1066, 898, 834, 749, 691 cmÀ1; MS (EI): m/z 284 (M+),
184 (M++1–COOtBu); HPLC: (CHIRALPAK AD-H, hexane/i-
PrOH = 99/1, 0.5 ml/min, 211 nm) tR (minor-isomer) = 14.3 min,
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25
tR (major-isomer) = 15.7 min (86% ee); aD À29.3 (c = 0.62, CHCl3
86% ee).
6a: Pale yellow oil; 1H NMR (CDCl3, 200 MHz): 1.45 (s, 3H), 1.49
(s, 9H), 2.38 (s, 3H), 7.29–7.43 (m, 5H); 13C NMR (CDCl3, 50.3 MHz):
198.8, 168.5, 136.6, 129.5, 129.3, 128.7, 83.5, 66.5, 27.9, 26.1; IR
(neat): 3054, 2979, 2934, 1712, 1474, 1440, 1370, 1256, 1162,
1124, 853, 750, 692, 479 cmÀ1; MS (EI): m/z 280 (M+), 180 (M++1–
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25
mer) = 13.0 min (88% ee); aD À59.9 (c = 0.50, CHCl3 88% ee)
([a
]
À50.8 (c = 0.535, CH2Cl2 88% ee) [4 g]).
D
6b: Yellow oil; 1H NMR (CDCl3, 200 MHz): 0.90 (t, J = 7.6 Hz,
3H), 1.45 (s, 3H), 1.46 (s, 3H), 1.48 (s, 3H), 1.72–1.86 (m, 2H), 2.39
(m, 3H), 7.25–7.42 (m, 5H); 13C NMR (CDCl3, 50.3 MHz): 198.8,
168.4, 136.6, 129.5, 129.3, 128.7, 86.1, 66.5, 33.8, 26.2, 25.3, 20.9,
8.4; IR (neat): 2977, 2934, 1712, 1370, 1354, 1260, 1156, 1121, 926,
842, 749, 692, 463 cmÀ1; MS (EI): m/z 294 (M+), 194 (M++1–
COOtBu); HPLC: (CHIRALCEL OJ-H, hexane/iPrOH = 99/1, 0.8 ml/
min, 220 nm) tR (minor-isomer) = 17.8 min, tR (major-iso-
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25
mer) = 21.5 min (90% ee); aD À55.6 (c = 0.67, CHCl3 90% ee)
([a
]
À49.6 (c = 0.48, CH2Cl2 86% ee) [4g]).
D
8: Pale yellow crystal; 1H NMR (CDCl3, 200 MHz): 1.14 (t,
J = 7.2 Hz, 3H), 1.49 (s, 3H), 1.51 (s, 9H), 2.50 (dq, J = 17.9, 7.2 Hz,
1H), 3.08 (dq, J = 17.8, 7.2 Hz, 1H); 19F NMR (CDCl3, 188 MHz):
À160.1 to À159.8 (m, 2F), À148.0 (tt, J = 4.0, 20.4 Hz, 1F), À128.2
(ddd, J = 4.0, 5.3, 22.4 Hz, 2F); IR (KBr): 2994, 2943, 1710, 1642,
1519, 1489, 1374, 1281, 1163, 1128, 1094, 981, 862, 844, 772, 672,
480, 405 cmÀ1; MS (EI): m/z 384 (M+), 199 (M+–SC6F5); HPLC:
(CHIRALPAK AS-H, hexane, 0.2 ml/min, 220 nm) tR (major-
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25
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This study was financially supported in part by a Joint Project
JSPS-CNRS, as well as by Grants-in-Aid for Scientific Research (B)

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