Synthesis of mono-fluorinated functionalized cyclopropanes and aziridines using the α-fluorovinyl diphenyl sulfonium salt

Article abstract of DOI:10.1039/c3cc44519d

The α-fluorovinyl diphenyl sulfonium salt 1 is attractive due to its high potential for the synthesis of mono-fluorinated cyclopropanes and aziridines as useful three-membered rings. The synthetically useful salt 1 is readily prepared from α-fluorovinyl p

Full text of DOI:10.1039/c3cc44519d

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Synthesis of mono-fluorinated functionalized
cyclopropanes and aziridines using the a-fluorovinyl
diphenyl sulfonium salt†
Cite this: Chem. Commun., 2013,
49, 7965
Received 17th June 2013,
Accepted 15th July 2013
Kensuke Hirotaki, Yui Takehiro, Ryo Kamaishi, Yasunori Yamada and
Takeshi Hanamoto*
DOI: 10.1039/c3cc44519d
www.rsc.org/chemcomm
The a-fluorovinyl diphenyl sulfonium salt 1 is attractive due to its the quarternization of 2 with diphenyliodonium triflate in the
high potential for the synthesis of mono-fluorinated cyclopropanes presence of a catalytic amount of CuCl.4 Although the reaction
and aziridines as useful three-membered rings. The synthetically occurred giving the desired salt 1, the reaction mixture turned
useful salt 1 is readily prepared from a-fluorovinyl phenyl sulfide black during the progress of quarternization. The resulting
and diphenyl iodonium salt in one step.
contaminated reaction mixtures required tedious purification
steps, which resulted in decrease of the yield. In order to avoid this
Mono-fluorinated cyclopropanes have recently drawn much unfavorable color-change, we sought to develop more preferable
attention due to their wide utility as precursors of medicinal reaction conditions. When the reaction was carried out using 2
materials.1 A large number of examples using addition reactions (0.95 equiv.) and diphenyliodonium triflate (1.0 equiv.) in the
of fluorocarbenes to olefins or carbenes to fluoroolefins are presence of Cu powder (5.0 equiv.) in dichloroethane (DCE)
reported for their preparation in the literature.2 However, the under reflux conditions for 30 min, 1 was obtained as a white
facile synthesis of such molecules using annulation reactions is solid in 67% yield after purification by silica gel column
scarce.1a,3 We considered that these molecules may be accessible chromatography.‡ Gratifyingly, the key salt 1 is free-flowing,
from appropriate active methylene compounds and the mono- shelf-stable, and easy to handle.
fluorinated vinyl sulfonium salt under mild conditions on the
basis of our recent findings about the b-(trifluoromethyl)vinyl and 2-(phenylsulfonyl)acetonitrile
With 1 in hand, we conducted the reaction between 1 (1.2 equiv.)
(1.0 equiv.) at room
4
sulfonium salt.4 To the best of our knowledge, there is no report temperature, using DBU (1.2 equiv.) in DMSO in our initial
concerning the mono-fluorinated vinyl sulfonium salt so far. research.7 The cyclization reaction cleanly proceeded to give
This report discloses the first preparation of a-fluorovinyl the desired mono-fluorinated cyclopropane derivative 5a as a
sulfonium salt 1 and its synthetic applications.
mixture of diastereomers (92 : 8) in 89% combined yield. This
Our straightforward synthesis of 1 is shown in Scheme 1. We diasteromeric mixture could not be easily separated into its
have already reported the convenient preparation of the requisite components. In order to improve both chemical yield and
a-fluorovinyl phenyl sulfide 2 from a-(fluorovinyl)methyl-diphenyl- diastereoselectivity, we further examined the reaction conditions.
silane 3.5,6 According to the reported procedure, we next examined The results are shown in Table 1. Most reaction conditions still
keep the yield within an acceptable range with high diastereo-
selectivity. From this Table 1, we determined that the reaction
conditions of entry 2 were most suitable for this cyclization
reaction.§ As far as the stereochemistry of 5a is concerned, the
final structure of the major isomer 5a was confirmed by X-ray
analysis (Fig. 1).8 It is revealed that there was a cis-relationship
between the vicinal fluoro and cyano groups.
Scheme 1 Synthesis of a-fluorovinyl sulfonium salt 1.
Having found the optimal conditions, the substrate scope of
this cyclization protocol was explored (Table 2). A wide range
of active methylene compounds having a variety of electron-
withdrawing groups participated in this reaction, giving the
corresponding mono-fluorinated cyclopropane derivatives 5 in
good to excellent yields. Substrates containing highly polar
amide or imido groups also underwent efficient cyclization
(entries 3 and 8). The product 5d (entry 4) was more volatile
Department of Chemistry and Applied Chemistry, Saga University, Honjyo-machi 1,
Saga 840-8502, Japan. E-mail: hanamoto@cc.saga-u.ac.jp; Fax: +81-952-28-8548;
Tel: +81-952-28-8704
† Electronic supplementary information (ESI) available. CCDC 943864. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc44519d
c
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scopea
Entry
1
Substrate
Productb
Yieldc,d (%)
dre
Entry
Solvent
Base
Yieldb (%)
drc
1
2
3
4
5
6
7
8
9
DMSO
MeCN
DCM
DMSO–THF = 1/1
THF
DMSO
DMSO
DMSO
AcOEt
DBU
DBU
DBU
DBU
DBU
NaH
tbuOK
89
93
76
89
91
87
39
69
89
92/8
95/5
96/4
93/7
95/5
92/8
92/8
93/7
96/4
93
98
79
95/5
d
K2CO3d
2 f
91/9
98/2
K2CO3
a
The reaction of 1 (1.2 equiv.) with 4 (1.0 equiv.) was carried out in the
b
presence of a base (1.2 equiv.) at room temperature for 30 min. Isolated
yield. Determined by H NMR. K2CO3 (3.0 equiv.) was used.
c
1
d
3
4
5
6
70
91/9
79 (86)g
83 (94)
72/28
50/50
Fig. 1 X-ray structure of compound 5a.
7
8
77 (91)
—
than other products, which led to slightly reduced yields.
Despite considerable effort (prolonged reaction time, elevated
temperature, and increased amount of the base), incomplete
reactions were observed in entries 5–7, which also resulted in
slightly decreased yields. It is noteworthy that all active methylene
compounds bearing a cyano group gave high diastereoselectivity of
the product (entries 1–4). The stereochemistry of these major
products except for 5a was tentatively assigned by analogy as shown
in Table 2 on the basis of 1H and 19F NMR data in comparison with
that of 5a. Although t-butyl acetoacetate (entry 5) containing a
ketone functionality also participated in the cyclization reaction,
a small amount of an inseparable unidentified by-product in
addition to two diastereomers of the corresponding mono-
fluorinated cyclopropanes 5e was problematic.
93
96
—
—
9
a
The reaction of 1 (1.2 equiv.) with 4 (1.0 equiv.) was carried out in the
b
presence of a base (1.2 equiv.) at room temperature for 30 min. Major
c
d
stereoisomer is shown. Isolated yield. The yield based on the
consumed starting material in parentheses. Determined by 1H or
e
19F NMR. EE = ethoxyethyl. Percent yield including a small amount
f
g
We next examined the potential of the salt 1 for the reaction
with a primary amine to produce mono-fluorinated aziridine
(Scheme 2).9 According to our previous procedure for the
synthesis 2-trifluoromethyl-N-Ts-aziridine,10 the primitive reac-
tion of 1 and p-toluenesulfonamide (TsNH2) was conducted in
the presence of NaH in THF, affording the corresponding
2-fluoro-N-Ts-aziridine 6a in 72% yield as a white solid for the
first time.¶ The free-flowing and easy-to-handle 6a should be
expected to be a versatile mono-fluorinated building block of
nitrogen-containing biologically active molecules. In addition
to TsNH2, b-phenethylamine as a primary alkyl amine was
of an unidentified product.
Scheme 2 Synthesis of 2-fluoroaziridine 6.
c
7966 Chem. Commun., 2013, 49, 7965--7967
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under argon. To this solution was added NaH (67.2% oil dispersion,
35.0 mg, 0.234 mmol) and the mixture was stirred for 15 min. To the
resulting solution was added the salt 1 (78.0 mg, 0.205 mmol). After
the reaction mixture was stirred at room temperature for 30 min, the
reaction was quenched with saturated aqueous NaHCO3 solution. After
the organic layer was separated, additional extraction with hexane/ethyl
acetate = 3/1 was repeated twice. The combined organic solution was
dried over sodium sulfate. The solution was concentrated in vacuo and
the residual oil was purified by silica gel chromatography (hexane/ethyl
acetate = 3/1) to give the desired product 6a as a white solid (29.8 mg,
72%): Mp: 56.9–57.5 1C; 1H NMR (CDCl3, 400 MHz) d 7.86 (d, J = 8.1 Hz,
2H), 7.38 (d, J = 8.1 Hz, 2H), 5.40 (ddd, J = 72.2, 2.4, 2.2 Hz, 1H),
2.80–2.75 (m, 1H), 2.71–2.68 (m, 1H), 2.45 (s, 3H); 13C NMR (CDCl3, 101
MHz) d 145.3, 134.3, 129.9, 127.9, 76.7 (d, J = 255.3 Hz), 34.0 (d, J =
13.3 Hz), 21.6; 19F NMR (CDCl3, 376 MHz) d À178.3 (d, J = 72.2 Hz) ppm;
GC-MS m/z 215 (M+, 2), 184 (66), 155 (91), 139 (2), 107 (2), 91 (100),
77 (3), 65 (23); IR (KBr) 3077, 1595, 1448, 1381, 1324, 1254, 1168, 1124,
1095, 1061, 974, 882, 812, 731, 674, 573 cmÀ1; anal. calcd for C9H10FNO2S:
C, 50.22; H, 4.68; N, 6.51; found: C, 50.39; H, 4.73; N, 6.50%.
employed for this aziridination reaction. The preliminary reaction
of 1 and b-phenethylamine was carried out in the presence of
t-BuNH2 in DMSO at room temperature, giving the corresponding
2-trifluoromethyl-N-b-phenethyl-aziridine 6b9a in 48% yield.
In summary, we have successfully developed a new mono-
fluorinated vinyl sulfonium salt 1 in one step. We demonstrated
its high performance for the synthesis of mono-fluorinated
cyclopropanes and aziridines under mild conditions. Further
studies on the application of mono-fluorinated cyclopropanes
and aziridines are currently being performed in our laboratory.
Notes and references
‡ Preparation of 1: a 25 mL two-necked flask equipped with a magnetic
stir bar, a stopcock and a three-way stopcock was charged with
a-fluorovinyl phenyl sulfide (82.0 mg, 0.532 mmol) in 1 mL of
1,2-dichloroethane (CH2ClCH2Cl) under argon. To this solution was
added diphenyliodonium triflate (212.0 mg, 0.506 mmol, 0.95 equiv.)
and Cu powder (174.0 mg, 2.67 mmol, 5 equiv.). The reaction mixture
was refluxed for 30 min. After cooling to room temperature, the mixture
was directly purified by silica gel chromatography (CH2Cl2 then CH2Cl2/
acetone = 10/1–2/1) to give the desired product 1 as a white solid
(129.0 mg, 67%): Mp: 71.0–72.0 1C; 1H NMR (CDCl3, 400 MHz) d 7.91
(d, J = 8.0 Hz, 4H), 7.83 (t, J = 7.3 Hz, 2H), 7.76–7.71 (m, 4H), 6.60 (dd,
J = 42.7, 6.0 Hz, 1H), 6.14 (dd, J = 10.9, 6.0 Hz, 1H); 13C NMR (CDCl3,
101 MHz) d 146.0 (d, J = 315.3 Hz), 135.2, 131.6, 130.8, 121.2, 120.5
(q, J = 320.7 Hz), 114.9 (d, J = 7.8 Hz); 19F NMR (CDCl3, 376 MHz)
d À79.6 (s, 3F) À104.7 (dd, J = 42.7, 10.9 Hz, 1F) ppm; IR (KBr) 3128,
3047, 2996, 1645, 1579, 1478, 1452, 1265, 1143, 1028, 944, 749, 683, 637,
572, 548, 517, 486 cmÀ1; anal. calcd for C15H12F4O3S2: C, 47.36, H, 3.18;
found: C, 47.34, H, 3.14%.
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§ Typical procedure: a 25 mL two-necked flask equipped with a
magnetic stir bar, a stopcock and a three-way stopcock was charged
with phenylsulfonylacetonitrile 4a (39.9 mg, 0.22 mmol) and DBU
(39 mL, 0.261 mmol) in acetonitrile (1 mL) under argon. After stirring
for 5 min, to this solution was added the salt 1 (99.4 mg, 0.261 mmol).
The reaction mixture was stirred at room temperature for 30 min. The
reaction was quenched with a saturated aqueous NH4Cl solution and
extracted with hexane/ethyl acetate = 1/1. The extraction was repeated
twice. The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate = 5/1–1/1) to
give the desired product 5a as a white solid (46.0 mg, 93%): dr: 95/5;
Mp: 99.5–110.1 1C; 1H NMR (CDCl3, 400 MHz) d 7.99 (d, J = 7.2 Hz, 2H),
7.81 (t, J = 7.2 Hz, 1H), 7.68 (t, J = 7.2 Hz, 2H), 5.26 (dt, J = 60.8, 5.5 Hz,
1H), 2.39–2.20 (m, 2H); 13C NMR (CDCl3, 101 MHz) d 136.2, 135.5,
129.9, 128.8, 111.9 (d, J = 3.9 Hz), 72.8 (d, J = 248.3 Hz), 37.0 (d, J =
10.1 Hz), 21.5 (d, J = 9.4 Hz); 19F NMR (CDCl3, 376 MHz) d À207.2 (ddd,
J = 60.8, 19.1, 13.2 Hz); GC-MS m/z 225 (M+, 53), 160 (4), 141 (26), 125
(18), 109 (4), 97 (4), 77 (100), 73 (9), 65 (2), 51 (25); IR (ATR, Attenuated
Total Reflectance) 3111, 3021, 2245, 1583, 1450, 1422, 1327, 1306, 1180,
1155, 856, 723, 684 cmÀ1; anal. calcd for C10H8FNO2S: C, 53.32; H, 3.58;
N, 6.22. Found: C, 53.36; H, 3.38; N, 6.21%.
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8 CCDC 943864 (5a)†.
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¶ Preparation of 6a: a 25 mL two-necked flask equipped with a
magnetic stir bar, a stopcock and a three-way stopcock was charged 10 R. Maeda, K. Ooyama, R. Anno, M. Shiosaki, T. Azema and
with p-toluenesulfonamide (33.0 mg, 0.193 mmol) in 1 mL of THF
T. Hanamoto, Org. Lett., 2010, 12, 2548.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7965--7967 7967