Facile Preparation of β-Fluoro Amines by the Reaction of Aziridines with Potassium Fluoride Dihydrate in the Presence of Bu4NHSO 4

Article abstract of DOI:10.1021/jo034895k

Potassium fluoride combined with tetrabutylammonium bisulfate is an efficient reagent to convert a variety of aziridines derived from cyclic and acyclic alkenes to β-fluoro amine derivatives in high yield.

Full text of DOI:10.1021/jo034895k

F a cile P r ep a r a tion of â-F lu or o Am in es by th e Rea ction of
Azir id in es w ith P ota ssiu m F lu or id e Dih yd r a te in th e P r esen ce of
4 4
Bu NHSO
Ren-Hua Fan, Yong-Gui Zhou, Wan-Xuan Zhang, Xue-Long Hou,* and Li-Xin Dai‡
†
‡,§
‡
,†,‡
State Key Laboratory of Organometallic Chemistry and Shanghai-Hong Kong J oint Laboratory in
Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
54 Fenglin Road, Shanghai 200032, China
xlhou@mail.sioc.ac.cn
Received J une 25, 2003
Potassium fluoride combined with tetrabutylammonium bisulfate is an efficient reagent to convert
a variety of aziridines derived from cyclic and acyclic alkenes to â-fluoro amine derivatives in high
yield.
7
In tr od u ction
fluoride, hydrogen fluoride-pyridine (Olah’s reagent),
8
and diethylaminosulfur trifluoride (DAST). However, all
of these reagents have suffered from the fact that they
are highly toxic and corrosive to glass, so some special
care was needed. In addition, the acidity of Olah’s reagent
would cause the rearrangement of some aziridines. On
the other hand, alkali metal fluorides, as well as their
Organic compounds with low fluorine content have
received much interest because of their physiological
1
properties. Among them, â-fluoro amines exhibit biologi-
2
cal activity on the central nervous system. Although
9
many procedures have been developed to introduce
fluorine atom into organic molecules,3 reports on the
1
0
modifications, such as KF/18-crown-6, polymer-sup-
preparation of such â-fluoro amines is rare because of
ported fluoride,11 “spray-dried” KF, calcium fluoride
12
the reactivity of most fluorinating reagents toward the
1
3
14
4
4 2 3
supported on alkali metal fluoride, and Bu NH F ,
amino group. Since functionalized aziridines are now
5
have also been applied as fluorination reagents, but none
of them was reported to be used in the ring-opening
reaction of aziridines. In the course of our studies on the
easily accessible, the ring-opening reaction of them with
fluoride should be the most convenient route to â-fluoro
6
amines. Indeed, some reports appeared using hydrogen
synthesis and transformations of aziridines,1
5b,16
â-fluoro
*
Corresponding author.
Shanghai-Hong Kong J oint Laboratory in Chemical Synthesis,
amine derivative was detected from the reaction of
aziridines with allyltrimethylsilane in the presence of
tetrabutylammonium fluoride (TBAF). Further studies
showed that potassium fluoride dihydrate (KF‚2H O)
2
combined with tetrabutylammonium bisulfate is a more
efficient reagent for the ring-opening reaction of aziri-
†
Shanghai Institute of Organic Chemistry.
‡
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry.
§
Permanent address: Dalian Institute of Chemical Physics, Chinese
17
Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116230,
P. R. China.
(1) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320. (b)
Filler, R. In Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R., Ed.; Studies in Organic Chemistry
(6) (a) Wade, T. N.; Guedj, R. Tetrahedron Lett. 1978, 3247. (b)
Alvernhe, G. M.; Lacombe, S. M.; Laurent, A. J . Tetrahedron Lett. 1980,
21, 289. (c) Wade, T. N. J . Org. Chem. 1980, 45, 5328. (d) Alvernhe,
G. M.; Laurent, A. J .; Haufe, G. J . Fluorine Chem. 1986, 34, 147. (e)
Girault, Y.; Rouillard, M.; Decouzon, M.; Geribaldi, S. J . Fluorine
Chem. 1990, 49, 231.
(7) (a) Olah, G. A.; Nojima, M.; Kereskes, I. Synthesis 1973, 779.
(b) Olah, G. A.; Welch, J . T.; Vankar, Y. D.; Nojima, M.; Kereskes, I.;
Olah, J . A. J . Org. Chem. 1979, 44, 3872. (c) Alvernhe, G.; Laurent,
A.; Haufe, G. J . Fluorine Chem. 1986, 34, 147. (d) Girault, Y.; Geribaldi,
S.; Rouillard, M.; Azzaro, M. Tetrahedron 1987, 43, 2485.
(8) Berts, W.; Luthman, K. Tetrahedron 1999, 55, 13819.
(9) Alvernhe, G. M.; Ennakoua, C. M.; Lacombe, S. M.; Laurent, A.
J . J . Org. Chem. 1981, 46, 4938.
4
1
8; Elsevier: New York, 1993. (c) Percy, J . M. Contemp. Org. Synth.
995, 251.
(
2) (a) Molloy, B. B.; Fuller, R. w.; Hauser, K. L. U.S. Patent Appl.
1
62621; Chem. Abstr. 1973, 78, 110850. (b) Fuller, R. W.; Molloy, B.
B. Biochemistry Involving Carbon-Fluorine Bond; American Chemical
Society: Washington D.C., 1976. (c) Kollonitsch, J . Isr. J . Chem. 1978,
1
3
7, 53. (d) Alvernhe, G.; Laurent, A.; Haufe, G. J . Fluorine Chem. 1986,
4, 147. (e) Hamman, S.; Beguin, C. G.; Charlon, C.; Luu-Duc, C. J .
Fluorine Chem. 1987, 37, 343. (f) Toulgui, C.; Chaabouni, M. M.;
Baklouti, A. J . Fluorine Chem. 1990, 46, 385.
(3) (a) Gerstenberger, M. R. C.; Haas, A. Angew. Chem., Int. Ed.
Engl. 1981, 20, 647. (b) Mascaretti, O. A. Aldrichim. Acta 1993, 26,
4
7.
(
4) (a) Boswell, C. A., J r., Ripka, W. C.; Scribner, R. M. Org. React.
974, 21, 1. (b) Sharts, C. M.; Shoppard, W. A. Ibid. 1974, 21, 125.
5) For some reviews of syntheses and reactions of activated and
(10) Liotta, C. L.; Harris, H. P. J . Am. Chem. Soc. 1974, 96, 2250.
(11) Colonna, S.; Re, A.; Gelbard, G.; Cesarotti, E. J . Chem. Soc.,
Perkin Trans. 1 1979, 2248.
1
(
unactivated aziridines, see: (a) Padwa, A.; Woolhouse, A. D. In
Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.; Pergamon:
Oxford, 1984; Vol. 7. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994,
(12) Ishikawa, N.; Kitazume, T.; Yamazaki, T.; Mochida, Y.; Tat-
sumo, T. Chem. Lett. 1981, 761.
(13) (a) Clack, J . H.; Hyde, A. J .; Smith, D. K. J . Chem. Soc., Chem.
Commun. 1986, 791. (b) Ichihara, J .; Matsuo, T.; Hanafusa, T.; Ando,
T. J . Chem. Soc., Chem. Commun. 1986, 793.
3
3, 599. (c) Padwa, A.; Pearson, W. H.; Lian, B. W.; Bergmeier, S. C.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: New York, 1996; Vol. 1A.
(14) Landini, D.; Penso, M. Tetrahedron Lett. 1990, 31, 7209.
(15) (a) Wang, D. K.; Zhou, Y. G.; Tang, Y.; Hou, X. L.; Dai, L. X. J .
Org. Chem. 1999, 64, 4233. (b) Wu, J .; Hou, X. L.; Dai, L. X. J . Org.
Chem. 2000, 65, 1344;
(
(
d) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341.
e) Ibuka, T. Chem. Soc. Rev. 1998, 27, 145. (f) Aggarwal, V. K. Synlett
1
998, 329. (g) Stamm, H. J . Prakt. Chem. 1999, 319.
1
0.1021/jo034895k CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003
J . Org. Chem. 2004, 69, 335-338
335

Fan et al.
SCHEME 1
in high yields, but no reaction occurred when the non-
activated aziridines 1g and 1h were the starting mater-
ial.
Our previous studies on the mechanism of the reactions
of aziridines with trimethylsilyl compounds triggered by
+
TABLE 1. Rin g Op en in g of Azir id in e w ith TBAF a
TBAF showed that tetrabutylammonium cation (Bu
4
N )
played an important role in the reactions.1 Thus, several
5b
tetrabutylammonium salts (Bu
4
NX, X ) Cl, Br, and I)
were added into the reaction of aziridine 1a with KF, but
-
the X attacked products were obtained. These results
suggested that the selection of counterion of quaternary
ammonium salt with less nucleophilicity is important in
order to avoid the formation of undesired products. Thus,
1
8
Bu
In the presence of 100 mol % of Bu
reaction of aziridine 1a with KF‚2H O in THF provided
product 2a in 64% yield. The optimization of the reaction
conditions showed that CH CN is the best solvent, in
which the yield increased to 96%, but no product was
detected if anhydrous KF and Bu NHSO in CH CN were
used as reagent. With the decrease of the amount of Bu
NHSO to 10 mol %, the yield of product was also dropped
to 8%. However, when 1 equiv of Bu NNO was used, only
3% yield was obtained under the same reaction condi-
tions. No reaction occurred in the presence of 1 equiv of
NaHSO , but the reaction proceeded slowly to provide
4
NHSO
4
(TBAHS) and Bu
4
NNO
3
were chosen.
4
NHSO
4
, the
2
3
4
4
3
4
-
4
4
3
2
4
4 3
product 2a in 56% yield if 1 equiv of Bu NNO was added
into the above reaction mixture.
Table 2 illustrates that the ring-opening reactions of
activated and nonactivated aziridines derived from a
a
All reactions were conducted in THF at 45 °C under Ar.
b
Isolated yield.
variety of kind of cyclic alkenes with KF‚2H
2
O in the
presence of Bu NHSO to provide the corresponding
4
4
dines to give rise to â-fluoro amine derivatives. In this
paper, we present an efficient method for the synthesis
of â-fluoro amines under mild conditions from the ring-
â-fluoro amines in moderate to high yields. The substitu-
ent on nitrogen atom of aziridines can be Ts, Bz, Bs, Ph,
and Bn. In the case of aziridine 1f (entry 6, Table 2), only
one product was obtained. To the reaction of N-benzoyl-
aziridine 1c, no corresponding rearrangement product
oxazolidones, which would be formed using Olah’s re-
agent, were detected (entry 3, Table 2).9
opening reactions of aziridines with KF‚2H
presence of Bu NHSO
2
O in the
4
4
.
Resu lts a n d Discu ssion
In our previous work,15 Bu
NF (TBAF) was found as a
4
It is unexpected that the reactions of aziridines derived
from acyclic alkenes 1i and 1j were very complex under
the same conditions (entries 9 and 10, Table 2), and no
corresponding â-fluoro amines could be separated from
the mixtures. Some isolated compounds showed the
presence of the skeleton of aziridine and fluorine atom,
good trigger for the reactions of imines or aziridines with
trimethylsilyl compounds. However, when we tried the
reaction of aziridine 1a with allyltrimethylsilane in the
presence of 10 mol % Bu NF in THF, no expected
4
allylation product was obtained; instead, an unexpected
â-fluoro amine 2a was isolated in 9% yield. When the
4
amount of Bu NF was increased to 120 mol %, 99% yield
of 2a was provided (Scheme 1).
To show the capacity of TBAF and the scope of the
reaction, many different types of aziridines were exam-
ined, and the results are shown in Table 1. It can be seen
that the reactions proceeded with activated aziridines
1
but their H NMR spectra were too complex to determine
their structure. The reaction also failed to provide
â-fluoro amine using some other fluoride sources, for
example, Bu NF, CsF, LiF, and NaF, in different sol-
4
vents, such as DMF, DMSO, EtOAc, and t-BuOH.
It is interesting, however, that the addition of water
as cosolvent made the fluorination reaction of aziridine
1
a -f to give rise to the corresponding â-fluoro amines
1
i proceed smoothly. Whereas the reactions were very
complex in pure CH CN, this reaction occurred at 50 °C
3
(16) (a) Li, A. H.; Dai, L. X.; Hou, X. L.; Chen, M. B. J . Org. Chem.
with the addition of 33% (v/v) water to the mixture, and
â-fluoro amines 2i and 3i were formed in 36% yield with
the hydrolysis product as byproduct in 60% yield. Further
experiments showed that the amount of water was vital
1
996, 61, 4641. (b) Li, A. H.; Zhou, Y. G.; Dai, L. X.; Hou, X. L.; Xia, L.
J .; Lin, L. Angew. Chem., Int. Ed. Engl. 1997, 36, 1317. (c) Hou, X. L.;
Wu, J .; Dai, L.-X. Chinese J . Chem. 1998, 16, 557. (d) Zhou, Y. G.;
Hou, X. L.; Dai, L. X.; Xia, L. J .; Tang, M. H. J . Chem. Soc., Perkin
Trans. 1 1999, 77. (e) Li, B. F.; Zhang, M. J .; Hou, X. L.; Dai, L. X. J .
Org. Chem. 2002, 67, 2902. (f) Yang, X. F.; Zhang, M. J .; Hou, X. L.;
Dai, L. X. J . Org. Chem. 2002, 67, 8097. (g) Hou, X. L.; Fan, R. H.;
Dai, L. X. J . Org. Chem. 2002, 67, 5295. (h) Fan, R. H.; Hou, X. L. J .
Org. Chem. 2003, 68, 726. (i) Fan, R. H.; Hou X. L. Tetrahedron Lett.
(18) (a) J effery, T. Tetrahedron Lett. 1990, 31, 6641. (b) D ´ı az-Ortiz,
A.; S a´ nchez-Verd u´ , P.; D ´ı ez-Barra, E.; Loupy, A.; de la Hoz, A.; Moreno,
A Synth. Commun. 1993, 23, 875. (c) Gregorio, C. V. Anal. Biochem.
2001, 290, 376.
2
003, 44, 4411.
17) Fan, R. H.; Hou, X. L. Org. Biomol. Chem. 2003, 1, 1565.
(
3
36 J . Org. Chem., Vol. 69, No. 2, 2004

Facile Preparation of â-Fluoro Amines
opening pathways for this type of aziridine.19 However,
for the alkyl-substituted aziridine 1j, two products 2j and
TABLE 2. Rin g Op en in g of Azir id in es w ith KF ‚2H2O in
th e P r esen ce of Bu 4NHSO4
3
j were formed in a ratio of 14:86, resulting from fluoride
attack at the less substituted carbon atom of the aziri-
dine.
The 19F NMR gave the signal at -148 ppm for KF‚
2
H
2
O/TBAHSO
ppm for KF‚2H
O in CH CN/H
ppm. These data are close to that for Bu
NH , and Bu NF, which gave the signal at -145, -160,
and -120 ppm, respctively. Landini reported the syn-
thesis of Bu NF, Bu NHF , and Bu NH using Bu
NHSO and KF and a stoichiometric amount of KHF or
excess KH
, respectively,20 and the ring-opening reac-
tion of epoxides with Bu
4
in CH
O/TBAHSO
O (v/v ) 3:1) gave the signal at -120
NHF , Bu
3
CN/H
2
O (v/v ) 3:1) and -156
2
4
in CH CN, whereas KF‚
3
2
H
2
3
2
4
2
4
-
2
F
3
4
2
0
4
4
2
4
2
F
3
4
-
4
2
2
F
3
1
4
4
2 3
NH F . However, only 30% and
4
5
2% yield of ring opening product 2a as well as 68% and
5% recovery of starting material 1a were provided when
the reaction proceeded in CH
NHF and Bu NH as reagent, respectively. Also, only
a trace of fluorinated product was detected if aziridine
e reacted with Bu NHF or Bu NH under the same
conditions. Even the reaction of aziridine 1j with Bu
NHF in CH CN/H O with a ratio of 3:1 as solvent gave
only 12% yield of 2j and 3j as well as 4% yield of
hydrolysis product and 78% recovery of 1j; if Bu NH
was used under the same conditions, a trace of products
3 4
CN at 45 °C using Bu -
2
4
2 3
F
1
4
2
4
2 3
F
4
-
2
3
2
4
2 3
F
-
was detected. Thus, the role of HSO
clear at moment.
4
and water is not
In conclusion, a facile and convenient approach to
formation of the â-fluoro amines via ring-opening reac-
tions of aziridines using KF‚2H
2 4
O in the presence of Bu -
NHSO under neutral conditions was devised. It is a mild,
4
economic, and environmentally benign process. Further
investigations of the reaction mechanism as well as the
reactions using other kinds of substrates are in progress.
a
b
Exp er im en ta l Section
Ts ) p-CH3C6H4SO2, Bs ) C6H5SO2, Bz ) C6H5CO;
Condition A ) 100 mol % Bu4NHSO4, 200 mol % KF‚2H2O,
CH3CN, 45 °C. Condition B ) 200 mol % Bu4NHSO4, 400 mol %
Gen er a l Exp er im en ta l Con d ition s. The commercially
c
d
available reagents were used as received without further
KF‚2H2O, CH3CN/H2O (v/v) ) 3:1, 30 °C. Isolated yield. Ratios
2
1
1
1
purification. Melting points are uncorrected. H NMR and
of the two regioisomers was determined by 300 MHz H NMR.
1
9
e
F NMR spectra were recorded on 300 and 282 MHz spec-
trometers, and the chemical shifts were referenced to tetra-
methylsilane, CF COOH, and CFCl in CDCl . IR spectra were
No other regioisomer was detected.
3
-
3
3
1
to the reaction. When the ratio of H
decreased to 1:6, the reaction was as complex as that in
CH CN. When the ratio increased to 1:2, only hydrolysis
2
O to CH
3
CN
measured in cm
Gen er a l P r oced u r e for Rin g-Op en in g Rea ction s of
Azir id in es 1 w ith Bu NF . To a stirred solution of aziridine
(0.5 mmol) in THF (2.0 mL) was added Bu NF (1 M in THF,
.
4
3
1
0
4
4
product was obtained. The reaction proceeded more
slowly at 35 °C, but â-fluoro amines became the major
products in 45% yield after 7 days. With the use of 2 equiv
.6 mL, 0.6 mmol), and the resulting mixture was stirred at
5 °C until complete consumption of the substrate (monitored
by TLC). The solvent was removed in a vacuum, and the crude
product was purified by flash column chromatography to
provide the corresponding product.
of Bu
4
NHSO
4
2
and 4 equiv of KF‚2H O, the yield of
â-fluoro amines increased to 65% at 35 °C after 7 days.
Under a lower temperature (30 °C) and a longer reaction
time (10 days), 78% yields of â-fluoro amines were
obtained.
Gen er a l P r oced u r e for Rin g-Op en in g Rea ction s of
Azir id in es 1 w ith KF ‚2H
P r oced u r e A. To a stirred solution of aziridine 1 (0.5 mmol)
and KF‚2H O (94 mg, 1 mmol) in CH CN (2.0 mL) was added
Bu NHSO (170 mg, 0.5 mmol), and the resulting mixture was
stirred at 45 °C until complete consumption of the substrate
2 4 4
O in th e P r esen ce of Bu NHSO .
2
3
Under the optimized conditions (condition B) in Table
4
4
2
, the reactions of aziridines 1i and 1j derived from the
acyclic terminal alkenes proceeded smoothly to afford the
corresponding â-fluoro amines in good yields with mini-
mal byproducts. The phenyl-substituted aziridine 1i led
to the formation of two regioisomers, incorporating the
fluoride at the phenyl-substituted carbon as the major
product, which reflected the expected competition of
(
19) (a) Bellos, K.; Stamm, H. J . Org. Chem. 1995, 60, 5661. (b)
Takano, S.; Yanase, M.; Ogasawara, K. Heterocycles 1989, 29, 249.
20) Landini, D.; Molinari, H.; Penso, M.; Rampoldi, A. Synthesis
1988, 953.
21) Bu
(
(
4 4 4
NF in THF solution was purchased from Aldrich, Bu NHSO
(
2
>98%) was purchased from TCI, and KF‚2H O (>99%) was purchased
from The Third Factory, Shanghai Chemical Reagent Co. Ltd., China.
J . Org. Chem, Vol. 69, No. 2, 2004 337

Fan et al.
(
monitored by TLC). The solvent was removed in a vacuum,
(m, 3H), 0.90 (s, 3H), 0.99 (s, 3H), 1.02-1.22 (m, 1H), 1.28 (d,
3
and the crude product was purified by flash column chroma-
tography to provide the corresponding product.
J F-H ) 7.5 Hz, 3H), 1.86-1.91 (m, 1H), 2.07-2.22 (m, 1H),
3.42-3.57 (m, 1H), 4.52 (d, J ) 9.0 Hz, 1H), 7.32 (d, J ) 8.1
1
9
P r oced u r e B. To a stirred solution of aziridine 1 (0.5 mmol)
3
Hz, 2H), 7.79 (d, J ) 8.4 Hz, 2H); F NMR (282 MHz, CDCl ,
and KF‚2H
added Bu NHSO
the corresponding temperature until complete consumption of
substrate (monitored by TLC). The mixture was extracted CH
Cl
2
O in the mixture of organic solvent with water was
25 °C, CF
3
COOH) δ -128.1 (m); IR (film) ν˜ ) 3260, 3017, 1598,
-1
+
4
4
, and the resulting mixture was stirred at
1463 cm ; EI-MS m/z 326 (MH , 2.3), 306 (32), 91 (100). Anal.
2
Calcd for C17H24FNO S: C, 62.74; H, 7.43; N, 4.30. Found: C,
62.96; H, 7.41; N, 4.15.
(2-F lu or ocycloh exyl)p h en yla m in e (2g): 61% yield; liq-
2
-
2
(2 × 5 mL), and then the solvent was removed in a vacuum
1
and the crude product was purified by flash column chroma-
tography to provide the corresponding product.
uid; H NMR (300 MHz, CDCl , 25 °C, TMS) δ 1.21-1.56 (m,
3
3H), 1.60-1.73 (m, 2H), 1.81-1.86 (m, 1H), 2.10-2.25 (m, 2H),
2
N -(2-F lu o r o c y c lo h e x y l)-4-m e t h y lb e n ze n e s u lfo n a -
3.35-3.48 (m, 1H), 3.64-3.75 (m, 1H), 4.37 (dddd, J
H-F
) 50.1
1
m id e (2a ): 96% yield; solid; mp 95-97 °C; H NMR (300 MHz,
CDCl
1
Hz, J
) 9.9, 9.0, 4.5 Hz, 1H), 6.67-6.74 (m, 3H), 7.15-
H-H
19
3
, 25 °C, TMS) δ 1.05-1.25 (m, 4H), 1.26-1.44 (m, 1H),
7.28 (m, 2H); F NMR (282 MHz, CDCl , 25 °C, CF COOH) δ
3
3
2
.45-1.62 (m, 1H), 1.87-2.08 (m, 2H), 2.38 (s, 3H), 3.02-3.21
-178.4 (double multiplet, J
H-F
= 52.1 Hz); IR (film) ν˜ ) 3421,
2
-1
+
(
5
7
m, 1H), 4.06 and 4.23 (double multiplet, J H-F ) 50.1 Hz, 1H),
1603, 1511 cm ; EI-MS m/z 193 (M , 57), 132 (100). Anal.
.03 (d, J ) 6.1 Hz, 1H), 7.22 (d, J ) 8.6 Hz, 2H). 7.71 (d, J )
Calcd for C H FNO S: C, 74.58; H, 8.74; N, 7.25. Found: C,
1
4
19
2
1
9
.9 Hz, 2H); F NMR (282 MHz, CDCl
3
, 25 °C, CF
3
COOH) δ
74.88; H, 8.98; N, 7.03.
Ben zyl(2-flu or ocycloh exyl)a m in e (2h ): 75% yield; liq-
2
-
178.8 (double multiplet, J H-F = 50.2 Hz); IR (film) ν˜ ) 3304,
951, 1598, 1496 cm-1; EI-MS m/z 271 (M , 37), 210 (100),
+
2
1
5
1
uid; H NMR (300 MHz, CDCl
3
, 25 °C, TMS) δ 1.05-1.42 (m,
55 (67). Anal. Calcd for C13 S: C, 57.54; H, 6.69; N,
H17FNO
2
3
2
1
J
H), 1.44-1.55 (m, 1H), 1.63-1.70 (m, 1H), 1.72-1.78 (m, 1H),
.16. Found: C, 57.49; H, 6.73; N, 4.96.
.00-2.12 (m, 2H), 2.62-2,74 (m, 1H), 3.77 (d, J ) 13.2 Hz,
N-(2-F lu or ocycloh exyl)ben zen esu lfon a m id e (2b): 95%
2
H), 3.90 (d, J ) 12.9 Hz, 1H), 4.34 (dddd, J H-F ) 50.4 Hz,
1
yield; solid; mp 105-107 °C; H NMR (300 MHz, CDCl
°
3
, 25
19
H-H ) 11.1, 9.0, 4.8 Hz, 1H), 7.21-7.34 (m, 5H); F NMR
C, TMS) δ 1.13-1.29 (m, 4H), 1.32-1.52 (m, 1H), 1.71-1.76
(
282 MHz, CDCl
3
, 25 °C, CF
3
COOH) δ -179.0 (double mul-
(
m, 1H), 2.04-2.15 (m, 2H), 3.20-3.28 (m, 1H), 4.21 (dddd,
2
-1
tiplet, J H-F = 51.0 Hz); IR (film) ν˜ ) 3331, 1604, 1496 cm
;
2
3
J
H-F ) 50.1 Hz, J H-H ) 9.9, 9.0, 4.5 Hz, 1H), 4.90 (d, J ) 5.7
+
EI-MS m/z 207 (M , 25), 146 (55), 91 (100). Anal. Calcd for
S: C, 75.33; H, 8.95; N, 6.88. Found: C, 75.12; H,
1
9
Hz, 1H), 7.51-7.60 (m, 3H), 7.90-7.93 (m, 2H); F NMR (282
14 2
C H19FNO
2
MHz, CDCl
IR (film) ν˜ ) 3262, 2943, 1459, 1329 cm ; EI-MS m/z 257 (M ,
6). Anal. Calcd for C12 S: C, 56.01; H, 6.27; N, 5.44.
3 3
, 25 °C, CF COOH) δ -178.5 (d, J H-F ) 49.1 Hz);
9
.19; N, 7.12.
-1
+
N-(2-F lu or o-2-p h en yleth yl)-4-m eth ylben zen esu lfon a -
3
H15FNO
2
m id e (2i) a n d N-(2-F lu or o-1-p h en yleth yl)-4-m eth ylben -
Found: C, 56.07; H, 6.44; N, 5.31.
1
zen esu lfon a m id e (3i): 78% yield (2i/3i ) 82:18); liquid; H
N-(2-F lu or ocycloh exyl)ben za m id e (2c): 91% yield; solid;
NMR (300 MHz, CDCl
3
, 25 °C, TMS) δ 2.35 (s, 3H, 3i), 2.38
1
mp 154-156 °C; H NMR (300 MHz, CDCl
3
, 25 °C, TMS) δ
(
s, 3H, 2i), 3.21-3.51 (m, 2H, 2i), 4.41-4.45 (m, 1H, 3i), 4.55-
1
4
9
2
(
1
.20-1.50 (m, 2H), 1.52-1.91 (m, 4H), 2.13-2.34 (m, 2H),
4
1
2
2
.63 (m, 2H, 3i), 4.82-4.87 (m, 1H, 2i), 5.17 (d, J ) 6.0 Hz,
2
3
.09-4.16 (m, 1H), 4.40 (ddt, J H-F ) 50.1 Hz, J H-H ) 4.8,
.6 Hz, 1H), 6.16 (br, 1H), 7.41-7.75 (m, 3H), 7.76-7.79 (m,
2
H, 3i), 5.48 (ddd, J F-H ) 48.3 Hz, J H-H ) 8.4, 3.6 Hz, 1H,
i), 7.11-7.40 (m, 7H), 7.58-7.61 (m, 2H, 3i), 7.70-7.80 (m,
1
9
H); F NMR (282 MHz, CDCl
3
, 25 °C, CF
3
COOH) δ -179.0
19
3 3
H, 2i); F NMR (282 MHz, CDCl , 25 °C, CF COOH) δ
2
double multiplet, J H-F = 52.1 Hz); IR (film) ν˜ ) 3309, 3032,
632, 1537 cm ; EI-MS m/z 221 (M , 0.26), 201 (40), 105 (100).
16FNO: C, 70.56; H, 7.29; N, 6.33.
2
-
183.2 (double multiplet, J H-F = 48.5 Hz, 2i), -223.5 (m, 3i);
-1
+
-1
+
IR (film) ν˜ ) 3303, 1599, 1328 cm ; EI-MS m/z 294 (MH , 1),
Anal. Calcd for C13
Found: C, 70.47; H, 7.27; N, 6.16.
H
+
2
3
93 (M , 1), 260 (38), 155 (100). Anal. Calcd for C19H23NSO :
C, 61.41; H, 5.50; N, 4.77. Found: C, 61.23; H, 5.46; N, 4.51.
N-(1-F lu or om et h ylp en t yl)-4-m et h ylb en zen esu lfon a -
m ide (2j) an d N-(2-Flu or oh exyl)-4-m eth ylben zen esu lfon a-
N -(2-F lu or ocyclop e n t yl)-4-m e t h ylb e n ze n e su lfon a -
1
m id e (2d ): 85% yield; solid; mp 75-77 °C; H NMR (300 MHz,
CDCl
2
and 4.96 (double multiplet, J H-F ) 51.9 Hz, 1H), 7.32 (d, J )
7
CDCl
5
3
, 25 °C, TMS) δ 1.35-1.42 (m, 1H), 1.61-2.09 (m, 5H),
1
m id e (3j): 74% yield (2j/3j ) 14:86); liquid; H NMR (300
.41 (s, 3H), 3.56-3.68 (m, 1H), 4.71 (d, J ) 6.1 Hz, 1H), 4.78
MHz, CDCl
3
, 25 °C, TMS) δ ) 0.80 (t, J ) 6.9 Hz, 3H, 3j),
2
0
2
)
4
.89 (t, J ) 7.2 Hz, 3H, 2j), 1.14-1.32 (m, 6H), 2.44 (s, 3H),
1
9
.5 Hz, 2H), 7.78 (d, J ) 7.6 Hz, 2H); F NMR (282 MHz,
2
.98-3.35 (m, 2H, 2j), 3.41-3.50 (m, 1H, 3j), 4.28 (ddd, J F-H
46.8 Hz, J H-H ) 9.6, 3.6 Hz, 2H, 3j), 4.50-4.85 (m, 1H, 2j),
.71 (d, J ) 8.5 Hz, 1H, 3j), 4.75-4.79 (m, 1H, 2j), 7.32 (d, J
2
3 3
, 25 °C, CF COOH) δ -175.9 (double multiplet, J H-F =
-
1
6.6 Hz); IR (film) ν˜ ) 3265, 3029, 1597, 1326 cm ; EI-MS
+
m/z 257 (M , 21), 210 (52), 155 (51), 91 (100). Anal. Calcd for
S: C, 56.01; H, 6.27; N, 5.44. Found: C, 56.11; H,
19
)
8.0 Hz, 2H), 7.78 (d, J ) 8.0 Hz, 2H); F NMR (282 MHz,
CDCl , 25 °C, CF COOH) δ -186.3 (m, 2j), -230.5 (m, 3j); IR
film) ν˜ ) 3279, 1599, 1496 cm ; EI-MS m/z 273 (M , 1), 240
73), 91 (100). Anal. Calcd for C19 : C, 57.12; H, 7.37;
12 2
C H15FNO
3
3
6
.24; N, 5.35.
-1
+
(
(
N -(2-F lu or ocycloh e p t yl)-4-m e t h ylb e n ze n e su lfon a -
H
23NSO
3
1
m id e (2e): 85% yield; solid; mp 64-66 °C; H NMR (300 MHz,
CDCl
N, 5.12. Found: C, 57.33; H, 7.53; N, 4.88.
3
, 25 °C, TMS) δ 1.35-1.71 (m, 7H), 1.73-1.98 (m, 3H),
2
2
.42 (s, 3H), 3.31-3.38 (m, 1H), 4.32 (ddt, J H-F ) 47.8 Hz,
3
Ack n ow led gm en t. This research was financially
supported by the National Natural Science Foundation
of China, the Major Basic Research Development Pro-
gram (Grant No. G2000077506), National Outstanding
Youth Fund, Chinese Academy of Sciences, and Shang-
hai Committee of Science and Technology. R.H.F. grate-
fully acknowledges the Hong Kong Croucher Foundation
for a Studentship.
J
H-H ) 3.9, 7.3 Hz, 1H), 4.95 (d, J ) 6.1 Hz, 1H), 7.29 (d, J )
19
8
.1 Hz, 2H), 7.76 (d, J ) 8.5 Hz, 2H); F NMR (282 MHz,
2
CDCl , 25 °C, CF COOH) δ -169.9 (double multiplet, J H-F =
4
m/z 285 (M , 20), 210 (100), 155 (78). Anal. Calcd for C14
FNO S: C, 58.92; H, 7.06; N, 4.91. Found: C, 59.20; H, 6.98;
N, 4.82.
3 3
-
1
7.9 Hz); IR (film) ν˜ ) 3265, 3066, 2937, 1898 cm ; EI-MS
+
19
H -
2
N-(4-F lu or o-4,7,7-t r im et h ylb icyclo[4.1.0]h ep t -3-yl)-4-
m eth ylben zen esu lfon a m id e (2f): 76% yield; solid; mp 130-
1
1
32 °C; H NMR (300 MHz, CDCl
3
, 25 °C, TMS) δ 0.63-0.76
J O034895K
3
38 J . Org. Chem., Vol. 69, No. 2, 2004