Efficient ring-opening reaction of epoxides and aziridines promoted by tributylphosphine in water

Article abstract of DOI:10.1021/jo025983s

Tributylphosphine was found to be an effective promoting reagent for the ring-opening reaction of various epoxides and aziridines with nucleophile to produce corresponding anti-bifunctional products in moderate to excellent yields in water.

Full text of DOI:10.1021/jo025983s

Efficien t Rin g-Op en in g Rea ction of Ep oxid es a n d Azir id in es
P r om oted by Tr ibu tylp h osp h in e in Wa ter
Ren-Hua Fan† and Xue-Long Hou*,†,‡
Shanghai-Hong Kong J oint Laboratory in Chemical Synthesis and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
xlhou@pub.sioc.ac.cn
Received May 28, 2002
Tributylphosphine was found to be an effective promoting reagent for the ring-opening reaction of
various epoxides and aziridines with nucleophile to produce corresponding anti-bifunctional products
in moderate to excellent yields in water.
In tr od u ction
their applications in organic synthesis,6 we developed a
novel phosphine-mediated ring-opening reaction of vari-
ous aziridines with a wide range of nucleophiles.7 Further
studies showed that this phosphine-mediated ring-open-
ing reaction is suitable not only for aziridines but also
for epoxides, and most importantly that the reaction can
proceed in water. We describe here efficient and practical
procedures for the ring-opening reactions of epoxides and
aziridines with various nucleophiles in water in the
presence of a catalytic amount of organophosphine.5b,8
Ever since Breslow studied Diels-Alder reactions in
aqueous media,1 many organic reactions that are tradi-
tionally carried out exclusively in organic solvents have
also been successfully performed in aqueous media.
Potential advantages of using water as a solvent are its
low cost, safety, and ease of use. Water is also environ-
mentally benign. Novel reactions in which the use of
water as a solvent is critical have also been sporadically
reported in the literature over the past few decades.2 On
the other hand, epoxides and aziridines have recently
attracted increasing attention as versatile intermediates
in organic synthesis.3,4 Considerable progress has been
achieved in the nucleophilic ring-opening reactions of
aziridines and epoxides. However, most of these reactions
have suffered from the fact that they require a strong
base or Lewis acid. Moreover, there is no general proce-
dure suitable for various aziridines, epoxides and nu-
cleophiles because of their different reactivities. Finally,
most of these reactions need to be carried out in organic
solvents. Therefore, a new methodology for the ring-
opening of epoxides and aziridines under more convenient
and general conditions is needed.5 In the course of our
studies on the synthesis of aziridines and epoxides and
Resu lts a n d Discu ssion s
Wittig reported that an epoxide could be deoxygenated
by phosphines, which occurs via the attack of a carbon
atom of epoxides by phosphine followed by an elimination
reaction.9 However, we found that in the presence of
p-CH3C6H4CH2SH as a nucleophile, the course of the
deoxygenation reaction was entirely altered from the
production of styrene oxide and tributylphosphine. In-
stead, a ring-opened addition product was obtained in
high yield (Scheme 1). A control experiment showed that
no reaction took place in the absence of Bu3P.
On the other hand, when cyclohexene oxide was used
as the substrate, no reaction took place under the same
† Shanghai-Hong Kong J oint Laboratory in Chemical Synthesis.
‡ State Key Laboratory of Organometallic Chemistry.
(1) Rideout, D. C.; Breslow, R. J . Am. Chem. Soc. 1980, 102, 7816.
(2) (a) Li, C. J .; Chang, T. H. Organic Reactions in Aqueous Media,
Wiley: New York, 1997. (b) Grieco, P. A., Ed. Organic Synthesis in
Water; Blackie Academic and Professional: London, UK, 1998. (c) Ribe,
S.; Wipf, P. Chem. Commun. 2001, 299.
(3) For some reviews of syntheses and reactions of activated and
unactivated aziridines, see: (a) Kasai, M.; Kono, M. Synlett 1992, 778.
(b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599. (c) Osborn,
H. M. I.; Sweeney, J . Tetrahedron: Asymmetry 1997, 8, 1693. (d)
Rayner, C. M. Synlett 1997, 11. (e) Ibuka, T. Chem. Soc. Rev. 1998,
27, 145. (f) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chem. Rev. 1997, 97,
2341. (g) Stamm, H. J . Prakt. Chem. 1999, 319.
(4) For some reviews of reactions of epoxides, see: (a) Pattenden,
G. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 3, p 223. (b) Hodgson, D. M.; Gibbs,
A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361. (c) J acobsen, E. N.; Wu,
M. H. In Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.: Springer: New York, 1999. (d) Willis, M. C.
J . Chem. Soc., Perkin. Trans. 1 1999, 1765.
(5) (a) Fringuelli, F.; Pizzo, F.; Vaccaro, L. Tetrahedron Lett. 2001,
42, 1131. (b) Reddy, L. R.; Reddy, M. A.; Bhanumathi, N.; Rao, K. R.
Synlett 2000, 339.
(6) (a) Li, A. H.; Dai, L. X.; Hou, X. L.; Huang, Y. Z.; Li, F. W. J .
Org. Chem. 1996, 61, 489. (b) Li, A. H.; Dai, L. X.; Hou, X. L.; Chen,
M. B. J . Org. Chem. 1996, 61, 4641. (c) Zhou, Y. G.; Li, A. H.; Hou, X.
L.; Dai, L. X. Chem. Commun. 1996, 1353. (d) 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. (e) Hou, X. L.; Yang, X. F.; Dai, L. X. Chem. Commun.
1998, 747. (f) Hou, X. L.; Wu, J .; Dai, L. X.; Xia, L. J .; Tang, M. H.
Tetrahedron: Asymmetry 1998, 9, 1747. (g) Hou, X. L.; Wu, J .; Dai,
L.-X. Chin. J . Chem. 1998, 16, 557. (h) Wu, J .; Hou, X. L.; Dai, L. X.;
Xia, L. J .; Tang, M. H. Tetrahedron: Asymmetry 1998, 9, 3431. (i) Xia,
L. J .; Wu, J .; Tang, M. H.; Hou, X. L.; Dai, L. X. Youji Huaxue (Chin.
J . Org. Chem.) 1999, 19, 625. (j) Zhou, Y. G.; Hou, X. L.; Dai, L. X.;
Xia, L. J .; Tang, M. H. J . Chem. Soc., Perkin Trans. 1 1999, 77. (k)
Zhou, Y. G.; Li, A. H.; Dai, L. X.; Hou, X. L. Hua Xue Xue Bao 2000,
58, 473. ( l) Wu, J .; Hou, X. L.; Dai, L. X. J . Org. Chem. 2000, 65,
1344.
(7) Hou, X. L.; Fan, R. H.; Dai, L. X. J . Org. Chem. 2002, 67, 5295.
10.1021/jo025983s CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/14/2002
726
J . Org. Chem. 2003, 68, 726-730

Efficient Ring-Opening Reaction of Epoxides and Aziridines
TABLE 1. Rin g-Op en in g Rea ction of Ep oxid es 1 w ith
SCHEME 1
Nu cleop h iles in Wa ter a n d in th e P r esen ce of n -Bu 3P a
sub-
yield [%]b yield [%]c yield [%]d
(2:3) (2:3) (2:3)
entry strate NuH product
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1d
1d
1e
A
B
C
B
D
E
B
E
B
E
B
2a A, 3a A 61 (90:10)e
0
trace
2a B, 3a B 88 (67:33)e 41 (20:80)e 96 (85:15)e
2a C, 3a C 88 (67:33)e trace
90 (81:19)e
0
2bB
2bD
2bE
2cB
2cE
2d B
2d E
2eB
72
78
64
78
72
83
78
15
39
25
16
26
34
34
trace
trace
trace
trace
trace
trace
trace
10
11
85 (>95:5) trace
a
Bu3P was purified by distillation from CuI and the reactions
b
were carried out at room temperature under Ar. Isolated yields.
c Isolated yields in the absence of n-Bu3P. Isolated yields from
d
SCHEME 2
the reactions run in CH3CN in the presence of Bu3P. e Ratios of
the two regioisomers were determined by 300-MHz 1H NMR.
SCHEME 3
conditions. However, the reaction proceeded smoothly
with water as a solvent. To demonstrate the usefulness
of this novel aqueous organophosphine-mediated ring-
opening reaction of epoxides, a variety of nucleophiles
and epoxides were tested (Scheme 2, Table 1).
nucleophiles have not always been suitable for aliphatic
nucleophiles. For example, several reported reactions of
epoxides with aromatic amines could not be applied to
benzylamine.10a,11 Ring-opening reactions of epoxides with
benzylamine have been reported to occur only in the
presence of Yb(OTf)312 or 100 mol % of LiClO413 in organic
solvent. In our case, the corresponding product 2bD was
obtained in 78% yield in water at room temperature in
the presence of tributylphosphine (entry 5, Table 1), while
the reaction of aromatic amine also gave product 2bE in
good yield (entry 6, Table 1). The reaction can be easily
scaled up to 100 mmol, and many products can be easily
isolated by simple filtration and washing with petroleum
ether. Interestingly, the presence of Bu3P affects not only
the yield but also the regioselectivity of the reactions of
1a (entry 2). In the presence of Bu3P, the normal mode
of epoxide opening was observed, and the product 2, for
which the nucleophile attacked the least-hindered carbon
atom, is favored. On the other hand, in the absence of
Bu3P, the regiochemistry of the epoxide was reversed.
Further studies showed that this aqueous ring-opening
reaction can also be extended to aziridines, and water is
also a good solvent for the ring-opening of aziridines in
the presence of a catalytic amount of tributylphosphine
(Scheme 3, Table 2).
As shown in Table 1, various epoxides and nucleo-
philes, including phenol, thiophenol, aliphatic mercaptan,
and aromatic and aliphatic amines, are suitable for this
aqueous phosphine-catalyzed reaction to give the corre-
sponding ring-opened products in moderate to good yield,
while no reaction took place or the product was obtained
only in low yield in the absence of tributylphosphine. The
anti-stereochemistry of all of the products was confirmed
from their coupling constants. Another notable feature
of this method is that many reactions which did not take
place in organic solvent proceeded smoothly in aqueous
media (entries 1 and 4-11 in Table 1). In the literature,
various reaction conditions have been used for ring-
opening reactions of epoxides with different nucleo-
philes.10,11 Reaction conditions suitable for aromatic
(8) Some other examples of phosphine-catalyzed reactions, see: (a)
Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535 and references
therein. (b) Vedejs, E.; Fuchs, P. L. J . Am. Chem. Soc. 1973, 95, 822.
(c) Trost, B. M.; Li, C. J . J . Am. Chem. Soc. 1994, 116, 10819. (d) Trost,
B. M.; Dake, G. R. J . Org. Chem. 1997, 62, 5670. (e) Zhang, C.; Lu, X.
J . Org. Chem. 1995, 60, 2906. (f) Guo, C.; Lu, X. J . Chem. Soc., Chem.
Commun. 1993, 394. (g) Zhang, C.; Lu, X. Synlett 1995, 645. (h) Xu,
Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (i) Xu, Z.; Lu, X. J . Org.
Chem. 1998, 63, 5031. (j) Matsukawa, S.; Okano, N.; Imamoto, T.
Tetrahedron Lett. 2000, 41, 103. (k) Vedejs, E.; Bennett, N. S.; Conn,
L. M.; Diver, S. T.; Gingras, M.; Lin, S.; Oliver, P. A.; Peterson, M. J .
J . Org. Chem. 1993, 58, 7286. (l) Hayase, T.; Shibata, T.; Soai, K.;
Wakatsuki, Y. Chem. Commun. 1998, 1271. (m) Kobayashi, S.;
Tsuchiya, Y.; Mukaiyama, T. Chem. Lett. 1991, 537. (n) Vedejs, E.;
Daugulis, O.; MacKay, J . A.; Rozners, E. Synlett 2001, 1499. (o) Shi,
M.; Xu, Y. M. Chem. Commun. 2001, 1876. (p) Shi, M.; Xu, Y. M. Eur.
J . Org. Chem. 2002, 696.
As shown in Table 2, various aziridines, regardless of
whether the substituent at the nitrogen atom of the
aziridine ring is an electron-withdrawing or an electron-
(11) Sekar, G.; Singh, V. K. J . Org. Chem. 1999, 64, 287.
(12) Meguro, M.; Asao, N.; Yamamoto, Y. J . Chem. Soc., Perkin.
Trans. 1 1994, 2597.
(13) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31,
4661.
(9) Wittig, G.; Hagg, W. Chem. Ber. 1955, 88, 1654.
(10) (a) Das, U.; Crousse, B.; Kesavan, V.; Delpon, D. B.; Be´gue´, J .
P. J . Org. Chem. 2000, 65, 6749. (b) Kesavan, V.; Delpon, D. B.; Be´gue´,
J . P. Tetrahedron Lett. 2000, 40, 2895.
J . Org. Chem, Vol. 68, No. 3, 2003 727

Fan and Hou
TABLE 2. Th e Rin g-Op en in g Rea ction of Azir id in es 4 in
SCHEME 4
Wa ter Ca ta lyzed by n -Bu 3P a
sub-
yield
[%]b
yield
%]c
yield
[%]d
entry strate NuH
product
5a A
5a B
5a C
5a G
5a D
5a E
5a F
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4b
4c
4c
A
B
C
G
D
E
F
B
B
E
85e
98
99
88
99
98
61
0
25
0
90
trace 89
trace 72
65
50
SCHEME 5
85
89
trace 80
5bB, 6bB 98 (50/50)f trace 98 (50:50)f
5cB
5cE
62
91
trace 95
27 62
10
a
Bu3P was purified by distillation from CuI and the reactions
b
were carried out at room temperature under Ar. Isolated yields.
c Isolated yields in the absence of n-Bu3P. Isolated yields in
d
CH3CN in the presence of Bu3P. e 0.2 mL of CH3CN was added to
the reaction. f The ratios of the two regioisomers was determined
by 300-MHz 1H NMR.
nucleophile A, B, or C. However, product 5a C was
isolated in 48% yield when the aziridine 4a reacted with
nucleophile C in water in the presence of deprotonated
phosphonium salt 8 (Scheme 5). In addition, in the
presence of 10 mol % of deprotonated product 5a C, the
reaction of 4a with C also took place under the same
conditions. These observations are similar to those in
organic solvent.7
On the basis of these results, phosphine plays the same
role in aqueous solution as it does in organic solvent.
Phosphine attacks the ring of epoxide or aziridine to form
the salt, which acts as a base to generate the anion of
the nucleophile. The Nu- reacts with aziridine or epoxide
to give the ring-opened intermediate, which reacts with
another nucleophile to provide the product and regener-
ate the Nu- to complete the catalytic cycle.7 In addition,
a hydrophobic effect may play a role in accelerating this
reaction.2a
donating group, and various nucleophiles, including
phenol, thiophenol, aliphatic mercaptan, and aromatic
and aliphatic amines, are suitable for this phosphine-
catalyzed reaction. The corresponding ring-opening reac-
tion products were obtained in good to excellent yield,
while no reaction took place or the products were
obtained in only low yield in the absence of tributylphos-
phine. Reactions carried out in water were faster than
those in organic solvent. For example, to achieve the
same yields, the reaction of 4a with nucleophiles B-G
needed 36-56 h in organic solvent, but only 12 h in
water. Also, the reaction of aziridine 1a with phenol
failed to give the desired product in organic solvent in
the presence of 10 mol % of tributylphosphine, unless it
was warmed from room temperature to reflux. However,
this reaction occurred at room temperature with the
addition of 20% (v/v) water to the mixture. Under optimal
conditions, a 1:10 mixture of CH3CN and water was the
best solvent, while no reaction occurred in water alone.
Again, the anti-stereochemistry of the products was
established by NMR spectroscopy.
In summary, we developed a novel, efficient, and
general aqueous nucleophilic ring-opening reaction of
various aziridines and epoxides that proceed with a wide
range of nucleophiles in the presence of tributylphos-
phine, which offers the potential of being both economical
and environmentally benign. Further studies of this
reaction are in progress.
The structure of an organophosphine strongly influ-
ences its catalytic activity. The reaction of aziridine 1a
with nucleophile C was more sluggish when tricyclohex-
ylphosphine or triphenylphosphine was used as a catalyst
instead of tributylphosphine, and no product was ob-
tained in the presence of triethyl phosphite.
Exp er im en ta l Section
We have shown that in the tributylphosphine-promoted
ring-opening reaction of aziridines with nucleophiles, the
tributylphosphine acts as a nucleophilic trigger to attack
the carbon atom of the aziridine ring, and thus initiates
the reaction.7 To show the role of phosphine in aqueous
solution, PhSH and Bu3P were mixed in a 2:1 ratio in a
1:1 mixed solvent of D2O and THF. Except for the signal
of Bu3P, no new signal of 31P NMR was observed.
However, for the mixture of epoxide 1e and Bu3P in a
1:1 ratio in a 1:2 mixed solvent of D2O and THF, new
signals at δ 37.2 and 37.3 ppm were observed, in addition
to the original signal (δ -28.2 ppm).
Treatment of the reaction mixture of aziridine 4a and
Bu3P with 60% HClO4 gave phosphonium salt 7, which
was confirmed to be identical with that prepared in
organic solvent7 (Scheme 4). Deprotonation of phospho-
nium 7 with n-BuLi provided phosphonium salt 8, which
failed to give a displacement product when reacted with
Gen er a l Exp er im en ta l Con d ition s. All reactions were
performed under an atmosphere of either dry argon or nitrogen
using oven-dried glassware. Solvents were distilled under an
atmosphere of nitrogen before use. THF and toluene were
distilled from sodium benzophenone ketal. Dichloromethane
and Acetonitrile were distilled from calcium hydride. Com-
mercially available reagents were used as received without
further purification. Melting points are uncorrected. 1H NMR
spectra were recorded in CDCl3. Chemical shifts are given in
parts per million relative to tetramethylsilane as an internal
standard. IR spectra were measured in cm-1
.
Gen er a l P r oced u r e of Aqu eou s Rin g Op en in g of Ep -
oxid es 1 or Azir id in es 4 w ith Nu cleop h ile A-G Ca ta -
lyzed by Bu 3P . To a stirred solution of epoxide 1 or aziridine
4 (0.5 mmol) and nucleophile A-G (0.55 mmol) was added
tributylphosphine (0.014 mL, 0.05 mmol) and water (2.0 mL)
under argon, and the resulting mixture was stirred at room
temperature for 12 h. The mixture was extracted by CH2Cl2
(2 × 5 mL), and the crude product was purified by flash column
chromatography to provide the corresponding product.
728 J . Org. Chem., Vol. 68, No. 3, 2003

Efficient Ring-Opening Reaction of Epoxides and Aziridines
P r oced u r e of Rin g-Op en in g of Azir id in es 4a w ith
P h en ol Ca ta lyzed by Bu 3P in Mixed Aqu eou s/Or ga n ic
Solven t. To a stirred solution of aziridine 4a (126 mg, 0.5
mmol) and phenol (52 mg, 0.55 mmol) in 0.2 mL of CH3CN
was added tributylphosphine (0.014 mL, 0.05 mmol) followed
by water (2.0 mL) under argon, and the resulting mixture was
stirred at room temperature for 12 h. The mixture was
extracted by CH2Cl2 (2 × 5 mL), and the crude product was
purified by flash column chromatography to provide the
corresponding product 5a A.
1-P h en oxym eth yl-ben zen em eth an ol (2aA).14 White solid;
mp 62-64 °C; 1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ 2.80
(d, 3J ) 2.4 Hz, 1H, OH), 3.95-4.03 (m, 1H), 4.07-4.12 (m,
1H), 5.08-5.13 (m, 1H, CH), 6.88-6.95 (m, 3H), 7.23-7.45 (m,
7H); IR (film) νj 3292 (OH), 1598 cm-1 (Ph); EI-MS m/z (%)
214 (20) [M +], 197 (33) [M+ - OH], 108 (100); HRMS calcd for
3.13 (ddd, J ) 11.1, 9.3, 4.0 Hz, 1H), 3.35 (ddd, J ) 9.7, 9.4,
4.1 Hz, 1H), 6.70-6.85 (m, 3H), 7.10-7.20 (m, 2H); EI-MS m/z
(%) 192 (MH+, 7), 191 (M+, 43), 174 (1), 148 (13), 132 (100),
118(25), 106 (35), 93(11,), 77(14).
2-(P h en ylth io)cyclop en ta n ol (2cB).15 Colorless liquid; 1H
NMR (300 MHz, CDCl3, 25 °C, TMS) δ 1.50-1.70 (m, 2H),
1.70-1.90 (m, 3H), 2.01-2.15 (m, 1H), 2.20-2.30 (m, 1H),
3.30-3.45 (m, 1H), 4.10-4.20 (m, 1H), 7.20-7.30 (m, 3H),
7.35-7.50 (m, 2H); EI-MS m/z (%) 195 (MH+, 13), 194 (M+,
100), 110 (91).
2-(P h en yla m in o)cyclop en ta n ol (2cE).11 White solid; mp
1
57-58 °C; H NMR (300 MHz, CDCl3, 25 °C, TMS) δ 1.35-
1.45 (m, 1H), 1.60-1.65 (m, 1H), 1.68-1.84 (m, 2H), 1.86-
2.01 (m, 1H), 2.10-2.20 (m, 1H), 2.40-3.10 (br, 2H), 3.55-
3.65 (m, 1H), 4.00-4.10 (m, 1H), 6.65-6.80 (m, 3H), 7.10-
7.25 (m, 2H).
3-(P h en ylth io)-2-bu ta n ol (2d B).17 Colorless liquid; 1H
NMR (300 MHz, CDCl3, 25 °C, TMS) δ 1.25 (d, J ) 6.3 Hz,
3H), 1.30 (d, J ) 6.9 Hz, 3H), 2.30 (br, 1H), 3.10-3.20 (m, 1H),
3.60-3.75 (m, 1H), 7.20-7.30 (m, 3H), 7.35-7.50 (m, 2H); MS
m/z (%) 183 (MH+, 17), 182 (M+, 100), 137 (96).
C
14H14O2 214.1034, found 214.1045.
2-P h en oxy-ben zen eeth a n ol (3a A).14 White solid; mp 76-
1
78 °C; H NMR (300 MHz, CD3COCD3, 25 °C, TMS) δ 2.24-
2.29 (m, 1H. OH), 3.75-3.94 (m, 2H, CH2), 5.24 (dd, J ) 8.2
3
Hz, 3.7 Hz, 1H, CH), 6.84-6.87 (m, 3H), 7.14-7.34 (m, 7H);
IR (film) νj 3435 (OH), 1594 cm-1 (Ph); EI-MS m/z (%) 214 (1)
[M +], 94 (100) [PhOH]; HRMS calcd for C14H14O2 214.1034,
found 214.1039.
1-P h en ylth iom eth yl-ben zen em eth a n ol (2a B).15 Color-
less liquid; 1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ 2.86 (s,
1H, OH), 3.08 (dd, 2J ) 13.8 Hz, 3J ) 9.4 Hz, 1H), 3.30 (dd, 2J
3-P h en yla m in o-2-bu ta n ol (2d E).18 1H NMR (300 MHz,
CDCl3, 25 °C, TMS) δ 1.15 (d, J ) 6.5 Hz, 3H), 1.25 (d, J ) 6.2
Hz, 3H), 2.60 (br, 1H), 3.30-3.40 (m, 1H), 3.60-3.70 (m, 1H),
6.65-6.85 (m, 3H), 7.20 (m, 2H).
1-P h en ylth io-2-h exa n ol (2eB).19 1H NMR (300 MHz,
CDCl3, 25 °C, TMS) δ 0.88 (t, J ) 7.2 Hz, 3H), 1.26-1.56 (m,
6H), 2.60 (br s, 1H), 2.84 (dd, J ) 13.6, 8.5 Hz, 1H), 3.14 (dd,
J ) 13.6, 3.6 Hz, 1H), 3.62-3.67 (m, 1H), 7.18-7.38 (m, 5H);
EI-MS m/z (%) 210 (M+, 24), 124 (100).
3
3
) 13.8 Hz, J ) 3.6 Hz, 1H), 4.71 (d, J ) 9.3 Hz, CH), 7.20-
7.42 (m, 10H); EI-MS m/z (%) 230 (69) [M +], 213 (48) [M
-
+
OH], 124 (100).
2-P h en ylth ioben zen eeth a n ol (3a B).15 Colorless liquid;
N -(2-P h e n oxyl)cycloh e xyl-4-m e t h ylb e n ze n su lfon a -
m id e (5a A).7 White solid; mp 146-148 °C; 1H NMR (300 MHz,
CD3COCD3, 25 °C, TMS) δ 1.25-1.33 (m, 4H, CH2CH2), 1.56-
1.75 (m, 2H, CH2), 2.02-2.05 (m, 1H), 2.21-2.24 (m, 1H), 2.43
(s, 3H, CH3), 3.27-3.40 (m, 1H, CH), 4.11-4.25 (m, 1H, CH),
4.76 (d, 3J (H,H) ) 3.6 Hz, 1H, NH), 6.67 (d, 3J (H,H) ) 8.2 Hz,
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ 2.13 (s, 1H, OH),
3
3.88-3.89 (m, 2H, CH2), 4.29 (t, J ) 6.9 Hz, 1H, CH), 7.21-
7.42 (m, 10H); EI-MS m/z (%) 230 (37) [M +], 199 (100) [M
-
+
CH3OH].
1-[(4-Meth ylp h en yl)m eth ylth io]m eth yl-ben zen em eth -
3
1
2H), 6.94 (t, J (H,H) ) 7.5 Hz, 1H,), 7.21-7.30 (m, 4H), 7.76
a n ol (2a C). Colorless liquid; H NMR (300 MHz, CDCl3, 25
2
3
(d, 3J (H,H) ) 8.2 Hz, 2H); IR (film) νj 3297 (NH), 1601 cm-1
°C, TMS) δ 2.34 (s, 3H, CH3), 2.66 (dd, J ) 13.9 Hz, J ) 9.2
2
3
3
(Ph); EI-MS m/z (%) 346 (37) [M+ + H], 252 (100) [M+
-
Hz, 1H), 2.81 (dd, J ) 13.9 Hz, J ) 3.7 Hz, 1H), 2.87 (d, J
) 2.6 Hz, OH), 3.70 (s, 2H, CH2), 4.68 (m, 3J ) 9.1, 2.9 Hz,
1H, CH), 7.13-7.36 (m, 9H); IR (film) νj 3430 cm-1 (OH), 1514
(Ph), 1381 cm-1 (CH3); EI-MS m/z (%) 258 (1) [M+], 152 (53)
[M+ - C8H9], 105 (100); HRMS calcd for C16H18OS 258.1108,
found 258.1117. Anal. Calcd for C16H18SO: C, 74.38; H, 7.02.
Found: C, 74.27; H, 6.98.
PhOH]. Anal. Calcd for C19H23NSO3: C, 66.06; H, 6.71; N, 4.05.
Found: C, 65.91; H, 6.81; N, 3.81.
N-(2-P h en ylth iocycloh exyl)-4-m eth ylben zen esu lfon a -
m id e (5a B).7 White solid; mp 130-131 °C; 1H NMR (300 MHz,
CDCl3, 25 °C, TMS) δ 1.20-1.50 (m, 4H), 1.50-1.75 (m, 2H),
2.00-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.45 (s, 3H, CH3), 2.80-
3
3.00 (m, 2H), 5.10-5.20 (d, J ) 3.6 Hz, 1H, NH), 7.20-7.40
2-[(4-Meth ylp h en yl)m eth ylth io]ben zen eeth a n ol (3a C).
(m, 7H), 7.75 (d, 3J ) 8.3 Hz, 2H); IR (film) νj 3265 cm-1 (NH);
EI-MS m/z (%) 361 (7) [M+], 252 (13) [M+ - PhS]. Anal. Calcd
for C19H23NO2S2: C, 63.13; H, 6.41; N, 3.87. Found: C, 63.07;
H, 6.48; N, 3.91.
Colorless liquid; 1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ
3
2
1.89 (t, J ) 6.1 Hz, 1H, OH), 2.32 (s, 3H, CH3), 3.51 (d, J )
2
13.4 Hz, 1H), 3.64 (d, J ) 13.3 Hz, 1H), 3.78-3.87 (m, 3H),
7.08-7.14 (m, 4H), 7.25-7.34 (m, 5H); IR (film) νj 3399 (OH),
1600 (Ph), 1380 cm-1 (CH3); EI-MS m/z (%) 258 (8) [M+], 105
(100); HRMS calcd for C16H18OS 258.1108, found 258.1112.
Anal. Calcd for C16H18SO: C, 74.38; H, 7.02. Found: C, 74.41;
H, 7.12.
2-(P h en ylth io)cycloh exa n ol (2bB).16 Colorless liquid; 1H
NMR (300 MHz, CDCl3, 25 °C, TMS) δ 1.15-1.45 (m, 4H),
1.60-1.85 (m, 2H), 2.00-2.20 (m, 2H), 2.70 (br, 1H, OH), 2.75-
2.90 (m, 1H, CH), 3.30-3.40 (m, 1H, CH), 7.25-7.40 (m, 3H),
7.45-7.60 (m, 2H).
N-2-((4-Meth ylp h en yl)m eth ylth io)cycloh exyl)-4-m eth -
ylben zen esu lfon a m id e (5a C).7 White solid; mp 87-89 °C;
1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ 1.01-1.50 (m, 4H),
1.52-1.73 (m, 2H), 1.92-2.12 (m, 1H), 2.14-2.27 (m, 1H), 2.27
(s, 3H, CH3), 2.33-2.38 (m, 1H, CH), 2.41 (s, 3H, CH3), 2.78-
2.92 (m, 1H, CH), 3.45-3.57 (m, 2H, CH2), 5.03 (d, 3J ) 2.4
Hz, 1H), 7.10-7.30 (m, 6H), 7.74-7.77 (d, 3J ) 8.2 Hz); IR
(film) νj 3309 (NH), 1597 (Ph), 1383 cm-1 (CH3); EI-MS m/z
(%) 389 (1) [M+], 234 (100); HRMS calcd for C21H27NS2O2
389.1449, found 389.1456.
N-(2-P h en ylm eth yla m in o)cycloh exyl-4-m eth ylben ze-
n esu lfon a m id e (5a D).7 1H NMR (300 MHz, CD3COCD3, 25
°C, TMS) δ 1.06-1.41 (m, 6H), 156-1.63 (m, 2H), 1.77-1.82
(m, 1H), 2.29-2.34 (m, 1H), 2.38 (s, 3H, CH3), 2.84-2.92 (m,
1H, CH), 3.59 (d, 3J ) 13.2 Hz, 1H, CH), 3.75, (d, 3J ) 13.1
Hz, 1H, CH), 7.21-7.36 (m, 7H), 7,74 (d, 3J ) 8.2 Hz, 2H);
EI-MS m/z (%) 359 (MH+ 87), 91 (100).
2-(P h en ylm eth yl)a m in o-cycloh exa n ol (2bD).12 1H NMR
(300 MHz, CDCl3, 25 °C, TMS) δ 0.98 (m, 1H), 1.12-1.30 (m,
3H), 1.60-1.80 (m, 2H), 1.93-2.02 (m, 1H), 2.11-2.20 (m, 1H),
2.32 (ddd, J ) 11.3, 9.2, 3.8 Hz, 1H), 2.80 (br, 2H), 3.22 (ddd,
J ) 9.2, 9.2, 3.8 Hz, 1H), 3.70 (d, J ) 12.9 Hz, 1H), 4.00 (d, J
) 12.9 Hz, 1H), 7.20-7.40 (m, 5H).
2-P h en yla m in o-1-cycloh exa n ol (2bE).11 1H NMR (300
MHz, CDCl3, 25 °C, TMS) δ 1.00-1.10 (m, 1H), 1.25-1.41 (m,
3H), 1.70-1.81 (m, 2H), 2.05-2.20 (m, 2H), 3.02 (br s, 2H),
(17) Beckwith, A. L. J .; Wagner, R. D. J . Org. Chem. 1981, 46, 3638.
(18) Alcaide, B.; Arjona, O.; Fernandez, P. R.; Plumet, J .; Rodriguez,
I.; Santesmases, M. J . J . Chem. Res. Synop. 1988, 98.
(19) Hosomi, A.; Ogata, K.; Hoashi, K.; Kora, S.; Yominaga, Y. Chem.
Pharm. Bull. 1988, 36, 3736.
(14) Davis, S.; Thieffry, A. J . Org. Chem. 1983, 48, 441.
(15) Maiti, A. K.; Bhattacharyya, P. Tetrahedron 1994, 50, 10483.
(16) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 1643.
J . Org. Chem, Vol. 68, No. 3, 2003 729

Fan and Hou
N-P h en yl-N′-ben zyl-1,2-cycloh exa n ed ia m in e (5cE).7 1
NMR (300 MHz, CDCl3, 25 °C, TMS) δ 1.10-1.13 (m, 1H),
1.20-1.23 (m, 3H), 1.70-1.72 (m, 2H), 2.10 (br s, 1H), 2.18
(m, 2H), 2.33 (ddd, J ) 9.9, 9.9, 4.2 Hz, 1H), 3.12 (ddd, J )
10.2, 10.2, 3.6 Hz, 1H), 3.37 (br s, 1H), 3.80 (AB, J ) 13.5 Hz,
2H), 6.64 (m, 3H), 7.13 (m, 2H), 7.25 (m, 5H); EI-MS m/z (%)
281 (23) [MH+ ].
N-(2-P h en ylam in o)cycloh exyl-4-m eth ylben zen esu lfon a-
m id e (5a E).7 1H NMR (300 MHz, CD3COCD3, 25 °C, TMS) δ
1.01-1.45 (m, 4H), 1.50-1.67 (m, 2H), 1.95-2.20 (m, 2H), 2.40
(s, 3H, CH3), 2.85-3.05 (m, 3H), 5.08 (br, 1H, NH), 6.45 (d, 3J
) 7.4 Hz, 2H), 6.38-6.5 (m, 1H), 7.05-7.30 (m, 4H), 7.81 (d,
3J ) 7.3 Hz, 2H); EI-MS m/z (%) 344 (20) [M+], 96 (100).
N-[2-(1-Meth yleth yla m in o)]cycloh exyl-4-m eth ylben ze-
n esu lfon a m id e (5a F ).7 White solid; mp: 112-114 °C; 1H
NMR (300 MHz, CD3COCD3, 25 °C, TMS) δ 0.94 (dd, 3J ) 6.1,
2.4 Hz, 6H, CH(CH3)2), 1.11-1.26 (m, 4H), 1.61-1.67 (m, 2H),
2.05-2.09 (m, 1H), 2.16-2.23 (m, 2H), 2.42 (s, 3H, CH3), 2.45-
2.47 (m, 1H), 2.86 (m, 1H), 5.68 (br, 1H, NH), 7.30 (d, 3J ) 8.1
Hz, 2H), 7.76 (d, 3J ) 8.2 Hz, 2H); IR (film) νj 3244 (NH), 1597
cm-1 (Ph); EI-MS m/z (%) 311 (28) [M + H+], 155 (100). Anal.
Calcd for C16H26NO2S: C, 61.90, H, 8.44, N, 9.02. Found: C,
61.77, H, 8.38, N, 8.78.
H
Th e P r ep a r a tion of P h osp h on iu m Sa lt 7. To a mixture
of Bu3P (0.26 mL, 1 mmol) with aziridine 4a (252 mg, 1 mmol)
was added 4 mL of water. The mixture was then stirred for
48 h at room temperature. After the addition of 60% aqueous
perchloric acid (2 mL) CH2Cl2 (10 mL) was added, and the
resulting mixture was cooled at 0 °C to give some solid. After
recrystallization from CH2Cl2, a good crystal could be obtained
in 26% yield. 1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ 0.99-
1.03 (m, 11H), 1.10-1.37 (m, 3H), 1.55-1.63 (m, 13H), 1.74-
1.77 (m, 1H), 1.91-1.93 (m, 1H), 2.30-2.40 (m, 6H), 2.42 (s,
3H), 2.93-2.98 (m, 1H), 3.41-3.46 (m, 1H), 7.30 (d, J ) 8.0
Hz, 2H), 7.78 (d, J ) 8.2 Hz, 2H); 31P NMR (162 MHz, CDCl3,
25 °C, 85% H3PO4) δ 35.46; EI-MS m/z (%):283 (100), 253 (6).
Anal. Calcd for C25H45NO6PS: C, 54.19; H, 8.19; N, 2.53.
Found: C, 54.13; H, 7.93; N, 2.38.
Rea ction of 4a w ith Nu cleop h ile C in th e P r esen ce of
P h sp h on iu m 7. To a stirred solution of 7 (28 mg, 0.05 mmol)
in THF (0.2 mL) was added n-BuLi (0.031 mL, 1.6 M in
hexane, 0.05 mmol) at -78 °C under argon and the resulting
mixture was stirred for 15 min, then 4a (126 mg, 0.5 mmol)
and C (0.03 mL 0.5 mmol) were added. The mixture was
warmed to room temperature and then stirred for 48 h. The
mixture was extracted by CH2Cl2 (2 × 5 mL) and the crude
product was purified by flash column chromatography to
provide corresponding product 5a C in 48% yield.
N-[2-(1,1-Dim eth yl)eth ylth io]cycloh exyl-4-m eth ylben -
zen esu lfon a m id e (5a G).7 Colorless liquid; 1H NMR (300
MHz, CDCl3, 25 °C, TMS) δ 1.29 (s, 9H, C(CH3)3), 1.45-1.67
(m, 6H), 2.04-2.17 (m, 2H), 2.42 (s, 3H, CH3), 2.43-2.58 (m,
1H, CH), 2.59-2.81 (m, 1H, CH), 5.37 (br, 1H, NH), 7.30 (d,
3
3J ) 7.9 Hz, 2H), 7.76 (d, J ) 8.0 Hz, 2H); IR (film) νj 3275
(NH), 1598 (Ph), 1393 cm-1(CH3); EI-MS m/z (%) 341 (44) [M+],
286 (10) [M+ - C4H9], 252 (11) [M+ - C4H9SH]; HRMS calcd
for C17H27NS2O2 341.1407, found 341.1510.
1-(P h e n ylt h io)m e t h yl-S -(4-m e t h ylp h e n yl)b e n ze n e -
m eth a n su lfon a m id e a n d 2-P h en ylth io-S-(4-m eth ylp h en -
yl)ben zen eeth a n su lfon a m id e (5bB a n d 6bB).7 Colorless
liquid; 1H NMR (300 MHz, CDCl3, 25 °C, TMS) δ 2.35 (s, 3H,
CH3), 2.42 (s, 3H, CH3), 3.18-3.22 (m, 2H, CH2), 3.34-3.39
3
3
(m, 2H, CH2), 4.13 (t, J ) 7.2 Hz, 1H, CH), 4.30 (q, J ) 6.7
Hz, 1H, CH), 4.74 (br, 1H, NH), 5.33 (br, 1H, NH), 7.08-7.27
3
3
(m, 24H), 7.50 (d, J ) 8.2 Hz, 2H), 7.64 (d, J ) 8.2 Hz, 2H);
IR (film) νj 3290 (NH), 1599 cm-1(Ph); EI-MS m/z (%) 383 (2),
[M+], 260 (100). Anal. Calcd for C21H21NO2S2: C, 65.76; H,
5.52; N, 3.65. Found: C, 65.66; H, 5.75; N, 3.58.
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), the National Outstand-
ing Youth Fund, the Chinese Academy of Sciences, and
the Shanghai Committee of Science and Technology.
R.H.F. gratefully acknowledged Hong Kong Croucher
Foundation for a Studentship.
N-(2-(P h en ylt h io)cycloh exyl)b en zen em et h a n a m in e
(5cB).7 Yellow liquid; 1H NMR (300 MHz, CDCl3, 25 °C, TMS)
δ 1.25-1.42 (m, 4H), 1.69-1.72 (m, 2H), 2.02-2.21 (m, 2H),
2.43-2.46 (m, 1H), 2.92-3.00 (m, 2H), 3.71-3.98 (m, 2H),
7.23-7.51 (m, 10H); IR (film) νj 3280 (NH), 1583 cm-1 (Ph);
EI-MS m/z (%) 297 (2), [M+], 188 (24) [M+ - PhSH]; HRMS
calcd for C19H23NS 297.1551, found 297.1507.
J O025983S
730 J . Org. Chem., Vol. 68, No. 3, 2003