A highly cis-selective synthesis of 2-ethynylaziridines by intramolecular amination of chiral bromoallenes: Improvement of stereoselectivity based on the computational investigation

Article abstract of DOI:10.1021/ja0262277

The base-mediated intramolecular amination of bromoallenes having an axial chirality is described. The treatment of (4S,aR)-4-alkyl-4-[N-(arylsulfonyl)amino]-1-bromobuta-1,2-dienes with NaH in DMF affords 2,3-cis-2-ethynylaziridines in good to excellent s

Full text of DOI:10.1021/ja0262277

Published on Web 11/28/2002
A Highly cis-Selective Synthesis of 2-Ethynylaziridines by
Intramolecular Amination of Chiral Bromoallenes:
Improvement of Stereoselectivity Based on the Computational
Investigation
Hiroaki Ohno,† Kaori Ando,*,‡ Hisao Hamaguchi,† Yusuke Takeoka,† and
Tetsuaki Tanaka*,†
Contribution from the Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan and College of Education,
UniVersity of Ryukyus, Nishihara-cho, Okinawa 903-0213, Japan
Received March 19, 2002
Abstract: The base-mediated intramolecular amination of bromoallenes having an axial chirality is described.
The treatment of (4S,aR)-4-alkyl-4-[N-(arylsulfonyl)amino]-1-bromobuta-1,2-dienes with NaH in DMF affords
2,3-cis-2-ethynylaziridines in good to excellent selectivity (2,3-cis:trans ) 92:8-99:1). The reaction of
(4S,aS)-bromoallenes with NaH/DMF also gives 2,3-cis-2-ethynylaziridines selectively (79:21-91:9). These
experimental results have been rationalized by B3LYP density functional calculations together with the
6-31+G(d) basis set and the Onsager solvation model. The transition structures for cis-aziridine formation
of both (4S,aR)- and (4S,aS)-bromoallenes in DMF are favored over the corresponding trans transition
structures by 4.35 and 1.41 kcal/mol, respectively. Furthermore, the calculations predicted that a less polar
solvent gives higher cis selectivity for (4S,aS)-bromoallenes. In fact, improvement of the cis selectivity to
99:1 has been realized by using a less polar solvent such as THF. The cyclization of bromoallenes bearing
a â- or γ-amino group also affords four- and five-membered azacycles in a highly cis-selective manner.
CuBr/LiBr4 and alkylation of the resulting bromoallenes by
organocopper reagents proceed with inversion of configuration.5
Introduction
Reactions of bromoallenes have attracted much interest in
recent years, because of their cumulated double bonds and high
reactivity. These reactions involve organocopper-mediated
substitutions,1 palladium-catalyzed cross-coupling reactions,2
and the formation of nucleophilic allenylmetal reagents.3 Among
them, the organocopper-mediated substitution of bromoallenes
is extremely useful in that the substitution of propargylic oxygen
by an alkyl group can be carried out with overall retention of
configuration:1c,d both the bromination of propargyl esters with
In contrast, the reaction of bromoallenes with nitrogen nucleo-
philes is relatively limited. Although the intermolecular ami-
nation of racemic bromoallenes has been already reported,6 an
intramolecular reaction and a stereochemical course of the
amination toward chiral bromoallenes are unprecedented as far
as we are aware.
In connection with a research program directed toward the
reactions of 2-ethynylaziridines both as carbon electrophiles7
and nucleophiles,8,9 we required a reliable synthetic method of
* Corresponding author for the computational investigation: Kaori Ando
(ando@edu.u-ryukyu.ac.jp). Other correspondence should be addressed to
Tetsuaki Tanaka (t-tanaka@phs.osaka-u.ac.jp).
(4) (a) Montury, M.; Gore´, J. Synth. Commun. 1980, 10, 873-879. (b) Elsevier,
C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.; Vermeer, P.
J. Org. Chem. 1982, 47, 2194-2196.
† Osaka University.
‡ University of Ryukyus.
(5) Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org. Chem. 1985,
50, 364-367.
(1) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3059-3062. (b)
Caporusso, A. M.; Polizzi, C.; Lardicci, L. Tetrahedron Lett. 1987, 28,
6073-6076. (c) D′Aniello, F.; Mann, A.; Taddei, M. J. Org. Chem. 1996,
61, 4870-4871. (d) D′Aniello, F.; Mann, A.; Schoenfelder, A.; Taddei,
M. Tetrahedron 1997, 53, 1447-1456. (e) Bernard, N.; Chemla, F.;
Normant, J. F. Tetrahedron Lett. 1999, 40, 1649-1652. (f) Chemla, F.;
Bernard, N.; Normant, J. Eur. J. Org. Chem. 1999, 2067-2078. (g)
Caporusso, A. M.; Filippi, S.; Barontini, F.; Salvadori, P. Tetrahedron Lett.
2000, 41, 1227-1230. (h) Conde, J. J.; Mendelson, W. Tetrahedron Lett.
2000, 41, 811-814.
(6) (a) Mavrov, M. V.; Voskanyan, E. S.; Kucherov, V. F. Tetrahedron 1969,
25, 3277-3285. (b) Mavrov, M. V.; Rodionov, A. P.; Kucherov, V. F.
Tetrahedron Lett. 1973, 10, 759-760. (c) Caporusso, A. M.; Geri, R.;
Polizzi, C.; Lardicci, L. Tetrahedron Lett. 1991, 32, 7471-7472. (d) Joshi,
R. V.; Zemlicka, J. Tetrahedron 1993, 49, 2353-2360.
(7) (a) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Fujii, N.; Ibuka, T. Tetrahedron
Lett. 1999, 40, 349-352. (b) Ohno, H.; Toda, A.; Fujii, N.; Takemoto, Y.;
Tanaka, T.; Ibuka, T. Tetrahedron 2000, 56, 2811-2820. (c) Ohno, H.;
Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka, Y.; Fujii, N.; Ibuka,
T. J. Org. Chem. 1999, 64, 2992-2993. (d) Ohno, H.; Anzai, M.; Toda,
A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka, T. J. Org. Chem.
2001, 66, 4904-4914.
(8) (a) Ohno, H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2000, 2, 2161-2163.
(b) Ohno, H.; Hamaguchi, H.; Tanaka, T. J. Org. Chem. 2001, 66, 1867-
1875.
(2) (a) Ma¨rkl, G.; Attenberger, P.; Kellner, J. Tetrahedron Lett. 1988, 29, 3651-
3654. (b) Gillmann, T.; Hu¨lsen, T.; Massa, W.; Wocadlo, S. Synlett 1995,
1257-1259. (c) Saalfrank, R. W.; Haubner, M.; Deutscher, C.; Bauer, W.;
Clark, T. J. Org. Chem. 1999, 64, 6166-6168. (d) Saalfrank, R. W.;
Haubner, M.; Deutscher, C.; Bauer, W. Eur. J. Org. Chem. 1999, 2367-
2372.
(3) (a) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1997, 62, 8976-8977.
For a reaction of iodoallenes, see: (b) Marshall, J. A.; Grant, C. M. J.
Org. Chem. 1999, 64, 8214-8219.
(9) 2-Ethynylaziridines are also known as a versatile building block for the
synthesis of 1H-azepine: Mannisse, N.; Chuche, J. J. Am. Chem. Soc. 1977,
99, 1272-1273.
9
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J. AM. CHEM. SOC. 2002, 124, 15255-15266
15255

A R T I C L E S
Ohno et al.
Table 1. Synthesis of (S,aS)- and (S,aR)-Haloallenes 7 and 9a,e
Scheme 1. Aziridination of Bromoallenes
amino
entry alcohol
1
2
c
d
R
R
X
product ratiob
yield (%)
[R]D
1
2
3
4
5
6
7
8
9
6a
i-Pr
Boc Br 7a:9a ) >99:1
Mts Br 7b:9b ) 95:5
88
76
82
65
81
81
82
65
63
82
60
93
+118
+153
+231
+116
+85
6b i-Pr
6b i-Pr
6d i-Pr
6e
6f
Mts
Ts
I
7c:9c ) >99:1
Br 7d:9d ) 92:8
Br 7e:9e ) 93:7
Bn
Ts
TBSOCH2 Mts Br 7f:9f ) 89:11
i-Pr
+82
chiral 2-ethynylaziridines in a stereoselective manner. Ethynyl-
aziridines can be synthesized by the reaction of N-tosylimines
with sulfonium ylide,10 reaction of lithium acetylides11 or
allenylzincs12 with imines, or the Mitsunobu reaction of amino
alcohols bearing an ethynyl group;13 however, the stereoselective
synthesis of enantiopure 2-ethynylaziridines is still difficult.
Apparently, one of the simplest methods for the synthesis of
enantiopure ethynylaziridines 3 is the Mitsunobu reaction of
the propargyl alcohol 2 (Scheme 1), which in turn could be
readily prepared from amino aldehydes 1 derived from R-amino
acids. However, a highly diastereoselective synthesis of either
syn- or anti-2 by the reaction of amino aldehydes with metal
acetylides has proven to be difficult,13 with the exception of
some examples.14 Since aziridination under the Mitsunobu
conditions proceeds with inversion of configuration, a mixture
of 2,3-cis- and 2,3-trans-2-ethynylaziridines 3 is always obtained
from a diastereomixture of 2.
8a
Boc Br 9a:7a ) >99:1
Mts Br 9b:7b ) >99:1
-304
-251
-344
-282
-130
-133
8b i-Pr
8b i-Pr
8d i-Pr
8e
8f
Mts
Ts
Ts
I
9c:7c ) >99:1
10
11
12
Br 9d:7d ) >99:1
Br 9e:7e ) 91:9
Bn
TBSOCH2 Mts Br 9f:7f ) 75:25
a Amino alcohols were converted into bromoallenes by mesylation with
MsCl (2 equiv) and Et3N (5 equiv) in THF, followed by bromination using
CuBr‚Me2S (2 equiv) and LiBr (2 equiv) in THF. Similarly, iodoallenes
were synthesized using CuI/LiI. bDiastereomeric ratios of 7 and 9 were
determined by 1H NMR. cIsolated overall yields based on the starting amino
alcohols. dOptical rotations were measured in CHCl3 after separation of
the diastereomers except for entry 5 (96% de) and entry 11 (82% de):
e
separation of 7e and 9e was extremely difficult. Abbreviations: Mts )
2,4,6-trimethylphenylsulfonyl, TBS ) tert-butyldimethylsilyl.
Results and Discussion
Synthesis of Bromoallenes Bearing a Protected Amino
Group. To reveal the stereochemical course of the intramo-
lecular amination using diastereomerically pure bromoallenes,
mixtures of amino alcohols 6 and 813b,16 were carefully separated
by repeated flash column chromatography and converted into
the bromoallenes, as shown in Table 1. Thus, the treatment of
6 with MsCl and Et3N gave the corresponding mesylates, and
the crude mesylates were then allowed to react with CuBr‚Me2S/
LiBr4 or CuI/LiI3b to afford the desired (S,aS)-haloallenes 7.
Similarly, the anti-amino alcohols 8 were converted into (S,aR)-
allenes 9 in good to high yields. Although diastereoselectivities
of the bromination reaction were not high in some cases,
diastereomerically pure allenes 7 and 9 were obtained by flash
column chromatography or recrystallization. However, the
separation of the diastereomixtures of 7e and 9e (entries 5 and
11) was extremely difficult.
The stereochemistries of the synthesized haloallenes could
be deduced by the well-documented anti-SN2′ reaction course.4,5
Furthermore, the (S,aS)-haloallenes 7 show positive signs of the
optical rotation, as can be seen from Table 1 (entries 1-6),
while (S,aR)-allenes 9 exhibit negative values (entries 7-12).
This trend is in good agreement with Lowe’s rule17 and the
optical rotations of the related compounds.7b
To establish a stereoselective synthetic method for chiral
2-ethynylaziridines, we have been involved in the investigation
of the intramolecular amination of the bromoallene 4,15 which
can be prepared from the propargyl alcohol 2 (Scheme 1). In
this paper, we present a full account of our study of the base-
mediated aziridination of chiral bromoallenes. We found that
the 2,3-cis-2-ethynylaziridines can be obtained in good to high
selectivities by the reaction of both (S,aS)- and (S,aR)-bromoal-
lenes bearing an N-sulfonylated amino group with NaH/DMF,
and the experimental results have been well rationalized by the
computational investigation [B3LYP/6-31+G(d)]. Furthermore,
as the calculations predicted, the improvement of the 2,3-cis
selectivities up to 99:1 has been realized by the use of a less
polar solvent such as THF. This is a striking example of the
calculation finely contributing to the improvement of the
experimental results.
(10) (a) Li, A.-H.; Zhou, Y.-G.; Dai, L.-X.; Hou, X.-L.; Xia, L.-J.; Lin, L. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1317-1319. (b) Li, A.-H.; Zhou, Y.-G.;
Dai, L.-X.; Hou, X.-L.; Xia, L.-J.; Lin, L. J. Org. Chem. 1998, 63, 4338-
4348.
(11) Florio, S.; Troisi, L.; Capriati, V.; Suppa, G. Eur. J. Org. Chem. 2000,
3793-3797.
(12) Chemla, F.; Hebbe, V.; Normant, J. F. Tetrahedron Lett. 1999, 40, 8093-
8096.
(13) (a) Ohno, H.; Toda, A.; Fujii, N.; Ibuka, T. Tetrahedron: Asymmetry 1998,
9, 3929-3933. (b) Ohno, H.; Toda, A.; Takemoto, Y.; Fujii, N.; Ibuka, T.
J. Chem. Soc., Perkin Trans. 1 1999, 2949-2962. For another related
synthesis, see: (c) Chen, S.-T.; Fang, J.-M. J. Org. Chem. 1997, 62, 4347-
4357.
(14) In limited cases, the reaction of metal acetylide with amino aldehydes
proceeds in a highly stereoselective manner. For example, see: (a) Garner,
P.; Park, J. M. J. Org. Chem. 1990, 55, 3772-3787. (b) D′Aniello, F.;
Schoenfelder, A.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 9631-
9636. For related works, see: (c) Frantz, D. E.; Fa¨ssler, R.; Carreira, E.
M. J. Am. Chem. Soc. 2000, 122, 1806-1807. (d) Boyall, D.; Lo´pez, F.;
Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett. 2000, 2, 4233-4236.
(15) A portion of this study was reported in a preliminary communication: Ohno,
H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2001, 3, 2269-2271.
Base-Mediated Aziridination of Bromoallenes. First, the
intramolecular amination of the bromoallenes bearing an (N-
Boc)amino group was investigated (Scheme 2). The (S,aS)-7a
was treated with NaH in DMF to give the expected 2,3-cis-
and 2,3-trans-2-ethynylaziridines 10a and 11a (10a:11a )
60:40),13b although in low yield (35%). A similar result was
obtained using KH as a base. The treatment of 7a with LDA/
(16) The amino alcohols 6d,e and 8d,e were also synthesized by an identical
procedure described in the literature.13b For details, see the Supporting
Information.
(17) Lowe, G. J. Chem. Soc., Chem. Commun. 1965, 411-413.
9
15256 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

cis-Selective Synthesis of 2-Ethynylaziridines
A R T I C L E S
Scheme 2. Aziridination of Bromoallenes Bearing an
(N-Boc)amino Group
Figure 1. Stereochemical Course of the NaH-Mediated Aziridination of 7
and 9 in DMF.
Scheme 3. Conversion of the trans-Aziridines 11 into the
cis-Isomers 10a
Table 2. Aziridination of Bromoallenes Bearing an
(N-ArSO2)amino Group in DMFa
a Reagents and conditions: (a) MeSO3H (2 equiv), CH2Cl2, 0 °C, 15
min; (b) CuBr‚Me2S (2 equiv), LiBr (2 equiv), THF, 50 °C, 1 h; (c) NaH
(1.3 equiv), DMF, 25 °C, 3 h.
trans-2-ethynylaziridines in which the cis-isomers 10 predomi-
nated (79:21-91:9, entries 4-7). Interestingly, we observed the
highest 2,3-cis selectivity in the reaction of bromoallene 7g
bearing the smallest substituent (R1 ) Me) at C-4 (91:9, entry
7). Furthermore, upon the treatment of (S,aR)-bromoallenes
9b-g with NaH/DMF (entries 9-14), 2,3-cis-aziridines 10b-g
were obtained in higher selectivities (>92:8). When the allenes
9b-d bearing an isopropyl group were used (entries 9-11),
only the cis-isomers 10b and d were obtained. The cyclization
of 9f bearing a siloxy group was relatively slow; however,
increased reaction temperature (50 °C) led to completion of the
reaction within 30 min, and the desired cis-aziridine 10f was
obtained in a high yield (91%, entry 13). From these observa-
tions, the aziridination of the (S,aS)-bromoallenes 7 with
NaH/DMF proceeds in a syn-SN2′ manner, while an anti-SN2′
pathway predominates in the reaction of the (S,aS)-allenes 9
(Figure 1).
c
entry
allene
base
time (min)
ratiob cis:trans
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
7b
7b
7c
7d
7e
t-BuOKd
NaH
NaH
NaH
NaH
10
60
30
60
90
60
180
10
30
20
10b:11b ) 40:60
10b:11b ) 82:18
10b:11b ) 86:14
10d:11d ) 88:12
10e:11e ) 89:11
10f:11f ) 79:21
10g:11g ) 91:9
10b:11b ) 77:23
10b:11b ) >99:1
10b:11b ) >99:1
10d:11d ) >99:1
10e:11e ) 97:3
10f:11f ) 92:8
88
93
98
99
88
76
85
73
99
98
84
78
91
76
7f
NaH
7ge
9b
9b
9c
NaH
t-BuOKd
NaH
NaH
NaH
NaH
NaH
9d
9ee
9f
30
150
30f
240
9ge
NaH
10g:11g ) 93:7
a Reactions were carried out at 25 °C in DMF using diastereomerically
pure bromoallenes and a base (1.2 or 1.3 equiv) unless otherwise stated.
bRatios were determined by H NMR (270 MHz) or isolation of products.
1
cCombined isolated yields. The reaction was conducted at -78 °C using
d
2 equiv of t-BuOK. eDiastereomixture of the bromoallenes was used (96:4
This reaction is also useful for the conversion of the 2,3-
trans-2-ethynylaziridines 11 into the corresponding 2,3-cis-
isomers 10 (Scheme 3). Typically, a methanesulfonic-acid-
mediated ring-opening reaction19 of 11b in CH2Cl2 gave a crude
mesylate 12b, which was directly converted into the bromoallene
9b without purification (77% yield, 2 steps). The intramolecular
amination of 9b with NaH in DMF afforded the expected 2,3-
cis-2-ethynylaziridine 10b as a single isomer in 99% yield. The
overall yield of the three-step sequence for the inversion of
trans-11b at C-2 was 76%. Similarly, the trans-aziridine 11h13b
was converted into the cis-isomer 10h in 69% yield in three
steps.
f
for 7g, 91:9 for 9e, and 97:3 for 9g). Reaction was conducted at 50 °C.
THF resulted in the expected aziridines in higher yield (77%);
however, diastereoselectivity was poor (10a:11a ) 52:48).
Although the reaction of 7a with t-BuOK in DMF gave a
promising result (85% yield, 10a:11a ) 22:78), almost no
selectivity was observed starting from (S,aR)-9a (10a:11a )
41:59) under the identical reaction conditions.
In contrast, the reaction of N-arylsulfonylated amino allenes
showed good to high 2,3-cis selectivity. The results are
summarized in Table 2. Although the aziridination reaction of
7b using t-BuOK gave a 40:60 mixture of the corresponding
aziridines 10b and 11b (entry 1), the NaH-mediated reaction
afforded 2,3-cis-aziridines 10b in both good diastereoselectivity
(82:18) and high yield (93%, entry 2). As one might expect,
iodoallene 7c was more reactive (entry 3) than the corre-
sponding bromoallene 7b (entry 2). Similarly, other (S,aS)-
bromoallenes 7d-g18 yielded mixtures of 2,3-cis- and 2,3-
(18) For synthesis of bromoallenes 7g and 9g bearing a methyl group, see the
Supporting Information.
(19) For a methanesulfonic acid mediated ring-opening reaction of vinylaziri-
dines, see: (a) Tamamura, H.; Yamashita, M.; Muramatsu, H.; Ohno, H.;
Ibuka, T.; Otaka, A.; Fujii, N. Chem. Commun. 1997, 23, 2327-2328. (b)
Tamamura, H.; Yamashita, M.; Nakajima, Y.; Sakano, K.; Otaka, A.;
Ohno, H.; Ibuka, T.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 1999, 2983-
2996.
9
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A R T I C L E S
Ohno et al.
Scheme 4. Aziridination of Bromoallene (S)-13
a Determined by comparison of optical rotations with that of the authetic
sample.
Scheme 5. Aziridination of Bromoallenes Bearing a TMS Group
Figure 2. NaH-Mediated Isomerization of 2,3-trans-Aziridine 11b.
(96% yield, 10d:11d ) 87:13). The reaction of 7d with KHMDS
in THF gave aziridines 10b and 11b in 82% yield (10b:11b )
69:31), while a slightly improved result was obtained when the
same reaction was conducted in the presence of 18-crown-6
(96% yield, 10b:11b ) 83:17). From these observations, it has
proven to be difficult to improve the 2,3-cis selectivities without
understanding the origin of the selectivities. Accordingly, we
next turned our attention to the elucidation of the selectivities.
Influence of Isomerization of the Bromoallenes and
2-Ethynylaziridines on the Stereoselectivity. It is known that
abstraction of a proton on the allenic carbon substituted by a
bromine or chlorine atom gives an allenic anion species.20
Evidence for the generation of allene carbene intermediates by
elimination of bromide or chloride from such allenic anion
species has been also reported.20 Accordingly, a base-mediated
racemization of the bromoallene moiety, which could be possible
via such a process, might exert significant influence on our
aziridination reaction. To check the importance of the isomer-
ization of the starting bromoallenes on the observed stereose-
lectivity, we exposed the related compounds 18 and 19 bearing
a tertiary amino group to the aziridination conditions (Scheme
6). These allenes were synthesized by methylation of bromoal-
lenes 7b and 9b by the Mitsunobu reaction with MeOH (see
the Experimental Section). A slight degree of epimerization of
the (S,aS)-bromoallene 18 was observed (18:19 ) 5:1, 1H NMR)
by exposure to the cyclization conditions (NaH/DMF) for 3 h.
A similar result was obtained starting from (S,aR)-19 (19:18 )
4:1). However, these results suggest that the racemization of
the bromoallene moiety is not a predominant factor for the cis-
selective aziridination.
Scheme 6. Isomerization of Bromoallenes under the Aziridination
Conditions
To reveal the effect of the 4-substituent on the aziridination
reaction, we synthesized bromoallene (S)-13 (Scheme 4) from
L-serine, lacking an alkyl substituent at C-4 (see the Supporting
Information). Unfortunately, the treatment of 13 with NaH or
KH in DMF afforded no aziridine, and the starting material was
recovered unchanged. The allene 13 was also inert to the
cyclization conditions using t-BuOK in THF. In contrast, a
reaction with a metal amide base such as KHMDS, LDA, or
LHMDS in THF yielded mixtures of (R)- and (S)-aziridines 14,
although in low yields. From these observations, an alkyl
substituent at the 4-position is quite important for the efficient
and stereoselective conversion of bromoallenes into ethynyl-
aziridines, and the syn- and anti-SN2′ processes compete when
bromoallenes lacking the 4-alkyl group are used.
Aziridination of terminally silylated bromoallenes 15 and
16 accompanied desilylation (Scheme 5). Interestingly, while
(S,aS)-bromoallene 15 yielded completely desilylated cis-
aziridine 10b and trans-isomer 11b, cyclization of 16 afforded
cis-aziridines 10b and 17,13b the latter of which still has the
TMS group on the acetylene terminus. In both cases, the reaction
proceeded in high 2,3-cis selectivities and high yields.
Although deprotonation with NaH is usually accompanied
with the evolution of hydrogen gas, the formation of water from
NaOH present in NaH was reported.21 Mediated by the generated
water and alkaline in the reaction mixture, equilibration of 2,3-
cis- and 2,3-trans-2-ethynylaziridines might occur during the
aziridination. However, such equilibration of 2-ethynylaziridines
Since the 2,3-cis selectivities in the reaction of (S,aS)-allenes
7 were relatively low (entries 2-7, Table 2), we investigated
other reaction conditions using 7d. The addition of HMPA (10
equiv) to the NaH/DMF reaction mixture was less effective
(20) (a) Hennion, G. F.; Maloney, D. E. J. Am. Chem. Soc. 1951, 73, 4735-
4737. (b) Shiner, V. J.; Humphrey, J. S., Jr. J. Am. Chem. Soc. 1967, 89,
622-630. See also ref 6a and b.
(21) Organ, M. G.; Miller, M.; Konstantinou, Z. J. Am. Chem. Soc. 1998, 120,
9283-9290.
9
15258 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

cis-Selective Synthesis of 2-Ethynylaziridines
A R T I C L E S
Figure 3. Transition structures for the cyclization reaction of A and B [B3LYP/6-31+G(d), SCRF (Dipole, solvent ) DMF)]. cis-A and trans-A are the cis
and trans transition stuctures of A, respectively. cis-B and trans-B are the cis and trans transition stuctures of B, respectively. ∆E and ∆G are the differences
between the transition structures in energy and the Gibbs free energy at 298.15 K, respectively. µ shows the dipole moment.
has proven to be less important from the following observa-
tion: by monitoring the change in 2,3-trans-2-ethynylaziridine
11b under the cyclization conditions (NaH, DMF, room temper-
ature), the epimerization of 11b at C-2 did occur but slowly
(Figure 2), and the complete isomerization into the correspond-
ing 2,3-cis-aziridine 10b required over 10 h.22 This result cannot
explain the extremely high 2,3-cis selectivity on the aziridination
within 0.5-4 h. As expected, no isomerization of trans-aziridine
11b was observed by treatment with NaBr in DMF, which in
turn is produced from the reaction of bromoallene with NaH.
From these results, the origin of the cis selectivity would be
mainly assumed to be preference of the transition state for the
2,3-cis-aziridines over the trans-isomers, although the equilibra-
tion of the products might assist the increase of the selectivity.
Furthermore, the 2,3-cis-2-ethynylaziridine 10b was found to
be more stable than the corresponding trans-isomer 11b, which
is in good agreement with the relative thermodynamic stability
of 2-vinylaziridines.23
reactions of the amino anions A and B (Figure 3) were chosen
as model systems for the reactions of 7 and 9 in the presence
of NaH/DMF, respectively, which both gave the cis-aziridines
selectively (Table 2). All calculations were performed using the
Gaussian 98 program.24 Gibbs free energies are the values at
298.15 K and 1.00 atm obtained from frequency calculations.
The thermal energy corrections are not scaled.25 Vibrational
frequency calculations gave only one imaginary frequency for
(23) The thermodynamic preference of the related 2,3-cis-aziridines over their
trans-isomers is well documented in our previous study; see: (a) Ibuka,
T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.; Taga, T.;
Nakai, K.; Tamamura, H.; Fujii, N.; Yamamoto, Y. J. Org. Chem. 1997,
62, 999-1015. (b) Ibuka, T.; Mimura, N.; Ohno, H.; Nakai, K.; Akaji, M.;
Habashita, H.; Tamamura, H.; Miwa, Y.; Taga, T.; Fujii, N.; Yamamoto,
Y. J. Org. Chem. 1997, 62, 2982-2991. (c) Ohno, H.; Ishii, K.; Honda,
A.; Tamamura, H.; Fujii, N.; Takemoto, Y.; Ibuka, T. J. Chem. Soc., Perkin
Trans. 1 1998, 3703-3716. (d) Ohno, H.; Toda, A.; Fujii, N.; Miwa, Y.;
Taga, T.; Yamaoka, Y.; Osawa, E.; Ibuka, T. Tetrahedron Lett. 1999, 40,
1331-1334.
(24) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.9;
Gaussian, Inc.: Pittsburgh, PA, 1998.
Computational Investigation on the 2,3-cis Selective Aziri-
dination Reaction and Improvement of the Stereoselectivity.
To understand the stereoselectivity of this cis-aziridine formation
reaction, we have studied it computationally. The cyclization
(22) Although the 2,3-cis selective synthesis of 2-ethynylaziridines was possible
by the treatment of bromoallenes with NaH/DMF for a prolonged reaction
time, yields of the one-pot aziridination-equilibration reaction are unsat-
isfactory.
(25) For the scale factors for B3LYP, see: Bauschlicher, C. W., Jr.; Partridge,
H. J. Chem. Phys. 1995, 103, 1788-1791.
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15259

A R T I C L E S
Ohno et al.
Figure 4. Representative intermediates on the IRC of the cis cyclization reaction of B [B3LYP/6-31G(d)] together with those energies (kcal/mol). The
side-views without the PhSO2 and Me groups are also shown below.
all transition structures and confirmed that those structures are
authentic transition structures.
We further performed an intrinsic reaction coordinate (IRC)
analysis28 of the cis-cyclization reaction of B for deeper
understanding of this cyclization reaction. The IRC analysis was
carried out at the B3LYP/6-31G(d) level.29 Several representa-
tive intermediates on the IRC are shown together with those
energies in Figure 4. From the starting point of the reactant B,
the energy increases with the increase in the distance of the
C-Br bond. At the transition state (cis-B), the C-Br bond is
almost broken, while the C-N bond just starts to form. After
going beyond the transition state (cis-B), the energy decreases
rapidly with the decrease in the distance between the carbon
and the nitrogen atoms. The side-views of these structures
without the PhSO2 and Me groups clearly show that the allenic
carbon indicated by * starts to pyramidalize after the transition
state.
The transition structures for both cis- and trans-aziridine
cyclization of A and B were located by the B3LYP hybrid
functional26 together with the 6-31+G(d) basis set and the
Onsager solvation model (ꢀ ) 37.06 for DMF).27 The cis
transition structure (cis-A1) is favored over the trans transition
structure (trans-A1) by 1.41 kcal/mol. In the same way, the cis
transition structure (cis-B1) is favored over the trans transition
structure (trans-B1) by 4.35 kcal/mol. These energy differences
correspond to the product ratios 91.5:8.5 and 99.94:0.06 at
298.15 K, respectively. These calculations predict the stereo-
chemistry of the products correctly, and the predicted relative
selectivity is in good agreement with experimental results (see
entries 2-7 and 9-14 in Table 2). The transition structures
cis-A2 and trans-B2 have a different conformation of SO2Ph
part with much higher energies. Both cis-A2 and trans-B2 have
a small dipole moment (5.36 and 7.58) and an interaction
between the Ph-H and the leaving Br. The distances between
Ph-H and Br are 2.86 and 2.60 Å, which are less than the sum
of their van der Waals radii (3.05 Å).
In the cis transition structures (cis-A1 and cis-B1) in Figure
3, the sulfonamide oxygen is close enough to the allenic
hydrogen to interact with it and stabilize the transition state.
On the other hand, the sulfonamide oxygen in the trans transition
structures cannot interact with the allenic hydrogen; therefore,
it moved to the direction of the hydrogen connected to the next
(26) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(27) (a) Wong, M. W.; Frisch, M. J.; Wiberg, K. B. J. Am. Chem. Soc. 1991,
113, 4776-4782. (b) Wong, M. W.; Wiberg, K. B.; Frisch, M. J. J. Am.
Chem. Soc. 1992, 114, 523-529. (c) Wong, M. W.; Wiberg, K. B.; Frisch,
M. J. J. Am. Chem. Soc. 1992, 114, 1645-1652.
(28) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363-368. (b) Ishida, K.;
Morokuma, K.; Komornicki, A. J. Chem. Phys. 1977, 66, 2153.
(29) The calculations at B3LYP/6-31G(d) level gave similar energy differences
[e.g., ∆G (trans-B-cis-B) ) 3.92 kcal/mol, vs 4.35 kcal/mol] and similar
transition structures with the ones at B3LYP/6-31+G(d). Compare cis-B1
in Figure 3 with cis-B in Figure 4.
9
15260 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

cis-Selective Synthesis of 2-Ethynylaziridines
A R T I C L E S
Figure 5. cis-C, -C′ and trans-C, -C′ are the transition structures for the cylization reaction of C [B3LYP/6-31+G(d), SCRF (Dipole, solvent ) DMF)].
cis-C-H, cis-C′-H, trans-C-H, and trans-C′-H are the structures in which the ester group of cis-C, cis-C′, trans-C, and trans-C′ is replaced by hydrogen,
respectively. ∆E (gas) and ∆E show the energy difference in a gas phase and in DMF, respectively. µ shows the dipole moment.
carbon with some conformational change. This conformational
change may cause the increase of the energy. If the hydrogen
bond with the sulfonamide oxygen controls the stereochemistry,
then the change in the stereoselectivity depending on the
N-protecting group is explainable. We investigated the cycliza-
tion reaction of the amino anion C as a model system for the
reaction of N-Boc substrate 7a, which showed poor diastereo-
selectivity (Scheme 2). Figure 5 shows the transition structures
for both cis- and trans-aziridine cyclization of C located by
B3LYP/6-31+G(d) with the Onsager solvation model (ꢀ )
37.06 for DMF). The transition structure cis-C′ has the lowest
energy; on the other hand, trans-C is the most favorable
transition structure on the basis of the Gibbs free energy. The
product ratios (cis:trans) calculated from a Boltzmann distribu-
tion including all transition structures (cis-C, C′ and trans-C,
C′) are 58:42 by the potential energy and 31:69 by the Gibbs
free energy. These results show the selectivity of the reaction
is poor in accord with the experimental results (Scheme 2). Both
cis-C and trans-C have a similar dipole moment and a similar
ester conformation. The differences of these are only the
arrangement of methyl and bromoallenyl groups and the
direction of the leaving bromide. The steric repulsion between
methyl and bromoallenyl groups is plausible for cis-C. To
investigate the effect of the interactions between the protecting
group and the reaction center, we calculated the energies of the
structures cis-C-H and trans-C-H, in which the ester group
of cis-C and trans-C was replaced by hydrogen [B3LYP/
6-31+G(d), SP, SCRF (Dipole, DMF)]. The energy of trans-
C-H is lower than that of cis-C-H by 1.33 kcal/mol (∆E).
This energy difference can be explained by the steric repulsion.
Thus, trans-C is sterically favored over cis-C. In the same way,
the energies of cis-C′-H and trans-C′-H were calculated.
Since the dipole moments of cis-C-H and trans-C-H are
nearly equal to those of cis-C′-H and trans-C′-H, respectively,
those solvation energies (∆E - ∆Egas) are about the same (cis-
C-H and cis-C′-H, ∼2.8 kcal/mol; trans-C-H and trans-
C′-H, ∼0). In other words, transition structures with a larger
dipole moment can be better stabilized in a polar solvent such
as DMF. From these results, we can conclude that cis-C′ with
a larger dipole moment is favored by a polar solvent, while the
steric factor favors trans-C. Thus, the cis/trans selectivity is
low.
Furthermore, the energies of the structures cis-A1-H and
trans-A1-H, in which the arylsulfonyl group of cis-A1 and
trans-A1 was replaced by hydrogen, were calculated [B3LYP/
6-31+G(d), SP, SCRF (Dipole, DMF)] (Figure 6). The energy
of trans-A1-H is lower than that of cis-A1-H by 3.07 kcal/
mol in a gas phase and 0.84 kcal/mol in DMF (∆E). These
results show that trans-A1 is sterically favored over cis-A1. As
we discussed before, the sulfonamide oxygen of cis-A1 interacts
9
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A R T I C L E S
Ohno et al.
Figure 6. cis- and trans-A1-H, cis- and trans-B1-H, cis- and trans-gA2-H, cis-gB1-H, cis-gB2-H, and trans-gB2-H are the structures in which the
SO2Ph group of cis- and trans-A1, cis- and trans-B1, cis- and trans-gA2, cis-gB1, cis-gB2, and trans-gB2 is replaced by hydrogen, respectively. ∆E (gas)
and ∆E show the energy difference in a gas phase and in DMF, respectively [B3LYP/6-31+G(d), SCRF (Dipole, DMF)]. µ shows the dipole moment.
with the allenic hydrogen, while the sulfonamide oxygen of
trans-A1 interacts with the hydrogen connected to the next
carbon with some conformational change. This conformational
change or a weaker hydrogen bond disfavors trans-A1. Also,
cis-A1 with a larger dipole moment is favored over trans-A1.
After all, cis-A1 is favored over trans-A1 by 1.70 kcal/mol (∆E).
In the same way, the energies of cis-B1-H and trans-B1-H
were calculated. The energy of cis-B1-H is lower than that of
trans-B1-H by 3.91 kcal/mol in a gas phase and 2.51 kcal/
mol in DMF (∆E). Although the steric factor favors trans-B1-
H, the electrostatic repulsion between the attacking N- and the
leaving Br- is a great disadvantage for trans-B1-H. This
electrostatic repulsion and the hydrogen bond favor cis-B1 over
trans-B1 by 4.60 kcal/mol (∆E).
In addition, we studied the reaction of A and B in a gas phase
in order to see the solvent effect. The results are shown in Figure
7 [B3LYP/6-31+G(d)]. For the reaction of A, the cis transition
structure, cis-gA2, is favored over the trans transition structures,
trans-gA1 and trans-gA2, by 4.07 and 3.19 kcal/mol, respec-
tively. The structure corresponding to highly polar cis-A1
disappears in a gas phase, whereas the less polar structure like
trans-gA2 does not exist in solution. The energy difference
corresponds to the product ratio 99.4:0.6. From these data, we
can expect that the cis selectivity of the reaction of A will
increase in a solvent less polar than DMF. As will be described
in detail, this prediction is in excellent agreement with the
experimental results: the reaction of 7 in THF gave the cis
product in higher selectivity (>99:1, Table 3) than that in DMF
(79:21-91:9, Table 2). The reaction of B in a gas phase has
four kinds of transition structures. The energies of both cis-
gB1 and gB2 are similar to that of trans-gB2, while trans-gB1
has a much higher energy. From these data, the selectivity is
expected to drop in a solvent less polar than DMF. The energies
of the structures cis-gA2-H and trans-gA2-H, in which the
arylsulfonyl group of cis-gA2 and trans-gA2 was replaced by
hydrogen, were calculated [B3LYP/6-31+G(d), SP] (Figure 6).
The energy of trans-gA2-H is lower than that of cis-gA2-H
by 6.32 kcal/mol (∆E). Both the steric and electrostatic repulsion
disfavor cis-gA2-H. While, both the hydrogen bond and the
interaction between the Ph-H and the leaving Br favor cis-
gA2. These factors overwhelm the steric and electrostatic
repulsion. In the same way, the energies of cis-gB1-H, cis-
gB2-H, and trans-gB2-H were calculated. The energy of
cis-gB1-H is lower than that of cis-gB2-H by 0.56 kcal/mol
(∆E). Since the energy of cis-gB2 is lower than that of cis-
gB1, the stronger hydrogen bond in cis-gB2 is conceivable.
Although trans-gB2-H has a higher energy due to the
electrostatic repulsion, the energy of trans-gB2 is nearly equal
to those of cis-gB1 and cis-gB2 because of the interaction
between the Ph-H and the leaving Br. Thus, the combination
of the hydrogen bonds, the dipole moment of the transition
structures, and the steric and electrostatic repulsion controls the
stereochemistry.
We next investigated the reaction of 7 with NaH in a less
polar solvent, since computational calculations suggested that
use of a less polar solvent would give an improved selectivity.
The results are summarized in Table 3. As we expected, NaH-
mediated cyclization of 7b in toluene gave a slightly improved
selectivity (89:11, entry 1) compared with that in DMF (82:11,
Table 2). Furthermore, the reaction in THF afforded only 2,3-
cis-aziridine 10b as a single isomer (entry 2). Similarly, other
(S,aS)-bromoallenes 7d-g gave satisfactory results (entries 3-6).
A relatively low yield of the cis-aziridine 10f (48%, entry 5) in
the reaction of the bromoallene 7f bearing a siloxymethyl group
is due to the desilylation of 7f under the basic reaction conditions
(30% of the desilylated bromoallene was isolated). In sharp
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cis-Selective Synthesis of 2-Ethynylaziridines
A R T I C L E S
Figure 7. Transition structures for the cyclization reaction of A and B in a gas phase [B3LYP/6-31+G(d)]. cis-gA and trans-gA are the cis and trans
transition stuctures of A, respectively. cis-gB and trans-gB are the cis and trans transition stuctures of B, respectively. ∆E and ∆G are the differences
between transition structures in energy and the Gibbs free energy at 298.15 K, respectively. µ shows the dipole moment.
Table 3. NaH-Mediated Aziridination of Bromoallenes in Less
Scheme 7. Synthesis of Four- and Five-Membered Azacycles
Polar Solventsa
c
entry
allene
solvent
time (h)
ratiob (cis:trans)
yield (%)
1
2
3
4
5
6
7
8
9
7b
7b
7d
7e
7f
7g
9b
9b
9b
toluene
THF
THF
THF
THF
THF
toluene
THF
13
4
10b:11b ) 89:11
10b:11b ) >99:1
10d:11d ) >99:1
10e:11e ) >99:1
10f:11f ) >99:1
10g:11g ) >99:1
10b:11b ) 25:75
10b:11b ) 29:71
10b:11b ) 26:74
87
84
99
71
48e
77
20f
23g
92
17
22
5d
48
24
24
1d
are dependent on the structure of the starting materials (Scheme
7). Bromoallenes bearing a protected â-amino group (20 and
21) and γ-amino group (24 and 25) were prepared from L-valine
(see the Supporting Information). The exposure of 20 and 21
to the NaH-mediated cyclization conditions in DMF at room
temperature afforded 2,4-cis-4-alkyl-2-ethynylazetidine 227b
predominantly over the 2,4-trans-isomer 237b (22:23 ) 78:22
and 84:16, respectively), in good yields (70% and 84%). In
contrast, the cyclization of 24 and 25 with NaH/DMF at room-
temperature proceeded in excellent stereoselectivities (26:27 )
>99:1) and in good yields (77% and 94%, respectively). In these
cases, only a trace amount of trans-isomer 27 was detected by
1H NMR.
THF
a Reactions were carried out at 25 °C using NaH (1.2 or 1.3 equiv) unless
otherwise stated. bRatios were determined by 1H NMR (270 MHz) or
isolation of products. cCombined isolated yields. dThe reaction was
conducted at 50 °C. eDesilylated bromoallene (30%) was isolated. f76% of
g
9b was recovered. 72% of 9b was recovered.
contrast, treatment of (S,aR)-9b yielded the trans-aziridine 11b
in moderate selectivity (entries 7-9).
Synthesis of Four- and Five-Membered Azacycles. This
cyclization is also applicable to the synthesis of 2-ethynylaze-
tidines and 2-ethynylpyrrolidines, although the stereoselectivities
9
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A R T I C L E S
Ohno et al.
(4S,aS)-1-Iodo-5-methyl-4-[N-(2,4,6-trimethylphenylsulfonyl)ami-
no]hexa-1,2-diene (7c) (Table 1, Entry 3). By a procedure identical
to that described for the mesylation of the alcohol 6a, 6b (201 mg,
0.65 mmol) was converted into the corresponding crude mesylate.
According to the literature,3b a mixture of CuI (149 mg, 0.78 mmol)
and LiI (105 mg, 0.78 mmol) was dissolved in THF (3 mL) at room
temperature under nitrogen. After this solution was stirred for 1 h, a
solution of the crude mesylate in THF (1 mL) was added to this reagent
at room temperature. The mixture was stirred for 24 h at this
temperature, followed by quenching with saturated NH4Cl (1 mL) and
28% NH4OH (1 mL). The whole was extracted with Et2O, and the
extract was washed with water and dried over MgSO4. The filtrate was
concentrated under reduced pressure to give an oily residue, which was
purified by column chromatography over silica gel with n-hexane-
EtOAc (8:1) to give 7c (223 mg, 82% yield, >99% de) as colorless
Conclusion
We have developed a highly selective synthetic method of
2,3-cis-2-ethynylaziridines via the intramolecular amination of
bromoallenes. While the treatment of (S,aS)-bromoallenes 7 with
NaH/DMF gives 2,3-cis-aziridines 10 in good stereoselec-
tivity (2,3-cis:trans ) 79:21-91:9), the reaction of (S,aR)-
bromoallenes 9 with NaH/DMF shows high 2,3-cis selec-
tivity (91:9-99:1). These results are well supported by com-
putational investigations using the B3LYP density functional
calculations together with the 6-31+G(d) basis set and the
Onsager solvation model: the transition structures for the cis-
aziridines are more stable than those for trans-aziridines, both
in the aziridination of 7 and 9 in DMF. These energy dif-
ferences are ascribed to the combination of the hydrogen bonds
with the sulfonamide oxygen and the leaving Br, the dipole
moment of the transition structures, and the steric and electro-
static factors. Furthermore, the calculation predicted that use
of a less polar solvent could improve the cis selectivity in the
reaction of (S,aS)-allene 7. In fact, excellent selectivities
(>99:1) were observed when the reaction was carried out in
THF. This study clearly demonstrates that the computational
investigation can contribute to the improvement of the experi-
mental results.
crystals: mp 79 °C (n-hexane-Et2O); [R]24 +231 (c 1.00, CHCl3);
D
1
IR (KBr) cm-1 3296 (NHSO2), 1950 (CdCdC), 1323 (NHSO2); H
NMR (500 MHz, CDCl3) δ 0.85 (d, J ) 6.5 Hz, 3H, CMe), 0.92 (d, J
) 7.5 Hz, 3H, CMe), 1.83-1.92 (m, 1H, 5-H), 2.29 (s, 3H, PhMe),
2.64 (s, 6H, 2 × PhMe), 3.62-3.67 (m, 1H, 4-H), 4.80 (dd, J ) 7.5,
5.5 Hz, 1H, 3-H), 4.83 (d, J ) 8.5 Hz, 1H, NH), 5.62 (dd, J ) 5.5, 1.5
Hz, 1H, 1-H), 6.94 (s, 2H, Ph); 13C NMR (75 MHz, CDCl3) δ 18.0,
18.3, 20.9, 23.1 (2C), 33.2, 37.2, 57.3, 94.9, 132.0 (2C), 134.4, 138.9
(2C), 142.2, 204.0; MS (EI) m/z (%) 420 (M + 1, 0.05), 119 (100).
Anal. Calcd for C16H22INO2S: C, 45.83; H, 5.29; N, 3.34. Found: C,
45.72; H, 5.14; N, 3.32.
Experimental Section
(4S,aR)-1-Bromo-4-[(tert-butoxycarbonyl)amino]-5-methylhexa-
1,2-diene (9a) (Table 1, Entry 7). By a procedure identical to
that described for the preparation of the bromoallene 7a from 6a, the
alcohol 8a (455 mg, 2.0 mmol) was converted into 9a (477 mg,
82% yield, 99% de) as colorless needles: mp 50 °C (n-hexane);
General Methods. Melting points are uncorrected. Chemical shifts
are reported in parts per million downfield from internal Me4Si. Optical
rotations were measured in CHCl3. For flash chromatography, silica
gel 60 H (silica gel for thin-layer chromatography, Merck) or silica
gel 60 (finer than 230 mesh, Merck) was employed.
The known compounds 6a, 6b, 8a, 8b, and 11h were synthesized
according to the literature.13b For synthesis of 7b, 7d, 7e, 9b, and 25,
see the Supporting Information.
[R]27 -304 (c 0.61, CHCl3); IR (KBr) cm-1 3334 (NHCO2), 1959
D
(CdCdC), 1716 (NHCO2), 1502 (NHCO2); 1H NMR (300 MHz,
CDCl3) δ 0.94 (d, J ) 6.6 Hz, 3H, CMe), 0.96 (d, J ) 6.6 Hz, 3H,
CMe), 1.45 (s, 9H, CMe3), 1.85-1.93 (m, 1H, 5-H), 4.22 (br s, 1H,
4-H), 4.60 (d, J ) 7.8 Hz, 1H, NH), 5.44 (dd, J ) 5.7, 4.8 Hz, 1H,
3-H), 6.10 (dd, J ) 5.7, 2.7 Hz, 1H, 1-H); 13C NMR (75 MHz, CDCl3)
δ 17.9, 18.6, 28.3 (3C), 32.4, 53.8, 75.0, 79.6, 101.6, 155.4, 201.1;
MS (FAB) m/z 314 (MNa+, 81Br, 18), 312 (MNa+, 79Br, 18), 176 (100),
136 (48). HRMS (FAB) calcd for C12H20BrNNaO2 (MNa+, 79Br),
312.0575; found, 312.0567.
General Procedure for the Synthesis of Bromoallenes from
Propargyl Alcohols: Synthesis of (4S,aS)-1-Bromo-4-[(tert-butoxy-
carbonyl)amino]-5-methylhexa-1,2-diene (7a) (Table 1, Entry 1).
To a stirred mixture of the alcohol 6a (680 mg, 3.0 mmol) and Et3N
(2.08 mL, 15.0 mmol) in THF (5 mL) was added MsCl (0.465 mL,
6.0 mmol) at -78 °C. The stirring was continued for 0.5 h with
warming to -40 °C. The mixture was made acidic with 1 N HCl, and
the whole was extracted with Et2O. The extract was washed with water,
saturated NaHCO3, and brine and dried over MgSO4. Filtration and
solvent evaporation followed by a rapid filtration through a short pad
of SiO2 with Et2O gave a crude mesylate, which was used without
further purification. A mixture of CuBr‚Me2S (1.24 g, 6.0 mmol) and
LiBr (521 mg, 6.0 mmol) was dissolved in THF (7 mL) at room
temperature under nitrogen. After this solution was stirred for 2 min,
a solution of the crude mesylate in THF (3 mL) was added to this
reagent at room temperature. The mixture was stirred for 10 h at this
temperature and quenched with saturated NH4Cl (2 mL) and 28%
NH4OH (2 mL). The whole was extracted with Et2O, and the extract
was washed with water and dried over MgSO4. Filtration and solvent
evaporation followed by flash chromatography over silica gel with
n-hexane-EtOAc (1:8) gave 7a (762 mg, 88% yield) as a colorless
oil: [R]24D +118 (c 1.25, CHCl3); IR (KBr) cm-1 3342 (NHCO2), 1959
(CdCdC), 1701 (NHCO2), 1502 (NHCO2); 1H NMR (270 MHz,
CDCl3) δ 0.94 (d, J ) 7.0 Hz, 3H, CMe), 0.95 (d, J ) 6.8 Hz, 3H,
CMe), 1.46 (s, 9H, CMe3), 1.82-1.94 (m, 1H, 5-H), 4.18 (br s, 1H,
4-H), 4.55-4.65 (m, 1H, NH), 5.37 (dd, J ) 5.9, 5.4 Hz, 1H, 3-H),
6.09 (dd, J ) 5.9, 2.2 Hz, 1H, 1-H); 13C NMR (67.8 MHz, CDCl3) δ
18.1, 18.7, 28.5 (3C), 32.4, 54.2, 74.6, 79.6, 101.4, 155.2, 201.0; MS
(FAB) m/z 292 (MH+, 81Br, 12), 290 (MH+, 79Br, 15), 236 (92), 234
(100). HRMS (FAB) calcd for C12H21BrNO2 (MH+, 79Br), 290.0756;
found, 290.0745.
(4S,aR)-1-Iodo-5-methyl-4-[N-(2,4,6-trimethylphenylsulfonyl)ami-
no]hexa-1,2-diene (9c) (Table 1, Entry 9). By a procedure identical
to that described for the preparation of the iodoallene 7c from 6b, the
alcohol 8b (201 mg, 0.65 mmol) was converted into 9c (173 mg, 63%
yield, 99% de) as colorless crystals: mp 63 °C (n-hexane-Et2O);
[R]24 -344 (c 1.00, CHCl3); IR (KBr) cm-1 3286 (NHSO2), 1950
D
1
(CdCdC), 1325 (NHSO2); H NMR (300 MHz, CDCl3) δ 0.88 (d, J
) 6.6 Hz, 3H, CMe), 0.89 (d, J ) 6.9 Hz, 3H, CMe), 1.81-1.96 (m,
1H, 5-H), 2.30 (s, 3H, PhMe), 2.65 (s, 6H, 2 × PhMe), 3.79-3.87 (m,
1H, 4-H), 4.62 (d, J ) 9.0 Hz, 1H, NH), 4.95 (dd, J ) 5.7, 5.4 Hz,
1H, 3-H), 5.58 (dd, J ) 5.7, 2.7 Hz, 1H, 1-H), 6.95 (s, 2H, Ph); 13C
NMR (75 MHz, CDCl3) δ 17.8, 18.3, 20.9, 23.3 (2C), 33.5, 38.7, 56.0,
95.9, 132.0 (2C), 134.8, 138.8 (2C), 142.1, 203.7; MS (EI) m/z (%)
420 (MH+, 17), 136 (100). Anal. Calcd for C16H22INO2S: C, 45.83;
H, 5.29; N, 3.34. Found: C, 45.86; H, 5.19; N, 3.32.
General Procedure for the Synthesis of 2-Ethynylaziridines from
Bromoallenes. Synthesis of (2R,3S)-2-Ethynyl-3-isopropyl-N-(2,4,6-
trimethylphenylsulfonyl)aziridine (10b) and Its (2S,3S)-Isomer (11b)
from the Bromoallene (7b) (Table 2, Entry 2). To a stirred suspension
of NaH (9.6 mg, 0.24 mmol) in DMF (1 mL) under nitrogen was added
a solution of the bromoallene 7b (74.3 mg, 0.2 mmol) in DMF (1 mL)
at 0 °C. After the mixture was stirred at room temperature for 1 h, the
mixture was poured into ice-water (2 mL) saturated with NH4Cl. The
whole was extracted with Et2O, and the extract was washed with water
and dried over MgSO4. Filtration and solvent evaporation followed by
9
15264 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002

cis-Selective Synthesis of 2-Ethynylaziridines
A R T I C L E S
flash chromatography over silica gel with n-hexane-EtOAc (10:1) gave,
in order of elution, 2,3-cis-aziridine 10b (44.4 mg, 76% yield) and its
2,3-trans-isomer 11b (9.5 mg, 16% yield). When the reaction was
conducted in THF (room temperature, 4 h), the cis-aziridine 10b was
obtained as the single isomer in 84% yield (Table 3, entry 2). All the
spectroscopic data for 10b and 11b and the other known aziridines
10f, 10g, 11f, and 11g listed in Tables 2 and 3 were in good agreement
with the literature.13b,8
General Procedure for the Ring-Opening Reaction of Ethynyl-
aziridines. Synthesis of (4S,aR)-1-Bromo-4-[N-(2,4,6-trimethylphen-
ylsulfonyl)amino]-5-phenylpenta-1,2-diene (9h). To a solution of the
aziridine 11h (51.0 mg, 0.15 mmol) in CH2Cl2 (1 mL) was added
dropwise methanesulfonic acid (20 µL, 0.30 mmol) at 0 °C with stirring,
and the mixture was stirred for 15 min. The mixture was made alkaline
with saturated NaHCO3 at 0 °C and extracted with Et2O. The extract
was washed with water and dried over MgSO4. Concentration under
reduced pressure gave a crude mesylate 12h. A mixture of CuBr‚Me2S
(61.6 mg, 0.30 mmol) and LiBr (26.1 mg, 0.30 mmol) was dissolved
in THF (1 mL) at room temperature under nitrogen. After this solution
was stirred for 2 min, a solution of the crude mesylate 12h in THF (1
mL) was added to this reagent at room temperature. The mixture was
stirred for 1 h with warming to 50 °C and quenched with saturated
NH4Cl (0.5 mL) and 28% NH4OH (0.5 mL). The whole was extracted
with Et2O. The extract was washed with water and dried over MgSO4.
The filtrate was concentrated under reduced pressure to give an oily
residue, which was purified by column chromatography over silica gel
with n-hexane-EtOAc (5:1) to give 9h (50.7 mg, 80% yield, 88% de).
Recrystallization from n-hexane-Et2O gave 9h (94% de) as colorless
(2R,3S)-2-Ethynyl-3-isopropyl-N-(4-methylphenylsulfonyl)aziri-
dine (10d) and Its (2S,3S)-Isomer (11d) (Table 2, Entry 4). By a
procedure identical to that described for the preparation of the aziridines
10b and 11b from 7b, the bromoallene 7d (68.9 mg, 0.20 mmol) was
converted into the cis-aziridine 10d (46.0 mg, 87% yield) and the trans-
isomer 11d (6.5 mg, 12% yield). When the reaction was conducted in
THF (room temperature, 17 h), the cis-aziridine 10d was obtained as
the single isomer in 99% yield (Table 3, entry 3). Compound 10d:
colorless crystals; mp 111 °C (from n-hexane-Et2O); [R]25D -64.1 (c
1.05, CHCl3); IR (KBr) cm-1 3273 (NSO2), 2129 (CtC), 1329 (NSO2);
1H NMR (270 MHz, CDCl3) δ 0.84 (d, J ) 6.8 Hz, 3H, CMe), 1.00
(d, J ) 6.8 Hz, 3H, CMe), 1.55-1.69 (m, 1H, Me2CH), 2.19 (d, J )
1.9 Hz, 1H, CtCH), 2.45 (s, 3H, PhMe), 2.55 (dd, J ) 9.7, 7.0 Hz,
1H, 3-H), 3.35 (dd, J ) 7.0, 1.9 Hz, 1H, 2-H), 7.34 (d, J ) 8.1 Hz,
2H, Ph), 7.84 (d, J ) 8.1 Hz, 2H, Ph); 13C NMR (67.8 MHz, CDCl3)
δ 18.7, 20.2, 21.8, 28.4, 33.2, 50.7, 72.4, 76.6, 128.0 (2C), 129.6 (2C),
134.4, 144.7. Anal. Calcd for C14H17NO2S: C, 63.85; H, 6.51; N, 5.32.
Found: C, 63.59; H, 6.48; N, 5.26. Compound 11d: colorless oil;
crystals: mp 73-75 °C; [R]25 -182 (c 0.92, CHCl3, 94% de); IR
D
(KBr) cm-1 3356 (NHSO2), 1957 (CdCdC), 1329 (NHSO2); 1H NMR
(500 MHz, CDCl3) δ 2.28 (s, 3H, PhMe), 2.51 (s, 6H, 2 × PhMe),
2.85 (dd, J ) 13.5, 7.0 Hz, 1H, PhCHH), 2.89 (dd, J ) 13.5, 7.0 Hz,
1H, PhCHH), 4.09-4.15 (m, 1H, 4-H), 4.66 (d, J ) 7.0 Hz, 1H, NH),
5.38 (dd, J ) 5.5, 5.5 Hz, 1H, 3-H), 5.88 (dd, J ) 5.5, 2.5 Hz, 1H,
1-H), 6.88 (s, 2H, Ph), 7.04-7.06 (m, 2H, Ph), 7.13-7.23 (m, 3H,
Ph); 13C NMR (75 MHz, CDCl3) δ 20.9, 23.0 (2C), 41.7, 52.4, 75.4,
101.7, 127.0, 128.7 (2C), 129.3 (2C), 131.9 (2C), 133.8, 135.8, 139.0
(2C), 142.2, 200.9; MS (FAB) m/z (%) 422 (MH+, 81Br, 8), 420 (MH+,
[R]23 +29.1 (c 1.14, CHCl3); IR (KBr) cm-1 3267 (NSO2), 2125
D
(CtC), 1329 (NSO2); 1H NMR (300 MHz, CDCl3) δ 0.79 (d, J ) 6.6
Hz, 3H, CMe), 0.94 (d, J ) 6.6 Hz, 3H, CMe), 1.41-1.53 (m, 1H,
Me2CH), 2.45 (s, 3H, PhMe), 2.51 (d, J ) 1.8 Hz, 1H, CtCH), 2.92
(dd, J ) 7.8, 4.5 Hz, 1H, 3-H), 2.99 (dd, J ) 4.5, 1.8 Hz, 1H, 2-H),
7.33 (d, J ) 8.1 Hz, 2H, Ph), 7.88 (d, J ) 8.1 Hz, 2H, Ph); 13C
NMR (75 MHz, CDCl3) δ 19.0, 19.3, 21.6, 30.0, 33.8, 53.7, 74.9, 76.6,
128.1 (2C), 129.4 (2C), 136.1, 144.4; MS (FAB) m/z (%) 264 (MH+,
100). HRMS (FAB) calcd for C14H18NO2S (MH+), 264.1058; found,
264.1059.
79Br, 9), 136 (100); HRMS (FAB) calcd for C20H23BrNO2S (MH+, 79
Br), 420.0633; found, 420.0623.
-
(4S,aS)-1-Bromo-5-methyl-4-[N-(2,4,6-trimethylphenylsulfonyl)-
amino]-1-trimethylsilylhexa-1,2-diene (15). By a procedure identical
to that described for the synthesis of 7a from 6a, (3S,4S)-5-methyl-4-
[N-(2,4,6-trimethylphenylsulfonyl)amino]-1-trimethylsilylhex-1-yn-3-
ol13b (300 mg, 0.786 mmol) was converted into 15 (70 mg, 20% yield,
(2R,3S)-3-Benzyl-2-ethynyl-N-(4-methylphenylsulfonyl)aziri-
dine (10e) and Its (2S,3S)-Isomer (11e) (Table 2, Entry 5). By a
procedure identical to that described for the preparation of the aziri-
dines 10b and 11b from 7b, the bromoallene 7e (27.5 mg, 0.07
mmol) was converted into the cis-aziridine 10e (17.1 mg, 78% yield)
and the trans-isomer 11e (2.1 mg, 10% yield). When the reaction was
conducted in THF (room temperature, 22 h), the cis-aziridine 10e was
obtained as the single isomer in 71% yield (Table 3, entry 4). Com-
>99% de) as colorless crystals: mp 74-75 °C (n-hexane-Et2O); [R]27
D
+5.6 (c 0.51, CHCl3); IR (KBr) cm-1 3296 (NHSO2), 1940
1
(CdCdC), 1323 (NHSO2); H NMR (300 MHz, CDCl3) δ 0.18 (s,
9H, SiMe3), 0.83 (d, J ) 6.9 Hz, 3H, CMe), 0.88 (d, J ) 6.9 Hz, 3H,
CMe), 1.88-1.98 (m, 1H, 5-H), 2.30 (s, 3H, PhMe), 2.65 (s, 6H, 2 ×
PhMe), 3.70 (ddd, J ) 8.4, 5.7, 4.8 Hz, 1H, 4-H), 4.55 (d, J ) 8.4 Hz,
1H, NH), 5.01 (d, J ) 5.7 Hz, 1H, 3-H), 6.95 (s, 2H, Ph); 13C NMR
(75 MHz, CDCl3) δ -1.8 (3C), 17.9, 18.2, 20.9, 23.2 (2C), 32.9, 56.7,
90.6, 94.9, 132.1 (2C), 134.3, 138.8 (2C), 142.1, 202.6; MS (FAB)
m/z (%) 446 (MH+, 17, 81Br), 444 (MH+, 18, 79Br), 119 (100). HRMS
(FAB) calcd for C19H31BrNO2SSi (MH+, 79Br), 444.1028; found,
444.1028.
pound 10e: colorless needles; mp 115-116 °C (n-hexane-Et2O); [R]24
D
-48.1 (c 0.50, CHCl3); IR (KBr) cm-1 3288 (NSO2), 2127 (CtC),
1327 (NSO2); 1H NMR (500 MHz, CDCl3) δ 2.31 (d, J ) 1.5 Hz, 1H,
CtCH), 2.43 (s, 3H, PhMe), 2.85 (dd, J ) 14.5, 7.0 Hz, 1H, PhCHH),
2.95 (dd, J ) 14.5, 6.0 Hz, 1H, PhCHH), 3.07 (ddd, J ) 7.0, 6.5,
6.0 Hz, 1H, 3-H), 3.43 (dd, J ) 6.5, 1.5 Hz, 1H, 2-H), 7.10-7.18 (m,
5H, Ph), 7.22-7.23 (m, 2H, Ph), 7.68-7.70 (m, 2H, Ph); 13C
NMR (75 MHz, CDCl3) δ 21.6, 32.7, 34.5, 45.6, 73.3, 76.7, 126.6,
127.9 (2C), 128.5 (2C), 128.8 (2C), 129.7 (2C), 134.3, 136.7, 144.7;
MS (FAB) m/z (%) 312 (MH+, 68), 136 (100). HRMS (FAB) calcd
for C18H18NO2S (MH+), 312.1058; found, 312.1060. Compound
(4S,aR)-1-Bromo-5-methyl-4-[N-(2,4,6-trimethylphenylsulfonyl)-
amino]-1-trimethylsilylhexa-1,2-diene (16). By a procedure identical
to that described for the synthesis of 7a from 6a, (3R,4S)-5-methyl-
4-[N-(2,4,6-trimethylphenylsulfonyl)amino]-1-trimethylsilylhex-1-yn-
3-ol13b (840 mg, 2.2 mmol) was converted into 16 (296 mg, 30% yield,
>99% de) as colorless crystals: mp 97-99 °C (n-hexane-Et2O);
11e: colorless oil; [R]25 +34.6 (c 0.585, CHCl3); IR (KBr) cm-1
D
[R]24 -147 (c 1.00, CHCl3); IR (KBr) cm-1 3284 (NHSO2), 1940
1
D
3267 (NHSO2), 2127 (CtC), 1331 (NHSO2); H NMR (300 MHz,
1
(CdCdC), 1327 (NHSO2); H NMR (300 MHz, CDCl3) δ 0.21 (s,
CDCl3) δ 2.43 (s, 3H, PhMe), 2.47 (d, J ) 1.8 Hz, 1H, CtCH), 2.74
(dd, J ) 14.7, 6.9 Hz, 1H, PhCHH), 2.98 (dd, J ) 14.7, 5.7 Hz, 1H,
PhCHH), 3.08 (dd, J ) 4.2, 1.8 Hz, 1H, 2-H), 3.33 (ddd, J ) 6.9, 5.7,
4.2 Hz, 1H, 3-H), 6.99-7.03 (m, 2H, Ph), 7.13-7.23 (m, 5H, Ph),
7.68-7.71 (m, 2H, Ph); 13C NMR (75 MHz, CDCl3) δ 21.6, 34.2,
36.6, 48.9, 75.0, 76.5, 126.7, 127.8 (2C), 128.5 (2C), 128.7 (2C),
129.5 (2C), 136.2 (2C), 144.2; MS (FAB) m/z (%) 312 (MH+, 91), 91
(100). HRMS (FAB) calcd for C18H18NO2S (MH+), 312.1058; found,
312.1060.
9H, SiMe3), 0.75 (d, J ) 6.6 Hz, 3H, CMe), 0.84 (d, J ) 6.9 Hz, 3H,
CMe), 1.73-1.84 (m, 1H, 5-H), 2.23 (s, 3H, PhMe), 2.65 (s, 6H, 2 ×
PhMe), 3.75 (ddd, J ) 9.0, 5.4, 4.5 Hz, 1H, 4-H), 4.53 (d, J ) 9.0 Hz,
1H, NH), 5.05 (d, J ) 5.4 Hz, 1H, 3-H), 6.94 (s, 2H, Ph); 13C NMR
(75 MHz, CDCl3) δ -1.9 (3C), 17.7, 18.2, 20.9, 23.1 (2C), 33.0, 56.6,
91.0, 95.4, 132.0 (2C), 134.6, 138.8 (2C), 142.1, 202.8; MS (FAB)
m/z (%) 446 (MH+, 12, 81Br), 444 (MH+, 13, 79Br), 119 (100). HRMS
(FAB) calcd for C19H31BrNO2SSi (MH+, 79Br), 444.1028; found,
9
J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002 15265

A R T I C L E S
Ohno et al.
444.1026. Anal. Calcd for C19H30BrNO2SSi: C, 51.34; H, 6.80; N, 3.15.
Found: C, 51.45; H, 6.72; N, 3.00.
(MH+, 79Br), 386.0789; found, 386.0797. Anal. Calcd for C17H24-
BrNO2S: C, 52.85; H, 6.26; N, 3.63. Found: C, 52.68; H, 6.15; N,
3.63.
(4S,aS)-1-Bromo-5-methyl-4-[N-methyl-N-(2,4,6-trimethylphenyl-
sulfonyl)amino]hexa-1,2-diene (18). To a stirred solution of PPh3 (337
mg, 1.29 mmol) and 7b (68.4 mg, 0.184 mmol) in THF (2 mL) under
nitrogen were added MeOH (0.052 mL, 1.29 mmol) and DEAD (0.20
mL, 1.29 mmol) at 0 °C. The solution was stirred for 1.5 h at room
temperature, and the mixture was concentrated under reduced pressure.
The residue was purified by column chromatography over silica gel
with n-hexane-EtOAc (14:1) to give 18 (66.7 mg, 94% yield) as a
(5R,aR)-1-Bromo-6-methyl-5-[N-(2,4,6-trimethylphenylsulfonyl)-
amino]hepta-1,2-diene (21). By a procedure identical to that described
for the synthesis of 7a from 6a, (3S,5R)-6-methyl-5-[N-(2,4,6-trimeth-
ylphenylsulfonyl)amino]hept-1-yn-3-ol30 (113 mg, 0.35 mmol) was
converted into 21 (93 mg, 69% yield, >98% de). Recrystallization from
n-hexane-Et2O gave pure 21 as colorless crystals: mp 57 °C;
[R]25 -179 (c 0.87, CHCl3); IR (KBr) cm-1 3284 (NHSO2), 1956
D
1
colorless oil: [R]27 +45.5 (c 1.10, CHCl3); IR (KBr) cm-1 3056
(CdCdC), 1323 (NHSO2); H NMR (300 MHz, CDCl3) δ 0.77 (d, J
D
(NHSO2), 1957 (CdCdC), 1322 (NHSO2); 1H NMR (300 MHz,
CDCl3) δ 0.84 (d, J ) 6.0 Hz, 3H, CMe), 0.93 (d, J ) 6.3 Hz, 3H,
CMe), 1.81-1.95 (m, 1H, 5-H), 2.30 (s, 3H, PhMe), 2.61 (s, 6H, 2 ×
PhMe), 2.72 (s, 3H, NMe), 3.78-3.84 (m, 1H, 4-H), 5.40 (dd, J )
7.5, 5.7 Hz, 1H, 3-H), 6.01 (dd, J ) 6.0, 1.5 Hz, 1H, 1-H), 6.94 (s,
2H, Ph); 13C NMR (75 MHz, CDCl3) δ 19.5, 20.4, 20.9, 23.2 (2C),
28.1, 29.5, 61.1, 73.9, 97.0, 131.9 (2C), 132.7, 140.1 (2C), 142.4, 202.7;
MS (FAB) m/z (%) 388 (MH+, 81Br, 35), 386 (MH+, 79Br, 35), 119
(100). HRMS (FAB) calcd for C17H25BrNO2S (MH+, 79Br), 386.0789;
found, 386.0784.
) 6.9 Hz, 3H, CMe), 0.83 (d, J ) 6.9 Hz, 3H, CMe), 1.73-1.86 (m,
1H, 6-H), 2.23-2.29 (m, 2H, 4-CH2), 2.30 (s, 3H, PhMe), 2.64 (s, 6H,
2 × PhMe), 3.09-3.18 (m, 1H, 5-H), 4.46 (d, J ) 9.0 Hz, 1H, NH),
5.11 (ddd, J ) 7.5, 7.5, 5.7 Hz, 1H, 3-H), 5.91 (ddd, J ) 5.7, 2.1, 2.1
Hz, 1H, 1-H), 6.95 (s, 2H, Ph); 13C NMR (75 MHz, CDCl3) δ 17.4,
18.8, 20.9, 23.2 (2C), 30.9, 31.8, 58.6, 72.4, 96.4, 132.0 (2C), 134.7,
138.7 (2C), 142.1, 203.2; MS (FAB) m/z (%) 388 (MH+, 81Br, 29),
386 (MH+, 79Br, 32), 254 (100). HRMS (FAB) calcd for C17H25BrNO2S
(MH+, 79Br), 386.0789; found, 386.0783.
(2S,5R)-2-Ethynyl-5-isopropyl-N-(2,4,6-trimethylphenylsulfonyl)-
pyrrolidine (26). By a procedure identical to that described for the
preparation of the aziridines 10b and 11b from 7b, the bromoallene
25 (40 mg, 0.10 mmol) was converted into 2,5-cis-pyrrolidine 26 (30.0
mg, 94% yield, >99:1). Recrystallization from n-hexane-Et2O gave
pure 26. The stereochemistry of 26 was determined by NOE analysis.
(4S,aR)-1-Bromo-5-methyl-4-[N-methyl-N-(2,4,6-trimethylphen-
ylsulfonyl)amino]hexa-1,2-diene (19). By a procedure identical to that
described for the preparation of 18 from 7b, 9b (51.2 mg, 0.138 mmol)
was converted into 19 (52.6 mg, 99% yield): colorless oil; [R]25D -279
(c 0.955, CHCl3); IR (KBr) cm-1 3058 (NHSO2), 1957 (CdCdC), 1323
Colorless needles: mp 104 °C (n-hexane); [R]23 -35.8 (c 0.90,
1
D
(NHSO2); H NMR (300 MHz, CDCl3) δ 0.82 (d, J ) 6.6 Hz, 3H,
CHCl3); IR (KBr) cm-1 3261 (NSO2), 2114 (CtC), 1308 (NSO2); 1H
NMR (500 MHz, CDCl3) δ 0.72 (d, J ) 7.0 Hz, 3H, CMe), 0.83 (d, J
) 6.5 Hz, 3H, CMe), 1.72-1.81 (m, 1H, Me2CH), 1.91-2.00 (m, 3H,
3-CHH and 4-CH2), 2.10-2.17 (m, 1H, 3-CHH), 2.19 (d, J ) 2.5 Hz,
1H, CtCH), 2.30 (s, 3H, PhMe), 2.69 (s, 6H, 2 × PhMe), 3.80 (ddd,
J ) 6.0, 6.0, 6.0 Hz, 1H, 5-H), 4.64-4.66 (m, 1H, 2-H), 6.94 (s, 2H,
Ph); 13C NMR (75 MHz, CDCl3) δ 16.8, 19.9, 21.0, 22.9 (2C), 25.8,
30.3, 33.3, 50.3, 66.1, 71.4, 83.4, 131.8 (2C), 132.4, 140.6 (2C), 142.9;
MS (FAB) m/z (%) 320 (MH+, 100). HRMS (FAB) calcd for C18H26-
NO2S (MH+), 320.1684; found, 320.1674.
CMe), 0.97 (d, J ) 6.6 Hz, 3H, CMe), 1.81-1.98 (m, 1H, 5-H), 2.30
(s, 3H, PhMe), 2.61 (s, 6H, 2 × PhMe), 2.67 (s, 3H, NMe), 3.87 (ddd,
J ) 10.2, 6.3, 1.5 Hz, 1H, 4-H), 5.48 (dd, J ) 6.3, 5.7 Hz, 1H, 3-H),
5.97 (dd, J ) 5.7, 1.5 Hz, 1H, 1-H), 6.94 (s, 2H, Ph); 13C NMR (75
MHz, CDCl3) δ 19.6, 20.5, 20.9, 23.3 (2C), 28.2, 29.5, 60.8, 74.1,
97.8, 132.0 (2C), 132.9, 140.0 (2C), 142.4, 203.0; MS (FAB) m/z (%)
388 (MH+, 81Br, 37), 386 (MH+, 79Br, 38), 268 (72), 119 (100). HRMS
(FAB) calcd for C17H25BrNO2S (MH+, 79Br), 386.0789; found,
386.0769.
(5R,aS)-1-Bromo-6-methyl-5-[N-(2,4,6-trimethylphenylsulfonyl)-
amino]hepta-1,2-diene (20). By a procedure identical to that described
for the synthesis of 7a from 6a, (3R,5R)-6-methyl-5-[N-(2,4,6-tri-
methylphenylsulfonyl)amino]hept-1-yn-3-ol30 (113 mg, 0.35 mmol) was
converted into 20 (107 mg, 79% yield, >98% de). Recrystallization
from n-hexane-Et2O gave pure 20 as colorless crystals: mp 99 °C;
Acknowledgment. This work was supported by a Grant-in-
Aid for Encouragement of Young Scientists from the Ministry
of Education, Science, Sports and Culture of Japan. K.A. is
grateful for a Grant-in-Aid for Scientific Research on Priority
Areas (A) (403). Generous allotment of computational time from
the Institute for Molecular Science, Okazaki, Japan is deeply
acknowledged. H.H. is grateful to Research Fellowships of the
Japan Society for the Promotion of Science for Young Scientists.
[R]23 +81.0 (c 0.915, CHCl3); IR (KBr) cm-1 3288 (NHSO2), 1956
D
1
(CdCdC), 1323 (NHSO2); H NMR (300 MHz, CDCl3) δ 0.79 (d, J
) 6.6 Hz, 3H, CMe), 0.83 (d, J ) 6.9 Hz, 3H, CMe), 1.73-1.88 (m,
1H, 6-H), 2.23-2.28 (m, 2H, 4-CH2), 2.30 (s, 3H, PhMe), 2.65 (s, 6H,
2 × PhMe), 3.09-3.18 (m, 1H, 5-H), 4.50 (d, J ) 8.7 Hz, 1H, NH),
5.15 (ddd, J ) 7.2, 7.2, 5.7 Hz, 1H, 3-H), 5.89 (ddd, J ) 5.7, 2.1, 2.1
Hz, 1H, 1-H), 6.95 (s, 2H, Ph); 13C NMR (75 MHz, CDCl3) δ 17.6,
18.7, 20.9, 23.2 (2C), 30.7, 31.3, 58.4, 72.5, 96.3, 132.0 (2C), 134.6,
138.7 (2C), 142.1, 202.9; MS (FAB) m/z (%) 388 (MH+, 81Br, 31),
386 (MH+, 79Br, 30), 254 (100). HRMS (FAB) calcd for C17H25BrNO2S
Supporting Information Available: Synthetic procedures and
characterization for 6d, 6e, 7b, 7d-g, 8d, 8e, 9b, 9d-g, 13,
1
14, 24, and 25; H NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(30) For synthesis of the starting amino alcohols, see the Supporting Informa-
tion of ref 7d.
JA0262277
9
15266 J. AM. CHEM. SOC. VOL. 124, NO. 51, 2002