Stereoselective synthesis of 2-alkenylaziridines and 2-alkenylazetidines by palladium-catalyzed intramolecular amination of α- and β-amino allenes

Article abstract of DOI:10.1021/jo015683v

Whereas palladium-catalyzed reaction of N-arylsulfonyl-α-amino allenes with an aryl iodide (4 equiv) in the presence of potassium carbonate (4 equiv) in DMF at around 70 °C affords the corresponding 3-pyrroline derivatives, the reaction in refluxing 1,4-dioxane under otherwise identical conditions yields exclusively or most predominantly the corresponding 2-alkenylaziridines bearing an aryl group on the double bond. Similarly, N-arylsulfonyl-β-amino allenes can be also cyclized into the corresponding alkenylazetidines bearing a 2,4-cis-configuration under palladium-catalyzed cyclization conditions in DMF.

Full text of DOI:10.1021/jo015683v

4904
J . Org. Chem. 2001, 66, 4904-4914
Ster eoselective Syn th esis of 2-Alk en yla zir id in es a n d
2-Alk en yla zetid in es by P a lla d iu m -Ca ta lyzed In tr a m olecu la r
Am in a tion of r- a n d â-Am in o Allen es
Hiroaki Ohno,§ Miyuki Anzai,# Ayako Toda,# Shinya Ohishi,# Nobutaka Fujii,#
Tetsuaki Tanaka,*,§ Yoshiji Takemoto,# and Toshiro Ibuka†,#
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871,
and Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, J apan
t-tanaka@phs.osaka-u.ac.jp
Received April 13, 2001
Whereas palladium-catalyzed reaction of N-arylsulfonyl-R-amino allenes with an aryl iodide (4 equiv)
in the presence of potassium carbonate (4 equiv) in DMF at around 70 °C affords the corresponding
3-pyrroline derivatives, the reaction in refluxing 1,4-dioxane under otherwise identical conditions
yields exclusively or most predominantly the corresponding 2-alkenylaziridines bearing an aryl
group on the double bond. Similarly, N-arylsulfonyl-â-amino allenes can be also cyclized into the
corresponding alkenylazetidines bearing a 2,4-cis-configuration under palladium-catalyzed cycliza-
tion conditions in DMF.
In tr od u ction
been developed. Particularly, cyclization of amino allenes
using such metals as Pd(0 or II),5-7 Ag(I),8 and organo-
lanthanides9 has become quite useful methodology for the
synthesis of five- or six-membered azacycles, and several
groups have applied such cyclization to the total synthe-
sis of natural products.5c,8b,8g It is well documented that
cyclization of amino allene 1 with a one- or two-carbon
tether between the allene and the nitrogen atom (n ) 1
or 2) yields five- or six-membered azacycles selectively
by path A (Scheme 1), while an amino allene bearing a
longer carbon tether (n ) 3 or 4) also affords five- or six-
membered rings via path B. In contrast, ring-closure of
amino allenes bearing a shorter carbon chain (n ) 1 or
2) yielding three- or four-membered azacycles (path B)
had been unprecedented until quite recently.6,7
Currently, chiral aziridines bearing an alkenyl group
on one of the aziridine-ring carbons are widely used as
building blocks for the stereoselective synthesis of bio-
logically and synthetically important compounds.13,14
Chiral azetidines also constitute an important class of
compounds since they can be seen in several biologically
active compounds15 and used as efficient chiral ligands
for asymmetric syntheses.16 Recent development of aziri-
Transition metal-catalyzed cyclization of allenes1 bear-
ing a (pro-) nucleophilic functionality such as oxygen,2-4
nitrogen,5-10 and carbon11,12 has attracted much attention
in recent years, and many stereoselective processes have
* To whom correspondence should be sent.
§ Osaka University.
#
Kyoto University.
† Deceased J anuary 20, 2000.
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Chem. Soc. 1999, 121, 3633.
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10.1021/jo015683v CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/16/2001

Palladium-Catalyzed Intramolecular Amination
J . Org. Chem., Vol. 66, No. 14, 2001 4905
Sch em e 1. Cycliza tion of Am in o Allen es
Sch em e 2a
dine and azetidine chemistry prompts us to synthesize
these compounds bearing a wide variety of alkenyl groups
via cyclization of amino allenes. It was of considerable
interest to determine whether amino allenes can be
cyclized into strained aziridines and azetidines using a
transition-metal-based catalytic system and whether the
axial chirality of the amino allenes influences the chemo-
and stereoselectivity of the cyclization process.
a
Abbreviations: Mts ) 2,4,6-trimethylphenylsulfonyl; Mtr )
4-methoxy-2,3,6-trimethylphenylsulfonyl; TBS
methylsilyl.
) tert-butyldi-
Sch em e 3a
At almost the same time that we communicated our
palladium-catalyzed cyclization of amino allenes into
aziridines6a and azetidines,6b two independent communi-
cations describing a similar cyclization of â-amino allenes
1 (n ) 2, Scheme 1) into azetidines 3 (n ) 2) appeared.7
Thus, Kang and co-workers reported the palladium-
catalyzed cyclization of an N-protected amino allene with
hypervalent iodonium salts to afford a mixture of four-
and six-membered azacycles, albeit only in a single
example.7a Rutjes, Hiemstra, and their co-workers also
communicated that predominant formation of alkenyl-
azetidines over a six-membered ring can be accomplished
by exposure of some â-amino allenes to Pd(PPh3)4, K2CO3,
and aryl- or alkenyl halides (or triflates) in DMF only
when the reaction was stopped right after the consump-
tion of the starting material.7b They also described that
prolonged reaction time causes isomerization of alkenyl-
azetidines into the corresponding six-membered rings. In
a
Reagents: (a) (COCl)2, DMSO, CH2Cl2, then (i-Pr)2NEt; (b)
CBr4, PPh3, Et3N; (c) n-BuLi (3 equiv), then DMF; (d) NaBH4; (e)
MsCl, Et3N; (f) MeCu(CN)Li‚2LiCl; (g) TFA; (h) MtsCl, Et3N.
this paper, we present a full account of our investigation
into a highly stereoselective synthesis of N-protected-3-
alkyl-2-alkenylaziridines and azetidines from amino al-
lenes. This is a first example of metal-catalyzed azirid-
ination of amino allenes.17
(13) (a) Hudlicky, T.; Luna, H.; Price, J . D.; Rulin, F. J . Org. Chem.
1990, 55, 4683. (b) Pearson, W. H.; Bergmeier, S. C.; Degan, S.; Lin,
K.-C.; Poon, Y.-F.; Schkeryantz, J . M.; Williams, J . P. J . Org. Chem.
1990, 55, 5719. (c) Spears, G. W.; Nakanishi, K.; Ohfune, Y. Synlett
1991, 91. (d) Wipf, P.; Fritch, P. C. J . Org. Chem. 1994, 59, 4875. (e)
Davis, F. A.; Reddy, V. Tetrahedron Lett. 1996, 37, 4349. (f) J eong, J .
U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J . Am. Chem.
Soc. 1998, 120, 6844. (g) Cossy, J .; Blanchard, N.; Meyer, C. Tetrahe-
dron Lett. 1999, 40, 8361. (h) Chuang, T.-H.; Sharpless, K. B. Org.
Lett. 1999, 1, 1435. (i) Deng, W.-P.; Li, A.-H.; Dai, L.-X.; Hou, X.-L.
Tetrahedron 2000, 56, 2967.
(14) (a) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.;
Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
Engl. 1994, 33, 652. (b) 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. (c) 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. (d)
Toda, A.; Aoyama, H.; Mimura, N.; Ohno, H.; Fujii, N.; Ibuka, T. J .
Org. Chem. 1998, 63, 7053. (e) Ohno, H.; Ishii, K.; Honda, A.;
Tamamura, H.; Fujii, N.; Takemoto, Y.; Ibuka, T. J . Chem. Soc., Perkin
Trans. 1 1998, 3703. (f) Ishii, K.; Ohno, H.; Takemoto, Y.; Osawa, E.;
Yamaoka, Y.; Fujii, N.; Ibuka, T. J . Chem. Soc., Perkin Trans. 1 1999,
2155. (g) Ohno, H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2000, 2, 2161.
(15) (a) Knapp, S.; Dong, Y. Tetrahedron Lett. 1997, 38, 3813. (b)
Holladay, M. W.; Wasicak, J . T.; Lin, N.-H.; He, Y.; Ryther, K. B.;
Bannon, A. W.; Buckley, M. J .; Kim, D. J . B.; Decker, M. W.; Anderson,
D. J .; Campbell, J . E.; Kuntzweiler, T. A.; Donnelly-Roberts, D. L.;
Piattoni-Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric, S. P. J . Med.
Chem. 1998, 41, 407. (c) Dolle´, F.; Dolci, L.; Valette, H.; Hinnen, F.;
Vaufrey, F.; Guenther, I.; Fuseau, C.; Coulon, C.; Bottlaender, M.;
Crouzel, C. J . Med. Chem. 1999, 42, 2251.
Resu lts a n d Discu ssion s
Syn th esis of Am in o Allen es fr om r-Am in o Acid s.
The requisite nonracemic N-sulfonylated amino allenes
5 and 6 bearing a methyl group at the terminal sp2-
carbon atom were prepared in high yields starting from
natural R-amino acids following the published procedure
(Scheme 2).18 The terminal allene 8 was also prepared
by palladium(0)-catalyzed reduction of allylic bromo-
mesylate 7 as we described recently.19
The amino allene 14 bearing a methyl substituent on
the allenic carbon neighboring the amino group was
synthesized from (S)-valinol as shown in Scheme 3. Thus,
N-protected amino alcohol 9a was treated successively
with oxalyl chloride-DMSO-N,N-diisopropylethylamine
and CBr4-PPh3-Et3N affording the dibromide 10 in 53%
(17) For related cyclizations of allenes into three-membered rings,
see refs 2d, 2e, and 11f.
(16) (a) Starmans, W. A. J .; Thijs, L.; Zwanenburg, B. Tetrahedron
1998, 54, 629. (b) Starmans, W. A. J .; Walgers, R. W. A.; Thijs, L.; de
Gelder, R.; Smits, J . M. M.; Zwanenburg, B. Tetrahedron 1998, 54,
4991. (c) Shi, M.; J iang, J .-K. Tetrahedron: Asymmetry 1999, 10, 1673.
(d) Doyle, M. P.; Davies, S. B.; Hu, W. Chem. Commun. 2000, 867.
(18) Ohno, H.; Toda, A.; Fujii, N.; Takemoto Y.; Tanaka, T.; Ibuka,
T. Tetrahedron 2000, 56, 2811. See also: Ohno, H.; Toda, A.; Takemoto,
Y.; Fujii, N.; Ibuka, T. J . Chem. Soc., Perkin Trans. 1 1999, 2949.
(19) Ohno, H.; Toda, A.; Oishi, S.; Tanaka, T.; Takemoto, Y.; Fujii,
N.; Ibuka, T. Tetrahedron Lett. 2000, 41, 5131.

4906 J . Org. Chem., Vol. 66, No. 14, 2001
Ohno et al.
Sch em e 4a
Sch em e 5
Ta ble 2. P a lla d iu m (0)-ca ta lyzed Azir id in a tion of th e
r-Am in o Allen es 5 a n d 6a
a
Reagents: (a) TsCl, Et3N, DMAP; (b) NaI; (c) Zn, BrCH2CH2Br,
TMSCl, then CuCN, LiCl, then propargyl tosylate; (d) TFA; (e)
ArSO2Cl, Et3N.
Ta ble 1. Syn th esis of â-Am in o Allen es 18
SM
yield of 15
yield of 16
yield of 17
yield of 18
9a
9b
15a : 81%
15b: 70%
16a : 42%
16b: 57%
17a : 67%
17b: 62%
18a : 21%
18b: 74%
18c: 85%
18d : 66%
18e: 94%
18f: 80%
18g: 15%
18h : 45%
18i: 54%
reaction
yieldc
entry allene time (h)
ArI
PhI
product ratiob
(%)
1
2d
3
4
5
6
7
8
9
5a
5a
5a
5b
5c
5d
6a
6a
6b
6c
6d
6
2
6
4.5
4
1.2
2.5
3.5
4
4
1.2
21a /22a ) 82:18
21a /22a ) 84:16
80
83
64
79
79
74
79
44
73
77
71
9c
15c: 73%
16c: 19%
17c: 14%
PhI
4-MePhI 21b/22b ) 91:9
9d
9e
15d : 70%
16d : 27%
17d : 49%
17e: 65%
PhI
PhI
PhI
PhI
21c/22c ) 85:15
21d /22d ) 80:20
21e/22e ) 72:28
21a /22a /20a ) 2:90:8
15ea
16ea
a
For the synthesis of 15e and 16e, see ref 20a.
4-MePhI 21b/22b/20b ) 12:85:3
PhI
PhI
PhI
21c/22c/20c ) 17:67:16
21d /22d /20d ) 17:78:5
21e/22e/20e ) 23:64:13
10
11
yield (two steps). After treatment of 10 with n-BuLi and
DMF, the resulting aldehyde was reduced to the pro-
pargyl alcohol 11 with NaBH4 without purification. After
mesylation of 11, organocopper-mediated reaction of the
mesylate 12 gave 13, which was then converted into the
sulfonamide derivative 14.
a
All reactions were carried out in 1,4-dioxane under reflux using
Pd(PPh3)4 (4-20 mol %), K2CO3 (4 equiv) and ArI (4 equiv) unless
b
otherwise stated. Ratios were determined by 1H NMR (270 MHz)
or isolation. c Combined isolated yields. Pd(OAc)2/4PPh3 (10 mol
d
%) was used.
Next, â-amino allenes 18 were synthesized by the
reaction of amino acid-derived zinc/copper reagents with
propargyl tosylate (Scheme 4).20 Tosylation of the amino
alcohols 9 followed by iodination with NaI provided 16
in variable yields (Table 1). The zinc/copper reagents of
the type RCu(CN)ZnI were prepared by treatment of 16
with zinc and CuCN‚2LiCl, which were then allowed to
react with propargyl tosylate to yield the N-Boc-amino
allenes 17. The N-sulfonylated amino allenes 18 were
then synthesized by deprotection of 17 with TFA, followed
by sulfonylation with an Mts, Ts, or Mtr group. The yields
are summarized in Table 1.
Cycliza tion of r-Am in o Allen es in to Alk en yla zir i-
d in es. With the synthesized amino allenes in hand, we
next investigated the cyclization of R-amino allenes under
various reaction conditions. We first applied the known
cyclization condition of amino allenes according to the
literature.5e To our initial dismay, exposure of 5a and 6a
to Pd(PPh3)4, K2CO3, and iodobenzene in DMF afforded
undesired five-membered rings 19a and 20a , although
in a stereoselective manner (Scheme 5). Other known
cyclization using Ag(I) again resulted in the formation
of a five-membered ring as the sole isolable product.
After considerable unsuccessful experimentation, the
expected aziridine formation could be realized when the
palladium(0)-catalyzed cyclizations were conducted in
1,4-dioxane. The results are summarized in Table 2.
Typically, a dioxane solution of the amino allene 5a ,
iodobenzene (4 equiv), potassium carbonate (4 equiv), and
a catalytic amount of Pd(PPh3)4 (4 mol %) was refluxed
under argon yielding 2,3-cis- and 2,3-trans-2-alkenyl-
aziridines 21a and 22a in an 82:18 ratio in a good
combined yield (Table 2, entry 1). Arylation takes place
on the central carbon of the allenic moiety, in the same
manner as is described in the previous cyclization of
amino allenes.5,21 The most dominant factor in determin-
ing the site of intramolecular amination was found to be
the solvent employed. Although its exact role was un-
clear, dioxane was the solvent of choice for the aziridi-
nation of amino allenes. THF can also be used; however,
prolonged reaction time is necessary to achieve high
(20) (a) Dunn, M. J .; J ackson, R. F. W.; Pietruszka, J .; Turner, D.
J . Org. Chem. 1995, 60, 2210. (b) Duddu, J .; Eckhardt, M.; Furlong,
H.; Knoess, H. P.; Berger, S.; Knochel, P. Tetrahedron 1994, 50, 2415.
(c) Karstens, W. F. J .; Stol, M.; Rutjes, F. P. J . T.; Hiemstra, H. Synlett,
1998, 1126.
(21) In quite limited cases, arylation on the terminal carbon of the
allenic moiety, leading to the amination onto the central carbon, was
also reported by Hiemstra: Karstens, W. F. J .; Rutjes, F. P. J . T.;
Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275. See also, ref 5i.

Palladium-Catalyzed Intramolecular Amination
J . Org. Chem., Vol. 66, No. 14, 2001 4907
Sch em e 7a
F igu r e 1. Crystal structures of 20a and 21a .
Sch em e 6a
a
Reaction conditions: Ph-I (4 equiv), Pd(PPh3)4 (10 mol %),
K2CO3 (4 equiv), dioxane, reflux.
aziridine 26 and 2,3-trans-27 (74:26). Interestingly,
prolonged reaction time (2.5 h) raised the stereoselectivity
to 94:6, although such effect was hardly observed using
internal allenes 5 or 6 (Table 2). These results suggested
that the less stable 2,3-trans-2-alkenylaziridine 27 was
isomerized into the relatively more stable cis-isomer 26
under the cyclization conditions (vide infra). This 2,3-
cis-selectivity is in striking contrast to the formation of
related epoxides,2d,e in which the trans-alkenylepoxides
are preferably formed. Interestingly, the terminal amino
allene 14 bearing a methyl substituent gave an isomeric
mixture of 28 and 29 in which the trans-isomer 29
predominated (28:29 ) 4:96), presumably due to the
thermodynamic control.
Cycliza tion of â-Am in o Allen es in to Alk en yl-
a zetid in es. Having established the novel synthetic
method of various alkenylaziridines from R-amino al-
lenes, we next proceeded to cyclization of â-amino allenes
for the synthesis of alkenylazetidines. Considering the
results of the palladium-catalyzed cyclization of R-amino
allenes, we anticipated that the choice of 1,4-dioxane
would also be suitable for the cyclization of â-amino
allenes. Treatment of the â-amino allene 18a and iodo-
benzene, K2CO3, and catalytic Pd(PPh3)4 in dioxane
yielded an isomeric mixture of 2,4-cis- and 2,4-trans-3-
alkyl-2-alkenylazetidines 31a and 32 (82:18; Table 3,
entry 1), while in DMF, unexpectedly, 2,4-cis-isomer 31a
was afforded exclusively (entry 2).
Similar results were obtained using other â-amino
allenes 18b, 18c, 18e-i bearing a variety of alkyl
(isobutyl, benzyl, siloxymethyl, or methoxycarbonylethyl
group) and N-protecting groups (Mts, Ts, Mtr), affording
the 2,4-cis-4-alkyl-2-alkenylazetidines 31b, 31c, 31e-i
in good to excellent yields (entries 3, 4 and 6-10).
However, the amino allene 18d bearing a o-nitrophenyl-
sulfonyl (o-Ns) group yielded a considerable amount of
the six-membered ring 33 along with the desired azeti-
dine 31d (31d /33 ) 62:38; entry 5), in analogy with the
results reported by Hiemstra: an amino allene bearing
a strong electron-withdrawing p-nitrophenylsulfonyl (p-
Ns) group on the nitrogen atom yields a six-membered
ring exclusively under similar reaction conditions, while
N-toluenesulfonylated amino allene gives a four-mem-
bered ring predominantly.7b
a
Reaction conditions: â-bromostyrene (4 equiv), Pd(PPh3)4 (4
mol %), K2CO3 (4 equiv), dioxane, reflux, 1 h.
conversion. Although Pd(PPh3)4 proved to be the most
convenient catalyst, Pd(OAc)2/4PPh3 was equally effica-
cious (entry 2, Table 2). Similarly, by using p-iodotoluene
instead of iodobenzene, the expected aziridines 21b and
22b were obtained in good yield (entry 3).
As is revealed from Table 2, while all the (S,aS)-amino
allenes 5 yield the corresponding aziridines (21 and 22)
exclusively (entries 1-6), allenes 6 with (S,aR)-con-
figuration afford the desired aziridines (21 and 22) along
with a small amount of the corresponding pyrroline 20
(entries 7-11). Furthermore, although amino allenes 5
with (S,aS)-configuration yield the 2,3-cis-aziridines 21
predominantly (entries 1-6), the isomeric amino allenes
6 afford 2,3-trans-aziridines 22 as major products (entries
7-11). In all cases examined, the relative configuration
between the aryl and the methyl group on the double
bond in the aziridines is cis.
Confirmation of the structure and stereochemistry of
the pyrroline 20a and the alkenylaziridine 21a was based
on single-crystal X-ray data (Figure 1). The constitution
of the other aziridines was deduced from 1H NMR
spectral data (see the Supporting Information).
Alkenyl halides can be used instead of aryl halides in
the present aziridination of amino allenes (Scheme 6).
For example, when the (S,aS)-amino allene 5a was
subjected to palladium-catalyzed cyclization reaction in
dioxane in the presence of â-bromostyrene, 1,3-dienyl-
aziridines 23-25 were obtained as a chromatographically
separable mixture in 80% combined yield. However, it
should be noted that a small amount of 2,3-trans-Z-
alkenylaziridine 25 was isolated, although such isomers
could not be detected in the reaction mixture using aryl
halide (Table 2).
Next, cyclization of the terminal allenes 8 and 14
bearing no axial chirality was investigated (Scheme 7).
A mixture of the amino allene 8, Pd(PPh3)4 (10 mol %),
iodobenzene, and K2CO3 was heated in dioxane under
reflux for 1.5 h affording a separable mixture of 2,3-cis-
Other aryl- or alkenyl groups such as a 3-nitrophenyl,
(E)-styryl, or 4-methylphenyl group can also be intro-
duced on the double bond of the alkenylazetidines (entries
11-16).

4908 J . Org. Chem., Vol. 66, No. 14, 2001
Ohno et al.
Ta ble 3. P a lla d iu m (0)-Ca ta lyzed Azetid in e Syn th esis
Sch em e 9
fr om th e â-Am in o Allen esa
Con sid er a tion of th e Or igin of th e Ster eoselec-
tivities of th e P a lla d iu m -Ca ta lyzed Cycliza tion of
Am in o Allen es. Finally, we investigated the isomeriza-
tion reaction of alkenylaziridines and azetidines under
palladium-catalyzed cyclization conditions, to obtain
some information on the origin of the stereoselectivity
of the cyclization of the amino allenes. First, upon
exposure of the 2,3-trans-2-alkenylaziridine 22a having
a methyl substituent on the double bond to the cyclization
conditions, isomerization was observed only to a small
extent (Scheme 9). In contrast, the trans-aziridine 27
lacking a methyl substituent was easily isomerized into
the corresponding 2,3-cis-isomer under the identical
reaction conditions (cis/trans ) 85:15).
Our previous studies on the alkenylaziridines revealed
that 2,3-cis-2-alkenylaziridines are relatively more stable
than their 2,3-trans-isomers, and that 2,3-trans-isomers
can be easily isomerized into their cis-isomers upon
treatment with palladium(0), via η3-allylpalladium(II)
intermediates.14b,14c,22 Considering the results shown in
Scheme 9, the aziridine 27 is assumed to be reactive
enough toward palladium(0) to undergo equilibration
even in the presence of iodobenzene. However, since the
reactivity of 22a would be significantly low, presumably
due to steric hindrance, palladium(0) reacts with iodo-
benzene preferably than with 22a , to form phenylpalla-
dium(II) iodide. Accordingly, the stereoselective formation
of alkenylaziridines 22 and 23 bearing a methyl sub-
stituent (Table 2) would be controlled kinetically (vide
infra), while the 2,3-cis-selective formation of 26 (Scheme
7) would be thermodynamically controlled.
reaction
yieldc
(%)
entry allene
RI
time (h) product ratiob
1d
2
3
4
5
6
7
8
9
18a
18a
18b
18c
18d
18e
18f
18g
18h
18i
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
4
2
3.5
3
0.75
1
1
1.5
1
1.5
1
0.75
0.75
0.5
0.5
1.5
31a /32 ) 82:18
31a ) 100
31b ) 100
31c ) 100
31d /33 ) 62:38
31e ) 100
31f ) 100
31g ) 100
31h ) 100
31i ) 100
31j ) 100
31k ) 100
31l ) 100
31m ) 100
31n ) 100
31o ) 100
91
98
84
89
87
84
89
53
67
73
22
68
81
75
66
81
10
11
12
13
14
15
16
18b
18b
18c
18h
18e
18f
3-NO2PhI
PhCHdCHBr
PhCHdCHBr
PhCHdCHBr
4-MePhI
4-MePhI
a
All reactions were carried out in DMF at 70 °C using Pd(PPh3)4
(10 mol %), K2CO3 (4 equiv) and RI (4 equiv) without otherwise
stated. Ratios were determined by 1H NMR (270 MHz) or
b
d
isolation. c Combined isolated yields. Reaction was conducted in
1,4-dioxane under reflux.
Sch em e 8
A plausible rationale for the stereoselectivities of the
aziridination reaction of internal amino allenes is de-
picted in Figure 2.23 The phenylpalladium(II) iodide (37),
formed in situ from iodobenzene and Pd(0), would gener-
ate η3-allylpalladium complexes by the reaction with
(S,aS)-5 approaching from the less hindered face. Pre-
dominant formation of the complex A (path A) over B
(path B) can be expected due to the relatively small steric
repulsion of 37 with a methyl group than with an
aminomethyl group (RL). The cis-E-alkenylaziridine 21
Stereochemical assignments for the synthesized
alkenylazetidines were readily made by NOE experi-
ments (see the Supporting Information).
Unfortunately, as shown in Scheme 8, both isomers of
internal â-amino allenes 34 and 35, prepared from (S)-
valine (see the Supporting Information), afforded complex
mixtures of unidentified products under the palladium-
catalyzed cyclization conditions in DMF or dioxane. From
the above results, it is found that the cyclization of
terminal allenes bearing a protected amino group on the
â-position yields alkenylazetidines exclusively by proper
choice of the solvent and N-protecting group, although
internal â-amino allenes are not suitable for palladium-
catalyzed cyclization.
(22) Ohno, H.; Toda, A.; Fujii, N.; Miwa, Y.; Taga, T.; Yamaoka, Y.;
Osawa, E.; Ibuka, T. Tetrahedron Lett. 1999, 40, 1331.
(23) For another possible mechanism for palladium-catalyzed in-
tramolecular amination, see refs 5d, 5e, and 21.

Palladium-Catalyzed Intramolecular Amination
J . Org. Chem., Vol. 66, No. 14, 2001 4909
F igu r e 2. One plausible rationale for the stereoselective aziridination of (S,aS)-5 and (S,aR)-6.
would be formed as a main product by the intramolecular
nucleophilic attack of the nitrogen onto the stable syn-
η3-allylpalladium complex C derived from A24 via σ-π-σ
mechanism, reproducing palladium(0). Formation of the
minor cis-E-alkenylaziridine 22 can be rationalized by
path B, in that the allylpalladium complex B is isomer-
ized into the stable D, followed by cyclization (path B).
Similarly, the predominant formation of the trans-E-
alkenylaziridine 22 from (S,aR)-6 can be explained by
preferable complexation of 37 from the less hindered side
of 6, isomerization of the allylpalladium intermediate E
into D, and aziridination (path C). As described above,
the significant effect of the solvent on the regioselectivity
of the reaction was not rationalized at the present stage
of our understandings.
Figure 3 shows a plausible pathway for the preferable
formation of 2,4-cis-2-alkenylazetidine 31 over its 2,4-
trans isomer 32 (Table 3). The two π-allylpalladium
complexes G and I, which would be generated by the
reaction of â-amino allene 18 and phenylpalladium(II)
iodide, are expected to be interconvertible via a π-σ-π-
mechanism. Since unfavorable steric interaction between
the arylsulfonyl and allyl groups (in K) or arylsulfonyl
and R1 groups (in L) would destabilize these conformers,
predominant formation of 2,4-cis-azetidine 31 via the
(24) It is known that syn-η3-allylpalladium complexes are relatively
more stable than other isomers, even if the central carbon of the allyl
group is substituted by an aryl group. For example, see ref 1c.
F igu r e 3. Palladium-catalyzed stereoselective formation of
2,4-cis-azetidine 31 from â-amino allene 18.

4910 J . Org. Chem., Vol. 66, No. 14, 2001
Ohno et al.
conformer J is readily understood.25 In addition, the
predominant formation of 2,4-cis-azetidines would also
be influenced by palladium(0)-catalyzed equilibration, as
can be seen in the isomerization reaction of 36 (Scheme
9).
(10:1) to give 10 (5.26 g, 53% yield) as colorless needles from
n-hexane: mp 81 °C; [R]27 +29.6 (c 1.63, CHCl3); 1H NMR
D
(270 MHz, CDCl3) δ 0.95 (d, J ) 6.8 Hz, 3H), 0.96 (d, J ) 6.8
Hz, 3H), 1.45 (s, 9H), 1.77-1.90 (m, 1H), 4.12 (br s, 1H), 4.55
(br s, 1H), 6.30 (d, J ) 9.2 Hz, 1H). Anal. Calcd for C11H19
-
Br2NO2: C, 37.00; H, 5.36; N, 3.92. Found: C, 37.08; H, 5.31;
N, 3.62.
(4S)-4-[N-(ter t-Bu toxyca r bon yl)a m in o]-5-m eth ylh ex-2-
yn -1-ol (11). To a stirred solution of the dibromoalkene 10
(3.07 g, 8.6 mmol) in THF (17 mL) under argon was added
dropwise n-BuLi (1.53 M in n-hexane; 16.9 mL, 25.8 mmol) at
-78 °C. After 20 min, DMF (1.32 mL, 17.2 mmol) in THF (3
mL) was added dropwise at -78 °C and the mixture was
stirred for 1 h with warming to 0 °C. Saturated citric acid (5
mL) was added to the mixture at 0 °C and stirring was
continued for 10 min with warming to room temperature.
Concentration under reduced pressure gave an oily residue,
which was extracted with Et2O. The extract was washed with
water, and dried over MgSO4. Usual workup gave a crude
aldehyde. To a stirred solution of the crude aldehyde in EtOH
(10 mL) was added NaBH4 (325 mg, 8.6 mmol) at 0 °C and
the mixture was stirred for 10 min at this temperature. The
mixture was made acidic with citric acid, concentrated, and
extracted with a mixed solvent of Et2O-EtOAc (3:1). The
extract was washed with water and dried over MgSO4. Usual
workup followed by flash chromatography over silica gel with
Con clu sion
The described procedures provide reliable methodology
for the intramolecular amination of N-protected amino
allenes to the corresponding alkenylaziridines and
alkenylazetidines bearing an aryl or alkenyl group on the
double bond. Whereas palladium-catalyzed reaction of
(S,aS)-N-arylsulfonyl-2,3-dienylamines (R-amino allenes)
with an aryl iodine in the presence of potassium carbon-
ate in refluxing 1,4-dioxane yields 2,3-cis-E-2-alkenyl-
aziridines bearing an aryl group on the double bond
predominantly, reaction of (S,aR)-2,3-dienylamines af-
fords 2,3-trans-E-isomers preferably. In contrast, pal-
ladium-catalyzed cyclization of N-arylsulfonyl-3,4-dienyl-
amines (â-amino allenes) in DMF gives 2,4-cis-2-alkenyl-
azetidines exclusively, although a small amount of 2,4-
trans-isomers is formed when 1,4-dioxane is used as the
solvent. As far as we are aware, this is the first report
detailing the palladium-catalyzed cyclization of amino
allenes into three-membered azacycles.
n-hexane-EtOAc (3:1) gave 11 (1.50 g, 77% yield) as a colorless
1
oil: [R]21 -70.7 (c 1.08, CHCl3); H NMR (270 MHz, CDCl3)
D
δ 0.98 (d, J ) 6.8 Hz, 6H), 1.45 (s, 9H), 1.82-1.95 (m, 2H),
4.27-4.38 (m, 3H), 4.70-4.78 (m, 1H); MS (FAB) m/z 228
(MH+), 172 (base peak), 154, 128, 57; HRMS (FAB) calcd for
12H22NO3 (MH+) 228.1600, found 228.1596.
Exp er im en ta l Section
C
(4S )-4-[N -(t er t -B u t o x y c a r b o n y l)a m in o ]-5-m e t h y l-
Gen er a l Meth od s. Melting points are uncorrected. 1H
NMR spectra were recorded in CDCl3. Chemical shifts are
reported in parts per million downfield from internal Me4Si
(s ) singlet, d ) doublet, dd ) double doublet, ddd ) doublet
of double doublet, t ) triplet, q ) quartet, m ) multiplet).
Optical rotations were measured in CHCl3. For flash chroma-
tography, silica gel 60 H (silica gel for thin-layer chromatog-
raphy, Merck) or silica gel 60 (finer than 230 mesh, Merck)
was employed.
O-m eth a n esu lfon ylh ex-2-yn -1-ol (12). To a stirred mixture
of the alcohol 11 (750 mg, 3.3 mmol) and Et3N (2.28 mL, 16.5
mmol) in THF (7 mL) was added dropwise methanesulfonyl
chloride (0.767 mL, 9.9 mmol) at -78 °C. The mixture was
stirred for 30 min with warming to 0 °C. Saturated NaHCO3
(2 mL) was added at -78 °C, and stirring was continued
vigorously for 30 min at room temperature. The whole was
extracted with Et2O, and the extract was washed successively
with saturated citric acid, water, saturated NaHCO3, and
water and dried over MgSO4. Usual workup followed by flash
chromatography over silica gel with n-hexane-EtOAc (3:1)
(3S)-1,1-Dibr om o-3-[N-(ter t-bu toxyca r bon yl)a m in o]-4-
m eth ylp en t-1-en e (10). To a stirred solution of oxalyl chloride
(3.49 mL, 36.4 mmol) in CH2Cl2 (60 mL) at -78 °C under argon
was added dropwise a solution of DMSO (9.93 mL, 140 mmol)
in CH2Cl2 (10 mL). After 30 min, a solution of the alcohol 9a
(5.69 g, 28 mmol) in CH2Cl2 (15 mL) was added to the above
reagent at -78 °C, and the mixture was stirred for 1 h.
Diisopropylethylamine (34.3 mL, 196 mmol) was added to the
above solution at -78 °C and the mixture was stirred for 30
min with warming to 0 °C. The mixture was made acidic with
saturated citric acid and the whole was extracted with Et2O.
The extract was washed successively with water, 5% NaHCO3,
and water and dried over MgSO4. Concentration under reduced
pressure gave a crude aldehyde. To a stirred solution of CBr4
(18.6 g, 56 mmol) in CH2Cl2 (100 mL) was added PPh3 (29.4 g,
112 mmol) at 0 °C, and the mixture was stirred at this
temperature for 20 min. To the stirred mixture was added
Et3N (4.26 mL, 30.8 mmol) at 0 °C and the stirring was
continued for 10 min. The crude aldehyde in CH2Cl2 was added
dropwise to the above reagent at -78 °C with stirring, and
the mixture was stirred for 2 h with warming to 0 °C.
n-Hexane (300 mL) was added to the mixture, and insoluble
materials were removed by filtration. Concentration under
reduced pressure gave an oily residue, which was purified by
flash chromatography over silica gel with n-hexane-EtOAc
gave 12 (744 mg, 74% yield) as a colorless oil: [R]27 -61.5 (c
D
1
0.81, CHCl3); H NMR (270 MHz, CDCl3) δ 0.99 (d, J ) 7.0
Hz, 6H), 1.45 (s, 9H), 1.85-1.97 (m, 1H), 3.12 (s, 3H), 4.32-
4.41 (m, 1H), 4.70-4.77 (m, 1H), 4.87-4.88 (m, 2H); MS (FAB)
m/z 306 (MH+), 250 (base peak), 206, 154, 110, 93, 57; HRMS
(FAB) calcd C13H24NO5S (MH+) 306.1375, found 306.1387.
(4S)-4-[N-(ter t-Bu t oxyca r b on yl)a m in o]-3,5-d im et h yl-
h exa -1,2-d ien e (13). To a stirred solution of CuCN (823 mg,
9.2 mmol) and LiCl (778 mg, 18.4 mmol) in dry THF (10 mL)
under argon was added by syringe MeLi (1.14 M in Et2O; 8.07
mL, 9.2 mmol) at -78 °C, and the mixture was stirred for 10
min with warming to 0 °C. The mesylate 12 (702 mg, 2.3 mmol)
in dry THF (4 mL) was added to the above reagent at -78 °C
with stirring, and the stirring was continued for 30 min
followed by quenching with a solution of 1:1 saturated NH4Cl-
28% NH4OH (10 mL). The mixture was extracted with Et2O,
and the extract was washed with water and dried over MgSO4.
Usual workup followed by flash chromatography over silica
gel with n-hexane-EtOAc (15:1) gave 13 (509 mg, 98% yield)
as colorless crystals from cold n-hexane: mp 31 °C; [R]26D -67.9
(c 0.95, CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.86 (d, J ) 7.0
Hz, 3H), 0.96 (d, J ) 6.8 Hz, 3H), 1.45 (s, 9H), 1.69 (t, J ) 3.0
Hz, 3H), 1.82-1.93 (m, 1H), 3.84 (br s, 1H), 4.48-4.57 (m, 1H),
4.68-4.78 (m, 2H); 13C NMR (67.8 MHz, CDCl3) δ 16.9, 17.1,
22.2, 28.6, 30.5, 57.7, 76.6, 79.3, 100.3, 156.1, 205.9; MS (FAB)
m/z 226 (MH+), 170 (base peak), 169, 126, 116, 109, 57; HRMS
(FAB) calcd C13H24NO2 (MH+) 226.1807, found 226.1809.
(4S)-3,5-Dim eth yl-4-[N-(2,4,6-tr im eth ylph en ylsu lfon yl)-
a m in o]h exa -1,2-d ien e (14). Trifluoroacetic acid (1 mL) was
added to 13 (253 mg, 1.12 mmol) at room temperature with
stirring, and the mixture was stirred for 30 min at this
(25) Formation of aza-anionic planar intermediates cannot be ruled
out. However, these planar intermediates would not explain the
observed 2,4-cis-selective azetidine formation since there would be no
unfavorable steric interaction in such intermediates leading to the 2,4-
trans-azetidines. As shown in Figure 1 (X-ray), a nitrogen of the
sulfonamide group has a tetrahedral geometry. Accordingly, if the
anionic intermediate is formed, it will be cyclized into the azetidine
via a nonplanar transition state similar to J , K, and L.

Palladium-Catalyzed Intramolecular Amination
J . Org. Chem., Vol. 66, No. 14, 2001 4911
temperature. Concentration under reduced pressure gave a
residual oil, which was dissolved in CHCl3 (1 mL). To the above
solution, Et3N (1 mL) and 2,4,6-trimethylphenylsulfonyl
chloride (295 mg, 1.35 mmol) were added at 0 °C, and the
mixture was stirred for 1.5 h at room temperature. Saturated
NaHCO3 (0.5 mL) was added to the mixture with vigorous
stirring, and stirring was continued for 30 min at room
temperature. The whole was extracted with Et2O, and the
extract was washed successively with saturated citric acid,
water, 5% NaHCO3, and water and dried over MgSO4. Usual
workup followed by flash chromatography over silica gel with
n-hexane-EtOAc (10:1) gave 14 (261 mg, 76% yield) as
(200 mg, 2.2 mmol) and LiCl (190 mg, 4.4 mmol) in dry THF
(5 mL) was added to the mixture at -78 °C, and stirring was
continued for 10 min. Propargyl tosylate (2.91 g, 15 mmol) in
dry THF (3 mL) was added to the above stirring reagent at
-78 °C, and the mixture was stirred for 30 min with warming
to 0 °C and an additional 30 min at 0 °C. The mixture was
quenched with NH4Cl and the whole was extracted with Et2O.
The extract was washed successively with saturated citric acid,
water, 5% NaHCO3, and water and dried over MgSO4. Usual
workup followed by flash chromatography over silica gel with
n-hexane-EtOAc (5:1) gave 17a (1.5 g, 67% yield) as a
colorless oil: [R]15D -55.4 (c 1.03, CHCl3); 1H NMR (600 MHz,
CDCl3) δ 0.89 (d, J ) 6.8 Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H),
1.44 (s, 9H), 1.75-1.80 (m, 1H), 2.04-2.10 (m, 1H), 2.19-2.25
(m, 1H), 3.47-3.53 (m, 1H), 4.35-4.40 (m, 1H), 4.67 (ddd, J
colorless needles from n-hexane: mp 128 °C; [R]30 -14.6 (c
D
1
0.99, CHCl3); H NMR (270 MHz, CDCl3) δ 0.83 (d, J ) 6.5
Hz, 3H), 0.88 (d, J ) 6.5 Hz, 3H), 1.47 (t, J ) 3.2 Hz, 3H),
1.71-1.83 (m, 1H), 2.29 (s, 3H), 2.63 (s, 6H), 3.36-3.42 (m,
1H), 4.53-4.57 (m, 2H), 4.66 (d, J ) 9.2 Hz, 1H), 6.93 (s, 2H);
13C NMR (67.8 MHz, CDCl3) δ 16.0, 17.8, 19.8, 21.1, 23.4, 31.3,
61.7, 77.1, 99.1, 132.0, 135.0, 139.0, 142.0, 205.9. Anal. Calcd
for C17H25NO2S: C, 66.41; H, 8.20; N, 4.56. Found: C, 66.34;
H, 7.97; N, 4.34.
) 7.0, 2.7, 2.7 Hz, 2H), 5.05 (tdd, J ) 7.0, 7.0, 7.0 Hz, 1H); 13
C
NMR (150 MHz, CDCl3) δ 17.7, 19.3, 28.4, 31.4, 31.9, 55.5,
74.5, 86.4, 155.8, 209.5. MS (FAB) m/z 226 (MH+), 170 (base
peak), 130, 116; HRMS (FAB) calcd C13H24NO2 (MH+) 226.1807,
found 226.1797.
Gen er a l P r oced u r e for Syn th esis of (18) fr om (17).
(5R)-6-Meth yl-5-[N-(2,4,6-tr im eth ylph en ylsu lfon yl)am in o]-
h ep ta -1,2-d ien e (18a ). Trifluoroacetic acid (3 mL) was added
to 17a (1.4 g, 6.22 mmol) at room temperature with stirring,
and the mixture was stirred for 4 h at this temperature.
Concentration under reduced pressure gave a residual oil,
which was dissolved in CHCl3 (2 mL). To the above solution,
Et3N (4 mL) and 2,4,6-trimethylphenylsulfonyl chloride (1.5
g, 6.84 mmol) were added at 0 °C, and the mixture was stirred
for 3 h at room temperature. Saturated NaHCO3 was added
to the mixture with vigorous stirring, and stirring was
continued for 10 min at room temperature. The whole was
extracted with Et2O, and the extract was washed successively
with saturated citric acid, water, 5% NaHCO3, and water and
dried over MgSO4. Usual workup followed by flash chroma-
tography over silica gel with n-hexane-EtOAc (4:1) gave 18a
as a crystalline mass, which was recrystallized from n-hexane
to give pure 18a (400 mg, 21% yield) as colorless crystals: mp
99 °C; [R]23D -68.0 (c 0.63, CHCl3); 1H NMR (270 MHz, CDCl3)
δ 0.78 (d, J ) 6.8 Hz, 3H), 0.83 (d, J ) 6.8 Hz, 3H), 1.79-1.90
(m, 1H), 2.04-2.11 (m, 2H), 2.30 (s, 3H), 2.64 (s, 6H), 3.07
(dddd, J ) 8.4, 5.9, 5.9, 5.9 Hz, 1H), 4.47 (d, J ) 8.4 Hz, 1H),
4.63 (ddd, J ) 6.8, 2.8, 2.8 Hz, 2H), 4.80 (tdd, J ) 6.8, 6.8, 6.8
Hz, 1H), 6.94 (s, 2H); 13C NMR (67.8 MHz, CDCl3) δ 18.1, 18.8,
21.1, 23.4, 30.9, 31.4, 59.0, 73.5, 85.5, 132.1, 135.0, 138.9, 142.1,
209.7. Anal. Calcd for C17H25NO2S: C, 66.41; H, 8.20; N, 4.56.
Found: C, 66.25; H, 8.47; N, 4.56.
(2S ,5S )-5-I s o p r o p y l-2-m e t h y l-N -(2,4,6-t r im e t h y l-
p h en ylsu lfon yl)-3-p h en yl-3-p yr r olin e (19a ). To a stirred
mixture of the amino allene 5a (46.1 mg, 0.15 mmol), Pd(PPh3)4
(6.9 mg, 0.006 mmol; 4 mol %), and K2CO3 (82.8 mg, 0.6 mmol)
in DMF (1 mL) under argon was added PhI (0.0673 mL, 0.6
mmol), and the mixture was heated at 70 °C for 4 h. Water (2
mL) was added to the mixture, and the whole was extracted
with Et2O. The extract was washed with water and dried over
MgSO4. Usual workup followed by flash chromatography over
silica gel with n-hexane-EtOAc (9:1) gave 19a (23 mg, 40%
yield). Colorless oil: [R]27D +226 (c 0.92, CHCl3); 1H NMR (300
MHz, CDCl3) δ 0.51 (d, J ) 6.7 Hz, 3H), 0.90 (d, J ) 7.0 Hz,
3H), 1.34 (d, J ) 6.2 Hz, 3H), 1.99-2.10 (m, 1H), 2.29 (s, 3H),
2.69 (s, 6H), 4.74 (ddd, J ) 5.0, 3.4, 2.0 Hz, 1H), 5.13-5.21
(m, 1H), 5.88 (dd, J ) 2.0, 1.4 Hz, 1H), 6.93 (m, 2H), 7.27-
7.37 (m, 5H); MS (FAB) m/z 384 (MH+), 382, 341, 340 (base
peak), 200, 158, 119; HRMS (FAB) calcd C23H30NO2S (MH+)
384.1997, found 384.1991.
Gen er a l P r oced u r e for Syn th esis of th e Tosyla tes (15)
fr om (9). Syn th esis of (2S)-2-[N-(ter t-Bu toxyca r bon yl)-
a m in o]-3-m et h yl-O-(4-m et h ylp h en ylsu lfon yl)b u t a n -1-
ol (15a ). To a stirred solution of the alcohol 9a (2.03 g, 10
mmol) and Et3N (5.0 mL, 36 mmol) in THF (15 mL) were added
p-toluenesulfonyl chloride (2.28 g, 12 mmol) at room temper-
ature, and the mixture was stirred for 48 h at this tempera-
ture. Saturated NaHCO3 was added to the mixture, and the
whole was extracted with Et2O. The extract was washed
successively with saturated citric acid, water, 5% NaHCO3,
and water and dried over MgSO4. Usual workup gave a
crystalline mass, which was recrystallized from n-hexane-
Et2O (2:1) to give 15a (2.9 g, 81% yield) as colorless crystals:
mp 74 °C; [R]10 -26.7 (c 1.25, CHCl3); 1H NMR (270 MHz,
D
CDCl3) δ 0.86 (d, J ) 6.5 Hz, 3H), 0.90 (d, J ) 6.5 Hz, 3H),
1.41 (s, 9H), 1.73-1.88 (m, 1H), 2.45 (s, 3H), 3.45-3.55 (m,
1H), 4.01 (dd, J ) 10.0, 3.5 Hz, 1H), 4.08 (dd, J ) 10.0, 3.5
Hz, 1H), 4.60 (d, J ) 8.9 Hz, 1H), 7.34-7.37 (m, 2H), 7.77-
7.80 (m, 2H). Anal. Calcd for C17H27NO5S: C, 57.12; H, 7.61;
N, 3.92. Found: C, 56.96; H, 7.57; N, 3.67.
Gen er a l P r oced u r e for Syn th esis of th e Iod id es (16)
fr om (15). Syn th esis of (2S)-2-[N-(ter t-Bu toxyca r bon yl)-
a m in o]-1-iod o-3-m eth ylbu ta n e (16a ). To a stirred solution
of the tosylate 15a (14.5 g, 40.6 mmol) in Me2CO (100 mL)
was added NaI (12.2 g, 81.2 mmol) at room temperature, and
the mixture was stirred in the dark at this temperature for
24 h. Concentration under reduced pressure gave a crystalline
residue. Water was added and the whole was extracted with
Et2O. The extract was washed with water and dried over
MgSO4. Usual workup gave a crystalline mass, which was
recrystallized from cold n-hexane to give 16a (6.28 g, 42%
yield) as colorless crystals: mp 68 °C; [R]28 -24.1 (c 1.12,
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.92 (d, J ) 6.8 Hz, 3H),
0.96 (d, J ) 6.8 Hz, 3H), 1.45 (s, 9H), 1.70-1.84 (m, 1H), 3.06-
3.16 (m, 1H), 3.33 (dd, J ) 10.3, 4.3 Hz, 1H), 3.41 (dd, J )
10.3, 4.3 Hz, 1H), 3.57 (d, J ) 8.9 Hz, 1H). Anal. Calcd for
C
10H20INO2: C, 38.35; H, 6.44; N, 4.47. Found: C, 38.42; H,
6.22; N, 4.53.
Gen er a l P r oced u r e for Syn th esis of â-Am in o Allen es
(17) fr om (16). Syn th esis of (5R)-5-[N-(ter t-Bu toxyca r -
bon yl)a m in o]-6-m eth ylh ep ta -1,2-d ien e (17a ). Zinc powder
(5.23 g, 80 mmol) was washed successively with 0.1 N HCl (3
× 4 mL), EtOH (3 × 4 mL), and Et2O (3 × 4 mL), and was
dried by heating under reduced pressure at 120 °C for 2 h.
Dry DMF (4 mL) and 1,2-dibromoethane (0.2 mL, 1.6 mmol)
was added at room temperature. After exothermic reaction was
completed, the mixture was stirred for 5 min at 60 °C. After
cooling, TMSCl (0.2 mL, 1.6 mmol) was added to the mixture
at room temperature, and the mixture was sonicated at this
temperature for 30 min. The zinc was allowed to settle and
the supernatant was removed by syringe. Dry DMF (5 mL)
was added and the iodide 16a (3.13 g, 10 mmol) in dry DMF
(8 mL) was added at 0 °C with stirring, and the mixture was
stirred for 30 min at this temperature. A solution of CuCN
Gen er a l P r oced u r e for P a lla d iu m (0)-Ca ta lyzed
Cycliza tion of Am in o Allen es in 1,4-Dioxa n e. Syn th esis
of (4R,5S,2E)-4,5-Ep im in o-6-m eth yl-N-(2,4,6-tr im eth yl-
p h en ylsu lfon yl)-3-p h en ylh ep t-2-en e (21a ) a n d Its (4S,
5S,2E)-Isom er (22a ) fr om th e Am in o Allen e (5a ) (En tr y
1 in Ta ble 2). To a stirred mixture of the amino allene 5a
(23.1 mg, 0.075 mmol), Pd(PPh3)4 (8.7 mg, 0.0075 mmol; 10
mol %), and K2CO3 (41.4 mg, 0.3 mmol) in 1,4-dioxane (1 mL)
under argon was added PhI (0.0336 mL, 0.3 mmol), and the
mixture was heated under reflux for 6 h. Water (1 mL) was

4912 J . Org. Chem., Vol. 66, No. 14, 2001
Ohno et al.
added to the mixture, and the whole was extracted with Et2O.
The extract was washed with water and dried over MgSO4.
Usual workup followed by flash chromatography over silica
gel with n-hexane-EtOAc (15:1) gave, in order of elution, 2,3-
trans-aziridine 22a (4.1 mg, 14% yield) and 2,3-cis-aziridine
21a (18.9 mg, 65% yield). Compound 21a : colorless crystals
from n-hexane; mp 82 °C; [R]28D -39.2 (c 0.40, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 0.67 (d, J ) 6.3 Hz, 3H), 0.70 (d, J ) 6.4
Hz, 3H), 1.35-1.47 (m, 1H), 1.64 (dd, J ) 7.1, 1.3 Hz, 3H),
2.31 (s, 3H), 2.50 (dd, J ) 9.8, 7.1 Hz, 1H), 2.74 (s, 6H), 3.71
(ddq, J ) 7.1, 1.3, 1.3 Hz, 1H), 5.82 (qd, J ) 7.1, 1.3 Hz, 1H),
6.95-6.96 (m, 2H), 7.13-7.17 (m, 2H), 7.22-7.35 (m, 3H).
Anal. Calcd for C23H29NO2S: C, 72.03; H, 7.62; N, 3.65.
Found: C, 72.11; H, 7.82; N, 3.46. Compound 22a : colorless
of 5a , the amino allene 5c (116 mg, 0.3 mmol) was converted
into 21d (88 mg, 63% yield) and 22d (22 mg, 16% yield) by
treatment with Pd(PPh3)4 (13.9 mg, 0.012 mmol; 4 mol %), K2-
CO3 (166 mg, 1.2 mmol), and PhI (0.135 mL, 1.2 mmol) in 1,4-
dioxane under reflux for 4 h. Compound 21d : colorless needles
from n-hexane-Et2O (3:1); mp 94 °C; [R]30 -120 (c 0.66,
D
1
CHCl3); H NMR (270 MHz, CDCl3) δ 1.74 (dd, J ) 7.3, 1.4
Hz, 3H), 2.09 (s, 3H), 2.51 (dd, J ) 14.3, 9.2 Hz, 1H), 2.52 (s,
3H), 2.57 (s, 3H), 2.72 (dd, J ) 14.3, 4.3 Hz, 1H), 3.04 (ddd, J
) 9.2, 7.0, 4.3 Hz, 1H), 3.75 (ddd, J ) 7.0, 1.4, 1.4 Hz, 1H),
3.86 (s, 3H), 6.08 (qd, J ) 7.3, 1.4 Hz, 1H), 6.41 (s, 1H), 6.83-
7.02 (m, 5H), 7.17-7.39 (m, 5H). Anal. Calcd for C28H31NO3S:
C, 72.85; H, 6.77; N, 3.03. Found: C, 72.69; H, 6.76; N, 2.97.
Compound 22d : colorless oil; [R]29 +56.0 (c 0.68, CHCl3); 1H
D
oil; [R]29 +25.8 (c 1.25, CHCl3); 1H NMR (500 MHz, CDCl3) δ
NMR (270 MHz, CDCl3) δ 1.43 (d, J ) 7.0 Hz, 3H), 2.16 (s,
3H), 2.62 (s, 3H), 2.66 (s, 3H), 2.75 (ddd, J ) 10.0, 4.3, 4.1 Hz,
1H), 3.27 (dd, J ) 14.3, 10.0 Hz, 1H), 3.48 (dd, J ) 14.3, 4.1
Hz, 1H), 3.67 (d, J ) 4.3 Hz, 1H), 3.88 (s, 3H), 5.69 (q, J ) 7.0
Hz, 1H), 6.55 (s, 1H), 6.71-6.76 (m, 2H), 7.08-7.32 (m, 8 H);
MS (FAB) m/z 462 (MH+), 247, 246 (base peak), 213, 158, 149,
119, 91; HRMS (FAB) calcd C28H32NO3S (MH+) 462.2103,
found 462.2110.
D
1.00 (d, J ) 6.7 Hz, 3H), 1.14 (d, J ) 6.4 Hz, 3H), 1.43 (dd, J
) 7.0, 0.9 Hz, 3H), 2.20-2.29 (m, 1H), 2.30 (s, 3H), 2.34 (dd,
J ) 9.8, 4.3 Hz, 1H), 2.64 (s, 6H), 3.44 (ddd, J ) 4.3, 0.9, 0.6
Hz, 1H), 5.70 (qd, J ) 7.0, 0.6 Hz, 1H), 6.80-6.84 (m, 2H),
6.91 (s, 2H), 7.18-7.21 (m, 3H); MS (FAB) m/z 384 (MH+), 201,
200 (base peak), 185, 158, 119, 91, 73; HRMS (FAB) calcd
C
23H30NO2S (MH+) 384.1997, found 384.1991.
(4R,5S,2E)-4,5-Ep im in o-6-m eth yl-3-(4-m eth ylp h en yl)-
(4R,5R,2E)-6-(ter t-Bu tyld im eth ylsiloxy)-4,5-ep im in o-N-
(2,4,6-tr im eth ylp h en ylsu lfon yl)-3-p h en ylh ep t-2-en e (21e)
a n d Its (4S,5R,2E)-Isom er (22e) (En tr y 6 in Ta ble 2). By
a procedure identical with that described for the aziridination
of 5a , the amino allene 5d (41 mg, 0.1 mmol) was converted
into 21e (26 mg, 54% yield) and 22e (10 mg, 21% yield) by
treatment with Pd(PPh3)4 (23.1 mg, 0.02 mmol; 20 mol %), K2-
CO3 (55.2 mg, 0.4 mmol), and PhI (0.0443 mL, 0.4 mmol) in
1,4-dioxane under reflux for 1.2 h. Compound 21e: colorless
N-(2,4,6-tr im eth ylp h en ylsu lfon yl)h ep t-2-en e (21b) a n d
Its (4S,5S,2E)-Isom er (22b) (En tr y 3 in Ta ble 2). By a
procedure identical with that described for the aziridination
of 5a with PhI, the amino allene 5a (500 mg, 1.63 mmol) was
converted into 21b (376 mg, 58% yield) and 22b (35 mg, 6%
yield) by treatment with Pd(PPh3)4 (188 mg, 0.163 mmol; 10
mol %), K2CO3 (900 mg, 6.52 mmol), and 4-iodotoluene (1.42
g, 6.52 mmol) in 1,4-dioxane under reflux for 6 h. Compound
21b: colorless crystals from n-hexane; mp 85-87 °C; [R]27
oil; [R]27 -62.4 (c 0.67, CHCl3); 1H NMR (270 MHz, CDCl3) δ
D
D
-36.8 (c 0.95, CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.67 (d, J
) 6.5 Hz, 3H), 0.70 (d, J ) 6.2 Hz, 3H), 1.34-1.48 (m, 1H),
1.63 (dd, J ) 7.3, 1.1 Hz, 3H), 2.31 (s, 3H), 2.35 (s, 3H), 2.50
(dd, J ) 9.7, 7.3 Hz, 1H), 2.74 (s, 6H), 3.68-3.71 (m, 1H), 5.79
(qd, J ) 7.3, 1.1 Hz, 1H), 6.96 (s, 2H), 7.04-7.15 (m, 4H). Anal.
Calcd for C24H31NO2S: C, 72.51; H, 7.86; N, 3.52. Found: C,
-0.10 (s, 6H), 0.79 (s, 9H), 1.65 (dd, J ) 7.3, 1.4 Hz, 3H), 2.31
(s, 3H), 2.70 (s, 6H), 3.08 (ddd, J ) 7.3, 6.2, 6.2 Hz, 1H), 3.53-
3.56 (m, 2H), 3.62 (ddq, J ) 7.3, 1.4, 1.4 Hz, 1H), 5.85 (qd, J
) 7.3, 1.4 Hz, 1H), 6.95 (s, 2H), 7.17-7.34 (m, 5H); MS (FAB)
m/z 486 (MH+), 428, 303, 302, 170, 158, 119, 89, 75, 73 (base
peak); HRMS (FAB) calcd C27H40NO3SSi (MH+) 486.2498,
72.22; H, 7.99; N, 3.42. Compound 22b: colorless oil; [R]27
found 486.2490. Compound 22e: colorless oil; [R]27 +50.0 (c
D
D
+37.1 (c 0.65, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.00 (d, J
) 6.8 Hz, 3H), 1.15 (d, J ) 6.2 Hz, 3H), 1.43 (d, J ) 7.0 Hz,
3H), 2.18-2.29 (m, 1H), 2.30 (s, 6H), 2.35 (dd, J ) 9.5, 4.3 Hz,
1H), 2.64 (s, 6H), 3.43 (d, J ) 4.3 Hz, 1H), 5.68 (q, J ) 7.0 Hz,
1H), 6.70-6.73 (m, 2H), 6.91 (s, 2H), 6.99-7.02 (m, 2H); MS
(FAB) m/z 398 (MH+), 215, 214 (base peak), 200, 199, 172, 157,
119; HRMS (FAB) calcd C24H32NO2S (MH+) 398.2154, found
398.2154.
0.66, CHCl3); H NMR (270 MHz, CDCl3) δ 0.06 (s, 3H), 0.07
1
(s, 3H), 0.89 (s, 9H), 1.50 (d, J ) 7.0 Hz, 3H), 2.31 (s, 3H),
2.63 (s, 6H), 2.74 (ddd, J ) 8.4, 4.1, 3.8 Hz, 1H), 3.54 (d, J )
3.8 Hz, 1H), 4.02 (dd, J ) 10.8, 8.4 Hz, 1H), 4.29 (dd, J ) 10.8,
4.1 Hz, 1H), 5.71 (q, J ) 7.0 Hz, 1H), 6.93 (s, 2H), 6.96-7.00
(m, 2H), 7.19-7.23 (m, 3H); MS (FAB) m/z 486 (MH+), 428,
303, 302, 170, 147, 119, 89, 75, 73 (base peak); HRMS (FAB)
calcd C27H40NO3SSi (MH+) 486.2498, found 486.2504.
(4R ,5S ,2E )-4,5-E p im in o -N -(2,4,6-t r im e t h y lp h e n y l-
su lfon yl)-3,6-d ip h en ylh ex-2-en e (21c) a n d Its (4S,5S,2E)-
Isom er (22c) (En tr y 4 in Ta ble 2). By a procedure identical
with that described for the aziridination of 5a , the amino allene
5b (107 mg, 0.3 mmol) was converted into 21c (87 mg, 67%
yield) and 22c (15 mg, 12% yield) by treatment with Pd(PPh3)4
(13.9 mg, 0.012 mmol; 4 mol %), K2CO3 (166 mg, 1.2 mmol),
and PhI (0.135 mL, 1.2 mmol) in 1,4-dioxane under reflux for
(3R,4S)-3,4-Ep im in o-5-m eth yl-N-(2,4,6-tr im eth ylp h en -
ylsu lfon yl)-2-p h en ylh ex-1-en e (26) a n d Its (3S,4S)-Isom er
(27). By a procedure identical with that described for the
aziridination of 5a , the amino allene 8 (50 mg, 0.17 mmol) was
converted into 26 (48 mg, 76% yield) and 27 (2 mg, 3% yield)
by treatment with Pd(PPh3)4 (19.6 mg, 0.017 mmol; 10 mol
%), K2CO3 (94 mg, 0.68 mmol), and PhI (0.076 mL, 0.68 mmol)
in 1,4-dioxane (0.5 mL) under reflux for 2.5 h. Compound 26:
colorless crystals from n-hexane; mp 83 °C; [R]23D -95.5 (c 0.33,
CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.72 (d, J ) 6.8 Hz, 3H),
0.77 (d, J ) 6.8 Hz, 3H), 1.34-1.48 (m, 1H), 2.31 (s, 3H), 2.68-
2.79 (m, 1H), 2.76 (s, 6H), 3.83 (d, J ) 7.3 Hz, 1H), 5.26 (s,
1H), 5.57 (s, 1H), 6.97 (s, 2H), 7.29-7.37 (m, 3H), 7.45-7.48
(m, 2H); MS (FAB) m/z 370 (MH+), 187, 186 (base peak), 171,
144, 119, 117, 116, 91; HRMS (FAB) calcd C22H28NO2S (MH+)
4.5 h. Compound 21c: colorless oil; [R]31 -98.6 (c 0.69,
D
1
CHCl3); H NMR (270 MHz, CDCl3) δ 1.73 (dd, J ) 7.3, 1.4
Hz, 3H), 2.29 (s, 3H), 2.53 (dd, J ) 14.3, 8.9 Hz, 1H), 2.57 (s,
6H), 2.70 (dd, J ) 14.3, 4.9 Hz, 1H), 3.06 (ddd, J ) 8.9, 6.8,
4.9 Hz, 1H), 3.74 (ddd, J ) 6.8, 1.4, 1.1 Hz, 1H), 6.05 (qd, J )
7.3, 1.1 Hz, 1H), 6.81-7.36 (m, 12H); MS (FAB) m/z 432 (MH+),
249, 248 (base peak), 233, 158, 156, 119, 91; HRMS (FAB) calcd
C
27H30NO2S (MH+) 432.1997, found 432.1989. Compound
370.1841, found 370.1847. Compound 27: colorless oil; [R]23
D
1
22c: colorless oil; [R]28 +61.2 (c 1.15, CHCl3); H NMR (270
-2.94 (c 0.34, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.08 (d, J
) 6.8 Hz, 3H), 1.20 (d, J ) 6.5 Hz, 3H), 2.20-2.34 (m, 1H),
2.29 (s, 3H), 2.60 (dd, J ) 9.5, 4.6 Hz, 1H), 2.68 (s, 6H), 3.58
(d, J ) 4.3 Hz, 1H), 5.08 (s, 1H), 5.30 (s, 1H), 6.91 (s, 2H),
7.23-7.29 (m, 5H); MS (FAB) m/z 370 (MH+), 187 (base peak),
186, 144, 119, 117, 55; HRMS (FAB) calcd C22H28NO2S (MH+)
370.1841, found 370.1831.
D
MHz, CDCl3) δ 1.42 (d, J ) 6.8 Hz, 3H), 2.32 (s, 3H), 2.66 (s,
6H), 2.75 (ddd, J ) 10.3, 3.8, 3.8 Hz, 1H), 3.26 (dd, J ) 14.3,
10.3 Hz, 1H), 3.50 (dd, J ) 14.3, 3.8 Hz, 1H), 3.66 (d, J ) 3.8
Hz, 1H), 5.66 (q, J ) 6.8 Hz, 1H), 6.69-6.72 (m, 2H), 6.94 (s,
2H), 7.08-7.29 (m, 8H); MS (FAB) m/z 432 (MH+), 249, 248,
233, 221, 207, 158, 147, 119, 91, 73 (base peak), 55; HRMS
(FAB) calcd C27H30NO2S (MH+) 432.1997, found 432.2004.
(4 R ,5 S ,2 E )-4,5 -E p i m i n o -N -(4 -m e t h o x y -2 ,3,6 -t r i -
m eth ylp h en ylsu lfon yl)-3,6-d ip h en ylh ex-2-en e (21d ) a n d
Its (4S,5S,2E)-Isom er (22d ) (En tr y 5 in Ta ble 2). By a
procedure identical with that described for the aziridination
(3R,4S)-3,4-E p im in o-3,5-d im et h yl-N-(2,4,6-t r im et h yl-
p h en ylsu lfon yl)-2-p h en ylh ex-1-en e (28) a n d Its (3S,4S)-
Isom er (29). By a procedure identical with that described for
the aziridination of 5a , the amino allene 14 (61.5 mg, 0.20
mmol) was converted into 28 (4 mg, 5% yield) and 29 (59 mg,

Palladium-Catalyzed Intramolecular Amination
J . Org. Chem., Vol. 66, No. 14, 2001 4913
77% yield) by treatment with Pd(PPh3)4 (23.1 mg, 0.02 mmol;
10 mol %), K2CO3 (110 mg, 0.80 mmol), and PhI (0.090 mL,
aziridination of 5a , the amino allene 18d (40 mg, 0.12 mmol)
was converted into 31d (26 mg, 54% yield) and 33 (16 mg, 33%
yield) by treatment with Pd(PPh3)4 (19 mg, 0.012 mmol; 10
mol %), K2CO3 (66 mg, 0.48 mmol), and PhI (0.054 mL, 0.48
mmol) in DMF at 70 °C for 0.75 h. Compound 31d : colorless
0.80 mmol) in 1,4-dioxane (1.5 mL) under reflux for 1 h.
1
Compound 28: colorless oil; [R]35 -72.9 (c 0.78, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 0.40 (d, J ) 6.7 Hz, 3H), 0.92 (d, J
) 6.7 Hz, 3H), 1.27-1.32 (m, 1H), 2.00 (s, 3H), 2.28 (s, 3H),
2.67 (s, 6H), 2.80 (d, J ) 8.9 Hz, 1H), 5.51-5.53 (m, 2H), 6.92
(s, 2H), 7.28-7.35 (m, 3H), 7.42-7.44 (m, 2H); MS (FAB) m/z
oil; [R]18 -65.9 (c 0.18, CHCl3); 1H NMR (270 MHz, CDCl3) δ
D
0.89 (d, J ) 6.5 Hz, 3H), 0.90 (d, J ) 6.5 Hz, 3H), 1.53-1.69
(m, 2H), 1.76 (ddd, J ) 11.1, 7.6, 7.6 Hz, 1H), 1.96-2.04 (m,
1H), 2.58 (ddd, J ) 11.1, 8.4, 8.4 Hz, 1H), 4.32-4.44 (m, 1H),
5.04 (dd, J ) 8.4, 7.6 Hz, 1H), 5.39 (s, 1H), 5.58 (s, 1H), 7.30
(m, 5H), 7,60-7.75 (m, 3H), 7.95-7.99 (m, 1H); MS (FAB) m/z
401 (MH+), 271 (base peak), 214, 186, 156, 130, 105, 61, 59,
41; HRMS (FAB) calcd C21H25N2O4S (MH+) 401.1535, found
384 (MH+), 200 (base peak), 119; HRMS (FAB) calcd C23H30
-
NO2S (MH+) 384.1997, found 384.2001. Compound 29: color-
less oil; [R]35D -165 (c 0.45, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 0.51 (d, J ) 6.7 Hz, 3H), 0.96 (d, J ) 6.7 Hz, 3H), 1.51-1.54
(m, 1H), 1.65 (s, 3H), 2.28 (s, 3H), 2.63 (d, J ) 9.8 Hz, 1H),
2.66 (s, 6H), 5.68 (s, 1H), 5.69 (s, 1H), 6.90 (s, 2H), 7.26-7.34
(m, 3H), 7.41-7.44 (m, 2H); MS (FAB) m/z 384 (MH+), 201,
200 (base peak); HRMS (FAB) calcd C23H30NO2S (MH+)
384.1997, found 384.1983.
401.1527. Compound 33: colorless oil; [R]28 -54.2 (c 0.16,
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.87 (d, J ) 6.3 Hz, 3H),
0.91 (d, J ) 6.3 Hz, 3H), 1.26-1.39 (m, 1H), 1.50-1.68 (m,
2H), 2.05-2.11 (m, 1H), 2.52-2.60 (m, 1H), 4.00-4.07 (m, 1H),
4.19-4.27 (m, 1H), 4.57 (d, J ) 17.8 Hz, 1H), 6.03-6.07 (m,
1H), 7.28-7.40 (m, 5H), 7.63 (m, 3H), 8.05 (m, 1H); MS (FAB)
m/z 401 (MH+, base peak), 343, 271, 214, 186, 154, 136, 130,
91, 77, 55, 41; HRMS (FAB) calcd C21H25N2O4S (MH+) 401.1535,
found 401.1545.
(2S,4R)-4-Isop r op yl-N-(2,4,6-tr im eth ylp h en ylsu lfon yl)-
2-(1-p h en ylvin yl)a zetid in e (31a ) a n d Its (2R,4R)-Isom er
(32) (En tr y 1 in Ta ble 3). By a procedure similar to that
described for the aziridination of 5a , the amino allene 18a (50
mg, 0.16 mmol) was converted into 31a (47 mg, 75% yield)
and 32 (10 mg, 16% yield) by treatment with Pd(PPh3)4 (18.5
mg, 0.016 mmol; 10 mol %), K2CO3 (88 mg, 0.64 mmol), and
PhI (0.072 mL, 0.64 mmol) in 1,4-dioxane under reflux for 4
h. Compound 31a : colorless crystals from n-hexane; mp 75
(2S,4S)-4-Ben zyl-N-(2,4,6-tr im eth ylp h en ylsu lfon yl)-2-
(1-p h en ylvin yl)a zetid in e (31e) (En tr y 6 in Ta ble 3). By a
procedure similar to that described for the aziridination of 5a ,
the amino allene 18e (48 mg, 0.14 mmol) was converted into
31e (49 mg, 84% yield) by treatment with Pd(PPh3)4 (16.2 mg,
0.014 mmol; 10 mol %), K2CO3 (77.3 mg, 0.56 mmol), and PhI
(62.8 µL, 0.56 mmol) in DMF at 70 °C for 1 h. Colorless oil:
[R]28D +12.4 (c 1.27, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.81
(ddd, J ) 10.7, 8.1, 8.1 Hz, 1H), 2.30 (s, 3H), 2.45 (ddd, J )
10.6, 8.5, 8.5 Hz, 1H), 2.68 (s, 6H), 2.82 (dd, J ) 13.2, 10.4
Hz, 1H), 3.29 (dd, J ) 13.2, 4.0 Hz, 1H), 4.51 (dddd, J ) 10.4,
8.5, 8.1, 4.0 Hz, 1H), 4.98 (dd, J ) 8.5, 8.1 Hz, 1H), 5.13-5.15
(m, 2H), 6.92-6.93 (m, 2H), 7.09-7.28 (m, 10H); MS (FAB)
m/z 432 (MH+), 340, 302, 248, 183, 119 (base peak), 91; HRMS
(FAB) calcd C27H30NO2S (MH+) 432.1997, found 432.1983.
(2S ,4S )-4-Be n zyl-N -(4-m e t h ylp h e n ylsu lfon yl)-2-(1-
p h en ylvin yl)a zetid in e (31f) (En tr y 7 in Ta ble 3). By a
procedure similar to that described for the aziridination of 5a ,
the amino allene 18f (42 mg, 0.128 mmol) was converted into
31f (46 mg, 89% yield) by treatment with Pd(PPh3)4 (14.8 mg,
0.0128 mmol; 10 mol %), K2CO3 (70.7 mg, 0.512 mmol), and
°C; [R]25 -14.0 (c 0.29, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
0.82 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 6.8 Hz, 3H), 1.80 (ddd,
J ) 10.7, 8.1, 8.1 Hz, 1H), 2.00-2.11 (m, 1H), 2.28 (s, 3H),
2.42 (ddd, J ) 10.7, 8.9, 8.9 Hz, 1H), 2.64 (s, 6H), 4.31 (ddd, J
) 8.9, 8.1, 5.0 Hz, 1H), 4.98 (dd, J ) 8.9, 8.1 Hz, 1H), 5.12 (m,
1H), 5.14 (m, 1H), 6.90 (m, 2H), 7.15-7.20 (m, 2H), 7.24-7.30
(m, 3H). Anal. Calcd for C23H29NO2S: C, 72.03; H, 7.62; N,
3.65. Found: C, 71.83; H, 7.70; N, 3.70. Compound 32:
colorless oil; [R]25 +75.9 (c 0.49, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 0.80 (d, J ) 6.7 Hz, 3H), 1.17 (d, J ) 7.0 Hz, 3H),
2.05 (ddd, J ) 11.0, 8.6, 6.7 Hz, 1H), 2.27 (s, 3H), 2.37 (ddd, J
) 11.0, 8.9, 4.8 Hz, 1H), 2.56 (s, 6H), 2.67-2.77 (m, 1H), 4.53
(ddd, J ) 8.6, 4.8, 3.8 Hz, 1H), 5.01 (m, 1H), 5.05 (d, J ) 0.8
Hz, 1H), 5.21 (ddd, J ) 8.9, 6.7, 0.8 Hz, 1H), 6.86 (m, 2H),
7.13-7.18 (m, 2H), 7.23-7.27 (m, 3H); MS (FAB) m/z 384
(MH+), 254, 183, 120, 119 (base peak), 91; HRMS (FAB) calcd
C
23H30NO2S (MH+) 384.1998, found 384.2003.
(2S,4S)-4-Isobu t yl-N-(2,4,6-t r im et h ylp h en ylsu lfon yl)-
PhI (57.3 µL, 0.512 mmol) in DMF at 70 °C for 1 h. Colorless
1
2-(1-p h en ylvin yl)a zetid in e (31b) (En tr y 3 in Ta ble 3). By
a procedure similar to that described for the aziridination of
5a , the amino allene 18b (48 mg, 0.15 mmol) was converted
into 31b (50 mg, 84% yield) by treatment with Pd(PPh3)4 (17
mg, 0.015 mmol; 10 mol %), K2CO3 (83 mg, 0.60 mmol), and
PhI (0.067 mL, 0.60 mmol) in DMF at 70 °C for 3.5 h. Colorless
crystals from n-hexane: mp 85 °C; [R]25D -19.5 (c 0.92, CHCl3);
1H NMR (270 MHz, CDCl3) δ 0.86 (d, J ) 6.2 Hz, 6H), 1.50-
1.63 (m, 2H), 1.72 (ddd, J ) 10.8, 8.1, 8.1 Hz, 1H), 1.79-1.90
(m, 1H), 2.29 (s, 3H), 2.60-2.70 (m, 1H), 2.63 (s, 6H), 4.34-
4.45 (m, 1H), 5.01 (dd, J ) 8.6, 8.1 Hz, 1H), 5.10 (s, 2H), 6.90
(s, 2H), 7.16-7.32 (m, 5H). Anal. Calcd for C24H31NO2S: C,
72.51; H, 7.86; N, 3.52. Found: C, 72.67; H, 7.94; N, 3.37.
(2S,4S)-4-Isob u t yl-N-(4-m et h ylp h en ylsu lfon yl)-2-(1-
p h en ylvin yl)a zetid in e (31c) (En tr y 4 in Ta ble 3). By a
procedure similar to that described for the aziridination of 5a ,
the amino allene 18c (50 mg, 0.17 mmol) was converted into
31c (55 mg, 88% yield) by treatment with Pd(PPh3)4 (20 mg,
0.017 mmol; 10 mol %), K2CO3 (94 mg, 0.68 mmol), and PhI
(0.076 mL, 0.68 mmol) in DMF at 70 °C for 3 h. Colorless oil:
[R]28D -79.4 (c 1.04, CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.86
(d, J ) 6.2 Hz, 6H), 1.50-1.67 (m, 3H), 1.85-1.96 (m, 1H),
2.40 (ddd, J ) 10.5, 8.6, 8.6 Hz, 1H), 2.46 (s, 3H), 3.87-3.99
(m, 1H), 4.61 (dd, J ) 8.6, 7.8 Hz, 1H), 5.46 (s, 1H), 5.66 (s,
1H), 7.25-7.37 (m, 7H), 7.25-7.76 (m, 2H); MS (FAB) m/z 370
(MH+), 368, 240 (base peak), 214, 155, 91, 69, 55, 43; HRMS
(FAB) calcd C22H28NO2S (MH+) 370.1841, found 370.1833.
(2S ,4S )-4-Isob u t y l-N -(2-n it r o p h e n y lsu lfon yl)-2-(1-
p h en ylvin yl)a zetid in e (31d ) a n d 2-Isobu tyl-N-(2-n itr o-
p h en ylsu lfon yl)-5-p h en yl-2H,3H,6H-a zin e (33) (En tr y 5
in Ta ble 3). By a procedure similar to that described for the
oil: [R]30 -39.5 (c 0.98, CHCl3); H NMR (270 MHz, CDCl3)
D
δ 1.74 (ddd, J ) 11.1, 7.6, 7.6 Hz, 1H), 2.24 (ddd, J ) 11.1,
8.6, 8.6 Hz, 1H), 2.45 (s, 3H), 2.96 (dd, J ) 13.5, 9.2 Hz, 1H),
3.21 (dd, J ) 13.5, 3.5 Hz, 1H), 4.03-4.14 (m, 1H), 4.55 (dd, J
) 8.6, 7.6 Hz, 1H), 5.41 (s, 1H), 5.57 (s, 1H), 7.12-7.33 (m,
10H), 7.34-7.38 (m, 2H), 7.75-7.78 (m, 2H); MS (FAB) m/z
404 (MH+), 312, 274, 248, 155, 91 (base peak); HRMS (FAB)
calcd C25H26NO2S (MH+) 404.1684, found 404.1682.
(2S ,4R )-4-(t er t -B u t y ld im e t h y ls ilo x y )-N -(2,4,6-t r i-
m eth ylp h en ylsu lfon yl)-2-(1-p h en ylvin yl)a zetid in e (31g)
(En tr y 8 in Ta ble 3). By a procedure similar to that described
for the aziridination of 5a , the amino allene 18g (30 mg, 0.073
mmol) was converted into 31g (18 mg, 53% yield) by treatment
with Pd(PPh3)4 (8.5 mg, 0.0073 mmol; 10 mol %), K2CO3 (40
mg, 0.29 mmol), and PhI (0.031 mL, 0.29 mmol) in DMF at 70
°C for 1.5 h. Colorless oil: [R]28D +14.9 (c 0.25, CHCl3); 1H NMR
(270 MHz, CDCl3) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.87 (s, 9H),
2.13 (ddd, J ) 10.5, 7.8, 7.8 Hz, 1H), 2.28 (s, 3H), 2.48 (ddd, J
) 10.5, 8.9, 8.9 Hz, 1H), 2.63 (s, 6H), 3.63 (dd, J ) 8.1, 2.7 Hz,
1H), 3.84 (dd, J ) 10.5, 4.6 Hz, 1H), 4.42-4.51 (m, 1H), 5.03
(dd, J ) 8.9, 7.8 Hz, 1H), 5.09 (s, 1H), 5.13 (s, 1H), 6.88 (s,
2H), 7.16-7.28 (m, 5H); MS (FAB) m/z 486 (MH+), 428, 356,
298, 173, 119 (base peak), 73; HRMS (FAB) calcd C27H40NO3-
SSi (MH+) 486.2498, found 486.2506.
Meth yl (2′S,4′R)-3-[N-(2,4,6-Tr im eth ylp h en ylsu lfon yl)-
4-(1-p h en ylvin yl)a zetid in -2-yl]p r op a n oa te (31h ) (En tr y
9 in Ta ble 3). By a procedure similar to that described for
the aziridination of 5a , the amino allene 18h (28 mg, 0.080
mmol) was converted into 31h (23 mg, 67% yield) by treatment
with Pd(PPh3)4 (9.2 mg, 0.0080 mmol; 10 mol %), K2CO3 (44
mg, 0.32 mmol), and PhI (0.036 mL, 0.32 mmol) in DMF at 70

4914 J . Org. Chem., Vol. 66, No. 14, 2001
Ohno et al.
°C for 1 h. Colorless oil: [R]25D -24.1 (c 0.34, CHCl3); 1H NMR
(270 MHz, CDCl3) δ 1.72 (ddd, J ) 10.5, 8.2, 8.2 Hz, 1H), 1.93-
2.06 (m, 1H), 2.14-2.25 (m, 1H), 2.29 (s, 3H), 2.31-2.39 (m,
2H), 2.56-2.67 (m, 1H), 2.63 (s, 6H), 3.67 (s, 3H), 4.36-4.46
(m, 1H), 5.00 (dd, J ) 8.6, 8.1 Hz, 1H), 5.07 (s, 1H), 5.09 (s,
1H), 6.90 (s, 2H), 7.13-7.29 (m, 5H); MS (FAB) m/z 428 (MH+),
298, 244, 229, 183, 154, 119 (base peak), 98, 91, 77; HRMS
(FAB) calcd C24H30NO4S (MH+) 428.1896, found 428.1900.
213, 197, 149 (base peak), 134, 119, 91; HRMS (FAB) calcd
C25H32NO5S (MH+) 458.2002, found 458.2010.
Ack n ow led gm en t. This article is dedicated to the
memory of Prof. Toshiro Ibuka, the conceptual origina-
tor of this treatise, deceased on J anuary 20, 2000. The
authors are grateful to Professor Tooru Taga and Dr.
Yoshihisa Miwa (Graduate School of Pharmaceutical
Sciences, Kyoto University) for X-ray analyses of 20a
and 21a . This work was supported by the J apan Health
Sciences Foundation and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science,
Sports and Culture of J apan.
Met h yl
(2′S,4′R)-3-[N-(4-Met h oxy-2,3,6-t r im et h yl-
p h e n y ls u lfo n y l)-4-(1-p h e n y lv in y l)a ze t id in -2-y l]p r o -
p a n oa te (31i) (En tr y 10 in Ta ble 3). By a procedure similar
to that described for the aziridination of 5a , the amino allene
18i (35 mg, 0.092 mmol) was converted into 31i (30 mg, 73%
yield) by treatment with Pd(PPh3)4 (10.6 mg, 0.0092 mmol; 10
mol %), K2CO3 (50 mg, 0.36 mmol), and PhI (0.040 mL, 0.36
mmol) in DMF at 70 °C for 1.5 h. Colorless oil: [R]22D -15.8 (c
0.22, CHCl3); 1H NMR (270 MHz, CDCl3) δ 1.73 (ddd, J ) 11.1,
7.8, 7.8 Hz, 1H), 1.94-2.06 (m, 1H), 2.12 (s, 3H), 2.15-2.24
(m, 1H), 2.33-2.39 (m, 2H), 2.58-2.67 (m, 1H), 2.61 (s, 3H),
2.63 (s, 3H), 3.66 (s, 3H), 3.84 (s, 3H), 4.36-4.46 (m, 1H), 5.01
(dd, J ) 8.4, 7.8 Hz, 1H), 5.11 (s, 1H), 5.13 (s, 1H), 6.50 (s,
1H), 7.12-7.27 (m, 5H); MS (FAB) m/z 458 (MH+), 328, 244,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 15b -d , 16b -d , 17b -e, 18b -i, 20a -e, 23-25,
31j-o, 34, and 35; NOE experiment of the synthesized
1
aziridines and azetidines; H NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O015683V