Iodine atom transfer [3 + 2] cycloaddition reaction with electron-rich alkenes using N-tosyliodoaziridine derivatives as novel azahomoallyl radical precursors

Article abstract of DOI:10.1021/jo0266846

Treatment of N-tosyliodoaziridine derivatives with Et₃B efficiently produces various azahomoallyl radical (2-akenylamidyl radical) species which give oxygen-functionalized pyrrolidine derivatives through iodine atom transfer [3 + 2] cycloadditi

Full text of DOI:10.1021/jo0266846

Iod in e Atom Tr a n sfer [3 + 2] Cycloa d d ition Rea ction w ith
Electr on -Rich Alk en es Usin g N-Tosyliod oa zir id in e Der iva tives a s
Novel Aza h om oa llyl Ra d ica l P r ecu r sor s
Osamu Kitagawa, Shinsaku Miyaji, Yoichiro Yamada, Hiroki Fujiwara, and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, J apan
taguchi@ps.toyaku.ac.jp
Received November 11, 2002
Treatment of N-tosyliodoaziridine derivatives with Et3B efficiently produces various azahomoallyl
radical (2-akenylamidyl radical) species which give oxygen-functionalized pyrrolidine derivatives
through iodine atom transfer [3 + 2] cycloaddition with electron-rich alkenes such as enol ethers
and ketene acetal. The present cycloaddition reaction proceeds regioselectively via C-N bond
cleavage of an aziridinylalkyl radical intermediate and addition of the resulting azahomoallyl
radicals to the terminal carbon of an alkene. The reaction of alkenes with the cyclohexenylamidyl
radical generated from an optically active bicyclic iodoaziridine [(1S,2S,6S)-2-iodo-7-(p-toluene-
sulfonyl)-7-azabicyclo[4.1.0]heptane, 94% ee] also proceeds to give optically active octahydroindole
derivatives (84-93% ee).
In tr od u ction
centered radicals and the lack of a suitable radical
precursor.3,5
The [3 + 2] cycloaddition reaction of homoallyl radical
(3-alkenyl radical) species with an alkene is well-known
as a powerful means for one-step construction of a
cyclopentane skeleton from simple substrates.1 In con-
trast to many reports in relation to homoallyl radicals,
the reaction of an azahomoallyl radical (2-alkenylaminyl
radical), which should provide a useful synthetic method
to pyrrolidine derivatives, has previously been reported
in only one example.2 Most of the reported reactions of
nitrogen-centered radicals with an alkene have been
limited to intramolecular 5-exo-cyclization of 4-pentenyl-
aminyl radicals,3 while the intermolecular reaction is
uncommon.3,4 This fact may be due to the lower reactivity
of nitrogen-centered radicals in comparison with carbon-
In 1990, Newcomb et al. reported radical [3 + 2]
cycloaddition with an alkene using an azahomoallyl
radical species which was produced from N-allyl-N-
hydroxypyridine-2-thione carbamate (PTOC carbamate)
(eq 1).2 As far as we know, this report is the only example
* To whom correspondence should be addressed.Fax and Tel: +81-
426-76-3257. E-mail: (O.K.) kitagawa@ps.toyaku.ac.jp.
of the generation of an azahomoallyl radical and its
annulation reaction. However, this method using PTOC
carbamate still poses many problems: (1) a large excess
(100 equiv) of the alkene partner is required to get the
pyrrolidine product in reasonable yield (52-59%) because
of lower reactivity of the allylaminyl radical; (2) since the
application to alkenes other than enol ethers and reac-
tions with other 2-alkenylaminyl radicals except for the
allylaminyl radical were not investigated, the scope and
limitation of the reaction are unclear; (3) addition of a
(1) The reaction with electron-deficient alkenes: (a) Clieve, D. L.
J .; Angoh, A. G. J . Chem. Soc., Chem. Commun. 1985, 980-982. (b)
Cekovik, Z.; Saicic, R. Tetrahedron Lett. 1986, 27, 5893-5896. (c)
Curran, D. P.; Chen, M. J . Am. Chem. Soc. 1987, 109, 6558-6560. (d)
Barton, D. H. R.; Zard, S. Z.; daSilva, E. J . Chem. Soc., Chem. Commun.
1988, 285-287. (e) Feldman, K. S.; Romanelli, A. L.; Ruckle, R. E.,
J r.; Miller, R. F. J . Am. Chem. Soc. 1988, 110, 3300-3302. (f) Curran,
D. P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I,
Eds.; Pergamon Press: New York, 1991; Vol. 4, pp 779-831 and
references therein. The reaction with simple alkenes: (g) Miura, K.;
Fugami, K.; Ohshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29,
5135-5138. (h) Curran, D. P.; Chen, M.; Spletzer, E. J . Am. Chem.
Soc. 1989, 111, 8872-8878. (i) Chuang, C. P.; Hou, S. S.; Ngoi, T. H.
J . J . Chem. Res., Synop. 1991, 216-217. (j) Curran, D. P.; Seong, C.
M. Tetrahedron 1992, 48, 2157-2174. (k) Curran, D. P.; Seong, C. M.
Tetrahedron 1992, 48, 2175-2190. (l) Maslak, V.; Cekovic, Z.; Saicic,
R. N. Synlett 1998, 1435-1437. (m) McCarroll, A. J .; Walton, J . C. J .
Chem. Soc., Perkin Trans. 1 2001, 3215-3229. (n) Kitagawa, O.;
Fujiwara, H.; Taguchi, T. Tetrahedron Lett. 2001, 42, 2165-2167. (o)
Kitagawa, O.; Yamada, Y.; Fujiwara, H.;. Taguchi, T. J . Org. Chem.
2002, 67, 922-927. (p) Kitagawa, O.; Yamada, Y.; Sugawara, A.;
Taguchi, T. Org. Lett. 2002, 4, 1011-1013.
(3) For reviews, see: (a) Stella, L. Angew. Chem., Int. Ed. Engl. 1983,
22, 337-350. (b) Esker, J . L.; Newcomb, M. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: San Diego, 1993;
Vol. 58, pp 1-45. (c) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543-17593.
(4) For a review, see: Mackiewicz, P.; Furstoss, R. Tetrahedron 1978,
34, 3241-3260.
(5) (a) Newcomb, M.; Burchill, M. T.; Deeb, T. M. J . Am. Chem. Soc.
1988, 110, 6528-6535. (b) Musa, O. M.; Horner, J . H.; Shahin, H.;
Newcomb, M. J . Am. Chem. Soc. 1996, 118, 3862-3868.
(2) Newcomb, M.; Kumar, M. U. Tetrahedron Lett. 1990, 31, 1675-
1678.
10.1021/jo0266846 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/06/2003
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J . Org. Chem. 2003, 68, 3184-3189

Novel Azahomoallyl Radical Precursor
Brønsted acid for the generation of a more reactive
allylaminium radical6 and thiol as a hydrogen donor for
the resulting pyrrolidinylmethyl radical are required; (4)
further functionalization of the product should be dif-
ficult, because the resulting pyrrolidinylmethyl radical
is trapped by the hydrogen atom transferred from the
thiol. Thus, to achieve an efficient [3 + 2] cycloaddition
reaction with an azahomoallyl radical, the development
of a new precursor which generates a more reactive
radical species may be required.
such as allyl-, prenyl-, and cycloalkenylamidyl radicals
could be easily generated from the precursors, and the
[3 + 2] cycloaddition reaction with electron-rich alkenes
proceeded efficiently (eq 2).7
We report in detail an iodine atom transfer [3 + 2]
cycloaddition reaction with electron-rich alkenes using
various N-tosyliodoaziridine derivatives as new azaho-
moallyl radical precursors. The reaction with an azaho-
moallyl radical species generated from an optically active
iodoaziridine derivative is also described.
Quite recently, we and Oshima’s group independently
found that [3 + 2] cycloaddition of the N-tosyl-N-
allylamidyl radical with electron-rich alkenes and styrene
derivatives proceeds smoothly to give the pyrrolidine
products in good yields (eq 2 and 3).7,8 The success of
these reactions may be due to the use of the respective
(reactive) N-tosyl-N-allylamidyl radical generated from
N-tosyliodoaziridine derivatives 1 and N-allyl-N-chloro-
tosylamide 1′.
Resu lts a n d Discu ssion
Con cep t of th e Rea ction . We previously reported
that iodomethylcyclopropane derivatives having two
electron-withdrawing groups on the ring effectively work
as allylated active methine radical precursors, and the
iodine atom transfer [3 + 2] cycloaddition of these with
various alkenes proceeds to give the iodoalkylated cyclo-
pentane derivatives in good yields.1n-p As new azaho-
moallyl radical precursors, N-tosyliodoaziridine deriva-
tives 1 having a similar iodoalkylated three-membered
ring skeleton attracted our attention for the following
reasons: (1) when 1a is treated with a suitable radical
initiator, azahomoallyl radical species 1A might be
efficiently generated via regioselective cleavage of the
C-N bond of an aziridinylmethyl radical intermediate
(eq 2);9 (2) the reaction of 1A with an alkene would
possibly give an iodoalkylated pyrrolidine derivative
through an iodine atom-transfer mechanism (eq 2);10 (3)
since it is well-known that the reactivity of a nitrogen-
centered radical toward an alkene increases with de-
creasing electron density on the nitrogen atom,6 the
N-tosylamidyl radical may show higher reactivity than
a simple aminyl radical;11 (4) the mild conditions for the
generation of 1A and its addition to alkenes would make
it possible to use a wide range of alkenes; (5) the
generation of other 2-alkenylamidyl radicals in addition
to a simple allylamidyl radical may also be possible,
because various iodoaziridine derivatives 1a -1e can be
easily prepared through an iodoaziridination reaction of
N-allyl-N-tosylamide derivatives, previously reported by
our group (eq 4).12
Oshima’s method using N-allyl-N-chlorotosylamide 1′
affords the reaction with various styrene derivatives to
proceed efficiently to give the [3 + 2] cyloaddition
products in excellent yields, while with an electron-rich
alkene such as an enol ether, a considerable decrease in
the chemical yield is observed (eq 3).8 The reaction with
other 2-alkenylamidyl radicals was not investigated
except for that with the allylamidyl radical. On the other
hand, although our method using N-tosyliodoaziridine
derivatives 1 still has some problems to be solved in the
reaction with alkyl-substituted alkenes and styrene
derivatives (vide infra), various azahomoallyl radicals
(6) It has been well-known that electrophilic aminium cation radicals
and metal-complexed aminyl radicals formed by the addition of
Brønsted acid and Lewis acid are more reactive to alkenes than simple
aminyl radicals. (a) Neals, R. S.; Marcus, N. L. J . Org. Chem. 1967,
32, 3273-3284. (b) Surzur, J . M.; Stella, L.; Tordo, P. Bull. Soc. Chim.
Fr. 1970, 115-120. (c) Neale, R. S. Synthesis 1971, 1-15. (d) Dickinson,
J . M.; Murphy, J . A. J . Chem Soc., Chem. Commun. 1990, 434-436.
(e) Ha, C.; Musa, O.; Martinez, M. F.; Newcomb, M. J . Org. Chem.
1997, 32, 2704-2710. (f) Hemmerling, M.; Sjo¨holm, A.; Somfai, P.
Tetrahedron: Asymmetry 1999, 10, 4091-4094 and references therein.
(7) Our preliminary communication: Kitagawa, O.; Yamada, Y.;
Fujiwara, H.; Taguchi, T. Angew. Chem., Int. Ed. 2001, 40, 3865-3867.
(8) Tsuritani, T.; Shinokubo, H.; Ohshima, K. Org. Lett. 2001, 3,
2709-2711.
(9) Reports in relation to regioselective cleavage of aziridinylcarbinyl
radicals and their application to intramolecular radical cyclization: (a)
Dickinson, J . M.; Murphy, J . A. Tetrahedron 1992, 48, 1317-1326. (b)
De Kimpe, N.; J olie, R.; De Smaele, D. J . Chem Soc., Chem. Commun.
1994, 1221-1222. (c) De Smaele, D.; Bogaert, P.; De Kimpe, N.
Tetrahedron Lett. 1998, 39, 9797-9800. For a review, see: (d) Li, J . J .
Tetrahedron 2001, 57, 1-24.
(10) Since the formation of an aziridinyl methyl radical is
a
thermodynamically favorable process, an iodine-transfer process lead-
ing to the resulting pyrrolidinyl methyl radical intermediate from
iodoaziridine 1 should proceed efficiently.
J . Org. Chem, Vol. 68, No. 8, 2003 3185

Kitagawa et al.
TABLE 1. Ra d ica l [3 + 2] Cycloa d d ition of
Iod oa zir id in es 1a w ith En ol Eth er s
TABLE 2. Ra d ica l [3 + 2] Cycloa d d ition of Va r iou s
Iod oa zir id in es 1 w ith Vin yloxytr im eth ylsila n e
a
b
Yield of isolated product. The ratio was determined by 300
MHz 1H NMR.
[3 + 2] Cycloa d d ition of Va r iou s Aza h om oa llyl
Ra d ica ls w ith Vin yl Eth er Der iva tives. Initially, the
[3 + 2] cycloaddition of 1a with butyl vinyl ether (2 equiv)
was investigated under several free-radical iodine atom
transfer conditions [Et3B/O2, (n-Bu3Sn)2/hν, AIBN/∆]
(Table 1). The reaction with 1 equiv of Et3B13 in C6H6 or
CH2Cl2 gave good results; thus, 3-butoxy-4-iodomethyl-
pyrrolidine 2a was obtained in 62% and 64% yield,
respectively (entries 3, 4).
a
b
Yield of isolated product. The ratio was determined on the
basis of isolated products. c The product (tert-iodide) was subse-
quently treated with DBU. A mixture of internal double bond
d
Under the optimized conditions [enol ether (2 equiv),
Et3B (1 equiv), 0.13 M 1a in CH2Cl2 at room temperature
for 10 h], the cycloaddition reaction with various azaho-
moallyl radicals was further examined (Table 2). Since
the present reaction using Et3B proceeds under mild
conditions, application to vinyloxytrimethylsilane, which
can be easily deprotected at the product stage, is also
possible. The reaction with 1a followed by treatment with
HCl gave desilylated 3-hydroxy-4-iodomethylpyrrolidine
3a in 66% yield (entry 1).14 The reaction of silyl enol ether
with other iodoaziridines 1b and 1c which produce
prenyl- and methallyl-amidyl radicals also proceeded
smoothly (entries 2, 3). In the reaction with 1b, the
unstable product (tert-iodide) was treated with DBU and
alkenyl product 3b was isolated in 63% yield (entry 2).
With 1c, a mixture of iodine atom transfer product 3c
and reduced product 3c′ was obtained in a ratio of 3.8:1
(67% yield) (entry 3). Although the formation of such
reduced product was also observed in the reaction of 1a
with butyl vinyl ether and vinyloxytrimethylsilane, the
yields were less than 5%. In the reaction with bicyclic
iodoaziridines 1d and 1e which leads to cycloalkenyl
amidyl radicals, bicyclic nitrogen-containing compounds
such as hydrocyclopentapyrrole 3d and hydroindole 3e
product and terminal double bond product was obtained in a ratio
of 4:1.
were obtained in 60% and 62% yields, respectively
(entries 4 and 5).
All reactions shown in Tables 1 and 2 were performed
in the presence of 2 equiv of alkenes to yield the products
at a synthetically useful level. Unfortunately, the ste-
reoselectivities were generally low; the products 3a -e
were obtained with cis/trans ratios in the range of
1-4.3.15 In the reaction with bicyclic iodoaziridines 1d
and 1e, among four or eight possible diastereomers, two
diastereomers based on R- and â-OH were produced in
low diastereoselectivity (R-3d /â-3d ) 1.5, R-3e/â-3e )
1/1.4) (entries 4 and 5).15,16 On the other hand, the
formation of a regioisomer was not observed in all
reactions. Thus, both cleavage of the C-N bond in the
N-tosylaziridinylalkyl radical and the attack of the
resulting N-tosylamidyl radical on the terminal carbon
atom of the alkene proceeded with complete regioselec-
tivity.
[3 + 2] Cycloa d d ition of Aza h om oa llyl Ra d ica ls
w ith Va r iou s Electr on -Rich Alk en es. Iodine atom
transfer [3 + 2] cycloaddition of azahomoallyl radicals
with various electron-rich alkenes was conducted in the
(11) Horner, J . H.; Musa, O.; Bouvier, M. A.; Newcomb, M. J . Am.
Chem. Soc. 1998, 120, 7738-7748.
(12) Kitagawa, O.; Suzuki, T.; Taguchi, T. J . Org. Chem. 1998, 63,
4842-4845.
(15) The streochemistries of the products were determined on the
basis of NOESY measurement. In addition, comparison of the 13C
chemical shift of the iodomethyl group is also useful for the determi-
nation of the stereochemistry. For example, the chemical shift of the
iodomethyl group in cis-isomers of 2a , 3a , 3b, 4a , and 8a appears
upfield from that of trans-isomers.
(16) In the preliminary communication (ref 7), the diastereomer ratio
(R-2d /â-2d ) 1/1.5, R-2e/â-2e ) 1.4) which corresponds to compound
3d and 3e in this paper, was found to be a typographical errors due to
our carelessness. As shown in entries 4 and 5 of Table 2, we must now
correct the ratio as R-2d /â-2d ) 1.5 and R-2e/â-2e ) 1/1.4 in ref 7.
(13) Oshima, K.; Uchimoto, K. J . Synth. Org. Chem. J pn. 1989, 47,
40-50.
(14) In the reaction of 1a with silyl enol ether, (n-Bu3Sn)2 gave a
better result than Et3B. That is, under irradiation of a sunlamp, when
to the benzene solution of 1a and silyl enol ether was added (n-Bu3-
Sn)2 in portionwise (0.1 equiv × 3), the product 3a was obtained in
80% yield. However, in the reaction with other iodoaziridines and
alkenes, this method resulted in the decrease in the chemical yield in
comparison with the Et3B-mediated method.
3186 J . Org. Chem., Vol. 68, No. 8, 2003

Novel Azahomoallyl Radical Precursor
TABLE 3. Ra d ica l [3 + 2] Cycloa d d ition of Va r iou s
Iod oa zir id in es 1 w ith Va r iou s Alk en es
1e with the ketene acetal afforded bicyclic nitrogen-
containing compounds 6d and 6e in 64% and 59% yields,
respectively (entries 4, 5). With 1d , a considerable
amount (28%) of reduced product 6d ′ was isolated
together with an iodine atom transfer product 6d (36%)
(entry 4). In both cases of 1d and 1e, the formation of
other stereoisomers was not observed.15 These results
indicate that in the reaction of a cycloalkenylamidyl
radical with alkenes, the 5-exo-cyclization leading to a
cis-fused ring system and subsequent iodination of the
cycloalkyl radicals from the convex (exo) side proceed
with almost complete stereoselectivity (see also entries
4, 5 in Table 2).
With alkyl-substituted alkenes, considerable decrease
in the chemical yield was observed. For example, under
the above conditions, the reaction of 1a with methyl-
enecyclohexane gave the product 7a in low yied (28%),
and N-allyltosylamide was formed as a side product. This
result may indicate that the reactivity of the N-tosyla-
midyl radical toward the alkene decreases with decreas-
ing electron richness of the alkene. Indeed, 1-hexene,
with lower electron density in comparison with 1,1-
disubstituted alkene, did not give the product. On the
other hand, it was found that gradual generation of an
N-tosylamidyl radical by portionwise addition of Et3B (3
× 0.5 equiv) led to increase in product yield.18 The
reaction with methylenecyclohexane and with 1-hexene
by this procedure gave the products 7a and 8a in 56%
and 34% yield, respectively (entries 6, 7). Although the
reaction of 1a with styrene which gave a good result by
Oshima’s method was also investigated, the yield of the
[3 + 2] cycloadduct was very minor. Similar to the
reactions in Tables 1 and 2, no regioisomer was detected
in any of reactions shown in Table 3.
Gen er a tion a n d [3 + 2] Cycloa d d ition of Op tica lly
Active Cycloh exen yla m id yl Ra d ica l. An octahydroin-
dole skeleton is an important basic structure of several
natural alkaloids.19 We expected that the asymmetric
synthesis of an octahydroindole skeleton might also be
possible through the reaction of an alkene with a cyclo-
hexenylamidyl radical produced from optically active
iodoaziridine 1e. Optically active (+)-1e could be pre-
pared in accordance with eq 5. That is, catalytic asym-
metric tosylamidation of 2-cyclohexenyl benzoate by
Trost’s method20 and subsequent iodoaziridination12 of
the resulting N-tosylcyclohexenylamide (-)-9 gave (+)-
1e in 57% overall yield. Ee values of both (-)-9 and (+)-
1e were estimated to be 94% by HPLC analysis using a
CHIRALPACK AS column. Thus, it is obvious that
iodoaziridination of (-)-9 proceeds without any racem-
a
b
Yield of isolated product. The ratio was determined on the
basis of isolated products. c Other stereoisomers were not detected.
d
The reaction was carried out by portionwise addition of Et3B (3
× 0.5 equiv) in CH2Cl2. e The ratio was determined by 300 MHz
1H NMR.
presence of Et3B (1 equiv) (Table 3). In addition to vinyl
ethers, other enol ethers such as 2-propenyl methyl ether
and 2,3-dihydrofuran also reacted efficiently (entries 1,
2). The reaction of 1a with 2-propenyl methyl ether (2
equiv) gave the products cis- and trans-4a in good yield
(71%) but in low diastereoselectivity (cis-4a /trans-4a )
1/1.7) (entry 1). In the reaction of 1a with 2,3-dihydro-
furan (2 equiv), bicyclic products 5a , 5a ′ having an endo-
iodomethyl or endo-methyl group were obtained with
complete stereoselectivity in 62% yield (entry 2).15 Such
high endo selectivity is also observed in the reaction of a
homoallyl radical species with cyclopentene and 2,3-
dihydrofuran.1o,17 In these reactions, high concentration
conditions (1 M 1a in C6H6) were required for complete
consumption of 1a .
(18) Ca u tion : When Et3B was added to the reaction mixture under
high concentration of O2, we once experienced an explosion. Thus,
further addition of Et3B must be performed under Ar or N2 atmosphere.
(19) Recent reports in relation to hydroindole alkaloids: (a) Banker,
R.; Carmeli, S. Tetrahedron 1999, 55, 10835-10844. (b) Valls, N.;
Vallribera, M.; Lo´pez-Canet, M.; Bonjoch, J . J . Org. Chem. 2002, 67,
4945-4950. (c) Ishida, K.; Okita, H.; Matsuda, H.; Okino, T.; Mu-
rakami, M. Tetrahedron 1999, 55, 10971-10988. (d) Valls, N.; Lo´pez-
Canet, M.; Vallribera, M.; Bonjoch, J . Chem. Eur. J . 2001, 7, 3446-
3460. (e) Wipf, P.; Methot, J .-L. Org. Lett. 2000, 2, 4231-4216. (f)
Padwa, A.; Brodney, M. A.; Lynch, S. M. J . Org. Chem. 2001, 66, 1716-
1724. (g) Tamura, O.; Matsukida, H.; Toyao, A.; Takeda, Y.; Ishibashi,
H. J . Org. Chem. 2002, 67, 5537-5545.
The present reaction can be applied not only to enol
ethers but also ketene acetals. For example (Table 3), the
reaction of 1a with a ketene acetal (2 equiv) in C6H6 gave
[3 + 2] cycloadducts 6a in 62% yield (entry 3). In CH2-
Cl2, a slight decrease in the chemical yield was observed
(6a : 56%). The reaction of bicyclic iodoaziridines 1d and
(20) (a) Trost, B. M.; Vranken, D. L. V.; Bingel, C. J . Am. Chem.
Soc. 1992, 114, 9327-9343. (b) Trost, B. M.; Patterson, D. E. J . Org.
Chem. 1998, 63, 1339-1341. (c) Stragies, R.; Blechert, S. J . Am. Chem.
Soc. 2000, 122, 9584-9591.
(17) The model to rationalize such endo selectivity in the bicyclo-
[3.3.0]octane system has been reported by Curran and co-workers:
Curran, D. P.; Rakiewicz, D. M. Tetrahedron 1985, 41, 3943-3953.
J . Org. Chem, Vol. 68, No. 8, 2003 3187

Kitagawa et al.
ization. The absolute stereochemistry was determined by
comparison of the [R]D value with the reported values of
9.21
F IGURE 1. Possible mechanism of partial racemization.
as novel precursors of azahomoallyl radicals. Although
there are still problems to address in the reaction with
alkyl-substituted alkenes, the reaction described here
should provide new and efficient methodology for the
synthesis of oxygen-fuctionalized pyrrolidine derivatives.
Similar to that of racemic 1e, the reaction of (+)-1e
(94% ee) with silyl enol ether gave a diastereomeric
mixture of cycloadduct (+)-3e in 54% yield (eq 6).
Surprisingly, decrease in the ee of each diastereomeric
product, R-(+)-3e (90%ee) and â-(+)-3e (84%ee), was
observed. The same result was obtained in each of the
three reactions attempted. The degree of racemizaion
strongly depends on the kind of alkene counterpart. For
example, the reaction of (+)-1e (94%ee) with ketene
acetal gave optically active product (+)-6e in 93%ee (61%
yield) (eq 7). This result suggests that the degree of such
racemization depends on the nature of the alkene.
Exp er im en ta l Section
1
Melting points were uncorrected. H and 13C NMR spectra
1
were recorded on a 300-MHz spectrometer. In H and 13C NMR
spectra, chemical shifts were expressed in δ (ppm) downfield
from CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm), respectively.
Mass spectra were recorded by electron impact or chemical
ionization. Column chromatography was performed on silica
gel (75-150 µm). Medium-pressure liquid chromatography
(MPLC) was performed on a 30 × 4 cm i.d. prepacked column
(silica gel, 50 µm) with a UV detector. High-performance liquid
chromatography (HPLC) was performed on a 25 × 0.4 cm i.d.
chiral column with a UV detector.
Sta r tin g Ma ter ia ls. Iodoaziridine derivatives 1a -e were
prepared through iodoaziridination of N-allyltosylamide de-
rivative which was previously reported by our group.12
cis- a n d tr a n s-N-(p -Tolu en esu lfon yl)-3-n -b u t oxy-4-
iod om eth ylp yr r olid in e (cis-2a a n d tr a n s-2a ). Et3B (0.5
mL, 1 M hexane solution) was added to a solution of iodoaziri-
dine 1a (169 mg, 0.5 mmol) and butyl vinyl ether (0.13 mL, 1
mmol) in CH2Cl2 (4 mL) under Ar atmosphere. Dry air (20 mL)
was subsequently introduced with a syringe. After the mixture
was stirred for 10 h at room temperature, aqueous NH4Cl
solution (4 mL) was added, and the mixture was extracted with
Et2O. The extracts were washed with brine, dried over MgSO4,
and evaporated to dryness. Purification of the residue by
column chromatography (hexane/AcOEt ) 20) gave a mixture
of pyrrolidine cis-2a and trans-2a (141 mg, 64%, cis/trans )
1). The inseparatable mixture of cis-2a and trans-2a was
converted to 4-methylenepyrrolidine derivative 2a ′ in ac-
cordance with the following procedure.
N-(p-Tolu en esu lfon yl)-3-n -bu toxy-4-m eth ylen ep yr r ol-
id in e (2a ′). DBU (0.05 mL, 0.36 mmol) was added to a solution
of the mixture (131 mg, 0.3 mmol) of cis-2a and trans-2a in
DMF (4 mL). After being stirred for 8 h at 80 °C, the mixture
was poured into 2% HCl and extracted with Et2O. The extracts
were worked up as noted above. Purification of the residue by
column chromatography (hexane/AcOEt ) 4) gave 2a ′ (88 mg,
95%). 2a ′: colorless solid; mp 51-52 °C; IR (KBr) 1346, 1161
cm-1; 1H NMR (CDCl3) δ 7.71 (d, J ) 8.0 Hz, 2H), 7.31 (d, J )
8.0 Hz, 2H), 5.17 (m, 1H), 5.11 (m, 1H), 4.12 (m, 1H), 3.91 (d,
J ) 13.8 Hz, 1H), 3.79 (d, J ) 13.8 Hz, 1H), 3.60 (dd, J ) 5.2,
10.2 Hz, 1H), 3.26-3.42 (m, 2H), 3.18 (dd, J ) 3.0, 10.2 Hz,
1H), 2.41 (s, 3H), 1.36-1.48 (m, 2H), 1.18-1.22 (m, 2H), 0.86
(t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3) δ 143.7, 143.5, 133.0,
129.5, 127.7, 110.9, 78.6, 68.6, 53.5, 50.3, 31.6, 21.4, 19.1, 13.7;
MS (m/z) 309 (M+); HRMS calcd for C16H24NO3S (M+ + 1)
310.1477, found 310.1456.
Partial racemization may be brought about by hydro-
gen abstraction by radical intermediate 1EA (Figure 1).
That is, after addition of cyclohexenylamidyl radical 1E
to alkene, the resulting radical intermediate 1EA has an
active allyllic hydrogen which is located at the appropri-
ate position for the abstraction by the radical. Moreover,
it has been reported that 5-exo-cyclization of an alkoxy-
carbon radical is slower in comparison with that of a
simple carbon radical.8 Therefore, in the reaction with
silyl enol ether, allylic hydrogen abstraction (1EB from
1E A) may competitively occur together with 5-exo-
cyclization (1EC from 1EA). We assume that the hydro-
gen abstraction process (1EA and 1EB) is in equilibrium
to form racemized 1EA from 1EB in part, by which the
partial racemic product 6e was resulted.
In conclusion, we have succeeded in developing a
radical iodine atom transfer [3 + 2] cycloaddition reaction
with electron-rich alkenes using various iodoaziridines
cis- a n d tr a n s-N-(p -Tolu en esu lfon yl)-3-h yd r oxy-4-
iod om eth ylp yr r olid in e (cis-3a a n d tr a n s-3a ). Et3B (0.5
mL, 1 M hexane solution) was added to a solution of iodoaziri-
dine 1a (169 mg, 0.5 mmol) and trimethylsilyl vinyl ether (0.15
(21) (a) Mu¨ller, P.; Nury, P. Helv. Chim. Acta 2001, 84, 662-678.
(b) Kohmura, Y.; Katsuki, T. Tetrahedron Lett. 2001, 42, 3339-3342.
3188 J . Org. Chem., Vol. 68, No. 8, 2003

Novel Azahomoallyl Radical Precursor
mL, 1 mmol) in CH2Cl2 (4 mL) under Ar atmosphere. Dry air
(20 mL) was subsequently introduced with a syringe. After
the mixture was stirred for 10 h at room temperature, 5% HCl
(4 mL) and MeOH (15 mL) were added, and the mixture was
then stirred for 2 h at room temperature. The MeOH was
removed by evaporation, the residue was extracted with Et2O,
and the extracts were worked up as noted above. Purification
of the residue by column chromatography (hexane/AcOEt )
1) gave a mixture of cis-3a and trans-3a . Further purification
of the mixture by MPLC (hexane/AcOEt ) 2) gave cis-3a (71
mg, 37%, less polar) and trans-3a (56 mg, 29%, more polar),
respectively. cis-3a : colorless solid; 130-131 °C; IR (KBr)
gave (-)-9 (1.01 g, 80%, 94% ee). The ee (94% ee) of (-)-9 was
determined by HPLC analysis using CHIRALPACK AD col-
umn [25 cm × 0.46 cm i.d.; 10% i-PrOH in hexane; flow rate,
1.0 mL/min; (+)-9 (minor); tR ) 13.5 min, (-)-9 (major); tR
)
14.5 min]. (-)-9: [R]D ) -80.0 (c ) 1.5, CHCl3).21 1H NMR
data of (-)-9 coincided with those reported in the literature.21a
(1S,2S,6S)-2-Iod o-7-(p -t olu en esu lfon yl)-7-a za b icyclo-
[4.1.0]h ep t a n e [(+)-1e]. (+)-1e was prepared from (-)-9
(1.0 g, 4 mmol) in accordance with the procedure of our
iodoaziridination method.12 Purification of the residue by
column chromatography (hexane/AcOEt ) 10) gave (+)-1e
(1.09 g, 72%, 94%ee). The ee (94% ee) of (+)-1e was determined
by HPLC analysis using CHIRALPACK AS column [25 cm ×
0.46 cm i.d.; 10% i-PrOH in hexane; flow rate, 1.0 mL/min;
(-)-1e (minor); tR ) 8.5 min, (+)-1e (major); tR ) 9.9 min].
[R]D ) +57.2 (c ) 1.0, CHCl3). 1H NMR data of (+)-1e coincided
with those reported in the literature.12
(3S,3a R,4S,7a S)- a n d (3R,3a R,4S,7a S)-N-(p-Tolu en e-
su lfon yl)-4-iodooctah ydr o-1H-in dol-3-ol [(+)-â-3e an d (+)-
r-3e]. (+)-3e was prepared from iodoaziridine 1e (377 mg, 1.0
mmol) and trimethylsilyl vinyl ether (0.3 mL, 2 mmol) in
accordance with the procedure for the preparation of 3a .
Purification of the residue by column chromatography (hexane/
AcOEt ) 1) gave a mixture of (+)-â-3e and (+)-R-3e. Further
purification of the mixture by MPLC (hexane/AcOEt ) 2) gave
(+)-â-3e (147 mg, 35%, less polar) and (+)-R-3e (80 mg, 19%,
more polar), respectively. The ee (84%ee) of (+)-â-3e was
determined by HPLC analysis using CHIRALPACK AD col-
umn [25 cm × 0.46 cm i.d.; 10% i-PrOH in hexane; flow rate,
1.0 mL/min; (-)-â-3e (minor); tR ) 14.7 min, (+)-â-3e (major);
tR ) 16.4 min]. The ee (90% ee) of (+)-R-3e was determined
by HPLC analysis using CHIRALPACK AD column [25 cm ×
0.46 cm i.d.; 10% i-PrOH in hexane; flow rate, 1.0 mL/min;
(-)-R-3e (minor); tR ) 11.7 min, (+)-R-3e (major); tR ) 14.8
3492, 1322, 1152 cm-1 1H NMR (CDCl3) δ 7.72 (d, J ) 8.0
;
Hz, 2H), 7.34 (d, J ) 8.0 Hz, 2H), 4.31 (q, J ) 3.8 Hz, 1H),
3.60 (dd, J ) 7.9, 9.6 Hz, 1H), 3.51 (dd, J ) 3.8, 11.6 Hz, 1H),
3.43 (dd, J ) 1.0, 11.6 Hz, 1H), 3.17 (dd, J ) 9.0, 9.8 Hz, 1H),
3.10 (dd, J ) 6.8, 9.8 Hz, 1H), 3.01 (dd, J ) 9.6, 10.6 Hz, 1H),
2.44 (s, 3H), 2.42 (m, 1H), 1.59 (d, J ) 4.9 Hz, 1H); 13C NMR
(CDCl3) δ 143.7, 133.5, 129.7, 127.3, 71.1, 56.3, 50.8, 47.2, 21.4,
0.3; MS m/z 381 [M+]; HRMS calcd for C12H16INO3S [M+]
380.9896, found 380.9869. trans-3a : colorless solid; 136-137
1
°C; IR (KBr) 3501, 1338, 1160 cm-1; H NMR (CDCl3) δ 7.71
(d, J ) 8.3 Hz, 2H), 7.34 (d, J ) 8.3 Hz, 2H), 4.05 (m, 1H),
3.56 (dd, J ) 5.9, 10.5 Hz, 1H), 3.51 (dd, J ) 7.5, 10.5 Hz,
1H), 3.05-3.15 (m, 3H), 2.97 (dd, J ) 7.8, 10.5 Hz, 1H), 2.44
(s, 3H), 2.28 (m, 1H), 2.17 (brs, 1H); 13C NMR (CDCl3) δ 144.0,
132.8, 129.9, 127.5, 74.6, 54.3, 52.2, 48.7, 21.6, 4.9; MS (m/z)
381 (M+); HRMS calcd for C12H16INO3S (M+) 380.9896, found
380.9877.
N-(p -Tolu en esu lfon yl)-4-iod om et h yl-2-a za sp ir o[4.5]-
d eca n e (7a ). Under Ar atmosphere, to a solution of iodoaziri-
dine 1a (510 mg, 1.5 mmol) and methylenecyclohexane (0.36
mL, 3 mmol) in CH2Cl2 (12 mL) was added Et3B (2.25 mL, 1
M hexane solution) portionwise (0.75 mL, every 30 min). Dry
air (20 mL) was subsequently introduced with a syringe. After
the mixture was stirred for 2 h at room temperature, saturated
aqueous NH4Cl (12 mL) solution was added, and the mixture
was then extracted with Et2O. The extracts were worked up
as noted above. Purification of the residue by column chro-
matography (hexane/AcOEt ) 30) gave 7a (364 mg, 56%). 7a :
min]. (+)-â-3e: [R]D ) +66.1 (c ) 1.0, CHCl3). (+)-R-3e: [R]D
)
1
+79.2 (c ) 1.0, CHCl3). H NMR data of (+)-â-3e and (+)-R-
3e coincided with those of racemic â-3e and R-3e (see the
Supporting Information).
[(+)-6e]. (+)-6e was prepared from iodoaziridine 1e (189
mg, 0.5 mmol) and ketene acetal (63 mg, 0.55 mmol) in
accordance with the procedure for the preparation of 2a .
Purification of the residue by column chromatography (hexane/
AcOEt ) 10) gave (+)-6e (150 mg, 61%, 93% ee). The ee (93%
ee) of (+)-6e was determined by HPLC analysis using CHIRAL-
PACK AD column [25 cm × 0.46 cm i.d.; 10% i-PrOH in
hexane; flow rate, 1.0 mL/min; (-)-6e (minor); tR ) 11.2 min,
(+)-6e (major); tR ) 17.4 min]. (+)-6e: [R]D ) +50.4 (c ) 1.0,
CHCl3). 1H NMR data of (+)-6e coincided with those of racemic
6e (see the Supporting Information).
colorless oil; IR (neat) 1343, 1161 cm-1 1H NMR (CDCl3) δ
;
7.73 (d, J ) 8.0 Hz, 2H), 7.33 (d, J ) 8.0 Hz, 2H), 3.68 (dd, J
) 7.5, 10.2 Hz, 1H), 3.46 (d, J ) 10.2 Hz, 1H), 3.19 (dd, J )
3.4, 9.7 Hz, 1H), 3.11 (dd, J ) 8.2, 9.7 Hz, 1H), 3.02 (d, J )
10.2 Hz, 1H), 2.71 (t, J ) 10.2 Hz, 1H), 2.44 (s, 3H), 2.12 (m,
1H), 1.40-1.63 (m, 4H), 1.00-1.40 (m, 4H); 13C NMR (CDCl3)
δ 143.4, 133.7, 129.6, 127.3, 56.4, 53.1, 51.2, 45.6, 35.3, 28.2,
25.7, 23.3, 22.4, 21.5, 3.2; MS (m/z) 433 (M+). Anal. Calcd for
C
17H24INO2S: C, 47.12; H, 5.58, N, 3.23. Found: C, 47.52; H,
5.65, N, 3.24.
(S)-N-(p-Tolu en esu lfon yl)cycloh exen yla m in e [(-)-9].
NaH (60% assay, 250 mg, 6.25 mmol) was added to the
tosylamide (1.285 g, 7.50 mmol) in THF (25 mL) at 0 °C. After
the mixture was stirred for 1 h at room temperature, 3-cyclo-
hexenyl benzoate (1.01 g, 5 mmol) was added to the mixture.
Trost ligand (300 mg, 0.43 mmol) and Pd2(dba)3‚CHCl3 (128
mg, 0.12 mmol) in THF (5 mL) were subsequently added, and
then the mixture was stirred for 18 h at room temperature.
The mixture was poured into water and extracted with Et2O.
The extracts were worked up as noted above. Purification of
the residue by column chromatography (hexane/AcOEt ) 10)
Ack n ow led gm en t. This work was partly supported
by a Grant-in-Aid for Scientific Research (No. 14572015)
from the Ministry of Education, Science, Sports and
Culture of J apan.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation and characterization data of
products 3b-e, 4a , 5a , 6a ,d ,d ′,e, and 8a ,a ′. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0266846
J . Org. Chem, Vol. 68, No. 8, 2003 3189