T-BuOK-Mediated Iodoaziridination Reaction of N-Allylic Tosylamide Derivatives

Full text of DOI:10.1021/jo980371m

4842
J . Org. Chem. 1998, 63, 4842-4845
Sch em e 1
t-Bu OK-Med ia ted Iod oa zir id in a tion
Rea ction of N-Allylic Tosyla m id e
Der iva tives
Osamu Kitagawa, Takashi Suzuki, and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, J apan
Received February 26, 1998
In tr od u ction
In contrast to the preparation of five- or six-membered
heterocyclic compounds through halocyclization reac-
tions, a limited number of examples of three-membered
heterocyclic-forming reactions have appeared.1 The reac-
tion of an oxygen nucleophile such as haloepoxidation
with allyl alcohol derivatives has been reported, but the
chemical yields are generally not satisfactory or not
described in detail in the literature (Scheme 1, eq 1).2,3
In addition, as far as we know, a three-membered ring-
forming reaction via the attack of a nitrogen atom as an
intramolecular nucleophile has not been reported.
On the other hand, it is well-known that in an
intramolecular substitution reaction by a carbanion, a
three-membered ring-forming reaction is a more favor-
able process even in comparison with that for a five- or
six-membered ring.4 In addition, in the course of our
work on iodocarbocyclization reactions of alkenylma-
lonate,5 we found that a three-membered ring-forming
reaction with allylmalonate derivatives proceeds in the
presence of I2, Ti(OR)4, and CuO or pyridine to give
(iodomethyl)cyclopropane derivatives in good yields
(Scheme 1, eq 2).6,7 These results prompted us to
examine the preparation of three-membered heterocyclic
compounds through a halocyclization reaction.
the reaction of allyl, methallyl, or crotyl derivatives
proceeded in good yields, while the reaction of tosyl-
amides having a prenyl group or a cyclic olefin gave a
complex mixture or the iodoaziridine in poor yield. In
this paper, we report a t-BuOK-mediated iodoaziridina-
tion reaction that proceeds with complete regioselectivity
and stereospecificity (3-exo-cyclization and trans-addition
manner) and can be widely applied to various N-allylic
tosylamide derivatives (Scheme 1, eq 3). The present
reaction provides a stereoselective synthesis of iodoaziri-
dines with two consecutive chiral centers from simple
N-allylic amides.9,10
Resu lts a n d Discu ssion
Su r vey of Rea ction Con d ition s in Iod oa zir id in a -
tion Rea ction . The reaction of N-allylic tosylamide 1a
with I2, NIS, or NBS provided an addition product of I2
to olefin or resulted in the recovery of 1a because of the
low nucleophilicity of tosylamide. To activate the tosyl-
amide, a survey of various basic metallic reagents was
Previously, we reported the result of an iodoaziridina-
tion reaction of N-allylic tosylamide derivatives that
proceeds in a highly stereospecific manner in the pres-
ence of a base such as NaH.8 Under these conditions,
11
performed (Table 1). When Ti(Oi-Pr)45 or LiAl(Ot-Bu)4
was used as a base, no iodoaziridine 2a was obtained
(entries 1, 2). When n-BuLi (1 equiv) was used, a
considerable solvent effect was observed; that is, in THF
the reaction gave an iodination product at the ortho
position of the sulfonyl group (17% yield) without forma-
tion of the aziridine 2a (entry 3), while in Et2O 2a was
obtained in 53% yield (entry 4). In the present reaction,
* Corresponding author. Fax and Tel: 81-426-76-3257. E-mail:
kitagawa@ps.toyaku.ac.jp.
(1) (a) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: Orlando, 1984; Vol. 3, p 411. (b) Gardillo, G.; Orena,
M. Tetrahedron 1990, 46, 3321. (c) Harding, K. E.; Tiner, T. H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 4, p 363.
(2) Examples of haloepoxidation reactions of allyl alcohol derivatives
which proceed via an ionic mechanism: (a) Winstein, S.; Goodman, L.
J . Am. Chem. Soc. 1954, 76, 4368. (b) Ganem, B. J . Am. Chem. Soc.
1976, 98, 858. (c) Midland, M. M.; Halterman, R. J . Org. Chem. 1981,
46, 1227. (d) Evans, R. D.; Magee, J . W.; Schauble, J . H. Synthesis
1988, 862.
(3) Haloepoxide-forming reaction from allyl alcohol derivatives under
radical conditions has been also reported; see: (a) Suginome, H.; Wang,
J . B. J . Chem. Soc., Chem. Commun. 1990, 1629. (b) Galatsis, P.;
Millan, S. D.; Tetrahedron Lett. 1991, 32, 7493. (c) Rawal, V. H.; Iwasa,
S. Tetrahedron Lett. 1992, 33, 4687.
(4) Knipe, A. C.; Stirling, C. J . M. J . Chem. Soc. B 1968, 67.
(5) Our reviews in relation to Ti(OR)4-mediated iodocarbocyclization
reaction of alkenylmalonates: (a) Taguchi, T.; Kitagawa, O.; Inoue, T.
J . Synth. Org. Chem. J pn. 1995, 53, 770. (b) Kitagawa, O.; Inoue, T.;
Taguchi, T. Rev. Heteroat. Chem. 1996, 15, 243.
(6) (a) Kitagawa, O.; Inoue, T.; Taguchi, T. Tetrahedron Lett. 1992,
33, 2167. (b) Inoue, T.; Kitagawa, O.; Ochiai, O.; Taguchi, T. Tetrahe-
dron: Asymmetry 1995, 6, 691.
(8) Preliminary communication of this work: Kitagawa, O.; Suzuki,
T.; Taguchi, T. Tetrahedron Lett. 1997, 38, 8371.
(9) Preparation and utilization of aziridine derivatives: (a) Deyrup,
J . A. In Small Ring Heterocyclic Chemistry; Hassner, A., Ed.; Wiley:
New York, 1983; Vol. 1, p 1. (b) Kemp, J . E. G. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 7, p 469. (c) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599. (d) Osborn, H. M. I.; Sweeney, J . Tetrahedron: Asym-
metry 1997, 8, 1693.
(10) Preparation of halomethylaziridines by other methods and their
utilization: (a) Gensler, W. J . J . Am. Chem. Soc. 1948, 70, 1843. (b)
Gensler, W. J .; Brooks, B. A. J . Org. Chem. 1966, 31, 568. (c) Kimpe,
N. D.; Smaele, D. D.; Sakonyi, Z. J . Org. Chem. 1997, 62, 2448 and
references cited therein.
(11) Our work in relation to the regiocontrolled iodoaminocylization
of unsaturated amide derivatives mediated by LiAl(Ot-Bu)4: (a)
Kitagawa, O.; Fujita, M.; Li, F.; Taguchi, T. Tetrahedron Lett. 1997,
38, 615. (b) Fujita, M.; Kitagawa, O.; Suzuki, T.; Taguchi, T. J . Org.
Chem. 1997, 62, 7330.
(7) Beckwith et al. also reported an iodocarbocyclization reaction of
allylmalonate derivatives which proceeds in the presence of I2 and
NaH: Beckwith, A. L.; Zozer, M. J . Tetrahedron Lett. 1992, 33, 4975.
S0022-3263(98)00371-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/18/1998

Notes
Ta ble 1. Effect of Ba se in th e Iod ocycliza tion of 1a a
J . Org. Chem., Vol. 63, No. 14, 1998 4843
Ta ble 3. t-Bu OK-Med ia ted Iod oa zir id in a tion of Va r iou s
N-Allylic Tosyl Am id esa
a
Iodocyclization: 1a (1 mmol), additive (1.5 mmol), I2 (3 mmol),
b
solvent (5 mL), rt, 15 min-1 h. Isolated yield.
Ta ble 2. t-Bu OK-Med ia ted Iod ocycliza tion of Va r iou s
N-Allylic Am id esa
a
Iodocyclization: 1 (1 mmol), t-BuOK (1.5 mmol), I2 (3 mmol),
b
toluene (5 mL), rt, 15 min. Isolated yield.
a
Iodocyclization: 1 (1 mmol), t-BuOK (1.5 mmol), I2 (3 mmol),
the use of a strong base such as NaH or t-BuOK was
found to be more effective (rntries 5, 6); especially, in the
presence of t-BuOK (1.5 equiv) and I2 (3 equiv), the
reaction in toluene gave iodoaziridine 2a in 94% yield
(entry 6).12 Although the remarkable effect of t-BuOK
is not clear, it may act as not only an activating reagent
for the enhancement of the nucleophilicity of tosylamide
but also a neutralizing reagent for the trapping of HI. It
was also found that 3 equiv of I2 is required to obtain
the iodoaziridine 2a in good yield, while a decrease in
the chemical yield was observed with the use of 1 or 2
equiv of I2 (56% and 84%, respectively).
As shown in Table 2, a tosyl group was the most
effective as a substituent on the nitrogen atom. For
example, the reaction of mesylamide 1b proceeded, but
with a decrease in the chemical yield of 2b (entry 2, 45%).
Furthermore, in contrast to the sulfonylamides, the
reaction of carbamate 1c and benzamide 1d did not result
in the formation of the aziridine. With 1c, an addition
product of I2 to the olefin was obtained as a major product
(entry 3), while the reaction of 1d under these conditions
gave a five-membered ring compound (3d ) in 90% yield
through the attack of the amide carbonyl oxygen (entry
4).13
toluene (5 mL), rt. Isolated yield. c The chemical structures of
b
d
major isomers were drawn. The ratios were determined by 300-
MHz 1H NMR. e 2 equiv of t-BuOK was used.
tosylamides (1e-k ) subjected to the iodoaziridination
conditions mentioned above [t-BuOK (1.5 equiv) and I2
(3 equiv) in toluene]. As was found with allyl derivative
1a , the reactions of methallyl and prenyl derivatives 1e,f
proceeded in good yields (90% and 74%, respectively) to
give iodoaziridines 2e,f (entries 1, 2). In the reaction of
1f, the effect of t-BuOK was particularly noteworthy; that
is, the use of NaH, which gave a good result in the
reaction of 1a , led to the formation of byproducts to result
in a considerable decrease in the yield of 2f (37%).
In the reactions of crotyl derivatives E-1g (E/Z ) 3.6)
and Z-1g (E/Z ) 1/3.7), diastereomeric mixtures of
aziridine 2g were obtained in ratios of syn/anti ) 1/3.5
and syn/anti ) 3.9, respectively (entries 3, 4). The
relative configurations of syn- and anti-2g, which can be
easily separated by column chromatography, were de-
termined by converting to crotyl derivative 1g from syn-
and anti-2g through trans-elimination by Zn, respectively
(12) Haloaziridine product could not be obtained by the combination
of t-BuOK and NBS or NIS.
(13) Kitagawa, O.; Kikuchi, N.; Hanano, T.; Aoki, K.; Yamazaki, T.;
Okada, M.; Taguchi, T. J . Org. Chem. 1995, 60, 7161.
Iod oa zir id in a tion Rea ction s of Va r iou s N-Allylic
Tosyla m id es. Table 3 contains a variety of N-allylic

4844 J . Org. Chem., Vol. 63, No. 14, 1998
Notes
Sch em e 2
Sch em e 4
Sch em e 3
the reaction conditions; that is, product analysis by TLC
monitoring indicates that prolonged reaction time leads
to the decomposition of products 2 to give a complex
mixture. The best yield in each reaction was obtained
under the optimized reaction time shown in Table 3. On
the other hand, all the aziridines 2 isolated can be stored
at 0 °C for 1 week at least without appreciable decom-
position.
In conclusion, we have succeeded in the development
of a t-BuOK-mediated iodoaziridination reaction that
proceeds with complete stereospecificity and regioselec-
tivity (3-exo and trans-addition manner). The present
reaction can be applied to a number of N-allylic tosyl-
amide derivatives and provides a stereoselective synthe-
sis of iodoaziridines with two consecutive chiral centers
from simple N-allylic amides.
(Scheme 2).14 These results indicate that the present
reaction proceeds through a stereospecific trans-addition
of the amide nucleophile and iodine across the olefin
(Scheme 3, path a), but not through an addition of iodine
to the olefin and the subsequent substitution reaction of
the iodide by the amide nucleophile (path b).10a In
addition to the results of entries 3 and 4, the reaction of
stereochemically pure Z-olefin 1h with an oxygen func-
tionality was found to give syn-2h as a single stereoiso-
mer (entry 5); thus, the iodoaziridination reaction clearly
proceeds with almost complete stereospecificity.
Exp er im en ta l Section
The present reaction can be also applied to N-cycloal-
kenyl tosylamide derivatives. For example, the reaction
of cyclopentenyl and cycloheptenyl derivatives 1i,j pro-
ceeded with complete stereoselectivity to give 2i,j in
greater than 90% yield (entries 6, 7). The reaction of
cyclohexenyl derivative 1k also gave iodoaziridine 2k in
63% (entry 8). When NaH was used in the reaction of
1i-k instead of t-BuOK, as was seen previously with 1f,
a marked decrease in the yields of 2i-k was observed
(2i, 45%; 2j, 47%). In particular, the reaction of cyclo-
hexenyl derivative 1k hardly proceeded in the presence
of NaH (2k , <5%).
In all the reactions shown here, the formation of a
4-endo-cyclized product was not observed, indicating the
reactions proceed with complete 3-exo-selectivity.
We have also found that the rate of the iodoaziridina-
tion reaction is comparable with that of the corresponding
five-membered ring-forming reaction.15,16 As shown in
Scheme 4, the reaction of N-allyl tosylamide 1a (0.5
mmol) and N-pentenyl tosylamide 4 (0.5 mmol) gave
iodoaziridine 2a and iodopyrrolidine 5 in a ratio of 7:9
in the presence of t-BuOK (1.5 mmol) and I2 (0.5 mmol).
This result indicates that the three-membered ring-
forming reaction in a halocyclization should be an ef-
ficient process similar to five- and six-membered ring-
forming reactions.
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded on a 300-MHz spectrometer (Varian Gemini-300). In
1H and 13C NMR spectra, chemical shifts are 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 (Hitachi M-80). Column chromatography
was performed on silica gel, Wakogel C-200 (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.
Sta r tin g Ma ter ia ls. N-Allylic amides or carbamates 1a -d
were prepared in quantitative yields through reaction of allyl-
amine with TsCl, MsCl, ClCO2Et, or PhCOCl.17 N-Allylic
tosylamide derivatives 1e-h and N-pentenyl tosylamide 4 were
prepared from the corresponding bromides or chlorides according
to reported procedures.18 N-Cycloalkenyl tosylamides 1i-k were
prepared from the corresponding acetates according to reported
procedures.19
Gen er a l P r oced u r e of Iod oa zir id in a tion . To tosylamide
1a (212 mg, 1 mmol) in toluene (5 mL) was added t-BuOK (168
mg, 1.5 mmol) under an argon atmosphere at room temperature.
The mixture was stirred for 30 min, and I2 (762 mg, 3 mmol)
was added. The reaction mixture was then stirred for 15 min
at room temperature, was poured into aqueous Na2S2O3 solution
and extracted with EtOAc. The EtOAc extracts were washed
with brine, dried over MgSO4, and evaporated to dryness.
Purification of the residue by column chromatography (hexane/
EtOAc ) 9) gave 2a (317 mg, 94%).8
(2R*,3S*)- a n d (2R*,3R*)-N-Tosyl-1,2-im in o-3-iod obu ta n e
(a n ti-2g a n d syn -2g). anti- and syn-2g were prepared from E-1g
(1.13 g, 5.0 mmol, E/Z ) 3.6) in accordance with the general
procedure described for 2a . Purification of the residue by column
chromatography (hexane/EtOAc ) 9) gave anti-2g (1.09 g, 62%,
less polar) and syn -2g (0.31 g, 18%, more polar). anti-2g:
colorless solid; mp 67-69 °C; IR (KBr) 1326, 1159 cm-1; 1H NMR
(CDCl3) δ 7.82 (2H, d, J ) 8.2 Hz), 7.35 (2H, d, J ) 8.2 Hz), 3.50
(1H, qd, J ) 6.9, 9.5 Hz), 3.08 (1H, ddd, J ) 4.4, 6.9, 9.5 Hz),
2.77 (1H, d, J ) 6.9 Hz), 2.45 (3H, s), 2.13 (1H, d, J ) 4.4 Hz),
It was also found that the iodoaziridine derivatives 2
formed in these reactions are relatively unstable under
(14) The incomplete stereospecificity observed in the trans-elimina-
tion of stereochemically pure syn- or anti-2g by Zn may be due to the
contribution of a radical cleavage mechanism to some extent; See:
Kimpe, N. D.; J olie, R.; Smaele, D. D. J . Chem. Soc., Chem. Commun.
1994, 1221.
(15) Examples of bromoaminocyclization of N-pentenyl or N-hexenyl
amides: Tamaru, Y.; Kawamura, S.; Bando, T.; Tanaka, K.; Hojo, M.;
Yoshida, Z. J . Org. Chem. 1988, 53, 5491.
(18) (a) Gensler, W. J .; Frank, F. J .; Dheer, S. K.; Lauther, J . W. J .
Org. Chem. 1971, 36, 4102. (b) Fugami, K.; Ohshima, K.; Utimoto, K.
Bull. Chem. Soc. J pn. 1989, 62, 2050.
(19) Bystro¨m, S. E.; Aslanian, R.; Ba¨ckvall, J .-E. Tetrahedron Lett.
1985, 26, 1749.
(16) In the presence of t-BuOK and I2, iodocyclization reaction of
N-homoallyl tosylamide gave a mixture of 4-exo- and 5-endo-cyclized
products in yields of 20% and 54%, respectively.
(17) Ginzberg, S. Ber. 1903, 36, 2703.

Notes
J . Org. Chem., Vol. 63, No. 14, 1998 4845
1.73 (3H, d, J ) 6.9 Hz); 13C NMR (CDCl3) δ 144.8, 134.2, 129.6,
128.0, 47.1, 35.6, 25.6, 22.9, 21.6; MS (m/z) 351 (M+), 224. Anal.
Calcd for C11H14INO2S: C, 37.60; H, 4.02; N, 3.99. Found: C,
37.74; H, 4.15; N, 3.95. syn-2g: colorless oil; IR (neat) 1327,
Com p etitive Exp er im en t of Th r ee- a n d F ive-Mem ber ed
Rin g-F or m in g Rea ction s. To a mixture of N-allylic tosyl
amide 1a (106 mg, 0.5 mmol) and N-pentenyl tosylamide 4 (120
mg, 0.5 mmol) in toluene (5 mL) was addedd t-BuOK (168 mg,
1.5 mmol) under argon atmosphere at room temperature. The
mixture was stirred for 30 min, and I2 (127 mg, 0.5 mmol) was
added. The reaction mixture was then stirred for 15 min at room
temperature, poured into aqueous Na2S2O3 solution, and ex-
tracted with EtOAc. The EtOAc extracts were washed with
brine, dried over MgSO4, and evaporated to dryness. Purifica-
tion of the residue by column chromatography (hexane/EtOAc
) 9) gave the mixture of 2a (12 mg, 7%) and 520 (16 mg, 9%)
together with the recovery of 1a (78 mg, 74%) and 4 (95 mg,
79%). The yields of 2a and 520 were determined on the basis of
300-MHz 1H NMR of the mixture.
1163 cm-1 1H NMR (CDCl3) δ 7.85 (2H, d, J ) 8.0 Hz), 7.35
;
(2H, d, J ) 8.0 Hz), 3.79 (1H, quint, J ) 7.1 Hz), 3.07 (1H, m),
2.84 (1H, d, J ) 6.8 Hz), 2.44 (3H, s), 2.25 (1H, d, J ) 4.1 Hz),
1.79 (3H, d, J ) 7.1 Hz); 13C NMR (CDCl3) δ 144.8, 134.4, 129.6,
128.4, 46.9, 34.5, 23.9, 21.8, 21.6; MS (m/z) 351 (M+), 224. Anal.
Calcd for C11H14INO2S: C, 37.60; H, 4.02; N, 3.99. Found: C,
37.72; H, 4.14; N, 3.99.
Tr a n s-Elim in a tion of a n ti-2g by Zn (0). To a solution of
anti-2g (948 mg, 2.7 mmol) in THF (15 mL) was added Zn dust
(268 mg, 4.1 mmol) under argon atmosphere at room tempera-
ture. The mixture was stirred for 15 h at room temperature,
and then the mixture was poured into aqueous NH4Cl solution.
After removal of insoluble material by filtration with a Celite
pad, the filtrate was extracted with EtOAc. The EtOAc extracts
were washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane/EtOAc ) 8) gave a mixture of E- and Z-1g (522 mg,
86%, E/Z ) 4.0).
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and experimental pocedures of 2a ,b,e,f, syn-2h , and 2i-k
(3 pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(20) Tseng, C.; Terashima, S.; Yamada, S. Chem. Pharm. Bull. 1977,
25, 29.
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