Highly regioselective transformation of alkenyl bromides into α-bromoaziridines and α-bromohydrazones

Article abstract of DOI:10.1021/ol060336z

The synthetic utility of α-halohydrazones is an underexplored area due to the lack of chemo- and regioselective routes towards these molecules. Herein, we describe a general method for α-bromohydrazone synthesis via the rearrangement of α-bromoaziridines,

Full text of DOI:10.1021/ol060336z

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2011-2014
Highly Regioselective Transformation of
Alkenyl Bromides into
r
r
-Bromoaziridines and
-Bromohydrazones
Larissa B. Krasnova and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, The UniVersity of
Toronto, 80 St. George Street, Toronto, Canada M5S 3H6
ayudin@chem.utoronto.ca
Received February 8, 2006 (Revised Manuscript Received March 29, 2006)
ABSTRACT
The synthetic utility of
Herein, we describe a general method for
prepared for the first time from the corresponding alkenyl bromides. The rearrangement of
r
-halohydrazones is an underexplored area due to the lack of chemo- and regioselective routes towards these molecules.
-bromohydrazone synthesis via the rearrangement of -bromoaziridines, which can be readily
-bromoaziridines into -bromohydrazones proceeds
r
r
r
r
with high yields and with high selectivities.
R-Halogenated imines and hydrazones have been used for
the preparation of diimines,1 epoxyimines,2 cyclopropyl-
amines,3 pyrrolidines,4 and pyrroles.1a,5 However, the efficient
synthesis of R-halogenated imines and hydrazones6 is an
underdeveloped area in comparison with R-halogenated
aldehydes and ketones.7 This is due to the difficulties
encountered during the preparation of these intermediates.
The most common methods of R-haloimine or R-halohy-
drazone synthesis are R-halogenation of imines or hydrazones
and condensation of R-halogenated carbonyl compounds with
primary amines hydrazines. The condensation pathway
proceeds with low chemoselectivity, plagued by side-
reactions such as nucleophilic substitution of R-halogen,
base-promoted elimination of hydrogen halide, Favorskii
rearrangement, and formation of epoxide intermediates.8 In
turn, imine and hydrazone halogenation suffers from poor
regio- and chemoselectivity, affording mixtures of mono-
and dihalogenated compounds.8 Herein, we report a novel
route to R-bromoaziridines 2 and their rearrangement into
R-bromohydrazones 3 (Scheme 1). The electrocyclic nature
of the rearrangement allows for a highly regioselective
transposition of the halogen atom and control over the
product structure.
(1) (a) Duhamel, P.; Duhamel, L.; Valnot, J. Y. Tetrahedron Lett. 1973,
14, 1339-1342. (b) De Kimpe, N.; Yao, Z. P.; Schamp, N. Tetrahedron
Lett. 1986, 27, 1707-1710.
(2) Sulmon, P.; De Kimpe, N.; Schamp, N.; Declercq, J. P.; Tinant, B.
J. Org. Chem. 1988, 53, 4457-4462.
(3) De Kimpe, N.; Tehrani, K. A.; Fonck, G. J. Org. Chem. 1996, 61,
6500-6503.
(4) De Kimpe, N.; Palamareva, M.; Sulmon, P.; Verhe, R.; De Buyck,
L.; Schamp, N.; Declercq, J. P.; Tinant, B.; Van Meerssche, M. Tetrahedron
1986, 42, 71-80.
(5) Duhamel, L.; Valnot, J. Y. Tetrahedron Lett. 1974, 15, 3167-3170.
(6) Levkovskaya, G. G.; Drozdova, T. I.; Rozentsveig, I. B.; Mirskova,
A. N. Russ. Chem. ReV. (Engl. Transl.) 1999, 68, 581-604.
(7) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-
VCH: Weinheim, Germany, 2003.
(8) De Kimpe, N.; Schamp, N. Org. Prep. Proced. Int. 1979, 11, 115-
199 and references therein.
10.1021/ol060336z CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/13/2006

tion sequence.15 9-(2-Bromoallyl)-9H-carbazole was synthe-
sized from carbazole via the nucleophilic substitution of 2,3-
dibromopropene.16 The results of aziridination are sum-
marized in Table 1. In the case of 2-bromopropene, 9-(2-
Scheme 1
Table 1. Preparation of R-Bromoaziridines
Literature precedents of haloaziridine chemistry have been
limited to the synthesis and reactivity of 2,2-dichloroaziri-
dines.9 Several reports describe the synthesis of monochlo-
rinated aziridines via reductive dechlorination of 2,2-
dichloroaziridines.10 The addition of chloro- and bromo-
carbenes to imines is of less preparative value.11 Rearrange-
ment of di- and polyhalogenated aziridines into the corre-
sponding R-haloimines has been reported.12 Rearrangements
of 2,2-dichloroaziridines followed by the hydrolysis of the
intermediate R-chloro imidoyl chlorides result in the forma-
tion of amides.13 At the outset, we sought to develop a
general method for bromoaziridine synthesis with the goal
of further exploring the chemistry of these molecules.
R-Halogenated olefins are not suitable for aziridination using
nitrene transfer protocols under typical conditions that
involve olefin, chloramine-T, or N-tosyl-iminophenyliodinane
in the presence of a metal catalyst. Our attempts to obtain
monohalogenated aziridines using a range of metal-mediated
nitrene transfer reagents to the corresponding olefins have
been consistently unsuccessful. Regardless of their origin,
the nitrenoid species have not been reactive enough to
aziridinate alkenyl bromides. The N-aminophthalimide/
(diacetoxyiodo)benzene (DIB) system, recently described by
us and others, is versatile with regard to the electronic nature
of the olefin.14 To our delight, the nitrenoid species generated
from N-aminophthalimide using this metal-free protocol has
led to a successful aziridination of E-2-bromo-but-2-ene to
give aziridine 7 as a stable crystalline product in 90% yield.
Other commercially available brominated olefins were
subjected to the reaction conditions. 3-Bromo-4-phenyl-3-
butene-2-one and 2-bromo-1,3-diphenylpropenone were ob-
tained from chalcones via a bromination-dehydrobromina-
a Mixture of invertomers in a 60:40 ratio (determined by 1H NMR). b 57%
conversion. c 10% hydrazone was isolated. d 5% hydrazone was isolated.
bromoallyl)-9H-carbazole, 1-bromo-propene, and R-bromo
chalcones (entries 1-3, 6 and 7, Table 1), R-bromoaziridines
were the only products isolated. The aziridine 4 exists as a
mixture of invertomers in a 60:40 ratio, as determined by
1H NMR. E- and Z-2-bromobut-2-enes predominantly led
to aziridines 7 and 8, containing small amounts of hydrazones
(5-10%). All aziridines have been stored at -30 °C to avoid
decomposition. However, recrystallized 9 can be stored at
room temperature over several months without any signs of
degradation. In contrast to R-bromo-substituted E-chalcones,
which give aziridines in good yields, R-bromo-substituted
Z-chalcones 11 and 12 led to complicated mixtures of
products. Substrates 13 and 14 were found to decompose
under the aziridination conditions (Figure 1).
(9) (a) Fields, E. K.; Sandri, J. M. Chem. Ind. (London) 1959, 1216. (b)
Cook, A. G.; Fields, E. K. J. Org. Chem. 1962, 27, 3686-3687. (c) Seno˜,
M.; Shiraishi, S.; Suzuki, Y.; Asahara, T. Bull. Chem. Soc. Jpn. 1978, 51,
1413-1417. (d) Mihara, M.; Komatsu, M.; Ishino, Y.; Minakata, S. J. Org.
Chem. 2005, 70, 5320-5322.
(10) (a) Khlebnikov, A. F.; Kostikov, R. R.; Shklyaev, V. S.; Aleksan-
drov, B. B.; Dormidontov, M. Y. Khim. Geterotsikl. Soedin. 1990, 8, 1086-
1091. (b) Takahashi, M.; Takada, T.; Sakagami, T. J. Heterocycl. Chem.
1987, 24, 797-799. (c) Yamanaka, H.; Kikui, J.; Teramura, K.; Ando, T.
J. Org. Chem. 1976, 41, 3794-3797.
(11) (a) Deyrup, J. A.; Greenwald, R. B. J. Am. Chem. Soc. 1965, 87,
4538-4545. (b) Deyrup, J. A.; Greenwald, R. B. Tetrahedron Lett. 1965,
6, 321-324.
(12) (a) Anderson, D. J.; Gilchrist, T. L.; Horwell, D. C.; Rees, C. W. J.
Chem. Soc. C 1970, 4, 576-579. (b) Petrov, V. A. J. Fluorine Chem. 2000,
106, 25-34.
(13) (a) Abou-Gharbia, M. A.; Doukas, P. H. Heterocycles 1979, 12,
637-640. (b) Petrov, O. S.; Ognyanov, V. I.; Mollov, N. M. Synthesis 1987,
7, 637-638.
(14) (a) Li, J.; Liang, J.-L.; Chan, P. W. H.; Che, C.-M. Tetrahedron
Lett. 2004, 45, 2685-2688. (b) Krasnova, L. B.; Hili, R. M.; Chernoloz,
O. V.; Yudin, A. K. ARKIVOC 2005, 4, 26-38.
(15) Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem. 1982,
47, 5088-5093.
(16) Cuvigny, T.; Normant, H. J. Organomet. Chem. 1963, 1, 120-137.
2012
Org. Lett., Vol. 8, No. 10, 2006

Table 3. Aziridination of R-Bromo-Substituted Olefins and
Their Rearrangement into Hydrazones
Figure 1.
The R-bromoaziridines are thermally labile and undergo
a clean rearrangement into the corresponding hydrazones.
The conditions required to achieve full conversion are
summarized in Table 2. Hydrazones of high purity can be
obtained by evaporation of the reaction solvent and purifica-
Table 2. Thermal Rearrangement of R-Bromoaziridines
Halogenated cyclopropanes,17 epoxides,18 or thiiranes are
known19 to rearrange via an electrocyclic mechanism. Their
ring openings proceed in a disrotatory manner, and significant
torque selectivity can sometimes be observed.20
The X-ray structure of aziridine 7 reveals the C10-N2 bond
elongated by 0.023 Å compared to the C9-N2 bond,
suggesting the relative weakness of the former (Figure 2).
Figure 2. X-ray crystal structure of aziridine 7.
tion by crystallization from a hexanes-ethyl acetate mixture.
The aziridine 4, derived from a monosubstituted olefin,
requires microwave irradiation to reach completion in a
reasonable time. The aziridine 5 decomposed upon heating
without the formation of hydrazone.
During the reaction, transition-state stabilization would likely
occur upon partial overlap between the electron density
accumulated at the nitrogen of the C10-N2 bond undergoing
scission and the σ* of the C-Br bond (Scheme 2). For
The facility of rearrangement correlates with the stability
of the intermediate carbocation. The polar solvents facilitate
the ionization process. â-Bromostyrene, 1-bromo-2-methyl-
propene, and 2,3-dibromopropene, which are progenitors of
particularly stable carbocations, proceed directly to hydra-
zones upon exposure to N-aminophthalimide/DIB (Table 3).
Aziridine intermediacy can only be implicated in these cases.
The crystalline products 19 and 20 are stable compounds,
whereas hydrazone 21 was found to decompose over several
days even at 0 °C.
(17) (a) Fields, R.; Haszeldine, R. N.; Peter, D. J. Chem. Soc. C 1969,
1, 165-172. (b) Baird, M. S.; Lindsay, D. G.; Reese, C. B. J. Chem. Soc.
C 1969, 8, 1173-1178. (c) Werstiuk, N. H.; Roy, C. D. Tetrahedron Lett.
2001, 42, 3255-3258.
(18) (a) McDonald, R. N.; Tabor, T. J. Org. Chem. 1968, 33, 2934-
2941. (b) Ko¨brich, G.; Werner, W. Tetrahedron Lett. 1969, 10, 2181-
2183. (c) Gralak, J.; Valnot, J.-Y. Org. Prep. Proced. Int. 1979, 11, 107-
110.
(19) Schoenberg, A.; Knoefel, W.; Frese, E.; Praefcke, K. Tetrahedron
Lett. 1968, 9, 2487-2492.
(20) Woodward, R. B.; Hoffman, R. J. Am. Chem. Soc. 1965, 87, 3348-
3357.
Org. Lett., Vol. 8, No. 10, 2006
2013

To summarize, the N-aminophthalimide/DIB combination
is the method of choice for transforming readily available
bromo-olefins into the corresponding aziridines. The resulting
products undergo clean thermal rearrangement into R-bro-
mohydrazones. The regioselectivity of bromide migration and
the wide availability of brominated olefins allow for excellent
control over the site of substitution if a particular substituted
product is desired. Other useful reactions of R-haloaziri-
dines,22 particularly halogen/metal exchange,23 transition-
metal catalyzed reactions, and transformation into azirines,
can now be investigated with this straightforward method
in hand.
Scheme 2
Acknowledgment. We thank NSERC, CFI, ORDCF,
ACS-PRF, Amgen, and the University of Toronto for
financial support.
stereoelectronic reasons, the substituents anti to the leaving
group rotate outward as the ionization of the C-Br bond
takes place. The addition of Br- to the aza-allyl cation gives
the rearranged product of defined regiochemistry. The
lifetime of the formed aza-allyl cation is quite short. For
example, attempts to trap the aza-allyl cation with added
nucleophiles such as AcO- and I-, added in situ, were
unsuccessful.21 The addition of excess KOAc/18-crown-6 or
Bu4NI to the aziridination mixture in the case of 1-bromo-
2-methylpropene gave only R-bromo hydrazone 20 in
reduced yield. Neither acetoxy nor iodo derivatives have been
detected.
Supporting Information Available: The experimental
procedures and characterizations of compounds 4-10 and
15-21 and the X-ray crystal structure of 7 in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL060336Z
(22) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006.
(23) For recent examples of generating magnesiated aziridines from
sulfinylaziridines, see: (a) Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S.
Tetrahedron 2001, 57, 3891-3898. (b) Satoh, T.; Sato, T.; Oohara, T.;
Yamakawa, K. J. Org. Chem. 1989, 54, 3973-3978.
(21) A reviewer suggested the possibility of intramolecular bromide
migration.
2014
Org. Lett., Vol. 8, No. 10, 2006