Guanidinium ylides as a new and recyclable source for aziridines and their roles as chiral auxiliaries [1]

Full text of DOI:10.1021/ja0107024

J. Am. Chem. Soc. 2001, 123, 7705-7706
7705
Scheme 1
Guanidinium Ylides as a New and Recyclable Source
for Aziridines and Their Roles as Chiral Auxiliaries
Kihito Hada,† Toshiko Watanabe,† Toshio Isobe,‡ and
Tsutomu Ishikawa*,†
Graduate School of Pharmaceutical Sciences
Chiba UniVersity, 1-33 Yayoi, Inage
Chiba 263-8522, Japan
Central Research Laboratory
Shiratori Pharmaceutical Co. Ltd.
6-11-24 Tsudanuma, Narashino
Chiba 275-0016, Japan
ReceiVed March 16, 2001
Aziridines are very important molecules not only as key
components of biologically active natural products such as
mitomycins, but also as reactive synthetic intermediates for
nitrogen-containing compounds. Therefore, there have been many
approaches to their preparation, including asymmetric synthesis,
which could be classified into three types of reactions: (i)
intramolecular substitution by nitrogen nucleophiles, (ii) addition
of carbenes to imines, and (iii) addition of nitrenes to olefins.1
Guanidinium ylides have not hitherto been known to our
knowledge; however, these would be expected to act as stabilized
equivalents of azomethine ylides2 (see Scheme 1). In our
guanidine chemistry3 we found that treatment of guanidinium
bromides 3 (or 4) with aryl aldehydes 5 in the presence of a base
directly afforded 3-arylaziridine-2-carboxylates 6 (or 7) in high
yields with excellent to moderate trans diastereoselectivity.
Furthermore, the introduction of chiral centers into the guani-
dinium template resulted in effective asymmetric induction on
the aziridine formation. In this communication we present a new
aziridine synthesis from guanidinium ylides and an application
of the methodology to asymmetric synthesis.
Reaction of 3, prepared from 2-chloro-1,3-dimethylimidazo-
linium chloride (DMC)4 (1) according to the reported method3a
(see Scheme 1), with benzaldehyde (5a) (0.9 equiv) in DMF in
the presence of NaH (1.2 equiv) at -20 °C followed by SiO2
treatment5 afforded 3-phenylaziridine-2-carboxylate 6a in 84%
yield in a 27:73 ratio of cis and trans derivatives6,7 c-6a and t-6a
(entry 1, Table 1). Examination of the reaction conditions allowed
us to use tetramethylguanidine (TMG) as a base and a solvent.
Thus, stirring 3 and 5a with TMG (1.1 equiv) at room temperature
followed by SiO2 treatment5 similarly gave c-6a and t-6a in 28
and 41% yields, respectively (entry 2, Table 1).
particular, not only trans selectivity (ca. 90% de) but also
satisfactory conversion (68-95%) were observed when electron-
rich benzaldehydes 5b-d and indolyl aldehydes 5h-i (entries 3-6,
12, and 13, Table 1) were used. Cinnamaldehyde 5g could also
be converted to aziridines 6g in total 70% yield, in which no
1,4-addition occurred (entry 11, Table 1). Interestingly, replace-
ment of the ethyl ester function in 3 to a tert-butyl ester as in 4
led to a reversion of diastereoselectivity dependent upon the
substituent of aldehydes used. Thus, cis-excess products were
obtained in the cases of 5a and 5e (entries 15 and 18, Table 1).
In these reactions 1,3-dimethylimidazolidin-2-one (DMI) (8), a
synthetic precursor of 1, was isolated as an alternative product.
Thus, this reaction sequence could be regarded as an effective
cycle reaction, because of no waste of any of the key components
during reactions (see Scheme 1).
Next, this aziridine synthesis was applied to asymmetric syn-
thesis, because of the easy availability of chiral templates (Table
2). Smooth reaction was observed when the guanidinium bromide
9 (or ent-9)9 with a tert-butyl ester function was treated with
piperonal 5b under the same conditions on achiral salts, in which
TMG (entry 2, Table 2) was more effective in both chemical yield
and stereoselectivity than NaH in DMF (entry 1, Table 2). Thus,
optically active trans derivative t-7b was obtained in 82% yield
and with 97% ee in the former reaction, whereas in 75% yield
and with 72% ee in the latter case. In this reaction sequence a
chiral urea 10 was, as expected, recovered as a reuseable source
for 9 (or ent-9).
This synthetic method was found to be applicable to a variety
of aryl aldehydes, including heterocycles, as shown in Table 1,
in which trans aziridines8 t-6 were preferentially formed. In
† Chiba University.
‡ Shiratori Pharmaceutical Co. Ltd..
(1) Aube, J. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 835; Rosen, T. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, p 428; Kemp, J. E. G. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 469; Tanner, D.
Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619; Osborn, H. M. I.; Sweeney,
J. Tetrahedron: Asymmetry 1997, 18, 1693-1715; Atkinson, R. S. Tetrahe-
dron 1999, 55, 1519-1559; Mitchinson, A.; Nadin, A. J. Chem. Soc., Perkin
Trans. 1 2000, 2862-2892.
(5) Incomplete coversion of high polar substances into less polar ones during
SiO2 column chromatography of crude products made us modify the isolation
work. Thus, the solvent used was evaporated after the aldehyde disappeared
on TLC. The residue was stirred in CHCl3 with SiO2 and then the SiO2 was
removed. Evaporation of the filtrate followed by purification (SiO2) afforded
aziridines.
(2) Tsuge, O.; Kanemasa, S. AdV. Heterocycl. Chem. 1989, 45, 231-349;
Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 4, p 1085; Gothelf, K. V.; Jorgensen,
K. A. Chem. ReV. 1998, 98, 863-909.
(6) No isomerization was observed when each isomer was independently
treated under the conditions used in the reaction.
(7) In general, methine protons of cis derivatives were observed with larger
1
coupling constant (J ) ∼7 Hz) than those of trans one (J ) ∼4 Hz) in H
(3) (a) Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000, 65, 7770-
7773. (b) Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.; Yamaguchi, K.;
Ishikawa, T. J. Org. Chem. 2000, 65, 7774-7778. (c) Isobe, T.; Fukuda, K.;
Yamaguchi, K.; Seki, H.; Tokunaga T.; Ishikawa, T. J. Org. Chem. 2000, 65,
7779-7785.
NMR spectra of 2,3-disubstituted aziridine systems. In our case c-6a showed
the ring protons as doublets (J ) 6.7 Hz), whereas t-6a as either broad singlets
or doublets (J ) ∼2 Hz) (For example, see Davoli, P.; Moretti, I.; Prati, F.;
Alper, H. J. Org. Chem. 1999, 64, 518-521).
(8) Some aziridines showed the presence of invertomers at the nitrogen
atom in the 1H NMR spectra (See, Davoli, P.; Forni, A.; Moretti, I.; Prati, F.;
Torre, G. Tetrahedron 2001, 57, 1801-1812 and references therein).
(4) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 5832-5835; 6984-
6988; 6989-6992.
10.1021/ja0107024 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/12/2001

7706 J. Am. Chem. Soc., Vol. 123, No. 31, 2001
Communications to the Editor
Table 1. Reaction of Guanidinium Bromides 3 or 4 with Aryl
Aldehydes 5 Giving Aziridine Derivatives 6 or 7
Figure 1. A possible reaction path for the enantioselective formation of
(2R,3S)-trans-aziridine t-7 from ent-9 with 5.
lectivities were observed in the cases of indolyl aldehydes 5h
and 5i (entries 6 and 7, Table 2) in addition to 5b mentioned
above.
The absolute stereochemistries of aziridine products were
determined by chemical correlation of 3-phenylaziridine-2-car-
boxylates (c-7a: 79% ee; t-7a: 77% ee) obtained in entry 4 in
Table 2 with commercially available tert-butyl (S)-phenylalani-
nate. Independent hydrogenation10 of c-7a and t-7a with Pd(OH)2/C
in the presence of (Boc)2O afforded an identical N-Boc-protected
tert-butyl phenylalaninate, which was found to be an (R)-excess
product (77% ee for each) compared to an authentic (S)-derivative
(see SI), indicating that the (S,S)-guanidinium ylide mainly
produced (2R,3R)-cis and (2R,3S)-trans aziridines. Production of
(2R)-aziridines 7a from ent-9 suggested that the re-face of the
ylide has to be attacked by an aldehyde function in the C-C
bond formation to afford a spiro oxazolidine11 11 (see Figure 1).
Enantioselectivity of trans aziridine may be recognized by
assuming minimized steric replusion between the substituents of
each component in the benzylic cation/hydroxide ion pair
intermediate 12 derived from 11 as shown in Figure 1.
In conclusion, we have established an efficient preparation
method of 3-arylaziridine-2-carboxylates from guanidinium ylides
and aryl aldehydes applicable to asymmetric synthesis. It is known
that ammonium, azomethine, and nitrile ylides are useful and
reactive nitrogen ylides in organic synthesis.12 Therefore, our
results obtained here indicate a new entry of a guanidinium ylide
as a synthetically versatile nitrogen ylide.
a A: NaH. The reaction was carried out in DMF at -20 °C. B: TMG.
The reaction was carried out without solvent at rt. b Isolated, non-
optimized yield c Isolation was not attempted. d A mixture of two
invertomers at the nitrogen atom. e Deprotection of the Boc group was
observed during the reaction.
Table 2. Asymmetric Aziridine Synthesis Using Chiral
Guanidinium Bromides 9 or ent-9a
Supporting Information Available: Chiral conditions of HPLC
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0107024
(9) 9 and ent-9 were prepared from the corresponding ureas by successive
treatments with oxalyl chloride, tert-butyl glycinate, and benzyl bromide
(Preparation of the urea: see, Isobe, T.; Fukuda, K.; Ishikawa, T. Tetrahe-
dron: Asymmetry 1998, 9, 1729-1735).
a The reaction was carried out under the same conditions shown in
Table 1. b Isolated, nonoptimized yield. c See Supporting Information
for the separation conditions of enantiomeric aziridines by chiral HPLC.
d Isolation was not attempted.
(10) Reductive ring opening of the related aziridine system was reported
by Lee et al. (Chang, J. W.; Bae, J. H.; Shin, S. H.; Park, C. S.; Choi, D.;
Lee, W. K. Tetrahedron Lett. 1998, 39, 9193-9196).
We further examined the scope of this TMG-promoted asym-
metric aziridine synthesis using some aryl aldehydes. Introduction
of chiral units into the imidazolidine ring could cause rate
acceleration of the reaction and effective product formation with
satisfactory enantioselectivity, in which diastereoselectivites were
also observed. In particular, both high diastereo- and enantiose-
(11) The oxazolidine could be approached by two possible routes: (1)
stepwise reactions of the C-C bond formation followed by nucleophilic
addition or (2) direct connection by [2 + 3] cycloaddition.
(12) Brettle, R. In ComprehensiVe Organic Chemistry; Barton, D., Sir, Ollis,
W. D., Eds. Pergamon: Oxford, 1979; Vol. 1, p 978; Vol. 2, p 512; Huisgen,
R. Angew. Chem. 1963, 75, 604-637, 742-754; Zugravescu, I.; Petrovanu,
In N-Ylide Chemistry; McGraw-Hill: New York, 1976.