Table 2 The Sc(OTf)3-catalyzed condensation of 1 with ketonesa
in high yields (eqns (3)–(4)). Increasing the bulk of the alkyl
group from Me to iPr led to a slight decrease in regioselectivity
(cf. Table 1, entry 1 and eqn (4)).
ð2Þ
Isomer Major
Time/h ratiob
product
Conv. Yield
(%)
Entry Ketone
1d
(%)c
ð3Þ
ð4Þ
2
4
6.7 : 1
13 : 1e
100
76
2d
100
100
91f
78
3
2
10 : 1
In conclusion, we have demonstrated a highly efficient and
regioselective Sc(OTf)3-catalyzed condensation of 2-alkyl-
N-tosylaziridine with a variety of aldehydes and ketones.
Excellent regioselectivity can be achieved if the aldehyde
component possesses a secondary site that can coordinate to
the catalyst and direct the carbonyl to the aziridine substrate.
Financial support for this work was provided by the NIH
(NCI 1U54 CA119341-01) and DOE (DE-FG02-03ER15457).
4
1.5
1.5
41 : 1
13 : 1
100
100
73g
68
5h
a
Reaction conditions: 1 (0.5 mmol), ketone (2.5 mmol, 5.0 equiv.),
dried Sc(OTf)3 (0.1 mmol, 20 mol %), CH2Cl2 (0.5 mL), 40 1C,
N2 atmosphere. Ratio of 5-substituted to 4-substituted isomers
Notes and references
b
1 I. D. G. Watson, L. Yu and A. K. Yudin, Acc. Chem. Res., 2006,
39, 194–206.
2 J. B. Sweeney, Chem. Soc. Rev., 2002, 31, 247–258.
3 A. W. Miller and S. T. Nguyen, Org. Lett., 2004, 6, 2301–2304.
4 V. K. Yadav and V. Sriramurthy, J. Am. Chem. Soc., 2005, 127,
16366–16367.
c
determined by GC analysis. Isolated yield of major product.
d
e
Reaction was carried out in neat ketone. Determined by 1H NMR.
Diastereomeric product, [(2R,5S)-7b + (2S,5R)-7b] : [(2S,5S)-7b +
f
g
1.3 : 1. Diastereomeric product, [(2R,5S)-7d
(2R,5R)-7b]
=
+
h
(2S,5R)-7d] : [(2S,5S)-7d + (2R,5R)-7d] = 1 : 1.3. The reaction was
performed at 80 1C in 1,2-dichloroethane.
5 T. Munegumi, I. Azumaya, T. Kato, H. Masu and S. Saito, Org.
Lett., 2006, 8, 379–382.
6 H. Maas, C. Bensimon and H. Alper, J. Org. Chem., 1998, 63, 17–20.
7 T. Yamauchi, H. Fujikura, K. Higashiyama, H. Takahashi and
S. Ohmiya, J. Chem. Soc., Perkin Trans. 1, 1999, 2791–2794.
8 X. Hao, Y. Shen, L. Li and H. He, Curr. Med. Chem., 2003, 10,
2253–2263.
9 A. Monge, I. Aldana, H. Cerecetto and A. Rivero, J. Heterocycl.
Chem., 1995, 32, 1429–1439.
10 G. P. Moloney, D. J. Craik, M. N. Iskander and T. L. Nero,
J. Chem. Soc., Perkin Trans. 2, 1998, 199–206.
11 E. D. Bergmann, Chem. Rev., 1953, 53, 309–352.
12 G. B. Kumar, H. V. Patel, A. C. Shah, M. Trenkle and
C. J. Cardin, Tetrahedron: Asymmetry, 1996, 7, 3391–3396.
13 S. Gandhi, A. Bisai, B. A. B. Prasad and V. K. Singh, J. Org.
Chem., 2007, 72, 2133–2142.
14 M. K. Ghorai and K. Ghosh, Tetrahedron Lett., 2007, 48,
3191–3195.
15 C. Reichardt, Solvents and Solvent Effects in Organic Chemistry,
Wiley-VCH, Weinheim, 3rd edn, 2003.
In an attempt to rationalize the high regioselectivity for
2-furaldehyde, m-methoxybenzaldehyde, and m-hydroxy-
benzaldehyde (Table 1, entries 7, 9, and 11), we hypothesize
that these substrates may not coordinate to the (OTf)3Sc(2-
methylaziridine) intermediate through the carbonyl group.
Instead, the coordination is via the secondary site of the
aldehyde (furyl, methoxy, and hydroxy group, respectively),
which favors an intramolecular delivery of the carbonyl
oxygen to C2 (ESIw, Scheme S1) over the intermolecular
pathway shown in Scheme 2. DFT calculations for model
Cl3Sc(2-methylaziridine) complexes of 2-furaldehyde, m-methoxy-
benzaldehyde, and o-methoxybenzaldehyde (ESIw, Table S8)
again reveal an increased differentiation in the partial charges
present on the aziridine C2 and C3 carbons when compared to
that in free 2-methylaziridine, with the biggest differences, and
hence best selectivities, occurring for Sc(2-furaldehyde) and
Sc(m-methoxybenzaldehyde).
16 V. Rauniyar and D. G. Hall, J. Am. Chem. Soc., 2004, 126,
4518–4519.
17 This behavior is in stark contrast to that of Zn(OTf)2, used as a
catalyst in the condensation of 2-aryl-N-tosylaziridine to ketones and
aldehydes by Gandhi et al. (ref. 13). In our hands, Zn(OTf)2 remained
insoluble in CH2Cl2, with or without the presence of the aziridine.
18 S. Kobayashi and R. Akiyama, Chem. Commun., 2003, 449–460.
19 In CH2Cl2, 2-phenyl-N-tosylaziridine quickly converted to an
insoluble white polymer in the presence of 20 mol% Sc(OTf)3.
20 B. L. Rivas, K. E. Geckeler and E. Bayer, Eur. Polym. J., 1991, 27,
1165–1169.
21 T. H. Fife and J. E. C. Hutchins, J. Org. Chem., 1980, 45,
2099–2104.
22 S.-H. Lee, J. Yang and T.-D. Han, Tetrahedron Lett., 2001, 42,
3487–3490.
While reactions of 2-methyl-N-tosylaziridine with ketones
were slightly slower compared to those of aldehydes, the
corresponding 2,2-disubstituted-1,3-oxazolidines can still be
obtained in good yields (Table 2). Both acyclic and cyclic
aliphatic ketones afforded the expected products in high yields,
although bulkier substrates required longer reaction time
(Table 2, cf. entries 1–3).
The reaction depicted in eqn (1) (Table 1) can be extended to
other 2-alkyl-N-sulfonylaziridines. Oxazolidines 10a, 10b, and
12 can be obtained from 2-butyl-N-tosylaziridines, 2-isopropyl-
N-tosylaziridines, and 2-methyl-N-mesylaziridines, respectively,
23 The decrease in diastereomeric ratio for the increase of the reaction
temperature has been observed by Ghorai and Ghosh (see ref. 14).
24 J. E. Baldwin, A. C. Spivey, C. J. Schofield and J. B. Sweeney,
Tetrahedron, 1993, 49, 6309–6330.
ꢂc
This journal is The Royal Society of Chemistry 2009
3930 | Chem. Commun., 2009, 3928–3930