Sc(OTf)3-catalyzed condensation of 2-alkyl-N-tosylaziridine with aldehydes or ketones: An efficient synthesis of 5-alkyl-1,3-oxazolidines

Article abstract of DOI:10.1039/b902647a

Sc(OTf)₃ effectively catalyzes the condensation of 2-alkyl-N-tosylaziridine with a wide variety of aldehydes and ketones, producing 5-alkyl-1,3-oxazolidines in good yields and excellent regioselectivity at catalyst loadings as low as 1 mol%.

Full text of DOI:10.1039/b902647a

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Sc(OTf)3-catalyzed condensation of 2-alkyl-N-tosylaziridine with
aldehydes or ketones: an efficient synthesis of 5-alkyl-1,3-oxazolidinesw
Byungman Kang, Aaron W. Miller, Sandra Goyal and SonBinh T. Nguyen*
Received (in Cambridge, UK) 9th February 2009, Accepted 23rd March 2009
First published as an Advance Article on the web 26th May 2009
DOI: 10.1039/b902647a
Sc(OTf)3 effectively catalyzes the condensation of 2-alkyl-
N-tosylaziridine with a wide variety of aldehydes and ketones,
producing 5-alkyl-1,3-oxazolidines in good yields and excellent
regioselectivity at catalyst loadings as low as 1 mol%.
When 2-methyl-N-tosylaziridine (1) was combined with
2 equiv. of p-nitrobenzaldehyde (2e) in CH2Cl2 at room
temperature in the presence of several Lewis acids
(10 mol%) (ESIw, Table S2), only Sc(OTf)3 exhibited catalytic
activity, providing the oxazolidine product 3e in 32% yield after
13
18 h. While Zn(OTf)2 and Cu(OTf)214 have been reported to
The high ring strain of aziridines make them useful precursors
effect the cycloaddition of 2-aryl-N-tosylaziridine to aldehydes
and ketones, in our hands Cu(OTf)2 only afforded a trace
conversion of 1 and Zn(OTf)2 did not show any catalytic
activity. Similarly, SnCl4 and TiCl4 only yielded a trace of 3e.
Indeed, while Zn(OTf)2 can catalyze the cycloaddition of
2-phenyl-N-tosylaziridine to benzaldehyde (ESIw, Table S1,
entry 8), it does not have any effect on the cycloaddition of
2-methyl-N-tosylaziridine to p-nitrobenzaldehyde, arguably a
more activated carbonyl (ESIw, Table S2, entry 8). Thus, we
selected Sc(OTf)3 for further optimization.
to
a wide range of functionalized nitrogen-containing
compounds.1,2 Among emerging reactions, the cycloaddition
of aziridines to dipolarophiles provides a facile entry to hetero-
cycles such as oxazolidinone,3 oxazolidine,4 iminooxazolidine,5
and iminopyrrolidine.6 In particular, 1,3-oxazolidines have
found ever-expanding uses in the syntheses of both natural
products7,8 and designed medicinal agents (as prodrugs for
1,2-amino alcohols or carbonyl-containing pharmacophores).9,10
However, traditional syntheses of 1,3-oxazolidines largely rely
on the condensation of 1,2-amino alcohols with carbonyl
substrates, which typically requires high temperatures, has
limited scope, and can lead to many side products.11,12
Among the solvents evaluated (ESIw, Table S3), 1,2-dichloro-
ethane and CH2Cl2, both polar and non-coordinating solvents,
produced the best yield of the desired product 3e. While
high temperatures (80 1C) increase the rate of the reaction
(ESIw, Table S3, entries 6–8), there is a significant amount of
product decomposition, reducing the yield to a point that is
only slightly higher than that obtained with CH2Cl2 at 40 1C.
Coordinating solvents such as CH3CN and THF gave a very
poor yield of 3e, most likely due to competitive solvent
coordination at the Sc center,15 which prevents aziridine
complexation and catalyst turnover.
Given the aforementioned impediments, the cycloaddition
of aziridines to carbonyls in the presence of a Lewis acid (LA)
is a more attractive strategy to 1,3-oxazolidine formation
(Scheme 1). Surprisingly, very few reports have appeared on
this method,4,13,14 and with only modest scope and generality.
For instance, because 2-alkyl-substituted aziridines are more
resistant to LA-assisted ring-opening reactions, current
reports are mostly limited to 2-aryl-substituted substrates.13,14
In addition, catalytic examples for the synthesis of
1,3-oxazolidines are rare: the reported Zn(OTf)2-catalyzed
cycloaddition of 2-aryl-N-tosylaziridine to organic carbonyls13
To confirm the aforementioned hypothesis, we investigated
the 45Sc NMR spectra of a [Sc(OTf)3 + aziridine 1] mixture in
both CD2Cl2 and CD3CN. While Sc(OTf)3 itself is poorly
soluble in CD2Cl2,16 the [Sc(OTf)3 + aziridine 1] mixture
becomes homogeneous in CD2Cl2 after 1 h, suggesting
formation of an aziridine–Sc complex.17 The 45Sc NMR
resonance of this mixture in CD2Cl2 appears as a broad signal
that is significantly downfield (d = 150 ppm) from the sharp
singlet observed at d = 0.4 ppm for the same mixture in
CD3CN.18 As free Sc(OTf)3 in CD3CN also exhibits a sharp
singlet at ꢁ2.5 ppm (ESIw, Fig. S1), it appears that 1 does not
significantly influence the coordination environment of
Sc(OTf)3 in CD3CN. Together, these data suggest that
aziridine 1 can readily coordinate to Sc(OTf)3 in a non-
coordinating solvent such as CD2Cl2, but this coordination
is weak and can be readily displaced by CD3CN.
does not give consistent results (ESIw, Table S1); a stoichiometric
amount of the Lewis acid (either BF3ꢀEt2O4 or Cu(OTf)2
)
14
was often required to achieve good yields. Herein, we
report an efficient and general Sc-catalyzed synthesis of
5-alkyl-1,3-oxazolidines from 2-alkyl-N-tosylaziridine and
either aldehydes or ketones.
Scheme 1 The cycloaddition of 2-alkyl-N-tosylaziridine with either
aldehydes or ketones catalyzed by Lewis acids.
Department of Chemistry and the Institute for Catalysis in Energy
Processes, Northwestern University, 2145 Sheridan Road, Evanston,
IL 60208-3113, USA. E-mail: stn@northwestern.edu;
As expected, higher catalyst loadings and a higher excess of
2e lead to faster conversions (ESIw, Table S4, entries 1–4).
Under optimal conditions (20 mol% Sc(OTf)3, 0.5 M or 1.0 M
in 1, 5 equiv. of 2e, 2 h), 3e can be formed in 490% yield.
Longer reaction times can reduce the yield of 3e, presumably
due to the LA-catalyzed polymerization of aziridine 119,20 and
Fax: +1 874-491-7713; Tel: +1 847-467-3347
w Electronic Supplementary Information (ESI) available: General
procedure for Sc(OTf)3-catalyzed synthesis of 5-alkyl-1,3-oxazolidines
and characterization data of all products; DFT calculations for model
complexes and potential intermediates. See DOI: 10.1039/b902647a
ꢂc
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the instability of product 3e in the presence of adventitious
water (ESIw, Table S4, cf. entries 4 and 5).21,22 For aldehydes
that are more soluble, such as valeraldehyde (2a), the loading
of Sc(OTf)3 can be reduced to 1 mol% without significantly
affecting the product yield, albeit with an increase in the
reaction time (ESIw, Table S4, entries 7–9). To reduce the
reaction time, neat substrate can be used in conjunction with
low catalyst loading, affording oxazolidine product 3a in 81%
yield after 6 h (ESIw, Table S4, entry 10).
ratio starts out high and degrades over time: for entry 5,
the diastereomeric ratio at B5% conversion was 2.6:1
(ESIw, Table S5).23 Presumably, the kinetically formed cis
product is isomerized to the trans isomer via Lewis
acid-activated carbon–oxygen bond cleavage (Scheme 2,
equilibrium shown on the lower left quadrant). This is indeed
the case: a sample of cis-enriched 3e (8.5: 1) was readily
isomerized to a 1.1 : 1 cis :trans mixture within 15 min in the
presence of Sc(OTf)3 (ESIw, Fig. S3).
Table 1 outlines the scope of the Sc(OTf)3-catalyzed
condensation of 2-alkyl-substituted aziridines to aldehydes.
Under our optimized reaction conditions, a wide range of
5-alkyl-1,3-oxazolidines are obtained with high regioselectivity
and can be easily isolated in pure form via chromatography.
Reactions with non-bulky aldehydes generally result in two
diastereomeric products of approximately equal proportions
(Table 1, entries 1–2 and 4–11). Interestingly, the diastereomeric
Our proposed mechanism for eqn (1) (Table 1) is shown in
Scheme 2 (see ESIw for justification of the intermediates based
on DFT calculations). The aziridine is first activated by
coordination to the Lewis acidic Sc3+ metal center, generating
intermediate 4 with differently polarized N–C bonds. Subsequent
nucleophilic ring-opening of the coordinated aziridine by the
oxygen atom of the carbonyl at the more substituted carbon
results in the highly reactive intermediate 5.13,14 Cyclization
finally leads to the formation of 1,3-oxazolidine product.
DFT calculations for
a model Cl3Sc(benzaldehyde)-
Table 1 The Sc(OTf)3-catalyzed condensation of 1 with aldehydesa
(2-methylaziridine) complex (ESIw, Table S8) indeed suggest
that coordination of the aziridine to the Lewis acidic Sc3+
center leads to increased differentiations in the partial charges
present on the aziridine C2 and C3 carbons compared to that in
free 2-methylaziridine. The increased electrophilic character of
the C2 carbon in the coordinated aziridine, coupled to an even
larger increase in the nucleophilic character of the C3 carbon
(ESIw, Table S8), would result in higher selectivity for
ring-opening at C2. Consistent with this hypothesis, optically
pure (R)-2-methyl-N-tosylaziridine is rapidly racemized in the
presence of Sc(OTf)3 in CH2Cl2 at 40 1C (ESIw, Fig. S6–S7).
Using the aforementioned model, the higher regioselectivity
for 2e over other para-substituted benzaldehydes (Table 1,
cf. entries 4–6 and 10), can then be attributed to a reactivity–
selectivity argument. Baldwin and co-workers have observed
that compared to stronger Grignard nucleophiles, softer
carbon nucleophiles such as cuprates preferentially attack
2-substituted N-tosylaziridine at the C2 position,24 which has
a partial positive charge (ESIw, Table S8). In the same vein, we
speculate that because the carbonyl oxygen of 2e is less
nucleophilic than those in other para-substituted benz-
aldehydes, it would preferentially ring-open the Sc-activated
aziridine species 4 at the partially cationic C2 over the partially
anionic C1 (ESIw, Table S8).
ð1Þ
Major product
cis :
Structure transc
Isomer
Conv. Yield
(%)d (%)e
Entry Aldehyde Time/h ratiob
1f
2f
3f
0.5
0.5
0.5
6.5 : 1
5.5 : 1
11 : 1
1.5 : 1 100
84
82
81
1.5 : 1 100
5.1 : 1 100
1.1 : 1 100
4
5
0.5
11 : 1
19 : 1
79
86
2
1.1 : 1 100
6
7
8
0.5
9.5 : 1 (2f)
450 : 1 (2g)
9.4 : 1 (2h)
1.2 : 1 100
1.2 : 1 100
1 : 1.1 100
74
n/a
n/a
9
1
450 : 1
1 : 1.6 100
82
10
11
12
0.5
11 : 1 (2j)
20 : 1 (2k)
n/ag (2l)
1.1 : 1 100
1 : 1.1 100
n/a
41
—
—
—
a
Reaction conditions: 1 (0.5 mmol), aldehyde (2.5 mmol, 5.0 equiv.),
Sc(OTf)3 (0.1 mmol, 20 mol%), CH2Cl2 (0.5 mL), 40 1C, ambient
atmosphere. Ratio of 5-substituted to 4-substituted isomers determined
b
c
by GC analysis. Confirmed by NOE experiments. Conversion
d
e
determined by GC analysis based on aziridine 1. Isolated yield of
f
g
major product. Reaction was carried out in neat aldehyde. Complete
Scheme
2 A proposed mechanism for the Sc(OTf)3-catalyzed
consumption of 1 but there was no characterizable major product.
condensation of 2-alkyl-N-tosylaziridine with aldehydes or ketones.
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Chem. Commun., 2009, 3928–3930 | 3929

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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
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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.
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2253–2263.
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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.
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This journal is The Royal Society of Chemistry 2009
3930 | Chem. Commun., 2009, 3928–3930