Efficient amination of sulfides with a ketomalonate-derived oxaziridine: application to [2,3]-sigmatropic rearrangements of allylic sulfimides.

Article abstract of DOI:10.1039/b201791a

A novel N-Boc-oxaziridine is reported, derived from diethyl ketomalonate, which effects efficient amination of sulfides to sulfimides. The reagent is applied to the [2,3]-sigmatropic rearrangement of allylic sulfimides.

Full text of DOI:10.1039/b201791a

Efficient amination of sulfides with a ketomalonate-derived oxaziridine:
application to [2,3]-sigmatropic rearrangements of allylic sulfimides†
Alan Armstrong* and Richard S. Cooke
Department of Chemistry, Imperial College, London, UK SW7 2AY. E-mail: A.Armstrong@ic.ac.uk;
Fax: +44 (0)20 75945804; Tel: +44 (0)20 75945876
Received (in Cambridge, UK) 19th February 2002, Accepted 13th March 2002
First published as an Advance Article on the web 26th March 2002
A novel N-Boc-oxaziridine is reported, derived from diethyl
ketomalonate, which effects efficient amination of sulfides
to sulfimides. The reagent is applied to the [2,3]-sigmatropic
rearrangement of allylic sulfimides.
sulfoxide and sulfimide are obtained, with highest levels of
amination (entry 3) being observed at low temperature in a more
polar solvent (CH3CN). Entries 4 and 5 indicate that the NBoc-
analogue 1a is less effective than 1b at amination, in line with
the idea that steric hindrance at nitrogen plays an important
role.6 Even at 235 °C in CH3CN (entry 5), the level of oxidation
was significant. Remarkably, however, a very high level of
amination was observed for oxaziridine 3, even in CDCl3
(entries 6-8). Selectivity was essentially complete at 240 °C. A
similar result was observed in several other solvents (CH2Cl2,
ether, THF, MeOH, CH3CN, toluene, EtOAc).
The precise factors that lead oxaziridine 3 to afford a higher
degree of nitrogen transfer than 1 require further experimental
and computational investigation. However, one pertinent fea-
ture may be that if 3 were to transfer oxygen, there would be a
developing steric interaction between the N-alkoxycarbonyl and
ester substituents in the transition state leading to the imine co-
product. For aldehyde-derived oxaziridine 1, the corresponding
interaction between the NBoc-group and a hydrogen atom
would be expected to be considerably less significant, so that
oxygen transfer is disfavoured to a lesser degree.
This property was then exploited in the efficient synthesis of
a range of sulfimides (Table 2). In all cases, 1H NMR analysis
of the crude reaction mixture indicated very clean reaction, with
essentially only the sulfimide product and diethyl ketomalonate
being present. Isolated yields were generally good, with the
result for dimethyl sulfide (entry 5) affected by the instability of
the product sulfimide to chromatography on silica. In contrast to
many amination reagents, oxaziridine 3 need not be used in
large excess. It is interesting to note that preparation of N-
alkoxycarbonylsulfimides is rare7 in comparison to their N-
sulfonyl counterparts,8 despite the higher potential utility of the
former due to the relative ease of N-deprotection. A notable
recent contribution came from Bach, who reported the use of
BocN3/FeCl2 for sulfide amination.9 The yields for this
Nitrogen-containing functional groups are widely represented
amongst bioactive compounds, making methods for their
selective introduction of prime importance in organic synthesis.
Electrophilic nitrogen sources offer a valuable strategic alter-
native to the more traditional nucleophilic reagents.1 In
continuation of our studies on asymmetric heteroatom transfer
from small-ring heterocycles (dioxiranes,2 oxaziridinium salts3)
we have been attracted to the use of oxaziridines as sources of
electrophilic nitrogen.4,5 The N-alkoxycarbonyl oxaziridines 1
pioneered by Collet, Vidal and co-workers6 are promising in
this regard, but their reactions often show low amination
efficiency. For example, reaction of 1a with enolates proceeds
in low yield due to competitive aldol reaction with the p-
cyanobenzaldehyde by-product.6 Reaction of thioanisole with
1b affords a mixture of sulfoxide and sulfimide,6 and we have
found that 1a behaves similarly (vide infra). We have started to
study the effect of substitution on the oxaziridine carbon on the
ratio of oxygen to nitrogen transfer, and report here a novel
oxaziridine that effects highly efficient amination of sulfides,
leading to sulfimides bearing the synthetically useful tert-
butoxycarbonyl (Boc) nitrogen protecting group. Additionally,
this reagent allows high yielding [2,3]-sigmatropic rearrange-
ment of allylic sulfimides.
N-Alkoxycarbonyloxaziridines are generally prepared by
oxidation of the corresponding imines, which in turn are
prepared from a carbonyl compound and an N-alkoxycarbonyl-
iminophosphorane via aza-Wittig reaction.6 Both imine oxida-
tion and subsequent heteroatom transfer are likely to be
facilitated by electron-withdrawing substituents, and compati-
bility with basic/nucleophilic reaction conditions likely necessi-
tates that the carbonyl compound is not enolisable. We therefore
selected commercially available diethyl ketomalonate 2 as a
suitable ketone starting material. We were pleased to find that
the novel NBoc-protected oxaziridine 3 could be prepared in
reasonable overall yield (Scheme 1). Oxaziridine 3 has proved
stable to storage at room temperature over several days, or in the
freezer (215 °C) over several weeks.‡
Scheme 1
Table 1 Reaction of oxaziridines 1a, 1b and 3 with thioanisole
Entry
Oxaziridine Solvent
Temp. (°C) Amination+oxidationa
1
2
3
4
5
6
7
8
1b
1b
1b
1a
1a
3
CDCl3
CDCl3
CH3CN
CDCl3
CH3CN
CDCl3
CDCl3
CDCl3
19
234
235
19
235
10
34+66b
52+48b
67+33b
27+73
62+38
90+10
95+5
As a test for the ability of 3 to act as a heteroatom transfer
reagent, we examined its reaction with thioanisole in compar-
ison to the oxaziridines 1. Entries 1–3 of Table 1 contain results
reported by Collet co-workers,6 indicating that a mixture of
3
3
0
240
> 98+2
† Electronic supplementary information (ESI) available: experimental
details and characterisation data. See http://www.rsc.org/suppdata/cc/b2/
b201791a/
a Measured by integration of the H NMR spectrum of the crude product.
1
b From ref. 6.
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CHEM. COMMUN., 2002, 904–905
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transformation using oxaziridine 3 compare extremely well
with those reported by Bach, with the efficient amination of the
hindered sulfide 4b being worthy of note (entry 2, Table 2),
since this substrate gave only 6% yield in the Bach system.
A particularly interesting application of sulfide amination is
the use of allylic sulfides as substrates, which is followed by
rapid [2,3]-sigmatropic rearrangement leading to an allylic
amine derivative.8,10,11 (Table 3). This was studied recently for
NBoc sulfimides by Bach using his BocN3/FeCl2 method-
ology.11 However, he obtained low yields for substrates bearing
groups capable of stabilising radicals (particularly CO2R) due to
competitive homolytic cleavage of the C–S bond prior to
rearrangement, leading to a stabilised allylic radical and thence
to several side products. On the assumption that amination by 3
proceeds via a concerted, non-radical mechanism, we were
optimistic that 3 would provide better yields than Bach’s
system. Pleasingly, this appears to be the case (Table 3). High
yields of the rearrangement product were obtained for several
substrates, with preparation of quaternary centres (entry 2) and
amino acid derivatives (entry 4) being particularly noteworthy.
versatile NBoc protecting group. Investigation of the ster-
eochemical aspects of this rearrangement process, including the
design and synthesis of chiral analogues of 3, are currently
under investigation along with the reaction of 3 with other
nucleophiles.
We thank Mark Atkin for preliminary studies on the synthesis
of 3, and Alisdair Falconer for work on reaction of sulfides with
1a. We are grateful to the EPSRC (GR/R54668) for their
support of this work, and for generous unrestricted funding from
Bristol-Myers Squibb, Pfizer, and Merck Sharpe and Dohme.
Notes and references
‡
Experimental procedures and characterisation data are provided in the
ESI.†
Data for 3: colourless oil, vmax(film)/cm21 2986, 1777, 1765, 1373, 1244,
1151, 1071, 845; dH (250 MHz, CDCl3) 4.41-4.31 (4H, m), 1.52 (9H, s),
1.37–1.31 (6H, m); dC (62.5 MHz, CDCl3) 162.2, 161.7, 156.2, 86.5, 75.8,
+
63.9, 63.2, 27.6, 13.8; m/z (CI) 307 (MNH4+, 90%); Found: MNH4
,
307.1517. C12H23N2O7 requires M, 307.1505.
Typical amination procedure (Tables 2 and 3): To a stirred solution of
oxaziridine 3 (250 mg, 0.86 mmol) in CH2Cl2 (5 ml) at 240 °C was added
dropwise a solution of sulfide (0.82 mmol) in CH2Cl2 (5 ml). The resulting
solution was allowed to warm to rt over 30 mins and then the solvent was
removed under reduced pressure. Chromatography yielded the required
product.
1
In all cases, the H NMR spectrum of the crude product from
reaction of 3 and the allylic sulfide 6 showed essentially only the
desired rearrangement product 7 and diethylketomalonate. The
absence of metals in the reaction system is an important
potential advantage with regard to product purification.
In summary, we have reported the first example of the use of
a ketomalonate-derived N-alkoxycarbonyloxaziridine in elec-
trophilic amination. Oxaziridine 3 effects highly efficient
amination of sulfides, and in the case of allylic sulfides provides
useful allylic amine derivatives bearing the synthetically
1 Reviews: E. Erdik and M. Ay, Chem. Rev., 1989, 89, 1947; C. Greck and
J. P. Genet, Synlett, 1997, 741; J. Mulzer and H. J. Altenbach, in
Organic Synthesis Highlights, VCH, Weinheim, 1991, 45; P. Dembach,
G. Seconi and A. Ricci, Chem. Eur. J., 2000, 6, 1281; Modern
Amination Methods, ed. A. Ricci, Wiley-VCH, Weinheim, 2000.
2 A. Armstrong and B. R. Hayter, Chem. Commun., 1998, 621; A.
Armstrong, B. R. Hayter, W. O. Moss, J. R. Reeves and J. S. Wailes,
Tetrahedron: Asymmetry, 2000, 11, 2057; A. Armstrong, W. O. Moss
and J. R. Reeves, Tetrahedron: Asymmetry, 2001, 12, 2779.
3 A. Armstrong and A. G. Draffan, J. Chem. Soc., Perkin Trans. 1, 2001,
2861.
Table 2 Reaction of sulfides 4 with oxaziridine 3
4 A. Armstrong, M. A. Atkin and S. Swallow, Tetrahedron Lett., 2000,
41, 2247; A. Armstrong, M. A. Atkin and S. Swallow, Tetrahedron :
Asymmetry, 2001, 12, 535.
Yield of 5
Entry
Substrate
R1
R2
(%)a
5 Recent use of oxaziridines for amination of alkoxides: O. F. Foot and D.
W. Knight, Chem. Commun., 2000, 975; I. C. Choong and J. A. Ellman,
J. Org. Chem., 1999, 64, 6528.
6 J. Vidal, S. Damestoy, L. Guy, J. Hannachi, A. Aubry and A. Collet,
Chem. Eur. J., 1997, 3, 1691.
1
2
3
4
5
4a
4b
4c
4d
4e
Ph
Me
Me
Bn
Et
97
75
77
75
49b
tBu
Ph
Bn
Me
Me
7 From alkoxycarbonylazides: W. Ando, N. Ogino and T. Nigita, Bull.
Chem. Soc. Japan, 1971, 44, 2278; Y. Hayahi and D. Swern,
Tetrahedron Lett., 1972, 1921; N. Numata, Y. Imashiro, I. Minimada
and M. Yamaoka, Tetrahedron Lett., 1972, 5097; W. Ando, H. Fujii, T.
Takeuchi, H. Higuchi, Y. Saiki and T. Migita, Tetrahedron Lett., 1973,
2117; D. C. Appleton, D. C. Bull, J. McKenna, J. M. McKenna and A.
R. Walley, J. Chem. Soc., Perkin Trans. 2, 1980, 385. From N-halo or
N-sulfonyloxycarbamates: G. F. Whitfield, H. S. Beilan, D. Saika and
D. Swern, Tetrahedron Lett., 1970, 3543; S. Oae, T. Masuda, K.
Tsujihara and N. Furukawa, Bull. Chem. Soc. Japan, 1972, 45, 3586; G.
F. Whitfield, H. S. Beilan, D. Saika and D. Swern, J. Org. Chem., 1974,
39, 2148; Y. Tamura, H. Ikeda, C. Mukai, I. Morita and M. Ikeda, J.
Org. Chem., 1981, 46, 1732. A catalytic method for preparing N-
(trifluoroacetyl)sulfimides was recently reported: C. S. Tomooka, D. D.
LeCloux, H. Sasaki and E. M. Carreira, Org. Lett., 1999, 1, 149.
8 A. L. Marzinzik and K. B. Sharpless, J. Org. Chem., 2001, 66, 594, and
references therein; H. Takada, Y. Nishibashi, K. Ohe, S. Uemura, C. P.
Baird, T. J. Sparey and P. C. Taylor, J. Org. Chem., 1997, 62, 6512.
9 T. Bach and C. Körber, Eur. J. Org. Chem., 1999, 1033.
10 T. L. Gilchrist and C. J. Moody, Chem. Rev., 1977, 77, 409.
11 T. Bach and C. Körber, J. Org. Chem., 2000, 65, 2358.
a Isolated yield after chromatography on silica. b Product unstable to
chromatography.
Table 3 Conversion of allylic sulfides 6 to allylic amines 7
Entry
Substrate
R1
R2
Yield of 7 (%)a
1
2
3
4
6a
6b
6c
6d
H
Me
H
Me
Me
Ph
CO2Me
94
93
73
85
H
a Isolated yield after chromatography.
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