Electrophilic amination of carbanions by N-carboxamido oxaziridines

Article abstract of DOI:10.1016/S0040-4039(00)00140-4

A range of 3-aryl-N-carboxamido oxaziridines have been prepared and tested as reagents for electrophilic amination of carbanions. The 3-(2- cyanophenyl)-derivative gave highest yields of amination product, and was used for amination of ketone, ester and a

Full text of DOI:10.1016/S0040-4039(00)00140-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2247–2251
Electrophilic amination of carbanions by N-carboxamido
oxaziridines
Alan Armstrong,a,∗ Mark A. Atkin a and Steven Swallow b
aSchool of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
bRoche Discovery Welwyn, Broadwater Road, Welwyn Garden City, Herts AL7 3AY, UK
Received 17 December 1999; accepted 18 January 2000
Abstract
A range of 3-aryl-N-carboxamido oxaziridines have been prepared and tested as reagents for electrophilic
amination of carbanions. The 3-(2-cyanophenyl)-derivative gave highest yields of amination product, and was
used for amination of ketone, ester and amide enolates, as well as sulfone-, phosphonate- and nitrile-stabilized
carbanions. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: amination; oxaziridines; carbanions; amino acids and derivatives; ureas.
The electrophilic amination of nucleophiles is of considerable current interest as it provides a poten-
tially powerful method for the introduction of nitrogen functionality.1 Methods for efficient asymmetric
electrophilic amination would be especially valuable.2 In this regard, we were attracted to the fascinating
observation by Vidal and Collet and co-workers3–7 that N-alkoxycarbonyl oxaziridines (e.g. 1) transfer
nitrogen (rather than oxygen) to various nucleophiles, including ester enolates, resulting in a conceptually
simple method for amino acid synthesis (Scheme 1).4,6 We have initiated a programme aimed at the
synthesis and testing of a range of chiral analogues of these oxaziridines as reagents for asymmetric
electrophilic amination and among our first targets were N-carboxamido oxaziridines 2. Ultimately, it
is intended that the exocyclic nitrogen will be derived from a chiral amine, allowing preparation of
diastereomerically pure oxaziridines and investigation of chirality transfer in nucleophile amination.
However, an essential initial requirement was the need to establish that N-carboxamido oxaziridines were
indeed capable of N-transfer to carbanions, and to discover the structural features necessary for efficient
reaction. An additional stimulus for this study was the realization that the products of enolate amination
by 2 — compounds containing an unsymmetrical urea residue α- to a carbonyl function — are of some
interest as hydrolytically stable peptidomimetics.8,9 Here we report the results of our early studies on the
reactivity of oxaziridines 2.
∗
Corresponding author. Present address: Department of Chemistry, Imperial College, London SW7 2AY, UK. E-mail:
a.armstrong@ic.ac.uk (A. Armstrong)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00140-4
tetl 16420

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Scheme 1.
A problem with the N-Boc oxaziridine 1 is that enolate amination often proceeds in low yields due
to competing aldol reaction with the aldehyde that is released when the oxaziridine transfers nitrogen
(Scheme 1).4,6 In common with Vidal and Collet,4,6 we reasoned that this aldol side reaction might be
suppressed by varying the aldehyde portion, in particular by the incorporation of ortho-substitutents
on the aromatic ring. The preparation of oxaziridines derived from a range of aromatic aldehydes was
therefore our first goal; this was easily accomplished by the sequence shown in Scheme 2. Thus, acid-
catalyzed condensation of 1,1-diethylurea with aromatic aldehydes 3a–e provided the imines 4a–e which
without purification were oxidized to the oxaziridines 5a–e (50–61% yield from 3) using mCPBA/BuLi
in a slight modification of the procedure described by Vidal and Collet.5,6,10 Attempted oxidation
using Oxone® was far less efficient and resulted in lower yields. The oxaziridines were formed as
predominantly a single stereoisomer (presumably trans) according to 1H NMR spectroscopy, with small
amounts (<8%) of the cis-isomer being observed in some cases.
Scheme 2.
With the synthesis of the oxaziridines accomplished, attention was focused on their use in carbanion
amination. tert-Butyl acetate, amination of the enolate of which using 1 (Scheme 1) has been reported,4,6
was selected as a suitable test substrate to assess the effect of the aromatic substituents on the ratio of
amination to aldol products (Scheme 3). In a typical reaction,11 a THF solution of the oxaziridine was
added to the lithium enolate of the ester in THF at −78°C; reaction was completed upon warming to room
temperature. It should be noted that oxaziridines 5 appear to be somewhat less reactive than 1, which will
effect amination at −78°C.4,6 The results of amination using 5a–e are given in Table 1. Entry 1 shows

2249
the result when using the 3-(4-cyanophenyl)-oxaziridine 5a, which provided a similar yield of amination
product (39% of 6a) to that obtained using 1, along with some of the expected aldol product 7a (20%).
Disappointingly, however, ortho-substituted chloro analogues 5b and 5c (entries 2 and 3) did not react
with the enolate, with the starting oxaziridines being recovered (ca. 75%). This lack of reactivity may
be due to steric effects since the amination did proceed with the 4-chloro analogue 5d (entry 4). Entry
5 shows that the oxaziridine 5e,10 derived from 2-cyanobenzaldehyde, proved to be the best reagent in
this study, giving a 55% yield of the amination product and just 7% of the aldol side-product. When
compared to entry 2, where no reaction was observed, the higher reactivity of 5e may be due to the
smaller relative size of the cyano group (A value of CN 0.2 kcal/mol; of Cl, 0.53–0.64 kcal/mol).12 Thus,
the 2-cyano analogue 5e appears to confirm that ortho-substitution is able to slow down the competing
aldol reaction, and improve product ratios in favour of electrophilic amination products. To the best of
our knowledge, these results represent the first examples of N-carboxamido oxaziridines transferring
electrophilic nitrogen to enolates.
Scheme 3.
Table 1
Amination of the lithium enolate of tert-butylacetate with oxaziridines 5a–ea
After highlighting the 3-(2-cyanophenyl)-oxaziridine 5e as the most effective aminating reagent in
our test reaction, a study was undertaken to extend the scope of this reagent and confirm its utility in
electrophilic amination of a variety of carbanions (Table 2). More highly-substituted ester enolates were
aminated in good yield (entries 1 and 2); entry 2 is particularly interesting since it generates an α,α-
disubstituted peptidomimetic.8,9 We were pleased to find that ketone enolates (acyclic and cyclic, entries
3 and 4) and amide enolates (entry 5) were also aminated in good yield. In addition, phosphonate and
sulfone carbanions were aminated, providing a novel and direct route to the corresponding α-amino
compounds (entries 6 and 7). The amination of an α-cyanocarbanion was also demonstrated (entry 8).
In summary, a range of new N-carboxamido oxaziridines have been prepared and shown to be effective
in the electrophilic amination of a range of carbon nucleophiles. Importantly, use of a 2-cyano-substituted
aromatic moiety results in improved product ratios in favour of electrophilic amination over aldol
reaction. Work is underway to prepare and test chiral N-carboxamido oxaziridines for use in asymmetric
electrophilic amination.

2250
Table 2
Carbanion amination using oxaziridine 5ea
Acknowledgements
We thank the EPSRC and Roche (CASE award to MAA) for funding this work. We wish to
acknowledge the use of the EPSRC Chemical Database Service.13
References
1. Reviews: Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947–1980. Greck, C.; Genet, J. P. Synlett 1997, 741–748. Mulzer, J.;
Altenbach, H.-J. In Organic Synthesis Highlights; VCH: Weinheim, 1991; pp. 45–53.
2. Recent examples: Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595–598. Harris, J. M.; McDonald, R.; Vederas, J. C. J.
Chem. Soc., Perkin Trans. 1 1996, 2669–2674. Svenstrup, N.; Bøgevig, A.; Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 1559–1565.
3. Vidal, J.; Drouin, J.; Collet, A. J. Chem. Soc., Chem. Commun. 1991, 435–437.
4. Vidal, J.; Guy, L.; Sterin, S.; Collet, A. J. Org. Chem. 1993, 58, 4791–4793.
5. Vidal, J.; Damestoy, S.; Collet, A. Tetrahedron Lett. 1995, 36, 1439–1442.

2251
6. Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J.; Aubry, A.; Collet, A. Chem. Eur. J. 1997, 3, 1691–1709.
7. Vidal, J.; Hannachi, J.-C.; Hourdin, G.; Mulatier, J.-C.; Collet, A. Tetrahedron Lett. 1998, 39, 8845–8848.
8. Xiao, X.; Ngu, K.; Choa, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968–6973.
9. Getman, D. P.; DeCrescenzo, G. A.; Heintz, R. M.; Reed, K. L.; Talley, J. J.; Bryant, M. L.; Clare, M.; Houseman, K. A.;
Marr, J. J.; Mueller, R. A.; Vasquez, M. L.; Shieh, H. S.; Stallings, W. C.; Stegeman, R. A. J. Med. Chem. 1993, 36, 288–291.
10. The procedure of Ref. 6 was employed using anhydrous mCPBA (1.6 equiv.) and nBuLi (1.5 equiv.), except that after
addition of the imine, the reaction was stirred at −78°C for 3 h, then brought to rt over 90 min before quenching and work-
up. This was found to reduce the amount of isomeric amide formed as by-product. Data for 5e: white solid (1.16 g, 61%); mp
41°C; νmax (CHCl3 solution)/cm−1 2972, 2937, 2361, 2228, 1698, 1601, 1430, 1271; δH (400 MHz, CDCl3) 7.75–7.55 (4H,
m), 5.62 (1H, s), 3.70–3.53 (2H, m), 3.47–3.38 (2H, m), 1.23 (3H, t, J 7.1 Hz), 1.21 (3H, t, J 7.1 Hz); δC (67 MHz, CDCl3)
160.0 (C), 136.4 (C), 133.2 (CH), 133.1 (CH), 130.7 (CH), 128.4 (CH), 116.3 (C), 112.7 (C), 74.8 (CH), 42.1 (CH2), 42.0
(CH2), 14.4 (CH3), 12.6 (CH3); MS (EI+) m/z 245 (M+, 3.48%); HRMS observed 245.1174, C13H15N3O2 requires 245.1164.
Anal. calcd for C13H15N3O2: C, 63.66; H, 6.16; N, 17.13. Found: C, 63.46; H, 6.23; N, 16.99.
11. Typical procedure for enolate/carbanion aminations: to diisopropylamine (77 µl, 0.55 mmol, 1.1 equiv.) in THF (850 µl)
at 0°C under nitrogen was added nBuLi (2.5 M, 211 µl, 0.53 mmol, 1.05 equiv.). The resulting mixture was stirred for 30
min, then cooled to −78°C. A solution of tert-butyl acetate (67 µl, 0.50 mmol) in THF (850 µl) was slowly added, and the
resulting mixture stirred at −78°C for 1 h. A solution of oxaziridine 5e (123 mg, 0.50 mmol) in THF (850 µl) was then added
in a single portion, and the reaction stirred for 3 h at −78°C before being allowed to reach rt over a period of 90 min. The
reaction was quenched by the addition of saturated sodium bicarbonate solution, and diluted with CH2Cl2. The layers were
separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with saturated
aqueous sodium bicarbonate solution, then saturated sodium chloride solution, dried over anhydrous magnesium sulfate,
and concentrated in vacuo. The crude product was purified by flash column chromatography to yield aminated product 6e
(63.5 mg, 55%) and aldol side product 7e (8.7 mg, 7%). Data for 6e: νmax (CHCl3 solution)/cm−1 3168, 2927, 2855, 1721,
1614, 1467, 1452, 1215, 1075; δH (400 MHz, CDCl3) 4.82 (1H, s), 3.94 (2H, d, J 4.9 Hz), 3.29 (4H, q, J 7.1 Hz), 1.48 (9H,
s), 1.17 (6H, t, J 7.1 Hz); δC (67 MHz, CDCl3) 170.5 (C), 156.8 (C), 81.7 (C), 43.2 (CH2), 41.2 (2×CH2), 27.9 (3×CH3),
13.7 (2×CH3); MS (EI+) m/z 231 (M+H, 20.5%), 175 (M-tBu, 60.4%); HRMS observed 231.1712, C11H23N2O3 requires
231.1708.
12. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994; pp. 694–697.
13. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comput. Sci. 1996, 36, 746–749.