Novel aziridination of α-halo ketones: an efficient nucleophile-induced cyclization of phosphoramidates to functionalized aziridines

Article abstract of DOI:10.1016/j.tetlet.2007.11.130

A novel and efficient aziridination of α-halo ketones is reported. The reaction of α-halo ketones with diethyl N-arylphosphoramidates affords diethyl N-aryl-N-(2-oxoalkyl)phosphoramidates which undergo reductive (H^--induced) cyclization with so

Full text of DOI:10.1016/j.tetlet.2007.11.130

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 687–690
Novel aziridination of a-halo ketones: an efficient
nucleophile-induced cyclization of phosphoramidates
to functionalized aziridines
Lal Dhar S. Yadav *, Ankita Rai, Vijai K. Rai, Chhama Awasthi
Green Synthesis Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Received 18 September 2007; revised 14 November 2007; accepted 21 November 2007
Abstract
A novel and efficient aziridination of a-halo ketones is reported. The reaction of a-halo ketones with diethyl N-arylphosphoramidates
affords diethyl N-aryl-N-(2-oxoalkyl)phosphoramidates which undergo reductive (HÀ-induced) cyclization with sodium borohydride fol-
lowed by sodium hydride to give 1,2-disubstituted and 1,2,3-trisubstituted aziridines. The cyclization induced by NCSÀ or PhSÀ affords
substituted aziridines functionalized at C-2. The reactions give excellent yields and are highly diastereoselective in favour of cis aziridines.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Aziridines; a-Halo ketones; Phosphoramidates; Nucleophile-induced; Reduction; Cyclization reactions
Owing to the inherent strain in small ring heterocycles,
they are useful as feedstocks in organic synthesis to provide
functionalized carbon chains. Aziridines have been syn-
thetic targets as well as building blocks in synthesis since
Gabriel’s 1888 discovery of the smallest nitrogen-contain-
ing heterocycle.1–3 In terms of synthetic transformations,
the utility of aziridines derives from their selective ring-
opening reactions,4,5 which often form the basis for more
complex target syntheses.6,7 Yudin and co-workers have
demonstrated a number of connections between aziridines
and the products of their ring-opening.8
Antibiotic, anticancer and antitumour activities of azir-
idine-containing natural products, such as azinomycins,9–11
mitomycins,12,13 FR-900482, FR-66979 and related com-
pounds,14 are of significant interest. Of these, azinomycins
possess a broad spectrum of activity against cancers,
including tumours, and mitomycin C has been in clinical
use since the 1960s for the treatment of a wide range of
tumours. FR-900482 and FR-66979 are structurally related
to mitomycins and show similar anticancer activity. The
activity of all these compounds lies in the role of aziridines
as powerful alkylating agents.15 Furthermore, several syn-
thetic aziridines have also been reported to exhibit useful
biological properties such as irreversible inhibition of
glutamate racemase,16 and diaminopimelic acid epimerase
(DAP),17 and high level cytotoxicity against melanoma cell
lines.18
Numerous methods are available for differently substi-
tuted aziridines, which include aziridination of olefins,19–21
carbene and ylide addition to imines,22–24 and cyclization
of b-amino alcohols,25,26 a-halo imines,27 b-amino
halides,25,26 and b-azido alcohols.25,26,28 Very recently, an
excellent review by De Kimpe and co-workers covered
the synthesis and reactivity of C-heteroatom-substituted
aziridines,29 which also includes C-sulfur-substituted aziri-
dines similar to those reported in the present Letter. a-Halo
imines are important intermediates in aziridine synthesis,
which involves a two-step process starting from a-halo
ketones or aldehydes.
In continuation of our efforts to develop new one-pot
cyclization processes,30 we report herein a two-step syn-
thetic protocol for the synthesis of aziridines starting from
*
Corresponding author. Tel.: +91 5322500652; fax: +91 5322461157.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.130

688
L. D. S. Yadav et al. / Tetrahedron Letters 49 (2008) 687–690
(i) 1 (1eq), NaH (1 eq)
O
O
R'
O
P
benzene, 60 oC, 30 min
EtO
EtO
X
R
(EtO)2PNHAr
+
R
N
Ar
(ii) 2 (1eq), benzene
O
R'
60 oC, 3 h
1
2
3
(i) NaBH4 (1 eq)
t
-BuOH, r.t., 2 h
t
60 oC, 2 h
R
R'
(ii) NaH (1 eq)
Y
N
Ar
t
-BuOH, r.t., 3 h
60 oC, 2 h
5
R
R'
Y = NCS, PhS
N
Ar
4
R'
Y
Ar
Yield (%)*
Product
R'
Y
Yield (%)*
R
R
Ar
Product
4d
4e
4f
3a
3b
3c
3d
3e
3f
H
Ph
H
H
H
4-FC6H4
Ph
Ph
89
88
78
81
84
91
85
83
79
77
80
Ph
Ph
Ph
Ph
82
81
83
78
4-ClC6H4
4-ClC6H4
Me
H
4-FC6H4
Ph
Me
Me
H
4-FC6H4
Ph
5a
Me
NCS
4-FC6H4
Ph
5b
5c
5d
5e
5f
Me
NCS 84
NCS 88
NCS 89
PhS 79
PhS 81
PhS 85
PhS 88
Me
4-FC6H4
Ph
4-ClC6H4
4-ClC6H4
Me
4-ClC6H4
4-ClC6H4
Me
H
H
4-FC6H4
Ph
3g
3h
4a
4b
4c
Me
Me
Me
Me
H
4-FC6H4
Ph
Me
Me
H
4-FC6H4
Ph
Me
Ph
Ph
Ph
Me
4-FC6H4
Ph
4-ClC6H4
4-ClC6H4
5g
5h
4-FC6H4
Ph
H
4-FC6H4
H
* Yields of isolated and purified products.
Scheme 1. Synthesis of aziridines 4 and 5 from a-halo ketones 2.
a-halo ketones. The synthesis involves a novel one-pot
nucleophile-induced intramolecular cyclization of a-halo
ketone-derived phosphoramidates 3 to yield aziridines 4
and 5 (Scheme 1). Thus, treatment of diethyl N-aryl-
phosphoramidates 1 with sodium hydride in benzene
followed by a-halo ketones 2 afforded diethyl N-aryl-N-
(2-oxoalkyl)phosphoramidates 331 in 78–91% yields.
Conventional reduction of phosphoramidates 3 with
sodium borohydride afforded the corresponding alcohols
in addition to a small amount of aziridines 4. Thus, phos-
phoramidates 3 were reduced with sodium borohydride in
t-butanol followed by treatment with sodium hydride in
the same vessel to produce the corresponding aziridines
432 in 77–83% yields (Scheme 1). Furthermore, phospho-
ramidates 3, on reaction with potassium thiocyanate, or
sodium thiophenolate in t-butanol afforded functionalized
aziridines 533 in 78–89% yields (Scheme 1). The synthesis
of a few aziridines similar to 5 has been previously reported
from 1,3-diphenyl-2-chloroaziridines via displacement of
the chloride ion by hydride or thiolates,29,34,35 however,
the present method provides a direct access to this class
of aziridines.
found to be diastereomeric mixtures containing 94–97% of
the cis isomer. Strong NOEs were observed between 2-H/
3-H and 2-Me/3-Me of these aziridines, which conclusively
demonstrate their cis stereochemistry (Fig. 1). The cis
stereochemistry of aziridines 4 was also supported by
comparison of the J values of 2-H and 3-H with those
reported in the literature.27g
The formation of aziridines 4 is best explained through
intramolecular attack of the alkoxide ion 7 on the phos-
phorus atom (Scheme 2). This assumption is supported
by the exclusive formation of aziridines 4 on addition of
a base, such as sodium hydride, to facilitate alkoxide ion
formation. On the other hand, aziridines 5 are formed by
11.1-11.8%
13.4-13.9%
H
Me
H
Me
Ph
Me
Y
H
N
N
Ar
Ar
The nucleophile-induced cyclization of (2-oxoalkyl)-
phosphoramidates 3 to aziridines 4 and 5 was highly diaste-
reoselective in favour of the cis isomers. Diastereomeric
5a, Ar = Ph; Y = NCS
4a, Ar = Ph
4b, Ar = 4-FC6H4
5b, Ar = 4-FC6H4; Y = NCS
5e, Ar = Ph; Y = PhS
1
ratios in the crude isolates were checked by H NMR to
5f, Ar = 4-FC6H4; Y = PhS
note any alteration of these ratios during subsequent puri-
Fig. 1. NOE experiments on aziridines 4 and 5.
fication. The crude isolates of 4a, 4b, 5a, 5b, 5e and 5f were

L. D. S. Yadav et al. / Tetrahedron Letters 49 (2008) 687–690
689
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O
O
X
R
NaH
(EtO)2PNHAr
(EtO)2PNAr
2
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6
1
O
R
Y
R'
R
O
O
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P
EtO
Y
EtO
P
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(Y = H, NCS,
PhS)
EtO
7
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O
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5
Scheme 2. Tentative mechanism for the nucleophile-induced cyclization of
phosphoramidates 3 to aziridines 4 and 5.
´
27. (a) De Kimpe, N.; Verhe, R.; De Buyck, L.; Schamp, N. Synth.
attack of a nucleophile (NCSÀ or PhSÀ) on the carbonyl
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ide ion on the phosphorus atom (Scheme 2).
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´
In summary, we have developed a general and efficient
method for the synthesis of substituted and functionalized
aziridines by nucleophile-induced cyclization of readily
available a-halo ketone-derived phosphoramidates in a
one-pot procedure, which may find application in organic
synthesis.
´
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Acknowledgement
30. (a) Yadav, L. D. S.; Awasthi, C.; Rai, V. K.; Rai, A. Tetrahedron
Lett. 2007, 48, 4899–4902; (b) Yadav, L. D. S.; Rai, V. K. Synlett
2007, 1227–1230; (c) Yadav, L. D. S.; Rai, V. K. Tetrahedron Lett.
2006, 47, 395–397; (d) Yadav, L. D. S.; Yadav, S.; Rai, V. K. Green
Chem. 2006, 8, 455–458; (e) Yadav, L. D. S.; Yadav, S.; Rai, V. K.
Tetrahedron 2005, 61, 10013–10017.
We sincerely thank SAIF, Punjab University, Chandi-
garh, for providing microanalyses and spectra.
References and notes
31. General procedure for the synthesis of diethyl N-aryl-N-(2-
oxoalkyl)phosphoramidates 3: To a solution of diethyl N-arylphospho-
ramidate 1 (5 mmol) in dry benzene (5 mL) was added dropwise a
solution of sodium hydride (120 mg, 5 mmol) in dry benzene (10 mL)
with stirring at rt. After the addition was complete and the evolution
of hydrogen gas (effervescence) had ceased, the reaction mixture was
stirred at 60 °C for 30 min and then cooled to rt. Next, a solution a-
halo ketone 2 (5 mmol) in dry benzene (5 mL) was added and the
reaction mixture was stirred at 60 °C for 3 h. The solvent was
evaporated under reduced pressure, the residue washed with water
and crystallized from n-hexane to afford an analytically pure sample
of 3. Physical data of representative compounds: Compound 3a:
White crystals, Yield 89%, mp 161–163 °C. IR (KBr) mmax 3046, 2951,
1. Gabriel, S. Chem. Ber. 1888, 21, 1049–1057.
2. Tanner, D. Angew. Chem., Int. Ed 1994, 33, 599–619.
3. Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006.
4. Hu, X. E. Tetrahedron 2004, 60, 2701–2743.
5. Stamm, H. J. Prakt. Chem. Chem. Ztg. 1999, 341, 319–331.
6. Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258.
7. Graham, M. A.; Wadsworth, A. H.; Thornton-Pett, M.; Rayner, C.
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1736–1739.
1745, 1599, 1508, 1463, 1383, 758, 704 cmÀ1 1H NMR (400 MHz;
.
CDCl3/TMS) d: 1.19 (t, 6H, J = 7.4 Hz, 2 Â Me), 4.12 (q, 4H,
J = 7.4 Hz, 2 Â OCH2), 4.57 (s, 2H,CH2), 7.13–7.92 (m, 10Harom).
13C NMR (100 MHz; CDCl3/TMS) d: 15.3, 52.7, 61.2, 125.9, 126.7,
128.5, 130.7, 131.9, 132.8, 135.7, 138.3, 193.7. EIMS (m/z): 347 (M+).
Anal. Calcd for C18H22NO4P: C, 62.24; H, 6.38; N, 4.03. Found: C,
62.58; H, 6.27; N, 4.22. Compound 3g: White crystals, Yield 85%, mp
143–145 °C. IR (KBr) mmax 3042, 2949, 1748, 1603, 1511, 1460, 1378,
1035, 761, 706 cmÀ1 1H NMR (400 MHz; CDCl3/TMS) d: 1.21 (t,
.
12. Kasai, M.; Kono, M. Synlett 1992, 778–790.

690
L. D. S. Yadav et al. / Tetrahedron Letters 49 (2008) 687–690
6H, J = 7.4 Hz, 2 Â Me), 1.45 (d, 3H, J = 7.8 Hz, Me–C), 2.12 (s, 3H,
(m/z): 229, 231 (M+, M++2). Anal. Calcd for C14H12ClN: C, 73.20;
H, 5.27; N, 6.10. Found: C, 73.03; H, 5.39; N, 5.89.
Me–CO), 3.72 (q, 1H, J = 7.8 Hz, CH), 4.10 (q, 4H, J = 7.4 Hz,
2 Â OCH2), 6.93–7.21 (m, 5Harom). 13C NMR (100 MHz; CDCl3/
TMS) d: 15.5, 16.3, 27.2, 57.6, 61.5, 122.9, 126.4, 129.9, 137.5, 193.6.
EIMS (m/z): 299 (M+). Anal. Calcd for C14H22NO4P: C, 56.18; H,
7.41; N, 4.68. Found: C, 55.91; H, 7.19; N, 4.82.
33. General procedure for the synthesis of functionalized aziridines 5: A
mixture of phosphoramidate 3 (5 mmol) and potassium thiocyanate,
or sodium thiophenolate (5 mmol) in t-butanol (25 mL) was heated at
40 °C for 5 h. Water (30 mL) was added and the mixture was
extracted with dichloromethane (3 Â 50 mL), the combined organics
dried over anhydrous sodium sulfate, filtered and evaporated to
dryness. The crude product thus obtained was recrystallized from n-
hexane twice to afford an analytically pure sample 5. Physical data of
representative compounds: Compound 5a: White crystals, Yield 78%,
mp 58–59 °C. IR (KBr) mmax 3042, 2947, 1602, 1507, 1461, 1377, 1035,
32. General procedure for the synthesis of substituted aziridines 4: A
mixture of phosphoramidate 3 (5 mmol) and sodium borohydride
(190 mg, 5 mmol) in dry t-butanol (25 mL) was stirred at rt for 2 h,
then at 60 °C for 2 h. Sodium hydride (120 mg, 5 mmol) was added to
the above reaction mixture at rt. Stirring was continued for 3 h at rt,
then at 60 °C for 2 h. Water (30 mL) was added, the mixture was
extracted with ether (3 Â 50 mL), the combined organics dried over
anhydrous sodium sulfate, filtered and evaporated to dryness. The
crude product thus obtained was crystallized from n-hexane twice to
afford an analytically pure sample of 4. Physical data of representative
compounds: Compound 4a: White crystals, Yield 79%, mp 30–31 °C.
IR (KBr) mmax 3040, 2943, 1605, 1508, 1462, 1380, 1032, 762,
759, 705 cmÀ1 1H NMR (400 MHz; CDCl3/TMS) d: 1.32 (d, 3 H,
.
J = 5.6 Hz, 3-Me), 1.81 (s, 3H, 2-Me), 2.47 (q, 1H, J = 5.6 Hz, 3-H),
6.81–7.10 (m, 5Harom). 13C NMR (100 MHz; CDCl3/TMS) d: 19.3,
29.5, 48.7, 112.5, 123.1, 132.3, 133.7, 138.7. EIMS (m/z): 204 (M+).
Anal. Calcd for C11H12N2S: C, 64.67; H, 5.92; N, 13.71. Found: C,
64.35; H, 5.97; N, 13.81. Compound 5g: White crystals, Yield 85%,
mp 79–81 °C. IR (KBr) mmax 3041, 2948, 1601, 1510, 1460, 1383, 765,
.
703 cmÀ1 1H NMR (400 MHz; CDCl3/TMS) d: 1.40 (d, 3H,
J = 5.8 Hz, Me), 3.02–3.12 (m, 1H, 3-H), 3.41 (d, 1H, J = 7.3 H,
2-H), 6.89–7.18 (m, 10Harom). 13C NMR (100 MHz; CDCl3/TMS) d:
21.3, 41.7, 55.1, 122.8, 123.9, 126.4, 132.5, 133.1, 135.5, 137.8, 138.9.
EIMS (m/z): 209 (M+). Anal. Calcd for C15H15N: C, 86.08; H, 7.22;
N, 6.69. Found: C, 86.29; H, 7.08; N, 6.35. Compound 4e: White
crystals, Yield 81%, mp 41–43 °C. IR (KBr) mmax 3043, 2942, 1601,
703 cmÀ1 1H NMR (400 MHz; CDCl3/TMS) d: 1.99 (d, 1H,
.
J = 11.1 Hz, 3-Ha), 2.56 (d, 1H, J = 11.1 Hz, 3-Hb), 6.93–7.21 (m,
12Harom), 7.39–7.42 (m, 2Harom). 13C NMR (100 MHz; CDCl3/TMS)
d: 44.3, 60.5, 122.6, 124.6, 126.7, 130.5, 131.7, 132.5, 133.7, 134.6,
136.8, 138.1, 138.8, 139.7. EIMS (m/z): 337, 339 (M+, M++2). Anal.
Calcd for C20H16ClNS: C, 71.10; H, 4.77; N, 4.15. Found: C, 71.37;
H, 4.61; N, 4.29.
1511, 1465, 1381, 761, 706 cmÀ1 1H NMR (400 MHz; CDCl3/TMS)
.
d: 1.73 (dd, 1H, J = 10.9, 7.5 Hz, 3Ha), 2.13 (dd, 1H, J = 10.9, 5.9 Hz,
3Hb), 2.87 (dd, 1H, J = 7.5, 5.9 Hz, 2-H), 6.73–7.11 (m, 7Harom),
7.31–7.36 (m, 2Harom). 13C NMR (100 MHz; CDCl3/TMS) d: 37.1,
45.4, 125.7, 126.7, 132.2, 133.5, 134.9, 136.2, 137.2, 139.5. EIMS
34. Hassner, A.; Burke, S. S.; Cheng-Fan, I. J. J. Am. Chem. Soc. 1975,
97, 4692–4700.
35. Deyrup, J. A.; Greenwald, R. B. J. Am. Chem. Soc. 1965, 87, 4538–
4545.