Facile preparation of α-amino ketones from oxidative ring-opening of aziridines by pyridine N-oxide

Article abstract of DOI:10.1039/b711638a

The oxidative ring-opening reaction of a variety of activated aziridines by pyridine N-oxide provided α-amino ketones or α-amino aldehydes in good yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b711638a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Facile preparation of a-amino ketones from oxidative ring-opening of
aziridines by pyridine N-oxide†
Zhi-Bin Luo, Jing-Yu Wu, Xue-Long Hou* and Li-Xin Dai
Received 31st July 2007, Accepted 17th September 2007
First published as an Advance Article on the web 26th September 2007
DOI: 10.1039/b711638a
The oxidative ring-opening reaction of a variety of activated
aziridines by pyridine N-oxide provided a-amino ketones or
a-amino aldehydes in good yields.
(1)
Aziridine derivatives are versatile intermediates in organic synthe-
sis because of their ability to function as carbon electrophiles.1
Different amine oxides were also tested (Table 1). This showed
that the presence of an electron-donating group on the pyridine
ring improved the reaction rate, but not the yield (entry 2), and
that an electron-withdrawing group on the pyridine ring resulted
in very little product after 40 h (entry 3). Both quinoline and
3-methylpyridine N-oxides gave moderate yields, but collidine N-
oxide delivered a lower yield of product (entries 4 and 6 vs. entry 5)
for steric reasons. Aliphatic amine oxides provided lower yields of
a-amino ketones as well as the undesired a-amino alcohols 4 in
moderate yields (entries 7 and 8).
Using pyridine N-oxide in toluene, various aziridines were
tested, and the results are shown in Table 2. Both Ts and PhCO
substituents at the aziridine nitrogen give the desired product
(entry 4). The reaction of symmetrically disubstituted meso-
aziridines 1a and 1b afforded the corresponding a-amino ketones
in good yields (entries 1 and 2), while aziridine 1c (derived
from cycloheptene) gave only a trace of product (entry 3). Both
aziridines 1e (derived from styrene) and 1f (derived from indene)
gave only products resulting from benzylic attack (entries 5 and
6). For aziridine 1i, reaction gave more of the benzyl-attacked
product 3i (entry 9), but for a disubstituted aziridine derived
Ring-opening reactions of aziridines with various heteroatom
nucleophiles as well as some carbon nucleophiles have been
well documented;2 some other transformations of aziridines have
also been reported.3 In contrast, few reports have appeared in
the literature on the direct conversion of aziridines to a-amino
carbonyl derivatives,4,5 even though they are an important subunit
of biologically active natural products6a and are also useful
intermediates in organic synthesis.6b Nozaki and Heine reported
that the direct oxidative ring-opening of aziridines in DMSO gave
a-amino ketones respectively.4a,b Recently, Rao and co-workers
reported that the oxidative ring-opening of aziridines by IBX in
the presence of b-CD, or by NBS combined with CAN, resulted
in a-amino ketones.4c,4e During studies on the organophosphine-
mediated transformation of aziridines and on extension of the
reaction scope,2a,7 we studied the conversion of aziridines to a-
amino ketones. It was found that heating the aziridines in DMSO
provided a simple synthesis of a-amino carbonyl derivatives;4a,b
however, all reactions require DMSO as solvent. No product
resulted when 1–10 eq. of DMSO was used in several common
solvents, such as CH2Cl2, THF, MeCN, benzene, AcOEt and Et2O,
even when mixed solvents (MeCN or THF with DMSO in a 1 :
1 ratio) were used. Recognizing that DMSO is an oxide of a sulfide,
we deduced that amine N-oxides should also play a similar role
in this transformation. In this communication, we would like to
report that the reaction of aziridines with a stoichiometric amount
of pyridine N-oxide afforded a-amino carbonyl compounds in
good to high yields.8
Table 1 Oxidative ring opening of aziridine 1b with different amine
oxidesa
Reaction of aziridine 1b with 1.2 eq. of pyridine N-oxide 2a
in DMF at 80 ◦C provided the desired a-amino ketone in 60%
yield (eqn (1)). Screening of solvents showed that the reaction in
toluene gave 3b in 76% yield, while that in other solvents, such as
CH2Cl2, CH3CN, THF and iPrOH, gave a lower yield. Increasing
the amount of pyridine N-oxide to 2–3 eq. did not improve the
yield of product.
Entry
Amine N-oxide 2
Time/h
Yield of 3b (%)
1
2
3
4
5
6
7
8
Pyridine N-oxide
24
5
40
15
24
15
4
76
75
Trace
62
41
4-Methoxypyridine N-oxide
4-Acetylpyridine N-oxide
3-Methylpyridine N-oxide
Collidine N-oxide
Quinoline N-oxide
Me3N N-oxide
N-Morpholine N-oxide
60
22b
14b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai, 200032, P. R. China. E-mail: xlhou@mail.sioc.ac.cn
† Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b711638a
5
a Run at 80 ◦C in toluene using 1.2 eq. of amine oxide. b 60% yield of
product 4 was also separated.
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Table 2 Oxidative ring-opening of aziridines using pyridine N-oxide8
Entry
1
Aziridine
Time/h
24
Product
Isolated yield (%)
77
2
3
48
64
76
Trace
4
5
6
12
10
10
80
40
55
7a
20
74
8a
24
24
20
82
9a
a Ratio of products was determined by 1H NMR spectroscopy.
from an aliphatic alkene, 1g, the regioselectivity of reaction
was low (entry 7). Overall, reactions of disubstituted aziridines
provided the corresponding carbonyl products in satisfactory yield
(entries 1, 2, 4, 6, 7, and 9), but those of monosubstituted aziridines
gave lower yields accompanied by some unidentified byproducts
(entries 5 and 8).
The conversion of benzyl bromides to benzaldehydes in the
presence of amine oxides is well-documented reaction.9 The
oxidative ring-opening reaction of aziridine with pyridine N-oxide
may proceed in a similar way: nucleophilic attack of amine oxide
to the aziridine gives rise to the intermediate A, proton-transfer
and elimination of pyridine then affording a-amino ketones
(Scheme 1).9
In summary, pyridine N-oxide was found to be an efficient
reagent for oxidative ring-opening of activated aziridines, pro-
viding good yields of a-amino carbonyl compounds. Further
investigations on the asymmetric version and extension of the
reaction are in progress.
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Scheme 1 Possible mechanism of oxidative ring-opening reaction of
aziridine with amine oxide.
Acknowledgements
Financially supported by the National Natural Science Foun-
dation of China, Major Basic Research Development Program
(2006CB806100), the Chinese Academy of Sciences, and the
Science and Technology Commission of Shanghai Municipality.
8 Typical procedure for the oxidative ring opening of aziridines by pyridine
N-oxide: An oven-dried tube was charged with 1b (126 mg, 0.5 mmol),
pyridine N-oxide (57 mg, 0.6 mmol) and toluene (2 mL) under Ar, the
mixture warmed to 80 ◦C and stirred at this temperature until the starting
material 1b disappeared (monitored by TLC). The solvent was removed
under reduced pressure and the residue was purified by chromatography
(silica gel: petroleum ether–AcOEt = 3 : 1) to afford 3b as a white solid
(102 mg, 76% yield), mp 116–118 ◦C. 1H NMR (300 MHz, CDCl3/TMS)
(ppm): d = 1.50–1.66 (m, 3H), 1.82–1.85 (m, 1H), 2.03–2.09 (m, 1H),
2.21–2.25 (m, 1H), 2.40 (s, 3H), 2.44–2.55 (m, 2H), 3.74 (m, 1H), 5.78
(d, J = 4.5 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H).
13C NMR (CDCl3/TMS) (ppm): d = 21.4 (Ar-CH3), 23.8 (CH2), 27.3
(CH2), 36.7 (CH2), 40.7 (CH2), 60.5 (NCH), 126.9 (Ar-C), 129.6 (Ar-C),
Notes and references
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1347.
2 For some reviews on ring opening of aziridines, see: (a) X. L. Hou,
J. Wu, R. H. Fan, C. H. Ding, Z. B. Luo and L. X. Dai, Synlett,
2006, 181; (b) X. E. Hu, Tetrahedron, 2004, 60, 2701; (c) W. K. Lee
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L. A. Zavialov, Curr. Opin. Drug Discovery Dev., 2002, 5, 918; (e) R. S.
Atkinson, Tetrahedron, 1999, 55, 1519.
=
136.8 (Ar-C), 143.5 (Ar-C), 205.7 (C O) EI-MS m/z (intensity): 267
(10) [M+], 91 (100) [p-MeC6H4+]. IR (cm−1): 1708 (s, C O), 3276 (s,
=
NH).
3 For examples, see: (a) S. J. Hedley, W. J. Moran, D. A. Price and J. P. A.
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3430 | Org. Biomol. Chem., 2007, 5, 3428–3430
This journal is
The Royal Society of Chemistry 2007
©