The influence of substituents on the hydroxyl-bearing carbon in the Aza-Payne rearrangement of Aziridinemethanols

Article abstract of DOI:10.2174/157017809788681310

A new series of α, α-disubstituted aziridinemethanols have been synthesized and their aza-Payne rearrangement reactions were studied. The results show that α, α-disubstituted aziridinemethanols with electron-withdrawing groups accelerate the aza-Payne rea

Full text of DOI:10.2174/157017809788681310

412
Letters in Organic Chemistry, 2009, 6, 412-415
The Influence of Substituents on the Hydroxyl-Bearing Carbon in the
Aza-Payne Rearrangement of Aziridinemethanols
Wenjin Xu, Jun Zhang, Hao Guo, Qifeng Zhu and Xianming Hu*
State Key Laboratory of Virology, College of Pharmacy, Wuhan University, Wuhan 430072, China
Received January 17, 2009: Revised June 01, 2009: Accepted June 01, 2009
Abstract: A new series of ꢀ,ꢀ-disubstituted aziridinemethanols have been synthesized and their aza-Payne rearrangement
reactions were studied. The results show that ꢀ,ꢀ-disubstituted aziridinemethanols with electron-withdrawing groups
accelerate the aza-Payne rearrangement than those with electron-donating groups. All of the rearrangements proceeded
through an inversion of configuration at the C-2 carbon.
Keywords: Aziridinemethanols, aza-Payne rearrangement, inversion of configuration, electron-withdrawing groups, electron-
donating groups.
The aza-Payne rearrangement of aziridinemethanols [1]
has emerged as an important synthetic endeavor for the
synthesis of bioactive compounds [2-4] owing, among other
things, to the important role played by aziridinemethanols as
chiral auxiliaries [5,6] and building blocks in the preparation
of biologically active compounds [7-13] and their biological
activities [14-20].
inhibited by an O-tosyl side reaction. A possible explanation
may be that the electron density of the p-methoxy phenyl
groups favored formation of the O-tosyl. However,
compound 4b substituted with 3-methoxyphenyl groups was
successfully acylated. The other derivatives of compounds 3
and 4 reacted smoothly.
Except for compounds 10c and 10d, all aziridines
protected by N-Ts and N-Boc afforded the corresponding
rearranged products in reasonable isolated yields. N-Ts
aziridinemethanols having inductive electron-withdrawing
groups (3-methoxyphenyl group, 4-fluorophenyl group, 3-
fluorophenyl group, 4-trifluoromethylphenyl group, 3-
trifluoromethylphenyl group) substituted on methanol
reacted equally well to yield epoxy sulfonamides in high
isolated yields (>95%) within 1 h, whereas the electron-
releasing group (4-methoxy phenyl group) substituted N-Ts
aziridinemethanols 5a rearranged to epoxy sulfonamide in a
high yield (97%) in 24 h. The same behavior was observed
in the N-Boc aziridinemethanol (9a-h, 10b, 10e-h) (10c and
10d didn’t afford the rearrangement products even with NaH
in THF/HMPA (10:1) [24]), although they reacted distinctly
more slowly compared with the N-Ts aziridinemethanols
under the same conditions (0.28mol/L NaOH in t-
BuOH/H2O/THF (4:5:1) rt) [21, 23]. Compound 9a afforded
only a 30% yield. Compounds with 3-trifluoromethylphenyl
group have the greatest tendency to rearrange than the
others.
Aziridinemethanols having a primary or secondary
hydroxymethyl group at the C-2 position afford high yields
of
rearranged
products.
On
the
other
hand,
aziridinemethanols possessing a tertiary hydroxyl group
rearrange slowly in THF in the presence of KH to give solely
the epoxy sulfonamide [21]. The mechanism of which is
intramolecular SN2, with an inversion of configuration at the
C-2 carbon [22]. Obviously the substituents on the hydroxy-
bearing carbon have great influences on the aza-Payne
rearrangement of aziridine methanols. Our previous studies
[23, 24] have primarily reported such electronic effects.
However, further studies are still necessary to validate the
correlations between the efficiency of the rearrangement and
the substituents effects of the aromatic groups. So we
designed and synthesized a series of novel ꢀ,ꢀ-disubstituted
aziridinemethanols to extend the expected influence of
substituents on the hydroxyl-bearing carbon.
Compounds 3 and 4 were synthesized starting from the
methyl N-tritylaziridinecarboxylic acid esters 1 and 2, which
were prepared from L-serine and L-threonine, respectively
[25]. The N-Ts and N-Boc aziridinemethanols 5, 6, 9 and 10
were synthesized from 3 and 4 in high yields. The aza-Payne
rearrangement reactions of 5, 6, 9 and 10 to epoxy amides 7,
8, 11, 12 were shown in Scheme 1 and the results were
summarized in Table 1.
Compounds 5 rearranged faster than compounds 6. The
methyl group on the C-3 position of aziridine has a positive
effect on the rearrangement. It can be concluded that the
mechanism responsible for the methyl group increases the
strain of the aziridine ring, therefore the ring is opened easily
in the alkali condition. Disubstitution with electron-
withdrawing groups on hydroxyl-bearing carbon is more
favourable to the rate of aza-Payne rearrangement than those
with electron-releasing groups. It is believed that the
mechanism responsible for the stability of the oxa anion [22]
is proposed for the conjugative effect of phenyl group and
the electron-withdrawing effect of the substituents on the
phenyl group. The activating groups contribute to the
Compound 4a substituted on the hydroxyl-bearing
carbon by 4-methoxyphenyl groups did not provide N-Ts
and N-Boc protected products, the N-tosylation was
*Address correspondence to this author at the State Key Laboratory of
Virology, College of Pharmacy, Wuhan University, Wuhan 430072, China;
E-mail: xmhu@whu.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

The Influence of Substituents on the Hydroxyl-Bearing Carbon
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
413
H
H
H
H
H
H
R2
R2
R2
R2
i
CO2Me
iii
R1
R1
R1
N
N
H
N
ii
OH
OH
Trt
Ts
(2S) or (2S, 3S)
(2S) or (2S, 3S)
(2S) or (2S, 3S)
1 R1=Me
2 R1=H
3 R1=Me
4 R1=H
5 R1=Me
6 R1=H
O
H
R2
R2
a
R2=p-CH3OC6H4
R1
b
c
d
e
f
R2=m-CH3OC6H4
R2=p-CH3C6H4
R2=Ph
v
NH
Ts
R2=p-FC6H4
(2R) or (2R, 3S)
R2=m-FC6H4
R2=p-CF3C6H4
R2=m-CF3C6H4
g
h
7 R1=Me
8 R1=H
O
H
H
H
H
H
R2
R2
R2
R2
R2
R2
R1
iv
v
R1
R1
N
N
H
OH
OH
NH
Boc
Boc
(2S) or (2S, 3S)
R1=Me
4 b-h R1=H
Reagents and conditions: i) R2Br, Mg, THF; ii) MeOH/H2O/H2SO4(60:8:3); iii)
TsCl (1eq.), Py; iv)(Boc)2O NEt3, THF; v) 0.28mol/L NaOH in tBuOH/H2O/THF(4:5:1) rt.
(2S) or (2S, 3S)
R1=Me
10 b-h R1=H
(2R) or (2R, 3S)
11 R1=Me
12 b,d-h R1=H
9
3
Scheme 1. The aza-Payne rearrangement of ꢀ,ꢀ-disubstituted aziridinemethanols.
Table 1. Aza-Payne Rearrangement of ꢀ,ꢀ-Disubstituted Aziridinemethanol to Epoxy Amide
NaOHa
Entry
Starting Material
Product
Reaction Time
Yield(%)b
1
2
5a
5b
5c
5d
5e
5f
24h
1h
97
98
98
96
98
98
97
98
96
97
95
98
97
99
97
30c
98
56c
70c
97
7a
7b
7c
3
2h
4
1h
7d
7e
5
30min
30min
30min
5min
<1h
6
7f
7
5g
5h
6b
6c
6d
6e
6f
7g
8
7h
8b
8c
9
10
11
12
13
14
15
16
17
18
19
20
2h
1h
8d
8e
50min
50min
50min
20min
24h
8f
6g
6h
9a
9b
9c
9d
9e
8g
8h
11a
11b
11c
11d
11e
11h
24h
24h
8h

414 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Xu et al.
(Table 1). Contd…..
NaOHa
Entry
Starting Material
Product
Reaction Time
Yield(%)b
21
22
23
24
25
26
27
28
29
30
9f
6h
2h
98
99
97
92
11f
11g
11h
12b
9g
9h
2h
10b
10c
10d
10e
10f
10g
10h
24h
24h
24h
12h
12h
<3h
2h
d
d
—
—
d
d
—
—
93
95
98
97
12e
12f
12g
12h
asolvent: t-BuOH/H2O/THF (4:5:1), rt.; bisolated yield; cdetected by HPLC; dno reaction.
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In conclusion, aziridinemethanols ꢀ,ꢀ-disubstituted with
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