A new synthesis of β-nitroenamines by animation of nitroolefins with methoxyamines

Article abstract of DOI:10.1039/a805844j

The amination of nitroolefins with methoxyamines in the presence of a base gives β-nitroenamines in good yields.

Full text of DOI:10.1039/a805844j

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A new synthesis of â-nitroenamines by amination of nitroolefins
with methoxyamines
Shinzo Seko*† and Ichiro Komoto
Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd., Tsukahara, Takatsuki,
Osaka 569-1093, Japan
Received (in Cambridge) 27th July 1998, Accepted 12th August 1998
Table 1 Amination of nitroolefins 1 with methoxyaminesa
The amination of nitroolefins with methoxyamines in the
presence of a base gives â-nitroenamines in good yields.
Yieldsb
(%) of 2
Entry
R1
R2
R3
β-Nitroenamines have attracted an increasing interest as
versatile intermediates in organic synthesis1 due to their “push–
pull” nature,2 and are known to be part of the structure of
many biologically active compounds such as antiulcerative
pharmaceuticals (nizatidine,3 ranitidine,4 etc.) or some pesti-
cides.5 Although many synthetic approaches to these com-
pounds have been explored,1a,6 there has been no report on their
direct synthesis from nitroolefins by nucleophilic substitution
of vinylic hydrogen. Vicarious nucleophilic substitution (VNS)7
of nitroarenes has been intensively studied and extended to
electrophilic alkenes.8 However, few examples concerning VNS
amination in aliphatic systems are known. We have recently
described the direct aminations of nitroarenes with methoxy-
amines by the VNS mechanism.9 Herein we report a new
amination of simple nitroolefins with methoxyamines to give
β-nitroenamines.
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Me
Me
᎐(CH2)4᎐
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
61c
78c
91
87c
94
51
75
56
59
31
0
hexyl
Ph
Ph
3-NO2C6H4
3-ClC6H4
3-MeOC6H4
3-HOC6H4
4-HOC6H4
2-furyl
H
Me
Me
Me
Me
Me
10d
11d
12
j
k
l
30c
a Unless otherwise noted, the amination of 1 with NHR3OMe (1.25
equiv.) was performed in the presence of ButOK (3.0 equiv.) in DMF at
room temperature for 0.1–3 h. b Isolated yields. c After completion of
the reaction, the reaction mixture was applied to a silica gel short
column directly without general work-up because of the instability of
the product. d Five equivalents of ButOK were used.
We found that methoxyamines readily aminated nitroolefins
in the presence of a base to afford β-nitroenamines, even in the
case of nitroolefins with no leaving group at the β-position
(Scheme 1). Metal catalysts were not required in this reaction,
carrying a 3-nitrophenyl substituent, amination of the nitro-
olefin moiety preceded amination of the nitroaromatic nucleus.
Amination of the nitrophenyl group did not occur, and
1-amino-2-nitro-1-(3-nitrophenyl)ethylene 2g was obtained in
75% yield (entry 7). In the case of 1-(4-hydroxyphenyl)-2-
nitropropene 1k, no reaction occurred since a highly conjugated
quinoid nitronate ion, which was inactive toward nucleophilic
reaction, was formed by facile deprotonation of the hydroxy
group in the presence of a base (entry 11). On the other hand,
the amination of 1-(3-hydroxyphenyl)-2-nitropropene 1j took
place because such an inactive species could not be formed
(entry 10). In the absence of a base, nitroolefins 1a, 1b, 1c, 1d
and 1g reacted with methoxyamine to give the corresponding
1,4-adducts, O-methyl-N-(β-nitroethyl)hydroxylamine deriv-
atives 3, quantitatively. This indicates that the 1,4-adduct of the
methoxyamine with the nitroolefin could be one of the inter-
mediates in this reaction. In fact, treatment of the isolated 1,4-
adducts, 3c and 3g, with two equivalents of a base resulted in
the corresponding β-nitroenamines, 2c and 2g, in 79 and 88%
yields, respectively (Scheme 2). In this amination, more than
NHR3
R2
O2N
O2N
R1
ButOK
+ NHR3OMe
R1
R2
DMF, r.t.
2
1
Scheme 1
although they were necessary for the efficient amination of
nitroarenes with methoxyamines.9 The newly formed double
bond of the products was determined to possess the Z con-
figuration by the chemical shifts of the olefinic protons and/or
NH protons in the H NMR spectra.10 When R3 was H, they
1
indicated the existence of two nonidentical broad peaks assign-
able as two NH protons of an amino group at 5.7–9.1 and 8.6–
10.2 ppm in CDCl3 due to intramolecular hydrogen bonding
between the amino and nitro groups.
The general procedure for the reaction is as follows. A solu-
tion of the methoxyamine (2.5 mmol) and the nitroolefin (2
mmol) in DMF (2 ml) was added dropwise to a stirred solution
of ButOK (6 mmol) in DMF (8 ml) over 5 minutes at room
temperature. After the solution was stirred for 0.1–3 h at the
same temperature, the reaction was quenched with saturated
aq. NH4Cl, and the product was extracted with CH2Cl2. The
combined organic layers were dried and concentrated. The
crude product obtained was purified by silica gel thin layer
chromatography to afford the pure β-nitroenamine.
O2N
R1
NHOMe
R2
2 eq. ButOK
DMF, r.t.
O2N
R1
NH2
R2
3
2
c: R1,R2 = -(CH2)4-
c: 79%
g: 88%
g: R1 = H, R2 = 3-NO2C6H4
Representative results are shown in Table 1. Nitroolefins 1
having various alkyl and/or aryl groups could readily be con-
verted into the corresponding β-nitroenamines 211 in one step
in good yields. Methylamination using N,O-dimethylhydroxyl-
amine as the aminating agent also proceeded to give the
expected product 2f, although in lower yield than amination
using a methoxyamine (entries 5 and 6). With a nitroolefin
g: ca.50%(1 eq. ButOK)
Scheme 2
two equivalents of base were necessary to complete the reac-
tion, because the reaction of 3g with one equivalent of base
gave 2g in approximately 50% yield, and the starting material
J. Chem. Soc., Perkin Trans. 1, 1998, 2975–2976
2975

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was recovered in 40–50% yield. Predicted pKa values of the
Acknowledgements
1,4-adduct in DMSO by CAMEO12 are depicted in Scheme 3.
We are grateful to Professor Z. Yoshida and Professor
M. Tokuda for helpful discussions.
O
N
O–
23
20
+
+
– O
NHOMe
– O
N
NHOMe
α
β
Notes and references
17 40
17
Alkyl
Alkyl
Alkyl
Alkyl
† E-mail: seko@sc.sumitomo-chem.co.jp
5
4
pKa of β-deprotonated
1,4-adduct
pKa of 1,4-adduct
1 (a) S. Rajappa, Tetrahedron, 1981, 1453 and references cited therein;
(b) T. Tokumitsu and T. Hayashi, J. Org. Chem., 1985, 50, 1547;
(c) T. Tokumitsu, Bull. Chem. Soc. Jpn., 1986, 59, 3871.
2 D. Lloyd and H. McNab, Angew. Chem., Int. Ed. Engl., 1976, 15,
459.
Scheme 3
The CAMEO predicts that the lowest pKa value in the 1,4-
adduct 4 is 17 at the β-position, and after deprotonation of
the β-position, the pKa value of the α-position is considerably
lowered from the initial 40 to 17 as indicated in 5. A similar
tendency was observed in all cases, even when the α-substituent
R2 was aryl or hydrogen. This suggests that as soon as a base
abstracts a β-proton in the 1,4-adduct, another equivalent of
base can abstract an α-proton. Therefore, the amination would
proceed via an α,β-dianion intermediate. The formation of
α,β-dianions of nitroalkanes has been extensively studied by
Seebach and co-workers, and many β-substitution reactions of
nitroalkanes have been reported.13 In the case of an ester
derivative, methyl 3-(methoxyamino)propionate, derived from
1,4-addition of methoxyamine to methyl acrylate, a similar
drop of the pKa at the carbon center adjacent to the meth-
oxyamino group was not predicted by the CAMEO. Accord-
ingly, treatment of methyl 3-(methoxyamino)propionate with
two equivalents of base did not give the methyl β-amino
acrylate. A proposed reaction mechanism is illustrated in
Scheme 4. After deprotonation of the β-position in the
3 A. H. Price and R. N. Brogden, Drugs, 1988, 36, 521.
4 T. J. Cholerton, J. H. Hunt, G. Klinkert and M. Martin-Smith,
J. Chem. Soc., Perkin Trans. 2, 1984, 1761.
5 I. Minamida, K. Iwanaga, T. Tabuchi, H. Uneme, H. Dantsuji and
T. Okauchi, J. Pesticide Sci., 1993, 18, 31.
6 J. P. Freeman and W. D. Emmons, J. Am. Chem. Soc., 1956, 78, 3405
and references cited therein; M. Faulques, L. Rene and R. Royer,
Synthesis, 1982, 260; T. Tokumitsu and T. Hayashi, Nippon Kagaku
Kaishi, 1983, 88; A. Krowczynski and L. Kozerski, Synthesis, 1983,
489.
7 M. Makosza and J. Winiarski, Acc. Chem. Res., 1987, 20, 282.
8 M. Makosza and A. Kwast, J. Chem. Soc., Chem. Commun., 1984,
1195.
9 S. Seko and N. Kawamura, J. Org. Chem., 1996, 61, 442; S. Seko and
K. Miyake, Chem. Commun., 1998, 1519.
10 A. I. Fetell and H. Feuer, J. Org. Chem., 1978, 43, 497.
1
11 H NMR spectral data are as follows (J values in Hz). 2a: δH(270
MHz, CDCl3) 2.07 (s, 3H), 6.03 (br s, 1H), 7.02 (t, 1H, J 11.55), 8.62
(br s, 1H). 2b: δH(270 MHz, CDCl3) 2.12 (s, 3H), 2.18 (s, 3H), 7.94
(br s, 1H), 10.08 (br s, 1H). 2c: δH(270 MHz, CDCl3) 1.63–1.78 (m,
4H), 2.53 (t, 2H, J 6.27), 2.62 (t, 2H, J 6.27), 6.73 (br s, 1H), 9.69 (br
s, 1H). 2d: δH(270 MHz, CDCl3) 0.89 (m, 3H), 1.30 (m, 6H), 1.61 (m,
2H), 2.24 (m, 2H), 6.54 (s, 1H), 6.67 (br s, 1H), 9.22 (br s, 1H). 2e:
δH(270 MHz, CDCl3) 6.64 (br s, 1H), 6.81 (s, 1H), 7.45–7.59 (m, 5H),
9.29 (br s, 1H). 2f: δH(270 MHz, CDCl3) 2.99 (d, 3H, J 5.61), 6.58 (s,
1H), 7.34–7.39 (m, 2H), 7.47–7.54 (m, 3H), 10.22 (br s, 1H). 2g:
δH(400 MHz, DMSO-d6) 6.93 (s, 1H), 7.79 (t, 1H, J 8.05), 8.09 (m,
1H), 8.40 (m, 1H), 8.45 (m, 1H), 9.09 (br s, 1H), 9.38 (br s, 1H). 2h:
δH(400 MHz, CDCl3) 1.96 (s, 3H), 5.72 (br s, 1H), 7.29 (td, 1H,
J 1.51, 7.39), 7.39–7.50 (m, 3H), 9.56 (br s, 1H). 2i: δH(270 MHz,
CDCl3) 1.96 (s, 3H), 3.84 (s, 3H), 6.00 (br s, 1H), 6.89–7.03 (m, 3H),
7.38 (t, 1H, J 7.92), 9.69 (br s, 1H). 2j: δH(270 MHz, DMSO-d6) 1.85
(s, 3H), 6.79–6.93 (m, 3H), 7.31 (t, 1H, J 7.92), 8.72 (br s, 1H), 9.83
(br s, 1H). 2l: δH(270 MHz, CDCl3) 2.39 (s, 3H), 6.62 (dd, 1H, J 1.65,
3.63), 6.89 (d, 1H, J 3.63), 7.65 (d, 1H, J 1.65), NH2 n.d.
O
+
NH2OMe
– O
N
NHOMe
O2N
R1
B –
R2
R1
R2
H
B –
O –
H
+
– O
N
N
OMe
– O2N
NH
R2
H3O+
B –
2
R1
R2
R1
H
B –
Scheme 4
12 CAMEO is an interactive computer program, which predicts the
products of organic reactions given starting materials and
conditions, as well as pKa values for organic compounds, developed
by W. L. Jorgensen. See A. J. Gushurst and W. L. Jorgensen, J. Org.
Chem., 1986, 51, 3513.
1,4-adduct, another equivalent of base abstracts an α-proton,
and subsequent elimination of the methoxy group furnishes the
product 2.
13 R. Henning, F. Lehr and D. Seebach, Helv. Chim. Acta, 1976, 59,
2213; D. Seebach, R. Henning, F. Lehr and J. Gonnermann,
Tetrahedron Lett., 1977, 1161; U. Brandli, M. Eyer and D. Seebach,
Chem. Ber., 1986, 119, 575; K. Yamada, S. Tanaka, S. Kohmoto and
M. Yamamoto, J. Chem. Soc., Chem. Commun., 1989, 110.
In conclusion, we have demonstrated that a new amination
of simple nitroolefins with methoxyamines gives β-nitro-
enamines in good yields. To the best of our knowledge, this
is the first example of a direct synthesis of β-nitroenamines
from nitroolefins bearing no leaving groups. β-Nitroenamines
can react with both electrophiles and nucleophiles to furnish
various useful polyfunctionalised compounds, since they are
“push–pull” alkenes. We are continuing to investigate the scope
and application of the present amination using methoxyamines.
Communication 8/05844J
2976
J. Chem. Soc., Perkin Trans. 1, 1998, 2975–2976