β-Formyl-β-nitroenamine: An Environmentally Benign Synthetic

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β-Formyl-β-nitroenamine:An Environmentally Ben
ign Synthetic Equivalent of Nitromalonaldehyde
西脇, 永敏
高知工科大学紀要, 10(1): 29-36
2013-07-20
http://hdl.handle.net/10173/1074
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publisher
Kochi, JAPAN
http://kutarr.lib.kochi-tech.ac.jp/dspace/
(Invited Paper)
An Environmentally
(3-Formyl-(3-nitroenamine:
Synthetic
Equivalent
Benign
of Nitromalonaldehyde
Nagatoshi Nishiwaki*
(Received:
March20th,2013)
School of Environmental Science and Engineering, Kochi University of Technology,
185 Tosayamadacho-Miyanokuchi, Kami, Kochi, 782-8502, JAPAN
*E -mail: nishiwaki
Abstract:
.nagatoshi@kochi-tech.ac.jp
Built-in method is one of the synthetic procedures for polyfunctionalized
compounds, in which a building
block having a functional group is incorporated into a new framework. f3-Formyl-f3-nitroenamine was found to be safe
synthetic equivalent of unstable nitromalonaldehyde.
The enamine is readily treatable because of high solubility into
almost organic solvents with high stability. These features enable to use the enamine for organic syntheses. Indeed,
nitrated pyrazoles, phenols and diazepines are available upon treatment of the nitroenamine with hyrazines, ketones, and
diamines, in which 5-7 membered rings are constructed.
1. Introduction
(i) Direct approach
Nitration
Nitro compounds constitute a large family among
organic compounds and are widely used for various
purposes; millions of tons of nitro compounds are
synthesized and consumed every year.' 3)A nitro group is
one of the important functional groups in organic
syntheses because of strong electron withdrawing ability
and diverse chemical behavior.' The nitro group
considerably decreases electron density of the scaffold
framework by both inductive and resonance electron
withdrawing effects in order to facilitate reactions with
nucleophiles. The a-hydrogen of a nitro group becomes
highly acidic to form a stable nitronate anion, which
reacts with both electrophilic and nucleophilic reagents.
Furthermore, a nitro group assists the cleavage of an
adjacent carbon-carbon bond, and can transform to
versatile functional groups by the Nef reaction or by
reduction.
Preparative methods for nitro compounds are generally
divided into three categories, namely: (i) the direct
approach to nitro compounds, (ii) built-in methods using
a nitrated building block, and (iii) ring transformations,
which are supplementary to each other.
EDNO2
Chemical
(Eq. 1)
conversion
NH2NO2
(Eq. 2)
Degradation
NO2NO2
_-C
(Eq. 3)
(ii)Ring transformation
NO2
NO2
_-40-+
1 B J
4
(Eq. 4)
(iii) Built-inmethod
C+
NO2
NO2
(Eq. 5)
In the direct approach, three strategies are mainly
employed; the most common of these is the nitration,
which directly introduces a nitro group into the scaffold
framework (Eq. 1). If other functional groups can be
easily introduced, chemical transformation of the
functional group into a nitro group becomes a useful
— 29 —
method for obtaining nitro compounds (Eq. 2). When
nitro compounds with an additional functional group are
necessary, degradation of nitrated heterocyclic
compounds is often employed (Eq. 3). Ring
transformation is also a useful method for synthesizing
complicated skeletons that are not easily available by
alternative methods (Eq. 4). The built-in method is
incorporation of a nitro compound bearing an additional
functional group as the building block, which is also
2.2 Preparation
of NMA-Na
The preparation
mucobromic
of NMA-Na8)
acid
3
furan-2-carboxylic
ring-opening
methods
acid
reaction
include
which
19) or
with
somewhat
and a small quantity
is achieved
is
easily
furfural
bromine.
2"
from
by
However,
troublesome
of hydrogen
by treating
available
cyanide
the
these
manipulations,
is evolved
in
each reaction_")
CO2H
powerful method in elaborate syntheses (Eq. 5). The
direct approach is not always available because severe
conditions are required, under which another functional
Br2
H2O
\\
group or a heterocyclic structure cannot tolerate. Hence,
the ring transformation and the built-in method are often
employed instead of the direct approach.
NO2
Br
1----
CHO
NaNO2Na'
HO2CBr
CHO
A
3
Et0,H
H2O
O
O
NMA-Na
2
2.3 Syntheses of nitro compounds using NMA-Na
2. Sodium nitromaloaldehyde
2.1 Synthetic equivalent of nitromalonaldehyde NMA-H
In designing synthetic schemes of nitro compounds by
use of the built-in method, building blocks often appear
as synthons in retrosyntheses, among which
nitromalonaldehyde (NMA-H) is an important
compound. NMA-H is a simple compound for a
theoretical study on an intramolecular hydrogen bond,
proton transfer and quasi-aromaticity.4'5) However,
NMA-H is too unstable in aqueous solutions to be
isolated, presumably due to easily occurring hydrolysis
accompanied by a C-C bond fission.' Thus, NMA-H is
prepared only by bubbling dry hydrogen chloride to a
suspension of sodium nitromalonaldehyde (NMA-Na) in
dry carbon tetrachloride.5)Hence, it is one of important
subjects to develop the synthetic equivalents of NMA-H.
From this viewpoint, NMA-Na has been employed for
the construction of nitro compounds from old time,
which was well reviewed by Fanta and Stein.7
NO2
NO2
Nu NuVO
O
+H—Nu
NMA-H
NO2
N a+
II
O
II
O
NMA-H
O
O
NMA- Na
Nu
NMA-Na has been used for synthesizing versatile
nitro cyclic compounds upon treatment with
dinucleophilic reagents.7 When NMA-Na is subjected to
reactions with hydrazines, a five membered ring is
readily formed to afford nitropyrazoles 4. As the
dinucleophilic reagents, carbon nucleophiles are also
usable. For example, glicine ethyl ester reveals
nucleophilicity both at the amino group and the a-carbon,
which enables to afford 5-nitropyrrole-2-carboxylic acid
ester 5.
Six membered rings can be constructed in the
reactions of NMA-Na with 1,3-dinucleophilic reagents.
Nitrophenols 6 are available by condensation of
NMA-Na with ketones, which is advantageous with
regard to easy modification of substituents. The present
method is applicable to the synthesis of condensed ring
systems such as 7 and 8 by using aminopyrazole and
aminonaphthalene as the dinucleophile, respectively.
As mentioned so far, NMA-Na has been widely
employed as the useful synthetic equivalent of NMA-H.7
However, this reagent suffers from the following
drawbacks. In addition to some problems mentioned in
Section 2.2, it is claimed that crude NMA-Na is
impact-sensitive and thermally unstable, and should be
handled as a potentially explosive material.'°8)
Furthermore, the reactions of NMA-Na require to use
water and/or ethanol as the solvent because of its low
solubility to common organic solvents. Hence,
development of the synthetic equivalent of NMA-H
treatable in organic media is highly demanded.
— 30 —
02N
NO2
N
%`
1) RNHNH2
in HClaq.
4
R1Thr- R2
OH
2) Na0Ac
O
NO2
-\
II
02N
>/ \\
6
Na+
I
II
0
H2NCO2EtO
• HCINMA
N
H
-Na
0100
NaOH
CO2Et
ZnCl2
i
5
I
Et—N ,
I
N%
R2
R1
NO2Et'NN
NO2
AcOH
NO2
NH2
Ni
8
7
NO2
NO2
3. (3-Formy1-(3-nitroenamine
t-BuNH2
3.1 Preparation of formylnitroenamine
Recently,
NMA-H
several
have
disadvantages
other
been
of
I
synthetic
developed
equivalents
to overcome
NMA-Na,12) dinitropyridone
nitro pyrimidinone
10,18)
nitroazadienamines
dinitropyrazole
12,20'21) and
\
NyN'
of
Me
HN
But
0 10
9,13_17)
12
11,19)
NO2
NO2
formylnitroenamine
O~
SiO2
(FNE).22,231Among these reagents, FNE is the most easily
treatable because of high solubility into organic solvents.
NO2
N
But
these
rt
HN\ I
HN,
But
97%
based on 10
NO2
\
But
(E/Z = 3/1)
FNE
II
N,M
02N
NyN
e
Me
FNEs
0
possessing
9
O10
NO2
NO2R,N
electron
upon heating
half
HN'R
of pyrimidinone
10 enables
occurs
3.2. Reactions
12 in good yields
with amines.21) When azadienamines
of E/Z isomers
which
exhibit
sites, and the amino group and the
of NMA-H.
FNE
to afford azadienamines
efficiently
density,
13-carbon are nucleophilic sites. In the reaction with a
dinucleophile, FNEs serve as dielectrophiles to give nitro
12 are
on silica gel for a few days at room temperature,
hydrolysis
mixture
deficiency
electron
alkenes
compounds; it means that FNE is a synthetic equivalent
12
the aminolysis
charged
II
0
HN'R
11
biased
are electrophilic
NO2
I
class of typical push-pull
versatile reactivity. The formyl group and the a-carbon
NO2
N—N
Highly
are one
to afford
FNEs
in a ratio of about 3/1.21)
Nitroisoxazole
condensation
from
as a
of FNE with N,0-and
its
of NMA-H
however,
by the reaction
the reaction
— 31 —
is considered
to be
available
with hyrozylamine
hydrochloride
triethylamine,
obtained
15
N,N-dinucleophiles
14
the
in
the
isoxazole
of NMA-Na
of FNE with hydroxylamine
by
13 liberated
presence
15
cannot
of
be
with 13. Indeed,
13 also afforded
a
complex
mixture
of unidentified
products.
This
NO2
problem is overcome by employing hydrochloride 14
itself as a dinucleophile to afford nitroisoxazole 15 even
though the yield is low.23)Since isolated isoxazole
reacts with hydroxylamine
13
O
NO2
H2NyNHR
I
NIH
HN, B
II
N~N
17
u1
13 under the same conditions
NH
FNE
to furnish unidentified products, decomposition is found
18
to be a major reason of the low yield of 13.
A seven
NO2
NH2OH
I
O
13
membered
6-nitro-1,4-diazepines
Complex
\
mixture
1,2-diamines
HN,
But
FNE
usable
NO2
NO2
NH2OH•HCI
33%
this
solution,
treatment
the
reaction
R1
15
prepared
other
solubility
to employ
consequently
having
nitropyrazoles
by the condensation
16.23) The high
enables
hand,
a bulky
aromatic
group
advantageous
synthetic
kinds
to the
alkyl
at
features
are
readily
1-position,
----------------•
in
a
21 are also
is
2
19
N
/N-R3
R1
R2
20
or an
one
of
R1
R2
R3
Yield/%
H
H
H
quant.
H
H
Et
80
H
Me
H
69
H
79
H
86
with a conventional
-(CH2)416
(cis)
—(CH2)4—(trans)
\ \
O
conducted
N'R3
HN,
NO2NO2
---------------•
the corresponding
products
FNE
NMA-Na.
NH2NHR
also
which
group,
which
are
But
solvents
of nitropyrazoles
a functional
in comparison
I
O
with hydrazines
organic
of hydrazines,
synthesis
group,
the
equivalent,
of FNE
of FNE into
various
leads
4
with
reaction,
HNO
R2
the
of FNE
diamines
is
oligomeric
to afford
present
to afford
H2N
On
formed
formed.
N-O
FNE
In
be
2,3-disubstituted
When
concentrated
But
and
as the dinucleophile
diazepines.
14
can
20 upon
19.23'24)
N-Substituted
I \
O
HN,
ring
HNB
H
N
utN-N, R
FNE4
02N
Yield/%
R
H
87
Me
96
t-Bu
59
CH2OOOEt
When
guanidines
dinucleophiles,
afford pyrimidines
3.3 Reactions of FNE with C,N-and C,C-dinucleophiles
Carbon nucleophiles (C-nucleophiles) are also usable
as the dinucleophiles instead of nitrogen nucleophiles
47
17
are
a six membered
18.23)
21
35
p-MeC6H4
NO2
N
N
H
90
Ph
c
N
employed
ring
as
is constructed
the
to
(N-nucleophiles). Glycine ethyl ester 22 is one of the
C,N-dinucleophiles which has both
C- and
N-nucleophilic sites. Indeed, condensation of FNE with
22 readily proceeds to form a five membered product,
ethyl 4-nitropyrrole-2-carboxylate 5, in 59% yield.23)
— 32 —
NO2H2NL
OEtNO2
22
0
HN,
above. By applying this method, nitrophenols with
diverse substituents are available, which are further used
for developing functional materials.
O
But59%
HN /
FNE 5COOEt
FNE
reacts
with
condensation
ketones
affording
6.22) In a industrial
often prepared
23
to undergo
2,6-disubstituted
process,
4-nitrophenols
substituted
by the Friedel-Crafts
followed
by
nitration,25)
restrictions
to be overcome.
the control
of regioselectivity
nitrophenols
alkylation
which
a double
are
of phenols
includes
In electrophilic
several
substitutions,
is especially
a significant
problem;
it is difficult
to prepare
successively
trisubstituted
benzenes. In addition to this problem, an
4. Conclusion
FNE serves as a synthetic equivalent of NMA-H to
afford nitro cyclic compounds. FNE does not show an
explosive property and is highly soluble into organic
solvents. These features are advantageous for practical
use, compared with NMA-Na, with regard to safety and
treatability. Furthermore, FNE undergoes the reactions
with versatile dinucleophiles efficiently, which
diminished the amount of reagents, wastes and energies.
Hence, FNE is concluded to be an environmentally
benign synthetic equivalent of NMA-H.
aryl group nor an alkyl chain longer than an ethyl group
cannot
be introduced
polyalkylation
by the Friedel-Crafts
is another
reaction,
and
5. References
1) Ono, N. The nitro group in organic synthesis;
problem.
NO2
NO2
R1(R2
0
I
O
Wiley-VCH: New York, 2001.
2) Feuer, H.; Nielsen, A. T. Nitro compounds; John
23
----------------------
HN,
OEt
Bu1
R1
or
OH
FNE
6
R1
R2
Yield/%
i-Pr
H
quant.
Et
Me
74
Ph
Ph
77
Pr
H
quant.
Pr
Pr
quant.
i-Pr
i-Pr
12
Ph
Pr
76
H
55
COOEt
COOEt
COOEt
80
COOMe
OMe
51
On the other
hand,
advantageous
with
substituents,
which
encountered
Wiley & Sons: New York, 1990.
3) Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V.
M.; Efremov, D. A. Niroalkenes; John Wiley &
Sons: New York, 1994.
4) N. Zarycz, G. A. Aucar, and C. O. Della Vedova, J.
Phys. Chem. A, 2010, 114, 7162; S. F. Tayyari, M.
Zahedi-Tabrizi, H. Azizi-Toupkanloo, S. S.
Hepperle, and Y. A. Wang, Chem. Phys., 2010, 368,
62; M. Palusiak, S. Simon, and M. Sola, Chem.
Phys., 2007, 342, 43; W. Caminati, J. Chem. Soc.,
Faraday Trans. 2, 1982, 78, 825.
5) S. F. Tayyari, Z. Moosavi-Tekyeh, M.
Zahedi-Tabrizi, H. Eshghi, J. S. Emampour, H.
Rahemi, and M. Hassanpour, J. Mol. Struct., 2006,
782, 191. This literature affords the 'H NMR of
R2
OH
in the
our approach
regard
to
to 6 using
easy
FNE
modification
is
of
dissolves
several
problems
Friedel-Crafts
reaction
mentioned
NMA-H as follows: 'H NMR (CDC13)S 9.5 (s, 1H,
CH) and 13.75 (s, 1H, OH).
6) Y. Nakaike, N. Taba, S. Itoh, Y. Tobe, N. Nishiwaki,
and M. Ariga, Bull. Chem. Soc. Jpn., 2007, 80,
2413; R. Ballini, G. Bosica, and D. Fiorini,
Tetrahedron, 2003, 59, 1143.
7) P. E. Fanta and R. A. Stein, Chem. Rev., 1960, 60,
261.
8) P. E. Fanta, Org. Synth., 1963, Coll. Vol.4, 844.
— 33 —
Ariga, Lett. Org. Chem., 2006, 3, 629.
18) N. Nishiwaki, Y. Tohda, and M. Ariga, Synthesis,
1997, 1277.
19) R. Jedrysiak, M. Sawicki, P. Wagner, and J.
9) C. F. H. Allen and F. W. Spangler, Org. Synth., 1955,
Coll. Vol.3, 621.
10) G. A. Taylor, Org. Synth., 1963, Coll. Vol.4, 688.
11) This is described as a Warning in Org. Synth., 1966,
46, 1004, and author's name is not shown.
12) N. Nishiwaki, S. Hirao, J. Sawayama, K. Saigo,
Heterocycles, 2012, 84, 115.
13) E. Matsumura, M. Ariga, and Y. Tohda, Bull. Chem.
Suwinski, ARKIVOC,2007, vi, 103.
20) Y. Tohda, M. Ariga, T. Kawashima, and E.
Matsumura, Bull. Chem. Soc. Jpn., 1987, 60, 201.
21) N. Nishiwaki, Y. Tohda, and M. Ariga, Bull. Chem.
Soc. Jpn., 1979, 52, 2413.
N. Nishiwaki and M. Ariga, "Ring Transformation
of Nitropyrimidinone Leading to Versatile
Azaheterocyclic Compounds", in Top. Heterocycl.
Chem., 8, 43, ed. by S. Eguchi, Springer, Berlin,
2007.
Y. Tohda, M. Eiraku, T. Nakagawa, Y. Usami, M.
Ariga, T. Kawashima, K. Tani, H. Watanabe, and Y.
Mori, Bull. Chem. Soc. Jpn., 1990, 63, 2820.
E. Matsumura, Y. Tohda, and M. Ariga, Bull. Chem.
Soc. Jpn., 1982, 55, 2174.
N. Nishiwaki, H. Tatsumichi, M. Tamura, and M.
Soc. Jpn., 1996, 69, 1997.
Y. Nakaike, Y. Kamijo, S. Mori, M. Tamura, N.
Nishiwaki, and M. Ariga, J. Org. Chem., 2005, 70,
10169.
N. Nishiwaki, T. Ogihara, T. Takami, M. Tamura,
and M. Ariga, J. Org. Chem., 2004, 69, 8382.
N. Nishiwaki, T. Ogihara, M. Tamura, N. Asaka, K.
Hori, Y. Tohda, and M. Ariga, Heterocycles, 2002,
57, 425.
M. Shi, S.-C. Cui, and W.-P. Yin, Eur J. Org. Chem.,
2005, 2379; H. A. Muathen, Molecules, 2003, 8,
593.
14)
15)
16)
17)
-
22)
23)
24)
25)
34 -
(招 待 論 文)
β 一ホ ル ミル ーβ一ニ ト ロ エ ナ ミ ン:環
境負荷 の
少 な い ニ トロマ ロ ン ア ル デ ヒ ドの 合 成 等 価 体
西脇 永敏
(受 領 日:2013年3月20日)
高知 工科 大 学環 境 理 工 学群
〒782-8502高
知 県香 美 市 土佐 山 田町 宮 ノ ロ185
*E -mail:nishiwaki
.nagatoshi@kochi-tech.ac.jp
要 約:多
官 能 化 合 物 を 合 成 す る 方 法 の1つ
に 、 官 能 基 を 有 す る ビル デ ィ ン グ を 組 み 込 む 方 法 が あ る。 本 研 究
で は 、 ホ ル ミル 基 を 有 す る ニ トロ エ ナ ミ ン に 着 目 し 、 合 成 ユ ニ ッ ト と して し ば し ば 見 られ る ニ トロ マ ロ ン ア
ル デ ヒ ドの 合 成 等 価 体 と し て 利 用 で き る こ と を 明 らか に した 。本 化 合 物 は 爆 発 性 を 示 す こ と な く 安 定 で あ る 。
ま た 、 ほ と ん どの 有 機 溶 媒 に 溶 解 す る こ と か ら 、 簡 便 に 取 り扱 う こ とが で き 、 そ の 汎 用 性 が 期 待 され る。 実
際 に 、 ヒ ドラ ジ ン 類 、ケ トン 類 、1,2一 ジ ア ミ ン 類 な ど の 二 座 求 核 種 を 作 用 させ れ ば 、5-7員
環 を効 率 良 く構
築 す る こ と が で き 、 そ れ ぞ れ 対 応 す る ニ ト ロ ピ ラ ゾ ー ル 類 、 ニ トロ フ ェ ノ ー ル 類 、 ニ ト ロ ジ ア ゼ ピ ン類 を得
る こ と が 可 能 で あ る。
一35一