Synthesis of 7-Amino-1-nitro-2-heptanone Derivatives

Article abstract of DOI:10.1081/SCC-120026853

New N-substituted 7-amino-1-nitro-2-heptanone derivatives have been obtained starting from readily accessible 2-(nitromethylidene)-hexahydro-1H-azepine. These compounds have been further used as starting materials for the synthesis of some heterocycles with 5-aminopentyl fragment.

Full text of DOI:10.1081/SCC-120026853

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Synthesis of 7-Amino-1-nitro-2-heptanone Derivatives
Konstantin G. Nazarenko a , Konstantin V. Shvidenko a , Alexander M. Pinchuk a & Andrei A.
Tolmachev a
a Institute of Organic Chemistry , National Academy of Sciences of Ukraine , Kyiv, Ukraine
Published online: 21 Aug 2006.
To cite this article: Konstantin G. Nazarenko , Konstantin V. Shvidenko , Alexander M. Pinchuk & Andrei A. Tolmachev
(2003) Synthesis of 7-Amino-1-nitro-2-heptanone Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:24, 4241-4252, DOI: 10.1081/SCC-120026853
To link to this article: http://dx.doi.org/10.1081/SCC-120026853
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 24, pp. 4241–4252, 2003
Synthesis of 7-Amino-1-nitro-2-heptanone
Derivatives
*
Konstantin G. Nazarenko, Konstantin V. Shvidenko,
Alexander M. Pinchuk, and Andrei A. Tolmachev
Institute of Organic Chemistry, National Academy of
Sciences of Ukraine, Kyiv, Ukraine
ABSTRACT
New N-substituted 7-amino-1-nitro-2-heptanone derivatives have
been obtained starting from readily accessible 2-(nitromethylidene)-
hexahydro-1H-azepine. These compounds have been further used as
starting materials for the synthesis of some heterocycles with
5-aminopentyl fragment.
It is known that 6-aminocaproic acid effectively blocks the action
of plasminogen’s activators.[1] We supposed that compounds bearing
5-aminopentyl fragment linked with group of high CH-acidity can also
possess a high biological activity. The objective of our work was
*Correspondence: V. Shvidenko, Institute of Organic Chemistry, National
Academy of Sciences of Ukraine, Murmanskaya 5, Kyiv-94, 02094, Ukraine;
Fax: þ380 44 5590480; E-mail: shved@i.com.ua.
4241
DOI: 10.1081/SCC-120026853
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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4242
Nazarenko et al.
the synthesis of 7-amino-1-nitro-2-heptanone derivatives, analogs of
6-aminocaproic acid, which have their carboxylic group replaced with
nitroacetyl fragment. On the one hand this group possesses high acidic
properties, on the other hand molecules bearing an active methylene
group along with the carbonyl have a great potential to construct
different heterocyclic systems with 5-aminopentyl fragment. One needs
to note, that a-nitroketones with amino group at the end of the methylene
bridge are not described in the literature.
In the present article we report on the synthesis of 7-amino-1-nitro-
2-heptanone and its derivatives by means of the ring opening of 2-(nitro-
methylidene)hexahydro-1H-azepine I[2] using a variety of electrophiles in
the water medium. Earlier cyclic nitroenamines have not been used for
this purpose, though some examples are known, when the ring opening of
I occurs.[3,4]
The easy hydrolysis of I in the water-ethanolic solution of HCl
leads to 7-amino-1-nitro-2-heptanone hydrochloride II. The salt II was
separated as colorless hygroscopic crystals.
Treatment of nitroenamine I with acid chlorides, ethyl chloroformate
or t-butyl pyrocarbonate in 5% aqueous solution of sodium hydroxide
followed by acidification with concentrated HCl afforded crystalline
products, representing N-acyl aminonitroketone V. We suppose that
anion III generated in basic media reacts with acid chlorides to give
N-acyl derivative IV. An introduction of an additional acceptor, the
acyl group, at the N-atom of the compound IV increases the susceptibility
of nucleophilic attack, so that an easy hydrolysis occurs in basic
media giving rise to the N-acyl aminonitroketone V. The acylation of
I in nonaqueous media in the case of strong base (DMF/NaH) followed
by treatment of the reaction mixture with water also results in
compounds V. In our opinion this can be a proof of the given reaction
scheme.
Like acid chlorides, sulfonyl chlorides react analogously giving rise
to sulfonamides VI a–d. In case of diphenylchlorophosphate the reaction
is accompanied by partial hydrolysis of phosphoryl residue affording
compound VII.
NO2
H3O
NH3
NO2
NH
O
II
I
Scheme 1.

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7-Amino-1-nitro-2-heptanone Derivatives
4243
O
O
N+
NO2
OH-
NO2
OH-
RCOCl
NH
N
N
R
I
IV
III
O
O
OH-
R
N
H
NO2
O
V a - e
For compounds V: a R =Ph, b R = 4-MeOC6H4, c R = 4-O2NC6H4, d R = 1-Ad, e R = EtO,
f R = tBuO
Scheme 2.
O–
O
O
O–
O
O
N+
O
S
N+
O
P
R
N
H
PhO
N
H
O
OH
VII
VI a-d
For compounds VI: a R = 4-CH3C6H4 , b R = 4-MeOC6H4, c R = 4-O2NC6H4, d a-thienyl
Scheme 3.
Acyl isocyanates and acyl isothiocyanates react with nitroenamines
of type I at b-carbon, while alkyl and aryl isothiocyanates do not.[5]
We have found, that aliphatic and aromatic isothiocyanates as well as
isocyanates react with I in ethanol–water or dioxane–water solution of
NaOH with the ring opening of the saturated cycle to give thioureas
VIII a–c or ureas VIII d–f respectively.
The structures of nitroketones II, V–VIII are confirmed by elemental
1
analysis data, and also by IR, NMR H and 13C spectra. There is the
intensive band in IR spectrum at 1740 cmꢀ1 corresponding to ꢀC ¼ O of
a-nitroketone and also two intensive bands at 1310–1340 cmꢀ1 and
1560–1570 cmꢀ1 corresponding to ꢀs(NO2) and ꢀas(NO2) respectively.
Additional evidences of the nitroketone structure are 198 ppm shift in
13C NMR spectra, which stands for carbonyl carbon and 84 ppm shift

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4244
Nazarenko et al.
X
R
OH-
N
H
N
H
NO2
RNCX
I
+
O
VIII a - f
For compounds VIII a - f: a - c X = S, d - f X = O; a R = allyl, b, d R = Ph, c R = 4-MeOC6H4,
e R = 4Cl-C6H4, f R = 3,4Cl2-C6H3.
Scheme 4.
Ph
H2N
NO2
V b, f, VI b
+
PhCO
N
(CH2)5NHR
IX a - c
For compounds IX a - c: a R = H, b R = 4-MeOC6H4CO, c R = 4-MeOC6H4SO2
Scheme 5.
that corresponds to the nitromethylene group. There is also 5.7 ppm shift
in 1H spectra, which corresponds to CH2NO2 protons and is the common
feature of all compounds of this type.
Nitroketones
V
and VI were used as starting materials
for the synthesis of some heterocycles with 5-aminopentyl fragment.
Thus, the reaction of V b and VI b with o-aminobenzophenone in
[6,7]
acetic acid in the presence of catalytic amount of H2SO4
gives rise
to 3-nitroquinoline derivatives IX b,c. Under this reaction conditions the
reaction of nitroketone V f with o-aminobenzophenone is accompanied
by the hydrolysis of carbamoyl residue affording 2-(5-aminopentyl)qui-
noline with the free amino group.
The use of amide V b and carbamate V e as methylene components in
the Biginelli reaction[8] resulted in 5-nitro-3,4-dihydro-2(1H)-pyrimidone
derivatives X a,b in good yields.
It was shown that heating of nitroketones with acetylene derivatives
in the presence of catalytic amount of H2SO4 (conc.) gives rise to
substituted isoxazoles.[9] In the case of nitroketones V–VIII this
method appeared to be less successful. Thus heating of equimolar
amounts of nitroketone and phenyl acetylene in benzene in the presence
of catalytic amount of H2SO4 (conc.) leads to tarred products and only

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7-Amino-1-nitro-2-heptanone Derivatives
4245
R
NO2
HN
H2NCONH2
+
OHCR
V b, e
+
O
N
H
(CH2)5NHR1
X a - b
For compounds X a - b: a R = 4-ClC6H4CO, R1 = 4-MeOC6H4CO; b R = 4-MeOC6H4CO,
R1 = EtOCO;
Scheme 6.
O
O
H2SO4
Ph
+
VI b
MeO
SNH(CH2)5
N
O
O
XI
Scheme 7.
in case of sulfonamide derivative we have succeeded in obtaining
isoxazole XI in poor yield.
EXPERIMENTAL
Commercial reagents were used without further purification unless
1
stated. All m.p.’s are uncorrected. NMR H spectra were recorded on a
VXR 300 spectrometer in DMSO-d6 and in CDCl3 (for VI a). Chemical
shifts are expressed in ppm downfield of tetramethylsilane. NMR 13C
spectra were recorded on a VXR 300 spectrometer in DMSO-d6 and in
CDCl3 (for VI a). Infrared spectra were obtained as KBr discs on
Perkin–Elmer 1600 FTIR spectrometer.
7-Amino-1-nitro-2-heptanone hydrochloride(II). To 0.01 mol I in
ethanol 0.03 mol HCl (conc.) was added. The resulted mixture was kept
for 10 min at r.t., evaporated in vaccuo to dryness and triturated with
acetone. Yield 51%. M.p.: 155–156ꢁC, decomp. (iPrOH-heptane).
1H NMR 1.25–1.40 (2H, m, 5-CH2), 1.52–1.68 (4H, m, 4-CH2, 6-CH2),
2.58 (2H, t, J ¼ 6.6 Hz, 3-CH2), 2.64–2.82 (2H, m, 7-CH2), 5.77 (2H, s,
CH2NO2), 8.14 (3H, bs, NH3þ).

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4246
Nazarenko et al.
The General Method for the Preparation
of Compounds V a–f
To a suspension of nitroenamine (0.01 mol) in water a 25% aqueous
solution of NaOH (0.03 mol) was added. The mixture was stirred until a
clear solution resulted. Then an acid chloride was added (0.01 mol) and a
stirring continued for another 2 h. The mixture was brought to pH 2, the
precipitate was filtered.
N-(7-nitro-6-oxoheptyl)benzeneamide (V a). Yield 68%. M.p.:
105–107ꢁC (iPrOH). Anal. calcd. for C14H18N2O4: C, 60.43; N,
1
10.07. Found: C, 60.72; N, 10.23. H NMR: 1.22–1.38 (2H, m, 3-CH2),
1.45–1.60 (4H, m, 4-CH2, 2-CH2), 2.57 (2H, t, J ¼ 6.6 Hz,
5-CH2), 3.22–3.30 (2H, m, 1-CH2), 5.80 (2H, s, CH2NO2), 7.41–7.57
(3H, m, arom.), 7.84 (2H, d, J ¼ 7.7 Hz, arom.), 8.38 (1H, bs, NH).
13C NMR: 22.14 (4-C), 25.7 (3-C), 28.88 (2-C), 39.03 (1-C), 39.78 (5-C),
83.84 (CH2NO2), 127.5, 127.76, 131.0, 134.85, 161.21, 165.41
(CONHCH2), 197.52 (COCH2NO2). IR ꢀ (cmꢀ1): 1728 (C ¼ O st), 1558
and 1338 (NO2 st).
4-Methoxy-N-(7-nitro-6-oxoheptyl)benzeneamide (V b). Yield 63%.
M.p.: 117–119ꢁC (iPrOH). Anal. calcd. for C15H20N2O5: C, 58.44; N,
1
9.09. Found: C, 58.35; N, 9.23. H NMR: 1.23–1.38 (2H, m, 3-CH2),
1.45–1.60 (4H, m, 4-CH2, 2-CH2), 2.55 (2H, t, J ¼ 7.3 Hz, 5-CH2),
3.20–3.28 (2H, m, 1-CH2), 3.81 (3H, s, CH3O), 5.76 (2H, s, CH2NO2),
6.91 (2H, d, J ¼ 8.7 Hz, arom.), 7.77 (2H, d, J ¼ 8.7 Hz, arom.), 8.20 (1H,
t, J ¼ 5 Hz, NH). 13C NMR: 22.14 (4-C), 25.7 (3-C), 28.88 (2-C), 39.03
(1-C), 39.78 (5-C), 55.04 (CH3O), 83.84(CH2NO2), 113.04, 126.89, 128.8,
161.21, 165.41(CONHCH2), 197.52 (COCH2NO2). IR ꢀ (cmꢀ1): 1729
(C ¼ O st), 1563 and 1334 (NO2 st).
4-Nitro-N-(7-nitro-6-oxoheptyl)benzeneamide (V c). Yield 69%.
M.p.: 158–160ꢁC (CH3COOH). Anal. calcd. for C14H17N3O6: C,
1
52.01; N, 13.00. Found: C, 52.25; N, 12.87. H NMR: 1.26–1.38 (2H,
m, 3-CH2), 1.50–1.62 (4H, m, 4-CH2, 2-CH2), 2.57 (2H, t, J ¼ 7.3 Hz,
5-CH2), 3.24–3.36 (2H, m, 1-CH2), 5.76 (2H, s, CH2NO2), 8.04 (2H, d,
J ¼ 8.4 Hz, arom.), 8.27 (2H, d, J ¼ 8.4 Hz, arom.), 8.70 (1H, t, J ¼ 5 Hz,
NH). IR ꢀ (cmꢀ1): 1727 (C¼O st), 1558 and 1337 (NO2 st).
N-(7-nitro-6-oxoheptyl)-1-adamantancarboxamide (V d). Yield 77%.
M.p.: 88–90ꢁC (heptane-iPrOH). Anal. calcd. for C18H28N2O4: C, 64.29;
1
N, 8.33. Found: C, 64.15; N, 8.45. H NMR: 1.18–1.28 (2H, m, 3-CH2),
1.34–1.44 (2H, m, 4-CH2), 1.48–1.58 (2H, m, 2-CH2), 1.66–1.78 (12H, m,
adam.), 1.97 (3H, m, adam.), 2.49 (2H, t, J ¼ 6.6 Hz, 5-CH2), 2.96–3.06
(2H, m, 1-CH2), 5.74 (2H, s, CH2NO2), 7.17 (1H, t, J ¼ 5.4 Hz, NH). IR
ꢀ (cmꢀ1): 1728 (C ¼ O st), 1559 and 1338 (NO2 st).

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7-Amino-1-nitro-2-heptanone Derivatives
4247
Ethyl 7-nitro-6-oxoheptylcarbamate (V e). Yield 74%. M.p.: 64–66ꢁC
(heptane-iPrOH). Anal. calcd. for C10H18N2O5: C, 48.78; N, 11.38.
Found: C, 48.65; N, 11.35. 1H NMR: 1.17 (3H, t, J ¼ 6 Hz, CH3),
1.20–1.30 (2H, m, 3-CH2), 1.36–1.44 (2H, m, 4-CH2), 1.48–1.58 (2H,
m, 2-CH2), 2.53 (2H, t, J ¼ 7.3 Hz, 5-CH2), 2.90–2.99 (2H, m, 1-CH2),
3.92–4.01 (2H, m, CH2O), 5.73 (2H, s, CH2NO2), 6.89 (1H, t, J ¼ 5.3 Hz,
NH). IR ꢀ (cmꢀ1): 1728 (C ¼ O st), 1558 and 1338 (NO2 st).
Butyltert 7-nitro-6-oxoheptylcarbamate (V f ). Yield 72%. M.p.:
78–80ꢁC (heptane-iPrOH). Anal. calcd. for C12H22N2O5: C, 52.55; N,
1
10.22. Found: C, 52.74; N, 10.35. H NMR: 1.21–1.32 (2H, m, 3-CH2),
1.35 (9H, s, (CH3)3), 1.39–1.52 (4H, m, 4, 2-CH2), 2.50 (2H, t, J ¼ 7.5 Hz,
5-CH2), 2.82–2.94 (2H, m, 1-CH2), 5.70 (2H, s, CH2NO2), 6.59 (1H, t,
J ¼ 5.4 Hz, NH). IR ꢀ (cmꢀ1): 1726 (C ¼ O st), 1555 and 1337 (NO2 st).
The General Method for the Preparation
of Compounds VI a–d
To a nitroenamine (0.01 mol) in water an 25% aqueous solution
of NaOH (0.03 mol) was added. The mixture was stirred until a clear
solution resulted. Then sulfonyl chloride (0.01 mol) was added and a
stirring continued for another 4 h. The mixture was brought to pH 2,
the precipitate was filtered.
4-Methyl-N-(7-nitro-6-oxoheptyl)benzenesulfonamide (VI a). Yield
63%. M.p.: 60–62ꢁC (heptane). Anal. calcd. for C14H20N2O5S: C,
1
51.22; N, 8.54. Found: C, 51.35; N, 8.77. H NMR: 1.25–1.38 (2H, m,
3-CH2), 1.44–1.56 (2H, m, 4-CH2), 1.58–1.68 (2H, m, 2-CH2), 2.44 (3H, s,
CH3), 2.54 (2H, t, J ¼ 7.3 Hz, 5-CH2), 2.84–2.96 (2H, m, 1-CH2), 4.72
(1H, t, J ¼ 5 Hz, NH), 5.29 (2H, s, CH2NO2), 7.31 (2H, d, J ¼ 8.2 Hz,
arom.), 7.73 (2H, d, J ¼ 8.2 Hz, arom.). 13C NMR: 22.41 (4-C), 23.31
(3-C), 26.52 (2-C), 29.96 (1-C), 40.06 (5-C), 43.71 (CH3Ar), 84.23
(CH2NO2), 127.96, 130.70, 137.88, 144.38, 197.52 (COCH2NO2). IR
ꢀ (cmꢀ1): 1720 (C ¼ O st), 1557 and 1310 (NO2 st).
4-Methoxy-N-(7-nitro-6-oxoheptyl)benzenesulfonamide (VI b). Yield
59%. M.p.: 86–87ꢁC (iPrOH). Anal. calcd. for C14H20N2O6S: C, 48.84;
1
N, 8.14. Found: C, 49.03; N, 8.37. H NMR: 1.20–1.25 (2H, m, 3-CH2),
1.26–1.49 (4H, m, 4-CH2, 2-CH2), 2.51 (2H, t, J ¼ 7.4 Hz, 5-CH2),
2.62–2.70 (2H, m, 1-CH2), 3.84 (3H, s, CH3O), 5.72 (2H, s, CH2NO2),
7.03 (2H, d, J ¼ 8.2 Hz, arom.), 7.30 (1H, t, J ¼ 5.3 Hz, NH), 7.67 (2H, d,
J ¼ 8.2 Hz, arom.). IR ꢀ (cmꢀ1): 1719 (C ¼ O st), 1556 and 1309 (NO2 st).
4-Nitro-N-(7-nitro-6-oxoheptyl)benzenesulfonamide (VI c). Yield
48%. M.p.: 158–160ꢁC (CH3COOH). Anal. calcd. for C13H17N3O7S:

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4248
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1
C, 47.13; N, 12.69. Found: C, 47.23; N, 12.67. H NMR: 1.18–1.28 (2H,
m, 3-CH2), 1.40–1.58 (4H, m, 4-CH2, 2-CH2), 2.46–2.56 (2H, m, 5-CH2),
2.70–2.82 (2H, m, 1-CH2), 5.71 (2H, s, CH2NO2), 7.86 (1H, t, J ¼ 5.4 Hz,
NH), 8.00 (2H, d, J ¼ 8.2 Hz, arom.), 8.38 (2H, d, J ¼ 8.2 Hz, arom.). IR ꢀ
(cmꢀ1): 1722 (C ¼ O st), 1548 and 1313 (NO2 st).
N-(7-nitro-6-oxoheptyl)thiophene-2-sulfonamide (VI d). Yield 44%.
M.p.: 49–51ꢁC (iPrOH-heptane). Anal. calcd. for C11H16N2O5S2: C,
1
41.25; N, 8.75. Found: C, 41.03; N, 8.57. H NMR: 1.20–1.28 (2H, m,
3-CH2), 1.38–1.56 (4H, m, 4-CH2, 2-CH2), 2.50 (2H, t, J ¼ 7.2 Hz,
5-CH2), 2.76–2.84 (2H, m, 1-CH2), 5.71 (2H, s, CH2NO2), 7.14(1H, dd,
J ¼ 4 Hz, J 0 ¼ 1 Hz, 4-thienyl), 7.51(1H, d, J ¼ 1 Hz, 3-thienyl), 7.66 (1H,
t, J ¼ 5.3 Hz, NH), 7.83(1H, d, J ¼ 1 Hz, 5-thienyl). IR ꢀ (cmꢀ1): 1724
(C ¼ O st), 1550 and 1317 (NO2 st).
Phenyl hydrogen 7-nitro-6-oxoheptylphosphoramidoate (VII). To a
nitroenamine (0.01 mol) in water an 25% aqueous solution of NaOH
(0.03 mol) was added. The mixture was stirred until a clear solution
resulted. Then a diphenylchlorophosphate (0.01 mol) was added and a
stirring continued until a clear solution resulted (appr. 5 h). The mixture
was then filtered, brought to pH 2, the precipitate was filtered. Yield
53%. M.p.: 130–132ꢁC (EtOH). Anal. calcd. for C13H19N2O6P: C,
1
47.27; N, 8.48. Found: C, 47.35; N, 8.57. H NMR: 1.18–1.28 (2H, m,
3-CH2), 1.32–1.54 (2H, m, 2, 4-CH2), 2.48 (2H, t, J ¼ 7.3 Hz, 5-CH2),
2.70–2.82 (2H, m, 1-CH2), 5.73 (2H, s, CH2NO2), 6.41 (2H, bs, NH,
OH), 7.04–7.18 (3H, m, arom.), 7.22–7.35 (2H, m, arom.). IR ꢀ (cmꢀ1):
1710 (C ¼ O st), 1560 and 1290 (NO2 st).
The General Method for the Preparation
of Compounds VIII a–c
To a nitroenamine (0.01 mol) and a 30% aqueous solution of NaOH
(0.03 mol) in EtOH an isothiocyanate (0.01 mol) was added and a mixture
was stirred for 1 h, water was added, brought to pH 2, the precipitate was
filtered.
N-(7-nitro-6-oxoheptyl)-N 0-allylthiourea (VIII a). Yield 60%. M.p.:
97–99ꢁC (iPrOH). Anal. calcd. for C11H19N3O3S: C, 48.33; N, 15.37.
Found: C, 48.56; N, 15.61. 1H NMR: 1.20–1.32 (2H, m, 3-CH2),
1.40–1.60 (4H, m, 4-CH2, 2-CH2), 2.56 (2H, t, J ¼ 7.3 Hz, 5-CH2),
3.29–3.58 (2H, m, 1-CH2), 3.98–4.06 (2H, m, NHCH2 allyl), 5.04–5.20
(2H, m, CH2 allyl), 5.80 (2H, s, CH2NO2), 5.82 (1H, m, CH allyl),
7.36–7.47 (2H, m, NH þ NH). IR ꢀ (cmꢀ1): 1730 (C ¼ O st), 1565 and
1320 (NO2 st).

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7-Amino-1-nitro-2-heptanone Derivatives
4249
N-(7-nitro-6-oxoheptyl)-N 0-phenylthiourea (VIII b). Yield 72%. M.p.:
97–100ꢁC (iPrOH). Anal. calcd. for C14H19N3O3S: C, 54.37; N, 13.59.
Found: C, 54.35; N, 13.43. 1H NMR: 1.22–1.34 (2H, m,
3-CH2), 1.48–1.63 (4H, m, 4-CH2, 2-CH2), 2.52 (2H, t, J ¼ 7 Hz,
5-CH2), 3.34–3.49 (2H, m, 1-CH2), 5.82 (2H, s, CH2NO2), 7.02–7.19
(1H, m, arom.), 7.26–7.48 (4H, m, arom.), 7.71 (1H, bs, NH),
9.42 (1H, bs, PhNH). IR ꢀ (cmꢀ1): 1732 (C ¼ O st), 1563 and 1321
(NO2 st).
N-(4-methoxyphenyl)-N 0-(7-nitro-6-oxoheptyl)thiourea (VIII c). Yield
60%. M.p.: 112–114ꢁC (iPrOH). Anal. calcd. for C15H21N3O4S: C, 53.10;
N, 12.39. Found: C, 53.25; N, 12.23. 1H NMR: 1.22–1.36 (2H, m,
3-CH2), 1.44–1.61 (4H, m, 4-CH2, 2-CH2), 2.55 (2H, t, J ¼ 7.3 Hz,
5-CH2), 3.36–3.48 (2H, m, 1-CH2), 3.74 (3H, s, CH3O), 5.74 (2H, s,
CH2NO2), 6.82 (2H, d, J ¼ 12.0 Hz, arom.), 7.20 (2H, d, J ¼ 12.0 Hz,
arom.), 7.36 (1H, bs, NH), 9.13 (1H, s, ArNH). 13C NMR: 22.20
(4-C), 25.7 (3-C), 28.31 (2-C), 39.40 (1-C), 43.56 (5-C), 55.04
(CH3OAr), 83.87(CH2NO2), 113.67, 125.67, 131.77, 156.40, 180.66
(CS), 198.08 (COCH2NO2). IR ꢀ (cmꢀ1): 1731 (C ¼ O st), 1561 and
1325 (NO2 st).
The General Method for the Preparation
of Compounds VIII d–f
To a nitroenamine (0.01 mol) in dioxane an 25% aqueous solution of
NaOH (0.03 mol) was added. Then an isocyanate (0.01 mol) was added
and a stirring continued for 1 h. The mixture was diluted with water,
filtered, brought to pH 2, the precipitate was filtered.
N-(7-nitro-6-oxoheptyl)-N 0-phenylurea (VIII d). Yield 40%.
M.p.: 143–145ꢁC (iPrOH). Anal. calcd. for C14H19N3O4: C, 57.34; N,
1
14.34. Found: C, 57.35; N, 14.47. H NMR: 1.24–1.36 (2H, m, 3-CH2),
1.40–1.60 (4H, m, 2-CH2, 4-CH2), 2.49 (2H, t, J ¼ 7.4 Hz, 5-CH2),
3.02–3.12 (2H, m, 1-CH2), 5.75 (2H, s, CH2NO2), 6.02 (1H, t, J ¼ 5 Hz,
NH), 6.84 (1H, t, J ¼ 8.7 Hz, arom.), 7.17 (2H, t, J ¼ 8.7 Hz, arom.), 7.33
(2H, d, J ¼ 8.7 Hz, arom.), 8.28 (1H, s, PhNH). 13C NMR: 22.20 (4-C),
25.74 (3-C), 29.59 (2-C), 39–40 (1-C, 5-C), 83.92 (CH2NO2), 117.49,
120.67, 128.36, 140.56, 155.07 (NHCONH), 197.52 (COCH2NO2). IR ꢀ
(cmꢀ1): 1710 (C ¼ O st), 1565 and 1320 (NO2 st).
N-(3-chlorophenyl)-N 0-(7-nitro-6-oxoheptyl)urea (VIII e). Yield 37%.
M.p.: 128–130ꢁC (iPrOH). Anal. calcd. for C14H18ClN3O4: C, 51.29; N,
1
12.82. Found: C, 51.35; N, 12.87. H NMR: 1.24–1.36 (2H, m, 3-CH2),
1.42–1.62 (4H, m, 2-CH2, 4-CH2), 2.56 (2H, t, J ¼ 7.1 Hz, 5-CH2),

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4250
Nazarenko et al.
3.02–3.16 (2H, m, 1-CH2), 5.75 (2H, s, CH2NO2), 6.10 (1H, t, J ¼ 5 Hz,
NH), 6.85 (1H, d, J ¼ 8.7 Hz, arom.), 7.10–7.22 (2H, m, arom.), 7.63 (1H,
s, arom.), 8.51 (1H, s, PhNH). IR ꢀ (cmꢀ1): 1717 (C ¼ O st), 1557 and
1323 (NO2 st).
N-(3,4-dichlorophenyl)-N 0-(7-nitro-6-oxoheptyl)urea (VIII f ). Yield
36%. M.p.: 127–129ꢁC (iPrOH). Anal. calcd. for C14H17Cl2N3O4: C,
1
46.41; N, 11.60. Found: C, 46.35; N, 11.57. H NMR: 1.22–1.36 (2H,
m, 3-CH2), 1.42–1.61 (4H, m, 2-CH2, 4-CH2), 2.55 (2H, t, J ¼ 7.5 Hz,
5-CH2), 3.01–3.12 (2H, m, 1-CH2), 5.75 (2H, s, CH2NO2), 6.17 (1H, t,
J ¼ 5.3 Hz, NH), 7.20 (1H, d, J ¼ 11.3 Hz, arom.), 7.32 (1H, d, J ¼ 11.3 Hz,
arom.), 7.80 (1H, s, arom.), 8.64 (1H, s, PhNH). IR ꢀ (cmꢀ1): 1720 (C ¼ O
st), 1559 and 1325 (NO2 st).
The General Method for the Preparation
of Compounds IX a–c
To an appropriate nitroketone V b, V f, or VI (0.01 mol) and
o-aminobenzophenone (0.01 mol) in glacial acetic acid 3 drops of
H2SO4(conc.) were added. The mixture was then boiled for 6 h,
evaporated in vaccuo to dryness and triturated with water.
5-(3-Nitro-4-phenyl-2-quinolinyl)pentylamine hydrochloride (IX a).
Yield 75%. M.p.: 189–192ꢁC (EtOH). 1H NMR: 1.38–1.55 (2H, m, 3-CH2),
1.62–1.80 (4H, m, 2-CH2, 4-CH2), 2.76–2.88 (4H, m, 1-CH2,
5-CH2), 3.20–3.80 (3H, bs, NH3þ), 7.26–7.34 (2H, m, arom.), 7.42–7.58
(5H, m, arom.), 7.77 (1H, t, J ¼ 5.3 Hz, arom.), 8.05 (1H, d, J ¼ 8.3 Hz,
arom.).
4-Methoxy-N-[5-(3-nitro-4-phenyl-2-quinolinyl)pentyl]benzamide (IX b).
Yield 85%. M.p.: 139–141ꢁC (EtOH). Anal. calcd. for C28H27N3O4: C,
1
71.62; N, 8.95. Found: C, 71.45; N, 9.12. H NMR: 1.42–1.64 (4H, m,
3-CH2, 4-CH2), 1.82–1.98 (2H, m, 2-CH2), 2.91 (2H, t, J ¼ 7.3 Hz,
5-CH2), 3.25 (2H, m, 1-CH2), 3.81 (3H, s, CH3O), 6.93 (2H, d,
J ¼ 9.3 Hz, arom.), 7.34–7.40 (2H, m, arom.), 7.46–7.64 (5H, m, arom.),
7.77 (2H, d, J ¼ 9.3 Hz, arom.), 7.88 (1H, t, J ¼ 7.2 Hz, arom.), 8.09 (1H, d,
J ¼ 9.3 Hz, arom.), 8.19 (1H, t, J ¼ 5.4 Hz, NH).
4-Methoxy-N-[5-(3-nitro-4-phenyl-2-quinolinyl)pentyl]benzenesulfona-
mide (IX c). Yield 87%. M.p.: 140–142ꢁC (iPrOH). Anal. calcd. for
1
C27H27N3O5S: C, 64.14; N, 8.31. Found: C, 64.37; N, 8.61. H NMR:
1.32–1.55 (4H, m, 3-CH2, 4-CH2), 1.72–1.82 (2H, m, 2-CH2), 2.66–2.75
(2H, m, 1-CH2), 2.76–2.85 (2H, m, 5-CH2), 3.83 (3H, s, CH3O), 7.06 (2H,
d, J ¼ 9.4 Hz, arom.), 7.30–7.40 (3H, m, arom. þ NH), 7.44–7.66

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7-Amino-1-nitro-2-heptanone Derivatives
4251
(7H, m, arom.), 7.90 (1H, t, J ¼ 7.3 Hz, arom.), 8.10 (2H, d, J ¼ 9.4 Hz,
arom.).
N-{5-[6-(4-chlorophenyl)-5-nitro-2-oxo-1,2,3,6-tetrahydro-4-pyrimi-
dinyl] pentyl}-4-methoxybenzamide (X a). To V b (0.01 mol) in dry
ethanol 4-chlorobenzaldehyde (0.01 mol), urea (0.02 mol), 0.2 mL of
HCl(conc.) are added and a mixture was refluxed for 10 h, cooled,
the resulted precipitate was filtered. Yield 57%. M.p.: 203–205ꢁC
(EtOH). Anal. calcd. for C23H25ClN4O5: C, 58.41; N, 7.50. Found:
C, 58.85; N, 7.74. 1H NMR: 1.40–1.50 (2H, m, 3-CH2), 1.55–1.73
(4H, m, 4-CH2, 2-CH2), 2.82 (2H, t, J ¼ 7.6 Hz, 5-CH2), 3.19–3.30
(2H, m, 1-CH2), 3.82 (3H, s, CH3O), 5.51 (1H, d, J ¼ 3 Hz, CH), 6.93
(2H, d, J ¼ 8.3 Hz, arom.), 7.26–7.36 (4H, m, arom.), 7.78 (2H,
d, J ¼ 8.3 Hz, arom.), 8.16 (1H, t, J ¼ 5.2 Hz, CH2NH ), 8.23 (1H, s,
NH), 10.00 (1H, s, NH). 13C NMR: 25.93 (2-C), 26.65 (3-C), 28.23
(4-C), 30.80 (5-C), 38.70 (1-C), 53.02 (CHCNO2), 54.71 (CH3OAr),
112.82, 121.89, 126.44, 127.73, 128.09, 128.32, 131.93, 140.72, 149.64,
153.98(NHCONH), 160.83, 165.08 (ArCONH).
Ethyl 5-[6-(4-methoxyphenyl)-5-nitro-2-oxo-1,2,3,6-tetrahydro-4-pyri-
midinyl]pentylcarbamate (X b). To V e (0.01 mol) in dry ethanol
anisic aldehyde (0.01 mol), urea (0.02 mol), 0.2 mL of HCl (conc.) were
added and a mixture was refluxed for 10 h, evaporated in vaccuo
to dryness and triturated with ether. The crude product was boiled
with EtOAc and decanted from a tar. To a hot solution heptane
was added until crystallization occurs. Yield 54%. M.p.: 139–141ꢁC.
Anal. calcd. for C19H26N4O6: C, 56.15; N, 13.79. Found: C, 56.34; N,
1
13.97. H NMR: 1.18 (3H, t, J ¼ 7 Hz, CH3), 1.35–1.70 (4H, m, 3-CH2,
4-CH2), 1.72–1.82 (2H, m, 2-CH2), 2.79 (2H, t, J ¼ 7 Hz, 5-CH2),
2.95–3.01 (2H, m, 1-CH2), 3.82 (3H, s, CH3O), 3.94–4.01 (2H, m,
CH2O), 5.44 (1H, d, J ¼ 3.1 Hz, CH), 6.88 (2H, d, J ¼ 8.9 Hz, arom. þ
1H, t, CH2NH ), 7.15 (2H, d, J ¼ 8.9 Hz, arom.), 8.13 (1H, bs, NH), 9.89
(1H, s, NH).
4-Methoxy-N-[5-(5-phenyl-3-isoxazolyl)pentyl]benzenesulfonamide (XI).
To VI b (0.1 mol) and phenylacetylene (0.1 mol) in benzene 0.001 mol
of H2SO4(conc.) was added and a mixture was refluxed for 4 h, cooled,
a benzene layer was separated and evaporated. The residue was triturated
with ether. Yield 10%. M.p.: 112–114ꢁC (EtOAc-heptane). Anal. calcd.
for C21H24N2O4S: C, 62.98; N, 6.99. Found: C, 63.13; N, 7.23. 1H NMR:
1.28–1.47 (4H, m, 3-CH2, 4-CH2), 1.57–1.66 (2H, m, 2-CH2), 2.66–2.73
(2H, m, 1-CH2), 3.25 (2H, t, J ¼ 7.4 Hz, 5-CH2), 3.83 (3H, s, CH3O), 7.05
(2H, d, J ¼ 8.4 Hz, arom.), 7.28 (1H, s, arom.), 7.31 (1H, t, J ¼ 5.3 Hz,
NH), 7.51–7.56 (3H, m, arom.), 7.68 (2H, d, J ¼ 8.4 Hz, arom.), 7.90–7.94
(2H, m, arom.).

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Received in the UK July 4, 2003