Synthesis of heterocyclic [3.3.3]propellanes via a sequential four-component reaction

Article abstract of DOI:10.1021/jo300457m

A highly chemoselective heteroannulation protocol for the synthesis of unreported polysubstituted heterocyclic [3.3.3]propellanes has been developed by sequential four-component reaction of ninhydrin, malononitrile, primary amines, and dialkyl acetylenedicarboxylates under mild conditions in water. To the best of our knowledge, there are no previous reports for the synthesis of these classes of heterocyclic [3.3.3]propellanes. The merit of this sequential Knoevenagel condensation/enamine formation/Michael addition/cyclization sequence is highlighted by its high atom-economy, excellent yields, the use of water as reaction media, and the efficiency of production without the use of any activator or metal promoters. This synthesis serves as a nice addition to group-assistant-purification (GAP) chemistry in which purification via chromatography and recrystallization can be avoided, and the pure products were obtained simply by washing the crude products with 95% ethanol.

Full text of DOI:10.1021/jo300457m

Article
pubs.acs.org/joc
Synthesis of Heterocyclic [3.3.3]Propellanes via a Sequential Four-
Component Reaction
Abdolali Alizadeh,*,† Atieh Rezvanian,† and Long-Guan Zhu‡
†Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
‡Department of Chemistry, Zhejiang University, Hangzhou 310027, PR of China
S
* Supporting Information
ABSTRACT: A highly chemoselective heteroannulation protocol for the synthesis of unreported polysubstituted heterocyclic
[3.3.3]propellanes has been developed by sequential four-component reaction of ninhydrin, malononitrile, primary amines, and
dialkyl acetylenedicarboxylates under mild conditions in water. To the best of our knowledge, there are no previous reports for
the synthesis of these classes of heterocyclic [3.3.3]propellanes. The merit of this sequential Knoevenagel condensation/enamine
formation/Michael addition/cyclization sequence is highlighted by its high atom-economy, excellent yields, the use of water as
reaction media, and the efficiency of production without the use of any activator or metal promoters. This synthesis serves as a
nice addition to group-assistant-purification (GAP) chemistry in which purification via chromatography and recrystallization can
be avoided, and the pure products were obtained simply by washing the crude products with 95% ethanol.
The propellane moiety is a part of many natural products,
such as batrachotoxin (A), a steroidal alkaloid skin neurotoxin
from the South American frog Phyllobates terribilis,19 hasubanan
alkaloids20 (B), and merrilactone A (C), with therapeutic
potential in the treatment of neurodegenerative diseases such as
Alzheimer’s disease and Parkinson’s disease (Figure 2).21 Total
synthesis of many different propellane-containing natural
products have recently been reviewed.14
INTRODUCTION
■
Propellanes are annulated tricyclic systems exhibiting a Y-
shaped bridgehead−bridgehead central bond (Figure 1).1 They
Figure 1. General structure of propellanes.
can be found as scaffolds of non-naturally and naturally
occurring products having many applications, including
bioactive medicinal compounds2 or polymers.3 The first
propellanes were synthesized in the 1930s during investigations
into the Diels−Alder reaction.4−9 However, the first
“propellane by design” was synthesized much later, in
1965.10,11 The term propellane was proposed in 1966 by
Ginsburg’s group12 because of the characteristic propeller shape
of these molecules. Since their discovery in 1965,13 these
polycyclic structures have received attention by many research
groups14 due to their extended use and challenging architecture.
Some modern synthetic approaches to form carbocyclic or
heterocyclic propellanes include [4 + 2]cycloadditions,15
palladium16 or manganese17 catalysis, and nucleophilic
substitutions of 1,1,2,2-tetrasubstituted alkenes.18
Figure 2. Biologically active propellane-based natural products.
The conventional multistep methods for the preparation of
complex molecules involve a large number of synthetic
operations, including extraction and purification processes for
each individual step, that lead to synthetic inefficiency and the
Received: March 7, 2012
Published: April 6, 2012
© 2012 American Chemical Society
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Scheme 1. Synthetic Scheme for the Generation of 3 and 5
generation of large amounts of waste. Multicomponent
reactions (MCRs) allow the creation of several bonds in a
single operation and offer remarkable advantages like
convergence, operational simplicity, facile automation, reduc-
tion in the number of workups, extraction and purification
processes, and hence minimized waste generation rendering the
transformations green. One aspect of multicomponent
reactions that has received relatively little attention is their
development in aqueous environments.22 In this regard, water
is nature’s reaction medium and constitutes a nonflammable,
nonhazardous, nontoxic, uniquely redox-stable, inexpensive
solvent that has the additional advantage of being a
nonexhaustible resource that is almost freely available, even in
the least-developed countries.23 For these reasons, the
development of synthetically useful multicomponent reactions
using water as the green reaction medium has gained
considerable interest.
Our research goal during the past few years has been the
synthesis of a library of pharmacologically relevant fused
polyheterocyclic systems employing enamines and dien-
amines.24 The chemistry of enamines has numerous attractive
features that have made them important building blocks in
current organic trends.25 Over the decades, they have been used
for the synthesis of a wide variety of heterocyclic compounds,
natural products,26 and precursors of chiral amines upon
asymmetric transformations.27
Table 1. One-Pot, Four-Component Synthesis of
Aza[3.3.3]propellane Derivatives 3a−j
a
b
entry
R1
R2
products 3
yield (%)
1
2
Me
Me
Et
n-ethyl
3a
3b
3c
3d
3e
3f
90
93
91
84
87
94
90
83
88
85
n-propyl
3
n-propyl
4
Me
Et
i-butyl
5
i-butyl
6
Me
Et
n-butyl
7
n-butyl
3g
3h
3i
8
Me
Me
Et
p-methylbenzyl
p-methoxybenzyl
p-methoxybenzyl
9
10
3j
a
Reactions were performed at 1 mmol scale of substrates in H2O (4
mL) at room temperature. Reaction time was typically 2 h (see the
b
Supporting Information). Isolated yield.
experimental results showed that the reaction proceeded with
excellent yields when water and triethylamine were utilized as
the solvent and base.
In view of the success of the above reaction and having
established the optimal conditions, we explored the scope of
this promising reaction by varying the structure of the primary
amine 2 and dialkyl acetylenedicarboxylate 1 component
(Table 1). The reaction proceeded very cleanly under mild
conditions at room temperature, and no undesirable side
reactions were observed.
Being inspired by the above results, it was thought
worthwhile to replace the dialkyl acethylenedicarboxylate with
alkyl acetoacetate in order to get some newly substituted
aza[3.3.3]propellane. For this aim, we have examined the
reaction of ninhydrin, malononitrile, alkyl acetoacetate 4, and
primary amine 2 under the same previous reaction conditions.
Fortunately, the desired reaction took place successfully to
afford a series of aza[3.3.3]propellane derivatives 5 in excellent
yields. The results are shown in Table 2.
RESULTS AND DISCUSSION
■
Inspired by these results and with given our interest and
experience in the area of one-pot-multicomponent reactions,
we became attracted to how Knoevenagel adduct generated in
situ from ninhydrin and malononitrile could be trapped by
enamine to give a heterocycle product. For this purpose, we
investigated the reaction of ninhydrin, malononitrile, dialkyl
acetylenedicarboxylate 1, and primary amine 2 in water at room
temperature. Quite surprisingly, instead of the anticipated
spiropyridine product 10 (Scheme 1), we observed an
unexpected process leading to heterocyclic propellane 3 in
excellent yields (Table 1). To the best of our knowledge, no
analogous products have been reported in the literature yet.
Initially, we explored the reaction of ninhydrin with
malononitrile at room temperature in the presence of
triethylamine (0.1 mmol) that afforded the expected
Knoevenagel adduct intermediate. Next, the sequential one-
pot addition of dialkyl acetylenedicarboxylate 1 and primary
amine 2 successfully gave the aza[3.3.3]propellane derivatives 3
in 83−94% yields (Table 1). Several solvent and basic catalysts
were examined to set up a standard reaction condition, and
The structures all of the products 3a−j and 5a−d were
1
deduced from their IR, mass, H NMR, and 13C NMR spectra
(see the Supporting Information) and unambiguously con-
firmed by X-ray crystal structure analysis of 3b and 5c (see the
Supporting Information).28
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(path A). But considering IR, 1H and 13C NMR spectra, and X-
ray diffraction, this product was not created, and another
considerable event occurs. In fact, in this stage, chemoselective
nucleophilic addition of amino group to CO bond afforded
intermediate 11. Then, O-cyclization and the tautomerization
of imino group to amino group of could lead to aza[3.3.3]-
propellanes 3 and 5 (path B).
Table 2. One-Pot, Four-Component Synthesis of
Aza[3.3.3]propellane Derivatives 5a−d
a
b
entry
R1
R2
products 3
yield (%)
CONCLUSIONS
■
1
2
3
4
Me
Et
n-propyl
n-propyl
n-butyl
5a
5b
5c
5d
93
90
88
90
We have discovered a novel and convenient four-component
synthesis of efficient assembly of heterocyclic [3.3.3]-
propellanes, through sequential Knoevenagel/Michael/intra-
molecular cyclization sequences in water. This class of
compounds is not only prepared by a multicomponent reaction
for the first time, but also to our knowledge, there is no other
efficient method for their synthesis. This reaction includes
some important aspects like simple operation under mild
conditions, easy accessibility of reactants and workup
procedure, absence of transition metal catalysts, high atom
economy, and the use of water as a green reaction medium.
Further investigations in this area are currently under way and
will be reported in due course.
Me
Et
n-butyl
a
Reactions were performed at 1 mmol scale of substrates in H2O (4
mL) at room temperature. Reaction time was typically 2 h (see the
Supporting Information). Isolated yield.
b
We have believed that the reaction mechanism is a special
case, and on the basis of the results obtained above, a plausible
reaction scenario for this one-pot four-component reaction is
outlined in Scheme 2. It is conceivable that initially the
ninhydrin undergoes triethylamine promoted Knoevenagel
condensation with malononitrile to give adduct 6, which acts
as Michael acceptor. Next, the formation of enamine 7 occurs
through condensation of amine 2 with acethylene compound 1
or alkyl acetoacetate 4. Then, the enamine 7 attacks to
Knoevenagel adduct 6 in a Michael-type addition to produce an
open chain intermediate 8, which transformed to intermediate
9 through the migration of the hydrogen atom. At this stage,
considering the previous articles, we would normally expect
that 9 undergoes N-cyclization via attack to the CN triple
bond and tautomerization to give the desired spiropyridines 10
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Dialkyl-8c-amino-
8b-cyano-8-oxo-3-alkyl-3H,8H-8d-oxa-3-azapentaleno[3a,6a-
a]indene-1,2-dicarboxylate 3a−j. To a solution of ninhydrin (1
mmol) and malononitrile (1 mmol) in water (4 mL) was added
triethylamine (0.1 mmol), and the solution was stirred for 1 h at room
temperature. Then, dialkyl acetylenedicarboxylate 1 (1 mmol) and
primary amine 2 (1 mmol) were added at once and dropwise over 15
min, respectively. Upon completion (50−60 min) as monitored by
Scheme 2. Mechanistic Rationalization for the Formation of 3 and 5
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TLC, the reaction mixture was filtered to give the crude product,
which was further washed by 95% ethanol to give pure product 3a−j.
Dimethyl-8c-amino-8b-cyano-8-oxo-3-ethyl-3H,8H-8d-oxa-
3-azapentaleno[3a,6a-a]indene-1,2-dicarboxylate (3a). White
100.0, 109.9, 117.2, 125.3, 125.3, 131.8, 136.1, 136.6, 142.3, 150.7,
161.1, 162.4, 167.3, 194.1; IR (KBr) ν 3337, 3256, 2196, 1732, 1658,
1590, 1437, 1374 cm−1; MS m/z 451 (M+), 436, 408, 362, 334, 278,
261, 234, 205, 151, 97, 57. Anal. Calcd for C24H25N3O6: C, 63.85; H,
5.58; N, 9.31. Found: C, 63.78; H, 5.52; N, 9.33.
1
crystals: 0.35 g, 90% yield; mp 177−179 °C; H NMR (400 MHz,
DMSO) δ 1.13 (t, J = 7.2 Hz, 3H), 3.46−3.59 (m, 2H), 3.65 (s, 3H),
3.84 (s, 3H), 7.63 (s, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.91−7.98 (m,
2H), 8.11 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, DMSO) δ 15.8,
50.6, 53.3, 53.3, 56.0, 68.0, 100.2, 109.4, 117.0, 125.0, 125.2, 131.8,
136.0, 136.7, 143.1, 150.4, 161.6, 162.9, 167.2, 194.0; IR (KBr) ν 3376,
3321, 2197, 1725, 1652, 1593, 1441, 1344 cm−1; MS m/z 396, (M+ +
1), 377, 366, 352, 320, 305, 291, 261, 249, 233, 205, 179, 151, 102, 76,
59. Anal. Calcd for C20H17N3O6: C, 60.76; H, 4.33; N, 10.63. Found:
C, 60.68; H, 4.24; N, 10.59.
Dimethyl-8c-amino-3-butyl-8b-cyano-8-oxo-3H,8H-8d-oxa-
3-azapentaleno[3a,6a-a]indene-1,2-dicarboxylate (3f). White
1
crystals: 0.39 g, 94% yield; mp 178−180 °C; H NMR (500 MHz,
DMSO) δ 0.85 (t, J = 7.1 Hz, 3H), 1.22−1.30 (m, 2H), 1.45−1.49 (m,
1H), 1.57−1.61 (m, 1H), 3.25−3.31 (m, 1H), 3.44−3.48 (m, 1H),
3.62 (s, 3H), 3.81 (s, 3H), 7.58 (s, 2H), 7.77 (t, J = 7.2 Hz, 1H), 7.91
(d, J = 7.6 Hz, 1H), 7.96 (t, J = 7.3 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H);
13C NMR (125 MHz, DMSO) δ 13.9, 19.5, 32.3, 44.1, 51.0, 53.7, 68.0,
100.7, 110.0, 117.4, 125.5, 125.7, 132.3, 136.5, 137.1, 143.3, 151.0,
162.0, 163.3, 167.7, 194.5; IR (KBr) ν 3441, 3338, 2191, 1727, 1642,
1588, 1441, 1355 cm−1; MS m/z 423 (M+), 394, 380, 348, 321, 292,
260, 234, 205, 178, 97, 57. Anal. Calcd for C22H21N3O6: C, 62.41; H,
5.00; N, 9.92. Found: C, 62.37; H, 5.08; N, 9.87.
Dimethyl-8c-amino-8b-cyano-8-oxo-3-propyl-3H,8H-8d-
oxa-3-azapentaleno[3a,6a-a]indene-1,2-dicarboxylate (3b).
1
White crystals: 0.38 g, 93% yield; mp 180−182 °C; H NMR (500
MHz, DMSO) δ 0.84 (br, 3H), 1.51−1.60 (m, 2H), 3.24−3.44 (m,
2H), 3.63 (s, 3H), 3.81 (s, 3H), 7.55 (s, 2H), 7.76−8.02 (m, 4H); 13C
NMR (125 MHz, DMSO) δ 11.2, 23.5, 45.9, 51.0, 53.7, 68.5, 100.7,
110.0, 117.4, 125.5, 125.6, 132.2, 136.5, 137.0, 143.4, 151.0, 162.0,
163.3, 167.7, 194.4; IR (KBr) ν 3350, 3310, 2202, 1721, 1650, 1592,
1437, 1336 cm−1; MS m/z 409 (M+), 366, 334, 317, 292, 260, 232,
205, 192, 129, 91, 59. Anal. Calcd for C21H19N3O6: 61.61; H, 4.68; N,
10.26. Found: C, 61.52; H, 4.59; N, 10.30. Crystal data for 3b
C21H19N3O6 (CCDC 846789): MW = 409.39, monoclinic, space group
P21/n, a = 9.9784(5) Å, b = 13.6537(7) Å, c = 14.6285(7) Å, α =
90.00, β = 104.214(5), γ = 90.00, V = 1932.00(17) Å3, Z = 4, Dc =
1.407 mg/m3, F(000) = 856, crystal dimension 0.43 × 0.39 × 0.35
mm, radiation, MoKα (λ = 0.71073 Å), 2.83 ≤ 2θ ≤ 25.10, intensity
data were collected at 295(2) K, and employing ω/2θ scanning
technique, in the range of −11≤ h ≤ 11, −15≤ k ≤ 16, −16≤ l ≤ 17;
the structure was solved by a direct method, all non-hydrogen atoms
were positioned and anisotropic thermal parameters refined from 2686
observed reflections with R(into) = 0.0528 by a full-matrix least-
squares technique converged to R = 0.0371 and Raw = 0.0961 [I >
2σ(I)].
Diethyl-8c-amino-3-butyl-8b-cyano-8-oxo-3H,8H-8d-oxa-3-
azapentaleno[3a,6a-a]indene-1,2-dicarboxylate (3g). White
1
crystals: 0.40 g, 90% yield; mp 182−184 °C; H NMR (400 MHz,
DMSO) δ 0.89 (t, J = 6.4 Hz, 3H), 1.24−1.33 (m, 8H), 1.46.1.52 (m,
1H), 1.58−1.63 (m, 1H), 3.26−3.32 (m, 1H), 3.45−3.52 (m, 1H),
4.06−4.14 (m, 2H), 4.27−4.28 (m, 2H), 7.60 (s, 2H), 7.79 (t, J = 7.6
Hz, 1H), 7.92−7.99 (m, 2H), 8.05 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, DMSO) δ 13.5, 13.6, 14.1, 19.1, 31.9, 43.6, 53.3, 59.4, 62.5, 68.1,
100.2, 109.6, 117.1, 125.1, 125.2, 131.8, 136.1, 136.6, 142.9, 150.5,
161.1, 162.4, 167.3, 193.9; IR (KBr) ν 3430, 3183, 2202, 1721, 1650,
1592, 1437, 1336 cm−1; MS m/z 451 (M+), 436, 408, 345, 317, 290,
261, 234, 189, 151, 97, 57. Anal. Calcd for C24H25N3O6: C, 63.85; H,
5.58; N, 9.31. Found: C, 63.81; H, 5.61; N, 9.33.
Dimethyl-8c-amino-8b-cyano-3-(4-methylbenzyl)-8-oxo-
3H,8H-8d-oxa-3-azapentaleno[3a,6a-a]indene-1,2-dicarboxy-
1
late (3h). White crystals: 0.37 g, 83% yield; mp 188−190 °C; H
NMR (400 MHz, DMSO) δ 2.25 (s, 3H), 3.44 (s, 3H), 3.67 (s, 3H),
4.67 (d, J = 16.4 Hz, 1H), 4.81 (d, J = 16.8 Hz, 1H), 6.96 (d, J = 8.2
Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.67 (s, 2H), 7.76 (t, J = 7.2 Hz,
1H), 7.88 (t, J = 7.2 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6
Hz, 1H); 13C NMR (100 MHz, DMSO) δ 20.6, 50.6, 52.8, 53.4, 56.0,
68.0, 101.3, 109.4, 117.0, 125.2, 125.19, 127.4, 128.9, 131.8, 133.1,
136.0, 136.6, 136.8, 143.4, 149.7, 161.2, 162. 8, 167.2, 194.0; IR (KBr)
ν 3554, 3360, 2190, 1710, 1659, 1596, 1438, 1334 cm−1; MS m/z 453,
428, 397, 364, 337, 292, 250, 205, 179, 135, 105, 77, 51. Anal. Calcd
for C26H21N3O6: C, 66.24; H, 4.49; N, 8.91 Found C, 66.18; H, 4.46;
N, 8.98.
Diethyl-8c-amino-8b-cyano-8-oxo-3-propyl-3H,8H-8d-oxa-
3-azapentaleno[3a,6a-a]indene-1,2-dicarboxylate (3c). White
1
crystals: 0.039, 91% yield; mp 182−184 °C; H NMR (500 MHz,
DMSO) δ 0.84 (t, J = 6.6 Hz, 3H), 1.24 (s, 6H), 1.50−1.62 (m, 2H),
3.20−3.31 (m, 1H), 3.41−3.48 (m, 1H), 4.08 (m, 2H), 4.28 (m, 2H),
7.57 (s, 2H), 7.77 (t, J = 6.8 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.95 (t,
J = 7.1 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H); 13C NMR (125 MHz,
DMSO) δ 11.2, 14.0, 14.5, 23.5, 45.8, 59.8, 62.8, 62.9, 100.0, 110.0,
117.5, 125.6, 125.7, 132.3, 136.5, 137.0, 143.4, 148.1, 150.9, 161.5,
162.8, 167.8, 194.4; IR (KBr) ν 3386, 3325, 2198, 1728, 1655, 1594,
1436, 1379 cm−1; MS m/z 437 (M+), 422, 394, 348, 320, 261, 234,
205, 178, 151, 130, 102, 56. Anal. Calcd for C23H23N3O6: C, 63.15; H,
5.30; N, 9.61. Found: C, 63.08; H, 5.25; N, 9.56.
Dimethyl-8c-amino-8b-cyano-3-(4-methoxylbenzyl)-8-oxo-
3H,8H-8d-oxa-3-azapentaleno[3a,6a-a]indene-1,2-dicarboxy-
late (3i). White crystals: 0.42 g, 88% yield; mp 188−190 °C; 1H NMR
(400 MHz, DMSO) δ 0. 3.45 (s, 3H), 3.63 (s, 3H), 3.71 (s, 3H), 4.64
(d, J = 16.4 Hz, 1H), 4.79 (d, J = 16.4 Hz, 1H),), 6.86 (d, J = 8.4 Hz,
2H), 6.10 (d, J = 8.8 Hz, 2H), 7.67 (s, 2H), 7.78 (t, J = 7.6 Hz, 1H),
7.89−7.95 (m, 2H), 8.08 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
DMSO) δ 46.6, 50.6, 52.8, 53.5, 55.1, 67.9, 101.2, 109.3, 113.8, 117.0,
125.1, 127.8, 129.0, 131.9, 134.2, 136.0, 136.7, 143.4, 149.6, 158.7,
161.2, 162.8, 167.2, 194.0; IR (KBr) ν 3430, 3321, 2193, 1731, 1647,
1592, 1438, 1333 cm−1; MS m/z 487 (M+), 458, 444, 380, 309, 292,
234, 205, 151, 121, 91, 77, 59. Anal. Calcd for C26H21N3O7: C, 64.06;
H, 4.34; N, 8.62 Found C, 63.99; H, 4.37; N, 8.64.
Diethyl-8c-amino-8b-cyano-3-(4-methoxylbenzyl)-8-oxo-
3H,8H-8d-oxa-3-azapentaleno[3a,6a-a]indene-1,2-dicarboxy-
late (3j). White crystals: 0.43 g, 85% yield; mp 186−188 °C; 1H NMR
(400 MHz, DMSO) δ 0.92 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz,
3H), 3.71(s, 3H), 3.87 (q, J = 7.2 Hz, 2H), 4.07−4.11 (m, 2H), 4.65
(d, J = 16.4 Hz, 1H), 4.80 (d, J = 16.4 Hz, 1H), 6.86 (d, J = 8.4 Hz,
2H), 6.99 (d, J = 8.8 Hz, 2H), 7.67 (s, 2H), 7.77 (t, J = 7.6 Hz, 1H),
7.85 (t, J = 7.6 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 8.09 (t, J = 7.6 Hz,
1H); 13C NMR (100 MHz, DMSO) δ 13.1, 14.1, 46.5, 53.6, 56.0, 59.4,
62.1, 68.0, 101.3, 109.4, 113.7, 117.1, 125.1, 125.2, 128.0, 128.9, 131.8,
136.0, 136.6, 143.5, 149.6, 158.8, 160.8, 162.2, 167.3, 193.9; IR (KBr)
ν 3421, 3324, 2202, 17236, 1648, 1596, 1436, 1327 cm−1; MS m/z 516
(M+ + 1), 472, 427, 380, 323, 261, 234, 205, 137, 121, 91, 77, 57. Anal.
Dimethyl-8c-amino-8b-cyano-3-isobutyl-8-oxo-3H,8H-8d-
oxa-3-azapentaleno[3a,6a-a]indene-1,2-dicarboxylate (3d).
1
White crystals: 0.35 g, 84% yield; mp 182−184 °C; H NMR (500
MHz, DMSO) δ 0.83 (s, 3H), 0.92 (s, 3H), 2.03 (br, 1H), 2.82−2.90
(m, 1H), 3.31 (br, 1H), 3.62 (s, 3H), 3.80 (s, 3H), 7.57 (s, 2H), 7.77−
7.96 (m, 4H); 13C NMR (125 MHz, DMSO) δ 19. 8, 20.0, 28.4, 51.0,
51.8, 53.7, 68.5, 100.5, 110.3, 117.4, 125.7, 125.8, 132.3, 132.7, 136.5.
137.0, 142.9, 152.0, 162.0, 163.4, 167.7, 194.6; IR (KBr) ν 3384, 3310,
2154, 1720, 1644, 1588, 1432, 1328 cm−1; MS m/z 423 (M+), 394,
380, 348, 292, 261, 234, 205, 164, 130, 57. Anal. Calcd for
C22H21N3O6: C, 62.41; H, 5.00; N, 9.92. Found: C, 62.38; H, 4.95;
N, 9.90.
Diethyl-8c-amino-8b-cyano-3-isobutyl-8-oxo-3H,8H-8d-oxa-
3-azapentaleno[3a,6a-a]indene-1,2-dicarboxylate (3e). White
1
crystals: 0.39 g, 87% yield; mp 186−188 °C; H NMR (400 MHz,
DMSO) δ 0.86 (t, J = 6.4 Hz, 3H), 0.95 (t, J = 6.8 Hz, 3H), 1.26 (dd, J
= 13.2 Hz, J = 6.8 Hz, 6H), 2.05−2.09 (m, 1H), 2.86−2.92 (m, 1H),
3.37−3.39 (m, 1H), 4.06−4.15 (m, 2H), 4.24−4.27 (m, 2H), 7.59 (s,
2H), 7.80 (t, J = 7.2 Hz, 1H), 7.93−8.0 (m, 3H); 13C NMR (100
MHz, DMSO) δ 13.5, 14.1, 19.4, 19.6, 27.9, 51.3, 53.2, 59.4, 62.4, 68.1,
4388
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The Journal of Organic Chemistry
Article
Calcd for C28H25N3O7: C, 65.24; H, 4.89; N, 8.15 Found C, 65.27; H,
5.85; N, 8.17.
cm−1; MS m/z 393 (M+), 350, 322, 304, 248, 235, 164, 125, 111, 97,
83, 69, 57. Anal. Calcd for C22H23N3O4: C, 67.16; H, 5.89; N, 10.68.
Found: C, 67.22; H, 6.85; N, 10.66.
General Procedure for the Synthesis of Alkyl-8c-amino-8b-
cyano-2-alkyl-8-oxo-3-alkyl-3H,8H-8d-oxa-3-azapentaleno-
[3a,6a-a]indene-1,2-dicarboxylate 5a−d. To a solution of
ninhydrin (1 mmol) and malononitrile (1 mmol) in water (4 mL)
was added triethylamine (0.1 mmol), and the solution was stirred for 1
h at room temperature. Then, alkyl acetoacetate 4 (1 mmol) and
primary amine 2 (1 mmol) were added at once and dropwise over 15
min, respectively. Upon completion (50−60 min) as monitored by
TLC, the reaction mixture was filtered to give the crude product,
which was further washed by 95% ethanol to give pure product 5a−d.
Methyl-8c-amino-8b-cyano-2-methyl-8-oxo-3-propyl-
3H,8H-8d-oxa-3-azapentaleno[3a,6a-a]indene-1-carboxylate
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, copies of H and 13C NMR spectra of
1
products, crystallographic data, and ORTEP/X-ray structure for
3a and 5c. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: aalizadeh@rmodares.ac.ir.
■
1
(5a). White crystals: 0.33 g, 93% yield; mp 177−179 °C; H NMR
(500 MHz, DMSO) δ 0.92 (br, 3H), 1.52 (br, 1H), 1.72 (br, 1H), 2.23
(s, 3H), 3.29 (s, 3H), 3.55 (br, 1H), 3.69 (br,1H) 7.65 (s, 2H), 7.81−
8.48 (m, 4H); 13C NMR (125 MHz, DMSO) δ 11.6, 13.4, 22.8, 43.9,
50.5, 58.0, 65.0, 96.5, 113.0, 113.4, 124.1, 125.1, 131.3, 134.7, 136.7,
149.1, 159.0, 160.9, 164.8, 195.1; IR (KBr) ν 3310, 3228, 2136, 1722,
1624, 1541, 1440, 1369 cm−1; MS m/z 365 (M+), 350, 322, 290, 247,
208, 180, 152, 126, 96, 76. Anal. Calcd for C20H19N3O4: C, 65.74; H,
5.24; N, 11.50. Found: C, 65.70; H, 5.21; N, 11.56.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support of this research from Tarbiat Modares
University, Iran is gratefully acknowledged.
■
Ethyl-8c-amino-8b-cyano-2-methyl-8-oxo-3-propyl-3H,8H-
8d-oxa-3-azapentaleno[3a,6a-a]indene-1-carboxylate (5b).
1
White crystals: 0.34 g, 90% yield; mp 190−192 °C; H NMR (400
REFERENCES
■
MHz, DMSO) δ 0.89 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 6.8 Hz, 3H),
1.41−1.50 (m, 1H), 1.60−1.68 (m, 1H), 2.27 (s, 3H), 3.47 (t, J = 8.0
Hz, 2H), 4.04−4.18 (m, 2H), 7.35 (s, 2H), 7.73 (t, J = 7.2 Hz, 1H),
7.87 (d, J = 7.2 Hz, 1H), 7.92 (t, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz,
1H); 13C NMR (100 MHz, DMSO) δ 10.9, 11.9, 14.4, 23.2, 43.7, 54.5,
58.2, 67.9, 98.0, 108.9, 118.0, 124.9, 125.0, 131.3, 136.0, 136.3, 143.6,
159.6, 164.8, 167.3, 195.0; IR (KBr) ν 3409, 3335, 2188, 1717, 1642,
1594, 1430, 1325 cm−1; MS m/z 379 (M+), 304, 248, 194, 125, 111,
97, 83, 69, 57. Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.05; N,
11.08. Found: C, 66.39; H, 5.5.10; N, 11.12.
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8d-oxa-3-azapentaleno[3a,6a-a]indene-1-carboxylate (5c).
1
White crystals: 0.33 g, 88% yield; mp 180 °C; H NMR (500 MHz,
DMSO) δ 0.89 (t, J = 7.0 Hz, 3H), 1.29−1.43 (m, 3H), 1.57−1.62 (m,
1H), 2.25 (s, 3H), 3.34 (s, 3H), 3.48 (t, J = 7.0 Hz 1H), 3.61 (br, 1H),
7.32 (s, 2H), 7.72 (t, J = 7.3 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.91 (t,
J = 7.3 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H); 13C NMR (125 MHz,
DMSO) δ 11.9, 13.6, 19.4, 31.9, 41.4, 49.4, 54.5, 68.0, 97.7, 108.9,
117.8, 124.9, 125.0, 131.3, 136.0, 136.2, 143.6, 159.7, 165.2, 167.2,
195.1; IR (KBr) ν 3409, 3328, 2187, 1717, 1642, 1590, 1429, 1332
cm−1; MS m/z 379 (M+), 351, 337, 256, 211, 149, 125, 111, 97, 84, 71,
57. Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.05; N, 11.08. Found:
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864461): MW = 377.39, triclinic, space group P1, a = 9.6045(5) Å, b =
̅
17.1080(7) Å, c = 11.7885(5) Å, α = 90.00, β = 97.614(4), γ = 90.00,
V = 1919.93(15) Å3, Z = 4, Dc = 1.306 mg/m3, F(000) = 792, crystal
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−20≤ k ≤ 19, −11≤ l ≤ 14; the structure was solved by a direct
method, all non-hydrogen atoms were positioned and anisotropic
thermal parameters refined from 2485 observed reflections with
R(into) = 0.1026 by a full-matrix least-squares technique converged to
R = 0.0784 and Raw = 0.2240 [I > 2σ(I)].
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1
White crystals: 0.35 g, 90% yield; mp 194−196 °C; H NMR (500
MHz, DMSO) δ 0.91 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 6.8 Hz, 3H),
1.32−1.39 (m, 1H), 1.39−1.45 (m, 2H), 1.58−1.65 (m, 1H), 2.27 (s,
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J = 7.2 Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz,
DMSO) δ 11.9, 13.6, 14.37, 19.40, 31.9, 41.9, 56.0, 67.9, 98.0, 109.0,
118.0, 124.9, 125.0, 131.3, 136.0, 136.3, 143.6, 159.6, 164.8, 167.2,
195.0; IR (KBr) ν 3382, 3317, 2189, 1724, 1638, 1594, 1424, 1324
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