One-pot, three-component synthesis of 7-azaindole derivatives from N-substituted 2-amino-4-cyanopyrroles, various aldehydes, and active methylene compounds

Article abstract of DOI:10.1021/co300042v

An efficient and practical route to 7-azaindole framework has been developed by one-pot, three-component cyclocondensation of N-substituted 2-amino-4-cyanopyrroles, various aldehydes, and active methylene compounds in ethanol or acetic acid at reflux. Rea

Full text of DOI:10.1021/co300042v

Research Article
pubs.acs.org/acscombsci
One-Pot, Three-Component Synthesis of 7-Azaindole Derivatives
from N-Substituted 2-Amino-4-cyanopyrroles, Various Aldehydes,
and Active Methylene Compounds
Marcelo Vilches-Herrera,† Ingo Knepper,† Nayane de Souza,† Alexander Villinger,†
Vyacheslav Ya. Sosnovskikh,‡ and Viktor O. Iaroshenko*,†,§
†Institut fur Chemie, Universitat Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
̈
̈
‡Department of Chemistry, Ural Federal University, 51 Lenina Ave., 620083 Ekaterinburg, Russia
§National Taras Shevchenko University, 62 Volodymyrska Str., 01033 Kyiv, Ukraine
S
* Supporting Information
ABSTRACT: An efficient and practical route to 7-azaindole
framework has been developed by one-pot, three-component
cyclocondensation of N-substituted 2-amino-4-cyanopyrroles,
various aldehydes, and active methylene compounds in ethanol
or acetic acid at reflux. Reactions involving tetronic acid,
indane-1,3-dione, dimedone, and 5-phenylcyclohexane-1,3-
dione gave carbocyclic fused 7-azaindoles, whereas Meldrum’s
acid, benzoylacetonitrile, and malononitrile resulted in the
highly substituted 7-azaindole derivatives, making this strategy
very useful in diversity-oriented synthesis (DOS).
KEYWORDS: multicomponent reaction, heterocyclisation, 7-azaindoles, 2-aminopyrroles, aromatic aldehydes,
active methylene compounds
derivatives were identified as inhibitors of Cdc7 kinase,4 Met
INTRODUCTION
■
kinase,5 AKT kinase,6 and B-Raf kinase.7
Multicomponent reactions (MCRs) have been used extensively
to form carbon−carbon bonds in synthetic chemistry.1 They
provide a powerful tool toward the one-pot synthesis of diverse
and complex compounds, as well as small and druglike
heterocycles. Such reactions offer a wide range of possibilities
for the efficient construction of complex molecules in a single
procedural step and are perfectly amenable to automation for
combinatorial synthesis. Because of their convergence and
productivity, the MCRs have attracted considerable attention
from the point of view of combinatorial and medicinal
chemistry and are particularly useful for the preparation of
polycondensed heterocyclic systems. The synthesis of hetero-
cyclic compounds is a central issue in MCRs research, since
heterocycles make up the majority of pharmaceuticals, natural
products, and drug-like molecules.
The indole moiety is probably the most well-known
heterocycle and is a common and important feature of a
variety of natural products and medicinal agents.2 Azaindoles
have attracted considerable synthetic interest primarily as
bioisosteres of the indole nucleus with interesting biological,
pharmaceutical, and material properties. Although naturally
occurring azaindoles are relatively scarce compared to indoles, a
series of such compounds, particularly 7-azaindoles (1H-
pyrrolo[2,3-b]pyridines) are very attractive targets for combi-
natorial library synthesis because of their wide range of valuable
biological activities.3 Recently, some 1H-pyrrolo[2,3-b]pyridine
Given the broad utility of 7-azaindoles in medicinal
chemistry, we were interested in developing a simple
multicomponent reaction approach, commencing with 2-
aminopyrrole-based substrates, which would allow access to
these interesting heterocyclic compounds. In this paper we
detail the successful realization of this goal with an efficient
synthesis of 5,6-carbocyclic fused and highly substituted 7-
azaindole derivatives by a one-pot, three-component reaction.
RESULTS AND DISCUSSION
■
On the basis of the retrosynthetic analysis and on previous
experience of the Iaroshenko’s laboratory related to the
development of new cyclocondensation reactions of electron-
rich aminoheterocycles,8 we envisioned that 2-aminopyrroles 3
are suitable substrates for the synthesis of 7-azaindole
derivatives. It is known that unsubstituted 1H-pyrrol-2-amine
is hard to access and it is not stable.9 For our current study the
stable and easily accessible 1-substituted 5-aminopyrrole-3-
carbonitriles 3 were used.10 The N-protective group and the
electron-withdrawing cyano functional group maintain the
stability of these heterocycles. Previously, methods giving rise
Received: April 10, 2012
Revised: May 20, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
to pyrrolo[2,3-b]pyridines via annulation of the pyridine ring to
an aminopyrrole moiety by condensation with 1,3-dicarbonylic
compounds have been reported.10,11 However, so far 2-
aminopyrroles have not been used in multicomponent synthesis
for the construction of more complex heterocyclic compounds
despite their potential interest as building blocks in organic
synthesis. On the other hand, various heterocyclic amines such
as 5-aminopyrazoles,12 6-aminopyrimidin-4-one,13 5-amino-3-
methylisoxazole,14 and 6-amino-1,3-dimethyluracil,15 are widely
used as valuable synthetic intermediates in the multicomponent
synthesis of pharmacologically relevant products and new
heterocyclic systems.
We are reporting now on the formation of 7-azaindole
derivatives from active methylene compounds (tetronic acid 1a,
indane-1,3-dione 1b, dimedone 1c, 5-phenylcyclohexane-1,3-
dione 1d, Meldrum’s acid 1e, benzoylacetonitrile 1f, malononi-
trile 1g), different aldehydes (aromatic aldehydes 2a−q,
heterocyclic aldehydes 2r,s, aliphatic aldehydes 2t−v) (Figure
1) and N-substituted 2-amino-4-cyanopyrroles (Figure 2).
Figure 2. Diversity of 2-aminopyrroles 3.
Scheme 1. Reactions of Tetronic Acid 1a with 2 and 3
a
b
c
Without L-proline. From 4. From 1a.
catalyst and EtOH as the solvent. It was found that treatment of
tetronic acid 1a with various aromatic aldehydes 2 and pyrroles
3a, b, and d in refluxing ethanol without catalyst resulted in the
formation of furo[3,4-b]pyrrolo[3,2-e]pyridines 4 with excellent
regioselectivity and in moderate to high yields (35−80%).
Performing the reaction in the presence of L-proline led to only
slightly higher yields (43−82%). In most cases, the reaction was
complete after 3−4 h and the products could be isolated by
simple filtration of the precipitate formed or by column
chromatography over silica gel. The progress of the reaction
was monitored by TLC, and the results are summarized in
Scheme 1. It is important that a wide range of aldehydes 2 can
effectively participate in the reaction with 1a and 3, providing a
variety of dihydropyridines 4 with high purity. It can be
observed that the process tolerates both electron-donating
(hydroxy, methoxy, ethyl) and electron-withdrawing (fluoro,
chloro) substituents on the aromatic aldehydes. The structures
Figure 1. Diversity of active methylene compounds 1 and aldehydes 2.
Thus, seven commercially available active methylene com-
pounds 1a−g, twenty two aldehydes 2a−v, and four easily
accessible substituted aminopyrroles 3a−d were chosen for the
library validation.
In the initial study, we have developed the synthesis of the
hitherto unknown heterocyclic system 4 starting from tetronic
acid 1a by a one-pot, three-component reaction depicted in
Scheme 1. Different bases and solvents were first briefly
examined and the best result was obtained by using L-proline as
1
of all products 4 were characterized by IR, H, 13C NMR
spectral data as well as HRMS analysis. The regiochemistry of
4ma was unambiguously confirmed by X-ray single crystal
analysis (Figure 3, see the Supporting Information).
B
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
It should be noted that under these reaction conditions, the
major products are the fused dihydropyridines 4, and only in
the case of 5-methylfurfural 2r and octanal 2u the final products
were carbocyclic fused 7-azaindoles 5ra and 5ua, indicating that
air oxidation of the dihydropyridine ring had occurred. The
oxidation of compounds 4 by 4,5-dichloro-3,6-dioxocyclohexa-
1,4-diene-1,2-dicarbonitrile (DDQ, 1.2 equiv) in acetonitrile at
room temperature for 4 h afforded the corresponding 7-
azaindoles 5 in good to excellent yields (Scheme 1). Taking
into account that the tert-butyl and cyano groups could easily
be removed from the pyrrolopyridine derivative,11b,16 this is
also a method for preparing diverse 7-azaindoles with an
unsubstituted pyrrole ring. To the best of our knowledge, this
new multicomponent reaction provides the first example of a
catalyst-free synthesis of compounds 4 and 5, which can be
regarded as heterocyclic analogues of 1-arylnaphthalene lignans
and podophyllotoxin.17
Scheme 2. Reactions of Indane-1,3-dione 1b with 2 and 3
To expand the scope of the present reaction, indane-1,3-
dione 1b was examined to replace tetronic acid 1a. This is
particularly attractive because compounds with the indenopyr-
idine framework (4-azafluorenones) exhibit a wide range of
biologically activities, for example, cytotoxic18 and antidepres-
sant activities.19 These compounds have also been investigated
for the treatment of hyperlipoproteinemia and arteriosclerosis20
as well as neurodegenerative diseases.21
Scheme 3. Reactions of Dimedone 1c with 2 and 3
We found that the reaction of 1b with benzaldehydes 2a−e
and o and pyrroles 3a, b, and d under the same condition
(ethanol, reflux, 3 h) afforded only 5-oxo-4-aryl-1,5-
dihydroindeno[1,2-b]pyrrolo[3,2-e]pyridine-3-carbonitriles 6
in variable 44−80% yields. Heteroaromatic and aliphatic
aldehydes, such as 5-methylfurfural 2r, thiophene-2-carbalde-
hyde 2s, acetaldehyde 2t, and decanal 2v, are also reactive in
this three-component annulation, producing compounds 6ra,
6sa, 6ta, and 6va in 43%, 37%, 27%, and 80% yields,
respectively. In the all cases, the initially formed dihydropyr-
idine 6′ is oxidized by air to afford aromatized 7-azaindoles 6.
This result and the absence of the nonaromatized products
seem to indicate that the indenone fragment activates the
intermediate toward formation of the aromatic pyridine ring
(Scheme 2).
Our literature survey at this stage revealed that, there is no
report yet available on the synthesis of furo[3,4-b]pyrrolo[3,2-
e]pyridines 5 and indeno[1,2-b]pyrrolo[3,2-e]pyridines 6 in
one-pot via three-component coupling of 2-aminopyrroles,
aldehydes, tetronic acid, and indane-1,3-dione. It should be also
noted that the catalyst-free reactions carried out in ethanol are
considerably safer, nontoxic, environmentally friendly, and
inexpensive.
Next we examined the cycloaddition behavior of dimedone
1c using various reaction conditions. After some optimization,
it was found that generally good yields of compounds 7 are
obtained when mixtures of the three starting components are
refluxed in ethanol with L-proline (10 mol %) or acetic acid (for
2f, i, and o) for 6 h. A variety of aromatic aldehydes with
electron-donating or electron-withdrawing groups were em-
ployed as the reaction substrates; in general, the presence of
substituents on aromatic aldehydes appeared to have only a
slight influence on the reactivity in most cases. As expected,
treatment of dihydropyridine 7 with DDQ in acetonitrile at
room temperature provides the aromatized carbofused 7-
azaindoles 8 in high yield (Scheme 3). The structures of 8fa
and 8ha are confirmed by X-ray diffraction analysis (Figures 4
and 5, see the Supporting Information).
a
b
Using ethanol with L-proline as catalyst (10 mol%). Using acetic
acid.
Furthermore, when dimedone 1c was replaced by 5-
phenylcyclohexane-1,3-dione 1d, target products, 1-substituted
4-aryl-5-oxo-7-phenyl-4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]-
quinoline-3-carbonitriles 9, were obtained in good yields (45−
81%) in refluxing ethanol in the absence of any catalyst for 6 h.
Aromatization of these compounds with DDQ in acetonitrile
gave 7-azaindoles 10 in 43−97% yields, the structures of which
agree well with the data of elemental analysis, IR, H, and 13C
1
NMR spectroscopy and mass spectrometry (Scheme 4).
Next, taking into account the above results and that the
pyrrole ring is important structural fragment of many natural
and biologically active substances,2a it was of interest to
C
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
can be applied not only to aromatic aldehydes with either
electron-donating groups or electron-withdrawing groups, but
also to aliphatic aldehydes. In this case, unlike indane-1,3-dione
1b, the yield of 11ta from acetaldehyde 2t was 78%. The exact
structure of 11 was established by 1H and 13C NMR spectra, in
which we have observed the appearance of the CH2CH
fragment in the partially hydrogenated pyridine ring (ABX-
system at δ 2.4−4.9 ppm with JAB = 15.7−16.2 Hz, JAX = 7.0−
8.1 Hz, JBX = 2.9−5.4 Hz). Furthermore, the structures of 11aa,
11ga, and 11ma were established by X-ray crystallographic
analysis (Figures 6, 7, and 8, see the Supporting Information).
Interestingly, although the chemistry of the pyrrole system has
been well documented,2a we have found that these simple
compounds are hitherto unreported.
Scheme 4. Reactions of 5-Phenylcyclohexane-1,3-dione 1d
with 2 and 3
Thus, the reaction of cyclic-1,3-dicarbonyls and aldehydes
with 2-aminopyrroles 3 makes the latter compounds very useful
for a combinatorial approach to the synthesis of various 7-
azaindole derivatives with potential biological activity. Given
the actual interest in these compounds as pharmaceutical
intermediates,3−7 this simple entry to novel 1H-pyrrolo[2,3-
b]pyridines is useful and will complement the published
synthetic methods.3 It is notable that when the reaction of
aldehydes 2a and g and aminopyrrole 3a was carried out with
acyclic-1,3-dicarbonylic compounds, such as acetylacetone,
methyl acetoacetate, ethyl benzoylacetate, N-phenyl acetoace-
tamide, and (2-thenoyl)trifluoroacetone in various conditions
(EtOH, EtOH/base, AcOH, DMF, DMF/TMSCl, CH2Cl2) at
evaluate the behavior of 2-aminopyrroles 3 in their reactions
with Meldrum’s acid 1e and aldehydes 2. In this context, two
papers are of interest when Meldrum’s acid and aromatic
aldehydes are reacted with 5-amino-3-methylisoxazole14 and 5-
amino-3-methylpyrazole22 to obtain the corresponding fused
dihydropyridinones. We anticipated that aminopyrroles 3 might
undergo a similar cycloaddition with 1e and 2 to give 2,3-
heteroannulated pyrroles 11. In fact, it was found that
treatment of 1e with aromatic aldehydes 2 and pyrroles 3a−c
in ethanol at reflux for 5 h resulted in the formation of 6-oxo-
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridine-3-carbonitriles 11
in variable 40−90% yields. As shown in Scheme 5, this protocol
1
room temperature or reflux, TLC and H NMR spectra of the
reaction mixture showed a complex mixture of products, which
was not investigated in detail.
Compounds 4−11 are likely formed via initial condensation
of aldehydes 2 with cyclic-1,3-diones 1a−e to afford the
Knoevenagel product A,14 which then undergoes in situ
Michael addition with 2-aminopyrroles 3 to yield the
intermediate B. Because of the ambident character of
heterocyclic amine, a nucleophilic attack of carbon or nitrogen
on intermediate A would lead to linear or angular products.
The first step of the reaction leading to heterocyclization
apparently involves an attack of the internal enamine β-carbon
(in general, this atom is more nucleophilic than the primary
amino group) at the CC bond of the initial Knoevenagel
product A; the alternative addition including the nitrogen atom
to give angular product was not observed at all. In the case of
1a−d, intramolecular attack of the amino group at the carbonyl
group (intermediate B) with concomitant elimination of water
molecule leads to the linear fused dihydropyridine derivatives 4,
7, and 9. When the 1,3-dicarbonyl compound is Meldrum’s
acid, the intermediate product B subsequently underwent
intramolecular cyclization and then released acetone and
carbon dioxide to give pyrroles 11 (Scheme 6).
Scheme 5. Reactions of Meldrum’s Acid 1e with 2 and 3
Further experiments were conducted to expand the utility of
the reaction and substrate scope with a series of cyano
derivatives, such as benzoylacetonitrile, malononitrile, and ethyl
cyanoacetate. The results observed for the first two compounds
were no exception from the general rule, however, ethyl
cyanoacetate did not work under various conditions. As can be
seen from Scheme 7, benzoylacetonitrile 1f underwent pyridine
ring annulation with aromatic aldehydes 2 and aminopyrroles
3a, b, and d, leading to the formation of highly substituted 7-
azaindoles 12 in moderate to good yields (37−66%) in boiling
acetic acid in the presence of ammonium acetate as catalyst for
6 h. In all cases, conjugated addition at the intermediate
D
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Scheme 6. Possible Mechanism for the Formation of
Scheme 8. Reactions of Malononitrile 1g with 2 and 3
Products 4−11
Scheme 7. Reactions of Benzoylacetonitrile 1f with 2 and 3
compounds were prepared using this synthesis route. Given the
easy access to substituted 2-aminopyrroles and the large
number of commercially available aldehydes and cyclic-1,3-
diones, the present method should be applicable to synthesis of
libraries with high diversity. This 2-aminopyrrole-based
approach may be of value for constructing highly functionalized
biologically and medicinally important products. The biological
evaluation of the synthesized compounds is under study in our
laboratories.
EXPERIMENTAL PROCEDURES
■
1. General Procedure for the Synthesis of Com-
pounds 4 and 6. A mixture of tetronic acid 1a or 1,3-
indanedione 1b (1 equiv), the corresponding aldehyde 2 (1
equiv), and 5-amino-1-R-pyrrole-3-carbonitrile 3 (1 equiv.) was
refluxed in ethanol for 3 h. The precipitate was collected and, if
necessary, purified by column chromatography (eluent, n-
heptane/ethylacetate).
1-tert-Butyl-5-oxo-4-phenyl-4,5,7,8-tetrahydro-1H-furo-
[3,4-b]pyrrolo[3,2-e]pyridine-3-carbonitrile (4aa). The prod-
uct was isolated as a gray solid, yield 43%, mp 238−239 °C. 1H
NMR (250 MHz, DMSO-d6): δ 1.57 (s, 9H, t-Bu), 4.82−4.94
(m, 3H, CH, CH2), 7.17−7.19 (m, 3H, Ar), 7.24−7.29 (m, 2H,
Ph), 7.36 (s, 1H, H-2), 9.70 (s, 1H, NH). 13C NMR (63 MHz,
DMSO-d6): δ 29.1 C(CH3)3), 36.5 (CH), 57.3 (C(CH3)3),
65.7 (CH2), 88.1 (C), 97.2 (C), 105.9 (C), 116.0 (C), 123.6
(CH), 126.5 (CH), 128.0 (CH), 128.2 (CH), 128.7 (C), 145.0
(C), 157.6 (C), 171.9 (CO). IR (ATR, cm−1): 3305 (w),
3235 (w), 3153 (w), 3029 (w), 2981 (w), 2943 (w), 2858 (w),
2217 (m), 1711 (m), 1644 (w), 1629 (s), 1536 (s), 1514 (s),
1495 (w), 1433 (w), 1405 (w), 1378 (w), 1355 (w), 1325 (w),
1272 (w), 1222 (w), 1209 (w), 1181 (m), 1078 (w), 1027 (s),
835 (w), 823 (w), 813 (w), 798 (w), 758 (w), 747 (m), 732
(m), 702 (m), 687 (w), 646 (w). MS (EI, 70 eV): m/z (%) 331
(M+, aromatized, 35), 275 (100), 246 (59), 217 (7), 191 (8),
164 (7), 57 (4), 41 (4). MS (EI, 70 eV): m/z (%) 333 (M+, not
aromatized, 36), 318 (100), 277 (60), 259 (25), 233 (26), 221
(9), 204 (9), 193 (6), 164 (6), 140 (4), 57 (8), 41 (7). HRMS
(ESI): calcd for C20H18N3O2 ([M + H]+, aromatized)
332.13935, found 332.13872.
Knoevenagel product takes place with subsequent annulation
and dehydrogenation of the pyridine core.
The reaction of malononitrile 1g with aromatic aldehydes 2
and aminopyrroles 3a,b, and d under the same conditions gave
the expected aromatized 7-azaindoles 13 in 40−63% yields
(Scheme 8). The formation of the other regioisomer was not
observed in these examples as well. Previously, heteroanalogues
of compounds 13 were obtained by the reaction of 5-amino-3-
methyl-1-phenylpyrazole with benzylidene derivatives of
malononitrile.23 The structures of all the compounds were
1
deduced from their satisfactory elemental and spectral (IR, H,
13C NMR, and MS) studies; their mass spectra displayed
molecular ion peaks at the appropriate m/z values.
CONCLUSION
■
In conclusion, we have developed a rapid route to the synthesis
of a wide range of 7-azaindole derivatives by the three-
component reaction of active methylene compounds, various
aldehydes, and 2-aminopyrroles. In this study a total of 81
E
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
1-tert-Butyl-5-oxo-4-phenyl-1,5-dihydroindeno[1,2-b]-
pyrrolo[3,2-e]pyridine-3-carbonitrile (6aa). The product was
isolated as a yellow solid, yield 67%, mp 262−264 °C. 1H NMR
(250 MHz, CDCl3): δ 1.83 (s, 9H, t-Bu), 7.29−7.34 (m, 1H,
Ar), 7.42−7.56 (m, 7H, Ar), 7.72 (s, 1H, H-2), 7.81 (d, J = 8.0
Hz, 1H, Ar). 13C NMR (63 MHz, CDCl3): δ 29.2 (C(CH3)3),
59.4 (C(CH3)3), 86.3 (C), 114.6 (C), 119.6 (C), 119.9 (C),
120.5 (CH), 123.6 (CH), 127.9 (CH), 129.4 (CH), 129.6
(CH), 130.8 (CH), 131.6 (C), 134.7 (CH), 134.8 (CH), 136.5
(C), 143.1 (C), 143.6 (C), 149.4 (C), 160.7 (C), 190.6 (C
O). IR (ATR, cm−1): 3145 (w), 3062 (w), 3030 (w), 3016 (w),
2981 (w), 2965 (w), 2216 (m), 1709 (m), 1604 (w), 1584 (w),
1561 (m), 1520 (w), 1501 (w), 1467 (w), 1448 (w), 1384 (w),
1368 (w), 1347 (w), 1336 (w), 1295 (m), 1260 (w), 1240 (w),
1204 (m), 1178 (w), 1115 (m), 1086 (w), 1078 (w), 948 (w),
866 (w), 766 (m), 749 (m), 726 (s), 715 (s), 698 (s), 656 (m),
621 (s). MS (EI, 70 eV): m/z (%) 377 (M+, 33), 321 (100),
293 (4), 265 (9), 238 (6), 212 (2), 57 (3), 41 (3). Anal. Calcd
for C25H19N3O (377.44): C, 79.55; H, 5.07; N, 11.13. Found:
C, 79.31; H, 5.04; N, 11.03.
1-tert-Butyl-4-(4-hydroxyphenyl)-5-oxo-7-phenyl-5,6,7,8-
tetrahydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile (10da).
The product was isolated as a white solid, yield 56%, mp 328−
330 °C. 1H NMR (300 MHz, DMSO-d6): δ 1.85 (s, 9H, t-Bu),
2.81 (br s, 1H, CHH), 3.00−3.09 (m, 1H, CHH), 3.50−3.65
(m, 3H, CH, CH2), 6.86 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.3
Hz, 2H), 7.27−7.53 (m, 5H, Ph), 8.55 (s, 1H, H-2), 9.53 (s,
1H, OH). 13C NMR (62.9 MHz, DMSO-d6): δ 28.5 (3C), 38.5,
41.4, 46.9, 58.8, 83.7, 114.3, 114.4, 119.6, 120.5, 126.6, 126.8,
127.0, 128.5, 129.4, 138.3, 143.4, 145.3, 146.7, 156.9, 158.2,
196.3. MS (GC, 70 eV): m/z (%) 435 (M+, 61), 379 (100), 275
(79). HR (EI): calcd for C28H25N3O2 (M) 435.19413, found
435.19443. IR (ATR, cm−1): 3252 (w), 2965 (w), 2218 (s),
1667 (s), 1574 (m), 1511 (m), 1453 (m), 1399 (m), 1266 (m),
1198 (s), 818 (m), 698 (s), 569 (m).
3. General Procedure for the Synthesis of Com-
pounds 7. A mixture of dimedone 1c (1 equiv), the
corresponding aldehyde 2 (1 equiv), and 5-amino-1-R-
pyrrole-3-carbonitrile 3 (1 equiv) was refluxed in ethanol
with L-proline as catalyst or in acetic acid for 6 h. The
precipitate was collected and, if necessary, purified by column
chromatography (eluent, n-heptane/ethylacetate).
2. General Procedure for the Synthesis of Com-
pounds 5, 8, and 10. A mixture of the corresponding
dihydropyridine (1 equiv.) and 4,5-dichloro-3,6-dioxocyclo-
hexa-1,4-diene-1,2-dicarbonitrile (DDQ) (1.2 equiv.) was
stirred in acetonitrile (10 mL) at room temperature for 4 h.
The crude product was purified by column chromatography
(eluent, n-heptane/ethylacetate).
1-tert-Butyl-4-(4-hydroxyphenyl)-7,7-dimethyl-5-oxo-
4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-3-carboni-
trile (7da). The product was isolated as a white solid, yield 69%,
1
mp 247−248 °C. H NMR (300 MHz, DMSO-d6): δ 0.94 (s,
3H, Me), 1.04 (s, 3H, Me), 1.58 (s, 9H, t-Bu), 1.98 (d, J = 16.1
Hz, 1H), 2.18 (d, J = 16.1 Hz, 1H), 2.56 (d, J = 17.0 Hz, 1H),
2.69 (d, J = 17.0 Hz, 1H), 4.92 (s, 1H, H-4), 6.59 (d, J = 8.5
Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 7.29 (s, 1H, H-2), 8.56 (s,
1H, NH), 9.06 (s, 1H, OH). 13C NMR (62.9 MHz, DMSO-d6):
δ 26.4, 29.1 (3C), 29.3, 31.8, 35.2, 50.3, 56.9, 87.1, 107.9, 108.3,
114.5, 116.2, 122.4, 127.2, 127.9, 138.3, 150.4, 155.2, 193.9. MS
(GC, 70 eV): m/z (%) 387 (M+, 45), 331 (100) 275 (38).
HRMS (ESI): calcd for C24H28N3O2 (M + 1) 390.2176, found
390.21842. IR (ATR, cm−1): 3341 (w), 3164 (w), 2956 (w),
2217 (w), 1608 (m), 1524 (s), 1494 (s), 1422 (m), 1343 (m),
1268 (m), 1248 (m), 1226 (m), 1191 (s), 1168 (m), 1153 (m),
766 (m), 596 (m), 546 (m). Anal. Calcd for C24H27N3O2: C,
74.01; H, 6.99; N, 10.79. Found: C, 73.80; H, 7.16; N, 10.79.
4. General Procedure for the Synthesis of Com-
pounds 9 and 11. A mixture of 5-phenyl-1,3-cyclo-
hexanedione 1d or Meldrum’s acid 1e (1 equiv), the
corresponding aldehyde 2 (1 equiv) and 5-amino-1-R-pyrrole-
3-carbonitrile 3 (1 equiv) was refluxed in ethanol for 5−6 h.
The precipitate was collected and, if necessary, purified by
column chromatography (eluent, n-heptane/ethylacetate).
1-tert-Butyl-4-(4-hydroxyphenyl)-5-oxo-7-phenyl-
4,5,6,7,8,9-hexahydro-1H-pyrrolo[2,3-b]quinoline-3-carboni-
trile (9da). The product was isolated as a white solid, yield 81%,
1-tert-Butyl-5-oxo-4-phenyl-5,7-dihydro-1H-furo[3,4-b]-
pyrrolo[3,2-e]pyridine-3-carbonitrile (5aa). The product was
isolated (column chromatography, n-heptane/ethylacetate, 1:1)
1
as a white solid, yield 80%, mp 244−246 °C. H NMR (300
MHz, DMSO-d6): δ 1.84 (s, 9H, t-Bu), 5.48 (s, 2H, CH2),
7.52−7.57 (m, 5H, Ph), 8.73 (s, 1H, H-2); 13C NMR (63 MHz,
DMSO-d6): δ 28.4 (C(CH3)3), 59.4 (C(CH3)3), 68.9 (CH2),
83.6 (C), 110.2 (C), 114.3 (C), 119.2 (C), 127.5 (CH), 129.3
(CH), 129.7 (CH), 130.7 (C), 139.7 (CH), 143.4 (C), 149.5
(C), 162.1 (C), 168.0 (CO); IR (ATR, cm−1): 3130 (w),
3055 (w), 2984 (w), 2939 (w), 2222 (m), 1758 (s), 1587 (m),
1570 (m), 1525 (w), 1506 (w), 1481 (w), 1471 (w), 1394 (m),
1372 (m), 1350 (m), 1324 (w), 1295 (m), 1256 (w), 1209 (s),
1184 (m), 1146 (m), 1103 (w), 1077 (w), 1050 (m), 1022
(m), 990 (w), 929 (w), 871 (m), 851 (m), 806 (w), 799 (w),
758 (s), 745 (w), 708 (s), 660 (s), 624 (m), 605 (w); MS (EI,
70 eV): m/z (%) 331 (M+, 33), 275 (100), 246 (64), 217 (9),
191 (10), 164 (11), 57 (9), 41 (8). Anal. Calcd for C20H17N3O2
(331.37): C, 72.49; H, 5.17; N, 12.68. Found: C, 72.30; H,
5.48; N, 12.69.
1-tert-Butyl-4-(4-hydroxyphenyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile
(8da). The product was isolated as a white solid, yield 86%, mp
1
1
285 °C. H NMR (300 MHz, CDCl3): δ 1.07 (s, 6H, 2Me),
mp 241−242 °C. H NMR (300 MHz, DMSO-d6): δ 1.55 (s,
1.77 (s, 9H, t-Bu), 2.46 (s, 2H, CH2), 3.11 (s, 2H, CH2), 5.93
(br s, 1H, OH), 6.82 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz,
2H), 7.76 (s, 1H, H-2). 13C NMR (62.9 MHz, CDCl3): δ 27.3
(2C), 28.1 (3C), 31.5, 47.3, 53.2, 57.9, 84.1, 114.1, 119.4,
119.4, 127.2, 128.3, 134.5, 139.1, 145.0, 146.7, 155.3, 157.5,
197.4. MS (GC, 70 eV): m/z (%) 387 (M+, 42), 331 (100), 274
(39). HR (EI): calcd for C24H25N3O2 (M) 387.19413, found
387.19392. IR (ATR, cm−1): 3266 (w), 2955 (w), 2221 (s),
1663 (s), 1565 (m), 1518 (m), 1463 (m), 1393 (m), 1305 (m),
1233 (m), 1225 (m), 1168 (m), 1119 (m), 830 (m), 811 (m),
794 (m), 633 (m), 565 (m).
9H, t-Bu), 2.52−2.65 (m, 2H, CH2), 2.93−3.14 (m, 2H, CH2),
3.36−3.51 (m, 1H, CH), 4.94 (s, 1H, H-4), 6.53 (d, J = 8.0 Hz,
2H), 6.85 (d, J = 8.2 Hz, 2H), 7.16−7.37 (m, 6H, Ph, H-2),
8.61 (s, 1H, NH), 9.02 (s, 1H, OH). 13C NMR (62.9 MHz,
DMSO-d6): δ 29.2 (3C), 34.2, 35.4, 38.4, 43.6, 56.9, 87.1,
108.1, 108.6, 114.4, 116.3, 122.5, 126.4, 126.9, 127.0, 128.1,
128.3, 138.0, 143.6, 151.2, 155.1, 193.2. MS (GC, 70 eV): m/z
(%) 435 (M+, 79), 379 (100), 275 (88). HRMS (ESI): calcd for
C28H26N3O2 (M + 1) 436.20195, found 436.20257. IR (ATR,
cm−1): 3312 (w), 2220 (m), 1603 (m), 1572 (m), 1522 (s),
1495 (s), 1421 (m), 1392 (m), 1374 (w), 1342 (m), 1210 (s),
F
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
1192 (m), 1177 (m), 1157 (m), 981 (m), 883 (m), 855 (m),
819 (m), 758 (m), 698 (m), 548 (m).
ACKNOWLEDGMENTS
■
Financial support by the BMBF “REMEDIS”-project “Hohere
̈
1-tert-Butyl-6-oxo-4-phenyl-4,5,6,7-tetrahydro-1H-
pyrrolo[2,3-b]pyridine-3-carbonitrile (11aa). The product was
isolated as a white solid, yield 82%, mp 230−231 °C. 1H NMR
(300 MHz, CDCl3): δ 1.53 (s, 9H, t-Bu), 2.80 (dd, J = 16.0, 5.1
Hz, 1H, H-5″), 2.96 (dd, J = 16.0, 7.2 Hz, 1H, H-5′), 4.18 (dd, J
= 7.2, 5.1 Hz, 1H, H-4), 6.91 (s, 1H, H-2), 7.12−7.27 (m, 5H,
Ph), 8.44 (br s, 1H, NH). 13C NMR (62.9 MHz, CDCl3): δ
29.7 (3C), 35.7, 39.6, 57.3, 89.1, 108.2, 115.6, 121.4, 127.0,
127.2, 128.6, 128.9, 141.8, 170.7. MS (GC, 70 eV): m/z (%)
293 (M+, 77), 237 (100), 194 (87). HRMS (ESI): calcd for
C18H20N3O (M + 1) 294.16009, found 294.15997; IR (ATR,
cm−1): 3150 (w), 2217 (m), 1668 (s), 1524 (m), 1492 (m),
1358 (m), 1190 (s), 1031 (w), 983 (w), 767 (s), 685 (s), 631
(s), 561 (s).
5. General Procedure for the Synthesis of Com-
pounds 12 and 13. A mixture of benzoylacetonitrile 1f or
malononitrile 1g (1 equiv), the corresponding aldehyde 2 (1
equiv) and 5-amino-1-R-pyrrole-3-carbonitrile 3 (1 equiv) was
refluxed in acetic acid with 6 equiv of ammonium acetate as a
catalyst for 6 h. The product was purified by column
chromatography (eluent n-heptane/ethylacetate).
Lebensqualitat durch neuartige Mikroimplantate” (Grant No.
̈
03IS2081A) is gratefully acknowledged. Financial support by
the DAAD (scholarships for M. V.-H. and N. de S.) is
acknowledged.
REFERENCES
■
(1) (a) Toure, B. B.; Hall, D. G. Natural Product Synthesis Using
Multicomponent Reaction Strategies. Chem. Rev. 2009, 109, 4439−
4486. (b) Domling, A. Recent Developments in Isocyanide Based
Multicomponent Reactions in Applied Chemistry. Chem. Rev. 2006,
106, 17−89. (c) Chebanov, V. A.; Gura, K. A.; Desenko, S. M.
Aminoazoles as Key Reagents in Multicomponent Heterocyclizations.
Top. Heterocycl. Chem. 2010, 23, 41−84. (d) Kumaravel, K.; Vasuki, G.
Multicomponent Reactions in Water. Curr. Org. Chem. 2009, 13,
1820−1841. (e) Multicomponent Reactions; Zhu, J.-P., Bienayme, H.,
Eds.; Wiley-VCH: Weinheim, Germany, 2005; p 1499.
(2) (a) Sundberg, R. D. In Pyrroles and Their Benzo Derivatives:
Synthesis and Application; Katritzky, A. R., Rees, C. W., Eds.;
Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, 1984;
Vol. 4, pp 313−376. (b) Gribble, G. W. Recent Developments in
Indole Ring SynthesisMethodology and Applications. J. Chem. Soc.,
Perkin Trans. 1 2000, 1045−1075.
(3) (a) Yakhontov, L. N.; Prokopov, A. A. Advances in the Chemistry
1-tert-Butyl-4,6-diphenyl-1H-pyrrolo[2,3-b]pyridine-3,5-di-
carbonitrile (12aa). The product was isolated as a brown solid,
́
of Azaindoles. Russ. Chem. Rev. 1980, 49, 814−847. (b) Merour, J.-Y.;
Joseph, B. Synthesis and Reactivity of 7-Azaindole (1H-Pyrrolo[2,3-
b]pyridine). Curr. Org. Chem. 2001, 5, 471−506. (c) Popowycz, F.;
1
yield 48%, mp 260−261 °C. H NMR (300 MHz, DMSO-d6):
δ 1.85 (s, 9H, t-Bu), 7.56−7.71 (m, 8H), 7.96−8.01 (m, 2H),
8.80 (s, 1H, H-2). 13C NMR (62.9 MHz, DMSO-d6): δ 28.6
(3C), 59.6, 83.1, 101.2, 114.2, 117.0, 117.7, 128.3, 128.5, 129.3,
129.5, 129.7, 129.9, 133.1, 138.0, 140.2, 146.7, 148.5, 155.2. MS
(GC, 70 eV): m/z (%) 376 (M+, 24), 320 (100), 319 (85).
HRMS (ESI): calcd for C25H21N4 (M + 1) 377.16070, found
377.17552. IR (ATR, cm−1): 3140 (w), 2986 (w), 2230 (m),
1585 (m), 1571 (m), 1516 (m), 1401 (s), 1371 (m), 1359 (m),
1305 (s), 1209 (s), 756 (s), 707 (s), 697 (s), 644 (m).
6-Amino-1-tert-butyl-4-phenyl-1H-pyrrolo[2,3-b]pyridine-
3,5-dicarbonitrile (13aa). The product was isolated as a brown
solid, yield 60%, mp 194−196 °C. 1H NMR (300 MHz,
CDCl3): δ 1.69 (s, 9H, t-Bu), 5.12 (s, 2H, NH2), 7.47 (br s, 5H,
Ph), 7.59 (s, 1H, H-2). 13C NMR (62.9 MHz, CDCl3): δ 28.9
(3C), 58.7, 84.5, 88.1, 111.8, 114.8, 117.0, 128.5, 129.2, 130.2,
133.1, 133.6, 147.8, 149.6, 155.8. MS (GC, 70 eV): m/z (%)
315 (M+, 19), 259 (100). HRMS (ESI): calcd for C19H18N5 (M
+ 1) 316.15567, found 316.15526. IR (ATR, cm−1): 3355 (m),
2216 (m), 2205 (m), 1610 (s), 1592 (m), 1555 (m), 1525 (m),
1484 (m), 1397 (s), 1367 (m), 1305 (s), 1207 (m), 759 (s),
709 (m), 700 (m), 651 (m).
́
Routier, S.; Joseph, B.; Merour, J.-Y. Synthesis and Reactivity of 7-
Azaindole (1H-Pyrrolo[2,3-b]pyridine). Tetrahedron 2007, 63, 1031−
1064.
(4) Ermoli, A.; Bargiotti, A.; Brasca, M. G.; Ciavolella, A.; Colombo,
N.; Fachin, G.; Isacchi, A.; Menichincheri, M.; Molinari, A.;
Montagnoli, A.; Pillan, A.; Rainoldi, S.; Sirtori, F. R.; Sola, F.;
Thieffine, S.; Tibolla, M.; Valsasina, B.; Volpi, D.; Santocanale, C.;
Vanotti, E. Cell Division Cycle 7 Kinase Inhibitors: 1H-Pyrrolo[2,3-
b]pyridines, Synthesis and Structure−Activity Relationships. J. Med.
Chem. 2009, 52, 4380−4390.
(5) Kim, K. S.; Zhang, L.; Schmidt, R.; Cai, Z. W.; Wei, D.; Williams,
D. K.; Lombardo, L. J.; Trainor, G. L.; Xie, D.; Zhang, Y.; An, Y.; Sack,
J. S.; Tokarski, J. S.; Darienzo, C.; Kamath, A.; Marathe, P.; Zhang, Y.;
Lippy, J.; Jeyaseelan, R., Sr.; Wautlet, B.; Henley, B.; Gullo-Brown, J.;
Manne, V.; Hunt, J. T.; Fargnoli, J.; Borzilleri, R. M. Discovery of
Pyrrolopyridine-Pyridone Based Inhibitors of Met Kinase: Synthesis,
X-ray Crystallographic Analysis, and Biological Activities. J. Med. Chem.
2008, 51, 5330−5341.
(6) Seefeld, M. A.; Rouse, M. B.; McNulty, K. C.; Sun, L.; Wang, J.;
Yamashita, D. S.; Luengo, J. I.; Zhang, S. Y.; Minthorn, E. A.; Concha,
N. O.; Heerding, D. A. Discovery of 5-Pyrrolopyridinyl-2-thiophene-
carboxamides as Potent AKT Kinase Inhibitors. Bioorg. Med. Chem.
Lett. 2009, 19, 2244−2248.
(7) Tang, J.; Hamajima, T.; Nakano, M.; Sato, H.; Dickerson, S. H.;
Lackey, K. E. Knowledge-Based Design of 7-Azaindoles as Selective B-
Raf Inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 4610−4614.
(8) (a) Kotljarov, A.; Irgashev, R. A.; Iaroshenko, V. O.; Sevenard, D.
V.; Sosnovskikh, V. Y. 3-(Polyfluoroacyl)chromones and Their Hetero
Analogues as Valuable Substrates for Syntheses of 4-(Polyfluoroalkyl)-
pyrimidines. Synthesis 2009, 3233−3242. (b) Kotljarov, A.;
Iaroshenko, V. O.; Volochnyuk, D. M.; Irgashev, R. A.; Sosnovskikh,
V. Y. Reactions of 3-(Polyfluoroacyl)chromenones with Heterocyclic
Amines: Novel Synthesis of Polyfluoroalkyl-Containing Fused
Pyridines. Synthesis 2009, 3869−3879. (c) Iaroshenko, V. O.;
Mkrtchyan, S.; Ghazaryan, G.; Hakobyan, A.; Maalik, A.; Supe, L.;
Villinger, A.; Tolmachev, A.; Ostrovskyi, D.; Sosnovskikh, V. Y.;
Ghochikyan, T. V.; Langer, P. 3-(Dichloroacetyl)chromone; A New
Building Block for the Synthesis of Formylated Purine Isosteres:
Design and Synthesis of Fused α-(Formyl)pyridines. Synthesis 2011,
469−479. (d) Mkrtchyan, S.; Iaroshenko, V. O.; Dudkin, S.;
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and 1H and 13
C
NMR spectra of all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: 00 49 381 49864112. Tel: 0049 381 4986410. E-mail:
viktor.iaroshenko@uni-rostock.de; iva108@googlemail.com.
Notes
The authors declare no competing financial interest.
G
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
Gevorgyan, A.; Vilches-Herrera, M.; Ghazaryan, G.; Volochnyuk, D.;
Ostrovskyi, D.; Ahmed, Z.; Villinger, A.; Sosnovskikh, V. Y.; Langer, P.
3-MethoxalylchromoneA Novel Versatile Reagent for the Regiose-
lective Purine Isostere Synthesis. Org. Biomol. Chem. 2010, 8, 5280−
5284. (e) Iaroshenko, V. O.; Mkrtchyan, S.; Gevorgyan, A.; Vilches-
Herrera, M.; Sevenard, D. V.; Villinger, A.; Ghochikyan, T. V.;
Saghiyan, A.; Sosnovskikh, V. Y.; Langer, P. Synthesis of
Heteroannulated 3-Nitro- and 3-Aminopyridines by Cyclocondensa-
tion of Electron-Rich Aminoheterocycles with 3-Nitrochromone.
Tetrahedron 2012, 2532−2543. (f) Iaroshenko, V. O.; Mkrtchyan, S.;
Gevorgyan, A.; Miliutina, M.; Villinger, A.; Volochnyuk, D.;
Sosnovskikh, V. Y.; Langer., P. 2,3-Unsubstituted Chromones and
Their Enaminone Precursors as Versatile Reagents for the Synthesis of
Fused Pyridines. Org. Biomol. Chem. 2012, 10, 890−894.
(20) Brandes, A.; Logers, M.; Schmidt, G.; Angerbauer, R.; Schmeck,
C.; Bremm, K.-D.; Bischoff, H.; Schmidt, D.; Schuhmacher, J. Bicyclic-
Fused Pyridines. U.S. Patent 6063788, 2000.
̈
(21) (a) Heintzelman, G. R.; Averill, K. M.; Dodd, J. H.; Demarest,
K. T.; Tang, Y.; Jackson, P. F. 5-Oxo and 5-Thio Derivatives of 5H-
Indeno-1,2-bipyridine with Adenosine A2A Receptor Binding and
Phosphodiesterase Inhibiting Activity for the Treatment of Neuro-
degenerative Disorders and Inflammation Related Diseases. Int. Patent
WO 03/088963, 2003. (b) Paul, S.; Das, A. R. An efficient green
protocol for the synthesis of coumarin-fused highly decorated
indenodihydropyridyl and dihydropyridyl derivatives. Tetrahedron
Lett. 2012, 53, 2206−2210.
(22) Lipson, V. V.; Desenko, S. M.; Shirobokova, M. G.; Shishkin, O.
V.; Shishkina, S. V. Heterocyclizations of 3-Methylpyrazol-5-amine
with Unsaturated Arylaliphatic Carboxylic Acid Derivatives. Russ. J.
Org. Chem. 2006, 42, 1022−1027.
(9) De Rosa, M.; Issac, R. P.; Houghton, G. First Synthesis of Z-
Aminopyrrole and Simple 1-Substituted-2-Aminopyrroles. Observa-
tion of Fast Proton Exchange at C-5. Tetrahedron Lett. 1995, 36,
9261−9264.
(23) Quiroga, J.; Alvarado, M.; Insuasty, B.; Moreno, R.; Ravina, E.;
̃
Estevez, I.; de Almeida, R. H. Synthesis of 5-Cyanopyrazolo[3,4-
b]pyridines in the Reaction of 5-Amino-3-methyl-1-phenylpyrazole
with Arylidene Derivatives of Malonodinitrile and Ethyl Cyanoacetate.
J. Heterocycl. Chem. 1999, 36, 1311−1316.
(10) Brodrick, A.; Wibberley, D. G. 1H-Pyrrolo[2,3-b]pyridines. Part
III. A Novel Synthetic Route from 1-Substituted 2-Aminopyrroles. J.
Chem. Soc., Perkin Trans. 1 1975, 1910−1913.
́
(11) (a) Benoit, R.; Dupas, G.; Bourguignon, J.; Queguiner, G. Facile
Synthesis of Annelated NADH Model Precursors. Synthesis 1987,
1124−1126. (b) Iaroshenko, V. O.; Wang, Y.; Sevenard, D. V.;
Volochnyuk, D. M. Synthesis of Fluorinated Pyrrolo[2,3-b]pyridine
and Pyrrolo[2,3-d]pyrimidine Nucleosides. Synthesis 2009, 1851−
1857.
(12) Ghahremanzadeh, R.; Sayyafi, M.; Ahadi, S.; Bazgir, A. Novel
One-Pot, Three-Component Synthesis of Spiro[Indoline-pyrazolo-
[4′,3′:5,6]pyrido[2,3-d]pyrimidine]trione Library. J. Comb. Chem.
2009, 11, 393−396.
(13) Jiang, B.; Cao, L.-J.; Tu, S.-J.; Zheng, W.-R.; Yu, H.-Z. Highly
Diastereoselective Domino Synthesis of 6-Spirosubstituted Pyrido[2,3-
d]pyrimidine Derivatives in Water. J. Comb. Chem. 2009, 11, 612−616.
(14) Tu, S.-J.; Zhang, X.-H.; Han, Z.-G.; Cao, X.-D.; Wu, S.-S.; Yan,
S.; Hao, W.-J.; Zhang, G.; Ma, N. Synthesis of Isoxazolo[5,4-
b]pyridines by Microwave-Assisted Multi-Component Reactions in
Water. J. Comb. Chem. 2009, 11, 428−432.
(15) Verma, G. K.; Raghuvanshi, K.; Kumar, R.; Singh, M. S. An
Efficient One-Pot Three-Component Synthesis of Functionalized
Pyrimido[4,5-b]quinolines and Indeno Fused Pyrido[2,3-d]-
pyrimidines in Water. Tetrahedron Lett. 2012, 53, 399−402.
(16) Allegretti, M.; Anacardio, R.; Cesta, M. C.; Curti, R.;
Mantovanini, M.; Nano, G.; Topai, A.; Zampella, G. A Practical
Synthesis of 7-Azaindolylcarboxy-endo-tropanamide (DF 1012). Org.
Process Res. Dev. 2003, 7, 209−213.
(17) (a) Hitotsuyanagi, Y.; Kobayashi, M.; Fukuyo, M.; Takeya, K.;
Itokawa, H. A Facile Synthesis of the 4-Aza-analogs of 1-
Aryinaphthalene Lignans Chinensin, Justicidin B, and Taiwanin C.
Tetrahedron Lett. 1997, 38, 8295−8296. (b) Hitotsuyanagi, Y.;
Kobayashi, M.; Morita, H.; Itokawa, H.; Takeya, K. Synthesis of
(-)-4-Aza-4-deoxypodophyllotoxin From (−)-Podophyllotoxin. Tetra-
hedron Lett. 1999, 40, 9107−9110. (c) Tratrat, C.; Giorgi-Renault, S.;
Husson, H.-P. A Multicomponent Reaction for the One-Pot Synthesis
of 4-Aza-2,3-didehydropodophyllotoxin and Derivatives. Ogr. Lett.
2002, 4, 3187−3189. (d) Shi, C.-L.; Shi, D.-Q.; Kim, S. H.; Huang, Z.-
B.; Ji, S.-J.; Ji, M. A Novel and Efficient One-Pot Synthesis of
Furo[3′,4′:5,6]pyrido[2,3-c]pyrazole Derivatives Using Organocata-
lysts. Tetrahedron 2008, 64, 2425−2432. (e) Shi, C.; Wang, J.;
Chen, H.; Shi, D. Regioselective Synthesis and in Vitro Anticancer
Activity of 4-Aza-podophyllotoxin Derivatives Catalyzed by L-Proline.
J. Comb. Chem. 2010, 12, 430−434.
(18) Miri, R.; Javidnia, K.; Hemmateenejad, B.; Azarpira, A.;
Amirghofran, Z. Synthesis, Cytotoxicity, QSAR, and Intercalation
Study of New Diindenopyridine Derivatives. Bioorg. Med. Chem. 2004,
12, 2529−2536.
(19) Kunstmann, R.; Lerch, U.; Gerhards, H.; Leven, M.; Schacht, U.
2,3,4,4a,5,9b-Hexahydro-1H-indeno[l,2-b]pyridines: Potential Antide-
pressants. J. Med. Chem. 1984, 27, 432−439.
H
dx.doi.org/10.1021/co300042v | ACS Comb. Sci. XXXX, XXX, XXX−XXX