3-Acylindoles as versatile starting materials for pyridine ring annulation: Synthesis of 1-deazapurine isosteres

Article abstract of DOI:10.1016/j.tet.2011.05.037

The reaction of electron-rich aminoheterocycles with 3-acyl- and 3-formylindoles results in indole ring opening and cyclocondensation to give heteroannulated pyridines, which can be regarded as purine isosteres. The transformations reported herein represe

Full text of DOI:10.1016/j.tet.2011.05.037

Tetrahedron 67 (2011) 5293e5303
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
3-Acylindoles as versatile starting materials for pyridine ring annulation:
synthesis of 1-deazapurine isosteres
,
b
,
a
a
a
Ingo Knepper a, Viktor O. Iaroshenko a , Marcelo Vilches-Herrera , Lutz Domke , Satenik Mkrtchyan ,
*
Muhammad Zahid a, Alexander Villinger a, Peter Langer a
,c,
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
c
€
€
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of electron-rich aminoheterocycles with 3-acyl- and 3-formylindoles results in indole ring
opening and cyclocondensation to give heteroannulated pyridines, which can be regarded as purine
isosteres. The transformations reported herein represent rare examples of domino reactions, which
include the cleavage of an indole moiety.
Received 17 January 2011
Received in revised form 28 April 2011
Accepted 9 May 2011
Available online 14 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
3-Acylindoles
1-Deazapurine isosteres
Cyclocondensation
Pyridine ring annulation
Regioselectivity
1. Introduction
properties.4 The 1H-pyrazolo[3,4-b]pyridine substructure occurs in
a set of potential drugs, such as BAY 41-2272, which is known to
Purines and purinomimetics play an important role in drug
design and drug discovery.1,2 Many commercially available anti-
cancer and anti-HIV drugs as well as various natural products
contain fused 5,6- and 6,6-heterocyclic frameworks, which are of-
ten classified as purinomimetics or purine isosteres.1 The applica-
tion of purines and purine-like scaffolds in medicinal chemistry is
of considerable current interest, due to the very good recognition of
purine analogues by the current enzymes. The electronically
modified synthetic purine analogues are often more active as the
natural products themselves, because substrate turnover is pre-
vented and the enzyme can be efficiently inhibited.1 A great variety
of purine analogues and corresponding nucleosides are used for the
treatment of cancer.2 Purine-like structures are also recognized as
important scaffolds3 for medicinal chemistry and drug design.
Purine isosteres (so-called pseudopurines) are derived from
purine by replacement of the nitrogen atoms by carbon or sulfur
atoms. For example, imidazo[4,5-b]pyridines (1-deazapurines)
constitute an important class of heterocyclic compounds, which
exhibit a wide range of biological activities and pharmacological
stimulate soluble guanylate cyclase (sGC) via a nitric oxide in-
dependent regulatory site and induces vasodilation.5 Some pyr-
azolo[3,4-b]pyridines are also reported as potent inhibitors of
glycogen synthase kinase-3 (GSK-3).6 Pyrrolo[2,3-b]pyridines can
be regarded as 1,7-deazapurines. The pharmacologically most sig-
nificant compound among them is 7-azaindolylcarboxy-endo-tro-
panamide (DF 1012). The latter is the best candidate of a new class
of non-narcotic antitussive compounds and is currently under in-
vestigation in phase II clinical trials.7 The heterocyclic system of
thiazolo[4,5-d]pyridines (1-deaza-7-thiopurines) have been
reported to show antibacterial,8a,b and antisecretory8c activities and
can play a role as non-imidazole histamine H3-antagonists.8d Pyr-
ido[2,3-d]pyrimidines have been reported to exhibit a high activity
against FGFR1 and VEGFR2,9 and have been recently identified as
FGFR3 inhibitors.10
Due to the great pharmacological relevance of these scaffolds,
the development of methods for the efficient synthesis of purines
and their analogues is of considerable current interest. In recent
years, we have studied the synthesis of purines and purine isosteres
by cyclization of electron-rich aminoheterocycles with various
1,3-CCC and 1,3-CNC bis-electrophiles (Fig. 1).11 In this context,
cyclocondensations of 3-formylchromone,12,13 its thio analogue,14
and perfluoroalkyl derivatives have been studied as 1,3-CCC-
* Corresponding authors. Fax: þ49 (0)381 498 6412; e-mail addresses:
viktor.iaroshenko@uni-rostock.de, iva108@googlemail.com (V.O. Iaroshenko).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.037

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I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
2. Results and discussion
O
O
O
X
O
R1
Our starting point was to find suitable conditions for the re-
action of aminoheterocycles with 3-formylindoles 2aec. These
reactions indeed proceeded, as expected, by cleavage of the indole
moiety and subsequent cyclocondensation to give annulated pyri-
dines. We have found that the reaction of various aminohetero-
cycles with 1-methyl-3-formylindole (2a) proceeded in very good
yields when the reactions were carried out in DMF using TMSCl as
a water scavenger.16 Therefore, no further optimization was
necessary for substrate 2a. For 3-formylindole (2b) and 1-phenyl-3-
formylindole (2c), the yields decreased significantly when the
system DMF/TMSCl was used. Therefore, we tested different
reaction conditions (see Scheme 1, Table 1). For both substrates we
obtained the best results when the reaction was carried out in
glacial acetic acid. The employment of the conditions reported by
Park et al. (AlCl3 in MeOH)17 usually resulted in a decrease of the
yield for formylindoles 2aec.
R1
O
1
XH
X=O, S; R1 = H, Alkyl, RF.
a: R1 = H, R2 = CH3;
b: R1 = H, R2 = H;
O
R1
O
c: R1 = H, R2 = Ph;
d: R1 = CH3, R2 = H;
e: R1 = CH3, R2 = CH3;
f: R1= CO2Me, R2 = H;
g: R1 =CCl2H, R2 = H
h: R1 = CF3, R2 = H;
i: R1= CF3, R2 = CH3.
R1
O
N
NH
R2
R2
2
Fig. 1. 3-Acyl-chromones and 3-acylindoles as masked 1,3-CCC-dielectrophiles.
NC
O
NC
dielectrophiles.14,15 4-Formyl-uracyl16 has been recently used as
a building block for the synthesis of condensed pyridine systems,
purine isosteres,11 and pyrimidines.12
See Table 1
+
N
NH2
NH2
N
N
N
Me
Me
It occurred to us that 3-formyl- and 3-acylindoles might be used
as bis-electrophiles for the synthesis of annulated pyridines. To the
best of our knowledge, there has been reported only a single re-
action so far, which proceeds by ring-cleavage of the indole moiety
and subsequent cyclocondensation, i.e., the synthesis of pyrazolo
[3,4-b]pyridines by reaction of indole-3-carboxaldehydes with
1-unsubstituted 5-aminopyrazoles reported by Park and co-
workers.17 Herein, we report, for the first time, the extension of this
concept to various aminoheterocycles (Fig. 2) and to diverse
3-formyl- and 3-acylindoles (Fig. 1).
H
Me
Me
Me
4c
Me
2b
13e
Scheme 1. Optimization of the reaction of 2b with 4c.
Table 1
Optimization of the reaction of 2b with 4c
Entry
System
Conditions
Yielda (%)
1
2
3
4
5
TMSCl/DMF
AcOH
AlCl3/MeOH
Formic acid/MeOH
HCl/MeOH
4 equiv TMSCl, 140 ꢀC, 4 h
100 ꢀC, 4 h
39
53
47
29
0
10 mol % AlCl3, 70 ꢀC, 4 h
10 mol % formic acid, 70 ꢀC, 4 h
10 mol % HCl, 70 ꢀC, 4 h
O
NC
Me
N
a
Yields of isolated products.
N
Ph
NH2
N
R
NH2
N
N
NH2
Ph
5
3
a: R= 4-OMe-Benzyl,
b: R= Cyclohexyl,
c: R= t-Butyl
4
With the results of the optimization studies in hand, we studied
the reaction of 3-formylindoles 2aec with different aminohetero-
cycles 4aec, 5, and 8 (Scheme 2). These reactions resulted in the
formation of the heteroannulated pyridines 13ael in good yields
(Table 2). In contrast, the amino-substituted imidazol-2-ones and
imidazol-2-thiones 6 proved to be unstable and decomposed under
the reaction conditions. As a result the yields of isolated products
were extremely low and inseparable mixtures of unidentified
products were formed. The reaction of 3-formylindoles with ami-
noheterocycle 7 and with anilines 10e12 failed. The analysis of the
product mixtures revealed that predominantly the starting mate-
rials were present (low conversion). The structures of scaffolds 13
were independently confirmed by X-ray crystal structure analyses
(Figs. 3e5).18
O
Me
NH2
a: X= S, R= Me,
HN
N
b: X= S, R= Ph,
c: X= S, R= Et,
X
d: X= S, R= 4-Me-Ph,
e: X= O, R= 4-Cl-Ph
O
N
N
NH2
H
6
7
R
OMe
S
O
R2N
NH2
N
HN
9
MeO
NH2
a: R2N = Piperidine
b: R2N = Morpholine
O
N
NH2
10
8
Me
OMe
O
MeO
MeO
Me2N
NH2
HN
NH2
N
NH2
N
R1
12
11
13a-l
R1
2a-c
3-12
Fig. 2. Structures of the aminoheterocycles and electron-rich anilines used in this
Scheme 2. Reagents and conditions: see Table 2.
study.

I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
5295
Table 2
Synthesis of heteroannulated pyridines 13, 16, 17
Amine
Product
Yielda (%)
NC
NC
NH2
N
HN
N
13a
60b
N
Me
OMe
OMe
4a
NC
NC
NH2
N
13b
65b
HN
N
N
Me
4b
NC
NC
NH2
N
13c
41c
HN
N
N
Ph
4b
NC
NC
NH2
N
13d
78b
HN
N
N
Me
Me
Me
Me
Me
Me
Me
4c
NC
NC
NH2
N
13e
53c
NH2
N
Me
N
Me
Me
Me
Me
Me
4c
NC
NC
NH2
N
13f
45c
HN
N
N
Ph
Me
Me
Me
Me
Me
Me
4c
Me
87b
Me
N
13g
N
N
NH2
HN
N
N
Me
Ph
Ph
(continued on next page)
5

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I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
Table 2 (continued )
Amine
Product
Yielda (%)
Me
Me
N
N
13h
57c
N
NH2
NH2
N
N
Ph
Ph
5
Me
H3C
N
N
13i
48c
N
NH2
HN
N
N
Ph
Ph
Ph
5
O
O
HN
HN
13j
58b
HN
O
N
NH2
O
N
N
Me
NH2
Ph
Me
Me
8
O
O
HN
HN
13k
45b
O
N
NH2
O
N
N
Me
Me
8
O
O
HN
HN
13l
33b
O
N
NH2
HN
O
N
N
Me
Me
8
NC
Me
NC
NH2
N
HN
N
16a
73d
N
Me
OMe
OMe
4a
NC
Me
NC
NH2
N
NH2
N
51d
N
16b
OMe
OMe
4a

I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
5297
Table 2 (continued )
Amine
NC
Product
Yielda (%)
Me
N
NC
NH2
N
16c
67d
HN
N
Me
4b
NC
Me
NC
NH2
N
16d
45d
NH2
N
N
4b
NC
Me
NC
NH2
N
16e
55d
HN
N
N
Me
Me
Me
Me
Me
Me
Me
4c
NC
Me
NC
NH2
N
16f
17a
17b
35d
40d
44d
NH2
N
Me
N
Me
Me
Me
Me
Me
4c
NC
H
O
N
NC
NH2
N
N
N
4b
NC
H
O
N
NC
NH2
N
Me
Me
N
N
Me
Me
Me
Me
4c
a
Yields of isolated products.
Procedure A, the DMF/TMSCl system.
Procedure B, AcOH, reflux.
b
c
d
Procedure C, AlCl3, MeOH.
The reaction of 3-formylindoles with the hydrochlorides of
proposed, which depicted in Scheme 5. The structure of 14 was in-
dependently confirmed by X-ray crystal structure analysis (Fig. 6).18
To get a more detailed understanding of the annulation process,
we studied the employment of 3-acetylindole (2d,e) instead of
3-formylindoles 2aec. While the reactions of 3-formylindoles 2aec
had no issue of regioselectivity, the reactions of 2d can theoretically
result in the formation of two different regioisomers. The reaction
4-aminothiazoles 9 and aminopyrazole 3 resulted in a simple aldol
condensation to give products 14 and 15 instead of the expected
annulated ring systems, respectively (Scheme 3). Even in boiling
acetic acid in the presence of 1.2 equiv of sodium acetate, used as
a base for the amine liberation, it was not possible to get the desired
pyridine system (Scheme 3). This result supports the mechanism

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I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
H
N
S
N
N
O
9
14
NH2
i
i
Cl
O
Me
N
N
Ph
3
R1
N
2 a,b
a: R1 = H
Fig. 3. Molecular structure of compound 13b.
N
b: R1 = Me
NH2
15
Scheme 3. Synthesis of 14 and 15. Reagents and conditions: (i) for compound 9: AcOH,
reflux, NaOAc (1.2 equiv); for compound 3: AcOH, reflux.
Fig. 4. Molecular structure of compound 13e.
Fig. 6. Molecular structure of compound 14.
O
Me
Me
i
HN
N
NH2
N
R1
R1
16a-f
2d,e
4a-c
Scheme 4. Reagents and conditions: (i) AlCl3, MeOH.
The formation of products 16aef can be explained by addition of
the enamine carbon atom of 4aec to the carbonyl group of 2d,e to
give intermediate A (Scheme 5). Subsequent attack of the amino
Fig. 5. Molecular structure of compound 13b.
of aminoheterocycles 4aec with an equivalent amount of 2d, car-
ried out in dry MeOH in the presence of 50 mol % of AlCl3 (best
conditions in further optimization reactions), afforded the
4-substituted heteroannulated pyridines 16aef in good to excellent
yields (Scheme 4, Table 2). The products were formed with excel-
lent regioselectivity. The structure of 16a was independently con-
firmed by X-ray crystal structure analysis (Fig. 7).18 The reactions of
aminoheterocycles with 3-acylindoles, which contain a COCF3
(2h,i) or COCCl2H (2g) group instead of an acetyl group, failed.
Analysis of the crude reaction mixture by HPLC and 19F NMR
showed the presence of a mixture of the starting materials and of
some unidentified products. Not even traces of the desired heter-
oanulated pyridines could be detected.
Fig. 7. Molecular structure of compound 16a.

I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
5299
3. Experimental section
3.1. General comments
O
N
R2
N
R2
Chemical yields refer to pure isolated substances. 1H and 13C
NMR spectra were obtained using a Bruker DPX-300 spectrometer.
Chemical shifts of the 1H and 13C NMR are reported in parts per
million using the solvent internal standard (CDCl3 7.26 ppm and
77.0 ppm, DMSO-d6 2.49 ppm and 39.7 ppm). IR spectra were
recorded on a PerkineElmer FT IR 1600 spectrometer for samples in
KBr discs. Mass spectra were obtained on a Hewlett-Packard HP GC/
MS 5890/5972 instrument (EI, 70 eV) by GC inlet or on an MX-1321
instrument (EI, 70 eV) by direct inlet. Elemental analyses were
carried out at the Microanalytical Laboratory of the University of
Rostock, Germany. Melting points are uncorrected. The solvents
DMF, methanol, and acetic acid were purchased directly from
ACROS and used without further purification. Analytical thin layer
chromatography was performed on 0.20 mm 60 A silica gel plates.
Column chromatography was performed using 60 A silica gel
(60e200 mesh).
HN
R1
NH2
16
R1
2
O
R2
R2
N
N
N
H
H
R1
NH2
R1
B
H
O
R2
3.2. Procedure A: general procedure of heteroannelated
pyridines synthesis in DMF/TMSCl
N
NH2
Appropriate indole of 1.0 equiv, 1.1 equiv of the corresponding
aminoheterocycle, and 4 equiv of TMSCl in 15 mL of anhydrous DMF
was heated at 100 ꢀC underdryargon atmosphere in a pressure tube.
After 6 h the solvent was removed under reduced pressure and the
residue was purified by silica gel flash chromatography.
R1
A
Scheme 5. A possible mechanism of the formation of 16aef.
group to carbon atom C-2 of the indole system results in the for-
mation of intermediate B, which undergoes cleavage of the indole
ring to give pyridines 16aef.
3.3. Procedure B: general procedure of heteroannelated
pyridines synthesis in acetic acid
The reaction of aminoheterocycles 4b,c with methyl 1H-indol-3-
yl-2-oxoacetates 2f containing an a-oxoester moiety, afforded the
Appropriate indole of 1.0 equiv and 1.1 equiv of the corre-
sponding aminoheterocycle were heated in 15 mL of acetic acid at
100 ꢀC under dry argon atmosphere in a pressure tube. After 4 h,
the solvent was removed under reduced pressure and the residue
was purified by silica gel flash chromatography.
heteroannulated benzo[c][2,6]naphthyridin-5(6H)-ones 17a,b
(Scheme 6, Table 2). The formation of the products can be explained
by a domino indole-cleavage/cyclocondensation reaction to give
intermediate C and subsequent lactam formation by attack of the
indole-derived amino group to the ester group.
3.4. Procedure C: general procedure of heteroannelated
pyridines synthesis in methanol with AlCl3
O
H
Appropriate indole of 1.0 equiv, 1.0 equiv of the corresponding
aminoheterocycle and 0.5 equiv of AlCl3 were heated in 20 mL of
dry methanol at 70 ꢀC. When the reaction was completed (TLC
control), the solvent was removed under reduced pressure and the
residue was purified by silica gel flash chromatography.
N
O
CO2Me
i
NH2
N
H
N
4b,c
17a,b
2f
3.5. Procedure D: procedure for the synthesis of compounds
14 and 15
MeO
O
Appropriate indole of 1.0 equiv and 1.0 equiv of the corre-
sponding aminoheterocycle (in the case of 9a 1.2 equivof NaOAcwas
added) were heated in 15 mL of acetic acid. After 4 h the solvent was
removed under reduced pressure and the residue was purified by
silica gel flash chromatography (compound 15) or the precipitate
was collected, washed with water and dried (compound 14).
NH2
N
C
Scheme 6. Reagents and conditions: (i) AlCl3, MeOH.
In conclusion, we have reported a new and convenient one-step
method for the synthesis of heteroannulated 3-(2-aminophenyl)-
pyridines by cyclocondensation of 3-acylindoles with electron-rich
aminoheterocycles. The reactions, which proceed under mild
conditions, allow the assembly of privileged condensed heteroaryl-
pyridine scaffolds with a wide scope and excellent regioselectivity.
The biological evaluation of the synthesized compounds is cur-
rently studied in our laboratories.
3.5.1. 3-Cyano-1-(p-methoxybenzyl)-5-(N-methyl-2-aminophenyl)
pyrrolo[2,3-b]pyridine (13a). Procedure A; brown solid; 60%; mp
128e130 ꢀC; 1H NMR (CDCl3, 250 MHz):
d
¼2.76 (s, 3H, CH3), 3.71 (s,
3H, OCH3), 5.37 (br, 2H, NH2), 6.65e6.82 (m, 4H, HAryl), 7.02 (dd, 1H,
3J¼1.5,7.5 Hz), 7.17e7.26 (m, 3H, HAryl), 7.60 (s, 1H, (CN)C]CH), 8.04
(d, 1H, 4J¼1.89 Hz), 8.42 (d, 1H, 4J¼1.89 Hz). 13C NMR (CDCl3,
63 MHz):
d
¼30.7, 48.3, 55.3, 84.8, 110.1, 114.4, 115.0, 117.1, 120.1,
123.9, 127.6, 128.9, 129.5, 129.6, 129.7, 130.1, 130.8, 135.2, 145.9,

5300
I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
146.6, 146.6, 159.8. IR (ATR, cmꢁ1):
n
¼ 3443ðwÞ, 3111 (w), 3067
1H NMR (DMSO-d6, 250 MHz):
d
¼1.85 (s, 9H, CH3), 4.99 (br, 2H,
~
(w), 3033 (w), 2958 (w), 2934 (w), 2865 (w), 2839 (w), 2814 (w),
2220 (w), 1599 (w), 1576 (w), 1525 (w), 1510 (s), 1483 (w), 1456 (w),
1440 (w), 1415 (m), 1395 (w), 1352 (w), 1340 (w), 1303 (w), 1293
(m), 1245 (s), 1210 (w), 1180 (m), 1166 (s), 1122 (w), 1068 (w), 1027
(m), 972 (w), 950 (w), 940 (w), 902 (w), 850 (m), 841 (w), 822 (m),
779 (m), 748 (s), 682 (w), 649 (m), 621 (m), 604 (m). MS (EI, 70 eV):
m/z (%)¼368 (Mþ, 66), 121 (100). HRMS (ESI): calcd for C23H20N4O
(MþHþ) 369.171, found 369.1712.
NH2), 6.69e6.75 (m, 1H, HAr), 6.86 (d, 3J¼7.7 Hz, 1H, HAr), 7.10e7.17
(m, 2H, HAr), 8.11 (d, 4J¼2.05 Hz, 1H, HHetar), 8.49 (d, 4J¼2.05 Hz, 1H,
HHetar), 8.59 (s, 1H, (CN)C]CH). 13C NMR (DMSO-d6, 63 MHz):
d
¼28.6, 58.4, 81.7, 115.4, 115.5, 116.8, 120.6, 122.5, 127.2, 128.6,
129.6, 130.7, 136.0, 144.4, 145.5, 145.8. IR (ATR, cmꢁ1):
~
n
¼ 3477ðwÞ, 3385 (w), 3148 (w), 3024 (w), 2975 (w), 2932 (w),
2870 (w), 2221 (m), 1613 (m), 1525 (m), 1501 (m); 1479 (m), 1447
(m), 1400 (m), 1347 (m), 1282 (m), 1202 (s), 916 (m), 850 (m), 781
(m), 749 (s), 637 (m). MS (EI, 70 eV): m/z (%)¼290 (Mþ, 56), 234
(100). HRMS (ESI): calcd for C18H18N4 (Mþ) 290.15260, found
290.152580.
3.5.2. 3-Cyano-1-cyclohexyl-5-(N-methyl-2-aminophenyl)pyrrolo
[2,3-b]pyridine (13b). Procedure A; white-brown solid; 65%; mp
184e185 ꢀC; 1H NMR (CDCl3, 250 Hz):
d¼1.14e1.31 (m, 1H, HCyclo-
hexyl), 1.42e1.78 (m, 5H, HCyclohexyl), 1.88e1.92 (m, 2H, HCyclohexyl),
2.13e2.14 (m, 2H, HCyclohexyl), 2.74 (s, 3H, NCH3), 4.72e4.83 (m, 1H,
HCyclohexyl), 6.69e6.79 (m, 2H, HAr), 7.04 (dd, 3J¼1.5, 8.0 Hz, 1H, HAr),
7.22e7.29 (m, 1H, HAr), 7.79 (s, 1H, (CN)C]CH), 8.05 (d, 4J¼2.1 Hz,
1H, HHetar), 8.39 (d, 4J¼2.1 Hz,1H, HHetar). 13C NMR (CDCl3, 63 MHz):
3.5.6. 1-tert-Butyl-3-cyano-5-(N-phenyl-2-aminophenyl)pyrrolo
[2,3-b]pyridine (13f). Procedure B; white-yellow solid; 45%; mp
95e97 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d¼1.75 (s, 9H, C(CH3)3),
6.66e6.84 (m, 1H, HAr), 6.84e6.87 (m, 2H, HAr), 7.08e7.14 (m, 3H,
HAr), 7.31e7.45 (m, 4H, HAr), 8.05 (d, 4J¼2.1 Hz, 1H, HHetar), 8.45
(d, 4J¼2.1 Hz, 1H, HHetar), 8.49 (s, 1H, (CN)C]CH). 13C NMR
d
¼25.3, 25.6, 30.7, 33.5, 54.4, 84.3, 110.0, 115.3, 117.1, 120.2, 124.0,
128.8, 129.5, 129.9, 130.7, 132.8, 145.4, 146.0, 146.5. IR (ATR, cmꢁ1):
(DMSO-d6, 63 MHz):
d
¼28.6, 58.4, 81.6, 115.4, 116.0, 118.8, 120.5,
~
n
¼ 3477ðwÞ, 3385 (w), 3148 (w), 3024 (w), 2975 (w), 2932 (w),
121.6, 122.8, 127.3, 128.7, 128.9, 129.5, 131.0, 131.6, 135.9, 140.6,
~
n
2870 (w), 2221 (m), 1613 (m), 1525 (m), 1501 (m); 1479 (m), 1447
(m), 1400 (m), 1347 (m), 1282 (m), 1202 (s), 916 (m), 850 (m), 781
(m), 749 (s), 637 (m). MS (EI, 70 eV): m/z (%)¼330 (Mþ, 100), 248
(62), 232 (16). HRMS (ESI): calcd for C21H22N4 (Mþ) 330.18390,
found 330.18318. Anal. Calcd for C21H22N4 (330.42): C, 76.33; H,
6.71; N, 16.96. Found: C, 76.33; H, 6.81; N, 16.75.
144.5, 145.0, 145.5. IR (ATR, cmꢁ1): ¼ 3319ðwÞ, 3093 (w), 3039
(w), 2969 (w), 2935 (w), 2871 (w), 2236 (w), 2216 (w), 1604 (w),
1589 (m), 1518 (m), 1495 (m), 1455 (m), 1403 (m), 1370 (m), 1347
(m), 1305 (m), 1290 (m), 1205 (m), 1090 (w), 1052 (m), 1027 (m),
1008 (m), 907 (m), 896 (m), 885 (m), 779 (m), 748 (s), 697 (m),
654 (m), 637 (m), 619 (m). MS (EI, 70 eV): m/z (%)¼366 (Mþ, 99),
310 (100). HRMS (ESI): calcd for C24H22N4 (Mþ) 366.18390, found
366.183715.
3.5.3. 3-Cyano-1-cyclohexyl-5-(N-phenyl-2-aminophenyl)pyrrolo
[2,3-b]pyridine (13c). Procedure B; brown solid; 41%; mp
188e189 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d¼1.25e2.00 (m, 10H,
3.5.7. 3-Methyl-(N-methyl-2-aminophenyl)-1-phenylpyrazolo[3,4-b]
HCyclohexyl), 4.70e4.79 (m, 1H, HCyclohexyl), 6.69e6.74 (m, 1H, HAryl),
6.85e6.88 (m, 2H, HAryl), 7.10e7.16 (m, 3H, HAryl), 7.33e7.45 (m,
4H, HAryl), 8.11 (d, 4J¼1.9 Hz, 1H, HHetaryl), 8.45 (d, 4J¼1.9 Hz, 1H,
HHetaryl), 8.63 (s, 1H, (CN)C]CHeN). 13C NMR (DMSO-d6, 63 MHz):
pyridine (13g). Procedure A; brown solid; 87%; mp155e157 ꢀC; 1H
NMR (DMSO-d6, 250 MHz):
d
¼2.58 (s, 3H, CH3), 2.74 (d, 3J¼4.9 Hz,
3H, NHCH3), 6.68 (d, 3J¼7.9 Hz, 1H, HAr), 6.73e6.78 (m, 1H, HAr),
7.07 (dd, 3J¼1.6, 7.8 Hz, 1H, HAr), 7.19e7.29 (m, 2H, HAr), 7.41e7.47
(m, 2H, HAr), 8.00 (d, 4J¼1.9 Hz, 1H, HHetar), 8.17e8.21 (m, 2H, HAr),
d
¼24.8, 25.2, 32.4, 54.0, 82.6, 115.4, 115.9, 118.8, 119.2, 121.7, 122.8,
127.5, 128.7, 128.9, 130.1, 131.2, 131.6, 135.3, 140.5, 144.7, 145.0,
8.57 (d, 4J¼1.9 Hz, 1H, HHetar). 13C NMR (DMSO-d6, 63 MHz):
¼12.5,
d
145.3. IR (ATR, cmꢁ1):
n
¼ 3359ðwÞ, 3114 (w), 3043 (w), 3020 (w),
30.8, 110.1, 117.1, 117.2, 120.9, 124.1, 125.7, 128.5, 129.1, 129.5, 130.1,
~
130.8, 139.5, 142.7, 146.7, 150.0, 150.5. IR (ATR, cmꢁ1):
¼ 3418ðwÞ,
~
n
2954 (w), 2927 (w), 2846 (w), 2219 (w), 1607 (w), 1592 (w), 1520
(w), 1504 (m), 1495 (m), 1460 (m), 1450 (m), 1350 (w), 1307 (m),
1290 (w), 1265 (w), 1184 (m), 1173 (w), 1150 (w), 1049 (w), 991
(w), 898 (m), 885 (w), 843 (w), 779 (w), 755 (s), 746 (s), 717 (w),
696 (m), 667 (w), 627 (m). MS (EI, 70 eV): m/z (%)¼392 (Mþ, 100),
310 (56). HRMS (ESI): calcd for C26H24N4 (Mþ) 392.19955, found
392.199201.
3331 (m), 3015 (w), 2988 (w), 2935 (w), 2842 (w), 2774 (w), 1651
(s), 1633 (s), 1563 (w), 1557 (w), 1504 (w), 1497 (w), 1442 (w), 1413
(w), 1390 (m), 1342 (w), 1315 (w), 1252 (m), 1167 (w), 1112 (m), 1076
(w), 1062 (w), 1028 (w), 957 (w), 905 (w), 773 (w), 744 (m). MS (EI,
70 eV): m/z (%)¼314 (Mþ, 100), 299 (5). HRMS (ESI): calcd for
C20H19N4 (MþHþ) 315.1604, found 315.1612.
3.5.4. 1-tert-Butyl-3-cyano-5-(N-methyl-2-aminophenyl)pyrrolo
[2,3-b]pyridine (13d). Procedure A; orange-brown solid; 78%; mp
3.5.8. 5-(2-Aminophenyl)-3-methyl-1-phenylpyrazolo[3,4-b]pyridine
(13h). Procedure B; white-brown solid; 57%; mp 135e136 ꢀC; 1H
132e133 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼1.75 (s, 9H, CH3),
NMR (DMSO-d6, 250 MHz):
d
¼2.62 (s, 3H, CH3), 4.97 (br, 2H, NH2),
2.59 (d, 3J¼4.9 Hz, 3H, CH3), 4.98 (q, 3J¼4.9 Hz, 1H, NHCH3),
6.65e6.71 (m, 1H, HAr), 6.79e6.82 (d, 3J¼7.6 Hz, 1H, HAr), 7.07e7.14
(m, 2H, HAr), 7.27e7.32 (m, 1H, HAr), 7.52e7.58 (m, 2H, HAr),
8.30e8.33 (m, 3H, HArþHetar), 8.63 (d, 4J¼2.05 Hz, 1H, HHetar). 13C
3
6.56e6.65 (m, 2H, CHAr), 6.98 (dd, JCH¼1.7,7.5 Hz, 1H, CHAr),
7.13e7.20 (m, 1H, CHAr), 7.93 (d, 4J¼2.1 Hz, 1H, CHHetar), 8.31 (d,
4JCH¼2.1 Hz, 1H, CHHetar), 8.48 (s, 1H, (CN)C]CH). 13C NMR (DMSO-
NMR (DMSO-d6, 63 MHz):
d
¼12.1, 115.3, 116.7, 116.8, 119.7, 122.4,
d6, 63 MHz):
d
¼28.7, 30.3, 58.4, 81.7, 109.7, 115.5, 116.0, 120.7, 123.5,
125.2, 128.7, 129.1, 129.2, 130.1, 130.7, 139.3, 143.0, 145.9, 149.3,
127.7, 129.1, 129.3, 130.6, 136.0, 144.7, 145.7, 147.0. IR (ATR, cmꢁ1):
150.0. IR (ATR, cmꢁ1):
¼ 3411ðwÞ, 3335 (m), 3222 (w), 3066 (w),
~
n
~
n
¼ 3405ðmÞ, 3139 (w), 3034 (w), 2981 (w), 2813 (w), 2219 (s),
3045 (w), 3035 (w), 2955 (w), 2920 (w), 1621 (w), 1593 (m), 1500
(m), 1456 (m), 1380 (m), 1347 (m), 1302 (w), 1263 (m), 1245 (m),
1201 (w), 1120 (m), 1076 (m), 1009 (m), 956 (w), 901 (m), 775 (m),
741 (m), 689 (m), 667 (m). MS (EI, 70 eV): m/z (%)¼300 (Mþ, 100),
258 (5). HRMS (ESI): calcd for C19H16N4 (Mþ) 300.13695, found
300.136872. Anal. Calcd for C19H16N4 (300.14): C, 75.98; H, 5.37; N,
18.65. Found: C, 75.59; H, 5.48; N, 18.53.
1714 (w), 1601 (m), 1579 (m), 1514 (s), 1474 (m), 1460 (m), 1405 (m),
1397 (m),1368 (m), 1317 (m),1288 (m), 1263 (m), 1202 (s),1167 (m),
898 (m), 855 (m), 780 (m), 739 (m), 731 (m), 638 (m). MS (EI,
70 eV): m/z (%)¼304 (Mþ, 100), 248 (93), 232 (25). HRMS (ESI):
calcd for C19H21N4 (Mþ) 305.1761, found 305.1762. Anal. Calcd for
C19H20N4 (304.39): C 74.97; H 6.62; N 18.41. Found: C, 74.61; H,
6.85; N, 17.98.
3.5.9. 3-Methyl-5-(N-phenyl-aminophenyl)-1-phenylpyrazolo[3,4-b]
3.5.5. 5-(2-Aminophenyl)-3-cyano-1-tert-butylpyrrolo[2,3-b]pyri-
dine (13e). Procedure B; white-brown solid; 53%; mp 151e153 ꢀC;
pyridine (13i). Procedure B; white-yellow solid; 48%; mp
197e199 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼2.61 (s, 3H, CH3),

I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
5301
6.70e6.75 (m, 1H, HAr), 6.87e6.90 (m, 2H, HAr), 7.10e7.20 (m, 3H,
HAr), 7.27e7.57 (m, 8H, HAr), 8.28e8.31 (m, 2H, HAr), 8.36 (d,
4J¼2.1 Hz, 1H, HHetar), 8.66 (d, 4J¼2.1 Hz, 1H, HHetar). 13C NMR
NMR (DMSO-d6, 63 MHz):
d
¼22.9, 25.0, 25.4, 49.1, 52.3, 111.1, 112.5,
116.5, 118.8, 121.5, 123.4, 127.2, 128.5, 129.7, 136.3, 173.6, 174.0. IR
(ATR, cmꢁ1):
¼ 3046ðwÞ, 2990 (w), 1667 (w), 1587 (w), 1574 (w),
~
n
(DMSO-d6, 63 MHz):
d
¼12.1, 115.9, 116.8, 118.9, 119.6, 120.1, 121.6,
1514 (m), 1487 (w), 1461 (w), 1442 (w), 1392 (m), 1374 (m), 1354
(m), 1343 (m), 1325 (m), 1305 (m), 1279 (m), 1253 (w), 1225 (m),
1143 (m), 1116 (m), 1074 (m), 1065 (m), 1032 (m), 1014 (m), 999 (m),
920 (w), 881 (w), 852 (w), 794 (w), 757 (w), 744 (s), 704 (s), 640
(m), 614 (m). MS (EI, 70 eV): m/z (%)¼310 (Mþ, 100), 295 (8), 281
(47), 267 (13), 254 (31), 241 (19), 227 (12), 207 (31), 173 (9), 155 (9),
140 (9). HRMS (ESI): calcd for C17H18N4S (MþHþ) 311.1325, found
311.1332.
122.8, 125.2, 128.8, 128.9, 129.1, 130.1, 130.8, 131.5, 139.2, 140.5,
143.0, 144.9, 149.2, 150.1. IR (ATR, cmꢁ1):
¼ 3288ðwÞ, 3041 (w),
~
n
2920 (w), 2849 (w), 1591 (m), 1576 (m), 1563 (w), 1520 (w), 1494
(s), 1468 (m), 1455 (m), 1438 (m), 1426 (m), 1411 (m), 1384 (w),
1343 (w), 1299 (m), 1255 (m), 1223 (w), 1172 (w), 1118 (w), 1076
(w), 1026 (w), 957 (w), 908 (w), 883 (w), 838 (w), 774 (w), 743 (s),
706 (m), 688 (m), 665 (m). MS (EI, 70 eV): m/z (%)¼376 (Mþ, 100).
HRMS (ESI): calcd for C25H20N4 (Mþ) 376.16825, found
376.167382.
3.5.14. (Z)-3-Amino-4-((1-methyl-1H-indol-3-yl)methylene)-1-
phenyl-1H-pyrazol-5(4H)-one (15). Procedure D; red-brown solid;
3.5.10. 1-Methyl-6-(N-methyl-2-aminophenyl)pyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (13j). Procedure A; yellow solid; 58%; mp
71%; mp 236e238 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼4.00 (s, 1H,
CH3), 6.30 (s, 2H, NH2), 7.06 (t, 3J¼7.4 Hz, 1H, HAr), 7.35e7.41 (m, 4H,
HAr), 7.64e7.67 (m, 1H, HAr), 8.01e8.04 (m, 2H, HAr), 8.11e8.15 (m,
1H, HAr), 8.24 (s, 1H, C]CHeC), 9.66 (s, 1H, C]CHeN). 13C NMR
240e242 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼2.68 (d, 3H,
3J¼4.6 Hz, CH3), 3.58 (s, 3H, NeCH3), 5.14 (q, 1H, 3J¼4.6 Hz,
NH(CH3)), 6.67e6.75 (m, 2H, HAr), 7.05e7.07 (m, 1H, HAr), 7.25e7.30
(m, 1H, HAr), 8.27 (d, 1H, 4J¼2.2 Hz, HHetar), 8.71 (d, 1H, 4J¼2.3 Hz,
(DMSO-d6, 63 MHz):
d
¼33.8, 110.3, 111.3, 113.4, 117.2, 118.4, 122.1,
122.6, 123.2, 128.5, 128.9, 133.9, 136.9, 139.3, 140.2, 153.2, 161.4. IR
HHetar), 11.82 (br, 1H, NH). 13C NMR (DMSO-d6, 63 MHz):
30.2, 110.0, 110.8, 116.2, 121.8, 129.6, 130.1, 130.2, 136.7, 147.0, 150.5,
d¼28.2,
(ATR, cmꢁ1):
¼ 3443ðwÞ, 3344 (w), 3294 (w), 3162 (w), 3128 (w),
~
n
3063 (w), 2922 (w), 2851 (w), 1732 (w), 1683 (w), 1669 (w), 1636
(w), 1604 (w), 1594 (m), 1497 (w), 1485 (w), 1470 (w), 1433 (m),
1382 (m), 1327 (s), 1311 (m), 1237 (w), 1211 (w), 1153 (m), 1124 (m),
1068 (m), 1016 (w), 919 (w), 891 (w), 871 (w), 786 (w), 772 (m), 741
(s), 702 (m), 689 (m). MS (EI, 70 eV): m/z (%)¼316 (Mþ, 100), 209
(14), 183 (37), 144 (9), 78 (19), 63 (21), 44 (12). HRMS (ESI): calcd for
C19H17N4O (Mþ) 317.1397, found 317.1395.
150.7, 154.2, 161.2. IR (ATR, cmꢁ1):
n
¼ 3404ðmÞ, 3014 (m), 2783
~
(m), 1722 (w), 1714 (w), 1678 (s), 1604 (s), 1580 (m), 1494 (m), 1466
(m), 1433 (m), 1371 (w), 1338 (w), 1306 (w), 1288 (m), 1253 (w),
1168 (m),1021 (m), 959 (w), 879 (w), 794 (s), 738 (s). MS (EI, 70 eV):
m/z (%)¼281 (MꢁHþ, 100). HRMS (ESI): calcd for C15H14O2N4 (Mþ)
282.11113, found 282.110628.
3.5.11. 6-(2-Aminophenyl)-1-methylpyrido[2,3-d]pyrimidine-
3.5.15. 3-Cyano-1-(p-methoxybenzyl)-4-methyl-5-(N-methyl-2-
2,4(1H,3H)-dione (13k). Procedure A; yellow solid; 45%; mp
aminophenyl)pyrrolo[2,3-b]pyridine (16a). Procedure C; white
243e244 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼3.59 (s, 3H, CH3),
solid; 73%; mp 154e155 ꢀC; 1H NMR (CDCl3, 250 MHz):
d¼2.47 (s,
5.03 (br, 2H, NH2), 6.69e6.74 (m, 1H, HAr), 6.83e6.85 (m, 1H, HAr),
3H, CH3), 2.72 (s, 3H, NCH3), 3.73 (s, 3H, OCH3), 5.36 (s, 2H, CH2),
6.66e6.84 (m, 4H, HAr), 6.92e6.95 (dd, 3J¼1.58, 8.0 Hz, 1H, HAr),
7.18e7.31 (m, 3H, HAr), 7.59 (s, 1H, HHetar), 8.18 (s, 1H, (CN)C]CH).
7.08e7.18 (m, 2H, HAr), 8.36 (d, 4J¼2.5 Hz, 1H), 8.78 (m, 4J¼2.5 Hz,
1H), 11.81 (br, 1H, NH). 13C NMR (DMSO-d6, 63 MHz):
d¼28.2, 110.8,
115.6, 116.9, 120.8, 129.1, 130.2, 130.4, 136.2, 145.9, 150.5, 153.9,
13C NMR (CDCl3, 63 MHz):
d
¼15.2, 30.7, 48.3, 55.3, 84.3, 110.0, 114.5,
161.2. IR (ATR, cmꢁ1):
¼ 3444ðwÞ, 3346 (w), 3170 (w), 3027 (w),
116.6,117.0,119.2, 122.9, 127.7,129.3, 129.4, 129.6, 130.8, 135.3, 140.7,
~
n
146.1, 146.8, 147.1, 159.7. IR (ATR, cmꢁ1):
n
¼ 3353ðwÞ, 3120 (w),
~
2846 (w), 1683 (s), 1633 (w), 1607 (s), 1580 (m), 1574 (m), 1503 (m),
1487 (m), 1447 (m), 1429 (m), 1409 (w), 1367 (m), 1345 (m), 1304
(m), 1292 (m), 1265 (m), 1239 (m), 1081 (w), 937 (w), 794 (m), 756
(s), 745 (s), 708 (w), 673 (w), 656 (w). MS (EI, 70 eV): m/z (%)¼267
(MꢁHþ, 100), 224 (6), 169 (7). HRMS (ESI): calcd for C14H12O2N4
(Mþ) 268.09548, found 268.095398.
3042 (w), 2978 (w), 2930 (w), 2904 (w), 2862 (w), 2809 (w), 2214
(s), 1606 (m), 1513 (s), 1410 (m), 1394 (m), 1304 (m), 1292 (m), 1255
(m), 1240 (m), 1179 (m), 1035 (m), 845 (m), 831 (m), 820 (m), 808
(m), 738 (m). MS (EI, 70 eV): m/z (%)¼382 (Mþ, 61), 122 (9), 121
(100). HRMS (ESI): calcd for C24H22N4O (Mþ) 382.17881, found
382.17813. Anal. Calcd for C24H22N4O (382.45): C, 75.37; H, 5.80; N,
14.65. Found: C, 75.37; H, 5.93; N, 14.49.
3.5.12. 1-Methyl-6-(N-phenyl-2-aminophenyl)pyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione (13l). Procedure A; brown solid; 33%; mp
292e293 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼3.53 (s, 1H, CH3),
3.5.16. 5-(2-Aminophenyl)-3-cyano-1-(p-methoxybenzyl)-4-
6.71e6.86 (m, 3H, HAr), 7.12e7.19 (m, 3H, HAr), 7.36e7.41 (m, 3H,
HAr), 7.51e7.56 (m, 1H, HAr), 8.35 (d, 4J¼2.5 Hz, 1H, HHetar), 8.77 (d,
methylpyrrolo[2,3-b]pyridine (16b). Procedure C; yellow solid; 51%;
mp 72e74 ꢀC; 1H NMR (CDCl3, 250 MHz):
d
¼2.52 (s, 3H, CH3), 3.72
4J¼2.5 Hz, 1H, HHetar). 13C NMR (DMSO-d6, 63 MHz):
d
¼116.0, 119.0,
(s, 3H, OCH3), 5.36 (s, 2H, CH2), 6.72e6.83 (m, 4H, HAr), 6.94e6.97
(dd, 3J¼1.5, 7.4 Hz, 1H, HAr), 7.13e7.23 (m, 3H, HAr), 7.59 (s, 1H,
121.7, 123.0, 128.9, 129.3, 129.3, 130.2, 130.9, 136.2, 140.5, 144.7,
150.4, 150.7, 153.9, 161.1. IR (ATR, cmꢁ1):
¼ 3346ðwÞ¼3346 (w),
HHetar), 8.21 (s, 1H, (CN)C]CH). 13C NMR (CDCl3, 63 MHz):
d
¼15.2,
~
n
3152 (w), 3044 (w), 2841 (w), 1693 (s), 1605 (m), 1591 (m), 1573
(m), 1519 (m), 1497 (m), 1477 (m), 1463 (m), 1370 (m), 1339 (m),
1306 (s), 1283 (m), 1262 (m), 1078 (w), 1058 (w),1037 (w), 1028 (w),
963 (w), 933 (w), 906 (w), 871 (m), 858 (m), 793 (m), 754 (s), 747
(s), 700 (m), 672 (m). MS (EI, 70 eV): m/z (%)¼344 (Mþ, 100), 243
(6). HRMS (ESI): calcd for C20H15O2N4 (Mþ) 343.11895, found
343.119401.
48.3, 55.3, 84.3, 114.5, 115.3, 116.6, 118.4, 119.2, 123.0, 127.7, 129.2,
129.5, 129.6, 131.1, 135.3, 140.4, 144.6, 146.1, 146.9, 159.7. IR (ATR,
cmꢁ1):
n
¼ 3454ðwÞ, 3109 (w), 2215 (s), 1611 (m), 1512 (s), 1414
~
(m), 1393 (m), 1294 (m), 1246 (m), 1172 (m), 1030 (m), 810 (m), 748
(m). MS (EI, 70 eV): m/z (%)¼368 (Mþ, 57), 121 (100). HRMS (ESI):
calcd for C23H21N4O (Mþ) 369.171, found 369.1708.
3.5.17. 3-Cyano1-cyclohexyl-4-methyl-5-(N-methyl-2-aminophenyl)
3.5.13. (Z)-5-((1H-Indol-3-yl)methylene)-2-(piperidin-1-yl)thiazol-
pyrrolo[2,3-b]pyridine (16c). Procedure C; white solid; 67%; mp
4(5H)-iminium chloride (14). Procedure D; orange solid; 83%; mp
159e160 ꢀC; 1H NMR (CDCl3, 250 MHz):
d¼1.17e1.31 (m, 1H, HCy-
297e299 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼1.71 (m, 6H, CH2),
clohexyl), 1.431.65 (m, 5H, HCyclohexyl), 1.78e1.93 (m, 2H, HCyclohexyl),
2.08e2.13 (m, 2H, HCyclohexyl), 2.48 (s, 3H, CH3), 2.72 (s, 3H, NCH3),
4.72e4.81 (m, 1H, HCyclohexyl), 6.67e6.77 (m, 2H, HAr), 6.94 (dd,
3J¼1.5, 8.1 Hz, 1H, HAr), 7.25e7.31 (m, 1H, HAr), 7.78 (s, 1H, HHetar),
3.73 (m, 2H, CH2), 3.99 (m, 2H, CH2), 7.24e7.32 (m, 2H, HAr),
7.52e7.58 (m, 1H, HAr), 8.00 (s, 1H, C]CHeC), 8.04e8.11 (m, 1H,
HAr), 8.98 (m, 1H, C]CHeN), 10.02 (br, NH3þ
), 12.54 (br, NH). 13C

5302
I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
8.15 (s, 1H, (CN)C]CH). 13C NMR (CDCl3, 63 MHz):
d
¼15.2, 25.3,
(m), 756 (m), 745 (s), 676 (m), 648 (m), 634 (m), 608 (m). HRMS
25.6, 30.6, 33.5, 54.1, 83.7, 109.7, 116.7, 117.0, 119.4, 122.8, 129.2,
(ESI): calcd for C21H18N4O (MþHþ) 343.1553, found 343.1551.
129.4, 130.7, 132.9, 140.6, 145.6, 146.6, 147.0. IR (ATR, cmꢁ1):
~
n
¼ 3326ðmÞ, 3130 (w), 2932 (m), 2855 (w), 2809 (w), 2215 (m),
3.5.22. 8-tert-Butyl-10-cyano-5H-6,8-dihydro-6-oxo-benzo[f]pyrrolo
[2,3-b][1,7]naphthyridine (17b). Procedure C; white solid; 44%; mp
2156 (w), 1575 (m), 1514 (s), 1486 (m), 1452 (m), 1391 (m), 1283 (m),
1184 (m), 1169 (m), 991 (m), 838 (m), 745 (s), 647 (s), 618 (s). MS (EI,
70 eV): m/z (%)¼344 (Mþ, 100), 262 (83), 247 (30), 231 (14). HRMS
(ESI): calcd for C22H24N4 (Mþ) 344.19955, found 344.19893.
356e357 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d
¼1.86 (s, 9H, (CH3)3),
7.30e7.56 (m, 1H, HAr), 8.61e8.71 (m, 2H, HAr), 9.74 (s, 1H, HAr),
11.99 (br, 1H, NH). 13C NMR (DMSO-d6, 63 MHz):
d
¼28.8, 58.9, 85.0,
114.5,116.1,116.2,116.7,122.6,123.0, 123.5, 124.4,129.5, 136.3, 139.0,
140.6, 146.0, 160.1 (CAr). IR (ATR, cmꢁ1):
¼ 3186ðwÞ, 3151 (w),
~
n
3.5.18. 5-(2-Aminophenyl)-3-cyano-1-cyclohexyl-4-methylpyrrolo
[2,3-b]pyridine (16d). Procedure C; yellow solid; 45%; mp
3055 (w), 3013 (w), 2967 (w), 2934 (w), 2873 (w), 2223 (m), 1665
(s),1395 (m), 1381 (m), 1370 (m), 1350 (m), 1329 (m), 1228 (m), 1186
(m), 1111 (s), 879 (m), 826 (m), 743 (s), 657 (s). MS (EI, 70 eV): m/z
(%)¼316 (Mþ, 24), 260 (100), 232 (14), 207 (13). HRMS (ESI): calcd
for C19H16N4O (Mþ) 316.13158, found 316.13186.
170e171 ꢀC; 1H NMR (CDCl3, 250 MHz):
d
¼1.18e1.31 (m, 1H, HCy-
clohexyl), 1.43e1.77 (m, 5H, HCyclohexyl), 1.86e1.91 (m, 2H, HCyclohexyl),
2.08e2.11 (m, 2H, HCyclohexyl), 2.52 (s, 3H, CH3), 3.42 (br, 2H, NH2),
4.71e4.81 (m, 1H, HCyclohexyl), 6.72e6.80 (m, 2H, HAr), 6.95 (dd,
3J¼1.5, 7.6 Hz, 1H, HAr), 7.13e7.18 (m, 1H, HAr), 7.77 (s, 1H, HHetar),
8.17 (s, 1H, (CN)C]CH). 13C NMR (CDCl3, 63 MHz):
d¼15.2 (CH3),
Acknowledgements
25.3 (CH2), 25.6 (CH2), 33.5 (CH2), 54.1 (CH), 83.7 (C]CeCN), 115.2
(CHAr), 116.9 (CHAr), 118.4 (CAr), 119.4 (CAr), 123.1 (CAr), 129.1 (CAr),
129.3 (CHAr), 131.1 (CHAr), 132.9 (CHAr), 140.3 (CAr), 144.5 (CAr), 145.6
~
Financial support by the BMBF (grant No. 03IS2081A, scholar-
ship for Habilitation of Dr. V.O.I.) is gratefully acknowledged.
(CHAr), 146.3 (CAr). IR (ATR, cmꢁ1):
n
¼ 3432ðmÞ, 3349 (w), 2932
(m), 2853 (w), 2212 (m), 2160 (w),1617 (m),1521 (s),1450 (m),1389
(m), 1201 (m), 1189 (m), 859 (m), 756 (s), 644 (s), 624 (s). MS (EI,
70 eV): m/z (%)¼330 (Mþ, 45.78), 248 (100), 233 (19). HRMS (ESI):
calcd for C21H22N4 (Mþ) 330.18390, found 330.183723.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.05.037.
References and notes
3.5.19. 1-tert-Butyl-3-cyano-4-methyl-5-(N-methyl-2-aminophenyl)
pyrrolo[2,3-b]pyridine (16e). Procedure C; white solid; 55%; mp
1. Silverman, R. B. The Organic Chemistry of Drug Design, and Drug Action, 2nd Ed.;
Elsevier Academic: San Diego, 2004; ISBN 0-12-643732-7, p 617.
2. Parker, W. B. Chem. Rev. 2009, 109, 2880.
151e152 ꢀC; 1H NMR (CDCl3, 250 MHz):
d
¼1.77 (s, 9H, (CH3)3), 2.46
(s, 3H, CH3) , 2.71 (s, 3H, NCH3), 6.63e6.74 (m, 2H, HAr), 6.92 (dd,
3J¼1.5, 7.4 Hz, 1H, HAr), 7.22e7.28 (m, 1H, HAr), 7.81 (s, 1H, (CN)C]
3. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,
V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield,
J. J. Med. Chem. 1988, 31, 2235; (b) Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. Mini-
Rev. Med. Chem. 2007, 7, 1108; (c) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.;
Darrow, J. W.; Pippin, D. A. Comb. Chem. High Throughput Screen. 2004, 7, 473;
(d) Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65.
4. (a) Dubey, P. K.; Kumar, R. V.; Naidu, A.; Kulkarni, S. M. A. Asian J. Chem. 2002,
14, 1129; (b) Lee, S. Ch.; Choi, J. S.; Oh, J. H.; Park, B.; Kim, Y. E.; Lee, J. H.; Shin,
D.; Kim, Ch. M.; Hyun, Y. -L.; Lee, Ch. S.; Cho, J. -M.; Ro, S. WO 2007083978,
2007; Chem. Abstr. 2007, 147, 817587; (c) Kelly, M. G.; Kincaid, J.; Duncton, M.;
Sahasrabudhe, K.; Janagani, S.; Upasani, R. B.; Wu, G.; Fang, Y.; Wei, Zh. -L. U.S.
Patent 2,006,194,801, 2006; Chem. Abstr. 2006, 145, 889269; (d) Randolph, J. T.;
Chen, H.; Degoey, D. A.; Flentge, Ch. A.; Flosi, W. J.; Grampovnik, D. J.; Huang, P.
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2,005,159,469, 2005; Chem. Abstr. 2005, 143, 641882; (e) Kivlighn, S. D.; Zin-
garo, G. J.; Gabel, R. A.; Broten, T. P.; Schorn, T. W.; Schaffer, L. W.; Naylor, E. M.;
Chakravarty, P. K.; Patchett, A. A. Am. J. Hypertens. 1995, 8, 58.
CH), 8.12 (s,1H, HHetar).13C NMR (CDCl3, 63 MHz):
d¼15.2, 29.2, 30.6,
58.5, 82.6, 109.7, 116.7, 117.2, 120.5, 123.0, 128.6, 129.3, 130.7, 133.7,
140.0, 145.9, 146.6, 147.1. IR (ATR, cmꢁ1):
¼ 3385ðwÞ, 3170 (w),
~
n
3039 (w), 2975 (w), 2904 (w), 2863 (w), 2810 (w), 2210 (m), 1593
(m), 1513 (s), 1486 (m), 1392 (m), 1289 (m), 1199 (m), 1167 (m), 753
(m), 743 (s), 650 (m), 622 (m). MS (EI, 70 eV): m/z (%)¼318 (Mþ,100),
262 (85), 247 (54), 231 (21). HRMS (ESI): calcd for C20H22N4 (Mþ)
318.18390, found 318.18350. Anal. Calcd for C20H22N4 (318.42): C,
75.44; H, 6.96; N, 17.60. Found: C, 75.31; H, 7.05; N, 17.50.
3.5.20. 5-(2-Aminophenyl)-1-tert-butyl-3-cyano-4-methylpyrrolo
[2,3-b]pyridine (16f). Procedure C; white-yellow solid; 35%; mp
150e151 ꢀC; 1H NMR (CDCl3, 500 MHz):
d
¼1.78 (s, 9H, (CH3)3), 2.52
5. Stasch, J. P.; Becker, E. M.; Alonso-Alija, C.; Apeler, H.; Dembowsky, K.; Feurer,
A.; Gerzer, R.; Minuth, T.; Perzborn, E.; Pleiss, U.; Schroder, H.; Schroeder, W.;
Stahl, E.; Steinke, W.; Straub, A.; Schramm, M. Nature 2001, 410, 212.
6. Witherington, J.; Bordas, V.; Gaiba, A.; Garton, N. S.; Naylor, A.; Rawlings, A. D.;
Slingsby, B. P.; Smith, D. G.; Takle, A. K.; Ward, R. W. Bioorg. Med. Chem. Lett.
2003, 13, 3055.
(s, 3H, CH3), 3.56 (br, 2H, NH2), 6.75e6.81 (m, 2H, HAr), 6.97 (dd,
3J¼1.5, 8.0 Hz, 1H, HAr), 7.14e7.19 (m, 1H, HAr), 7.82 (s, 1H, HHetar),
8.16 (s, 1H, HHetar). 13C NMR (CDCl3, 75 MHz):
d¼15.2, 29.2, 58.54,
82.6, 115.2, 117.2, 118.4, 120.5, 123.2, 128.7, 129.1, 131.1, 133.7, 139.7,
144.5, 145.6, 146.6. IR (ATR, cmꢁ1):
n
¼ 3434ðwÞ, 2969 (w), 2216
~
7. (a) Mantovanini, M.; Melillo, G.; Daffonchio, L. WO 9504742, 1995; Chem. Abstr.
1995, 122, 314537.
(m), 1614 (m), 1520 (s), 1393 (m),1349 (m), 1290 (m), 1206 (m), 1195
(m), 746 (s), 649 (m), 630 (m). MS (EI, 70 eV): m/z (%)¼304 (Mþ, 52),
248 (100), 247 (23), 233 (35), 232 (18). HRMS (ESI): calcd for
C19H20N4 (Mþ) 304.16825, found 304.169003.
8. (a) Tsushima, M.; Kano, I. EP 0605836, 1994; Chem. Abstr. 1995, 122, 31198; (b)
Sunagava, M; Yamaga, H.; Sumita, I. WO 9958536, 1999; Chem. Abstr. 1999, 131,
336878; (c) Kiyoaki, K.; Tamako, T.; Hiroko, O.; Naoki, Y.; Fumiya, H.; Yasuka-
katsu, Y.; Fukio, K.; Motohiro, N.; Tomoya, M.; Seiji, S.; Tacashi, T.; Shigeharu, I.
U.S. Patent 5,200,407, 1991; Chem. Abstr. 1991, 114, 228904; (d) Walczynski, K.;
Zuiderveld, O. P.; Timmerman, H. Eur. J. Med. Chem. Ther. 2005, 40, 15.
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Panek, R. L. Bioorg. Med. Chem. Lett. 1997, 7, 2415; (b) Thompson, A. M.; Delaney,
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3.5.21. 10-Cyano-8-cyclohexyl-5H-6,8-dihydro-6-oxo-benzo[f]pyr-
rolo[2,3-b][1,7]naphthyridine (17a). Procedure C; white solid; 40%;
mp 311e313 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
d¼1.28e1.33 (m,
1H, HCyclohexyl), 1.47e1.60 (m, 2H, HCyclohexyl), 1.74e1.78 (m, 1H,
HCyclohexyl), 1.91e2.10 (m, 2H, HCyclohexyl), 4.87e4.95 (m, 1H, HCyclo-
hexyl), 7.32e7.37 (m, 1H, HAr), 7.50e7.58 (m, 1H, HAr), 8.63 (d, 1H,
3J¼8.0 Hz, HHetar), 8.84 (s, 1H, (CN)C]CH), 9.74 (s, 1H, HHetar), 12.01
10. (a) Grand, E. K.; Chase, A. J.; Heath, C.; Rahemtulla, A.; Cross, N. C. P. Leukemia
2004, 18, 962; (b) Trudel, S.; Ely, S.; Farooqi, Y.; Affer, M.; Robbiani, D. F.; Chesi,
M.; Bergsagel, P. L. Blood 2004, 103, 3521.
11. (a) Iaroshenko, V. O.; Volochnyuk, D. M.; Wang, Y.; Vovk, M. V.; Boiko, V. J.;
Rusanov, E. B.; Groth, U. M.; Tolmachev, A. O. Synthesis 2007, 3309; (b) Iar-
oshenko, V. O.; Wang, Y.; Sevenard, D. V.; Volochnyuk, D. M. Synthesis 2009,
1851; (c) Iaroshenko, V. O.; Sevenard, D. V.; Volochnyuk, D. M.; Wang, Y.;
Martiloga, A.; Tolmachev, A. O. Synthesis 2009, 1865; (d) Volochnyuk, D. M.;
Pushechnikov, A. O.; Krotko, D. G.; Sibgatulin, D. A.; Kovalyova, S. A.; Tolmachev,
A. A. Synthesis 2003, 1531; (e) Iaroshenko, V. O.; Sevenard, D. V.; Kotljarov, A.;
Volochnyuk, D. M.; Tolmachev, A. O.; Sosnovskikh, V. Ya. Synthesis 2009, 731.
(s, 1H, NH). 13C NMR (DMSO-d6, 63 MHz):
d
¼24.8, 25.2, 32.4, 54.3,
86.0, 113.2, 116.1, 116.3, 116.6, 122.5, 122.9, 123.7, 125.0, 129.4, 136.2,
138.3, 141.4, 145.2, 160.1. IR (ATR, cmꢁ1):
¼ 3140ðwÞ, 3119 (w),
~
n
3054 (w), 3002 (w), 2923 (w), 2857 (w), 2221 (m), 1662 (m), 1651
(m), 1505(m), 1445 (m), 1348 (m), 1292 (m), 1178 (m), 882 (m), 823

I. Knepper et al. / Tetrahedron 67 (2011) 5293e5303
5303
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M.; Langer, P.; Tolmachev, A. A.; Sosnovskikh, V. Ya Synthesis 2010, 671.
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2009, 3719.
13. (a) Plaskon, A. S.; Ryabukhin, S. V.; Volochnyuk, D. M.; Gavrilenko, K. S.; Shi-
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Iaroshenko, V. O.; Ali, I.; Mkrtchyan, S.; Villinger, A.; Tolmachev, A.; Langer, P.
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kobyan, A.; Maalik, A.; Supe, L.; Villinger, A.; Tolmachev, A.; Ostrovskyi, D.;
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18. CCDC 801766e801770 contain the crystallographic data (excluding structure
factors) for the structures of 13e, 13l, 13h, 14 and 16b reported in this paper.
These data have been deposited with the Cambridge Crystallographic Data
Centre as Supplementary data and can be obtained free of charge on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/data_request/cif.