Efficient synthesis of aminomethylated azaindoles and corresponding pyrrole-fused derivatives by copper-catalyzed domino multicomponent coupling and cyclization

Article abstract of DOI:10.1016/j.tet.2011.12.059

Efficient methods for the synthesis of aminomethylated azaindole derivatives via domino copper-catalyzed multicomponent coupling and cyclization have been developed. Using various secondary amines and aldehydes, N-substituted 3-ethynyl-4-aminopyridine was

Full text of DOI:10.1016/j.tet.2011.12.059

Tetrahedron 68 (2012) 1695e1703
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Efficient synthesis of aminomethylated azaindoles and corresponding
pyrrole-fused derivatives by copper-catalyzed domino multicomponent coupling
and cyclization
*
*
Zengye Hou, Yamato Suzuki, Shinya Oishi, Nobutaka Fujii , Hiroaki Ohno
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient methods for the synthesis of aminomethylated azaindole derivatives via domino copper-
catalyzed multicomponent coupling and cyclization have been developed. Using various secondary
amines and aldehydes, N-substituted 3-ethynyl-4-aminopyridine was converted to substituted azain-
doles in moderate to excellent yields. By use of a 3,4-diaminopyridine derivative bearing two alkynyl
groups, the corresponding pyrrole-fused azaindoles were synthesized by controlled stepwise cyclization.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 19 November 2011
Received in revised form 19 December 2011
Accepted 21 December 2011
Available online 24 December 2011
Keywords:
CK2 inhibitor
Multicomponent reaction
Azaindole
Regioselective
Pyrrole-fused azaindole
(HCHO)n
NR2
1. Introduction
R2NH
CuBr
Azaindoles and related heteroaromatic ring systems are com-
mon scaffolds in biologically active natural and synthetic com-
pounds. Their widespread application as pharmaceutical agents1e7
makes them attractive synthetic targets. Several synthetic routes to
access azaindoles are described in the literature, most of which rely
on linear synthesis utilizing the conventional cyclization of ortho-
amino-alkynyl pyridines promoted by bases or transition met-
als.8e13 However, few methods have been reported for azaindole
synthesis based on multiple component reactions, which provide
a divergent approach to functionalized azaindoles in a single
step.14e17
We recently reported the direct synthesis of 2-(aminomethyl)
indoles 3 via copper-catalyzed domino three-component coupling
and cyclization reactions of ethynylaniline 1 (Scheme 1).18e20 The
mechanism of this reaction involves the formation of the prop-
argylamine intermediate 2 by Mannich-type three-component
coupling of 1 with paraformaldehyde and a secondary amine, and
subsequent copper-catalyzed intramolecular cyclization. Using
a modified protocol, we developed an efficient synthesis of a series
of aminomethylated dipyrroloarenes by direct biscyclization.21
N
NR2
NHTs
Ts
NHTs
1
2
3
Scheme 1. Copper-catalyzed domino three-component coupling and cyclization.
As a part of our ongoing project directed toward development of
novel CK2 inhibitors,22,23 we designed aminomethylated azaindole
derivatives 4 and more complicated pyrrole-fused azaindole de-
rivatives 5 as potential drug-like templates (Fig. 1). They are con-
sidered to be synthesized by a copper-catalyzed three-component
coupling and cyclization reaction. Here, we report our research on
the synthesis of aminomethylated azaindole derivatives 4 using
various aldehydes and secondary amines. The synthesis of corre-
sponding pyrrole-fused derivatives 5 by a controlled stepwise cy-
clization is also depicted.24,25
N
RN
4
N
RN
5
N
H
H2N
R2
R2
R2
N
N
R1
R2
R1
* Corresponding authors. E-mail addresses: nfujii@pharm.kyoto-u.ac.jp (N. Fujii),
hohno@pharm.kyoto-u.ac.jp (H. Ohno).
Fig. 1. Synthetic targets 4 and 5 as potential drug-like templates.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.059

1696
Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
2. Results and discussion
component coupling-cyclization (Table 1). We started our in-
vestigation by treating 6a with paraformaldehyde and dipropyl-
amine in dioxane at 80 ꢀC in the presence of 10 mol % of CuI (entry
1). The initial Mannich-type three-component coupling was found
to proceed readily to afford 8a by TLC. However, the subsequent
intramolecular hydroamination was rather slow to yield the de-
sired cyclization product 7a as the deacetylated form in low yield
(40%),26 accompanied by the formation of undesired bis-
aminomethylated side product 9a in 10% yield. Addition of
K3PO4 resulted in decomposition of the substrate (entry 2),
whereas Et3N slightly improved the yield of 7a (49%, entry 3).
According to the previous study, the counteranion of copper cat-
alysts considerably affects the reactivity of the alkyne toward
intramolecular hydroamination.18,21 Among the copper salts in-
vestigated (CuI, CuBr, CuCl, entries 3e5), CuCl afforded the highest
yield of 7a (61%, entry 5). Considering that AcOH (resulted in situ
from 6a by the deacetylation with water formed in the step of
Mannich reaction) might hinder intramolecular hydroamination,
we applied MS4A as an additive to remove water and/or AcOH. As
hoped, addition of MS4A dramatically accelerated the cyclization
rate to yield 7a in 85% yield without formation of the side product
9a (entry 6). Next, we examined the scope of the 2-(aminomethyl)
azaindole formation using several secondary amines (entries
7e10). All the secondary amines tested here proved to be ac-
ceptable as amine components to yield desired products 7be7e in
high yields (71e86%).
We also investigated the three-component synthesis of 2-(ami-
nomethyl)azaindoles using alkyl or aryl aldehydes (Scheme 3).
Treating 6a with butanal and piperidine under optimized conditions
afforded the three-component coupling intermediate 10a without
formation of the desired cyclization product 11a. Instead of Et3N, use
of the relatively strong base DBU was effective in promoting the
intramolecular hydroamination of 10a. After complete formation of
10a monitored by TLC, DBU (2 equiv) was added to the reaction
mixture to give the desired azaindole 11a in 68% yield in a one-pot
manner (Eq. 1). Meanwhile, treatment of 6a with benzaldehyde
and piperidine under standard conditions afforded the three-
component coupling intermediate 10b in 59% yield, mixed with an
inseparable co-product 12 in 18% yield. Although treatment of this
mixture even after isolation with DBU was ineffective (leading to
formation of undesired 1,6-naphthyridine 13 in 60% yield), re-
placement of DBU with K3PO4 as a base afforded the desired
azaindole 11b in a moderate yield (56%, Eq. 2). Formation of the
We initially designed a synthetic route to 4 and 5 through
a common starting material 6 (Scheme 2). The azaindoles 4
bearing an aminomethyl group can be directed from their nitro
congener 7 by reduction. The nitroazaindole 7 is considered to be
synthesized by the copper-catalyzed three-component coupling
and cyclization reaction of 6 with various aldehydes and second-
ary amines. The amino group of 4 is envisioned to facilitate
a regioselective ortho-bromination, permitting introduction of an
alkynyl group by Sonogashira coupling. Finally, the subsequent
intramolecular cyclization would afford the pyrrole-fused azain-
doles 5.
N
R1CHO, R22NH
N
[Cu]
O2N
O2N
R2
RN
N
NHR
R1
R2
three-component
reduction
coupling & cyclization
6
7
N
Br
H2N
N
H2N
R2
R2
RN
R2
RN
N
N
R1
R1
R2
Sonogashira
coupling
regioselective
bromination
4
N
N
N
PgHN
H
R2
N
R2
RN
R2
RN
N
R1
R1
R2
intramolecular
cyclization
5
Scheme 2. Initial strategy for the synthesis of 4 and 5.
In our previous study on three-component indole formation,
the intramolecular hydroamination required N-substituted ethy-
nylanilines.18,21 Therefore, 3-ethynyl-4-aminopyridine 6a having
an acetyl group was synthesized (see Experimental 4.2) and ap-
plied to optimize the reaction conditions for the domino three-
Table 1
Synthesis of azaindole derivatives 7 using paraformaldehyde
N
N
N
(HCHO)n (2 equiv), R2NH (1 equiv)
[Cu] (10 mol %)
N
base (2 equiv), additive
O2N
+
O2N
+
O2N
NR2
NR2
O2N
HN
NHAc
HN
dioxane, 80 ºC
NHAc
6a
NR2
NR2
7
8
9
Entry
[Cu]
Base
Additive
R2NH
Time (h)
Yielda % (product)
7
8
9
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
d
d
(n-Pr)2NH
(n-Pr)2NH
(n-Pr)2NH
(n-Pr)2NH
(n-Pr)2NH
(n-Pr)2NH
Piperidine
(i-Pr)2NH
Et2NH
10
2
10
10
10
2
2
1.5
2
40 (7a)
20 (8a)
Decomp.
17 (8a)
10 (8a)
13 (8a)
10 (9a)
K3PO4
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
d
d
49 (7a)
42 (7a)
61 (7a)
85 (7a)
71 (7b)
81 (7c)
73 (7d)
86 (7e)
4 (9a)
trace (9a)
5 (9a)
d
d
MS4A
MS4A
MS4A
MS4A
MS4A
Trace (8a)
10
Diallylamine
1
a
Isolated yields.

Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
1697
naphthyridine 13 is attributable to isomerization of the alkyne 10b to
the corresponding allene by the action of DBU followed by 6-endo
cyclization and elimination of piperidine.
azaindole 17. The three-component coupling-cyclization of 17
would afford the desired pyrroloazaindoles 5.
N
R1CHO
N
R22NH
[Cu]
n-PrCHO (2 equiv)
N
N
N
N
H
piperidine (1 equiv)
CuCl (10 mol %)
N
H
PgHN
R2
R2
RN
O2N
O2N
NHR
N
N
NH2
dioxane, 80 ºC
15 min
NHAc
10a
regioselective
cyclization
R1
NHAc
5
16
17
-Pr
n
6a
N
Scheme 5. Revised strategy for the synthesis of pyrroloazaindoles 5.
We started our synthesis from commercially available 3,4-
diaminopyridine 18 (Scheme 6). Treating 18 with bromine in 48%
aqueous HBr afforded the desired bis-brominated product 19.27
Sonogashira coupling of 19 with an excessive amount of trime-
thylsilylacetylene failed to introduce two alkynyl groups, instead
yielding a mono-alkynylated product 20 in 80% yield. We expected
that the nucleophilicity of the amino group of 20 at the 4-position
would be lower than that on the 3-position owing to delocalization
of the nitrogen non-bonding electrons into the pyridine ring. As
hoped, by treating 20 with 2 equiv of MsCl in pyridine in the
presence of DMAP, regioselective bis-mesylation of the amino
group at the 3-position proceeded readily to produce 21 in 73%
yield. Sonogashira coupling of 21 with trimethylsilylacetylene
afforded the desired aminopyridine derivative 22 with two alkynyl
groups. Introduction of electron-withdrawing Ms groups would
result in a decrease of electron density of the pyridine ring, facili-
tating a second Sonogashira coupling at the 5-position. Subsequent
deprotection of TMS groups and one of the Ms groups produced 23,
which underwent regioselective monocyclization in the presence
of Et3N and CuI to yield 24 in 57% yield in two steps. Then, by use of
standard methods for acetylation or mesylation, N-substituted
amino azaindoles 25 and 26 with Ac or Ms group, respectively, were
synthesized.
DBU (2 equiv)
O2N
HN
(1)
80 ºC, 30 min
68% (one-pot)
N
-Pr
n
11a
N
PhCHO (2 equiv)
piperidine (1 equiv)
CuCl (10 mol %)
N
O2N
N
6a
+ O2N
NHAc
dioxane, 80 ºC
30 min
HN
12 (18%)
Ph
10b (59%)
N
N
N
base (2 equiv)
CuCl (10 mol %)
O2N
O2N
HN
(2)
N
dioxane, 80 ºC
Ph
11b
Ph
13
DBU (0.5 h)
K3PO4 (4.5 h)
0%
56%
60%
0%
Scheme 3. Synthesis of azaindole derivatives 11 using n-PrCHO or PhCHO.
With a series of azaindole derivatives 7 and 11 bearing a nitro
group in hand, we tested the reduction of the nitro group and
subsequent regioselective ortho-bromination (Scheme 4). Treat-
ment of 7a with Pd/C under a H2 atmosphere enabled the reduction
to afford 14 bearing an amino group. However, bromination of 14
with 1.0 equiv Br2 or NBS failed to yield the desired product 15,
resulting in a mixture of mono- and bis-brominated products with
simultaneous decomposition of the substrate 14. 1H NMR indicated
that the 3-position of the azaindole 14 prefers to undergo bromi-
nation rather than the position ortho to the amino group. Protection
of the indole with a Ts or Boc group was unsuccessful. Faced with
the difficulty of regioselective bromination and the instability of 14,
we decided to abort this route and seek a new strategy for the
synthesis of 5.
TMS
N
Br
N
Br2, 48% HBr
PdCl2(PPh3)2, CuI, Et3N
H2N
TMS
H2N
Br
95 ºC, 5 h
(45%)
dioxane, 70 ºC, 1 h
(80%)
NH2
18
NH2
19
TMS
PdCl2(PPh3)2
CuI, Et3N
TMS
MsCl
DMAP
N
N
pyridine, rt
12 h
(73%)
dioxane, 70 ºC
4 h
H2N
Br
Ms2N
Br
NH2
N
NH2
N
(72%)
20
21
TMS
K2CO3
MeOH
CuI, Et3N
N
R
N
Ms2N
MsHN
rt, 30 min
(83%)
dioxane
70 ºC, 1 h
(69%)
Pd/C, H2
3
O2N
H2N
NH2
22
TMS
NH2
23
HN
Me OH, rt, 1 h
(85%)
HN
N( -Pr)
n
N( -Pr)2
n
2
7a
N
14 (R = H)
15 (R = Br)
Br2 or NBS
(1 equiv)
1) Ac2O, DMAP, Et3N, 70 ºC, 5 h
N
H
Scheme 4. Unsuccessful ortho-bromination of aminoazaindole 14.
2) K2CO3, MeOH, rt, 5 min
N
NHAc
25
(25% from 24)
N
Ms
Considering the difficulty in introduction of an alkynyl group
after formation of an azaindole framework, we designed a new
route to access 5 from a 3,4-diaminopyridine derivative 16 bearing
two alkynyl groups (Scheme 5). We expected that regioselective
introduction of an electron-withdrawing protecting group (Pg)
would facilitate controlled monocyclization of 16 to produce
N
NH2
24
MsCl, NaH
N
THF, –20 ºC to rt, 2 h
(53%)
Ms
NHMs
26
Scheme 6. Synthesis of azaindole derivatives 25 and 26.

1698
Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
Three-component coupling and cyclization of 25 with para-
N
N
formaldehyde and dipropylamine was first investigated under
the condition optimized in Table 1 (Scheme 7). The Mannich-
type coupling product 28 was isolated without formation of
the desired cyclization product 27 even with a prolonged re-
action time. In our previous study on three-component indole
formation, the rate of hydroamination was significantly de-
pendent upon the acidity of the proton on the nitrogen atom.18,21
CDCl3
N
N
(31/29 = 4:1)
N(n-Pr)2
Ms
Ms
rt, 24 h
NHMs
MsN
N(n-Pr)2
29
31
Scheme 8. Ring-cleavage reaction of 29 in CDCl3.
In case of substrate 6a (Scheme 3),
a highly electron-
withdrawing nitro group ortho to the amino group would con-
tribute to an increase in the acidity of the acetamide proton,
thereby facilitating hydroamination. The acidity of acetamide
proton of 25 (Scheme 7) was considered to be insufficient to
promote cyclization.
For suppressing this undesired ring-cleavage reaction and un-
dertaking further functionalization of the N-protected pyrroloa-
zaindole 29, we tested the deprotection of Ms groups (Scheme 9).
To our surprise, treating 29 with Cs2CO3 in MeOH at 70 ꢀC afforded
a mono-deprotected ring-cleavage product 32 in 12% yield, to-
gether with the major product 33, which was considered to be
generated from 32 by its recyclization. A plausible mechanism for
the formation of 33 is shown in Scheme 10. First, the carbanion 34
would be formed by deprotonation of the sulfonamide 32 derived
from the ring-cleavage reaction of 29. The subsequent 6-exo
cyclization of 34 followed by an isomerization of alkene would af-
ford 33.
(HCHO)n (2 equiv)
N
(n-Pr)2NH (1 equiv)
N
CuCl (10 mol %)
Et3N (2 equiv), MS4A
N
H
N
H
HN
dioxane, 80 ºC
5 h
NHAc
R
N(n-Pr)2
25 (R = H)
27 (0%)
28 [R = CH2N(n-Pr)2] (42%)
Scheme 7. Attempted synthesis of pyrroloazaindole derivative 27.
N
N
Cs2CO3
MeOH
We therefore tested three-component coupling and cycliza-
tion with more acidic methanesulfonamide 26 (Table 2). Treat-
ing 26 with paraformaldehyde and dipropylamine at room
temperature in the presence of 5 mol % of CuI afforded the de-
sired pyrroloazaindole 29 in a low yield (30%) accompanied by
generation of a considerable amount of the 2-unsubstituted
pyrroloazaindole 30 (entry 1). Use of a mixed solvent of tolu-
ene and dioxane partially suppressed the undesired cyclization
at the terminal alkyne before the Mannich-type reaction,
resulting in a slightly improved yield of 29 (45%, entry 2). For
accelerating the rate of the Mannich-type reaction, a mixture of
paraformaldehyde and dipropylamine in toluene was heated at
80 ꢀC for 5 min, then added to the mixture of 26 in dioxane. As
hoped, the desired product 29 was isolated in an improved yield
(70%) with only a trace amount of the undesired product 30
(entry 3). The pyrroloazaindole 29 is stable in a solid state,
whereas it was found to readily undergo a ring-cleavage reaction
in CDCl3. After 24 h at room temperature, formation of a ring-
cleavage product 31 (31/29¼4:1) was detected by 1H NMR
analysis (Scheme 8).
N
H
N
H
+
29
70 ºC, 3 h
NHMs
HN
O
33 (52%)
N(n-Pr)2
S
N(n-Pr)2
O
32 (12%)
Scheme 9. Attempted removal of the Ms groups of 29.
N
N
N
N
H
H
HN
N(n-Pr)2
NHMs
32
S
O
O
33
N( -Pr)2
n
base deprotonation
isomerization
N
N
N
R
N
R
HN
O
HN
S
N( -Pr)2
n
6-exo-dig
S
O
CH2 N(n-Pr)2
O
O
Table 2
Synthesis of pyrroloazaindole derivative 29a
34 (R = Ms or H)
35
(HCHO)n
(n-Pr)2NH
CuI
N
Scheme 10. Plausible mechanism for the formation of 33.
N
N
N
+
N
N
Ms
Ms
Ms
MsN
solvent, rt
30 min
MsN
NHMs
26
N(n-Pr)2
Faced with the difficulty of the deprotection of Ms groups from
29, we decided to remove the Ms group of 26 on the pyrrole ring
first (Scheme 11). The deprotection of 26 proceeded readily to give
36, which underwent three-component coupling and cyclization
with paraformaldehyde and dipropylamine under the condition
optimized in Table 2 to furnish the mono-deprotected pyrroloa-
zaindole 37 in a slightly decreased yield (65%). To our delight, fully
deprotected pyrroloazaindole 27 could be derived from 37 in 78%
yield by treating with Cs2CO3 in MeOH. The azaindoles 37 and 27
can be applied to further functional-group modifications, including
N-alkylation or N-acylation for identification of novel CK2
inhibitors.
29
30
Entry
Solvent
Yieldb
%
29
30
1
Dioxane
Toluene/dioxane (1:1)
Toluene/dioxane (1:1)
30
45
70
29
15
Trace
2
3c
a
Reactions were carried out with (HCHO)n (2 equiv) and (n-Pr)2NH (1 equiv)
using CuI (5 mol %) in toluene at rt.
b
Isolated yields.
c
A solution of (HCHO)n and (n-Pr)2NH in toluene (heated at 80 ꢀC for 5 min) was
added to the reaction mixture.

Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
1699
Na2S2O3 (10 mL), then the solvent was removed under reduced
pressure. The resulting yellow solid was collected by filtration and
washed with water (50 mL), then dried under vacuum. The crude
product was recrystallized from n-hexane/EtOAc (3:1) to give 39
(3.2 g, 67% yield) as yellow crystals. 1H and 13C NMR data were in
agreement with those previously reported.28
(HCHO)n (2 equiv)
(n-Pr)2NH (1 equiv)
CuI (5 mol %)
N
N
Cs2CO3, MeOH
N
N
H
50 ºC, 3 h
(82%)
toluene/dioxane
rt, 30 min
Ms
NHMs
26
NHMs
36
(65%)
N
N
4.2.2. N-(3-Bromo-5-nitropyridin-4-yl)acetamide (40). To a stirred
mixture of 39 (2.0 g, 9.2 mmol) and DMAP (113 mg, 0.92 mmol) in
DMF (10 mL) were added pyridine (3.7 mL, 46 mmol) and acetic
anhydride (4.3 mL, 46 mmol), and the mixture was stirred for 2 h at
100 ꢀC. After being cooled to room temperature, the resulting black
mixture was filtered through a pad of Celite. The filtrate was con-
centrated under reduced pressure and the residue was purified by
column chromatography over silica gel with n-hexane/EtOAc (2:1),
then recrystallized from n-hexane/EtOAc (3:1) to give 40 (1.1 g, 46%
yield) as colorless crystals; Rf¼0.50 (silica gel, n-hexane/
EtOAc¼1:1); mp 197 ꢀC; IR (neat, cmꢁ1) 1681 (C]O), 1487 (NO2);
Cs2CO3, MeOH
N
H
N
H
55 ºC, 1 h
(78%)
MsN
37
HN
N(n-Pr)2
N(n-Pr)2
27
Scheme 11. Synthesis of deprotected pyrroloazaindole derivatives 37 and 27.
3. Conclusion
We have developed efficient methodologies for the synthesis of
aminomethylated azaindoles using copper-catalyzed three-com-
ponent coupling and cyclization. A series of secondary amines and
aldehydes can be used in this reaction, indicating this reaction to be
synthetically useful for the diversity-oriented synthesis of azain-
doles and related compounds. Furthermore, the more complicated
pyrrole-fused azaindoles were also synthesized by controlled
stepwise cyclization. Further studies for the development of CK2
inhibitors utilizing these drug-like templates are in progress.
1H NMR (500 MHz, DMSO-d6)
s), 10.64 (1H, br s); 13C NMR (125 MHz, DMSO-d6)
d
: 2.15 (3H, s), 9.02 (1H, s), 9.09 (1H,
d
: 22.8 (q), 117.5
(s), 136.7 (s), 142.0 (s), 144.7 (d), 155.9 (d), 168.8 (s). Anal. Calcd for
C7H6BrN3O3: C, 32.33; H, 2.33; N, 16.16; O, 18.46. Found: C, 32.30; H,
2.22; N, 16.12; O, 18.56.
4.2.3. N-{3-Nitro-5-[(trimethylsilyl)ethynyl]pyridin-4-yl}acetamide
(41). A mixture of 40 (500 mg, 1.9 mmol), trimethylsilylacetylene
(0.4 mL, 2.8 mmol), CuI (19 mg, 0.1 mmol), PdCl2(PPh3)2 (70 mg,
0.1 mmol), and Et3N (1 mL) in THF (10 mL) was stirred at 60 ꢀC for
2 h under argon. After being cooled to room temperature, the
mixture was filtered through a pad of Celite. The filtrate was con-
centrated under reduced pressure and the residue was purified by
column chromatography over silica gel with n-hexane/EtOAc (3:1),
then recrystallized from n-hexane/EtOAc (5:1) to give 41 (348 mg,
65% yield) as brown crystals; Rf¼0.65 (silica gel, n-hexane/
EtOAc¼2:1); mp 135 ꢀC; IR (neat, cmꢁ1) 2157 (C^C), 1726 (C]O),
4. Experimental
4.1. General
1H NMR spectra were recorded using a JEOL ECA-500 spec-
trometer at 500 MHz frequency. Chemical shifts are reported in
(ppm) relative to Me4Si (in CDCl3 or DMSO-d6) as internal stan-
d
dard. 13C NMR spectra were recorded using a JEOL ECA-500 and
referenced to the residual CDCl3 or DMSO-d6 signal. 1H NMR spectra
are tabulated as follows: chemical shift, number of protons, mul-
tiplicity (br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, br s¼broad singlet) and coupling constant(s). Melting
points were measured by a hot stage melting points apparatus
(uncorrected). Exact mass (HRMS) spectra were recorded on a JMS-
HX/HX 110A mass spectrometer. All reagents and solvents were of
commercial quality and used without further purification.
1492 (NO2); 1H NMR (500 MHz, CDCl3)
d
: 0.32 (9H, s), 2.27 (3H, s),
8.21 (1H, br s), 8.76 (1H, s), 8.97 (1H, s); 13C NMR (125 MHz, CDCl3)
: 0.0 (3C, q), 24.2 (q), 95.7 (s), 108.8 (s), 115.0 (s), 138.6 (s), 139.4 (s),
d
145.7 (d), 156.2 (d), 167.7 (s). Anal. Calcd for C12H15N3O3Si: C, 51.97;
H, 5.45; N, 15.15. Found: C, 51.77; H, 5.48; N, 15.14.
4.2.4. N-(3-Ethynyl-5-nitropyridin-4-yl)acetamide (6a). To a stirred
mixture of 41 (300 mg, 1.1 mmol) in THF (5 mL) was added TBAF
(1.0 M in THF, 1.2 mL, 1.2 mmol) under argon, and the mixture was
stirred for 10 min at 0 ꢀC. The mixture was quenched with satu-
rated aqueous NH4Cl (1 mL) and extracted with EtOAc. The organic
layer was washed with water and brine, dried over MgSO4, and
evaporated. The residue was purified by column chromatography
over silica gel with n-hexane/EtOAc (2:1), then recrystallized from
n-hexane/EtOAc (3:1) to give 6a (158 mg, 71% yield) as brown
crystals; Rf¼0.25 (silica gel, n-hexane/EtOAc¼2:1); mp 190 ꢀC
(decomp.); IR (neat, cmꢁ1) 3271 (C^C),1694 (C]O),1484 (NO2); 1H
4.2. Preparation of 6a
N
N
N
Ac2O
Br2, NaOAc
DMAP
O2N
O2N
Br
O2N
Br
NHAc
40
pyridine
DMF
AcOH, rt, 48 h
(67%)
NH2
38
NH2
39
100 ºC, 2 h
(46%)
NMR (500 MHz, DMSO-d6)
d
: 2.14 (3H, s), 4.94 (1H, s), 8.94 (1H, s),
TMS
PdCl2(PPh3)2
CuI, Et3N
9.01 (1H, s), 10.71 (1H, s); 13C NMR (125 MHz, DMSO-d6)
d: 22.8 (q),
N
N
75.5 (s), 91.1 (d), 115.0 (s), 138.8 (s), 140.7 (s), 145.3 (d), 156.9 (d),
168.9 (s). Anal. Calcd for C9H7N3O3: C, 52.69; H, 3.44; N, 20.48; O,
23.39. Found: C, 52.65; H, 3.27; N, 20.43; O, 23.59.
TBA F, THF
O2N
O2N
THF, 60 ºC, 2 h
(65%)
0 ºC, 10 min
(71%)
NHAc
41
TMS
NHAc
6a
4.3. Copper-catalyzed three-component coupling and
cyclization of 6a with various aldehydes and secondary
amines
4.2.1. 3-Bromo-5-nitropyridin-4-amine (39). To a stirred mixture of
38 (3.0 g, 21.6 mmol) and NaOAc (2.7 g, 32.4 mmol) in glacial AcOH
(72 mL) was added dropwise a mixture of Br2 (3.8 g, 23.8 mmol) in
glacial AcOH (24 mL), then the mixture was stirred for 48 h at room
temperature. The reaction was quenched with saturated aqueous
4.3.1. General procedure for the synthesis of
7 using para-
formaldehyde: synthesis of N-[(7-nitro-1H-pyrrolo[3,2-c]pyridin-2-
yl)methyl]-N-propylpropan-1-amine (7a) (Table 1, entry 6). To
a stirred mixture of 6a (30 mg, 0.15 mmol), paraformaldehyde

1700
Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
(9 mg, 0.29 mmol), CuCl (1.5 mg, 0.015 mmol), Et3N (0.04 mL,
0.29 mmol), and MS4A (73 mg) in dioxane (1.5 mL) was added
dipropylamine (0.02 mL, 0.15 mmol), and the mixture was stirred
for 2.5 h at 80 ꢀC under argon. After being cooled to room tem-
perature, the mixture was filtered through a pad of Celite. The fil-
trate was concentrated under reduced pressure and the residue was
purified by column chromatography over alumina with n-hexane/
EtOAc (5:1) to give 7a (34 mg, 85% yield) as a yellow solid; Rf¼0.60
(alumina, n-hexane/EtOAc¼3:1); mp 123 ꢀC; IR (neat, cmꢁ1) 1510
d
: 3.16 (4H, d, J¼6.3 Hz), 3.83 (2H, s), 5.21e5.26 (4H, m), 5.85e5.94
(2H, m), 6.58 (1H, s), 9.00 (1H, s), 9.17 (1H, s), 10.15 (1H, br s); 13C
NMR (125 MHz, CDCl3) : 49.9 (t), 56.7 (2C, t), 101.1 (d), 118.5 (2C, t),
d
128.5 (s), 130.2 (s), 132.7 (s), 134.7 (2C, d), 138.0 (d), 141.5 (s), 147.6
(d); HRMS (FAB) calcd for C14H17N4O2 [MþHþ]: 273.1352, found:
273.1348.
4.3.6. N-{3-[3-(Dipropylamino)prop-1-ynyl]-5-nitropyridin-4-yl}
acetamide (8a) and N,N0-(7-nitro-1H-pyrrolo[3,2-c]pyridine-2,3-diyl)
bis(methylene)bis(N-propylpropan-1-amine) (9a) (Table 1, entry
(NO2); 1H NMR (500 MHz, CDCl3)
d
: 0.91 (6H, t, J¼7.4 Hz), 1.48e1.55
(4H, m), 2.45e2.48 (4H, m), 3.81 (2H, s), 6.56 (1H, s), 8.99 (1H, s),
9.16 (1H, s), 10.19 (1H, br s); 13C NMR (125 MHz, CDCl3)
: 11.8 (2C,
1). To
a stirred mixture of 6a (50 mg, 0.24 mmol), para-
d
formaldehyde (15 mg, 0.48 mmol), and CuI (4.6 mg, 0.024 mmol) in
dioxane (2.0 mL) was added dipropylamine (0.033 mL, 0.24 mmol),
then the mixture was stirred for 10 h at 80 ꢀC under argon. After
being cooled to room temperature, the mixture was filtered
through a pad of Celite. The filtrate was concentrated under re-
duced pressure and the residue was purified by column chroma-
tography over alumina with n-hexane/EtOAc (10:1) to give 7a
(26 mg, 40% yield), 8a (15 mg, 20% yield), and 9a (9 mg, 10% yield).
Compound 8a: light yellow solid; Rf¼0.25 (alumina, n-hexane/
EtOAc¼3:1); mp 151 ꢀC; IR (neat, cmꢁ1) 2217 (C^C), 1683 (C]O),
q), 20.1 (2C, t), 51.6 (t), 56.2 (2C, t), 100.0 (d), 128.8 (s), 130.2 (s),
132.4 (s), 137.8 (d), 142.8 (s), 147.5 (d); HRMS (FAB) calcd for
C14H21N4O2 [MþHþ]: 277.1664, found: 277.1660.
4.3.2. 7-Nitro-2-(piperidin-1-ylmethyl)-1H-pyrrolo[3,2-c]pyridine
(7b) (Table 1, entry 7). By a procedure identical with that described
for the preparation of 7a, 6a (30 mg, 0.15 mmol) was converted into
7b (27 mg, 71%) by the reaction with paraformaldehyde (9 mg,
0.29 mmol), CuCl (1.5 mg, 0.015 mmol), Et3N (0.04 mL, 0.29 mmol),
and piperidine (0.015 mL, 0.15 mmol): yellow solid; Rf¼0.70 (alu-
mina, n-hexane/EtOAc¼3:1); mp 174 ꢀC; IR (neat, cmꢁ1) 1514
1496 (NO2); 1H NMR (500 MHz, CDCl3)
d
: 0.94 (6H, t, J¼7.2 Hz),
1.50e1.57 (4H, m), 2.27 (3H, s), 2.50 (4H, t, J¼7.4 Hz), 3.72 (2H, s),
(NO2); 1H NMR (500 MHz, CDCl3)
d
: 1.48e1.49 (2H, m), 1.60e1.64
(4H, m), 2.42e2.46 (4H, m), 3.68 (2H, s), 6.58 (1H, s), 9.00 (1H, s),
9.18 (1H, s), 10.29 (1H, br s); 13C NMR (125 MHz, CDCl3)
: 24.1 (t),
8.24 (1H, br s), 8.76 (1H, s), 8.97 (1H, s); 13C NMR (125 MHz, CDCl3)
d: 11.8 (2C, q), 20.7 (2C, t), 23.9 (q), 42.9 (t), 56.0 (2C, t), 76.2 (s), 97.6
d
(s), 114.9 (s), 137.8 (s), 139.2 (s), 144.9 (d), 156.1 (d), 167.4 (s); HRMS
(FAB) calcd for C16H23N4O3 [MþHþ]: 319.1770, found: 319.1771.
Compound 9a: yellow oil; Rf¼0.75 (alumina, n-hexane/
EtOAc¼3:1); IR (neat, cmꢁ1) 1520 (NO2); 1H NMR (500 MHz, CDCl3)
25.9 (2C, t), 54.8 (2C, t), 55.9 (t), 101.3 (d), 128.5 (s), 130.3 (s), 132.9
(s), 138.1 (d), 141.2 (s), 147.6 (d); HRMS (FAB) calcd for C13H17N4O2
[MþHþ]: 261.1351, found: 261.1343.
d
: 0.83 (6H, t, J¼7.4 Hz), 0.91 (6H, t, J¼7.4 Hz), 1.46e1.55 (8H, m),
4.3.3. N-Isopropyl-N-[(7-nitro-1H-pyrrolo[3,2-c]pyridin-2-yl)
methyl]propan-2-amine (7c) (Table 1, entry 8). By a procedure
identical with that described for the preparation of 7a, 6a (30 mg,
0.15 mmol) was converted into 7c (33 mg, 81%) by the reaction with
paraformaldehyde (9 mg, 0.29 mmol), CuCl (1.5 mg, 0.015 mmol),
Et3N (0.04 mL, 0.29 mmol), and diisopropylamine (0.021 mL,
0.15 mmol): yellow solid; Rf¼0.65 (alumina, n-hexane/EtOAc¼3:1);
mp 141 ꢀC; IR (neat, cmꢁ1) 1523 (NO2); 1H NMR (500 MHz, CDCl3)
2.35 (4H, t, J¼7.4 Hz), 2.45 (4H, t, J¼7.4 Hz), 3.68 (2H, s), 3.77 (2H, s),
9.16 (1H, s), 9.24 (1H, s), 10.09 (1H, br s); 13C NMR (125 MHz, CDCl3)
d: 11.8 (2C, q), 12.0 (2C, q), 20.18 (2C, t), 20.20 (2C, t), 48.5 (t), 49.9
(t), 55.9 (2C, t), 56.4 (2C, t), 112.0 (s), 129.3 (s), 130.0 (s), 132.0 (s),
137.9 (d), 139.3 (s), 147.8 (d); HRMS (FAB) calcd for C21H36N5O2
[MþHþ]: 390.2869, found: 390.2863.
4.3.7. 7-Nitro-2-[1-(piperidin-1-yl)butyl]-1H-pyrrolo[3,2-c]pyridine
(11a). A mixture of 6a (60 mg, 0.29 mmol), butanal (0.055 mL,
0.58 mmol), piperidine (0.035 mL, 0.35 mmol), and CuCl (3 mg,
0.03 mmol) in dioxane (2 mL) was stirred at 80 ꢀC for 15 min under
argon. After Mannich-type three-component coupling was com-
pleted (monitored by TLC), DBU (0.09 mL, 0.58 mmol) was added.
The resulting mixture was stirred for additional 30 min at 80 ꢀC
under argon. After being cooled to room temperature, the mixture
was filtered through a pad of Celite. The filtrate was concentrated
under reduced pressure and the residue was purified by column
chromatography over alumina with n-hexane/EtOAc (4:1) to give
11a (58 mg, 68% yield) as an orange oil; Rf¼0.75 (alumina, n-hex-
ane/EtOAc¼3:2); IR (neat, cmꢁ1) 1523 (NO2); 1H NMR (500 MHz,
d
: 1.09 (12H, d, J¼6.3 Hz), 3.05e3.13 (2H, m), 3.89 (2H, s), 6.53 (1H,
s), 8.97 (1H, s), 9.14 (1H, s), 10.20 (1H, br s); 13C NMR (125 MHz,
CDCl3) : 20.7 (4C, q), 42.3 (t), 49.0 (2C, d), 98.6 (d), 129.3 (s), 132.0
d
(s), 137.5 (d), 139.1 (s), 145.1 (s), 147.2 (d); HRMS (FAB) calcd for
C14H21N4O2 [MþHþ]: 277.1664, found: 277.1666.
4.3.4. N-Ethyl-N-[(7-nitro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl]
ethan-1-amine (7d) (Table 1, entry 9). By a procedure identical with
that described for the preparation of 7a, 6a (30 mg, 0.15 mmol) was
converted into 7d (27 mg, 73%) by the reaction with para-
formaldehyde (9 mg, 0.29 mmol), CuCl (1.5 mg, 0.015 mmol), Et3N
(0.04 mL, 0.29 mmol), and diethylamine (0.017 mL, 0.15 mmol):
yellow solid; Rf¼0.70 (alumina, n-hexane/EtOAc¼3:1); mp 98 ꢀC; IR
CDCl3)
d: 0.94 (3H, t, J¼7.4 Hz), 1.28e1.44 (4H, m), 1.54e1.59 (4H,
(neat, cmꢁ1) 1523 (NO2); 1H NMR (500 MHz, CDCl3)
d
: 1.08 (6H, t,
J¼7.2 Hz), 2.60 (4H, q, J¼7.2 Hz), 3.81 (2H, s), 6.57 (1H, s), 8.99 (1H,
s), 9.17 (1H, s), 10.22 (1H, br s); 13C NMR (125 MHz, CDCl3)
: 11.7
m), 1.70e1.78 (1H, m), 1.90e1.97 (1H, m), 2.42e2.49 (4H, m), 3.66
(1H, dd, J¼8.9, 4.9 Hz), 6.54 (1H, s), 8.99 (1H, s), 9.15 (1H, s), 10.15
d
(1H, br s); 13C NMR (125 MHz, CDCl3)
d: 14.1 (q), 20.4 (t), 24.5 (t),
(2C, q), 47.2 (t), 50.5 (2C, t), 100.4 (d), 128.7 (s), 130.9 (s), 132.6 (s),
138.0 (d), 142.5 (s), 147.5 (d); HRMS (FAB) calcd for C12H17N4O2
[MþHþ]: 249.1352, found: 249.1353.
26.3 (2C, t), 31.9 (t), 51.0 (2C, t), 63.1 (d),100.8 (d),128.4 (s),130.2 (s),
132.4 (s), 137.9 (d), 144.9 (s), 147.5 (d); HRMS (FAB) calcd for
C16H23N4O2 [MþHþ]: 303.1821, found: 303.1818.
4.3.5. N-Allyl-N-[(7-nitro-1H-pyrrolo[3,2-c]pyridin-2-yl)methyl]
prop-2-en-1-amine (7e) (Table 1, entry 10). By a procedure identical
with that described for the preparation of 7a, 6a (30 mg,
0.15 mmol) was converted into 7e (34 mg, 86%) by the reaction with
paraformaldehyde (9 mg, 0.29 mmol), CuCl (1.5 mg, 0.015 mmol),
Et3N (0.04 mL, 0.29 mmol), and diallylamine (0.018 mL,
0.15 mmol): yellow solid; Rf¼0.65 (alumina, n-hexane/EtOAc¼3:1);
mp 131 ꢀC; IR (neat, cmꢁ1) 1522 (NO2); 1H NMR (500 MHz, CDCl3)
4.3.8. 7-Nitro-2-[phenyl(piperidin-1-yl)methyl]-1H-pyrrolo[3,2-c]
pyridine (11b). A mixture of 6a (50 mg, 0.24 mmol), benzaldehyde
(0.05 mL, 0.49 mmol), piperidine (0.025 mL, 0.24 mmol), and CuCl
(2.4 mg, 0.024 mmol) in dioxane (2 mL) was stirred at 80 ꢀC for
30 min under argon. After being cooled to room temperature, sol-
vent was removed under reduced pressure and the residue was
purified by column chromatography over alumina with n-hexane/
EtOAc (3:1) to give a mixture of 10b (54 mg, 59% yield) and 12

Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
1701
(7 mg, 18% yield). To this mixture were added CuCl (1.5 mg,
0.015 mmol), K3PO4 (62 mg, 0.29 mmol), and dioxane (2 mL), then
the mixture was stirred at 80 ꢀC for 4.5 h under argon. After being
cooled to room temperature, the mixture was filtered through
a pad of Celite. The filtrate was concentrated under reduced pres-
sure and the residue was purified by column chromatography over
alumina with n-hexane/EtOAc (5:1) to give 11b (28 mg, 56% yield
from 10b) as a brown oil; Rf¼0.80 (alumina, n-hexane/EtOAc¼1:1);
(silica gel, n-hexane/EtOAc¼1:1); mp 185 ꢀC; IR (neat, cmꢁ1) 3446,
3355, 3272, 3204 (NHꢂ4), 2144 (C^C); 1H NMR (500 MHz, CDCl3)
d
: 0.27 (9H, s), 3.93 (2H, br s), 4.46 (2H, br s), 8.00 (1H, s); 13C NMR
(125 MHz, CDCl3) d: 0.0 (3C, q),100.3 (s),101.1 (s),106.9 (s),127.8 (s),
133.2 (s), 139.9 (s), 143.0 (d). Anal. Calcd for C10H14BrN3Si: C, 42.26;
H, 4.96; N, 14.78; Br, 28.11. Found: C, 42.04; H, 4.92; N, 14.81; Br,
28.02.
IR (neat, cmꢁ1) 1522 (NO2); 1H NMR (500 MHz, CDCl3)
d: 1.43e1.45
4.4.2. N-{4-Amino-5-bromo-2-[(trimethylsilyl)ethynyl]pyridin-3-yl}-
N-(methylsulfonyl)methanesulfonamide (21). To a stirred mixture of
20 (2.24 g, 7.9 mmol) and DMAP (98 mg, 0.8 mmol) in pyridine
(10 mL) was added MsCl (3 mL, 40 mmol) at 0 ꢀC, then the mixture
was stirred at room temperature for 12 h under argon. To the
resulting mixture was added water (20 mL) and extracted with
EtOAc (50 mL). The organic layer was washed with brine, dried over
MgSO4, and evaporated. The residue was purified by column
chromatography over silica gel with n-hexane/EtOAc (3:1), then
recrystallized from n-hexane/EtOAc (5:1) to give 21 (2.53 g, 73%
yield) as yellow crystals; Rf¼0.60 (silica gel, n-hexane/EtOAc¼1:1);
mp 208 ꢀC (decomp.); IR (neat, cmꢁ1) 3477, 3385 (NHꢂ2), 2164
(2H, m), 1.63e1.64 (4H, m), 2.36e2.42 (4H, m), 4.77 (1H, s), 6.51
(1H, s), 7.33e7.40 (5H, m), 8.95 (1H, s), 9.17 (1H, s), 10.26 (1H, br s);
13C NMR (125 MHz, CDCl3)
d: 24.3 (t), 26.2 (2C, t), 52.1 (2C, t), 69.2
(d), 101.5 (d), 128.2 (d), 128.5 (s), 128.6 (2C, d), 128.8 (2C, d), 130.3
(s), 132.7 (s), 136.9 (s), 138.1 (d), 144.4 (s), 147.7 (d); HRMS (FAB)
calcd for C19H21N4O2 [MþHþ]: 337.1665, found: 337.1663.
4.3.9. 8-Nitro-2-phenyl-1,6-naphthyridine (13). By
a procedure
identical with that described for the preparation of 11b, 6a (50 mg,
0.24 mmol) was converted into 10b (54 mg, 59%) mixed with 12
(7 mg, 18% yield) by the reaction with benzaldehyde (0.05 mL,
0.49 mmol), CuCl (2.4 mg, 0.024 mmol), and piperidine (0.025 mL,
0.24 mmol). To this mixture were added CuCl (1.5 mg, 0.015 mmol),
DBU (0.043 mL, 0.29 mmol), and dioxane (2 mL), then the mixture
was stirred at 80 ꢀC for 30 min under argon. After being cooled to
room temperature, solvent was removed and the residue was pu-
rified by column chromatography over alumina with n-hexane/
EtOAc (5:1) to give 13 (21 mg, 60% yield from 10b) as a brown solid;
Rf¼0.60 (alumina, n-hexane/EtOAc¼1:1); mp 186 ꢀC (decomp.); IR
(C^C), 1366, 1156 (SO2); 1H NMR (500 MHz, CDCl3)
d
: 0.26 (9H, s),
3.56 (6H, s), 5.04 (2H, br s), 8.39 (1H, s); 13C NMR (125 MHz, CDCl3)
: 0.0 (3C, q), 45.8 (2C, q),101.5 (s),102.2 (s),108.4 (s),119.5 (s),144.3
d
(s), 151.2 (s), 152.4 (d); HRMS (FAB) calcd for C12H19BrN3O2S2Si
[MþHþ]: 439.9770, found: 439.9764.
4.4.3. N-{4-Amino-2,5-bis[(trimethylsilyl)ethynyl]pyridin-3-yl}-N-
(methylsulfonyl)methanesulfonamide (22). A mixture of 21 (1 g,
2.3 mmol), trimethylsilylacetylene (0.5 mL, 3.5 mmol), CuI (44 mg,
0.23 mmol), PdCl2(PPh3)2 (161 mg, 0.23 mmol), and Et3N (4 mL) in
dioxane (15 mL) was stirred at 70 ꢀC for 4 h under argon. After
being cooled to room temperature, the mixture was filtered
through a pad of Celite. The filtrate was concentrated under re-
duced pressure and the residue was purified by column chroma-
tography over silica gel with n-hexane/EtOAc (5:1), then
recrystallized from n-hexane/EtOAc (10:1) to give 22 (758 mg, 72%
yield) as a white solid; Rf¼0.70 (silica gel, n-hexane/EtOAc¼2:1);
mp 193 ꢀC; IR (neat, cmꢁ1) 3467, 3312 (NHꢂ2), 2141 (C^C), 1369,
(neat, cmꢁ1) 1521 (NO2); 1H NMR (500 MHz, CDCl3)
d: 7.53e7.56
(3H, m), 8.18 (1H, d, J¼8.7 Hz), 8.26e8.27 (2H, m), 8.45 (1H, d,
J¼8.7 Hz), 9.13 (1H, s), 9.39 (1H, s); 13C NMR (125 MHz, CDCl3)
d:
121.4 (d), 123.2 (s), 128.3 (2C, d), 129.2 (2C, d), 131.5 (d), 136.3 (d),
137.1 (s), 138.5 (s), 141.7 (d), 142.2 (s), 155.8 (d), 163.2 (s); HRMS
(FAB) calcd for C14H10N3O2 [MþHþ]: 252.0773, found: 252.0772.
4.3.10. 2-[(Dipropylamino)methyl]-1H-pyrrolo[3,2-c]pyridin-7-
amine (14). A mixture of 7a (50 mg, 0.18 mmol) and 10% Pd/C
(5 mg) in MeOH (2 mL) was stirred at room temperature for 1 h
under H2 atmosphere. Then, the mixture was filtered through a pad
of Celite. The filtrate was concentrated under reduced pressure and
the residue was purified by column chromatography over alumina
with CHCl3/MeOH (30:1) to give 14 (38 mg, 85% yield) as a brown
oil; Rf¼0.50 (alumina, CHCl3/MeOH¼10:1); IR (neat, cmꢁ1) 3400,
1164 (SO2); 1H NMR (500 MHz, DMSO-d6)
d
: 0.21 (9H, s), 0.26 (9H,
s), 3.60 (6H, s), 6.21 (2H, s), 8.18 (1H, s); 13C NMR (125 MHz, DMSO-
d6) : 0.0 (3C, q), 0.5 (3C, q), 46.2 (2C, q), 98.1 (s), 101.3 (s), 102.9 (s),
d
105.8 (s), 106.0 (s), 118.1 (s), 144.1 (s), 153.2 (d), 154.2 (s). Anal. Calcd
for C17H27N3O4S2Si2: C, 44.61; H, 5.95. Found: C, 44.21; H, 5.70.
3190 (NHꢂ2); 1H NMR (500 MHz, DMSO-d6)
d: 0.83 (6H, t,
J¼7.2 Hz), 1.41e1.49 (4H, m), 2.38 (4H, t, J¼7.4 Hz), 3.67 (2H, s), 5.16
4.4.4. N-(4-Amino-2,5-diethynylpyridin-3-yl)methanesulfonamide
(23). To a stirred mixture of 22 (500 mg, 1.1 mmol) in MeOH
(10 mL) was added K2CO3 (453 mg, 3.3 mmol) at 0 ꢀC, then the
mixture was stirred at room temperature for 30 min under argon.
The mixture was filtered through a pad of Celite. The filtrate was
concentrated under reduced pressure and the residue was purified
by column chromatography over silica gel with CHCl3/MeOH (9:1)
to give 23 (215 mg, 83% yield) as a white solid; Rf¼0.30 (silica gel,
CHCl3/MeOH¼9:1); mp 172 ꢀC; IR (neat, cmꢁ1) 3488, 3387, 3165
(NHꢂ3), 2100 (C^C), 1318, 1152 (SO2); 1H NMR (500 MHz, DMSO-
(2H, br s), 6.26 (1H, s), 7.51 (1H, s), 8.04 (1H, s), 10.71 (1H, s); 13C
NMR (125 MHz, DMSO-d6) d: 11.8 (2C, q), 19.5 (2C, t), 51.3 (t), 55.4
(2C, t), 99.4 (d), 124.6 (d), 125.2 (s), 128.9 (s), 129.8 (s), 131.4 (d),
137.5 (s); HRMS (FAB) calcd for C14H23N4 [MþHþ]: 247.1923, found:
247.1922.
4.4. Synthesis of pyrrole-fused azaindoles
Compound 19 was prepared from commercially available 3,4-
diaminopyridine 18 according to a reported literature.27
d6)
d
: 3.10 (3H, s), 4.47 (1H, s), 4.69 (1H, s), 6.16 (2H, s), 8.11 (1H, s),
9.21 (1H, s); 13C NMR (125 MHz, DMSO-d6)
d: 42.2 (q), 77.0 (d), 81.5
4.4.1. 5-Bromo-2-[(trimethylsilyl)ethynyl]pyridine-3,4-diamine
(20). A mixture of 19 (3 g, 11.3 mmol), trimethylsilylacetylene
(1.76 mL, 12.5 mmol), CuI (108 mg, 0.57 mmol), PdCl2(PPh3)2
(398 mg, 0.57 mmol), and Et3N (8 mL) in dioxane (30 mL) was
stirred at 70 ꢀC for 1 h under argon. After being cooled to room
temperature, the mixture was filtered through a pad of Celite. The
filtrate was concentrated under reduced pressure and the residue
was purified by column chromatography over silica gel with n-
hexane/EtOAc (5:1), then recrystallized from n-hexane/EtOAc
(10:1) to give 20 (2.56 g, 80% yield) as light yellow crystals; Rf¼0.55
(d), 84.7 (s), 89.6 (s), 103.6 (s), 119.2 (s), 141.2 (s), 151.0 (d), 153.3 (s);
HRMS (FAB) calcd for C10H10N3O2S [MþHþ]: 236.0494, found:
236.0500.
4.4.5. 6-Ethynyl-1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-7-
amine (24). A mixture of 23 (1 g, 4.3 mmol), CuI (43 mg,
0.22 mmol), and Et3N (0.6 mL, 4.3 mmol) in dioxane (10 mL) was
stirred at 60 ꢀC for 1 h under argon. After being cooled to room
temperature, the mixture was filtered through a pad of Celite. The
filtrate was concentrated under reduced pressure and the residue

1702
Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
was purified by column chromatography over alumina with n-
hexane/EtOAc (2:1), then recrystallized from n-hexane/EtOAc (5:1)
to give 24 (690 mg, 69% yield) as colorless crystals; Rf¼0.55 (alu-
mina, n-hexane/EtOAc¼1:1); mp 147 ꢀC; IR (neat, cmꢁ1) 3377, 3336
NMR (125 MHz, CDCl3) d: 11.8 (2C, q), 20.6 (2C, t), 24.8 (q), 42.8 (t),
55.7 (2C, t), 78.4 (s), 93.1 (s), 101.8 (s), 110.7 (d), 115.2 (s), 130.6 (d),
141.8 (s), 149.7 (s), 150.0 (d), 170.1 (s); HRMS (FAB) calcd for
C18H25N4O [MþHþ]: 313.2028, found: 313.2021.
(NHꢂ2), 2094 (C^C),1352, 1113 (SO2); 1H NMR (500 MHz, CDCl3)
d:
3.21 (3H, s), 3.57 (1H, s), 6.10 (2H, s), 6.82 (1H, d, J¼4.6 Hz), 7.66 (1H,
4.4.9. N-{[1,8-Bis(methylsulfonyl)-1,8-dihydrodipyrrolo[3,2-b:20,30-d]
pyridin-7-yl]methyl}-N-propylpropan-1-amine (29) (Table 2, entry
3). To a stirred mixture of 26 (100 mg, 0.32 mmol) and CuI (3 mg,
0.016 mmol) in dioxane (1 mL) was added a preheated solution
(80 ꢀC for 5 min) of paraformaldehyde (19 mg, 0.64 mmol) and
dipropylamine (0.044 mL, 0.32 mmol) in toluene (1 mL), and then
the mixture was stirred at room temperature for 30 min under
argon. Solvent was removed under reduced pressure and the resi-
due was purified by column chromatography over alumina with n-
hexane/EtOAc (2:1) to give 29 (95 mg, 70% yield) as a white solid;
Rf¼0.70 (alumina, n-hexane/EtOAc¼1:1); mp 102 ꢀC; IR (neat,
d, J¼4.6 Hz), 8.41 (1H, s); 13C NMR (125 MHz, CDCl3)
d: 42.7 (q), 78.0
(s), 85.5 (d), 100.5 (s), 111.0 (d),115.2 (s),131.1 (d), 142.8 (s), 150.5 (s),
150.6 (d); HRMS (FAB) calcd for C10H10N3O2S [MþHþ]: 236.0494,
found: 236.0500.
4.4.6. N-(6-Ethynyl-1H-pyrrolo[3,2-b]pyridin-7-yl)acetamide
(25). To a stirred mixture of 24 (166 mg, 0.7 mmol) and DMAP
(10 mg, 0.07 mmol) in dichloroethane (5 mL) were added Et3N
(0.3 mL, 2.1 mmol) and Ac2O (0.33 mL, 3.5 mmol), then the mixture
was stirred at 70 ꢀC for 5 h under argon. After being cooled to room
temperature, solvent was removed under reduced pressure and the
residue was purified by column chromatography over silica gel
with n-hexane/EtOAc (3:1) to give the corresponding bis-acetylated
product (90 mg, 0.32 mmol). Then, a mixture of this compound and
K2CO3 (45 mg, 0.32 mmol) in MeOH (2 mL) was stirred at room
temperature for 5 min. The resulting mixture was purified by col-
umn chromatography over alumina with n-hexane/EtOAc (3:1) to
give 25 (24 mg, 25% yield from 24) as a white solid; Rf¼0.40 (alu-
mina,]n-hexane/EtOAc¼2:1); mp 167 ꢀC; IR (neat, cmꢁ1) 3303
cmꢁ1) 1361, 1296, 1161, 1146 (SO2ꢂ2); 1H NMR (500 MHz, CDCl3)
d:
0.91 (6H, t, J¼7.4 Hz), 1.48e1.56 (4H, m), 2.44e2.48 (4H, m), 3.32
(3H, s),
d
: 3.44 (1H, dd, J¼15.5, 6.9 Hz), 3.47 (1H, dd, J¼15.5, 6.9 Hz),
3.82 (3H, s), 5.86 (1H, dd, J¼6.9, 6.9 Hz), 6.76 (1H, d, J¼4.0 Hz), 7.81
(1H, d, J¼4.0 Hz), 8.50 (1H, s); 13C NMR (125 MHz, CDCl3)
d: 11.8 (2C,
q), 20.3 (2C, t), 40.3 (q), 44.3 (q), 48.3 (t), 56.1 (2C, t), 107.5 (d), 111.7
(d), 120.3 (s), 131.3 (s), 135.4 (s), 142.8 (d), 145.6 (s), 151.2 (d), 152.0
(s); HRMS (FAB) calcd for C18H27N4O4S2 [MþHþ]: 427.1474, found:
427.1466.
(NH), 2253 (C^C), 1729 (C]O); 1H NMR (500 MHz, CDCl3)
d: 2.37
(3H, s), 3.64 (1H, s), 6.72 (1H, dd, J¼2.4, 2.4 Hz), 7.49 (1H, dd, J¼2.4,
4.4.10. 1,8-Bis(methylsulfonyl)-1,8-dihydrodipyrrolo[3,2-b:20,30-d]
pyridine (30) (Table 2, entry 1). To a stirred mixture of 26 (50 mg,
0.16 mmol) and CuI (1.5 mg, 0.008 mmol) in dioxane (1 mL) were
added paraformaldehyde (10 mg, 0.32 mmol) and dipropylamine
(0.022 mL, 0.16 mmol), then the mixture was stirred at room tem-
perature for 30 min under argon. The solvent was removed under
reduced pressure and the residue was purified by column chro-
matography over alumina with n-hexane/EtOAc (3:1) to give 29
(20 mg, 30% yield) and 30 (15 mg, 29% yield).
2.4 Hz), 8.26 (1H, br s), 8.48 (1H, s), 10.70 (1H, br s); 13C NMR
(125 MHz, CDCl3) d: 24.6 (q), 78.2 (s), 86.0 (d), 99.4 (s), 103.9 (d),
117.6 (s), 129.0 (d), 130.9 (s), 146.5 (d), 148.8 (s), 169.0 (s); HRMS
(FAB) calcd for C11H10N3O [MþHþ]: 200.0824, found: 200.0821.
4.4.7. N-[6-Ethynyl-1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-7-
yl]methanesulfonamide (26). A mixture of 24 (500 mg, 2.1 mmol)
and NaH (150 mg, 6.3 mmol) in THF (10 mL) was stirred at ꢁ20 ꢀC
for 30 min under argon. To the resulting mixture was added MsCl
(0.45 mL, 6.3 mmol) and stirred at room temperature for an addi-
tional 2 h under argon. The reaction mixture was acidified by
aqueous HCl (1 N) until pH <2, then extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO4, and
evaporated. The residue was purified by column chromatography
over silica gel with n-hexane/EtOAc (2:1), then recrystallized from
n-hexane/EtOAc (3:1) to give 26 (348 mg, 53% yield) as colorless
crystals; Rf¼0.65 (silica gel, n-hexane/EtOAc¼1:2); mp 168 ꢀC; IR
(neat, cmꢁ1) 3223 (C^C), 1356, 1330, 1148, 1121 (SO2ꢂ2); 1H NMR
Compound 30: white solid; Rf¼0.45 (alumina, n-hexane/
EtOAc¼1:1); mp 170 ꢀC; IR (neat, cmꢁ1) 1363, 1320, 1165, 1108
(SO2ꢂ2); 1H NMR (500 MHz, CDCl3)
d: 3.30 (3H, s), 3.82 (3H, s), 5.11
(1H, d, J¼3.4 Hz), 5.34 (1H, d, J¼3.4 Hz), 6.77 (1H, d, J¼3.9 Hz), 7.83
(1H, d, J¼3.9 Hz), 8.57 (1H, s); 13C NMR (125 MHz, CDCl3)
d: 49.5 (q),
53.8 (q), 105.7 (s), 117.2 (d), 119.4 (s), 129.8 (s), 141.1 (d), 145.2 (s),
152.7 (d), 161.1 (d), 161.3 (s); HRMS (FAB) calcd for C11H12N3O4S2
[MþHþ]: 314.0269, found: 314.0257.
4.4.11. N-{6-[3-(Dipropylamino)prop-1-ynyl]-1-(methylsulfonyl)-
1H-pyrrolo[3,2-b]pyridin-7-yl}methanesulfonamide (31). A solution
of 29 (20 mg, 0.05 mmol) in CDCl3 (0.5 mL) was placed in a NMR
tube. After 24 h at room temperature, 1H NMR analysis showed that
29 was converted to 31 with a ratio of 4:1 (31/29). The mixture was
purified by column chromatography over silica gel with CHCl3/
MeOH (9:1) to give 31 (13 mg, 65% yield) as an orange oil; Rf¼0.50
(silica gel, CHCl3/MeOH¼9:1); IR (neat, cmꢁ1) 2228 (C^C), 1349,
(500 MHz, CDCl3) d: 3.49 (1H, s), 3.59 (3H, s), 3.65 (3H, s), 6.94 (1H,
d, J¼4.0 Hz), 7.82 (1H, d, J¼4.0 Hz), 8.63 (1H, br s), 8.73 (1H, s); 13C
NMR (125 MHz, CDCl3) d: 44.1 (q), 44.5 (q), 80.6 (s), 84.4 (d), 105.3
(s), 109.7 (d), 112.4 (s), 131.5 (s), 132.4 (d), 150.8 (s), 152.3 (d); HRMS
(FAB) calcd for C11H12N3O4S2 [MþHþ]: 314.0270, found: 314.0266.
4.4.8. N-{6-[3-(Dipropylamino)prop-1-ynyl]-1H-pyrrolo[3,2-b]pyr-
idin-7-yl}acetamide (28). To
a
stirred mixture of 25 (24 mg,
1316, 1158, 1137 (SO2ꢂ2); 1H NMR (500 MHz, CDCl3)
d: 0.94 (6H, t,
0.12 mmol), paraformaldehyde (8 mg, 0.24 mmol), CuCl (1.3 mg,
0.012 mmol), Et3N (0.04 mL, 0.24 mmol), and MS4A (70 mg) in di-
oxane (1.5 mL) was added dipropylamine (0.02 mL, 0.12 mmol), and
the mixture was stirred for 5 h at 80 ꢀC under argon. After being
cooled to room temperature, the mixture was filtered through
a pad of Celite. The filtrate was concentrated under reduced pres-
sure and the residue was purified by column chromatography over
alumina with n-hexane/EtOAc (4:1) to give 28 (16 mg, 42% yield) as
J¼7.2 Hz), 1.52e1.57 (4H, m), 2.59 (4H, t, J¼7.4 Hz), 3.51 (3H, s), 3.66
(3H, s), 3.69 (2H, s), 6.88 (1H, d, J¼3.4 Hz), 7.78 (1H, d, J¼3.4 Hz),
8.63 (1H, s); 13C NMR (125 MHz, CDCl3)
d: 11.8 (2C, q), 20.3 (2C, t),
43.6 (q), 44.0 (q), 44.2 (t), 55.8 (2C, t), 82.4 (s), 92.0 (s), 109.3 (d),
113.0 (s), 123.2 (s), 131.8 (d), 136.2 (s), 149.9 (s), 152.0 (d); HRMS
(FAB) calcd for C18H27N4O4S2 [MþHþ]: 427.1474, found: 427.1478.
4.4.12. N-{6-[3-(Dipropylamino)prop-1-ynyl]-1H-pyrrolo[3,2-b]pyr-
idin-7-yl}methanesulfonamide (32) and 4-[2-(dipropylamino)ethyl]-
1,9-dihydropyrrolo[20,30:5,6]pyrido[4,3-c][1,2]thiazine 2,2-dioxide
(33). A mixture of 29 (94 mg, 0.22 mmol) and Cs2CO3 (216 mg,
0.66 mmol) in THF (2 mL) and MeOH (1 mL) was stirred at 70 ꢀC for
3 h under argon. After being cooled to room temperature, the
a
yellow solid; Rf¼0.50 (alumina, n-hexane/EtOAc¼2:1); mp
168 ꢀC; IR (neat, cmꢁ1) 3259 (NH), 2222 (C^C), 1668 (C]O); 1H
NMR (500 MHz, CDCl3)
d
: 0.94 (6H, t, J¼7.4 Hz), 1.50e1.58 (4H, m),
2.52 (4H, t, J¼7.4 Hz), 2.36 (3H, s), 3.72 (2H, s), 6.79 (1H, d,
J¼4.0 Hz), 7.62 (1H, d, J¼4.0 Hz), 8.36 (1H, s), 10.84 (1H, br s); 13C

Z. Hou et al. / Tetrahedron 68 (2012) 1695e1703
1703
solvent was removed under reduced pressure and the residue was
purified by column chromatography over silica gel with CHCl3/
MeOH (9:1) to give 33 (43 mg, 52% yield) and 32 (9 mg, 12% yield).
Compound 32: orange oil; Rf¼0.45 (silica gel, CHCl3/MeOH¼9:1);
IR (neat, cmꢁ1) 3440 (NH), 2249 (C^C), 1342, 1159 (SO2); 1H NMR
0.84 (6H, t, J¼7.4 Hz), 1.43e1.51 (4H, m), 2.40 (4H, t, J¼7.4 Hz), 3.73
(2H, s), 6.44 (1H, s), 6.54 (1H, dd, J¼2.5, 2.5 Hz), 7.34 (1H, dd, J¼2.5,
2.5 Hz), 8.47 (1H, s), 10.50 (1H, s), 10.72 (1H, s); 13C NMR (125 MHz,
DMSO-d6) d: 11.8 (2C, q), 19.6 (2C, t), 51.3 (t), 55.4 (2C, t), 100.5 (d),
102.7 (d), 115.2 (s), 120.1 (s), 123.1 (d), 126.7 (s), 134.8 (s), 136.7 (d),
139.5 (s); HRMS (FAB) calcd for C16H23N4 [MþHþ]: 271.1922, found:
271.1924.
(500 MHz, CDCl3)
d
: 0.94 (6H, t, J¼7.4 Hz), 1.53e1.58 (4H, m),
2.57e2.61 (4H, m), 3.13 (3H, s), 3.68 (2H, s), 6.48 (1H, dd, J¼2.9,
2.9 Hz), 7.38 (1H, dd, J¼2.9, 2.9 Hz), 8.07 (1H, s), 10.49 (1H, br s); 13C
NMR (125 MHz, CDCl3) d: 11.9 (2C, q), 20.2 (2C, t), 41.7 (q), 43.1 (t),
Acknowledgements
55.7 (2C, t), 79.6 (s), 90.6 (s), 100.2 (s), 105.1 (d), 111.5 (s), 120.6 (s),
129.5 (d), 137.4 (s), 141.5 (d); HRMS (FAB) calcd for C17H25N4O2S
[MþHþ]: 349.1698, found: 349.1688.
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Integrated Organic Synthesis’ (H.O.)
and the Targeted Proteins Research Program from the Ministry of
Education, Culture, Sports, Science and Technology of Japan, as well
as the Program for Promotion of Fundamental Studies in Health
Sciences of the National Institute of Biomedical Innovation (NIBIO).
Z.H. and Y.S. are supported by Kobayashi International Scholarship
Foundation and a JSPS Research Fellowship for Young Scientists,
respectively.
Compound 33: light yellow solid; Rf¼0.30 (silica gel, CHCl3/
MeOH¼9:1); mp 205 ꢀC; IR (neat, cmꢁ1) 3187 (NH), 1409, 1104
(SO2); 1H NMR (500 MHz, DMSO-d6)
d
: 0.84 (6H, t, J¼7.2 Hz),
1.36e1.44 (4H, m), 2.43 (4H, t, J¼7.4 Hz), 2.68 (2H, t, J¼7.2 Hz), 2.77
(2H, t, J¼7.2 Hz), 6.42 (1H, d, J¼2.9 Hz), 6.49 (1H, s), 7.47 (1H, d,
J¼2.9 Hz), 8.28 (1H, s), 12.26 (1H, br s); 13C NMR (125 MHz, DMSO-
d6) d: 11.7 (2C, q), 19.7 (2C, t), 29.5 (t), 52.9 (t), 55.1 (2C, t), 96.4 (d),
105.7 (s), 117.1 (d), 121.7 (s), 128.0 (d), 131.8 (s), 133.2 (d), 140.3 (s),
145.1 (s); HRMS (FAB) calcd for C17H25N4O2S [MþHþ]: 349.1698,
found: 349.1688.
References and notes
4.4.13. N-(6-Ethynyl-1H-pyrrolo[3,2-b]pyridin-7-yl)meth-
anesulfonamide (36). A mixture of 26 (100 mg, 0.32 mmol) and
Cs2CO3 (214 mg, 0.64 mmol) in THF (2 mL) and MeOH (1 mL) was
stirred at 50 ꢀC for 3 h under argon. After being cooled to room
temperature, solvent was removed under reduced pressure and the
residue was purified by column chromatography over silica gel
with CHCl3/MeOH (9:1) to give 36 (61 mg, 82% yield) as a white
solid; Rf¼0.40 (silica gel, CHCl3/MeOH¼9:1); mp 147 ꢀC; IR (neat,
cmꢁ1) 3282 (NH), 3226 (C^C), 1343, 1115 (SO2); 1H NMR (500 MHz,
1. Browner, M.; Chanda, S.; Cheng, S.; Comer, D. D.; Dalrymple, S. A.; Dunten, P.;
Lafargue, J.; Lovejoy, B.; Freire-Moar, J.; Lim, J.; Maintosh, J.; Miller, J.; Papp, E.;
Reuter, D.; Roberts, R.; Sanpablo, F.; Saunders, J.; Song, K.; Villasenor, A.; War-
ren, S. D.; Welch, M.; Weller, P.; Whiteley, P. E.; Zeng, L.; Goldstein, D. M. J. Med.
Chem. 2003, 46, 4702e4713.
2. Hodge, C. N.; Aldrich, P. E.; Wasserman, Z. R.; Fernandez, C. H.; Nemeth, G. A.;
Arvanitis, A.; Cheeseman, R. ,S.; Chorvat, R. J.; Ciganek, E.; Christos, T. E.; Gil-
ligan, P. J.; Krenitsky, P.; Scholfield, E.; Strucely, P. J. Med. Chem. 1999, 42,
819e832.
3. Marot, C.; Chavatte, P.; Morin-Allory, L.; Viaud, M. C.; Guillaumet, G.; Renard, P.;
Lesieur, D.; Michel, A. J. Med. Chem. 1998, 41, 4453e4465.
4. Henry, J. R.; Rupert, K. C.; Dodd, J. H.; Turchi, I. J.; Wadsworth, S. A.; Cavender,
D. E.; Fahmy, B.; Olini, G. C.; Davis, J. E.; Pellegrino-Gensey, J. L.; Schafer, P. H.;
Siekierka, J. J. J. Med. Chem. 1998, 41, 4196e4198.
DMSO-d6)
d
: 3.04 (3H, s), 4.13 (1H, s), 6.44 (1H, d, J¼3.0 Hz), 7.67
(1H, dd, J¼3.0, 3.0 Hz), 8.22 (1H, s), 11.16 (1H, s), 13.15 (1H, br s); 13C
5. Bamborough, P.; Brown, M. J.; Christopher, J. A.; Chung, C.; Mellor, G. W. J. Med.
Chem. 2011, 54, 5131e5143.
6. Prudhomme, M. Eur. J. Med. Chem. 2003, 38, 123e140.
NMR (125 MHz, DMSO-d6) d: 42.1 (q), 79.6 (s), 83.7 (d), 96.7 (s),
103.1 (s), 108.4 (d), 124.3 (s), 127.1 (d), 130.7 (s), 143.4 (d); HRMS
(FAB) calcd for C10H10N3O2S [MþHþ]: 236.0494, found: 236.0500.
7. Popowycz, F.; Merourb, J.; Josepha, B. Tetrahedron 2007, 63, 8689e8707.
8. Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P. Tetrahedron
2003, 59, 1571e1587.
9. Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2007, 48, 6951e6953.
10. Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. Synlett 2005, 3121e3125.
11. Mphahlele, M. J.; Lesenyeho, L. G.; Makelane, H. R. Tetrahedron 2010, 66,
6040e6046.
12. Carpita, A.; Ribecai, A.; Stabile, P. Tetrahedron 2010, 66, 7169e7178.
13. Majumdar, K. C.; Samanta, S.; Chattopadhyay, B. Tetrahedron Lett. 2008, 49,
7213e7216.
14. Cacchi, S.; Fabrizi, G.; Parisi, L. M. J. Comb. Chem. 2005, 7, 510e512.
15. Lu, X. L.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2002, 67, 5412e5415.
16. Zhang, S.; Zhang, W. X.; Zhao, J.; Xi, Z. Chem.dEur. J. 2011, 17, 2442e2449.
17. For synthesis of azaindolines by MCR, see: Fayol, A.; Zhu, J. Org. Lett. 2005, 7,
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4.4.14. N-{[8-(Methylsulfonyl)-1,8-dihydrodipyrrolo[3,2-b:20,30-d]
pyridin-7-yl]methyl}-N-propylpropan-1-amine (37). To
a stirred
mixture of 36 (53 mg, 0.23 mmol) and CuI (2.6 mg, 0.012 mmol) in
dioxane (1 mL) was added a preheated solution (80 ꢀC, 5 min) of
paraformaldehyde (14 mg, 0.46 mmol) and dipropylamine
(0.032 mL, 0.23 mmol) in toluene (1 mL), and then the mixture was
stirred at room temperature for 30 min under argon. The solvent
was removed under reduced pressure and the residue was purified
by column chromatography over alumina with n-hexane/EtOAc
(5:1) to give 37 (50 mg, 65% yield) as a white solid; Rf¼0.65 (alu-
mina, n-hexane/EtOAc¼1:1); mp 125 ꢀC; IR (neat, cmꢁ1) 3439 (NH),
1337, 1153 (SO2); 1H NMR (500 MHz, CDCl3)
d
: 0.81 (6H, t, J¼7.2 Hz),
1.42e1.48 (4H, m), 2.45e2.48 (4H, m), 3.60 (3H, s), 3.90 (2H, s), 6.71
(1H, s), 6.84e6.86 (1H, m), 7.35e7.37 (1H, m), 8.68 (1H, s), 9.95 (1H,
s); 13C NMR (125 MHz, CDCl3)
d: 11.7 (2C, q), 18.7 (2C, t), 42.1 (q),
52.0 (t), 54.8 (2C, t), 104.3 (d), 111.1 (d), 115.0 (s), 119.3 (s), 124.8 (d),
127.4 (s), 136.0 (s), 137.4 (d), 143.9 (s); HRMS (FAB) calcd for
C17H25N4O2S [MþHþ]: 349.1698, found: 349.1696.
24. For the synthesis of the related indole-fused carboline derivatives, see: Lean-
dro, B. Ann. Rome 1965, 55, 452e460.
25. Boyarintseva, O. N.; Kurilo, G. N.; Anisimova, O. S.; Grinev, A. N. Khim. Geter-
otsikl. 1977, 1, 82e84.
4.4.15. N-[(1,8-Dihydrodipyrrolo[3,2-b:20,30-d]pyridin-7-yl)methyl]-
N-propylpropan-1-amine (27). A mixture of 37 (50 mg, 0.14 mmol)
and Cs2CO3 (91 mg, 0.28 mmol) in THF (1 mL) and MeOH (0.5 mL)
was stirred at 55 ꢀC for 1 h under argon. After being cooled to room
temperature, solvent was removed under reduced pressure and the
residue was purified by column chromatography over alumina with
CHCl3/MeOH (30:1) to give 27 (30 mg, 78% yield) as a yellow solid;
26. Deprotection of the acetyl group is considered to proceed readily via hydrolysis
of the amide bond during the reaction and/or work-up. For examples of the
deprotection of trifluoroacetyl group during indole formation, see: Lu, B. Z.;
Zhao, W.; Wei, H.; Dufour, M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8,
3271e3274 See also, Ref. 9.
27. Blouin,ˇ N.; Michaud, A.; Gendron, D.; Wakim, S.; Blair, E.; Neagu-Plesu, R.;
Belletete, M.; Durocher, G.; Tao, Y.; Leclerc, M. J. Am. Chem. Soc. 2008, 130,
732e742.
Rf¼0.55 (alumina, CHCl3/MeOH¼15:1); IR (neat, cmꢁ1
) 3431
€
28. Antoine, M.; Czech, M.; Gerlach, M.; Gunther, E.; Schuster, T.; Marchand, P.
(NHꢂ2); mp 155 ꢀC (decomp.); 1H NMR (500 MHz, DMSO-d6)
d:
Synthesis 2011, 5, 794e806.