Synthesis of tetrahydro-5-azaindoles and 5-azaindoles using Pictet-Spengler reaction - Appreciable difference in products using different acid catalysts

Article abstract of DOI:10.1016/j.tet.2010.12.003

Pictet-Spengler condensation of 2-(aryl)-2-(1H-pyrrol-2-yl)ethanamines using conventional acid catalysts like TMSCl or TFA resulted in the formation of substituted 5-azaindoles involving a tandem one pot four steps reaction sequence. By contrast use of gl

Full text of DOI:10.1016/j.tet.2010.12.003

Tetrahedron 67 (2011) 936e942
Contents lists available at ScienceDirect
Tetrahedron
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Synthesis of tetrahydro-5-azaindoles and 5-azaindoles using PicteteSpengler
reactiondappreciable difference in products using different acid catalysts
,
Abdullah M.A. Shumaila a, Vedavati G. Puranik b, Radhika S. Kusurkar a
*
a Department of Chemistry, University of Pune, Ganeshkind Road, Pune 411007, Maharashtra, India
b Center for Materials Characterization, National Chemical Laboratory, Pune 411008, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
PicteteSpengler condensation of 2-(aryl)-2-(1H-pyrrol-2-yl)ethanamines using conventional acid cata-
lysts like TMSCl or TFA resulted in the formation of substituted 5-azaindoles involving a tandem one pot
four steps reaction sequence. By contrast use of glacial acetic acid furnished the targeted tetrahydro-5-
azaindoles in diastereoselective manner. These were readily dehydrogenated to 5-azaindoles.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 3 September 2010
Received in revised form 1 December 2010
Accepted 3 December 2010
Available online 9 December 2010
Keywords:
4,7-Disubstituted-tetrahydro-5-azaindoles
Diastereoselective PicteteSpengler reaction
2-(Aryl)-2-(1H-pyrrol-2-yl)ethanamines
4,7-Disubstituted-5-azaindoles
1. Introduction
compounds and phenyl ethylamines or tryptamines, respectively.15
There is only one report each for the synthesis of 5 and 6-azaindoles
The interests in azaindoles originated primarily from their me-
dicinal relevance and applications in material synthesis and co-
ordination chemistry. They are frequently exploited as indole
bioisosteres in the design of biologically interesting molecules.1
Many of these compounds show diverse biological activities, such
as anti-inflammatory,2 anti-psychotic,3 thrombin inhibitor,4 and
fVIIa.TF inhibitor5 activity. Tetrahydropyrrolo[3,2-c]pyridine de-
rivatives are known as inhibitors of ADP-stimulated platelet ag-
gregation in vitro6 and GnRH receptor antagonists that were both
potent against human and rat receptors in vitro.7
by PicteteSpengler reaction.16,17
We herein describe the formation of substituted-5-azaindoles
using catalysts like TMSCl or TFA involving an amazing tandem one
pot four steps reaction sequence and formation of tetrahydro-5-
azaindoles in diastereoselective manner using glacial acetic acid as
a catalyst during PicteteSpengler condensation. No tandem re-
action was observed during this condensation.
2. Results and discussions
The chemistry of azaindoles has been previously described.8
A
Use of silica gel as a solid and mild acidic catalyst for various
organic reactions is well reported.18,19 In the present work silica gel
has been used as a solid acidic catalyst for Michael addition re-
actions. Thus pyrroles 1 and 2 and nitro-olefins 4aej were loaded
on silica gel and heated at 150 ꢀC to furnish 2-alkyl pyrroles 5aek as
major products in good yield. In some cases 2,5-dialkyl pyrroles
6aec, 6e, and 6g were obtained in minor amounts along with 2-
alkyl pyrroles (Scheme 1, Table 1). The mono and dialkyl pyrroles
were characterized by comparing the spectral data with the
reported20 values. N-Benzoyl pyrrole 3 failed to give the Michael
adduct due to the withdrawing substituent at ring nitrogen.
Further, the nitro compounds 5a, 5b, 5c, and 5e were reduced
using freshly prepared Raney Nickel in methanol to obtain amino
compound 7, 8, 9, and 10, respectively, (Scheme 2).
few classical methods, such as Fischer, Madelung, and Reissert
procedures are the traditional methods used for the synthesis of
most of the azaindoles, which suffer from harsh reaction conditions
and modest yields.9 Azaindoles have been synthesized from ter-
minal alkynes using Sonogashira reaction,10 from internal alkynes
using heteroannulation11 and by Heck reaction.12 Recently, organ-
ometallic chemistry and other synthetic strategies have been used
for the preparation of azaindole derivatives.13
The PicteteSpengler reaction14 is an important acid catalyzed
transformation frequently used for the synthesis of tetrahy-
droisoquinolines or tetrahydro-b-carbolines from carbonyl
Keeping in view tetrahydro-5-azaindoles as target molecules,
PicteteSpengler cyclization was attempted using conventional
* Corresponding author. Tel.: þ91 20 25601400; fax: þ91 20 25691728; e-mail
address: rsk@chem.unipune.ac.in (R.S. Kusurkar).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.003

A.M.A. Shumaila et al. / Tetrahedron 67 (2011) 936e942
937
O2N
NO2
Ar
O2N
Ar
silica gel
150 oC
NO2
R1
+
R1
+
Ar
R1
R1
N
R
N
R
N
R
Ar
6a-6c, 6e, 6g
5a-5k
1, 2, 3
4a-4j
Scheme 1. Michael addition reaction of pyrrole 1 and 2 with nitro-olefins 4aej.
C6H. DEPT spectrum showed the presence of one CH2 group for
compound 11a and two for 12.
Table 1
Time and yield for the formation of Michael adducts 5 and 6
The formation of 11a and 12 can be explained by an amazing one
pot four step reaction sequence involving first PicteteSpengler
cyclization followed by substitution at C2 and C3 with one or two
molecules of benzaldehyde along with dehydration and subsequent
dehydrogenation.
To achieve the planned target it was decided to check the re-
actions using TFA. Thus the reaction of amino compound 7
(0.002 mol) with benzaldehyde (0.004 mol) carried out in TFA for
15 h at room temperature furnished exclusively product 11a in 61%
yield. To confirm the generality of tandem four steps reaction se-
quence, PicteteSpengler cyclization using amines 8, 9, and 10 with
benzaldehyde was attempted to get trisubstituted-5-azaindoles
11b, 11c, and 11d, respectively, as a single product (Scheme 2).
On the other hands, the reactions using substituted benzalde-
hydes with amino compound 10 led to different results in Pic-
teteSpengler cyclization. Trisubstituted-5-azaindole 11e was
Entry R Number (4e6) Ar
R1 Time (min) Yielda (%)
5b
85
90
84 10
84
83 10
82
82 11
6b
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
a
b
c
d
e
f
g
h
i
4-Methoxyphenyl
Phenyl
3,4-Dimethoxyphenyl
3,4-Methylenedioxyphenyl H
2-Furyl
4-Nitrophenyl
2-Thienyl
Phenyl
3,4-Dimethoxyphenyl
4-Nitrophenyl
Phenyl
H
H
H
4
1
4
3
1
5
1
9
6
d
H
H
H
Me 5
Me 5
Me 5
d
81
80
d
d
d
d
9
10
11
j
82
Me b
H
3
83c
a
Calculated according to the recovered starting electrophile.
Products 5hej and 6aec, 6e, and 6g are mixture of diastereomers.
Yield of Michael adduct 5k
b
c
Ph
Ph
Ph
N
N
O2N
Ar
H2N
Ar
(ii)
(i)
+
N
H
N
H
N
N
Ar
Ar
Ph
Ph
H
H
5a-5c,5e
7-10
12
11a
(iii)
+
(iv)
Ar1
Ar1
Ar1
Ar1
N
(v)
N
NH
NH
Ar
N
N
H
N
N
H
Ar
H
Ar
Ar
13e-13g
Ar1
H
14a-14f
13a-13f
11a-11f
Scheme 2. Reagents and conditions: (i) Raney Nickel, H2, MeOH; (ii) PhCHO, DCM, TMSCl, rt, 48 h.;(iii) Ar1CHO, DCM, TFA, rt, 12e24 h; (iv) Ar1CHO, DCM, AcOH (glacial), rt,
36e48 h; (v) Pd/C (5%), xylene, reflux. 5a, 7, 11a, 13a, 14a: Ar¼4-methoxyphenyl, Ar1¼phenyl; 5b, 8, 11b: Ar, Ar1¼phenyl; 5c, 9, 11c, 13b, 14b: Ar¼3,4-dimethoxyphenyl, Ar1¼phenyl;
5e, 10, 11d, 13c, 14c: Ar¼2-furyl, Ar1¼phenyl; 11e, 13d, 14d: Ar¼2-furyl, Ar1¼4-methoxyphenyl; 11f, 13e, 14e: Ar¼2-furyl, Ar1¼4-chlorophenyl; 13f, 13g, (diastereomers), 14f: Ar¼2-
furyl, Ar1¼4-nitrophenyl.
catalysts namely TMSCl and TFA. Initially, reaction of amine 7 with
equal equivalents of benzaldehyde in the presence of TMSCl/TFA in
dichloromethane was attempted. The reaction was very slow and
gave minor amount of mixture of products along with starting
amine. Thus excess of aldehydes was used for all the PicteteSpengler
cyclizations.
Treatment of amine 7 with excess of benzaldehyde in the
presence of TMSCl furnished two products, one as yellow crystals,
melting at 175e177 ꢀC in 28% yield and the other as an oily liquid in
15% yield (Scheme 2). From the spectral data, the products were
shown to be 11a and 12, respectively. Structure of 11a was estab-
lished by the presence of a singlet of two benzylic protons at
4.12 ppm and C6H as a downfield singlet at 8.28 in 1H NMR while
structure 12 was confirmed by the presence of three singlets, two at
4.06 and 3.88 ppm, each of two benzylic protons and one at 8.25 of
obtained exclusively in the reaction of amine 10 with 4-methox-
ybenzaldehyde, while in the reaction with 4-chlorobenzaldehyde
two products were formed; one was trisubstituted-5-azaindole 11f
and the other was one diastereomer of 4,7-disubstituted-4,5,6,7-
tetrahydro-5-azaindole 13e. Using 4-nitrobenzaldehyde, mixture of
diastereomers of tetrahydro-5-azaindole 13f and 13g were
obtained (Scheme 2). The separation of two diastereomers could be
achieved successfully using column chromatography. In 1H NMR,
13f showed separate signals for three protons of C6 and C7 at
as a doublet, 3.25 as a multiplet and 4.19 as a broad singlet while in
the spectrum of 13g the same three protons resonate at 3.21e3.4
d 2.98
d
as a multiplet for two protons and 4.11 as a broad doublet for one
proton.
By analyzing the results it was observed that in case of benzal-
dehyde and 4-methoxybenzaldehyde the reactions were fast to

938
A.M.A. Shumaila et al. / Tetrahedron 67 (2011) 936e942
furnish the trisubstituted-5-azaindoles by tandem four steps re-
action sequence. While using 4-nitrobenzaldehyde due to the
presence of electron-withdrawing group, reaction was slow and
hence afforded only PicteteSpengler cyclization furnishing two
diastereomers of tetrahydro-5-azaindoles. In the reaction with 4-
chlorobenzaldehyde mixed products were obtained due to lower
withdrawing effect of chloro as compared nitro group.
Dehydrogenation of tetrahydro-5-azaindoles 13e using 5% Pd/C
gave product 14e while that of the mixture of 13f and 13g gave
5-azaindoles 14f along with some amount of starting 13f. It was
interesting to observe the ease of dehydrogenation of both the in-
dividual isomers. Dehydrogenation of 13f furnished 14f after 15 h
along with 15% recovered starting while 13g got dehydrogenated
completely within 2 h. This indicated that 13g reacted faster than
13f, which suggested cis arrangement of the aryl and furyl groups at
C4 and C7, respectively, in 13g and trans in 13f (Chart 1). In the later
part X-ray analysis supported the trans stereochemistry.
O2N
H
N
H
N
H
H
H
H
4
H
7
H
O
Fig. 1. ORTEP diagram of compound 13b ellipsoid is drawn at 50% probability.
O
H
H
13f
NO2
13g
By analogy with 13b, the diastereomer 13f should have trans
geometry, which also explains the slow rate of dehydrogenation of
this compound. By comparing the 1H NMR and dehydrogenation
time (9e15 h), all products obtained in the reactions using glacial
acetic acid were suggested to have trans geometry.
Recalling the reaction of amine 7 with benzaldehyde in the pres-
ence of glacial acetic acid, an unknown product was obtained, which
was shown to be identical with the dehydrogenated product 14a.
During the PicteteSpengler reaction of amine 10 with 4-methox-
ybenzaldehyde, aromaticproduct 14d wasdetectedin10%yieldalong
with 4,7-disubstituted-tetrahydro-5-azaindole 13d. In all other sim-
ilar reactions, TLC indicated the presence of minor amount of dehy-
drogenated product. As the cis isomer was shown to dehydrogenate
faster, probably the initially formed small amount of cis isomer might
be getting converted to the 4,7-disubstituted-5-azaindoles.
Chart 1.
The instability due to the cis arrangement of the bulky groups at
C4 and C7 in 13g forces the molecule to react faster to achieve the
stable aromatic structure.
In case of PicteteSpengler reaction with 4-chlorobenzaldehyde,
the cis isomer initially formed might be undergoing further steps of
substitution along with dehydration and subsequent de-
hydrogenation very fast to give 11f. In contrast the isomer 13e, not
getting converted easily, must be having trans stereochemistry.
Itwasnot possible to achieve the synthesis of targeted tetrahydro-
5-azaindoles selectively using TMSCl or TFA in the PicteteSpengler
cyclizations, except in the reactions using benzaldehyde having
electron-withdrawing substituents.
With the aim to get selectively tetrahydro-5-azaindoles, glacial
acetic acid was used as a milder catalyst for this cyclization. As the
reaction with 1 equiv of benzaldehyde was very slow, reaction of
amine 7 with excess of benzaldehyde in the presence of glacial
acetic acid was carried out, which furnished tetrahydro-5-azain-
dole 13a as a single isomer in 68% yield, which was characterized by
spectral data (Scheme 2). The formation of a diastereoselective
product 13a can be attributed to the mild acidic catalyst. In addition
to the above product some amount of starting along with an un-
known compound in very minor amount was seen on TLC. Further,
dehydrogenation of 13a by refluxing with 5% Pd/C in xylene fur-
nished 4,7-disubstituted-5-azaindole 14a.
3. Conclusion
A diastereoselective method was established for the synthesis of
4,7-disubstituted-tetrahydro-5-azaindoles using glacial acetic acid
as a mild catalyst during PicteteSpengler reaction. The stereo-
chemistry was shown to be trans using X-ray analysis. The method
was used for synthesizing new 4,7-disubstituted-tetrahydro-5-
azaindoles 13aef, which were dehydrogenated to 4,7-di-
substituted-5-azaindoles 14aef. In a tandem four steps reaction
sequence using stronger acid TFA, unreported 2,4,7-trisubstituted-
5-azaindoles 11aef were synthesized in good yields.
Encouraged by the success in the diastereoselective cyclization
reaction with glacial acetic acid, the substituents at C4 and C7 were
changed to generalize the stereoselectivity in this reaction. Thus
condensation of the amines 9 and 10 with benzaldehyde gave
tetrahydro-5-azaindoles 13b and 13c as major products, re-
spectively. Reactions of amine 10 with 4-methoxybenzaldehyde
furnished 13d, with 4-chlorobenzaldehyde furnished 13e, and with
4-nitrobenzaldehyde furnished 13f in diastereoselective manner
(Scheme 2). The stereochemistry of 13b was unambiguously in-
vestigated using single crystal X-ray analysis indicating trans ge-
ometry as R, S configuration at C4 and C7 (Fig. 1).
4. Experimental section
4.1. General
Melting points recorded are uncorrected. All solvents were of
reagent grade and, when necessary, were purified and dried by
standard methods. Commercially available glacial acetic acid (from
Merck) was used. Reactions and products were routinely monitored
by thin layer chromatography (TLC) on silica gel (Kieselgel 60 F254
,
Merck). Column chromatographic purifications were performed
using 60e120 mesh silica gel. Visualization was made with UV light
(254 and 365 nm) or with an iodine vapor. IR spectra were recorded
on Shimadzu 8400 instrument. 1H NMR spectra were recorded on
(300 MHz) Varian Mercury instrument or Brucker AC 200
In the last step, refluxing 4,7-disubstituted-tetrahydro-5-
azaindoles 13bee and 13f with 5% Pd/C in xylene furnished 4,7-
disubstituted-5-azaindoles 14bee and 14f, respectively.

A.M.A. Shumaila et al. / Tetrahedron 67 (2011) 936e942
939
spectrometer (200 MHz) using TMS as an internal standard. 13C
NMR spectra were recorded on Varian Mercury instrument or
Brucker ACF 200 spectrometer (75 and 50 MHz, respectively). 1H
NMR peaks expressed as s, br, d, dd, t, and m correspond to singlet,
broad-singlet, doublet, doublet of doublet, triplet, and multiplet,
respectively. Mass were recorded on Shimadzu QP 5050. Elemental
analyses were recorded on Flash E. A. 1112 Thermo instrument.
46.9, 55.9 (2ꢂOCH3), 105.3, 107.9, 111.2, 111.3, 116.7, 120.1, 133.1,
133.8, 147.8, 148.9; MS m/z (%) 246 [Mþ, 10], 231 (2), 216 (100), 200
(16), 185 (14).
4.3.4. 2-(2-Furyl)-2-(1H-pyrrol-2-yl)ethanamine 10. Yield 89% as
a white crystals; mp 59e61 ꢀC; [found: C, 68.42; H, 6.52; N, 15.64.
C10H12N2O requires C, 68.16; H, 6.86; N, 15.90%]; IR (KBr) 3340,
3286, 3243 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 1.29 (2H, br, ex-
4.2. General procedure for Michael addition of pyrrole on
nitro-olefins
changeable with D2O, NH2), 3.21 (2H, br, C1H), 4.08 (1H, br, C2H),
5.98 (1H, br, ArH), 6.04(1H, br, ArH), 6.12 (1H, br, ArH), 6.29 (1H, br,
ArH), 6.68 (1H, br, ArH), 7.34 (1H, br, ArH), 8.99 (1H, br, ex-
changeable with D2O, NH of pyrrole ring); 13C NMR (75 MHz, CDCl3)
A mixture of pyrrole (1, 2 or 3; 0.0024 mol) and nitro-olefin
(4aei or 4j; 0.002 mol) was loaded on silica gel (60e120 mesh,
0.25 g) and heated on silica gel bath at 150 ꢀC for 1e5 min. After the
reaction was completed as judged by TLC, the same silica gel was
loaded on a silica-gel column. Chromatographic separation using
hexane/ethyl acetate furnished the products 5aek and 6a, 6b, 6d,
6f, and 6g.
d
41.5, 45.7, 105.7, 106.5, 107.9, 110.1, 116.9, 130.5, 141.5, 154.9; MS m/
z (%) 176 [Mþ, 14], 146 (100), 130 (12), 117 (95).
4.4. General procedure for PicteteSpengler reaction
A solution of amino compound (7, 8, 9 or 10; 0.002 mol) in
dichloromethane was treated at room temperature with aromatic
aldehyde (0.004 mol or 0.006 mol in case of TMSCl). The solution
was cooled and trimethyl silyl chloride or trifluoroacetic acid or
glacial acetic acid (0.004 mol) was slowly added over 15 min to it.
The reaction mixture was stirred at room temperature for 48 h in
case of TMSCl or for 12e24 h using TFA or for 36e48 h using glacial
acetic acid. The reaction mixture was diluted with dichloro-
methane. Sodium hydroxide (10%) (for the reaction in TMSCl) or
saturated aqueous sodium hydrogen carbonate (for the reactions in
other acids) was added and the organic phase was separated. The
aqueous phase was extracted with dichloromethane (2ꢂ50 ml); the
organic extracts were combined and dried over sodium sulfate. The
crude product obtained was chromatographed on silica gel using
pet. ether and ethyl acetate as an eluent yielding the pure products.
4.3. General procedure for Catalytic hydrogenation
The solution of 2-aryl-2-(2-pyrrolyl)-1-nitroethane (5a, 5b, 5d
or 5e, 0.002 mol) in methanol was taken in round bottom flask
(10 ml) and Raney Nickel (1.5 g) was added to it. The reaction
mixture was treated with hydrogen using balloon under hydro-
gen atmosphere and stirred for 2e12 h. The reaction was fol-
lowed by TLC. After completion of reaction, mixture was filtered
through Celite bed and filtrate was concentrated on rotary
evaporator and washed with ether to remove soluble impurities.
The semisolid product (7, 8, 9 or 10) was recrystallized from hot
pet. ether.
4.3.1. 2-(4-Methoxyphenyl)-2-(1H-pyrrol-2-yl)ethanamine 7. Yield
91% as a white crystals; mp 94e96 ꢀC; [found: C, 72.41; H, 7.66; N,
13.32. C13H16N2O requires C, 72.19; H, 7.46; N, 12.95%]; IR (KBr)
4.4.1. 2-Benzyl-4-phenyl-7-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]
pyridine 11a. Yield 61% (using TFA, stirring time 15 h), 28% (using
TMSCl, stirring time 48 h) as a yellow solid; mp 175e177 ꢀC; [found:
C, 82.84; H, 5.91; N, 6.89. C27H22N2O requires C, 83.05; H, 5.68; N,
3460, 3412, 3389 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 1.46 (2H, br,
exchangeable with D2O, NH2), 3.18 (1H, dd, J 6.6, 12.1 Hz, C1H), 3.3
(1H, dd, J 6.6, 12.1 Hz, C1H), 3.78 (3H, s, OCH3), 3.98 (1H, t, J 6.6 Hz,
C2H), 5.92 (1H, br, ArH), 6.13 (1H, d, J 2.5 Hz, ArH), 6.67 (1H, br, ArH),
6.84 (2H, d, J 8.5 Hz, ArH), 7.1 (2H, d, J 8.5 Hz, ArH), 8.84 (1H, br,
exchangeable with D2O, NH of pyrrole ring); 13C NMR (75 MHz,
7.17%]; Rf (30% EtOAc/hexane) 0.33; IR (KBr) 3367 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d 3.81 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.65 (1H, s,
ArH), 6.97 (2H, d, J 7.9 Hz, ArH), 7.15e7.29 (5H, m, ArH), 7.4 (1H, d, J
6.3 Hz, ArH), 7.46e7.48 (4H, m, ArH), 7.96 (2H, d, J 6.6 Hz, ArH), 8.28
(1H, s, ArH), 8.67 (1H, br, exchangeable with D2O, NH of pyrrole
CDCl3)
d
45.3, 46.5, 55.3, 105.5, 108.0, 114.1 (2ꢂArC), 116.9, 129.0
(2ꢂArC), 132.7, 133.0, 158.5; MS m/z (%) 216 [Mþ, 6], 199 (8), 186
(100), 171 (14).
ring); 13C NMR (75 MHz, CDCl3)
d
34.5, 55.3, 101.6, 114.6 (2ꢂArC),
119.5, 122.9, 126.8, 127.7, 128.4 (3ꢂArC), 128.5 (2ꢂArC), 128.6
(3ꢂArC), 128.7 (2ꢂArC), 129.2 (2ꢂArC), 137.6, 138.5, 139.3, 140.2,
149.2, 159.3; MS m/z (%) 390 [Mþ, 100], 375 (5), 359 (1), 313 (7), 299
(3.5), 281 (2.5), 91 (18), 77 (6). DEPT (75 MHz, CDCl3) showed the
presence of one CH2 group and one CH3 group.
4.3.2. 2-Phenyl-2-(1H-pyrrol-2-yl)ethanamine 8. Yield 94% as
a white crystals; mp 106e108 ꢀC; [found: C, 77.18; H, 7.75; N, 15.26.
C12H14N2 requires C, 77.38; H, 7.58; N, 15.04%]; IR (KBr) 3427 (br),
3267 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.33 (2H, br, exchangeable
with D2O, NH2), 3.21 (1H, dd, J 6.3, 12.4 Hz, C1H), 3.32 (1H, dd, J 6.3,
12.4 Hz, C1H), 4.01 (1H, t, J 6.3 Hz, C2H), 5.94 (1H, br, ArH), 6.13 (1H,
d, J 2.8 Hz, ArH), 6.67 (1H, br, ArH), 7.13e7.35 (5H, m, ArH), 8.88 (1H,
br, exchangeable with D2O, NH of pyrrole ring); 13C NMR (75 MHz,
4.4.2. 2-Benzyl-4,7-diphenyl-1H-pyrrolo[3,2-c]pyridine 11b. Yield
69% (using TFA, stirring time 12 h) as a white crystals; mp
170e172 ꢀC; [found: C, 86.41; H, 5.39; N, 8.03. C26H20N2 requires C,
86.64; H, 5.59; N, 7.77%]; Rf (30% EtOAc/hexane) 0.41; IR (KBr)
CDCl3)
d
46.9, 47.0, 105.3, 107.8, 116.7, 126.7, 128.0 (2ꢂArC), 128.5
(2ꢂArC), 133.0, 141.5; MS m/z (%) 186 [Mþ, 8], 156 (100), 141 (2), 91
3444 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 4.06 (2H, s, CH2), 6.61 (1H,s,
(2.7).
ArH), 6.98e7.29 (6H, m, ArH), 7.32e7.49 (5H, m, ArH), 7.52 (2H, d, J
7.2 Hz, ArH), 7.91 (2H, d, J 7.2 Hz, ArH), 8.27 (1H, s, ArH), 9.13 (1H, br,
exchangeable with D2O, NH of pyrrole ring); 13C NMR (75 MHz,
4.3.3. 2-(3,4-Dimethoxyphenyl)-2-(1H-pyrrol-2-yl)ethanamine
9. Yield 90% as a white crystals; mp 84e86 ꢀC; [found: C, 68.07; H,
7.65; N, 11.59. C14H18N2O2 requires C, 68.27; H, 7.37; N, 11.37%]; IR
CDCl3)
d
34.4, 101.5, 119.7, 122.9, 126.7, 127.8, 128.1 (2ꢂArC), 128.3
(2ꢂArC), 128.4 (2ꢂArC), 128.5 (2ꢂArC), 128.6 (3ꢂArC), 129.1
(2ꢂArC),135.7,137.6,138.9,139.1,139.4,140.0,149.9; MS m/z (%) 360
[Mþ, 100], 283 (6.7), 269 (4.4), 205 (2.2), 113 (2.2), 91 (3.3), 77 (2.2).
(KBr) 3365 (br), 3269 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 1.45 (2H,
br, exchangeable with D2O, NH2), 3.2 (1H, dd, J 6.6, 12.1 Hz, C1H),
3.33 (1H, dd, J 6.6, 12.1 Hz, C1H), 3.82 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 3.94 (1H, t, J 6.3 Hz, C2H), 5.94 (1H, br, ArH), 6.14 (1H, d, J
2.5 Hz, ArH), 6.65e6.83 (4H, m, ArH), 8.84 (1H, br, exchangeable
4.4.3. 2-Benzyl-4-phenyl-7-(3,4-dimethoxyphenyl)-1H-pyrrolo-[3,2-
c]pyridine 11c. Yield 70% (using TFA, stirring time 15 h) as a white
crystals; mp 185e187 ꢀC; [found: C, 80.23; H, 5.59; N, 6.91.
with D2O, NH of pyrrole ring); 13C NMR (75 MHz, CDCl3)
d 46.4,

940
A.M.A. Shumaila et al. / Tetrahedron 67 (2011) 936e942
C28H24N2O2 requires C, 79.98; H, 5.75; N, 6.66%]; Rf (30% EtOAc/
hexane) 0.29; IR (KBr) 3348 cmꢁ1 1H NMR (300 MHz, CDCl3)
3.82 (3H, s, OCH3), 3.92 (3H, s, OCH3), 4.17 (2H, s, CH2), 6.69 (1H,
s, ArH), 6.96e7.01 (2H, m, ArH), 7.12 (1H, d, J 8.3 Hz, ArH),
7.19e7.36 (5H, m, ArH), 7.42 (1H, t, J 7.2 Hz, ArH), 7.5 (2H, t, J
7.4 Hz, ArH), 7.99 (2H, d, J 7.4 Hz, ArH), 8.32 (1H, br, exchangeable
with D2O, NH of pyrrole ring), 8.35 (1H, s, ArH); 13C NMR (75 MHz,
(2ꢂArC), 129.1 (2ꢂArC), 129.2 (2ꢂArC), 136.2, 137.6, 138.5, 138.8,
140.5, 140.6, 152.2, 159.3; MS m/z (%) 480 [Mþ, 100], 448 (1), 403
(6.6), 389 (5.5), 374 (2.2), 311 (2.4), 297 (1), 91 (5.5), 77 (3.3). DEPT
(75 MHz, CDCl3) showed the presence of two CH2 groups and one
CH3 group.
;
d
4.4.8. 4-Phenyl-7-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo
[3,2-c]pyridine 13a. Yield 68% (using AcOH, stirring time 36 h) as
a white solid; mp 152e154 ꢀC; [found: 78.71; H, 6.84; N, 8.96.
C20H20N2O requires C, 78.92; H, 6.62; N, 9.20%]; Rf (50% EtOAc/
CDCl3)
d
34.5, 55.8 (2ꢂOCH3), 101.3, 111.1, 111.6, 119.6, 120.4, 122.8,
126.7, 128.23, 128.26, 128.33 (2ꢂArC), 128.49 (2ꢂArC), 128.5
(2ꢂArC), 128.6 (2ꢂArC), 137.7, 138.8, 139.2, 139.6, 139.9, 148.6,
149.3, 149.6; MS m/z (%) 420 [Mþ, 100], 419 (54), 403 (14), 389 (5),
343 (4), 91 (11), 77 (2).
hexane) 0.28; IR (KBr) 3398 (br) cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
2.7 (1H, br, exchangeable with D2O, NH), 2.94 (1H, dd, J 9.4,
12.3 Hz, C6H), 3.39 (1H, dd, J 5.2, 12.3 Hz, C6H), 3.78 (3H, s, OCH3),
4.1 (1H, t, J 5.8 Hz, C7H), 5.11 (1H, d, J 1.4 Hz, C4H), 5.74 (1H, t, J
2.3 Hz, ArH), 6.55 (1H, t, J 2.6 Hz, ArH), 6.84 (2H, d, J 8.5 Hz, ArH),
7.08 (2H, d, J 8.5 Hz, ArH), 7.21e7.44 (5H, m, ArH), 7.89 (1H, br,
exchangeable with D2O, NH of pyrrole ring); 13C NMR (75 MHz,
4.4.4. 2-Benzyl-4-phenyl-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine
11d. Yield 68% (using TFA, stirring time 16 h) as oily liquid; [found:
C, 82.02; H, 5.43; N, 7.69. C24H18N2O requires C, 82.26; H, 5.18; N,
7.99%]; Rf (30% EtOAc/hexane) 0.40; IR (KBr) 3462 cmꢁ1 1H NMR
;
(300 MHz, CDCl3)
d
4.23 (2H, s, CH2), 6.58 (1H, m, ArH), 6.68 (1H, br,
CDCl3)
d
41.3, 52.7, 55.3, 58.8, 105.8, 114.0 (2ꢂArC), 116.5, 120.2,
ArH), 6.84 (1H, d, J 3.6 Hz, ArH), 7.23e7.4 (5H, m, ArH), 7.44 (1H, d, J
7.2 Hz, ArH), 7.52 (2H, t, J 7.4 Hz, ArH), 7.57 (1H, br, ArH), 8.01 (2H, d,
J 7.2 Hz, ArH), 8.65 (1H, s, ArH), 9.15 (1H, br, exchangeable with D2O,
127.4, 128.2 (2ꢂArC), 128.3 (2ꢂArC), 128.7, 129.3 (2ꢂArC), 133.9,
144.0, 158.6; MS m/z (%) 304 [Mþ, 2.2], 275 (100), 260 (13.2), 244
(30), 198 (16.3), 91 (8.8), 77 (13.2).
NH of pyrrole ring); 13C NMR (75 MHz, CDCl3)
d 34.4, 101.0, 105.4,
109.5, 111.6, 123.2, 126.7, 128.1, 128.3 (2ꢂArC), 128.4 (2ꢂArC), 128.5
(2ꢂArC), 128.6 (2ꢂArC), 136.3, 136.4, 137.6, 139.7, 139.9, 141.9, 149.9,
151.4; MS m/z (%) 349 [Mþꢁ1, 100], 319 (14), 273 (12), 259 (9), 91
(20), 77 (12).
4.4.9. 4-Phenyl-7-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro-1H-
pyrrolo[3,2-c]pyridine 13b. Yield 66% (using AcOH, stirring time
36 h) as a white solid; mp 169e171 ꢀC; [found: C, 75.69; H, 6.85;
N, 8.67. C21H22N2O2 requires C, 75.42; H, 6.63; N, 8.38%]; Rf (50%
EtOAc/hexane) 0.25; IR (KBr): 3553, 3277 cmꢁ1
;
1H NMR
4.4.5. 2-(4-Methoxybenzyl)-4-(4-methoxyphenyl)-7-(2-furyl)-1H-
pyrrolo[3,2-c]pyridine 11e. Yield 61% (using TFA, stirring time 20 h)
as oily liquid; [found: C, 76.31; H, 5.57; N, 7.09. C26H22N2O3 requires
C, 76.08; H, 5.40; N, 6.82%]; Rf (30% EtOAc/hexane) 0.28; IR (KBr)
(300 MHz, CDCl3/DMSO-d6) d 3.04 (1H, t, J 11.7 Hz, C6H), 3.49 (1H,
dd, J 4.7, 12.0 Hz, C6H), 3.79 (3H, s, OCH3), 3.84 (3H, s, OCH3), 4.27
(1H, br, C7H), 5.35 (1H, br, C4H), 5.67 (1H, br, exchangeable with
D2O, NH), 6.61 (1H, s, ArH), 6.72 (2H, m, ArH), 6.82 (1H, d, J
7.9 Hz, ArH), 7.25e7.39 (3H, m, ArH), 7.44 (2H, t, J 6.5 Hz, ArH),
7.94 (1H, d, J 7.3 Hz, ArH), 9.51 (1H, br, exchangeable with D2O,
3456 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 3.82 (3H, s, OCH3), 3.89
(3H, s, OCH3), 4.16 (2H, s, CH2), 6.56 (1H, m, ArH), 6.63 (1H, br, ArH),
6.81 (1H, d, J 3.6 Hz, ArH), 6.88 (2H, d, J 8.5 Hz, ArH), 7.05 (2H, d, J
8.8 Hz, ArH), 7.19 (2H, d, J 8.5 Hz, ArH), 7.57 (1H, br, ArH), 7.95 (2H,
d, J 8.8 Hz, ArH), 8.61 (1H, s, ArH), 9.1 (1H, br, exchangeable with
NH of pyrrole ring); 13C NMR (75 MHz, CDCl3/DMSO-d6)
d 39.4,
50.4, 55.0, 55.1, 57.6, 104.5, 110.6, 110.7, 116.6, 117.2, 119.8, 126.8,
127.0, 127.5, 128.1, 128.6, 130.3, 133.3, 140.9, 147.2, 148.2; MS m/z
(%) 333 [Mþꢁ1, 2], 305 (34), 290 (6), 274 (22), 259 (3), 243 (2), 77
(100).
D2O, NH of pyrrole ring); 13C NMR (75 MHz, CDCl3)
d 33.7, 55.2,
55.3, 100.8, 105.1, 109.0, 111.6, 113.8 (2ꢂArC), 114.0 (2ꢂArC), 122.8,
129.5 (2ꢂArC), 129.7 (2ꢂArC), 132.6, 136.3, 136.4 (2ꢂArC), 139.9,
141.8, 149.7, 151.6, 158.2, 159.6; MS m/z (%) 410 [Mþ, 100], 395 (16),
381 (2.1), 303 (3), 108 (6.3), 91 (2.1), 77 (4.2).
4.4.10. 4-Phenyl-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]
pyridine 13c. Yield 60% (using AcOH, stirring time 36 h) as a white
solid; mp 129e131 ꢀC; [found: C, 77.54; H, 6.36; N, 10.89.
C17H16N2O requires C, 77.25; H, 6.10; N, 10.60%]; Rf (50% EtOAc/
4.4.6. 2-(4-Chlorobenzyl)-4-(4-chlorophenyl)-7-(2-furyl)-1H-pyrrolo
[3,2-c]pyridine 11f. Yield 31% (using TFA, stirring time 24 h) as
hexane) 0.48; IR (KBr): 3356, 3259 cmꢁ1
;
1H NMR (300 MHz,
a
yellowish solid; Rf (30% EtOAc/hexane) 0.36; IR (KBr)
CDCl3) d 2.0 (1H, br, exchangeable with D2O, NH), 3.19 (1H, dd, J
3363 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
4.19 (2H, s, CH2), 6.56
8.2, 12.3 Hz, C6H), 3.49 (1H, dd, J 5.3, 12.3 Hz, C6H), 4.24 (1H, t, J
6.5 Hz, C7H), 5.07 (1H, d, J 1.5 Hz, C4H), 5.79 (1H, t, J 2.6 Hz, ArH),
6.08 (1H, d, J 3.3 Hz, ArH), 6.34 (1H, m, ArH), 6.61 (1H, t, J 2.3 Hz,
ArH), 7.25e7.41 (6H, m, ArH), 8.32 (1H, br, exchangeable with D2O,
(1H, br, ArH), 6.81 (1H, d, J 3.0 Hz, ArH), 7.13e7.42 (6H, m, ArH),
7.46 (1H, d, J 6.9 Hz, ArH), 7.58 (1H, br, ArH), 7.9 (2H, d, J 6.9 Hz,
ArH), 8.61 (1H, s, ArH), 9.31 (1H, br, exchangeable with D2O, NH
of pyrrole ring); 13C NMR (75 MHz, CDCl3/DMSO-d6):
d
33.9,
NH); 13C NMR (75 MHz, CDCl3)
d 35.0, 47.8, 58.3, 105.6, 106.1, 110.2,
100.7, 105.9, 109.6, 110.8, 121.8, 126.9 (2ꢂArC), 127.5 (2ꢂArC),
128.9 (2ꢂArC), 129.2 (2ꢂArC), 130.9, 132.9, 134.5, 135.2, 136.4,
137.3, 140.7, 141.6, 147.8, 149.1. Additional signals of 13e were also
seen in the spectrum.
116.6, 119.6, 125.8, 127.3, 128.2 (2ꢂArC), 128.3 (2ꢂArC), 141.7,
144.0, 155.1; MS m/z (%) 235 [Mþꢁ29, 100%], 218 (7.6), 206 (65),
191 (7.8), 77 (28), 51 (33).
4.4.11. 4-(4-Methoxyphenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyr-
rolo[3,2-c]pyridine 13d. Yield 61% (using AcOH, stirring time 48 h)
as a white solid; mp 146e148 ꢀC; [found: C, 73.19; H, 6.38; N, 9.22.
C18H18N2O2 requires C, 73.45; H, 6.16; N, 9.52%]; Rf (50% EtOAc/
hexane) 0.29; IR (KBr) 3362, 3248 cmꢁ1; 1H NMR (300 MHz, DMSO-
4.4.7. 2,3-Dibenzyl-4-phenyl-7-(4-methoxyphenyl)-1H-pyrrolo-[3,2-
c]pyridine 12. Yield 15% (using TMSCl, stirring time 48 h) as oily
liquid; [found: C, 85.19; H, 6.09; N, 5.61. C34H28N2O requires C,
84.97; H, 5.87; N, 5.83%]; Rf (30% EtOAc/hexane) 0.24; IR (KBr)
3450 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
3.84 (3H, s, OCH3), 3.88
d6) d 1.87 (1H, br, exchangeable with D2O, NH), 2.90 (1H, dd, J 8.2,
(2H, s, CH2), 4.06 (2H, s, CH2), 6.66 (2H, br, ArH), 6.96e7.13 (7H, m,
ArH), 7.18e7.3 (6H, m, ArH), 7.34 (2H, t, J 6.6 Hz, ArH), 7.49 (2H, d, J
8.8 Hz, ArH), 8.25 (1H, s, ArH), 8.33 (1H, br, exchangeable with
12.3 Hz, C6H), 3.26 (1H, dd, J 5.3, 12.3 Hz, C6H), 3.71 (3H, s, OCH3),
4.16 (1H, br, C7H), 4.84 (1H, s, C4H), 5.46 (1H, s, ArH), 6.08 (1H, d, J
2.9 Hz, ArH), 6.38 (1H, m, ArH), 6.50 (1H, s, ArH), 6.83 (2H, d, J
8.5 Hz, ArH), 7.21 (2H, d, J 8.5 Hz, ArH), 7.56 (1H, d, J 0.9 Hz, ArH),
10.38 (1H, br, exchangeable with D2O, NH of pyrrole ring); 13C NMR
D2O, NH of pyrrole ring); 13C NMR (75 MHz, CDCl3)
d 30.4, 32.4,
55.4, 111.4, 114.8 (2ꢂArC), 119.0, 122.2, 125.3, 126.8, 127.5 (2ꢂArC),
127.6, 127.7 (2ꢂArC), 127.8 (2ꢂArC), 128.0, 128.4 (2ꢂArC), 128.8
(75 MHz, DMSO-d6) d 34.4, 48.0, 55.0, 56.8, 104.8, 105.9, 110.3, 113.2

A.M.A. Shumaila et al. / Tetrahedron 67 (2011) 936e942
941
(2ꢂArC), 116.6, 119.5, 124.8, 129.2 (2ꢂArC), 136.6, 141.7, 155.6, 158.2;
MS m/z (%) 295 [Mþþ1, 12], 283 (14), 207 (20), 110 (16), 44 (100).
8.0 Hz, ArH), 7.42 (2H, d, J 8.0 Hz, ArH), 7.66 (1H, s, ArH), 10.07
(1H, br, exchangeable with D2O, NH of pyrrole ring); 13C NMR
(50 MHz, CDCl3/DMSO-d6)
d
55.0, 102.2, 114.3 (2ꢂArC), 119.9,
4.4.12. 4-(4-Chlorophenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyr-
rolo[3,2-c]pyridine 13e. Yield 59% (using AcOH, stirring time 48 h),
33% (using TFA, stirring time 24 h) as a white solid; mp 164e166 ꢀC;
[found: C, 68.09; H, 4.89; N, 9.11. C17H15ClN2O: requires C, 68.34; H,
5.06; N, 9.38%]; Rf (50% EtOAc/hexane) 0.58; IR (KBr) 3362,
122.2, 126.4, 127.9, 128.1, 128.2 (2ꢂArC), 128.4 (2ꢂArC), 129.3
(2ꢂArC), 138.4, 138.7, 139.6, 150.1, 159.1; MS m/z (%) 300 [Mþ,
100%], 285 (39), 269 (2), 190 (1), 114 (23), 77 (4).
4.5.2. 4-Phenyl-7-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine
14b. Yield 68% as a white solid; mp 163e165 ꢀC; [found: C, 76.09;
H, 5.71; N, 8.21. C21H18N2O2 requires C, 76.34; H, 5.49; N, 8.48%];
3248 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 1.93 (1H, br, exchangeable
with D2O, NH), 3.17 (1H, dd, J 8.3, 12.4 Hz, C6H), 3.45 (1H, dd, J 5.2,
12.4 Hz, C6H), 4.23 (1H, t, J 7.15 Hz, C7H), 5.02 (1H, d, J 1.7 Hz, C4H),
5.73 (1H, t, J 2.5 Hz, ArH), 6.06 (1H, d, J 3.3 Hz, ArH), 6.32 (1H, m,
ArH), 6.62 (1H, t, J 2.8 Hz, ArH), 7.28e7.34 (4H, m, ArH), 7.37 (1H, m,
Rf (30% EtOAc/hexane) 0.18; IR (KBr) 3335 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d
3.91 (6H, s, 2ꢂOCH3), 6.91 (1H, d, J 2.2 Hz,
ArH), 6.98 (1H, d, J 8.3 Hz, ArH), 7.12 (1H, s, ArH), 7.18 (1H, d, J
8.3 Hz, ArH), 7.28 (1H, br, ArH), 7.38e7.46 (1H, m, ArH), 7.53 (2H,
t, J 7.4 Hz, ArH), 8.0 (2H, d, J 7.7 Hz, ArH), 8.37 (1H, s, ArH), 9.1
(1H, br, exchangeable with D2O, NH of pyrrole ring); 13C NMR
ArH), 8.22 (1H, br, exchangeable with D2O, NH of pyrrole ring); 13
C
NMR (75 MHz, CDCl3)
d 34.9, 47.7, 57.6, 105.7, 106.0, 110.2, 116.8,
119.3, 125.9, 128.4 (2ꢂArC), 129.6 (2ꢂArC), 132.9, 141.8, 142.6, 154.9;
MS m/z (%) 269 [Mþꢁ29, 100], 240 (30.8), 234 (22), 205 (35.4), 151
(6.6), 51 (30.8).
(75 MHz, CDCl3)
d
55.8 (2ꢂArC), 103.0, 111.3, 111.5, 120.3, 120.5,
122.3, 126.3, 127.8, 128.1, 128.4 (2ꢂArC), 128.6 (2ꢂArC), 138.5,
138.8, 139.2, 148.7, 149.2, 150.4; MS m/z (%) 330 [Mþ, 100], 315
(22), 297 (2), 194 (4), 109 (14).
4.4.13. 4-(4-Nitrophenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyrrolo
[3,2-c]pyridine 13f. Yield 52% (using AcOH, stirring time 48 h), 34%
(using TFA, stirring time 24 h) as
a yellow crystals; mp
163e164 ꢀC; [found: C, 65.79; H, 5.15; N, 13.36. C17H15N3O3 re-
quires C, 66.01; H, 4.89; N, 13.58%]; Rf (30% EtOAc/hexane) 0.29; IR
4.5.3. 4-Phenyl-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine
14c. Yield
63% as a white solid; mp 162e164 ꢀC; [found: C, 78.17; H, 4.89; N,
10.97. C17H12N2O requires C, 78.44; H, 4.65; N, 10.76%]; Rf (30%
EtOAc/hexane) 0.37; IR (KBr) 3222 cmꢁ1; 1H NMR (200 MHz, CDCl3/
(KBr) 3351, 3219, 1518, 1344 cmꢁ1 1H NMR (300 MHz, DMSO-d6)
;
d
2.50 (1H, br, exchangeable with D2O, NH), 2.98 (1H, br d, J 6.9 Hz,
DMSO-d6)
d 6.33 (1H, t, J 2.0 Hz, ArH), 6.56 (1H, d, J 2.0 Hz, ArH),
C6H), 3.25 (1H, m, with DMSO, C6H), 4.19 (1H, br, C7H), 5.09 (1H,
br, C4H), 5.46 (1H, br, ArH), 6.09 (1H, br, ArH), 6.38 (1H, br, ArH),
6.53 (1H, br, ArH), 7.55 (1H, br, ArH), 7.60 (2H, d, J 7.7 Hz, ArH), 8.19
(2H, d, J 7.2 Hz, ArH), 10.45 (1H, br, exchangeable with D2O, NH of
6.72 (1H, d, J 4.0 Hz, ArH), 7.15e7.36 (4H, m, ArH), 7.39 (1H, d, J
10.0 Hz, ArH), 7.72 (2H, d, J 8.0 Hz, ArH), 8.4 (1H, s, ArH), 10.83 (1H,
br, exchangeable with D2O, NH of pyrrole ring); 13C NMR (50 MHz,
pyrrole ring); 13C NMR (75 MHz, DMSO-d6):
d 34.3, 47.5, 56.4,
CDCl3/DMSO-d6)
d 102.2, 106.7, 110.5, 111.9, 123.0, 127.5, 128.6
(2ꢂArC), 128.7 (2ꢂArC), 135.7, 136.3, 139.9, 142.6 (2ꢂArC), 150.5,
104.5, 105.8, 110.1, 116.7, 118.1, 122.9 (2ꢂArC), 124.9, 128.9 (2ꢂArC),
141.4, 146.1, 152.9, 155.3; MS m/z (%) 280 [Mþꢁ29, 100], 279 (8),
263 (8), 233 (23), 217 (2.5), 51 (2.2).
150.6; MS m/z (%) 260 [Mþ, 100], 231 (34), 204 (10), 76 (8).
4.5.4. 4-(4-Methoxyphenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridi-ne
14d. Yield 65% as a white solid; mp 170e171 ꢀC; [found: C, 74.24; H,
5.11; N, 9.39. C18H14N2O2 requires C, 74.47; H, 4.86; N, 9.65%]; Rf
4.4.14. 4-(4-Nitrophenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyr-r-
olo[3,2-c]pyridine 13g. Yield 24% (using TFA, stirring time 24 h) as
a oily liquid; [found: C, 66.32; H, 4.59; N,13.42. C17H15N3O3 requires C,
66.01; H, 4.89; N, 13.58%]; Rf (30% EtOAc/hexane) 0.22; IR (KBr) 3416
(30% EtOAc/hexane) 0.23; IR (KBr) 3215 cmꢁ1 1H NMR (300 MHz,
;
CDCl3)
d 3.87 (3H, s, OCH3), 6.56 (1H, br, ArH), 6.88 (2H, br, ArH),
(br), 1518, 1346 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 2.69 (1H, br, ex-
7.03 (2H, d, J 8.5 Hz, ArH), 7.36 (1H, br, ArH), 7.59 (1H, br, ArH), 7.95
(2H, d, J 8.5 Hz, ArH), 8.64 (1H, s, ArH), 9.77 (1H, br, exchangeable
changeable with D2O, NH), 3.21e3.4 (2H, m, C6H), 4.11 (1H, br d, J
4.7 Hz, C7H), 5.15 (1H, br, C4H), 5.74 (1H, t, J 2.5 Hz, ArH), 6.05 (1H, d, J
3.0 Hz, ArH), 6.29 (1H, t, J 1.7 Hz, ArH), 6.68 (1H, t, J 2.5 Hz, ArH), 7.34
(1H, br, ArH), 7.52 (2H, d, J 8.5 Hz, ArH), 8.14 (2H, d, J 8.5 Hz, ArH), 8.32
(1H, br, exchangeable with D2O, NH of pyrrole ring); 13C NMR
with D2O, NH of pyrrole ring); 13C NMR (75 MHz, CDCl3)
d 55.3,
102.8, 105.4, 109.7, 111.7, 113.8 (2ꢂArC), 122.2, 125.8, 129.9 (2ꢂArC),
132.2, 135.9, 136.2, 142.0, 150.5, 151.3, 159.9; MS m/z (%) 290 [Mþ,
100], 275 (32), 191 (12), 115 (9), 109 (16).
(75 MHz, CDCl3) d 34.1, 46.2, 56.8,105.7,106.3,110.2,117.3,117.7,123.6
(2ꢂArC), 125.6, 129.2 (2ꢂArC), 141.8, 147.1, 150.9, 155.2; MS m/z (%)
4.5.5. 4-(4-Chlorophenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine
14e. Yield 55% as a white solid; mp 180e182 ꢀC; [found: C, 69.51; H,
3.99; N, 9.78. C17H11ClN2O requires C, 69.28; H, 3.76; N, 9.50%]; Rf
281 [Mþꢁ28, 30], 280 (100), 263 (14), 233 (24), 217 (4), 77 (5), 51 (2).
(30% EtOAc/hexane) 0.33; IR (KBr) 3257 cmꢁ1 1H NMR (300 MHz,
;
4.5. General procedure for dehydrogenation of disubstituted-
tetrahydro-5-azaindoles
CDCl3/DMSO-d6) d 6.59 (1H, t, J 1.7 Hz, ArH), 6.82 (1H, br, ArH), 7.02
(1H, d, J 3.0 Hz, ArH), 7.37e7.43 (1H, m, ArH), 7.5 (2H, t, J 8.0 Hz,
ArH), 7.68 (1H, br, ArH), 7.98 (2H, d, J 8.0 Hz, ArH), 8.66 (1H, s, ArH),
11.23 (1H, br, exchangeable with D2O, NH of pyrrole ring); 13C NMR
A mixture of tetrahydro-5-azaindole (13aef or 13g; 0.10 g), 5%
Pd/C (50 mg) and dry xylene (5 ml) was refluxed for 2e15 h. The
reaction mixture was cooled and ethyl acetate (10 ml) was added to
it. The catalyst was filtered off through Celite and the filtrate was
concentrated by rotary evaporator. The crude product obtained was
chromatographed on neutral alumina using pet. ether and ethyl
acetate as an eluent yielding disubstituted-5-azaindole.
(75 MHz, CDCl3/DMSO-d6)
d 101.4, 106.3, 109.8, 111.4, 122.3, 126.9,
127.8, 127.9 (2ꢂArC), 128.1 (2ꢂArC), 134.9, 136.0 (2ꢂArC), 139.6,
142.0,149.8; MS m/z (%) 294 [Mþ,10], 293 (6), 260 (100),192 (8),116
(98), 76 (58).
4.5.6. 4-(4-Nitrophenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine
14f. Yield 46% as a yellow solid; mp 155e157 ꢀC; [found: C, 67.11; H,
3.42; N, 14.03. C17H11N3O3 requires C, 66.88; H, 3.63; N, 13.76%]; Rf
4.5.1. 4-Phenyl-7-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine
14a. Yield 81% as a white solid; mp 195e197 ꢀC; [found: C, 79.72;
H, 5.16; N, 9.08. C20H16N2O requires C, 79.98; H, 5.37; N, 9.33%]; Rf
(30% EtOAc/hexane) 0.25; IR (KBr) 3217, 1518, 1377 cmꢁ1 1H NMR
;
(30% EtOAc/hexane) 0.22; IR (KBr) 3201 cmꢁ1 1H NMR (200 MHz,
;
(300 MHz, DMSO-d6)
d 6.77 (1H, t, J 3.3 Hz, ArH), 6.98 (1H, br, ArH),
CDCl3/DMSO-d6)
d 3.22 (3H, s, OCH3), 6.27 (1H, d, J 4.0 Hz, ArH),
7.31 (1H, d, J 3.8 Hz, ArH), 7.69 (1H, d, J 2.8 Hz, ArH), 7.94 (1H, br, ArH),
6.41 (2H, d, J 10.0 Hz, ArH), 6.67e6.95 (4H, m, ArH), 6.98 (2H, t, J

942
A.M.A. Shumaila et al. / Tetrahedron 67 (2011) 936e942
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8.32 (2H, d, J 8.8 Hz, ArH), 8.4 (2H, d, J 8.8 Hz, ArH), 8.78 (1H, s, ArH),
11.81 (1H, br, exchangeable with D2O, NH of pyrrole ring); 13C NMR
(75 MHz, DMSO-d6)
129.4, 129.6 (2ꢂArC), 135.1, 136.5, 143.8, 146.0, 146.8, 147.1, 149.4; MS
d
101.4, 108.2, 111.1, 112.4, 123.1, 123.9 (2ꢂArC),
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5. Crystallography
Crystallographic data in this paper have been deposited with the
Cambridge Crystallographic Data Centre. Deposition number is
CCDC 796855 for 13b. Copy of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ336033 1223 44 or e-mail: deposit@ccdc.cam.ac.uk).
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Acknowledgements
We are grateful to Prof. M.S. Wadia for helpful discussion, B.S.
Kalshetti for IR spectra, J.P. Choudhary for NMR spectra, and D.S.
Shishupal for GCeMS. A.M.A.S. is thankful to MOHE in Yemen for
the award of a fellowship.
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Supplementary data
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X-ray analysis of compound 13b are associated with this article as
supplementary data. Supplementary data associated with this ar-
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These data include MOL files and InChIKeys of the most important
compounds described in this article.
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