A rapid method toward the synthesis of new substituted tetrahydro α-carbolines and α-carbolines

Article abstract of DOI:10.1016/j.tet.2010.01.042

A rapid and efficient method for stereoselective synthesis of new substituted tetrahydro-α-carbolines using Diels-Alder reaction under microwave irradiation has been developed. Further, dehydrogenation of these adducts resulted in synthesis of new substit

Full text of DOI:10.1016/j.tet.2010.01.042

Tetrahedron 66 (2010) 1827–1831
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A rapid method toward the synthesis of new substituted tetrahydro
a-carbolines and a-carbolines
,
Neelam L. Chavan a, Sandip K. Nayak b, Radhika S. Kusurkar a
*
a Department of Chemistry, University of Pune, Ganeshkhind Road, Pune, Maharashtra 411007, India
b Bio-organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid and efficient method for stereoselective synthesis of new substituted tetrahydro-
using Diels–Alder reaction under microwave irradiation has been developed. Further, dehydrogenation of
these adducts resulted in synthesis of new substituted -carbolines.
Ó 2010 Elsevier Ltd. All rights reserved.
a-carbolines
Received 29 September 2009
Received in revised form 8 January 2010
Accepted 9 January 2010
a
Available online 18 January 2010
Keywords:
Tetrahydro-a-carbolines
a
-Carbolines
Microwave irradiation
Diels–Alder reaction
3-Vinyl-7-azaindole
1. Introduction
substituted tetrahydro-
maleimides as dienophile was based on the importance of imido
substituted
-carbolines in displaying anticarcinogenic activity.4
a-carbolines. The choice of N-substituted
Pyrido[2,3-b]indole (
a-carbolines) scaffold is prevalent in a vari-
a
ety of naturally occurring and synthetic molecules displaying various
biological properties. This skeleton is found in several alkaloids1 and
2. Result and discussion
carcinogenic metabolites.2 Moreover, some
a-carboline derivatives,
which are anxiolytic or neuroprotectant agents,3 also exhibit anti-
viral and antitumor activities.4 It is reported that replacement of
a carbon atom by a nitrogen atom in the carbazole unit could increase
the affinity for the binding site on the target enzyme(s) and also
modify the electronic distribution of the aromatic framework and
the lipophilicity of the molecule.5 Consequently, the development of
efficient ways to synthesize this class of compounds continues to be
an active area of research.
Formylation of 7-azaindole (1) using Vilsmeier Haack reaction8
at 85 ꢀC followed by protection using benzenesulphonylchloride
in presence of NaH furnished protected aldehyde 3 (Scheme 1).
Olefination of aldehyde by Wittig reaction afforded diene 4 in 68%
yield. The Diels–Alder reaction of diene 4 with N-phenyl maleimide
(5a) was carried out by adsorbing them on silica gel and irradiating
under microwave (700 watts) at 75 ꢀC 10 min to afford compound
6a in 88% yield. Elemental analysis and spectral data of purified
product revealed that Diels–Alder reaction has occurred with high
stereoselectivity furnishing endo product 6a and no traces of other
diasteromer (exo) was observed.
In our earlier work6 substituted carbazoles have been prepared
regio- and stereoselectively using Diels–Alder reactions from
3-vinyl indoles. In continuation of this work we have extended this
strategy of Diels–Alder reactions using 3-vinyl azaindole toward
the synthesis of substituted a-carbolines.
2.1. Sterochemistry of the Diels–Alder adduct 6a
Microwave irradiation is used to achieve fast, clean and high-
yielding transformations. There are various reviews7 in literature,
which reveals efficient use of microwave in organic synthesis. We
herein report the use of same technique for facile synthesis of
As Diels–Alder reaction involves supra–supra interaction, the
geometry at C7 and C8 must be cis. The only newly generated
stereocentre that needs to be established is C9. One isomer (endo)
will have H7, H8, and H9 all cis while the other isomer (exo) will have
H8 and H9 trans. The isomer 6a (Fig. 1) corresponds to endo geo-
metry, which is the one usually observed in Diels–Alder reaction
due to secondary orbital overlap. The value of JH8–H9 observed in
* Corresponding author. Tel.: þ91 020 25604100; fax: þ91 020 25601728.
E-mail address: rsk@chem.unipune.ernet.in (R.S. Kusurkar).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.042

1828
N.L. Chavan et al. / Tetrahedron 66 (2010) 1827–1831
O
O
H
H
DMF, POCl3
PhSO2Cl, NaH
85
°C,50%
0°C,98%
N
H
N
N
H
N
N
N
SO2Ph
1
3
2
+PPh3CH3I-, +K-OtBu,
C,68%
0
°
O
MW 800 watts
silica gel
O
X
N
H
N
N
N
O
SO2Ph
SO2Ph
6a-6d
X
4
81-88%
O
5a: X = NPh
5b: X = NMe
5c: X = NH
5d: X = O
Scheme 1.
bulky protecting group in the substrate. We modified the strategy
by carrying out deprotection at the first step followed by de-
hydrogenation. Various reagents like Na–MeOH, TBAF–THF, and
NaOH–MeOH were screened for the removal of phenylsulphonyl
group, but all remain unsuccessful and starting was recovered.
Similar results were observed during our previous work on the
synthesis of carbazole derivatives. This may be explained by the
steric hindrance of endo five membered ring for the approach of
the base.
Further, it was thought to use deprotected diene 8 for the Diels–
Alder reaction. Thus Wittig–Horner reaction of aldehyde 3 with
carbethoxymethylenetriphenyl phosphorane afforded the diene 7.
Deprotection of compound 7 with tetrabutylammonium fluoride in
dry THF furnished diene 8 in 99% yield. To our surprise Diels–Alder
reaction of diene 8 with dienophiles 5a resulted in the formation of
cycloadduct, which was a mixture of diastereomers as detected in
TLC. It was directly utilized for dehydrogenation without purifica-
6
5
H
O
4
H
3
2
1''
N
3''
4''
H
N
S
N
1
O
O
6''
1'
O
5''
6'
3'
5'
Figure 1.
4'
1H NMR was 6.8, which corroborates with the endo stereo structure
of 6a. In keeping with this structure JH7–H8¼9 Hz is consistent with
a dihedral angle w0ꢀ. Earlier Pfeuffer and Pindur9 using 3-vinyl
indole as diene also assigned endo geometry for a similar type
Diels–Alder adduct. The 1H NMR values and coupling constants
are consistent with those obtained by us.
Other dienophiles such as 5b–d were also used for the above
Diels–Alder reaction furnishing cycloadducts 6b–d in 81, 88, and
85% yields, respectively. All these cycloadducts showed spectral
data similar to 6a indicating the formation of endo adduct in all the
cases.
tion using 10% Pd/C to furnish
der reaction of 8 with other dienophiles 5b and 5c resulted in the
formation of -carbolines 9b and 9c (Scheme 2).
After establishing an efficient new route toward
desiredtoextendoursequenceofcycloadditionanddehydrogenation
to achieve the synthesis of N-methyl -carbolines. Thus aldehyde 2
a-carbolines 9a. Similarly Diels–Al-
a
a-carbolines, we
Next, dehydrogenation of 6a was attempted using DDQ in xy-
lene, but without success. This could be attributed to the presence
a
was protected to obtain N-methyl aldehyde 10, which intern was
O
O
COOEt
H
H
PPh3CHCOOEt,
Toluene, reflux, 5h
NaH, THF
PhSO2Cl/MeI
N
R
N
R
O
N
H
N
N
N
5a: X = NPh
5b: X = NMe
5c: X = NH
TBAF, THF,
reflux, 2h
7: R = SO2Ph, 88%
8: R = H, 96%
X
3: R = SO2Ph, 98%
10: R = Me, 99%
2
O
11: R = Me, 93%
MW 800 watts
silica gel
COOEt
O
COOEt
O
Pd/C, Xylene
reflux, 6h, 69-78%
X
X
N
R
N
N
N
O
O
R
9a: R = H, X = NPh; 9b: R = H, X = NMe
9c: R = H, X = NH; 12a: R = Me, X = NPh
12b: R = H, X = NMe
Scheme 2.

N.L. Chavan et al. / Tetrahedron 66 (2010) 1827–1831
1829
converted to diene 11. Diels–Alder reaction of diene 11 with 5a and 5b
resulted in the formation of cycloadducts, which were dehydro-
J¼6.6 Hz, C6H), 9.89 (s, 1H, CHO); 13C NMR (CDCl3): 31.93, 115.85,
117.20, 118.56, 130.12, 138.85, 144.77, 148.28, 184.10; m/z 160 (Mþ).
genated to N-methyl a-carbolines 12a and 12b (Scheme 2).
4.3. Preparation of phenylsulfonyl-3-vinyl-1H-pyrrolo[2,3-b]
pyridine (4)
3. Conclusion
Potassium-tert-butoxide was freshly prepared from potassium
(0.46 g, 0.012 mol) and anhydrous tert-butanol (5 ml) in nitrogen
atmosphere. In 100 ml three necked flask provided with a nitrogen
inlet and a dropping funnel was placed, the suspension of meth-
yltriphenyl phosphonium iodide (4.8 g, 0.012 mol) in freshly dis-
tilled anhydrous THF (20 ml). The apparatus was swept with dry
nitrogen at rt. To the stirred suspension of the salt, potassium-tert-
butoxide in dry THF (5 ml) was added dropwise for 10 min. The
resulting dark yellow colored phosphorane was kept stirring for
20 min. Protected 1-[H]-pyrrolo[2,3-b]–pyridine-3-carbaldehyde
(3) (1.7 g, 0.006 mol) in dry THF (5 ml) was added dropwise. After
complete addition of aldehyde, the color of reaction mixture turned
brown. Stirring was continued for two hours and it was decom-
posed with water. THF was distilled out and then extracted with
DCM. The DCM layer was dried over sodium sulfate and evaporated.
The residue was chromatographed on silica using 20% hexane–
ethyl acetate to give brown solid.
In conclusion a rapid and efficient method was established for
synthesis of tetrahydro-a-carbolines via Diels–Alder reaction under
microwave irradiation. Similar report10 on Diels–alder reactions
using other dienophiles under conventional heating required lon-
ger time and resulted in less yield (40–50%). During the present
study nine new substituted tetrahydro-a-carbolines were synthe-
sized, amongst those four compounds obtained stereoselectively,
were isolated and fully characterized. Other five were dehydro-
genated to the new substituted a-carbolines.
4. Experimental
4.1. General
Melting points determined are uncorrected. All solvents were of
reagent grade and, when necessary, were purified and dried by
standard methods. Reactions and products were routinely moni-
tored by thin layer chromatography (TLC) on silica gel (Kieselgel 60
F254, Merck). Column chromatographic purifications were per-
formed using 100–200 mesh silica gel.
4.3.1. Compound 4. Yield: 1.14 g, 68%; mp: 114–116 ꢀC; Elemental
analysis for C15H12N2O2S: requires: C, 63.36; H, 4.25; N, 9.85; found:
C, 63.39; H, 4.29; N, 9.81; Rf (30% Hexane/Ethyl Acetate) 0.39, IR
(CHCl3): 3075, 1628, 1342, 1145 cmꢁ1; 1H NMR (CDCl3): 5.37 (d, 1H,
J¼11.2 Hz, CH2), 5.77 (d, 1H, J¼17.6 Hz, CH2), 6.74 (dd, 1H J¼11.2,
17.8 Hz, CH), 7.22 (dd, 1H, J¼3.3, 7.9 Hz, ArH), 7.45–7.5 (m, 3H, ArH),
7.74 (s, 1H, ArH), 8.07 (d, 1H, J¼7.9 Hz, C4H), 8.19 (m, 2H, ArH), 8.44
(d, 1H, J¼4.6 Hz, C6H); 13C NMR (CDCl3): 115.18, 117.41, 118.81,
120.77, 123.80, 127.07, 127.54, 128.66, 128.74, 133.75, 137.67, 144.74,
147.17; m/z 284 (Mþ).
IR spectra were recorded on Shimadzu 8400 instrument. 1H
NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded on
Varian Mercury instrument using TMS as internal standard. 1H
NMR peaks expressed as s, br s, d, t, m correspond to singlet, broad-
singlet, doublet, triplet, and multiplet, respectively. Mass spectra
were recorded on Shimadzu QP 5050. Elemental analysis was
recorded on Flash E. A. 1112 Thermo instrument. Microwave acti-
vated reactions were carried out in Raga electromagnetic system
with IR sensor at 700 watt. All the analysis was carried out at
Department of Chemistry, University of Pune, Pune, India.
4.4. Cycloaddition reaction of 1-phenylsulfonyl-3-vinyl-1H-
pyrrolo[2,3-b]pyridine with maleic anhydride and different
maleimides in microwave (6(a–d))
4.2. Preparation of protected 1-[H]-pyrrolo[2,3-b]–pyridine-
3-carbaldehyde (3 and 10)
1-Phenylsulfonyl-3-vinyl-1H-pyrrolo[2,3-b]pyridine (0.0003 mol)
and the dienophile (5a/5b/5c/5d) (0.0003 mol) were adsorbed on
0.3 g silica (100–200 mesh) and irradiated in a microwave oven
(700 watts) at 75 ꢀC for 8–10 min. The progress of the reaction was
monitored by TLC. After completion, the reaction mixture was di-
rectly loaded on a silica gel column and eluted with hexane–ethyl
acetate to afford the products given below.
To a cooled (0 ꢀC) suspension of sodium hydride (0.40 g,
0.01 mol) in dry THF (30 ml), aldehyde 2 (1.46 g, 0.01 mol) was
added and stirred at rt for 15–20 min. To this, alkyl halide (benze-
nesulphonylchloride/methyl iodide 0.015 mol) was added drop-
wise. The solution was stirred for two hours and progress of the
reaction was monitored by TLC. After completion of the reaction, it
was quenched with water and THF was removed under vacuo. The
reaction mixture was then extracted with DCM, washed with brine
and dried. The solvent was removed and the residue thus obtained
was chromatographed on silica gel using 20% hexane–ethyl acetate
as an eluent to afford the product as colorless solid.
4.4.1. Compound 6a. Yield: 0.016 g, 88%; mp: 185–186 ꢀC; Ele-
mental analysis for C25H19N3O4S: requires: C, 65.63; H, 4.19; N, 9.18;
found: C, 65.59; H, 4.12; N, 9.11; Rf (2% CH2Cl2/MeOH) 0.66; IR (KBr):
3441, 2332, 1635 cmꢁ1 1H NMR (DMSO-d6): 2.32–2.40 (m, 1H,
;
C6H), 3.14 (dd, 1H, J¼7.4, 15.6 Hz, C6H), 3.41 (t, 1H, J¼7.7 Hz, C7H),
4.31 (dd, 1H, J¼6.8, 9.0 Hz, C8H), 5.06–5.10 (m, 1H, C9H), 6.27–6.32
(m, 1H, C5H), 6.86 (dd, 1H, J¼5.0, 7.4 Hz, C3H), 7.02–7.05 (m, 2H,
ArH), 7.27–7.36 (m, 3H, ArH), 7.46–7.59 (m, 4H, ArH), 8.15 (t, 1H,
4.2.1. Compound 3. Yield: 2.80 g, 98%; colorless solid, mp; 152–
153 ꢀC; Rf (30% Hexane/Ethyl Acetate) 0.42, IR (CHCl3): 3066, 1658,
1543 cmꢁ1
;
1H NMR (DMSO-d6): 7.42 (dd, 1H, J¼4.6, 7.7 Hz, ArH),
J¼3.5 Hz, C2H), 8.30 (m, 2H, C2 H, C6 H); 13C NMR (DMSO-d6):
25.78, 37.42, 42.55, 59.97, 115.70, 118.44, 119.25, 126.16, 128.47,
128.53, 128.63, 128.85, 131.33, 133.30, 135.03, 138.89, 149.07, 157.63,
172.94, 177.50; m/z 457(Mþ).
00
00
7.63–7.68 (m, 2H, ArH), 7.41–7.52 (t, 1H, J¼7.4 Hz, C4H), 8.22 (d, 2H,
J¼7.7 Hz, ArH), 8.40–8.47 (m, 2H, ArH), 8.99 (s,1H, C2H),10.06 (s,1H,
CHO); 13C NMR (DMSO-d6): 118.24, 118.74, 120.99, 128.02, 129.71,
130.63, 135.34, 136.45, 137.74, 146.26, 146.59, 186.73; m/z 286 (Mþ).
4.4.2. Compound 6b. Yield: 0.013 g, 81%; mp: oil; Elemental anal-
ysis for C20H17N3O4S: requires: C, 60.75; H, 4.33; N, 10.63; found: C,
60.68; H, 4.29; N, 10.58; Rf (2% CH2Cl2/MeOH) 0.44; IR (KBr): 3446,
2958, 1695 cmꢁ1; 1H NMR (DMSO-d6): 2.66–2.78 (m, 4H, CH3, C6H),
3.30–3.37 (m, 2H, C6H, C7H), 4.03 (t, 1H, J¼7.7 Hz, C8H), 5.12 (t, 1H,
J¼3.3 Hz, C9H), 6.39 (t, 1H, J¼3.3 Hz, C5H), 6.95 (t, 1H, J¼7.4 Hz,
4.2.2. Compound 10. Yield: 1.58 g, 99%; Elemental analysis for
C9H8N2O: requires: C, 67.46; H, 5.03; N, 17.49; found: C, 67.42; H,
4.98; N, 17.54; Rf (30% Hexane/Ethyl Acetate) 0.35, IR (CHCl3): 2247,
1645 cmꢁ1
;
1H NMR (CDCl3): 3.92 (s, 3H, NCH3), 7.21 (t, 1H, J¼2.7,
7.4 Hz, C5H), 7.80 (s,1H, C2H), 8.38 (d,1H, J¼3.0 Hz, C4H), 8.48 (d,1H,

1830
N.L. Chavan et al. / Tetrahedron 66 (2010) 1827–1831
0
0
0
C4 H), 7.55(m, 2H, C3 H, C5 H), 7.65 (t, 1H, J¼6.8 Hz, C4H), 7.79 (d, 1H,
under nitrogen atmosphere for 2 h. The completion of reaction was
confirmed by TLC. After workup and chromatographic separation
on silica gel column with hexane–ethyl acetate afforded product.
Yield: 0.21 g, 96%; mp: 108–110 ꢀC; Elemental analysis for
C12H12N2O2: requires: C, 66.65; H, 5.59; N, 12.96; found: C, 66.69, H,
5.64, N, 13.01; Rf (50% Hexane/Ethyl Acetate) 0.39 IR (KBr): 3441,
2332, 1635 cmꢁ1; 1H NMR (CDCl3): 1.35 (t, 3H, J¼6.8 Hz, CH3), 4.29
(q, 2H, J¼7.1 Hz, CH2), 6.40 (d, 1H, J¼15.9 Hz, olefinic proton), 7.25
(m, 1H, C5H), 7.69 (s, 1H, C2H), 7.85 (d, 1H, J¼15.9 Hz, olefinic pro-
0
0
J¼7.7 Hz, C3H), 8.06 (d, 1H, J¼4.4 Hz, C2H), 8.12 (m, 2H, C2 H, C6 H);
13C NMR (DMSO-d6): 24.49, 36.99, 43.02, 48.84, 59.88, 117.55,
118.64, 119.36, 127.75, 128.69, 129.25, 133.38, 133.44, 138.19, 147.89,
156.56, 174.61, 178.69; m/z 395 (Mþ).
4.4.3. Compound 6c. Yield: 0.013 g, 88%; mp: oil; Elemental anal-
ysis for C19H15N3O4S: requires: C, 59.83; H, 3.96; N, 11.02; found: C,
59.72; H, 3.91; N, 10.93; Rf (2% CH2Cl2/MeOH) 0.42; IR (KBr): 3362,
1665, 1358, 1156 cmꢁ1; 1H NMR (DMSO-d6): 2.31–2.49 (m, 1H, C6H),
2.71 (dd, 1H, J¼6.8, 14.5 Hz, C6H), 3.25 (t, 1H, J¼7.9 Hz, C7H), 3.98 (t,
1H, J¼7.1 Hz, C8H), 5.06–5.08 (m, 1H, C9H), 6.45 (t, 1H, J¼3.5 Hz,
ton), 8.30 (d, 2H, J¼7.9 Hz, C4H, NH), 8.38 (d, 1H, J¼4.4 Hz, C6H); 13
C
NMR (CDCl3): 14.46, 60.23, 111.57, 114.00, 116.82, 118.60, 129.55,
129.87, 137.48, 137.48, 149.05, 167.65; m/z 216 (Mþ).
0
0
C5H), 6.98 (dd, 2H, J¼5.2, 7.4 Hz, C3 H, C5 H), 7.53–7.65 (m, 1H, C4H),
0
0
0
7.82 (d, 2H, J¼7.4 Hz, C3H, C4 H), 8.07–8.13 (m, 3H, C2 H, C3 H, C2H),
11.11 (s, 1H, NH);13C NMR (DMSO-d6): 24.60, 31.12, 43.99, 59.94,
117.86, 118.77, 119.63, 127.89, 128.85, 129.36, 133.62, 138.35, 148.08,
156.77, 176.19, 180.28; m/z 381 (Mþ).
4.7. Cycloaddition reaction of (E)-ethyl 3-(1H-pyrrolo[2,3-b]-
pyridine-3-yl)acrylate with different maleimides in
microwave (9(a–c))
(E)-Ethyl 3-(1H-pyrrolo[2,3-b]pyridine-3-yl)acrylate (0.050 g,
0.0002 mol) and maleimides (0.0002 mol) were adsorbed on 0.3 g
silica (100–200 mesh) and irradiated in microwave (700 watts) at
75 ꢀC for 8–10 min. Reaction was monitored by TLC. The reaction
mixture was washed with acetone and filtrate was concentrated
and used for next step. Then Pd/C (5%) in xylene was added fol-
lowed by reflux for 24 h. The reaction was monitored by TLC and
xylene was distilled out. The residue was passed through Celite bed
and washed with methanol. The compound was purified by column
chromatography in hexane/ethyl acetate.
4.4.4. Compound 6d. Yield: 0.013 g, 85%; mp: 224–225 ꢀC; Ele-
mental analysis for C19H14N2O5S: requires: C, 59.68; H, 3.69; N,
7.33; found: C, 59.62; H, 3.65; N, 7.28; Rf (2% CH2Cl2/MeOH) 0.46; IR
(KBr): 3015, 1673, 1343, 1168 cmꢁ1 1H NMR (DMSO-d6): 2.78 (dd,
;
1H, J¼7.1, 15.4 Hz, C6H), 3.70 (dd, 1H, J¼7.7, 9.0 Hz, C6H), 4.38 (dd,
1H, J¼7.1, 9.3 Hz, C7H), 5.17 (dd, 1H, J¼3.3, 6.8 Hz, C8H), 6.52 (dd, 1H,
J¼3.8, 7.1 Hz, C9H), 7.01(m, 1H, C5H), 7.53–7.68 (m, 4H, ArH), 7.86
(dd, 1H, J¼1.3, 7.4 Hz, C2H), 8.10 (m, 3H, ArH); m/z 216 (Mþ).
4.5. Preparation of 1-alkyl-3-(2-carbethoxyvinyl)-1H-
pyrrolo[2,3-b]pyridine (7 and 11)
4.7.1. Compound 9a. Yield: 0.069 g, 78%; mp: 196–197 ꢀC; Ele-
mental analysis C22H15N3O4: requires: C, 68.57; H, 3.92; N, 10.90;
found: C, 68.51; H, 3.86, N, 10.87; Rf (5%CH2Cl2/MeOH) 0.51; IR
To the solution of protected aldehyde 3 or 10 (0.006 mol) in dry
toluene (20 ml), carbethoxymethylenetriphenyl phosphorane
(4.1 g, 0.012 mol) was added and the reaction mixture was refluxed
for 4–5 h. The progress of the reaction was monitored by TLC till the
aldehyde was consumed. After completion, the reaction mixture
was concentrated and directly loaded on a silica gel column and
eluted with hexane–ethyl acetate to afford the product.
(KBr): 3428, 3065, 1712 cmꢁ1 1H NMR (DMSO-d6): 1.39 (t, 3H,
;
0
0
J¼7.1 Hz, CH3), 4.30 (q, 2H, J¼7.4 Hz, CH2), 7.00 (m, 2H, C3 H, C5 H),
0
0
0
7.23 (m, 3H,C3H, C4H, C4 H), 7.56 (d, 2H, J¼7.7 Hz, C2 H, C6 H), 8.17
(m, 1H, C2H), 8.38 (s, 1H, C5H), 9.57 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6): 13.87, 61.45, 107.77, 118.94, 122.62, 127.40, 127.89,
129.53, 138.44, 142.17, 162.50, 168.13; m/z 385 (Mþ).
4.5.1. Compound 7. Yield: 88%; mp: 166–167 ꢀC; Elemental analy-
sis for C18H16N2O4S: requires: C, 60.66; H, 4.53; N, 7.86; found: C,
60.62, H, 4.49, N, 7.90; Rf (30% Hexane/Ethyl Acetate) 0.42, IR
4.7.2. Compound 9b. Yield: 0.051 g, 69%; mp: 183–185 ꢀC; Ele-
mental analysis for C17H13N3O4: requires: C, 63.16; H, 4.05; N,13.00;
found: C, 63.19, H, 4.09, N, 12.96; Rf (5%CH2Cl2/MeOH) 0.51; IR
(CHCl3): 2345, 1608, 1030, 756 cmꢁ1
;
1H NMR (CDCl3): 1.34 (t, 3H,
(KBr): 3294, 1680, 1653 cmꢁ1 1H NMR (DMSO-d6): 1.40 (t, 3H,
;
J¼6.7 Hz, CH3), 4.27 (q, 2H, J¼6.8 Hz, CH2), 6.45 (d, 1H, J¼15.9 Hz,
olefinic proton), 7.25 (dd, 2H, J¼4.4, 7.9 Hz, ArH), 7.46–7.58 (m, 2H,
ArH), 7.72 (d, 1H, J¼15.9 Hz, olefinic proton), 7.97 (s, 1H, C2H), 8.11
(dd, 1H, J¼1.3, 7.8 Hz, C4H), 8.19 (t, 2H, J¼1.3, 8.8 Hz, ArH), 8.46 (dd,
1H, J¼1.3, 4.6 Hz, C6H); 13C NMR (CDCl3): 14.42, 60.63, 114.97,
118.47, 119.50, 120.34, 128.12, 129.02, 129.19, 134.29, 135.23, 137.56,
142.19, 145.62, 166.63, 172.48; m/z 356 (Mþ).
J¼7.2 Hz, CH3), 3.21 (s, 3H, NCH3), 4.32 (q, 2H, J¼7.2 Hz, CH2), 7.11–
7.15 (m, 1H, C3H), 8.03–8.06 (m, 1H, C4H), 8.34–8.38 (m, 2H, C2H,
C5H), 9.23 (s, 1H, NH); 13C NMR (DMSO-d6): 13.93, 28.54, 62.09,
105.68, 114.64, 114.89, 116.62, 124.78, 125.42, 127.63, 129.42, 140.84,
145.13, 162.09, 171.96; m/z 323 (Mþ).
4.7.3. Compound 9c. Yield: 0.052 g, 74%; mp: 189–190 ꢀC; Ele-
mental analysis for C16H11N3O4: requires: C, 62.14; H, 3.58; N,13.59;
found: C, 62.09, H, 3.54, N, 13.55; Rf (2%CH2Cl2/MeOH) 0.40; IR
4.5.2. Compound 11. Yield: 93%; mp: 75–77 ꢀC; Elemental analysis
for C13H14N2O2: requires: C, 67.81; H, 6.13; N, 12.17; found: C, 67.84,
H, 6.17, N, 12.22; Rf (50% Hexane/Ethyl Acetate) 0.32, IR (CHCl3):
3054, 1684 cmꢁ1; 1H NMR (CDCl3): 1.34 (t, 3H, J¼7.1 Hz, CH3, CH2),
3.89 (s, 3H, NCH3), 4.25 (q, 2H, J¼6.8 Hz, CH2), 6.35 (d, 1H,
J¼15.9 Hz, olefinic proton), 7.16 (dd, 1H, J¼4.9, 7.7 Hz, C4H), 7.45 (s,
1H, C2H), 7.78 (d, 1H, J¼15.9 Hz, olefinic proton), 8.16 (d, 1H,
J¼7.7 Hz, C6H), 8.36 (d, 1H, J¼4.1 Hz, C5H); 13C NMR (CDCl3): 14.47,
31.55, 60.10, 110.28, 113.42, 116.86, 118.20, 128.68, 132.75, 137.23,
143.65, 148.40, 167.64; m/z 230 (Mþ).
(KBr): 3412, 1740, 1705 cmꢁ1 1H NMR (DMSO-d6): 1.39 (t, 3H,
;
J¼7.1 Hz, CH3), 4.31 (q, 2H, J¼7.1 Hz, CH2), 7.02–7.05 (m, 1H, C3H),
8.13–8.16 (m, 2H, C4H, NH), 8.36–8.39 (m, 2H, C2H, C5H),12.37 (s,1H,
NH); 13C NMR (DMSO-d6): 13.8, 61.35, 107.55, 116.31, 116.62, 119.45,
126.50, 127.65, 129.49, 142.82, 147.09, 162.41, 172.5; m/z 309 (Mþ).
4.8. Cycloaddition reaction of N-methyl(E)-ethyl 3-
(1H-pyrrolo[2,3-b]pyridine-3-yl)acrylate with different
maleimides in microwave (12a and 12b)
4.6. Preparation of (E)-ethyl 3-(1H-pyrrolo[2,3-b] pyridine-3-yl)
Same procedure was followed as mentioned above.
acrylate (8)
4.8.1. Compound 12a. Yield: 0.065 g, 76 %; mp: oil; Elemental
analysis for C23H17N3O4: requires: C, 69.17; H, 4.29; N, 10.52; found:
C, 69.13; H, 4.34; N, 10.47; Rf (5% CH2Cl2/MeOH) 0.78; IR (neat):
To the solution of compound 7 (0.36 g, 0.001 mol) in dry THF
(30 ml), TBAF (0.5 ml) was added and the mixture was refluxed

N.L. Chavan et al. / Tetrahedron 66 (2010) 1827–1831
1831
1699, 1651 cmꢁ1
;
1H NMR (DMSO-d6): 1.35 (t, 3H, J¼7.1 Hz, CH3),
spectra, and Mr. D.S. Shishupal for GCMS. N.L.C. is thankful to BARC
for the award of a fellowship.
4.37–4.43 (m, 5H, CH2, NCH3), 7.18–7.23 (m, 1H, ArH), 7.41–7.49 (m,
5H, ArH), 8.66 (d, 1H, J¼4.6 Hz, ArH), 8.78 (d, 1H, J¼7.7 Hz, ArH),
8.85 (d, 1H, J¼1.6 Hz, ArH); 13C NMR (DMSO-d6): 14.66, 48.03,
60.88, 108.51, 115.64, 116.08, 119.92, 122.05, 123.17, 128.22, 142.17,
146.14, 152.00, 166.94, 173.98; m/z 399 (Mþ).
References and notes
1. Molina, P.; Fresneda, P. M.; Sanz, M. A.; FocesFoces, C.; Ramirez de Arellano,
M. C. Tetrahedron 1998, 54, 9623.
2. (a) Bhatti, I. A.; Busby, R. E.; Bin Mohamed, M.; Parrick, J.; Granville Shaw, C. J.
J. Chem. Soc., Perkin Trans. 1 1997, 3581; (b) Kazerani, S.; Novak, M. J. Org.
Chem. 1998, 63, 895.
3. (a) Stolc, S. Life Sci. 1999, 65, 1943; (b) Barun, O.; Patra, P. K.; Ila, H.; Junjappa, H.
Tetrahedron Lett. 1999, 40, 3797.
4. He´non, H.; Messaoudi, S.; Hugon, B.; Anizon, F.; Pfeifferb, B.; Prudhommea, M.
Tetrahedron 2005, 61, 5599.
5. (a) MoquenPattey, C.; Guyot, M. Tetrahedron 1989, 45, 3445; (b) Abas, S. A.;
Hossain, M. B.; Helm, D. V.; Schmitz, F. J. J. Org. Chem. 1996, 61, 2709; (c) Chosi,
T.; Yamada, S.; Sugino, E.; Kuwada, T.; Hibino, S. J. Org. Chem. 1995, 60, 5899; (d)
Liger, F.; Popowycz, F.; Besson, T.; Picot, L.; Galmarinic, C. M.; Joseph, B. Bioorg.
Med. Chem. 2007, 15, 5615.
4.8.2. Compound 12b. 0.52 g, Yield: 71%; mp: oil; Elemental anal-
ysis forC18H15N3O4: requires: C, 64.09; H, 4.48; N, 12.46; found: C,
64.04; H, 4.53; N, 12.50; Rf (2% CH2Cl2/MeOH) 0.63; IR (neat): 3019,
1704, 1683 cmꢁ1
;
1H NMR (DMSO-d6): 1.36 (t, 3H, J¼7.2 Hz, CH3),
3.04 (s, 3H, NCH3), 4.32–4.41 (m, 5H, NCH3, CH2), 7.36–7.41 (m, 1H,
C3H), 7.65–7.68 (m, 1H, C4H), 8.61–8.63 (m, 1H, C2H), 8.73 (s, 1H,
C5H); 13C NMR (DMSO-d6): 14.48, 30.89, 42.18, 60.96, 107.18, 117.37,
126.48, 129.43, 132.55, 143.97, 148.85, 149.52, 166.32, 174.75; m/z
337 (Mþ).
6. Kusurkar, R.S.; Hingane, D.G. Unpublished work.
Acknowledgements
7. (a) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127; (b) Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250; (c) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325.
8. Ishida, J.; Wang, H. K.; Oyama, M.; Cosentino, L. M.; Hu, C. Q.; Lee, K. H. J. Nat.
Prod. 2001, 64, 958.
9. Pfeuffer, L.; Pindur, U. Helv. Chim. Acta 1987, 70, 1419.
10. Joseph, B.; Da Costa, H.; Me´rour, J.-Y.; Le´once, S. Tetrahedron 2000, 56, 3189.
We are grateful to Dr. C.V. Avadhani from National Chemical
Laboratory, Pune for microwave reactions. We are also grateful to
Mr. B.S. Kalshetti for IR spectra, Mrs. J.P. Choudhary for NMR