Palladium-catalyzed reductive N-heterocyclization of alkenyl-substituted nitroarenes as a viable method for the preparation of bicyclic pyrrolo-fused heteroaromatic compounds

Article abstract of DOI:10.1016/j.tet.2010.01.029

Palladium-catalyzed, carbon monoxide-mediated reductive N-heterocyclization of nitro-heteroaromatic compounds having an alkene adjacent to the nitro-group affords bicyclic pyrrolo-fused heteroaromatic molecules. This type of reaction was used to prepare the fused bicyclo[3.3.0] ring-system: thieno[3,2-b]pyrrole, thieno[2,3-b]pyrrole, furo[2,3-b]pyrrole, pyrrolo[3,2-d]thiazole, and pyrrolo[2,3-d]imidazole and the bicyclo[4.3.0] ring-systems: pyrrolo[3,2-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridazine, and pyrrolo[3,2-d]pyrimidine in 32-94% yield.

Full text of DOI:10.1016/j.tet.2010.01.029

Tetrahedron 66 (2010) 1800–1805
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed reductive N-heterocyclization of alkenyl-substituted
nitroarenes as a viable method for the preparation of bicyclic pyrrolo-fused
heteroaromatic compounds
*
´
¨
¨
Sobha P. Gorugantula, Grissell M. Carrero-Martınez, Shubhada W. Dantale, Bjorn C.G. Soderberg
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed, carbon monoxide-mediated reductive N-heterocyclization of nitro-heteroaromatic
compounds having an alkene adjacent to the nitro-group affords bicyclic pyrrolo-fused heteroaromatic
molecules. This type of reaction was used to prepare the fused bicyclo[3.3.0] ring-system: thieno[3,2-
b]pyrrole, thieno[2,3-b]pyrrole, furo[2,3-b]pyrrole, pyrrolo[3,2-d]thiazole, and pyrrolo[2,3-d]imidazole
and the bicyclo[4.3.0] ring-systems: pyrrolo[3,2-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyri-
dine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridazine, and pyrrolo[3,2-d]pyrimidine in 32–94% yield.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 November 2009
Received in revised form
6 January 2010
Accepted 7 January 2010
Available online 13 January 2010
Keywords:
Palladium-catalyzed
Fused pyrroles
Reductive-cyclization
1. Introduction
methods such as the Reissert, Madelung, Bartoli, Hemetsberger–
Knittel, and Leimgruber–Batcho syntheses in addition to the more
Palladium-catalyzed, carbon monoxide-mediated, cyclizations
of 2-alkenyl-1-nitrobenzenes have been developed into a very
versatile method for the synthesis of indole derivatives.1 The re-
action tolerates a wide variety of functional groups and high
chemical yields are often realized. In some of the earlier studies in
our laboratories, a handful of fused pyrrolopyridines were prepared
from nitropyridines having an alkene adjacent to the nitro-group.2
For example, reaction of 1 with carbon monoxide (6 atm) in the
presence of bis(dibenzylidenacetone)palladium (6 mol %), 1,3-bis-
(diphenylphosphino)propane (6 mol %), and 1,10-phenanthroline
(12 mol %) gave pyrrolopyridine 2 in good isolated yield (Scheme 1).
recently developed, palladium-catalyzed, Suzuki–Miyaura,4 Sono-
gashira,5 or Kosugi–Migita–Stille6 coupling reactions followed by
cyclization. One or more of these methods have been utilized for the
preparation of other ring systems including thienopyrrole, furo-
pyrrole, pyrrolothiazole, pyrroloimidazole, pyrrolopyridazine, and
pyrrolopyrimidine to be discussed herein.
Bicyclic [3.3.0] or [4.3.0] pyrrolo-fused heteroaromatic mole-
cules are scarce in nature but a significant number of compounds
have been synthesized in laboratories. The interest in pyrrolo-fused
heteroaromatic compounds mainly stems from the array of
interesting and potentially useful biological activity observed in
many cases. We report herein an extension of the palladium-cata-
lyzed, carbon monoxide-mediated cyclization, seen in Scheme 1, to
the synthesis of a selection of bicyclic [3.3.0] and [4.3.0] pyrrolo-
fused heteroaromatic compounds.
OEt
OEt
N
N
Pd(dba)2, dppp, CO (6 atm), DMF
1,10-phenanthroline, 120 °C, 85%
N
H
NO2
2. Results and discussion
1
2
Scheme 1.
A number of five- and six-membered heterocyclic cyclization
precursors 3–16 were prepared using either of two procedures: (1)
The Kosugi–Migita–Stille coupling reaction between ethenyltributyl
tin and a nitro-heteroaromatic compound having a triflate ora bromo
substituent on the adjacent carbon or (2) A Knoevenagel-type con-
densation between benzaldehyde and a nitro-heteroaromatic com-
pound having a methyl group on the adjacent carbon. All the
synthesized cyclization precursors are listed in Table 1. Substrates
A variety of methods have been developed for the synthesis of
bicyclic [3.3.0] or [4.3.0] pyrrolo-fused heteroaromatic molecules.
Pyrrolopyridines,3 for example, have been prepared using classical
* Corresponding author. Tel.: þ1 3042933435; fax: þ1 3042934904.
E-mail address: bjorn.soderberg@mail.wvu.edu (B.C.G. So¨derberg).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.029

S.P. Gorugantula et al. / Tetrahedron 66 (2010) 1800–1805
1801
Table 1
Cyclization to give heterocycle-fused pyrroles
Entry
Nitroalkenea,b
Condition
Fused pyrroleb
S
Ph
S
MeO2C
Ph
MeO2C
N
H
NO2
1
2
3
A (12 h)c
A (40 h)
17 (43%)d
17 (71%) [70%]
Ph
Ph
S
N
S
NO2
H
3
4
A (16 h)
18 (94%) [40%]
O
O
Ph
O
Ph
NC
Ph
N
H
N
H
HON
HON
NO2
4
5
6
5 (88%)
A (12 h)
B (22 h)e
B (50 h)
19 (63%)
19 (45%)
19 (29%)
20 (20%)
20 (21%)
N
Ph
N
Ph
S
N
H
S
NO2
7
8
6
A (72 h)
B (72 h)
21 (61%)
21 (16%)
Bn
N
Bn
N
Ph
Ph
N
N
H
N
NO2
9
7
B (139 h)
22 (77%)
Ph
Ph
N
N
N
N
Ph
Ph
N
H
NO2
Bn
Bn
10
8
B (72 h)
23 (32%)
O
O
N
N
N
H
NO2
11
12
910
9
A (96 h)f
B (96 h)g
24 (not observed)
24 (not observed)
Ph
Ts
N
Ph
Ts
N
N
NO2
H
13
14
10
B (84 h)
25 (not observed)
N
N
N
H
NO2
11
B (42 h)
26 (65%)
(continued on next page)

1802
S.P. Gorugantula et al. / Tetrahedron 66 (2010) 1800–1805
Table 1 (continued)
Entry
Nitroalkenea,b
Condition
B (180 h)
Fused pyrroleb
N
H
N
N
NO2
15
12 (73%)
27 (41%)
O
Ph
N
N
Ph
N
H
NO2
16
17
13
B (22 h)
B (24 h)
28 (91%) [14%]
Ph
Ph
N
N
N
NO2
14
H
29 (87%)
N
Ph
N
Ph
N
N
N
H
NO2
OMe
OMe
18
15 (41%)
B (24 h)
B (14 h)
30 (82%)
O
N
O
N
Ph
N
N
Ph
N
H
31 (57%)
NO2
16 (30%)
19
a
For experimental details, see Experimental Section.
b
c
d
e
f
Isolated yields in parentheses. Comparison with a Cadogan–Sundberg reaction in brackets.
Condition A: A catalyst system consisting of Pd(OAc)2–PPh3 in MeCN was used.
45% of 3 was recovered.
Condition B: A catalyst system consisting of Pd(dba)2-1,10-phenanthroline in DMF was used.
A mixture of dba and 9 was observed by 1H NMR of the crude product.
15% of 9 was recovered.
g
previously not described in the literature have yields by the com-
pound number (5, 15, and 16, entries 4, 18, and 19, respectively). One
compound was prepared in a new fashion (12, entry 15). The func-
tionalized pyrrole 10 (entry 13) was prepared by N-tosylation of the
previously described 3-nitro-4-(2-phenylethenyl)pyrrole.
a decrease in the amount of the oxime and the isolation of nitrile 20
(entries 5–6). Cyclization of 6–8 gave pyrrolo[3,2-d]thiazole (21),
pyrrolo[3,2-d]imidazole (22), and pyrrolo[2,3-d]imidazole (23), re-
spectively (entries 7–10). A large difference in yield was observed for
the two isomeric products 22 and 23. The reason for this difference is
unclear.
No cyclization was observed in two cases, neither the isoxazole
9 nor the pyrrole 10 formed the expected products (entries 11–13).
Using 9, some starting material was observed by NMR or isolated
(See Table 1). The starting material was consumed in the case of 10
leading to a complex mixture of unidentified products.
The six-membered heterocyclic substrates 11–16 were trans-
formed into the anticipated products 26–31 in 41–91% yield using
conditions B (entries 14–19). Concomitant deoxygenation of the
N-oxide was observed for pyridine 13 but not for pyrazine 16.
The cyclization substrate 3–16 were not selected with the in-
tent to directly compare the results obtained in this study with
results reported by other investigators using the related Cadogan–
Sundberg reaction. However, compound 17 was obtained in an
almost identical yield to a Cadogan–Sundberg reaction of 3 using
triethylphosphite at elevated temperature (entry 2).7 Reductive
cyclization of 4 and 13 with triethylphosphite has been reported
but in significantly lower yields (entries 37 and 168). And finally,
a complex mixture of products was obtained from the demethyl
analog of 16.9
Compounds 3–16 were treated with carbon monoxide (6 atm) in
the presence of either a palladium acetate–triphenyl phosphine
catalyst system in acetonitrile at 80–90 ꢀC (conditions A) or using
a bis(dibenzylideneacetone)palladium-1,10-phenanthroline cata-
lyst system in DMF at 120 ꢀC (conditions B). The reactions were
monitored by thin layer chromatography at 12 h intervals to assure
complete consumption of the substrate. No adverse effects were
observed from venting, removing a TLC sample, and repressurizing
the reaction vessel. Conditions B gave in most cases a higher yield of
cyclized product, when comparing the same substrate, although
longer reaction times were often required. Depending on the sub-
strate, the reactions times varied from 14 h to 7.5 days for the re-
actions to go to completion. For example, reaction of thiophene 3
under conditions A for 12 h gave 43% of thieno[3,2-b]pyrrole 17
together with 45% of recovered starting material (entry 1).
Extending the reaction time to 40 h furnished 17 in 71% (entry 2).
The nitro-thiophene 4 gave thieno[2,3-b]pyrrole (18) in an excel-
lent yield (entry 3).
Reductive cyclization of furanaloxime 5 gave the expected
furo[2,3-b]pyrrole 19 using conditions B for 12 h (entry 4). A rela-
tively clean 1H NMR spectrum of 19 was obtained immediately after
chromatography. However, the compound undergoes dehydration to
give the corresponding nitrile 20 upon standing in CDCl3. This is
evident by the appearance of new resonances from a second 1H NMR
experiment after a few minutes. Extension of the reaction time led to
In conclusion, we have shown that the palladium-catalyzed,
carbon monoxide-mediated, N-heterocyclization of nitro-hetero-
aromatic compounds having an alkene adjacent tothe nitro-group is
a viable methodology for the synthesis of an array of fused hetero-
aromatic molecules. For the cyclization reaction, yields in the range

S.P. Gorugantula et al. / Tetrahedron 66 (2010) 1800–1805
1803
of 32–94% were obtained from twelve of the starting materials ex-
amined. Two additional substrates did not undergo the expected
cyclization using either of the two catalyst systems examined.
(305 mg, 1.84 mmol), PdCl2(PPh3)2 (16.8 mg, 0.0239 mmol) in
MeCN (10 mL) was heated at reflux (67 h). The mixture was diluted
with CHCl3 (10 mL) and H2O (10 mL) and filtered through Celite.
The filtrate was extracted with CHCl3 (30 mL) and the organic phase
was washed with 10% NH4OH (aqueous, 3ꢂ15 mL). The organic
layer was dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude product was purified by chromatography
(hexanes/EtOAc, 8:2) to give 12 (236 mg, 1.57 mmol, 85%) as a yel-
3. Experimental section
3.1. General procedures
The chemical shifts are expressed in
d
values relative to SiMe4
low solid. Mp 34–36 ꢀC; 1H NMR (600 MHz, CDCl3)
d
8.46 (dd, J¼4.8,
(0.0 ppm, 1H and 13C) or CDCl3 (77.0 ppm, 13C) internal standards.
Results of APT (Attached Proton Test) 13C NMR experiments are
shown in parentheses, where relative to CDCl3, (ꢁ) denotes CH3 or
CH and (þ) denotes CH2 or C.
1.8 Hz, 1H), 8.09 (dd, J¼7.8, 1.8 Hz, 1H), 7.58 (dd, J¼7.8, 4.2 Hz, 1H),
6.98 (dd, J¼17.4, 11.4 Hz, 1H), 5.86 (d, J¼17.4 Hz, 1H), 5.61 (d,
J¼10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d
147.5 (ꢁ), 137.6 (ꢁ),
129.5 (ꢁ), 127.7 (ꢁ), 126.9 (þ), 121.2 (þ); IR (ATR) 1531 cmꢁ1. Anal.
Hexanes and ethyl acetate were distilled from calcium hydride.
Chemicals prepared according to literature procedures have been
footnoted the first time used; all other reagents were obtained from
commercial sources and used as received. All reactions were per-
formed under a nitrogen atmosphere in oven-dried glassware un-
less otherwise stated. Solvents were removed from reaction
mixtures and products on a rotary evaporator at water aspirator
Calcd for C7H6N2O2: C, 56.00; H, 4.03. Found: C, 56.28; H: 4.23.
3.1.4. 4-Methoxy-5-nitro-6-(2-phenylethenyl) pyrimidine (15). A
mixture of 4-methoxy-6-methyl-5-nitropyrimidine15 (163 mg,
0.964 mmol), benzaldehyde (125
mL, 1.23 mmol), and piperidine
(50 L, 0.506 mmol) in MeOH (5 mL) was heated at reflux (15.5 h).
m
The resulting precipitate was removed by filtration, redissolved in
acetone and purified bychromatography (hexanes/EtOAc, 6:4) to give
15 (101 mg, 0.393 mmol, 41%) as a pale yellow solid. Mp 135–137 ꢀC;
pressure. Chromatography was performed on silica gel (35–75 mm).
Melting points were determined on a MelTemp and are un-
corrected. Elemental analyses were performed in the Department
of Chemical Engineering, College of Engineering and Mineral Re-
sources, West Virginia University.
1H NMR (600 MHz, CDCl3)
d
8.74 (s, 1H), 8.17 (d, J¼15.6 Hz, 1H), 7.59
(dd, J¼7.8, 2.4 Hz, 2H), 7.42–7.39 (m, 3H), 7.02 (d, J¼15.0 Hz, 1H), 4.12
(s, 3H); 13C NMR (150 MHz, CDCl3)
d
161.4 (þ), 157.3 (ꢁ), 154.2 (þ),
142.1 (þ),142.1 (ꢁ),134.8 (þ),130.4 (ꢁ),129.0 (ꢁ),128.3 (ꢁ),117.5 (ꢁ),
55.3 (ꢁ); IR (neat) 1637, 1572, 1521 cmꢁ1; HRMS (ESI) calcd for
C13H12N3O3 (MþHþ) 258.0879; found, 258.0874.
3.1.1. 4-Nitro-5-(2-phenylethenyl)-2-furanaldoxime (5). A solution
of 5-methyl-4-nitro-2-furanaldoxime11 (80 mg, 0.471 mmol) in
absolute methanol (5 mL) was heated at reflux for 2 minwith 100 mL
of freshly distilled piperidine followed by the addition of freshly
distilled benzaldehyde (247 mg, 2.33 mmol). The resulting solution
was heated at reflux (3 h). An orange solid was seen appearing on
the walls of the flask after about 20 min. All volatiles were removed
under reduced pressure and the resulting orange solid was purified
by chromatography (hexanes/EtOAc, 8:2) to yield 5 (107 mg,
0.415 mmol, 88%) as an orange solid. Mp 182–185 ꢀC; 1H NMR
3.1.5. 6-Methyl-4-nitro-3-(2-phenylethenyl)pyridazine1-oxide (16). A
solution of 3,6-dimethyl-4-nitropyridazine 1-oxide16 (123 mg,
0.727 mmol), benzaldehyde (99.9 mg, 0.941 mmol), and piperidine
(38 mL, 0.386 mmol) in MeOH (4.0 mL) was heated at reflux (21 h).
Water (10 mL) was added and the mixture was extracted with CH2Cl2
(3ꢂ10 mL). The combined organic phases were dried (MgSO4), fil-
tered, and concentrated under reduced pressure. Purification of the
crude product by chromatography (hexanes/EtOAc, 6:4) gave 16
(56.5 mg, 0.220 mmol, 30%) as a yellow solid. Mp 170–172 ꢀC; 1H
(600 MHz, acetone-d6)
d
11.65 (br s,1H), 7.79 (d, J¼16.2 Hz,1H), 7.69
(d, J¼16.8 Hz, 1H), 7.76 (d, J¼7.2 Hz, 2H), 7.62 (s, 1H), 7.47–7.50 (m,
2H), 7.45 (tt, J¼7.2, 1.2 Hz, 1H), 7.73 (s, 1H); 13C NMR (150 MHz, ac-
NMR (600 MHz, CDCl3)
J¼16.2 Hz, 1H), 7.63 (dd, J¼7.8, 1.8 Hz, 2H), 7.44–7.39 (m, 3H), 2.56 (s,
3H); 13C NMR (150 MHz, CDCl3)
d
8.25 (s, 1H) 8.06 (d, J¼15.6 Hz, 1H), 7.76 (d,
etone-d6) d 152.3, 144.2, 139.1, 136.4, 135.8, 135.7, 131.1, 130.1, 128.8,
113.75, 113.70; IR (ATR) 1619, 1537, 1400, 1346 cmꢁ1; HRMS (ESI)
d
149.6 (þ), 143.1 (þ),141.8 (þ),135.1
calcd for C13H10N2O4 (MþHþ) 259.0721; found, 259.0713.
(ꢁ),134.2 (þ),130.3 (ꢁ),129.4 (ꢁ),129.0 (ꢁ),128.3 (ꢁ), 116.7 (ꢁ),17.7
(ꢁ); IR (ATR) 3057, 2666,1314,1214 cmꢁ1. Anal. Calcd for C13H11N3O3:
C, 60.70; H, 4.31; N, 16.33. Found: C, 61.07; H, 4.68; N, 16.28.
3.1.2. 3-Nitro-4-(2-phenylethenyl)-1-tosylpyrrole (10). To a solution
of 3-nitro-4-(2-phenylethenyl)pyrrole12 (190 mg, 0.888 mmol) in
anhydrous DMF (10 mL), was added t-BuOK (132 mg, 1.18 mmol) at
0 ꢀC and the resulting orange solution was allowed to stir at 0 ꢀC
under an inert atmosphere for 45 min. A solution of 4-methyl-
benzenesulfonyl chloride (224 mg, 1.18 mmol) in DMF (1 mL) was
added with a syringe whereupon the solution turned yellow. After
stirring for 2.5 h at 0 ꢀC, water (25 mL) was added. The mixture was
extracted with EtOAc (2ꢂ25 mL). The combined organic phases
were washed with water (2ꢂ25 mL), dried (MgSO4), and concen-
trated under reduced pressure. The crude product was purified on
Al2O3 (hexanes/EtOAc, 8:2) to afford 10 (257 mg, 0.698 mmol, 79%)
3.1.6. 5-Phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl
ester (17). To a threaded ACE glass pressure tube was added
methyl 4-nitro-5-(2-phenylethenyl)thiophene-2-carboxylate (3)4
(80 mg, 0.264 mmol), Pd(OAc)2 (4 mg, 0.0178 mmol), and PPh3
(16.3 mg, 0.062 mmol) in MeCN (5 mL). The tube was fitted with
a pressure head and the solution was saturated with carbon
monoxide (four cycles of 6 atm of CO). The reaction mixture was
heated at 90 ꢀC (oil bath temperature) under CO (6 atm) for 40 h,
cooled to ambient temperature, depressurized and the solvent
was removed under reduced pressure. The crude product was
purified by chromatography (hexane/EtOAc, 8:2) to yield 17
(32 mg, 0.118 mmol, 71%) as an off-white solid. Mp 244 ꢀC (lit.17
as a yellow solid. Mp 124–125 ꢀC; 1H NMR (600 MHz, CDCl3)
d 8.00
(d, J¼2.8 Hz, 1H), 7.87 (d, J¼8.5 Hz, 2H), 7.48 (d, J¼8.5 Hz, 2H), 7.34–
7.44 (m, 6H), 7.40 (dd, J¼16.2, 0.8 Hz, 1H), 7.30 (tt, J¼7.3, 1.7 Hz, 1H),
6.94 (d, J¼16.5 Hz, 1H), 2.46 (s, 3H); 13C NMR (67.5 MHz, CDCl3)
239–240 ꢀC); 1H NMR (600 MHz, DMSO-d6)
d 12.03 (s, 1H), 7.78
(dd, J¼8.4, 1.2 Hz, 2H), 7.67 (s, 1H), 7.45 (t, J¼7.8 Hz, 2H), 7.31 (t,
d
147.1, 137.3, 136.5, 134.2, 132.3, 130.8, 128.9, 128.4, 127.8, 126.8,
J¼7.5 Hz, 1H), 6.97 (t, J¼1.2 Hz, 1H), 3.82 (s, 3H); 13C NMR
22.3, 121.8, 117.0, 116.4, 21.9; IR (ATR) 1489, 1370, 1057, 964 cmꢁ1
;
(150 MHz, DMSO-d6) d 162.9, 141.2, 138.6, 131.8, 130.02, 128.9,
HRMS calcd for C19H16N2O4S (MþHþ) 369.0909; found 369.0903.
128.1, 127.5, 124.6, 117.4, 98.6, 51.8; HRMS (ESI) calcd for
C14H12NO2S (MþHþ) 258.0589; found, 258.0582.
3.1.3. 3-Ethenyl-2-nitropyridine (12)13. A mixture of 2-nitro-3-tri-
fluoromethanesulfonyloxypyridine14 (507 mg, 1.86 mmol), ethe-
nyltributyl tin (700 mg, 2.21 mmol), tetraethylammonium chloride
3.1.7. 5-Phenyl-6H-thieno[2,3-b]pyrrole (18). Reaction of 2-nitro-3-
(2-phenylethenyl)thiophene (4)7 (72 mg, 0.311 mmol), Pd(OAc)2

1804
S.P. Gorugantula et al. / Tetrahedron 66 (2010) 1800–1805
(6 mg, 0.026 mmol), and PPh3 (29 mg, 0.110 mmol) in MeCN
(10 mL) as described for 17 (6 atm CO, 80 ꢀC, 16 h), gave after
chromatography (hexanes/EtOAc, 9:1) 18 (58 mg, 0.291 mmol, 94%)
as a pale yellow solid. Mp 179 ꢀC (lit.7 186–187 ꢀC); 1H NMR
2H), 7.36–7.28 (m, 7H), 7.44 (s, 1H), 7.12 (t, J¼7.2 Hz, 1H), 6.55 (s,
1H), 5.37 (s, 2H); 13C NMR (150 MHz, acetone-d6)
138.5, 138.0,
136.2, 135.4, 129.7, 129.6, 128.6, 128.0, 126.3, 124.3, 95.9, 95.8, 49.4;
IR (ATR) 1599, 1383, 1219 cmꢁ1; HRMS (ESI) calcd for C18H15N3
(MþHþ) 274.1344; found, 274.1338.
d
(600 MHz, CDCl3)
d
8.49 (br s, 1H), 7.53 (d, J¼8.4 Hz), 7.40 (dt, J¼8.4,
7.2 Hz), 7.25 (t, J¼7.8 Hz, 1H), 7.02 (d, J¼5.4 Hz, 1H), 6.85 (d,
J¼5.4 Hz, 1H), 6.73 (d, J¼1.8 Hz, 1H); 13C NMR (150 MHz, CDCl3)
3.1.12. 1H-Pyrrolo[3,2-b]pyridine (26). A solution of 2-ethenyl-3-
nitropyridine20 (11) (190 mg, 1.27 mmol), Pd(dba)2 (36.1 mg,
0.0628 mmol), and 1,10-phenanthroline (25.0 mg, 0.126 mmol) in
anhydrous DMF (4 mL) was heated as described for 19/20 (6 atm
CO, 120 ꢀC, 42 h). The solvent was removed by bulb-to-bulb distil-
lation under reduced pressure and the resulting crude product was
purified by chromatography (hexanes/EtOAc, 3:7) to give 26
(97.6 mg, 0.826 mmol, 65%) as a pale yellow solid. Mp 126–128 ꢀC
(lit.21 127 ꢀC).
d
138.7, 134.9, 133.2, 132.6, 129.2, 126.9, 124.3, 118.5, 117.9, 99.2.
3.1.8. 2-Cyano-5-phenyl-4H-furo[3,2-b]pyrrole (20) and 5-phenyl-
4H-furo[3,2-b]pyrrole-2-aldoxime (19). A solution of 5 (75 mg,
0.291 mmol), Pd(dba)2 (10 mg, 0.0174 mmol) and 1,10-phenan-
throline (7 mg, 0.0353 mmol) in anhydrous DMF (3 mL) was
heated as described for 17 (6 atm CO, 120 ꢀC, 22 h). The mixture
was cooled to ambient temperature and water (10 mL) was
added. The mixture was extracted with EtOAc (3ꢂ20 mL) and the
combined organic layers were washed with water (2ꢂ50 mL),
dried (MgSO4), filtered, and concentrated under reduced pres-
sure. Purification of the resulting oil by chromatography (hex-
anes/EtOAc, 8:2) gave in order of elution 20 (12 mg, 0.058 mmol,
20%) and 19 (30 mg, 0.132 mmol, 45%). The latter compound
decomposed noticeable at ambient temperature within a few
minutes. Data for 20: Mp 162–163 ꢀC; 1H NMR (600 MHz, CDCl3)
3.1.13. 1H-Pyrrolo[2,3-b]pyridine (27). Reaction of 12 (506 mg,
3.37 mmol), Pd(dba)2 (95.8 mg, 0.167 mmol), and 1,10-phenan-
throline (67.1 mg, 0.338 mmol) in DMF (4 mL), as described for 19/
20 (6 atm CO, 120 ꢀC, 7.5 days), gave after chromatography (EtOAc/
MeOH, 9:1), 27 (163 mg, 1.38 mmol, 41%) as a pale yellow solid. Mp
103–104 ꢀC (lit.22 105–106 ꢀC).
d
8.16 (br s, 1H), 7.53 (d, J¼7.2 Hz, 2H), 7.48 (t, J¼7.8 Hz, 2H), 7.33
3.1.14. 2-Phenyl-1H-pyrrolo[3,2-c]pyridine (28). Reaction of 4-nitro-
3-(2-phenylethenyl)pyridine N-oxide23 (13) (102 mg, 0.421 mmol),
Pd(dba)2 (11.5 mg, 0.0200 mmol), and 1,10-phenanthroline (8.3 mg,
0.042 mmol) in DMF (5 mL), as described for 19/20 (6 atm CO,120 ꢀC,
22 h), gave after chromatography (EtOAc) 28 (74.4 mg, 0.383 mmol,
91%) as a yellow solid. Mp 282–283 ꢀC (lit.8 282–283 ꢀC).
(t, J¼7.2 Hz, 1H), 7.10 (s, 1H), 6.47 (s, 1H); 13C NMR (150 MHz,
CDCl3)
d 152.7, 141.6, 132.06, 129.2, 128.1, 126.3, 124.6, 123.5,
113.4, 109.6, 90.1; IR (ATR) 3310, 2209, 1707 cmꢁ1; HRMS (ESI)
calcd for C13H8N2O (MþHþ) 209.0716, found 209.0709.
Partial data for 19: 1H NMR (600 MHz, CDCl3)
d 8.05 (br s, 1H),
7.98 (s, 1H), 7.51(d, J¼7.8 Hz, 2H), 7.39 (t, J¼8.4 Hz, 2H), 6.64 (s, 1H),
6.46 (s, 1H).
3.1.15. 2-Phenyl-1H-pyrrolo[2,3-c]pyridine (29). Reaction of 3-
nitro-4-(2-phenylethenyl)pyridine24 (13) (131 mg, 0.579 mmol),
Pd(dba)2 (16.6 mg, 0.0289 mmol), and 1,10-phenanthroline
(11.6 mg, 0.0585 mmol) in anhydrous DMF (4 mL), as described for
19/20 (6 atm CO, 120 ꢀC, 24 h), gave after chromatography (EtOAc/
MeOH, 9:1) 29 (98.5 mg, 0.507 mmol, 87%) as a pale yellow solid.
Mp 224–226 ꢀC (lit.4 223–225 ꢀC).
3.1.9. 2-Methyl-5-phenyl-4H-pyrrolo[3,2-d]thiazole (21). Reaction
of 2-methyl-5-nitro-4-(2-phenylethenyl)thiazole (6)18 (60 mg,
0.244 mmol), Pd(OAc)2 (4 mg, 0.017 mmol), and PPh3 (19 mg,
0.0725 mmol) in MeCN (5 mL) as described for 17 (6 atm CO, 80 ꢀC,
three days) gave after chromatography (hexanes/EtOAc, 8:2) 21
(32 mg, 0.149 mmol, 61%) as a pale brown solid. Mp 257–258 ꢀC
(dec); 1H NMR (600 MHz, DMSO-d6)
2H), 7.39 (t, J¼7.8 Hz, 2H), 7.21 (t, J¼7.5 Hz,1H), 6.78 (d, J¼1.8 Hz,1H),
2.68 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
158.5, 147.3, 136.6,
d
11.82 (s,1H), 7.67 (d, J¼7.8 Hz,
3.1.16. 4-Methoxy-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine
(30). Reaction of 15 (251 mg, 0.976 mmol), Pd(dba)2 (27.7 mg,
0.0482 mmol), and 1,10-phenanthroline (19.3 mg, 0.973 mmol) in
anhydrous DMF (5 mL), as described for 19/20 (6 atm CO, 120 ꢀC,
24 h), gave after chromatography (in order hexanes/EtOAc, 2:8;
EtOAc; EtOAc/MeOH, 9:1) 30 (180 mg, 0.799 mmol, 82%) as
a white solid. Mp 222–223 ꢀC; 1H NMR (600 MHz, DMSO-d6)
d
132.8,128.8,127.1,126.2,123.5, 96.3; IR (ATR) 1602,1458,1184 cmꢁ1
;
HRMS (ESI) calcd for C12H10N2S (MþHþ) 215.0643; found, 215.0638.
3.1.10. 1-Benzyl-1,4-dihydro-5-phenylpyrrolo[3,2-d]imidazole
(22). Reaction of 1-benzyl-5-(2-phenylethenyl)-4-nitroimidazole
(7)19 (58 mg, 0.190 mmol), Pd(dba)2 (7 mg, 0.012 mmol), and
1,10-phenanthroline (5 mg, 0.134 mmol) in anhydrous DMF (2 mL)
as described for 19/20 (6 atm CO, 120 ꢀC, 139 h) gave after chro-
matography (hexanes/EtOAc, 8:2, followed by EtOAc) 22 (40 mg,
0.146 mmol, 77%) as a brown solid. Mp 244–247 ꢀC; 1H NMR
d
12.3 (br s, 1H), 8.41 (s, 1H), 8.01 (dd, J¼9.0, 1.2 Hz, 2H), 7.49 (t,
J¼8.4 Hz, 2H), 7.40 (t, J¼7.8 Hz, 1H), 7.05 (d, J¼1.8 Hz, 1H), 4.11
(s, 3H); 13C NMR (150 MHz, DMSO-d6)
d
155.2 (þ), 150.8 (þ),
149.4 (ꢁ), 142.4 (þ), 131.0 (þ), 128.9 (ꢁ), 128.7 (ꢁ), 126.1 (ꢁ),
115.5 (þ), 99.3 (ꢁ), 53.1 (ꢁ); IR (ATR) 2754, 1624, 1526, 1457,
1393, 1345, 1293, 1120 cmꢁ1. Anal. Calcd for C13H11N3O: C, 69.32;
H, 4.92. Found: C, 69.61; H, 5.19.
(600 MHz, acetone-d6)
1H), 7.39–7.29 (m, 7H), 7.13 (t, J¼7.2 Hz, 1H), 6.29 (s, 1H), 5.32 (s,
2H); 13C NMR (150 MHz, acetone-d6)
138.7, 138.5, 135.3, 135.25,
d
10.33 (s, 1H), 7.65 (d, J¼7.2 Hz, 2H), 7.53 (s,
d
3.1.17. 6-Methyl-2-phenyl-5H-pyrrolo[3,2-c]pyridazine
5-N-oxide
133.7, 129.58, 129.63, 128.7, 128.67, 126.5, 124.5, 88.85, 88.8, 50.9; IR
(ATR) 1599, 3111, 1470, 1452 cmꢁ1; HRMS (ESI) calcd for C18H15N3
(MþHþ) 274.1344; found, 274.1338.
(31). Reaction of 16 (45.9 mg, 0.178 mmol), Pd(dba)2 (5.40 mg,
0.00939 mmol), and 1,10-phenanthroline (3.80 mg, 0.0192 mmol) in
anhydrous DMF (4 mL), as described for 19/20 (6 atm CO, 120 ꢀC,
14 h), gave after chromatography (EtOAc, followed by EtOAc/MeOH,
9:1) 31 (22.8 mg, 0.101 mmol, 57%) as a yellow solid. Mp >250 ꢀC; 1H
3.1.11. 3-Benzyl-3,4-dihydro-5-phenylpyrrolo[2,3-d]imidazole
(23). Reaction of 1-benzyl-4-(2-phenylethenyl)-5-nitroimidazole
(8)16 (125 mg, 0.409 mmol), Pd(dba)2 (15 mg, 0.012 mmol), and
1,10-phenanthroline (27 mg, 0.1361 mmol) in anhydrous DMF
(3 mL) as described for 19/20 (6 atm CO, 120 ꢀC, three days) gave
after chromatography (hexanes/EtOAc, 8:2, followed by EtOAc) 23
(36 mg, 0.132 mmol, 32%) as a brown solid. Mp 216 ꢀC (dec); 1H
NMR (600 MHz, DMSO-d6)
(s, 1H), 7.53 (t, J¼7.8 Hz, 2H), 7.44 (t, J¼7.8 Hz, 1H), 7.01 (s, 1H), 2.45 (s,
3H); 13C NMR (150 MHz, DMSO-d6)
d
12.3 (br s,1H) 7.95 (d, J¼7.2 Hz, 2H), 7.87
d
146.1 (þ), 144.4 (þ), 137.4 (þ),
130.4 (ꢁ), 129.1 (ꢁ), 129.0 (ꢁ), 125.8 (ꢁ), 124.4 (þ), 115.4 (ꢁ), 95.5 (þ),
18.6 (ꢁ); IR (ATR) 3057, 2666, 1314, 1214 cmꢁ1; HRMS (ESI) calcd for
C13H12N3O (MþHþ) 226.0980; found, 274.0975.
NMR (600 MHz, acetone-d6)
d
10.28 (s, 1H), 7.58 (dd, J¼8.4, 2.4 Hz,

S.P. Gorugantula et al. / Tetrahedron 66 (2010) 1800–1805
1805
4. For an example, see Kuzmich, D.; Mulrooney, C. Synthesis 2003, 1671–1678.
5. For an example, see Majumdar, K. C.; Mondal, S. Tetrahedon Lett. 2007, 48, 6951–
6953.
Acknowledgements
This work was supported by a research grant from the National
Science Foundation (CHE 0611096). NSF-EPSCoR (Grant 1002165R)
is gratefully acknowledged for the funding of a 600 MHz Varian
Inova NMR and a Thermo-Finnigan LTQ-FT Mass Spectrometer and
the NMR and MS facilities in the C. Eugene Bennett Department of
Chemistry at West Virginia University.
6. For an example, see Palmer, M. A.; Mu¨nch, G.; Zimmermann, P. J.; Buhr, W.;
Feth, M. P.; Simon, W. A. Bioorg. Med. Chem. 2008, 16, 1511–1530.
7. Srinivasan, K.; Srinivasan, K. G.; Balasubramanian, K. K.; Swaminathan, S.
Synthesis 1973, 313–315.
8. Fisher, M. H.; Schwartzkopf, G.; Hoff, D. R. J. Med. Chem. 1972, 15, 1168–1171.
9. Cook, P. D.; Castle, R. N. J. Heterocycl. Chem. 1973, 10, 807–812; See also Cook,
P. D.; Castle, R. N. J. Heterocycl. Chem. 1973, 10, 551–557.
10. Rajanarendar, E.; Ramesh, P.; Karunakar, D. Indian J. Chem. B 2003, 42B,1994–1996.
11. Saldabol, N. O.; Slavinska, V.; Popelis, J.; Mazeika, I. Latv. Kim. Z. 2000, 73–77.
12. Ten Have, R.; Leusink, F. R.; Van Leusen, A. M. Synthesis 1996, 871–876.
13. This compound has previously been prepared from 2-bromo-3-nitropyridine in
a related palladium-catalyzed reaction. Only 1H NMR data were given. Cha-
turvedula, P.V.; Mercer, S.E.; Fang, H.; Han, X.; Luo, G.; Dubowchik, G.M.;
Poindexter, G.S. U.S. Patent 2007259851, 2007.
14. Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H. Heterocycles 1992, 34, 2379–2384.
15. Remennikov, G. Y.; Cherkasov, V. M. Ukr. Khim. Zh. 1985, 51, 313–316.
16. Itai, T.; Sako, S. Chem. Pharm. Bull. 1961, 9, 87–91.
References and notes
1. For some recent examples and references, see: (a) Clawson, R. W., Jr.; So¨derberg,
B. C. G. Tetrahedron Lett. 2007, 48, 6019–6021; (b) Kuethe, J. T.; Davies, I. W.
Tetrahedron 2006, 62, 11381–11390; (c) Davies, I. W.; Smitrovich, J. H.; Sidler, R.;
Qu, C.; Gresham, V.; Bazaral, C. Tetrahedron 2005, 61, 6425–6437; (d) So¨derberg,
B. C. G.; Hubbard, J. W.; Rector, S. R.; O’Neil, S. N. Tetrahedron 2005, 61,
3637–3649.
2. (a) Dacko, C. A.; Akhmedov, N. G.; So¨derberg, B. C. G. Tetrahedron Asymmetry.
2008, 19, 2775–2783; (b) So¨derberg, B. C. G.; Banini, S. R.; Turner, M. R.; Minter,
A. R.; Arrington, A. K. Synthesis 2008, 903–912; (c) Clawson, R. W., Jr.; Deavers,
R. E., III; Akhmedov, N. G.; So¨derberg, B. C. G. Tetrahedron 2006, 62, 10829–
10834; (d) Scott, T. L.; So¨derberg, B. C. G. Tetrahedron 2003, 59, 6323–6332.
3. For reviews, see: (a) Popowycz, F.; Me´rour, J.-Y.; Joseph, B. Tetrahedron 2007, 63,
8689–8707; (b) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake,
C. H. Chem. Soc. Rev. 2007, 36, 1120–1132; (c) Popowycz, F.; Routier, S.; Joseph,
B.; Me´rour, J.-Y. Tetrahedron 2006, 63, 1031–1064.
17. Known but no spectral data reported: Ref. 7.
18. Herrling, S.; Mueckter, H. DE 1159450, 1963.
19. Baker, D. C.; Putt, S. R. J. Am. Chem. Soc. 1979, 101, 6127–6128.
20. Li, J.; Chen, S. H.; Li, X.; Niu, C.; Doyle, T. W. Tetrahedron 1998, 54, 393–400.
21. Adler, T. K.; Albert, A. J. Chem. Soc. 1960, 1794–1797.
22. Allegretti, M.; Anacardio, R.; Cesta, M. C.; Curti, R.; Mantovanini, M.; Nano, G.;
Topai, A.; Zampella, G. Org. Process Res. Dev. 2003, 7, 209–213.
23. Taylor, E. C.; Crovetti, A. J. J. Org. Chem. 1960, 25, 850–852.
24. Herz, W.; Murty, D. R. K. J. Org. Chem. 1961, 26, 418–422.