Synthesis of novel substituted phenanthrenes and polycyclic heteroarenes by Pd-catalyzed, direct, intramolecular arylation/heteroarylation

Article abstract of DOI:10.1002/ejoc.200901036

A novel route to substituted phenanthrenes and polycyclic heteroarenes by direct, Pd-catalyzed, intramolecular aryl ation/heteroarylation of 2-(2-bromoaryl/heteroaryl)-3-(aryl/ heteroaryl)-3-(methylthio)acrylonitriles has been reported.

Full text of DOI:10.1002/ejoc.200901036

FULL PAPER
DOI: 10.1002/ejoc.200901036
Synthesis of Novel Substituted Phenanthrenes and Polycyclic Heteroarenes by
Pd-Catalyzed, Direct, Intramolecular Arylation/Heteroarylation
Ashok K. Yadav,[a] Hiriyakkanavar Ila,*[a] and Hiriyakkanavar Junjappa[a]
Keywords: Cyclization / Heteroarenes / Palladium / Phenanthrenes / Polycycles
A novel route to substituted phenanthrenes and polycyclic
ation/heteroarylation of 2-(2-bromoaryl/heteroaryl)-3-(aryl/
heteroarenes by direct, Pd-catalyzed, intramolecular aryl- heteroaryl)-3-(methylthio)acrylonitriles has been reported.
tor of glycogen synthase kinase 3. Furostifoline and eustifo-
Introduction
line D, two furo-fused carbazole alkaloids,[13] are used as
Angularly fused polycyclic aromatics such as phenan-
Chinese folk medicine for various ailments, whereas the
threne and its heterocyclic analogs are an important class
indolo[2,3-a]carbazole alkaloids[7,14] such as staurosporine
of compounds, since their structural motifs are present in
and its related natural and synthetic analogs,[9a,15,16] have
many biologically active natural products[1] such as the
been identified as some of the most potent D1-CDK4 in-
phenanthrene analogs of combretastatin A-4,[2] an excep-
hibitors and are presently under clinical trial.
tionally strong inhibitor of tubulin polymerization.[2a] Simi-
Because of the importance of these angularly fused poly-
larly, a number of polycyclic heteroarenes such as benzo-
arenes and related heteroarenes in medicinal chemistry as
thiophenes and benzobis(thiophenes) such as benzo[1,2-
well as in materials science, a number of powerful method-
b:4,5,-bЈ]dithiophene (BDT)[3a] and their polycyclic aro-
ologies, especially those involving biaryl (or heterobiaryl)
matic derivatives exhibit remarkable electrochemical and
bond construction, have been developed for this class of
optical properties making them useful candidates in materi-
compounds in recent decades.[17,18] The most important
als science[3,4] for optoelectronic devices, organic conduc-
methods for biaryl (or heterobiaryl) bond construction in-
tors,[3c,4b] narrow-band-gap polymers[3b] and field-effect
volve photochemical methods,[19] metal-catalyzed cross-
transistors.[3e,3f] A few of the angularly fused naphtho[2,1-b]-
coupling[9a,9d,18,20] and most recently, biomimetic oxidative
furan, naphtho[2,1-b]thiophene, benzothienofuran and
coupling[18,21] and radical-mediated coupling reactions.[22]
benzodithiophene derivatives are known to exhibit signifi-
During the course of our continued interest in the chem-
cant antiproliferative activity.[5,6]
istry of polarized ketene dithioacetals as versatile building
Among other angularly fused heteroaromatics, carba-
blocks for substituted and fused aromatic and heteroarom-
zoles[7] and their benzo- and hetero-fused analogs (espe-
atic compounds,[23,24] we became interested in exploring the
cially those fused to the a or c face of the carbazole nucleus)
synthetic applications of another class of related organosul-
display a wide range of biological activity. Thus, a number
fur compounds of type 1 [i.e. 2- and 3-(aryl/heteroaryl)-3-
of naphtho[a]-fused carbazoles[8,9] show significant cell-
(methylthio)acrylonitriles]. We have recently reported an
growth inhibition of a range of tumor cell lines,[8a–8c]
interesting anionic domino rearrangement of these interme-
whereas a benzo[c]carbazole derivative displayed a promis-
diates in the presence of n-butyllithium, leading to a new
ing selectivity profile for the inhibition of an intercyclin-
general synthesis of 2-(aryl/heteroaryl)-1-(o-cyanoaryl)-
dependant kinase.[10] Similarly, hetero[a]-fused carbazoles
acetylenes.[25] Also, we have developed an efficient route to
such as granulatimide[11a,11b] and isogranulatimide[11c] act as
2-(aryl/heteroaryl)-3-cyanobenzo[b]thiophenes by the tribu-
G2 check-point inhibitors,[11] whereas a pyrido[a]carbazole-
tyltin hydride (TBTH)-induced, intramolecular, radical cy-
derived organometallic[12] was shown to be the inhibi-
clization of these compounds.[26] In continuation of these
studies, we further examined the Pd0-catalyzed, direct, in-
tramolecular arylation of intermediates 1, providing a facile
[a] Department of Chemistry, Indian Institute of Technology,
access to functionalized phenanthrenes and a variety of
angularly fused heteroaryl scaffolds (Scheme 3). We have
successfully accomplished this goal, and the results are pre-
sented in this paper.
Kanpur 208016, India
Fax: +91-0512-2590260
E-mail: hila@iitk.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901036.
338
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 338–344

Novel Substituted Phenanthrenes and Polycyclic Heteroarenes
Table 1. Pd-catalyzed, intramolecular, Heck arylation of 1a to 2a.
Results and Discussion
Entry Reaction conditions
Yield of 2a [%]
We prepared the desired (o-bromoaryl/heteroaryl)acrylo-
nitriles 1a–p, according to the general methodology devel-
oped in our laboratory,[25,26] by the base-induced condensa-
tion of (2-bromoaryl/heteroaryl)acetonitriles with various
aryl/heteroaryl dithioesters followed by in situ S-methyl-
ation of the resulting enethiolate salts 1A with methyl io-
dide (Scheme 1). The 1H NMR spectra of 1a–p revealed
that we isolated 1a, 1e–g and 1o as pure stereoisomers,
whereas we found the other products to be inseparable mix-
tures of (E)/(Z) isomers with ratios varying from 1:1.2 to
1:4.4. The X-ray analysis of 1a and 1g established the (Z)
configuration for these compounds. Nevertheless, the NMR
analysis of either (E)/(Z) mixtures or of pure 1e,f and 1o did
not allow us to determine the double-bond configuration
in these compounds, which also underwent thermal (Z)/(E)
isomerization, probably due to the push-pull character of
the double bond in 1.[26,27]
1
Pd(OAc)2 (10 mol-%), nBu4NBr
(1 equiv.), K2CO3 (2.5 equiv.), DMF,
110 °C, 40 h
no reaction
2
3
4
5
6
Pd(PPh3)4 (4 mol-%), Et3N (2.5 equiv.),
CH3CN, 100 °C, 38 h
34
56
48
82
Pd(OAc)2 (10 mol-%), PPh3 (20 mol-%),
K2CO3 (2.5 equiv.), DMF, 110 °C, 24 h
Pd(OAc)2 (20 mol-%), PPh3 (40 mol-%),
Na2CO3 (2.5 equiv.), DMF, 110 °C, 24 h
Pd(OAc)2 (20 mol-%), PPh3 (40 mol-%),
K2CO3 (2.5 equiv.), DMF, 110 °C, 24 h
Pd(PPh3)4 (5 mol-%), KOAc (1.05 equiv.), no reaction
DMA, 130 °C, 28 h
Scheme 3. Synthesis of phenanthrenes and polycyclic heteroarenes
2.
Scheme 1. Synthesis of (o-bromoaryl/heteroaryl)acrylonitriles 1a–p.
We selected the acrylonitrile 1a as the model substrate
for optimizing reaction conditions for the intramolecular,
Heck-type arylation by changing Pd catalysts, ligands,
bases, solvents and additives (Scheme 2), and the results are
shown in Table 1. As is evident from Table 1, we obtained
the best yield of any phenanthrene (2a, 82%) when we
heated 1a with Pd(OAc)2 (20 mol-%), triphenylphosphane
(40 mol-%) and K2CO3 (2.5 equiv.) as base in DMF at 110–
115 °C (24 h, Table 1, Entry 5). We confirmed the structure
of phenanthrene 2a with the help of spectral and analytical
data.
Scheme 4. Pd0-catalyzed, intramolecular cyclization of 1o,p. Reac-
tion conditions: (a) Pd(OAc)2 (20 mol-%), PPh3 (40 mol-%) K2CO3
(2.5 equiv.), DMF, 110 °C, 24 h.
Similarly, the corresponding 2-arylacrylonitriles 1c–f,
bearing a five-membered heterocyclic ring at the 3-position,
underwent facile Pd0-catalyzed, intramolecular cyclization
Scheme 2. Synthesis of phenanthrene 2a.
We used these optimized reaction conditions throughout under these conditions, yielding substituted naphtho[2,1-b]-
our study of the intramolecular, Pd-catalyzed cyclization of furan 2c, naphtho[2,1-b]thiophene 2d and benzo[e]indole
other (aryl/heteroaryl)acrylonitriles 1b–p, and the results derivatives 2e,f in 58–74% yields (Table 2, Entries 2–5). We
are depicted in Schemes 3 and 4 and Table 2. Thus, the in- prepared the substituted benzo[a]carbazole derivative 2g in
tramolecular, Heck-type arylation of sterically crowded, tri- 68% yield when we subjected the 2-(2-bromo-5-meth-
methoxylated, diarylacrylonitrile 1b furnished the trime- oxyphenyl)-3-[3-(N-methyl-3-indolyl)]acrylonitrile (1g) to
thoxyphenanthrene 2b, a combrestatin analog,[2b] in 62% Pd-catalyzed cyclization under identical conditions
yield (Table 2, Entry 1).
(Table 2, Entry 6).
Eur. J. Org. Chem. 2010, 338–344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
339

A. K. Yadav, H. Ila, H. Junjappa
FULL PAPER
Table 2. Pd0-catalyzed, intramolecular cyclization of 1b–n.
We next extended this Pd-catalyzed, intramolecular,
Heck-type heteroarylation protocol to acrylonitriles 1h–p,
with a brominated heterocyclic ring as the electrophilic
partner in this cyclization, as shown in Table 2, Entries 7–
13. Thus, we obtained the regiospecifically substituted
thieno[2,3-e]benzo[b]thiophene 2h and the novel thieno-
[2,3-e]benzo[b]furan 2i in high yields from the correspond-
ing acyclic precursors 1h,i under the standard reaction con-
ditions (Table 2, Entries 7–8). The extension of the reaction
to
2-(4-bromo-1,3-diphenyl-5-pyrazolyl)-3-(4-methoxy-
phenyl)- and -3-(2-furyl)acrylonitriles 1j,k under identical
conditions provided novel highly substituted benzo[e]inda-
zole 2j and the corresponding furo[3,2-e]indazole 2k in 65%
and 70% yields, respectively (Table 2, Entries 9–10).
We next extended the intramolecular, Heck heteroaryl-
ation strategy to 2-(2-bromo-3-indolyl)-3-(heteroaryl)acry-
lonitriles 1l–p with a view to synthesizing indolo[2,3-a]- and
other heterocyclo[2,3-a]-fused carbazole frameworks 2l–p
because of the wide spectrum of biological activity dis-
played by this class of compounds. Thus, 2-(2-bromo-
indolyl)-3-(3-indolyl)acrylonitrile 1l underwent facile Pd-
catalyzed cyclization under the previously described reac-
tion conditions to yield the desired 5-cyano-6-(methylthio)-
indolo[2,3-a]carbazole derivative 2l in 72% yield (Table 2,
Entry 11). Similarly, we obtained the novel substituted thi-
eno[3,2-a]- and pyrrolo[3,2-a]carbazole frameworks 2m and
2n in high yields by subjecting the respective 2-(2-bromo-3-
indolyl)-3-(2-thienyl)- and -3-(2-pyrrolyl)acrylonitrile pre-
cursors 1m–n to catalytic cyclization under these conditions
(Table 2, Entries 12–13).
Interestingly, the attempted intramolecular Heck hetero-
arylation of the related 3-(2-furyl)acrylonitrile 1o under the
reported conditions did not furnish the desired furo[3,2-a]-
carbazole 2o. Instead, we isolated 3-cyano-2-furylthieno-
[3,2-b]indole 3o (68%) as the product on the basis of its
spectral and analytical data (Scheme 4).
Similarly, the 2-(2-bromo-3-indolyl)-3-(3-pyridyl)acrylo-
nitrile 1p failed to furnish the expected pyrido[3,2-a]carb-
azole 2p under these conditions and yielded only 3-cyano-
2-(3-pyridyl)thieno[3,2-b]indole
3p
in
66%
yield
(Scheme 4).[28]
The mechanistic pathway for the Pd-catalyzed, intramo-
lecular arylation of 1 to 2 is shown in Scheme 5. Thus, the
oxidative addition of the C–Br bond of 1 to the Pd0 species
affords the (aryl)Pd complex 4. The formation of an intra-
molecular C–C bond may proceed either by the electro-
philic palladation of the arene[29,30] in 4 or by C–H acti-
vation involving the oxidative addition of (aryl)Pd species
4 to the neighboring aryl C–H bond,[30b] to give seven-
membered palladacycle 5, which undergoes reductive elimi-
nation to afford the product 2, regenerating the active Pd0
species. However, there is growing evidence of an electro-
philic pathway in the direct arylation of heterocyclic ar-
enes.[30,31]
The failure of 3-(2-furyl)- and 3-(3-pyridyl)acrylonitriles
1o,p to afford furo- and pyrido-fused carbazoles 2o,p under
the present reaction conditions appears to be due to the
combined effect of the reduced electrophilicity of the C–Br
[a] Pure (Z) isomer. [b] Mixtures of (E)/(Z) isomers. [c] Yields calcu-
lated on the basis of either pure isomer or (E)/(Z) mixtures of iso-
mers.
340
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 338–344

Novel Substituted Phenanthrenes and Polycyclic Heteroarenes
propriate, all reagents were purified prior to use according to the
guidelines of Vogel, Perrin or Armarego.[34] 1H (400 MHz or
500 MHz) and 13C NMR (100 MHz or 125 MHz) spectra were re-
corded with Jeol JNM-LA 400 FT-NMR and Jeol JNM-LA 500
FT-NMR spectrometers with CDCl3 and [D6]DMSO as the sol-
vents. Tetramethylsilane was used as an internal reference. Melting
points were recorded with a Mel-Temp melting point apparatus
(capillary method) and are uncorrected. The IR spectra were re-
corded with a Perkin–Elmer 1320 spectrophotometer. The FAB
mass spectra were recorded with a JEOL SX 102/DA-6000 Mass
Spectrometer/Data System. HRMS (ESI) data were recorded with
a Waters Micromass Q-TOF Premier Mass Spectrometer and a
Bruker Daltonics APEXII FTICR spectrometer. Chromatographic
purification was conducted by column chromatography on 100–
200 mesh silica gel obtained from Acme Synthetic Chemicals (In-
dia).
Scheme 5. Mechanism for the formation of 2a–n.
bond of the electron-rich 2-bromoindole along with a re-
duced nucleophilicity of the π-deficient, 3-pyridyl and 2-
furyl heterocyclic rings, resulting in the failure to form pal-
ladacycle intermediate 5 by electrophilic displacement on
Pd complexes 4o,p (Scheme 5).[32] Therefore, the reaction
takes a different course with the formation of cyclopallad-
ated thioether complexes 6o,p by the intramolecular nucleo-
philic attack of the electron-rich methylthio group on the
Pd-insertion complexes 4o,p (Scheme 6). The subsequent
demethylation of the activated metal-bonded methylthio
group in 6o,p by some nucleophilic species followed by a
subsequent reductive elimination affords the corresponding
thienoindoles 3o,p in good yields (Scheme 6). The forma-
tion of these kinds of cyclopalladated thioether complexes
leading to thioheterocycles has been reported in the litera-
ture.[33]
General Procedure for the Preparation of 3-(Aryl/heteroaryl)-2-(2-
bromoaryl/heteroaryl)-3-(methylthio)-2-propenenitriles (1a–p):[25,26]
To a stirred suspension of NaH (0.44 g, 11.0 mmol, 60%) in dry
THF (15 mL) under N2 was added a solution of the corresponding
(2-bromoaryl/heteroaryl)acetonitrile (5.0 mmol) in dry THF
(15 mL) dropwise at 0 °C. The reaction mixture was stirred at room
temperature for 1 h, and a solution of the corresponding dithioester
(5.0 mmol) in dry THF (15 mL) was added dropwise at 0 °C over
15–20 min. The reaction mixture was further stirred at room tem-
perature for 3 h and cooled to 0 °C. MeI (0.46 mL, 7.5 mmol) was
added dropwise at 0 °C to the reaction mixture, which was further
stirred for 3 h. The reaction mixture was poured into ice-cold water.
The aqueous layer was extracted with EtOAc (3ϫ50 mL). The
combined organic extracts were washed with H2O (3ϫ50 mL) and
brine (50 mL) and dried with Na2SO4. The solvent was removed
under reduced pressure to give crude adducts 1a–p, which were
purified by column chromatography using hexane/EtOAc as the
eluent.
2-(2-Bromo-3,4,5-trimethoxyphenyl)-3-(methylthio)-3-phenyl-2-pro-
penenitrile (1b): Obtained as a 4:1 inseparable mixture of geometri-
cal isomers; yield 71% (1.48 g); white solid; m.p. 80–82 °C; Rf =
0.50 (hexane/EtOAc, 8:2). IR (CH Cl ): ν = 2937, 2204, 1562, 1481,
˜
2
2
1385, 1346, 1251, 1106, 1011, 730 cm–1 1H NMR (500 MHz,
.
CDCl3): δ = 7.23–7.21 (m, 3 H, Ar-H), 7.14–7.12 (m, 2 H, Ar-H),
6.75 (s, 0.2 H, Ar-H), 6.21 (s, 0.8 H, Ar-H), 3.92 (s, 0.60 H, OCH3),
3.92 (s, 0.60 H, OCH3), 3.88 (s, 0.60 H, OCH3), 3.81 (s, 2.40 H,
OCH3), 3.79 (s, 2.40 H, OCH3), 3.53 (s, 2.40 H, OCH3), 2.06 (s,
2.40 H, SCH3), 1.87 (s, 0.60 H, SCH3) ppm. 13C NMR (125 MHz,
CDCl3): δ = 163.4, 161.4, 153.3, 152.5, 151.9, 151.2, 144.0, 143.3,
135.0, 134.4, 130.2, 130.1, 129.6, 129.5, 129.3, 129.13, 129.12,
128.9, 128.8, 128.6, 117.5, 116.8, 111.4, 111.1, 109.9, 108.7, 61.3,
Scheme 6. Mechanism for the formation of 3o,p.
Conclusions
We have reported an efficient synthesis of a diverse array
of novel aryl/heteroaryl-annulated scaffolds by Pd-cata- 61.23, 61.17, 56.4, 56.12, 56.11, 16.36, 16.35 ppm. HRMS-ESI:
calcd. for C19H19BrNO3S [M + H]+ 420.0269; found 420.0266.
lyzed, direct, intramolecular arylation of easily accessible,
novel, functionalized, o-bromodiaryl/heteroarylstilbene pre-
cursors. To the best of our knowledge, there is only one
General Procedure for the Pd-Catalyzed Cyclization of 3-(Aryl/
heteroaryl)-2-(2-bromoaryl/heteroaryl)-3-(methylthio)-2-propeneni-
triles (1a–p): A solution of the corresponding 3-(aryl/heteroaryl)-2-
(2-bromoaryl/heteroaryl)-3-(methylthio)-2-propenenitrile 1a–p
report of phenanthrene synthesis by a Pd-catalyzed direct
arylation of cis-(o-chlorophenyl)stilbene,[30a] whereas other
examples of biaryl construction by Pd-catalyzed cross cou- (1 mmol) in dry DMF (5 mL, degassed with argon) was added to
a suspension of Pd(OAc)2 (20 mol-%), (Ph3)3P (40 mol-%) and
K2CO3 (2.5 mmol) in dry DMF (10 mL, degassed with argon) un-
der argon at room temperature. The reaction mixture was heated
at 110 °C for 24–26 h, and the reaction was monitored by TLC.
The mixture was cooled to room temperature, poured into water
and extracted with CH2Cl2 (3ϫ20 mL). The combined organic ex-
tracts were washed with H2O (3ϫ50 mL) and brine (50 mL) and
dried with Na2SO4. The solvent was removed under reduced pres-
pling employ 1,2-(o-haloaryl/heteroaryl)-substituted hetero-
cycles as precursors.[8b,9a,11c,18b,18c]
Experimental Section
General: Unless otherwise noted, all reactions were carried out in
oven-dried glassware under N2 in anhydrous solvents. Wherever ap-
Eur. J. Org. Chem. 2010, 338–344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
341

A. K. Yadav, H. Ila, H. Junjappa
FULL PAPER
sure to give crude products 2a–n and 3o,p, which were purified by
column chromatography on silica gel using hexane/EtOAc as the
eluent.
8.77 (d, J = 7.8 Hz, 1 H, Ar-H), 7.62–7.51 (m, 4 H, Ar-H), 7.43–
7.35 (m, 2 H, Ar-H), 4.22 (s, 3 H, NCH3), 4.17 (s, 3 H, NCH3),
2.58 (s, 3 H, SCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.1,
143.7, 131.6, 129.1, 127.8, 127.0, 126.6, 124.0, 123.8, 123.4, 122.1,
121.3, 121.2, 120.9, 118.6, 110.2, 110.0, 103.3, 36.8, 36.6, 19.8 ppm.
MS: m/z (%) = 355 (100) [M]+. HRMS-ESI: calcd. for C22H18N3S
[M + H]+ 356.1221; found 356.1223.
2,3-Dimethoxy-9-(methylthio)phenanthrene-10-carbonitrile (2a):
Yield 82% (0.25 g); white solid; m.p. 151–152 °C; Rf = 0.45 (hex-
ane/EtOAc, 6:1). IR (KBr): ν = 2927, 2198, 1598, 1554, 1513, 1440,
˜
1372, 1244, 1216, 1173, 1025, 755 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.27–7.24 (m, 2 H, Ar-H), 7.17–7.15 (m, 2 H, Ar-H), 2-(2-Furyl)-8-methyl-1-thia-8-azacyclopenta[a]indene-3-carbonitrile
6.93 (s, 1 H, Ar-H), 6.34 (s, 1 H, Ar-H), 3.81 (s, 3 H, OCH3), 3.56
(s, 3 H, OCH3), 2.08 (s, 3 H, SCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.2, 149.5, 148.0, 134.3, 129.4, 128.9, 128.5, 126.6,
116.8, 115.1, 114.7, 114.6, 108.6, 56.0, 55.9, 16.2 ppm. MS: m/z (%)
= 310 (74) [M + 1], 154 (100). HRMS-ESI: calcd. for C18H16NO2S
[M + H]+ 310.0902; found 310.0903.
(3o): Yield 68% (0.19 g); yellow solid; m.p. 111–112 °C; Rf = 0.69
(hexane/EtOAc, 9:1). IR (KBr): ν = 2924, 2214, 1497, 1459,
˜
736 cm–1 1H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 7.8,
.
0.7 Hz, 1 H, Ar-H), 7.46 (t, J = 0.98 Hz, 1 H, Ar-H), 7.35 (d, J =
1.2 Hz, 1 H, Ar-H), 7.34 (d, J = 3.2 Hz, 1 H, Ar-H), 7.27–7.23 (m,
1 H, Ar-H), 7.08 (d, J = 3.4 Hz, 1 H, Ar-H), 6.55 (dd, J = 3.5,
1.8 Hz, 1 H, Ar-H), 3.82 (s, 3 H, NCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 147.1, 142.3, 142.0, 141.2, 134.2, 123.4,
121.6, 120.6, 120.4, 119.2, 115.5, 112.5, 109.4, 108.1, 94.8,
32.3 ppm. HRMS-ESI: calcd. for C16H11N2OS [M + H]+ 279.0592;
found 279.0592.
4-(Methylthio)-3,7,9-trioxadicyclopenta[a,g]naphthalene-5-carboni-
trile (2c): Yield 74% (0.21 g); white solid; m.p. 199–200 °C; Rf =
0.56 (hexane/EtOAc, 6:1). IR (KBr): ν = 2924, 2216, 1473, 1267,
˜
1
1236, 1037, 859, 746 cm–1. H NMR (400 MHz, CDCl3): δ = 7.91
(d, J = 2.0 Hz, 1 H, Ar-H), 7.61 (s, 1 H, Ar-H), 7.39 (s, 1 H, Ar-
H), 7.18 (d, J = 1.9 Hz, 1 H, Ar-H), 6.15 (s, 2 H, OCH2O), 2.78
(s, 3 H, SCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.3,
148.9, 147.2, 127.5, 127.1, 125.8, 123.5, 117.1, 108.2, 106.1, 103.1,
101.9, 100.9, 18.2 ppm. MS: m/z (%) = 283 (100) [M+]. HRMS-
ESI: calcd. for C15H10NO3S [M + H]+ 284.0381; found 284.0380.
8-Methyl-2-(3-pyridyl)-1-thia-8-azacyclopenta[a]indene-3-carboni-
trile (3p): Yield 66% (0.19 g); yellow solid; m.p. 191–192 °C; Rf =
0.23 (hexane/EtOAc, 7:3). IR (KBr): ν = 2921, 2219, 1495, 1469,
˜
1410, 1327, 1089, 728 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.97
(br. s, 1 H, Ar-H), 8.65 (br. s, 1 H, Ar-H), 8.20 (d, J = 7.8 Hz, 1
H, Ar-H), 8.07 (dd, J = 7.9, 0.9 Hz, 1 H, Ar-H), 7.39–7.38 (m, 2
H, Ar-H), 7.31–7.25 (m, 2 H, Ar-H), 3.88 (s, 3 H, NCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 148.7, 147.1, 142.1, 142.0, 139.3,
134.8, 129.3, 124.1, 123.9, 122.8, 120.7, 120.5, 119.3, 115.3, 109.5,
98.9, 32.4 ppm. HRMS-ESI: calcd. for C17H12N3S [M + H]+
290.0752; found 290.0755.
7,8,9-Trimethoxy-3-methyl-4-(methylthio)benzo[e]indole-5-carboni-
trile (2f): Yield 58% (0.20 g); white solid; m.p. 164–165 °C; Rf =
0.23 (hexane/EtOAc, 9:1). IR (KBr): ν = 2930, 2209, 1509, 1455,
˜
1
1344, 1252, 1126, 1060, 744 cm–1. H NMR (400 MHz, CDCl3): δ
= 7.42 (s, 1 H, Ar-H), 7.34 (d, J = 2.9 Hz, 1 H, Ar-H), 7.23 (d, J
= 1.2 Hz, 1 H, Ar-H), 4.33 (s, 3 H, OCH3), 4.02 (s, 3 H, OCH3),
4.01 (s, 3 H, OCH3), 4.00 (s, 3 H, NCH3), 2.59 (s, 3 H, SCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 152.4, 149.3, 142.7, 133.7, 130.9,
126.9, 126.2, 126.1, 118.5, 118.2, 110.9, 104.3, 101.5, 61.2, 60.5,
56.0, 37.9, 21.6 ppm. MS: m/z (%) = 342 (100) [M]+. HRMS-ESI:
calcd. for C18H19N2O3S [M + H]+ 343.1116; found 343.1117.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures, characterization data of
1
1c,d, 1f, 1h–p, 2b, 2d,e, 2g, 2i,j, 2m and 2n and copies of H NMR
and 13C NMR spectra of 2a–n and 3o,p.
4-(Methylthio)thieno[2,3-e]benzo[b]thiophene-5-carbonitrile (2h):
Yield 78% (0.20 g); white solid; m.p. 157–158 °C; Rf = 0.49 (hex-
Acknowledgments
ane/EtOAc, 19:1). IR (KBr): ν = 2921, 2217, 1463, 1346, 1311,
˜
1095, 746 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J =
5.4 Hz, 1 H, Ar-H), 7.68 (d, J = 5.4 Hz, 1 H, Ar-H), 7.65 (d, J =
5.4 Hz, 1 H, Ar-H), 7.63 (d, J = 5.6 Hz, 1 H, Ar-H), 2.69 (s, 3 H,
SCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.6, 138.5, 135.7,
134.8, 133.0, 132.7, 127.4, 123.3, 122.7, 117.0, 108.5, 19.3 ppm.
MS: m/z (%) = 262 (100) [M + 1]+, 261 (98) [M]+. HRMS-ESI:
calcd. for C12H8NS3 261.9819; found 261.9816.
A. K. Y. thanks the Council of Scientific and Industrial Research
(CSIR) New Delhi for a Senior Research Fellowship. Financial as-
sistance under the Department of Science and Technology (DST)
project is also acknowledged.
[1] a) A. Iuliano, P. Piccioli, D. Fabbri, Org. Lett. 2004, 6, 3711–
3714 and references cited therein; b) E. R. Walker, S. Y. Leung,
A. G. M. Barrett, Tetrahedron Lett. 2005, 46, 6537–6540 and
references cited therein; c) T. R. Kelly, Q. Li, V. Bhushan, Tet-
rahedron Lett. 1990, 31, 161–164; d) R. X.-F. Ren, N. C.
Chaudhuri, P. L. Paris, S. I. V. Rumney, E. T. Kool, J. Am.
Chem. Soc. 1996, 118, 7671–7678; e) S. Kumar, J. Org. Chem.
1997, 62, 8535–8539; f) C. B. de Koning, J. P. Michael, A. L.
Rousseau, Tetrahedron Lett. 1998, 39, 8725–8728; g) S. Radix,
R. Barret, Tetrahedron 2007, 63, 12379–12387.
4-(Methylthio)-6,8-diphenylfuro[3,2-e]indazole-5-carbonitrile (2k):
Yield 70% (0.27 g); white solid; m.p. 219–220 °C; Rf = 0.56 (hex-
ane/EtOAc, 6:1). IR (KBr): ν = 2927, 2218, 1592, 1499, 1307, 1144,
˜
1
745 cm–1. H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 2.2 Hz, 1
H, Ar-H), 7.87 (d, J = 7.3 Hz, 2 H, Ar-H), 7.59–7.48 (m, 8 H, Ar-
H), 7.17 (d, J = 2.0 Hz, 1 H, Ar-H), 2.78 (s, 3 H, SCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 149.9, 148.4, 148.3, 146.5, 138.4,
137.7, 132.4, 129.8, 129.7, 128.9, 128.8, 128.6, 127.8, 123.4, 115.3,
114.1, 107.1, 93.6, 18.2 ppm. MS: m/z (%) = 382 (100) [M + 1]+,
381 (80) [M]+. HRMS-ESI: calcd. for C23H16N3OS 382.1014; found
382.1014.
[2] Review: a) G. M. Cragg, D. J. Newman, J. Nat. Product 2004,
67, 232–244; b) V. Mamane, P. Hannen, A. Fuerstner, Chem.
Eur. J. 2004, 10, 4556–4575.
[3] a) K. Takimiya, Y. Konda, H. Ebata, N. Niihara, T. Otsubo,
J. Org. Chem. 2005, 70, 10569–10571; b) S.-M. Yang, J.-J. Shie,
J.-M. Fang, S. K. Nandy, H.-Y. Chang, S.-H. Lu, G. Wang, J.
Org. Chem. 2002, 67, 5208–5215 and references cited therein;
c) Y. Kono, H. Miyamoto, Y. Aso, T. Otsubo, F. Ogura, T.
Tanaka, M. Sawada, Angew. Chem. Int. Ed. Engl. 1989, 28,
11,12-Dimethyl-6-(methylthio)-11,12-dihydro-11,12-diazaindeno-
[2,1-a]fluorene-5-carbonitrile (2l): Yield 72% (0.26 g); light yellow
solid; m.p. 199–200 °C; Rf = 0.46 (hexane/EtOAc, 6:1). IR (KBr):
1
ν = 2913, 2205, 1530, 1467, 1330, 1321, 1255, 1240, 744 cm–1. H
˜
NMR (400 MHz, CDCl3): δ = 9.05 (d, J = 8.0 Hz, 1 H, Ar-H),
342
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 338–344

Novel Substituted Phenanthrenes and Polycyclic Heteroarenes
1222–1224 and references cited therein; d) J. Roncali, Chem.
Rev. 1997, 97, 173–205; e) K. Takimiya, Y. Kunugi, Y. Toyosh-
ima, T. Otsubo, J. Am. Chem. Soc. 2005, 127, 3605–3612; f) Y.
Nicolas, P. Blanchard, J. Roncali, M. Allain, N. Mercier, A.-L.
Deman, J. Tardy, Org. Lett. 2005, 7, 3513–3516 and references
cited therein.
a) K. Kobayashi, C. L. Gajurel, J. Chem. Soc., Chem. Commun.
1986, 1779–1780; b) S. Yoshida, M. Fujii, Y. Aso, T. Otsubo,
F. Ogura, J. Org. Chem. 1994, 59, 3077–3081.
Lett. 2007, 48, 293–295; c) J. F. Almeida, L. Castedo, D. Fer-
nandez, A. G. Neo, V. Romero, G. Tojo, Org. Lett. 2003, 5,
4939–4941; d) E. M. Beccalli, A. Marchesini, T. Pilati, Tetrahe-
dron 1993, 49, 4741–4758; e) S. Samori, M. Hara, T.-I. Ho, S.
Tojo, K. Kawai, M. Endo, M. Fujitsuka, T. Majima, J. Org.
Chem. 2005, 70, 2708–2712.
a) M. Shimizu, K. Mochida, T. Hiyama, Angew. Chem. Int. Ed.
2008, 47, 9760–9764; b) Y. H. Kim, H. Lee, Y. J. Kim, B. T.
Kim, J.-N. Heo, J. Org. Chem. 2008, 73, 495–501.
[4]
[20]
[5]
[6]
K. Starcevic, M. Kralj, I. Piantanida, L. Suman, K. Pavelic, [21]
G. Karminski-Zamola, Eur. J. Med. Chem. 2006, 41, 925–939.
K. Wang, M. Lu, A. Yu, X. Zhu, Q. Wang, J. Org. Chem. 2009,
74, 935–938 and references therein.
W. D. Wilson, Y. H. Wang, S. Kusuma, S. Chandrasekaran,
N. C. Yang, D. W. Boykin, J. Am. Chem. Soc. 1985, 107, 4989–
4995.
[22]
Radical-mediated biaryl coupling: a) D. C. Harrowven, M. I. T.
Nunn, D. R. Fenwick, Tetrahedron Lett. 2002, 43, 3185–3187;
b) S. R. Flanagan, D. C. Harrowven, M. Bradley, Tetrahedron
Lett. 2003, 44, 1795–1798; c) C. Hoarau, A. Couture, E. De-
niau, P. Grandclaudon, Synthesis 2001, 1462–1470.
Reviews: a) H. Ila, H. Junjappa, P. K. Mohanta in Progress in
Heterocyclic Chemistry (Eds.: G. W. Gribble, T. L. Gilchrist),
Pergamon Press, Oxford, 2001, vol. 13, chapter 1, pp. 1–24; b)
H. Junjappa, H. Ila, C. V. Asokan, Tetrahedron 1990, 46, 5423–
5506; c) H. Ila, H. Junjappa, O. Barun, J. Organomet. Chem.
2001, 624, 34–40.
Recent papers: a) N. C. Misra, K. Panda, H. Ila, H. Junjappa,
J. Org. Chem. 2007, 72, 1246–1251; b) G. S. M. Sundaram, B.
Singh, C. Venkatesh, H. Ila, H. Junjappa, J. Org. Chem. 2007,
72, 5020–5023; c) C. Venkatesh, G. S. M. Sundaram, H. Ila, H.
Junjappa, J. Org. Chem. 2006, 71, 1280–1283; d) C. Venkatesh,
B. Singh, P. K. Mahata, H. Ila, H. Junjappa, Org. Lett. 2005,
7, 2169–2172; e) K. Panda, C. Venkatesh, H. Ila, H. Junjappa,
E. J. Org. Chem. 2005, 2045–2063; f) S. Peruncheralathan, T. A.
Khan, H. Ila, H. Junjappa, J. Org. Chem. 2005, 70, 10030–
10035; g) S. Peruncheralathan, A. K. Yadav, H. Ila, H. Jun-
jappa, J. Org. Chem. 2005, 70, 9644–9647; h) G. S. M. Sunda-
ram, C. Venkatesh, U. K. Syam Kumr, H. Ila, H. Junjappa, J.
Org. Chem. 2004, 69, 5760–5762; i) S. Peruncheralathan, T. A.
Khan, H. Ila, H. Junjappa, Tetrahedron 2004, 60, 3457–3464;
j) P. K. Mahata, C. Venkatesh, U. K. Syam Kumar, H. Ila, H.
Junjappa, J. Org. Chem. 2003, 68, 3966–3975; k) K. Panda,
J. R. Suresh, H. Ila, H. Junjappa, J. Org. Chem. 2003, 68, 3498–
3505.
[7]
[8]
Reviews: a) H.-J. Knoelker, K. R. Reddy, Chem. Rev. 2002, 102,
4303–4427; b) J. Leonard, Nat. Prod. Rep. 1999, 16, 319–338.
a) M. Rogge, G. Fischer, U. Pindur, D. Schollmeyer, Monatsh.
Chem. 1996, 127, 97–102; b) S. Routier, G. Coudert, J.-Y. Mer-
our, Tetrahedron Lett. 2001, 42, 7025–7080; c) C. Bailly, X. Qu,
J. B. Chaires, P. Colson, C. Houssier, M. Ohkubo, S. Nishi-
mura, T. Yoshinari, J. Med. Chem. 1999, 42, 2927–2935.
Synthesis: a) C. Sanchez-Martinez, M. M. Faul, C. Shih, K. A.
Sullivan, J. L. Grutsch, J. T. Cooper, S. P. Kolis, J. Org. Chem.
2003, 68, 8008–8014; b) R. Pathak, J. M. Nhlapo, S. Govender,
J. P. Michael, W. A. L. van Otterlo, C. B. de Koning, Tetrahe-
dron 2006, 62, 2820–2830; c) C. B. de Koning, J. P. Michael,
J. M. Nhlapo, R. Pathak, W. A. L. van Otterlo, Synlett 2003,
705–707; d) X. Cai, V. Snieckus, Org. Lett. 2004, 6, 2293–2295.
D. J. Carini, R. F. Kaltenbach, J. Liu, P. A. Benfield, J. Boylan,
M. Boisclair, L. Brizuela, C. R. Burton, S. Cox, R. Grafstrom,
B. A. Harrison, K. Harrison, E. Akamike, J. A. Markwalder, Y.
Nakano, S. P. Seitz, D. M. Sharp, G. L. Trainor, T. M. Sielecki,
Bioorg. Med. Chem. Lett. 2001, 11, 2209–2211.
[23]
[9]
[24]
[10]
[11]
a) E. Piers, R. Britton, R. J. Andersen, J. Org. Chem. 2000, 65,
530–535; b) J. Bergman, E. Desarbre, E. Koch, Tetrahedron
1999, 55, 2363–2370; c) S. Routier, P. Peixoto, J.-Y. Merour, G.
Coudert, N. Dias, C. Bailly, A. Pierre, S. Leonce, D.-H. Caig-
nard, J. Med. Chem. 2005, 48, 1401–1413.
[12]
[13]
a) H. Bregman, D. S. Williams, G. E. Atilla, P. J. Carroll, E.
Meggers, J. Am. Chem. Soc. 2004, 126, 13594–13595; b) C. B.
de Koning, J. P. Michael, A. L. Rousseau, J. Chem. Soc. Perkin
Trans. 1 2000, 1705–1713.
Reviews: a) W. Froehner, M. P. Krahl, K. R. Reddy, H. J. Kno-
elker, Heterocycles 2004, 63, 2393–2407; b) H. Hagiwara, T.
Choshi, J. Nobuhiro, H. Fujimoto, S. Hibino, Chem. Pharm.
Bull. 2001, 49, 881–886; c) S. C. Pelly, C. J. Parkinson, W. A. L.
van Otterlo, C. B. de Koning, J. Org. Chem. 2005, 70, 10474–
10481 and references cited therein.
[25]
[26]
[27]
S. Kumar, S. Peruncheralathan, H. Ila, H. Junjappa, Org. Lett.
2008, 10, 965–968.
P. P. Singh, A. K. Yadav, H. Ila, H. Junjappa, J. Org. Chem.
2009, 74, 5496–5501.
When 1d was heated in neat DMF at 115 °C, the former (E)/
(Z) [or (Z)/(E)] ratio of 1.37:1 changed to 1.9:1 (established by
1H NMR signals for the SMe groups). Similarly, heating of
pure (Z)-configured 1a under identical conditions caused the
formation of some amount of the (E) isomer [(E)/(Z) = 1:15].
No trace of thieno-fused heterocycles such as 3o,p were isolated
from the Pd-catalyzed cyclization.
a) A. M. Echavarren, B. Gomez-Lor, J. J. Gonzalez, O.
de Frutos, Synlett 2003, 585–597; b) B. Martin-Matute, C. Ma-
teo, D. J. Cardenas, A. M. Echavarren, Chem. Eur. J. 2001, 7,
2341–2348.
For a detailed mechanism, see: a) L.-C. Campeau, M. Parisien,
A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581–590 and
references therein; b) E. J. Hennessy, S. L. Buchwald, J. Am.
Chem. Soc. 2003, 125, 12084–12085 and references therein.
a) B. Sezen, D. Sames, J. Am. Chem. Soc. 2003, 125, 5274–
5275; b) B. Glover, K. A. Harvey, B. Liu, M. J. Sharp, M. F.
Tymoschenko, Org. Lett. 2003, 5, 301–304; c) B. S. Lane, M. A.
Brown, D. Sames, J. Am. Chem. Soc. 2005, 127, 8050–8057; d)
C. C. Hughes, D. Trauner, Angew. Chem. Int. Ed. 2002, 41,
1569–1572.
The 3-(2-furyl)acrylonitriles 1c and 1i undergo facile intramo-
lecular arylation to give furo-fused heteroarenes 2c and 2i in
good yields. However, in the case of 1o, geometrical and other
factors also appear to intervene, resulting in the different
course of reaction to give 3o instead of 2o.
[14]
[15]
Review: U. Pindur, Y.-S. Kim, F. Mehrabani, Curr. Med. Chem.
1999, 6, 29–69.
[28]
[29]
a) C. Sanchez-Martinez, C. Shih, G. Zhu, T. Li, H. B. Brooks,
B. K. R. Patel, R. M. Schultz, T. B. De Hahn, C. D. Spencer,
S. A. Watkins, C. A. Ogg, E. Considine, J. A. Dempsey, F.
Zhang, Bioorg. Med. Chem. Lett. 2003, 13, 3841–3846; b) L. J.
Wilson, C. Yang, W. V. Murray, Tetrahedron Lett. 2007, 48,
7399–7403.
M. M. Faul, T. A. Engler, K. A. Sullivan, J. L. Grutsch, M. T.
Clayton, M. J. Martinelli, J. M. Pawlak, M. Le Tourneau, D. S.
Coffey, S. W. Pedersen, S. P. Kolis, K. Furness, S. Malhotra,
R. S. Al-Awar, J. E. Ray, J. Org. Chem. 2004, 69, 2967–2975
and references cited therein.
[30]
[31]
[16]
[17]
[18]
Review: G. Bringmann, R. Walter, R. Weirich, Angew. Chem.
Int. Ed. Engl. 1990, 29, 977–991.
a) I. Moreno, I. Tellitu, E. Dominguez, R. San Martin, Eur. J.
Org. Chem. 2002, 2126–2135 and references cited therein; b) R.
Olivera, R. SanMartin, E. Dominguez, J. Org. Chem. 2000,
65, 7010–7019 and references cited therein; c) R. Olivera, R.
SanMartin, E. Dominguez, Synlett 2000, 1028–1030.
Recent papers: a) K. Hamza, R. Abu-Reziq, D. Avnir, J. Blum,
Org. Lett. 2004, 6, 925–927; b) K. Hamza, J. Blum, Tetrahedron
[32]
[19]
Eur. J. Org. Chem. 2010, 338–344
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
343

A. K. Yadav, H. Ila, H. Junjappa
FULL PAPER
[33] J. Spencer, M. Pfeffer, A. DeCian, J. Fischer, J. Org. Chem.
1995, 60, 1005–1012.
fication of Laboratory Chemicals, 3rd ed., Pergamon Press, Ox-
ford, 1988.
[34] a) B. S. Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatach-
ell, Vogel’s Textbook of Practical Organic Chemistry, 5th ed.,
ELBS edition, 1989; b) D. D. Perrin, W. L. F. Armarego, Puri-
Received: September 9, 2009
Published Online: November 18, 2009
344
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 338–344