Nucleophilic addition of hetaryllithium compounds to 3-Nitro-1- (phenylsulfonyl)indole: Synthesis of tetracyclic thieno[3,2-c]-δ- carbolines

Article abstract of DOI:10.3987/COM-09-S(S)99

3-Nitro-1-(phenylsulfonyl)indole undergoes addition of aryl- and hetaryllithium nucleophiles to produce 2-substituted-3-nitroindoles. Mild reductive-acylation provides excellent access to 3-amido-2-hetarylindoles from which new thieno[3,2-c]-δ-carbolines

Full text of DOI:10.3987/COM-09-S(S)99

HETEROCYCLES, Vol. 80, No. 2, 2010, pp. -. © The Japan Institute of Heterocyclic Chemistry
Received, 31st July, 2009, Accepted, 4th September, 2009, Published online, 10th September, 2009
DOI: 10.3987/COM-09-S(S)99
NUCLEOPHILIC ADDITION OF HETARYLLITHIUM COMPOUNDS TO
3-NITRO-1-(PHENYLSULFONYL)INDOLE: SYNTHESIS OF
TETRACYCLIC THIENO[3,2-c]-ꢀ-CARBOLINES
Philip E. Alford, Tara L. S. Kishbaugh, and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA;
ggribble@dartmouth.edu
Abstract – 3-Nitro-1-(phenylsulfonyl)indole undergoes addition of aryl- and
hetaryllithium nucleophiles to produce 2-substituted-3-nitroindoles. Mild
reductive–acylation provides excellent access to 3-amido-2-hetarylindoles from
which new thieno[3,2-c]-ꢀ-carbolines are synthesized by cyclodehydration.
The biochemical ubiquity and medicinal success of the indole motif has earned this substructure
‘privileged’ status in drug discovery and a deep history of investigation stretching well over a century.1
Typical of ꢁ-excessive heteroaromatics, the literature of indole is characterized by electrophilic
substitution.2 Reversal of this traditional reactivity offers an opposite and complementary utility; the
conception of electrophilic indole has captured the imagination of several groups.3 Early pioneers
employed a complicit leaving group at N-1 to facilitate a formal SN2’ by attack at C-3.4 The chemistry
of 1-hydroxyindole has proven to be a versatile methodology4b that continues to yield new applications,4c
though the substitution itself remains particularly specialized. Arylsulfonyl groups provide a flexible5
and accessible alternative in exchange for greatly attenuated reactivity. Although 1-(phenylsulfonyl)indole
does not engage in SNAr, if augmented with powerful withdrawing groups, the polarizable indole double
bond becomes receptive to a variety of nucleophiles.6
NO2
NO2
NO2
CO2Et
CO2Et
NaCH(CO2Et)2
THF
PhLi
THF
N
N
N
H
SO2Ph
SO2Ph
1
Scheme 1. 3-Nitro-1-(phenylsulfonyl)indole as a Michael acceptor
________________________________________________________________________________________________________________
† Dedicated to Professor Akira Suzuki in celebration of his 80th birthday

During our first survey of highly deactivated 3-nitro-1-(phenylsulfonyl)indole (1) we observed the direct
addition of diethyl malonate anion to furnish the trans-dihydroindole product.6a Due to the conventional
nucleophilicity of indole, formation of carbon-carbon bonds at C-2 often relies on ꢀ-lithiation7 and is
limited to electrophilic reagents; 2-hetarylindoles with ꢀ-excessive hetaromatics are especially
inaccessible without the use of precious metals.8 We now report our investigation of nucleophilic
addition to 3-nitro-1-(phenylsulfonyl)indole (1) using hetaryllithium compounds as a means of effecting
arylation at C-2. In contrast with our initial enolate example,6a conjugate addition of aryllithium
produces the unprotected 2-aryl-3-nitroindole (Scheme 1). Access to 2-hetaryl substituted indoles has
allowed us to synthesize the previously unknown tetracyclic hetero[3,2-c]-ꢁ-carboline ring system.
Me
N
Me
N
N
N
R
Me
S
N
N
N
N
H
H
H
2
3
4
5
Me
S
Figure 1. Cryptolepine (2), Quindoline (3), a potent phototherapeutic 4, and novel system 5
The relatively obscure ꢁ-carboline system is represented in only a handful of natural products,
predominantly the indoloquinoline alkaloids of Cryptolepis sanquinolenta.9 While the extensive
biological activity of the cryptolepine family encompasses antibacterial,10a antiplasmodial,10b
antihyperglycemic,10c antimuscarinic,10d and anti-inflammatory activity,10e synthetic benzo-ꢁ-carbolines
have primarily been investigated as antimalarial and anticancer agents.11 Isomeric and analogous
systems attract much of the same focus.12 Despite a renewed interest in novel heterocyclic ring
structures, reported new systems average fewer than 10 per year.13 The first thieno-ꢁ-carboline (4),
synthesized in 2006 as an ellipticine analogue, has found success as a photosensitizer against human
tumor cells.14 The indolo[3,2-b]thieno[2,3-d]pyridine system (5), isoelectronic with a score of
biologically active compounds, represents a novel ring system.
Synthesis of 2-aryl and 2-hetaryl-3-nitroindoles
Conjugate addition of hetaryllithium and aryllithium compounds to 3-nitro-1-(phenylsulfonyl)indole6a (1)
furnished 2-substituted-3-nitroindoles 6-13. Addition is presumed to proceed in a Michael fashion
producing a stabilized carbanion at C-3 (Scheme 2). Tandem loss of phenylsulfinate was prompt in most
cases and resulted in exclusive formation of the indole product (Table 1).
NO2
H
NO2
NO2
H
NO2
Nuc
Nuc
Nuc
N
SO2Ph
N
N
N
:Nuc
SO2Ph
H
Scheme 2. Proposed mechanism of addition/elimination

NO2
NO2
Ar
Li-Het
-78˚C to rt
N
N
H
THF
SO2Ph
Table 1. Addition of Hetaryllithiums to 3-Nitro-1-(Phenylsulfonyl)indole 1
Entry
Product
Yield
60%
Entry
Product
Yield
86%
NO2
NO2
N
S
6a
10b
N
H
S
N
H
NO2
NO2
7a
8a
64%
58%
11b
12b
67%
N
H
NO2
O
N
H
NO2
N
61%
75%
N
H
N
BOC
N
H
N
NO2
NO2
N
N
9a
79%
13c
N
H
N
H
Me
Hetaryllithium prepared by various methods: a. direct lithiation by LDA b. lithium-bromine
exchange with t-Buli c. lithium-iodine exchange with t-Buli
N-Protected pyrrolyllithium and indolyllithium nucleophiles (Table 2) produced mixtures of indole and
indoline products. Pyrrolylindole 8 was accompanied by a small amount of indoline product (9%) which
was minimized by long reaction times. Formation of indolines 14b-15b could be due in part to
stabilization of the intermediate lithium nitronate by the newly incorporated protecting group. Addition
of carboxylate protected indole gave indoline 15b as the major product.
NO2
NO2
NO2
Li
N
PG
+
N
N
N
R
N
N
R
H
-78˚C to rt
SO2Ph
PhO2S
THF
Table 2. 2-Lithio-N-protected indole and pyrroles produced both indoline and indole products
Entry
14a
Nucleophile
Indole
Indoline
Li
14a 31%
14b 27% R = SO2Ph
N
SO2Ph
Li
15b
15a trace
15b 53% R = H
N
CO2Li
a. t-BuLi. b. 1,2-Dilithio indolecarboxylate via Katritzky method15 i. t-BuL. ii. CO2 iii. t-BuLi

Synthesis of tetracyclic ꢀ-carbolines
Huang-Hsinmin and Mann demonstrated that 5-methylindolo[3,2-c]quinoline (17) could be generated
from 3-acetamido-2-phenylindole by a Bischler-Napieralski reaction, although in low yield.16 To
confirm our structure, we synthesized known acetamide 16 by extension of our earlier work.17 Classical
Bischler-Napieralski conditions18 furnished 17 in yields comparable to earlier methods.16
O
NH
NO2
N
Me
Zn, Ac2O
POCl3
CHCl3
22%
N
MeOH
83%
N
N
H
17
H
H 13
16
Scheme 3. Synthesis of 5-methylindolo[3,2-c]isoquinoline (17)
Since many hetero[c]-ꢀ-carbolines represent novel ring systems, we investigated the above sequence as a
route to these structures. Reductive-acylation of 2-hetaryl-3-nitroindoles proceeded readily at room
temperature to afford 3-acylaminoindoles 18-21; zinc metal was used to excellent effect in preference
over indium, tin, or iron. The advantage of such mild conditions is readily apparent in the case of the
labile furan and N-BOC pyrrole groups.
R
Product
R
X
Yield
O
O
O
NO2
NH
18
19
20
21
Me N-Boc 92%
R
O
R
Me
Me
Ph
O
S
S
95%
96%
94%
N
X
N
X
Zn, MeOH
H
H
Scheme 4. Mild reductive-acylation
Bischler-Napieralski reaction of 20-21 successfully produced the corresponding ꢀ-carbolines in higher
yields than the phenyl precedent. While previous work suggested difficulties with cyclodehydrations of
this type due to the unprotected indole nitrogen,16 hetaromatics 18-21 are more activated substrates.
Though our pyrrole 18 and furan 19 substrates gave complex mixtures under these conditions, thiophenes
20-21 were more tolerant and afforded good yield of tetracyclic thieno[3,2-c]-ꢀ-carbolines 22-23.
R
O
NH
N
R
Product
R
X
Yield
POCl3
CHCl3
22
23
Me
Ph
S
S
81%
88%
N
N
S
H
H
S
Scheme 5. Bischler-Napieralski reaction
In conclusion, we report a method for the hetarylation of 3-nitroindoles at C-2 by nucleophilic addition of
hetaryllithium compounds to 3-nitro-1-(phenylsulfonyl)indole. Reductive acylation of the resulting
3-nitro-2-hetarylindoles proceeds in high yields. A subsequent Bischler-Napieralski cyclodehydration

provides examples of the previously unknown thieno[3,2-c]-ꢀ-carboline ring system.
ACKNOWLEDGEMENTS
This work was supported by the Donors of the Petroleum Research Fund (PRF), administered by the
American Chemical Society, and by Wyeth.
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19. Representative procedure: A solution of thiophene (0.05 mL, 52.6 mg, 0.63 mmol) in dry THF (5
mL) at -78 ˚C was treated with a lithium diisopropylamide (2.0 M in THF, 0.35 mL, 0.70 mmol) and
stirred for 1 h. A solution of 3-nitro-1-(phenylsulfonyl)indole (0.160 g, 0.530 mmol) in dry THF (3
mL) was added dropwise and the mixture was stirred at -78 ˚C for 2 h and then allowed to warm to
RT overnight. The reaction was quenched with water, neutralized with 10% aqueous NH4Cl, and the
separated aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic extracts
were washed with water, brine, dried over MgSO4, and then concentrated by rotary evaporation.
Purification by column chromatography on silica gel (2:1 Hexanes:DCM) produced a bright yellow
solid which recrystallized from MeOH:Et2O to form yellow crystals of 6 (78 mg, 60%).
3-Nitro-2-(thien-2-yl)indole (6): bright yellow crystals; mp 246-247˚ C; 1H NMR (CDCl3) d 9.50 (s,
br, 1H), 8.40 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.39-7.46 (m,
3H), 6.72 (m, 1H); 13C NMR (CDCl3) ꢀ 145.0, 143.9, 133.4, 130.6, 125.7, 124.5, 122.4, 121.8, 118.7,

117.1, 113.8, 111.6; HRMS (ESI) m/z calcd for C12H19N2O2S (MH+) 245.0385, found 245.0383.
1
2-(Furan-2-yl)-3-nitroindole (7): bright yellow crystals; mp 230-231 ˚C (decomp); H NMR
(CDCl3) ꢀ 9.25 (s, br, 1H) 8.41-8.43 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 3.8 Hz, 1H), 7.68 (d, J = 1.6 Hz,
13
1H), 7.28-7.47 (m, 3H), 6.72-6.73 (m, 1H); C NMR (DMSO) ꢁ 147.0, 144.0, 134.7, 131.1, 125.8,
124.7, 123.7, 122.1, 120.9, 118.4, 114.0, 113.6; HRMS (ESI) m/z calcd for C12H9N2O3 (MH+)
229.0608, found 229.0613.
3-Nitro-2-(thiazol-2-yl)indole (8): yellow crystals; 223-224 °C (decomp); 1H NMR (CD3COCD3) ꢀ
12.2 (s, br, 1H), 8.31 (dd, J = 1.5, 7.0 Hz, 1H), 8.16 (d, J = 3.0 Hz, 1H), 8.04 (d, J = 3.0 Hz, 1H),
13
7.77 (dd, J = 1.5, 7.0 Hz, 1H), 7.45-7.48 (m, 2H); C NMR (CD3COCD3) ꢀ 154.5, 143.9, 134.3,
126.2, 125.1, 124.5, 121.9, 121.1, 113.3, 113.2; HRMS (ESI) m/z calcd for C11H8N3O2S (MH+)
246.0341, found 246.0337.
1
2-(1-Methylimidazol-2-yl)-3-nitroindole (9): yellow crystals; mp 258-261 ˚C (decomp); H NMR
(CDCl3) ꢀ 13.62 (s, br, 1H) 8.33 (d, J = 7.8 Hz, 1H), 7.25-7.42 (m, 4H), 7.19 (s, 1H) 3.78 (s, 3H); 13C
NMR (DMSO) ꢁ 137.9, 134.6, 131.1, 129.6, 127.2, 125.9, 125.0, 125.0, 121.3, 120.8, 113.9, 34.3;
HRMS (ESI) m/z calcd for C12H11N4O2 (MH+) 243.0882, found 243.0882.
tert-Butyl 2-(3-nitro-indol-2-yl)-pyrrole-1-carboxylate (10): bright yellow crystals, 124-128˚C
(decomp); 1H NMR (CDCl3) ꢁ 8.88 (s, br, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.52 (m, 1H), 7.30-7.48 (m,
3H), 6.53 (dd, J = 1.7, 3.4, 1H), 6.31 (t, J = 3.4, 1H), 1.64 (s, 9H); 13C NMR (CDCl3) ꢁ 148.8, 133.5,
132.9, 129.8, 129.3, 125.2, 125.1, 124.5, 121.8, 121.7, 121.3, 111.8, 111.0, 85.0, 27.7; HRMS (ESI)
m/z calcd for C17H18N3O4 (MH+) 328.1297, found 328.1296.
tert-Butyl 2-(3-nitro-indolin-2-yl)-pyrrole-1-carboxylate (10b): light yellow solid; 145-146˚C
1
(decomp); H NMR (CD3COCD3) 7.98 (d, J = 6.4 Hz, 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.68 (m, 1H),
7.54-7.61 (m, 3H), 7.46 (d, J = 7.6 Hz, 1H), 7.28 (m, 1H), 7.15 (td, J = 7.6, 1.0 Hz, 1H), 6.35 (s, 1H),
6.33 (1H, m), 6.14 (1H, t, 3.4 Hz), 1.62 (9H, s); 13C NMR (CD3COCD3) 149.4, 143.2, 138.0, 134.1,
132.6, 131.3, 129.5, 128.0, 126.8, 125.1, 124.8, 122.8, 115.4, 113.1, 110.7, 89.2, 85.1, 64.7, 27.4.
1
3-Nitro-2-(pyridin-2-yl)indole (11): yellow solid; mp 202-204 °C (decomp); H NMR (CDCl3) ꢀ
10.48 (br s, 1H), 8.68-8.71 (m, 2H), 8.39 (d, 1H, 7 Hz), 7.91 (m, 1H), 7.46 (m, 1 H), 7.39-7.43 (m,
3H); 13C (CDCl3) ꢀ 149.6, 147.2, 141.0, 137.8, 137.1, 133.2, 126.4, 126.1, 125.3, 124.9, 123.6, 122.3,
112.4; IR (film) 3455, 1477, 1361, 1216 cm-1; UV (EtOH) ꢁ max 276, 364 nm; HRMS (ESI) m/z
calcd for C13H10N3O2 (MH+) 240.0773, found 240.0784.
3-Nitro-2-(pyridin-3-yl)indole (12): mp 206-209 ˚C; 1H NMR (CDCl3) ꢀ 13.05 (s, 1H), 8.94 (d, 1H,
J = 1.7 Hz), 6.74 (dd, 1H, J = 1.7, 4.9 Hz), 8.17-8.22 (m, 2H), 7.57-7.61 (m, 2H), 7.39-7.43 (m, 2H);
13C NMR (CD3OD) ꢀ 150.0, 150.0, 145.1, 142.3, 140.6, 137.7, 130.2, 128.6, 128.1, 125.8, 125.8,
125.8, 118.0, 107.8; HRMS (ESI) m/z calcd for C13H10N3O2 (MH+) 240.0773, found 240.0781.

3-Nitro-2-phenylindole (13): yellow crystals; mp 237-238 ˚C; 1H NMR (CD3COCD3) ꢀ 11.62 (s, br,
1H), 8.27 (d, J = 7.6 Hz, 1H), 7.81 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.57 (m, 3H), 7.40 (m, 2H); 13C
(CD3COCD3) ꢀ 141.5, 1234.2, 130.5, 130.2, 120.1, 128.5, 128.0, 124.7, 124.0, 122.3, 120.8, 112.7;
HRMS (ESI) m/z calcd for C14H11N2O2 (MH+) 239.0821, found 239.0831.
1
2-(1’-(Phenylsulfonyl)indol-2’-yl)-3-nitroindole (14a): bright yellow crystals; mp 226-227 °C; H
(CD3COCD3) ꢀ 12.1 (s, br, 1H), 8.30-8.33 (m, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.67-7.71 (m, 4H), 7.62
13
(t, J = 7 Hz, 1H), 7.45-7.50 (m, 5H), 7.35 (t, J = 8 Hz, 1H) 7.28 (s, 1H); C (CD3COCD3) ꢀ 138.4,
138.3, 135.3, 130.6, 130.3, 129.8, 127.7, 127.1, 125.94, 125.92, 125.91, 125.3, 125.1, 125.0, 122.9,
122.2, 121.4, 117.5, 116.1, 113.6; IR (film) 3277, 2911, 1444, 1367, 1172, 744 cm-1; UV (EtOH) ꢁ
max 256, 364 nm; HRMS m/z calcd for C22H15N3O4S (M+) 417.0783, found 417.0785.
trans-2-(1’-(Phenylsulfonyl)indol-2’-yl)-3-nitro-1-(phenylsulfonyl)indoline (14b): clear colorless
crystals; mp 185-186 °C; 1H (CDCl3) ꢀ 8.13 (d, J = 8 Hz, 1H) 7.94-7.99 (m, 4 H), 7.88 (d, J = 8 Hz,
1H), 7.50-7.79 (m, 9H), 7.23-7.38 (m, 2H), 7.14 (t, J = 7 Hz, 1H), 7.00 (m, 1H), 6.81 (m, 1H), 5.93
13
(s, 1H); C NMR (CDCl3) ꢀ 142.5, 137.9, 137.8, 137.2, 136.6, 134.6, 134.3, 132.7, 129.7, 129.4,
129.1, 127.9, 127.1, 126.8, 125.8, 124.6, 124.4, 121.7, 115.5, 114.8, 113.0, 89.3, 64.5; HRMS (EI)
calcd for C28H21N2O4S2 (M+ -HNO2) 512.0864, found 512.0874.
trans-2-(Indol-2’-yl)-3-nitro-1-(phenylsulfonyl)indoline (15b): colorless crystals; mp 156-158 ˚C;
1H NMR (CDCl3) ꢁ 10.41 (s, br, 1H), 7.88 (m, 3H), 7.61 (m, 3H), 7.54 (d, J = 7.8 Hz, 1H), 7.43-7.5
(m, 3H), 7.24 (t, J = 7.6, 1H), 7.15 (t, J = 7.1, 1H), 7.06 (t, J = 7.1, 1H), 6.58 (s, 1H), 6.45 (s, 1H),
6.23 (s, 1H); 13C NMR (DMSO) ꢁ 142.9, 137.6, 137.3, 135.1, 134.2, 132.7, 129.5, 128.2, 128.2,
127.7, 125.2, 124.9, 122.5, 120.7, 120.0, 116.3, 111.8, 101.0, 89.3, 63.7; HRMS (ESI) calcd for
C22H18N3O4S (MH+) 420.1018, found 420.1033.
General Procedure for Reductive Acylation: A solution of 3-nitro-2-(thien-2-yl)indole (0.256 g, 1
mmol) in MeOH (5 mL) was treated with acetic anhydride (513 mg, 5 mmol), and zinc dust (0.327 g,
5 mmol). The bright yellow mixture was stirred at room temperature and monitored by TLC. The
solution become clear and nearly colorless by completion. The mixture was filtered and the solvent
was removed by rotary evaporation. The resulting oil was neutralized with sat. aqueous NaHCO3,
extracted with EtOAc (3 x 100 mL), washed with brine, dried over MgSO4, and concentrated in
vacuo. The resulting gray crude solid was purified by column chromatography (1:2 EtOAc/Hexanes)
to yield white crystals (236 mg, 92%). Recrystallization from methanol produced a mixture of
rotomers characteristic of these compounds.16
1
N-(2-Phenyl-1H-indol-3-yl)acetamide (16): colorless crystals, 190-192˚C; major isomer: H NMR
(CD3COCD3) ꢁ 10.60 (s, br, 1H), 9.29 (s, 1H), 8.16 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H),
7.51-7.93 (m, 2H), 7.42 (t, J = 8.1 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.17 (t, J = 7.1 Hz, 1H), 7.07 (t,

13
J = 7.3, 1H), 1.31 (s, 1.31); C NMR (CD3OD) ꢀ 170.3, 137.7, 134.0, 133.4, 129.2, 126.7, 125.3,
125.1, 123.4, 121.7, 118.3, 113.8, 110.0, 21.7; HRMS (ESI) m/z calcd for C16H14N2O (M+)
250.11062, found 250.10993.
tert-Butyl 2-(3-acetamido-1H-indol-2-yl)-pyrrole-1-carboxylate (18): clear colorless crystals,
128-131˚C (decomp); major isomer: 1H NMR (CD3COCD3) 10.23 (s, 1H), 8.47 (s, 1H), 7.49 (d, J =
8.1 Hz, 1H), 7.43 (m, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.01 (t, J = 7.1 Hz, 1H),
13
6.45 (m, 1H), 6.29 (t, J = 3.4 Hz, 1H), 2.06 (s, 3H), 1.31 (s, 9H); C NMR (CD3OD) 172.4, 149.3,
134.8, 125.7, 124.4, 123.9, 122.9, 121.9, 118.9, 118.2, 116.9, 111.7, 110.9, 110.6, 83.7, 26.7, 21.2;
HRMS (ESI) m/z calcd for C19H22N3O3 (MH+) 340.1661, found 340.1659.
N-(2-(Furan-2-yl)-1H-indol-3-yl)acetamide (19): colorless crystals, 183-185 ˚C; major isomer:1H
NMR (CD3OD) ꢀ 10.55 (s), 8.68 (s), 7.65 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H) 7.40 (d, J =
8.3 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.03 (t, J = 7.1 Hz, 1H), 6.77 (d, J = 3.4 Hz, 1H), 6.60 (dd, J =
1.7 Hz, 3.4 Hz, 1H), 2.23 (3H, s)13CNMR (CD3OD) ꢀ 172.3, 146.7, 142.1, 135.2, 125.5, 124.0, 122.4,
119.6, 117.9, 111.5, 111.2, 108.8, 107.0, 21.5; HRMS (EI) m/z calcd for C14H12N2O2 (M+)
240.008988, found 240.09005.
N-(2-(Thiophen-2-yl)-1H-indol-3-yl)acetamide (20): colorless crystals; 198-199˚C; major isomer:
1H NMR (DMSO-d6) ꢀ 11.46 (s, 1H), 9.38 (s, 1H), 7.58, (d, J = 4.2 Hz, 1H), 7.54 (d, J = 3.7 Hz,
1H), 7.34 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.17 (m, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.99 (d,
J = 7.3 Hz, 1H), 2.12 (s, 3H);13C NMR (CD3OD) ꢀ 173.2, 135.3, 133.3, 128.1, 127.0, 126.0, 125.5,
124.0, 122.5, 119.7, 117.6, 111.1, 109.2, 21.7 HRMS (ESI) m/z calcd for C14H13N2OS (MH+)
257.0749, found 257.0760.
N-(2-(Thiophen-2-yl)-1H-indol-3-yl)benzamide (21): colorless crystals, 195-197˚C; major isomer:
1H NMR (CD3COCD3) ꢀ 10.68 (s, 1H), 9.18 (s, 1H), 8.20 (d, J = 7.0, 2H), 7.64 (m, 1H), 7.57-7.63
(m, 3H), 7.49 (m, 2H), 7.34 (m, 1H), 7.13-7.16 (m, 2H), 7.06 (m, 1H), 13C NMR (CD3OD) ꢀ 169.8,
135.4, 134.6, 133.4, 133.4, 131.9, 128.6, 127.8, 127.0, 126.3, 125.5, 124.0, 122.5, 119.7, 117.8,
111.1, 109.5; HRMS (ESI) m/z calcd for C19H15N2OS (MH+) 319.0905, found 319.0913.
Representative Procedure for the Bischler-Naperalski reaction:
A
solution of
3-acetamido-2-(thien-2-yl)indole (50 mg, 0.20 mmol) in chloroform (3 mL) was treated with POCl3
(0.02 mL) 30 mg, 0.21 mmol) and refluxed for 1 d while being intermittently monitored by TLC.
The solvent was removed in vacuo and the resulting red residue was quenched with water then
neutralized with Na2CO3. The mixture was extracted with EtOAc (3 x 50 mL), washed with brine,
dried over MgSO4, then concentrated in vacuo. The resulting red oil was purified by column
chromatography (1:3 EtOAc/Toluene) to yield an orange-yellow solid. Recrystallization from MeOH
produced white crystals of 22 (38.5 mg, 81% yield).

5-Methyl-11H-indolo[3,2-c]isoquinoline (17): white crystals, mp 244-245˚C, 1H NMR
(CD3COCD3) 11.23 (s, br, 1H), 8.48 (d, J = 7.8 Hz, 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 7.8 Hz,
1H), 7.87 (t, J = 7.1, 1H), 7.71 (t, J = 8.1, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.30
(t, J = 8.0 Hz, 1H), 3.07 (s, 3H); 13C NMR (CD3COCD3) spots 150.5, 142.4, 137.6, 132.8, 129.7,
127.2, 126.0, 125.5, 125.4, 121.5, 119.9, 119.6, 116.7, 111.8, 110.0, 30.0; HRMS (EI) m/z calcd for
C16H12N2 (M+) 232.09938, found 232.10005.
1
4-Methyl-10H-indolo[3,2-b]thieno[2,3-d]pyridine (22): white crystals, mp 238-240 ˚C; H NMR
(CD3COCD3) ꢀ 11.99 (s, br, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 5.4
Hz, 1H), 7.58 (d, J = 4.08, 1H), 7.45 (t, J = 7.32, 1H), 7.26 (t, J = 7.32, 1H), 2.96 (s, 3H); 13C NMR
(CD3COCD3) ꢀ 153.8, 134.8, 128.6, 128.2, 126.2, 126.0, 125.1, 124.3, 124.1, 120.1, 120.1, 111.8,
110.0, 22.3; HRMS (ESI) m/z calcd for C14H11N2S (MH+) 239.0643, found 239.0649.
1
4-Phenyl-10H-indolo[3,2-b]thieno[2,3-d]pyridine (23): light orange crystals, 229-231˚C; H NMR
(CD3COCD3) ꢀ 11.95 (s, br, 1H), 8.34 (d, J =7.6, 1H), 7.98 (m, 2H), 7.83 (d, J = 5.5 Hz, 1H), 7.78
(d, J = 5.5 Hz, 1H), 7.67 (d, J = 8.4, 1H), 7.60 (t, J = 8.2, 2H), 7.51 (t, J = 8.2, 2H), 7.33 (t, J = 7.0
13
Hz, 1H); C NMR (CD3COCD3) ꢀ 148.3, 141.5, 140.3, 132.8, 131.6 129.6, 128.5, 128.1, 127.7,
126.7, 125.8, 125.1, 123.6, 120.4, 120.4, 114.3, 112.0; HRMS (ESI) m/z calcd for C19H13N2S (MH+)
301.0799, found 301.0790.