Synthesis of azapyrrolo[3,2,1-jk]carbazoles, azaindolo[3,2,1-jk]carbazoles, and carbazole-1-carbonitriles by gas-phase cyclization of aryl radicals

Article abstract of DOI:10.1055/s-0029-1218634

Flash vacuum pyrolysis of N-(2-nitroheteroaryl)indoles or-carbazoles at 875C gave aza analogues of strained pyrrolo[3,2,1-jk]carbazole (50-55%) and indolo[3,2,1-jk]carbazole (55-85%) ring systems, respectively, through generation of aryl radicals and cycl

Full text of DOI:10.1055/s-0029-1218634

PAPER
923
Synthesis of Azapyrrolo[3,2,1-jk]carbazoles, Azaindolo[3,2,1-jk]carbazoles,
and Carbazole-1-carbonitriles by Gas-Phase Cyclization of Aryl Radicals
A
zapyrrolo[3,2,
y
1-jk]carbazo
n
les and Azai
n
ndolo[3,2,1-
j
e
k
]carbazoles A. Crawford, Hamish McNab,* Andrew R. Mount, Jeanne Verhille, Stuart I. Wharton
School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK
Fax +44(131)6504743; E-mail: H.McNab@ed.ac.uk
Received 9 October 2009
However, the reactions of indole 3, carbazole 8, or 9H-py-
rido[2,3-b]indole (9; a-carboline) with chloro(nitro)py-
ridines 4 or 5 required individual optimization because of
the poor reactivity of the nucleophile and the sensitivity of
Abstract: Flash vacuum pyrolysis of N-(2-nitroheteroaryl)indoles
or -carbazoles at 875 °C gave aza analogues of strained pyrro-
lo[3,2,1-jk]carbazole (50–55%) and indolo[3,2,1-jk]carbazole (55–
85%) ring systems, respectively, through generation of aryl radicals
and cyclization. The corresponding reactions of N-(2-nitroheteroar- the halo compound; details are given in the experimental
yl)indazoles and -benzimidazoles at 850 °C, on the other hand, gave
section. In general, the most effective base was cesium
carbazole-1-carbonitrile derivatives (56–64%) by a mechanism in-
volving radical ring opening and hydrogen atom rearrangement.
carbonate, and anhydrous dimethyl sulfoxide or acetoni-
trile was the optimal solvent. Yields of products 6, 7, and
Key words: gas-phase reactions, cyclizations, heterocycles, pyro-
10–12 varied from 50 to 80% after chromatography
lysis, nitro compounds
(Scheme 1). At a late stage in the project, the use of palla-
dium-catalyzed coupling4 was studied for one case, and
this proved to be at least as efficient as the SNAr methods.
In previous papers,1,2 we have shown that flash vacuum
Reactions of benzimidazole 13 or indazole 14 with 1-
pyrolysis (FVP) of aromatic nitro compounds provides
aryl radical intermediates that, in appropriate frameworks,
cyclize efficiently to provide the strained pyrrolo[3,2,1-
jk]carbazole 1 or indolo[3,2,1-jk]carbazole 2 ring systems
(Figure 1) in just two steps from commercially available
starting materials.
fluoro-2-nitrobenzene (15) at 125 °C in N,N-dimethyl-
formamide provided the nitroaryl derivatives 16 and 17 in
yields of 81 and 57%, respectively (Scheme 1).
NO2
NO2
Cl
Cs2CO3
+
N
2
2
X
Y
3
1
3
1
NH
X
Y
3
4 X = N, Y = CH
5 X = CH, Y = N
4
12
10
10
4
6 X = N, Y = CH
7 X = CH, Y = N
N
8
N
5
11
9
6
5
7
9
7
8
6
1
2
NO2
Figure 1
NO2
Cl
Cs2CO3
N
+
X
Y
NH
Z
Because the indolo[3,2,1-jk]carbazoles 2, in particular,
show interesting properties under electrooxidation condi-
tions,2 we examined the effects on the ring synthesis of ni-
trogen atoms at various positions in the five- and six-
membered rings of the precursors. When the heteroatom
is present in a six-membered ring, the method provides
useful synthetic routes to azapyrrolo[3,2,1-jk]carbazoles
and azaindolo[3,2,1-jk]carbazoles. When a second het-
eroatom is present in the five-membered ring, ring open-
ing and rearrangement take place under the FVP
conditions to give carbazole-1-carbonitriles regiospecifi-
cally.
X
Y
4 X = N, Y = CH
5 X = CH, Y = N
Z
10 X = N, Y = Z = CH
11 X = Z = CH, Y = N
12 X = Z = N, Y = CH
8 Z = CH
9 Z = N
NO2
NO2
F
Cs2CO3
X
+
N
Y
X
NH
Y
13 X = N, Y = CH
14 X = CH, Y = N
15
16 X = N, Y = CH
17 X = CH, Y = N
Scheme 1
SNAr reactions of N-heterocyclic nucleophiles with car-
bonate bases in dipolar aprotic solvents are well known.1–3
FVP of the nitro derivatives 6, 7, and 10–12 took place
cleanly at 875 °C to provide the parent azapyrrolo[3,2,1-
jk]carbazoles 18–19 (50–55%) and azaindolo[3,2,1-
jk]carbazoles 20–22 (55–85%), all of which are new het-
SYNTHESIS 2010, No. 6, pp 0923–0928
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218634; Art ID: P14009SS
x
x
.
x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

924
L. A. Crawford et al.
PAPER
erocyclic systems (Scheme 2). Because of the reactivity
of the nitrogen oxide byproducts, some modifications to
the normal FVP trapping systems were required,1,2 and
these are described in the experimental section. Therefore,
the increased strain in the azapyrrolo[3,2,1-jk]carbazole
and azaindolo[3,2,1-jk]carbazole systems compared with
1 and 2, which is the result of the presence of short C–N
bonds in the six-membered ring(s), can clearly be accom-
modated, and the systems are stable even at 875 °C.
25
N
–C≡+N
N
H
N
H
X = N, Y = CH
NO2 FVP, 850 °C
X
N
N
Y
X
Y
NO2
FVP, 875 °C
23 X = N, Y = CH
24 X = CH, Y = N
N
16 X = N, Y = CH
17 X = CH, Y = N
N
Y
X
Y
X = CH, Y = N
X
18 X = N, Y = CH
19 X = CH, Y = N
6 X = N, Y = CH
7 X = CH, Y = N
N
FVP, 875 °C
NO2
N
N
25
H
N≡C
H
N
N
Y
Scheme 3
Z
Z
X
X
Y
20 X = N, Y = Z = CH
21 X = Z = CH, Y = N
22 X = Z = N, Y = CH
10 X = N, Y = Z = CH
11 X = Z = CH, Y = N
12 X = Z = N, Y = CH
R1
R1
R1
R1
R2
Scheme 2
FVP, 850 °C
NO2
X
N
N
N
NC
H
In contrast, FVP at 850 °C of the parent benzimidazole 16
and indazole 17 both gave carbazole-1-carbonitrile (25)
(57% and 64%, respectively) as the sole product that was
obtained in a significant yield. It is likely that the imida-
zolocarbazole (23) and the pyrazolocarbazole (24) are
formed as intermediates, but these are too strained to sur-
vive the pyrolysis temperatures needed to break the C–
NO2 bond. Radical cleavage of the five-membered ring
followed by hydrogen transfer gives the carbazole. In the
benzimidazole series, the initial formation of an isocya-
nide may be followed by thermal rearrangement to the ni-
trile (Scheme 3),5 although rearrangement at the imidoyl
radical stage is also possible.
30 R1 = Me, R2 = H, X = CH
31 R1 = H, R2 = Me, X = CH
32 R1 = R2 = Me, X = CH
33 R1 = R2 = H, X = N
X
R2
26 R1 = Me, R2 = H, X = CH
27 R1 = H, R2 = Me, X = CH
28 R1 = R2 = Me, X = CH
29 R1 = R2 = H, X = N
Scheme 4
ring systems have been made by FVP of nitro-substituted
pyridinylcarbazoles and -indoles. These results provide
further examples of the effectiveness of this strategy for
the formation of strained rings. In contrast to the thermal
stability of these systems, the five-membered rings of 23
and 24 cleaved under the conditions required for their for-
mation. Nevertheless, such reactions provide regio-
specific routes to a range of carbazole-1-carbonitrile
derivatives.
To explore the synthetic utility of this regiospecific route
to carbazole-1-carbonitriles, we briefly studied the FVP
reactions of the substituted benzimidazole precursors 26–
29 (made by the method shown in Scheme 1). The sites of
the substituents on the benzimidazole were chosen to
avoid regiochemical problems at the arylation stage; those
on the aryl ring (including the heteroatom) were chosen to
avoid similar problems due to hydrogen atom rearrange-
ments at the aryl radical stage.6 In each case, the corre-
sponding substituted carbazole-1-carbonitrile 30–33 was
obtained as the major product. Carbazole-1-carbonitriles
are relatively uncommon, and this synthetic route comple-
ments those involving stepwise functional group intercon-
versions,7 cycloaddition reactions,8 or Friedel–Crafts-
type processes.9
1H and 13C NMR spectra were recorded on a Bruker ARX250 spec-
trometer operating at 250 MHz and 63 MHz respectively. Chemical
shifts are given in ppm relative to TMS. Mass spectra were recorded
on a Kratos MS50 instrument under electron impact conditions, un-
less stated otherwise. All solvents were dried over molecular sieves.
Starting materials were purchased from Aldrich. Melting points
were recorded on a Gallenkamp apparatus and are uncorrected.
N-Arylation Reactions
Method 1: The indole (3) or carbazole (8) (6 mmol) and a chloroni-
tropyridine (0.95 g, 6 mmol) were dissolved in dry DMSO (20 mL).
Cs2CO3 (2.15 g, 6.6 mmol) was added to the soln with stirring. The
suspension was stirred for 18 h at 100 °C then cooled and diluted
with brine (50 mL). The mixture was extracted with CH2Cl2
In conclusion, the parent members of new azapyrro-
lo[3,2,1-jk]carbazole and azaindolo[3,2,1-jk]carbazole
Synthesis 2010, No. 6, 923–928 © Thieme Stuttgart · New York

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Azapyrrolo[3,2,1-jk]carbazoles and Azaindolo[3,2,1-jk]carbazoles
9-(3-Nitropyridin-2-yl)-9H-carbazole (10)
925
(4 × 100 mL) and the organic layers were combined and washed
with H2O (2 × 100 mL) then dried (MgSO4). The solvent was re-
moved under reduced pressure and the residue was pre-adsorbed
onto silica gel. The product was purified by dry flash chromatogra-
phy (hexane–EtOAc).
Prepared by Method 1 by using carbazole (8; 1.00 g, 6 mmol) and
2-chloro-3-nitropyridine (4; 0.95 g, 6 mmol); yield: 0.87–1.04 g
(50–60%); mp 143–144 °C.
Application of Method 2 also gave 10; yield: 0.649 g (75%); mp
144–145 °C. In practice, the product was easier to purify by using
Method 2 than by Method 1.
Method 2: Carbazole (8) (0.500 g, 3.0 mmol), a chloronitropyridine
4 or 5 (0.475 g, 3.0 mmol), and K2CO3 (8.270 g, 60.00 mmol) were
weighed and mixed. A soln of Pd(OAc)2 (0.027 g, 4 mol%) and rac-
BINAP (0.075 g, 4 mol%) in toluene (10 mL) was stirred for 10 min
under argon and then added to the pyridine–carbazole mixture un-
der argon. The remainder of the catalyst mix was washed into the
reaction mixture with toluene (15 mL). The mixture was refluxed
for 24 h, then cooled to r.t., diluted with CH2Cl2, and washed with
H2O (2 × 50 mL). The extracts were filtered through a pad of Celite
and then dried (MgSO4). The soln was concentrated onto silica gel
for purification by dry flash chromatography (hexane–EtOAc).
1H NMR (DMSO-d6): d = 9.06 (dd, 3J = 4.7 Hz, 4J = 1.7 Hz, 1 H),
3
4
8.82 (dd, J = 8.2 Hz, J = 1.6 Hz, 2 H), 8.27 (m, 1 H), 7.90 (dd,
3J = 8.2 Hz, 3J = 4.8 Hz, 1 H), 7.49–7.33 (m, 6 H).
13C NMR (DMSO-d6): d = 154.10 (CH), 142.48 (Cq), 141.78 (Cq),
139.09 (2 Cq), 136.24 (CH), 126.69 (2 CH), 124.52 (CH), 123.69 (2
Cq), 121.56 (2 CH), 120.83 (2 CH), 110.07 (2 CH).
MS: m/z (%) = 289 (100) [M+], 242 (89), 215 (15), 189 (5), 167
(19), 140 (6), 121 (26).
Method 3: The carbazole or indole (6.3 mmol) and a chloronitropy-
ridine 4 or 5 (1.50 g, 9.5 mmol) were dissolved in MeCN (30 mL),
and Cs2CO3 (2.50 g, 7.7 mmol) was added to the soln with stirring.
The suspension was stirred for 30 h at reflux, the MeCN was con-
centrated under reduced pressure, and the residue was redissolved
in EtOH. This soln was pre-adsorbed onto silica gel for separation
by dry flash chromatography (hexane–EtOAc).
Anal. Calcd for C17H11N3O2: C, 70.6; H, 3.8; N, 14.55. Found: C,
70.85; H, 3.9; N, 14.5.
9-(3-Nitropyridin-4-yl)-9H-carbazole (11)
Prepared by Method 3 from carbazole (8; 1.05 g, 6.29 mmol) and 4-
chloro-3-nitropyridine (5; 1.50 g, 9.46 mmol); yield: 1.45 g (80%);
mp 181–182 °C, after chromatography.
1H NMR (DMSO-d6): d = 9.50 (s, 1 H), 9.16 (d, 3J = 5.3 Hz, 1 H),
8.30 (d, 3J = 7.6 Hz, 1 H), 8.11 (d, 3J = 5.3 Hz, 1 H), 7.51–7.32 (m,
7 H).
13C NMR (DMSO-d6): d = 156.03 (CH), 147.04 (CH), 141.97 (Cq),
139.12 (2 Cq), 137.81 (Cq), 126.89 (2 CH), 124.73 (CH), 123.75 (2
Cq), 121.61 (2 CH), 121.00 (2 CH), 109.45 (2 CH).
Method 4: The appropriate benzimidazole or indazole (10 mmol),
K2CO3 (10.2 mmol), and the appropriate 1-fluoro-2-nitrobenzene
(10 mmol) were heated at 125 °C in DMF (30 mL) for 8 h. H2O (100
mL) was added to the cooled soln, which was extracted with Et2O
(3 × 100 mL). The combined organic fractions were washed with
H2O (3 × 100 mL), dried (MgSO4), and concentrated under reduced
pressure.
MS: m/z (%) = 289 (100) [M+], 242 (52), 215 (24), 140 (5), 107
(23).
1-(3-Nitropyridin-2-yl)-1H-indole (6)
Prepared by Method 1 from indole (3; 1.05 g, 9.0 mmol) and 2-chlo-
ro-3-nitropyridine (4; 1.56 g, 9.9 mmol); yield: 1.72 g (80%); mp
110–111 °C.
Anal. Calcd for C17H11N3O2: C, 70.6; H, 3.8; N, 14.55. Found: C,
71.15; H, 3.95; N, 14.4.
1H NMR (CDCl3): d = 8.64 (dd, 3J = 4.7 Hz, 4J = 1.7 Hz, 1 H), 8.23
9-(3-Nitropyridin-2-yl)-9H-pyrido[2,3-b]indole (12)
4
(dd, 3J = 8.1 Hz, J = 1.7 Hz, 1 H), 7.57 (m, 1 H), 7.40 (m, 1 H),
9H-Pyrido[2,3-b]indole (9, a-carboline; 0.328 g, 1.96 mmol) and 2-
chloro-3-nitropyridine (4; 0.464 g, 6 mmol) were dissolved in dry
DMF (10 mL). Cs2CO3 (0.763 g, 2.34 mmol) was added to the soln
with stirring. The suspension was stirred for 18 h at 125 °C before
being cooled and diluted with brine (50 mL). The suspension that
formed was extracted with CH2Cl2 (4 × 50 mL). The CH2Cl2 layers
were combined, washed with H2O (2 × 50 mL), and dried (MgSO4).
The CH2Cl2 soln was pre-adsorbed onto silica gel for separation by
dry flash chromatography (hexane–EtOAc) to give 12; yield: 0.209
g (37%); mp 167–169 °C.
7.28–7.10 (m, 4 H), 6.67 (d, 3J = 3.5 Hz, 1 H).
13C NMR (CDCl3): d = 152.31 (CH), 144.27 (Cq), 139.18 (Cq),
135.06 (Cq), 134.70 (CH), 129.81 (Cq), 126.37 (CH), 123.46 (CH),
121.93 (CH), 121.32 (CH), 121.20 (CH), 118.81 (CH), 107.09
(CH).
MS: m/z (%) = 239 (100) [M+], 181 (42), 154 (14), 89 (16), 63 (17).
HRMS: m/z [M+] calcd for C13H9N3O2: 239.0821; found: 239.0822.
1H NMR (DMSO-d6): d = 8.79 (dd, 3J = 6.4 Hz, 4J = 1.7 Hz, 1 H),
1-(3-Nitropyridin-4-yl)-1H-indole (7)
3
4
Prepared by Method 3 from indole (3; 1.05 g, 9.0 mmol), 4-chloro-
3-nitropyridine (5) (1.56 g, 9.9 mmol), and Cs2CO3 (3.51 g, 10.76
mmol); yield: 1.51 g (70%); mp 117–118 °C.
8.47 (dd, J = 8.1 Hz, J = 1.7 Hz, 1 H), 8.28–8.23 (m, 2 H), 8.01
(dq, 3J = 7.8 Hz, 4J = 1.5 Hz, 5J = 0.7 Hz, 1 H), 7.88 (dq, 3J = 8.1
4
5
Hz, J = 1.7 Hz, J = 0.8 Hz, 1 H), 7.51–7.39 (m, 2 H), 7.32 (td,
3J = 7.7 Hz, 4J = 1.1 Hz, 1 H), 7.17 (dd, 3J = 7.5 Hz, 3J = 4.5 Hz, 1
1H NMR (CDCl3): d = 9.40 (s, 1 H), 9.03 (d, 3J = 5.4 Hz, 1 H), 7.85
3
H).
(m, 1 H), 7.75 (d, J = 5.4 Hz, 1 H), 7.45-7.35 (m, 3 H), 7.28 (d,
3J = 3.5 Hz, 1 H), 6.97 (d, 3J = 3.5 Hz, 1 H).
13C NMR (DMSO-d6): d = 155.48 (Cq), 152.17 (CH), 150.35 (Cq),
145.81 (CH), 142.72 (Cq), 138.00 (Cq), 134.64 (CH), 128.53 (CH),
127.46 (CH), 122.31 (CH), 122.22 (Cq), 122.05 (CH), 120.90 (CH),
117.61 (CH), 117.43 (Cq), 112.33 (CH).
MS: m/z (%) = 290 (3) [M+], 190 (100), 168 (48), 155 (71), 128
(13), 78 (7).
13C NMR (CDCl3): d = 154.18 (CH), 147.28 (CH), 140.58 (Cq),
139.93 (Cq), 135.12 (Cq), 129.63 (Cq), 126.62 (CH), 123.72 (CH),
122.06 (CH), 121.73 (CH), 121.50 (CH), 109.47 (CH), 107.49
(CH).
MS: m/z (%) = 239 (100) [M+], 194 (97), 166 (35), 154 (35), 139
(46), 89 (49), 63 (37).
HRMS: m/z [M+] calcd for C16H10N4O2: 290.0804; found:
290.0802.
Anal. Calcd for C13H9N3O2: C, 65.3; H, 3.8; N, 17.6. Found: C,
65.75; H, 3.7; N, 17.15.
1-(2-Nitrophenyl)-1H-benzimidazole (16)
Application of Method 4 gave 16; yield; 1.94 g (81%); mp 80–81
°C (Lit.10 80–82 °C).
Synthesis 2010, No. 6, 923–928 © Thieme Stuttgart · New York

926
L. A. Crawford et al.
PAPER
1H NMR (CDCl3): d = 8.14 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz, 1 H), 8.01
(s, 1 H), 7.54–7.89 (m, 4 H), 7.10–7.38 (m, 3 H).
MS: m/z (%) = 281 (100) [M+], 239 (33), 223 (56), 219 (21), 208
(18).
13C NMR (CDCl3): d = 145.97 (Cq), 143.23 (Cq), 142.32 (CH),
134.17 (CH), 129.90 (CH), 129.62 (CH), 129.27 (Cq), 125.84 (CH),
124.09 (CH), 123.07 (CH), 120.66 (CH), 109.32 (CH) (one Cq not
apparent).
MS: m/z (%) = 239 (61) [M+], 222 (7), 192 (23), 181 (60), 140 (17),
77 (20).
HRMS: m/z [M+] calcd for C16H15N3O2: 281.11588; found:
281.11571.
1-(3-Nitropyridin-2-yl)-1H-benzimidazole (29)
Application of Method 4 on a 5.0 mmol scale gave 29; yield: 0.39 g
(33%); mp 45 °C.
1H NMR (CDCl3): d = 8.79 (dd, 3J = 4.7 Hz, 4J = 1.7 Hz, 1 H), 8.44
(dd, 3J = 8.1 Hz, 4J = 1.6 Hz, 1 H), 8.21 (s, 1 H), 7.82 (m, 1 H), 7.54
(m, 1 H), 7.33–7.19 (m, 3 H).
1-(2-Nitrophenyl)-1H-indazole (17)
Application of Method 4 gave 17; yield; 1.37 g (57%); mp 151–152
°C [Lit.11 152–153 °C].
13C NMR (CDCl3) (CH signals only): d = 152.97, 141.61, 135.06,
124.51, 123.77, 123.26, 120.98, 110.34.
1H NMR (CDCl3): d = 8.22 (s, 1 H), 7.22–8.03 (m, 8 H).
13C NMR (CDCl3): d = 142.85 (Cq), 139.45 (Cq), 136.89 (CH),
133.14 (CH), 132.72 (Cq), 128.16 (CH), 127.66 (CH), 127.15 (CH),
125.53 (CH), 124.95 (Cq), 122.02 (CH), 121.49 (CH), 109.19 (CH).
MS: m/z (%) = 240 (25) [M+], 195 (100), 194 (43), 169 (38), 118
(56).
HRMS: m/z [M+] calcd for C12H8N4O2: 240.06418; found:
240.06430.
MS: m/z (%) = 239 (100) [M+], 222 (86), 192 (54), 166 (49), 140
(37), 118 (63), 91 (50), 77 (60).
FVP Reactions of N-(2-Nitrophenyl) Heterocycles1,2
5,6-Dimethyl-1-(2-nitrophenyl)-1H-benzimidazole (26)
Application of Method 4 gave 26; yield: 2.54 g (>95%); mp 155 °C.
The nitro compound was sublimed under vacuum through a silica
furnace tube (35 × 2.5 cm). The solid product(s) were collected on
a cold-finger trap cooled with a dry-ice/acetone mixture and posi-
tioned at the exit point of the furnace. A U-tube trap, cooled with
liquid N2, was placed between the cold finger and the pump to trap
the NOx byproducts. Upon completion of the pyrolysis, N2 gas was
released through the system, which was then dismantled. The U-
tube was allowed to warm to r.t. in a fume cupboard. Pyrolysis con-
ditions are quoted as follows: substrate, quantity, furnace tempera-
ture (Tf), inlet temperature (Ti), pressure range (P), pyrolysis time
(t), and product(s). Each pyrolysate was dissolved in CH2Cl2 and
pre-adsorbed onto silica gel for purification by dry flash chromatog-
raphy.
1H NMR (CDCl3): d = 8.13 (dd, 3J = 7.9 Hz, 4J = 1.4 Hz, 1 H), 7.90
(s, 1 H), 7.81 (td, 3J = 7.6 Hz, 4J = 1.4 Hz, 1 H), 7.68 (ddd, 3J = 7,9,
7.6 Hz, 4J = 1.4 Hz, 1 H), 7.63 (s, 1 H), 7.56 (dd, 3J = 7.6 Hz, 4J =
1.4 Hz, 1 H), 6.91 (s, 1 H), 2.38 (s, 3 H), 2.32 (s, 3 H).
13C NMR (CDCl3): d = 146.20 (Cq), 142.34 (Cq), 142.00 (CH),
134.61 (CH), 133.94 (Cq), 133.27 (Cq), 132.59 (Cq), 130.14 (CH),
130.06 (CH), 126.28 (CH), 121.14 (CH), 109.96 (CH), 20.94 (CH3),
20.63 (CH3) (one Cq not apparent).
MS: m/z (%) = 267 (41) [M+], 255 (100), 254 (82), 209 (25), 73
(97), 43 (96).
HRMS: m/z [M+] calcd for C15H13N3O2: 267.10023; found:
267.10043.
Note that for small-scale reactions (< 100 mg), a standard U-tube
trap12 at the exit point of the furnace gives satisfactory results.
Pyrido[2,3-b]pyrrolo[3,2,1-hi]indole (7-Azapyrrolo[3,2,1-
jk]carbazole) (18)
The pyrolysate obtained by FVP of 1-(3-nitropyridin-2-yl)-1H-in-
dole [6, 0.500 g (2.09 mmol), Tf = 875 °C, Ti = 170 °C, P = 2.4 × 10–2
Torr, t = 40 min] was purified by dry flash chromatography (hex-
ane–EtOAc) to give 18; yield: 0.221 g (55%); mp 99–100 °C.
1H NMR (CDCl3): d = 8.42 (dd, 3J = 5.1 Hz, 4J = 1.6 Hz, 1 H), 8.29
(dd, 3J = 7.7 Hz, 4J = 1.6 Hz, 1 H), 7.93 (d, 3J = 3.5 Hz, 1 H), 7.86
(d, 3J = 7.4 Hz, 1 H), 7.83 (d, 3J = 7.4 Hz, 1 H), 7.53 (t, 3J = 7.4 Hz,
1 H), 7.24 (dd, 3J = 7.7 Hz, 3J = 5.1 Hz, 1 H), 6.91 (d, 3J = 3.5 Hz,
1 H).
13C NMR (CDCl3): d = 145.25 (Cq), 140.17 (CH), 130.66 (Cq),
124.55 (Cq), 123.83 (CH), 122.41 (Cq), 122.14 (CH), 122.01 (Cq),
121.95 (CH), 117.90 (CH), 117.69 (CH) 115.95 (CH), 110.84 (CH).
1-(4-Methyl-2-nitrophenyl)-1H-benzimidazole (27)
Application of Method 4 on a 3.3 mmol scale gave 27; yield: 0.81 g
(95%), mp 96 °C.
1H NMR (CDCl3): d = 7.90 (apparent d, 2 H), 7.80 (d, 3J = 7.8 Hz,
1 H), 7.53 (d, 3J = 7.3 Hz, 1 H), 7.36 (d, 3J = 8.0 Hz, 1 H), 7.19–
7.26 (m, 2 H), 7.05 (d, 3J = 7.8 Hz, 1 H), 2.50 (s, 3 H).
13C NMR (CDCl3): d = 146.24 (Cq), 143.06 (Cq), 141.54 (Cq),
135.23 (CH), 129.97 (CH), 127.17 (Cq), 126.58 (CH), 124.48 (CH),
123.44 (CH), 121.13 (CH), 109.90 (CH), 21.53 (CH3) (one CH
overlapping and one Cq not apparent).
MS: m/z (%) = 253 (100) [M+], 211 (31), 195 (83), 183 (25), 91
(22), 77 (96).
HRMS: m/z [M+] calcd for C14H11N3O2: 253.08458; found:
253.08481.
MS: m/z (%) = 192 (100) [M+], 164 (31), 138 (12), 96 (38), 82 (21),
69 (10).
5,6-Dimethyl-1-(4-methyl-2-nitrophenyl)-1H-benzimidazole
Anal. Calcd for C13H8N2: C, 81.25; H, 4.2; N, 14.6. Found: C, 81.0;
H, 4.25; N, 14.5.
(28)
Application of Method 4 on a 3.3 mmol scale gave 28; yield: 0.49 g
(53%); mp 182 °C.
Pyrido[4,3-b]pyrrolo[3,2,1-hi]indole (9-Azapyrrolo[3,2,1-
jk]carbazole) (19)
The pyrolysate obtained by FVP of 1-(3-nitropyridin-4-yl)-1H-in-
dole [7, 0.506 g (2.12 mmol), Tf = 875 °C, Ti = 140 °C, P = 4.0 × 10–2
Torr, t = 35 min] was purified by dry flash chromatography (hex-
ane–EtOAc) to give 19; yield: 0.203 g (50%); mp 122–123 °C.
1H NMR (CDCl3): d = 7.87 (d, 4J = 1.1 Hz 1 H), 7.81 (s, 1 H), 7.51
(m, 2 H), 7.36 (d, 3J = 8.1 Hz, 1 H), 6.81 (s, 1 H), 2.50 (s, 3 H), 2.31
(s, 3 H), 2.24 (s, 3 H).
13C NMR (CDCl3): d = 145.37 (Cq), 141.65 (CH), 140.65 (Cq),
134.61 (CH), 133.16 (Cq), 132.91 (Cq), 131.88 (Cq), 129.30 (CH),
126.85 (Cq), 125.87 (CH), 120.45 (CH), 109.44 (CH), 20.90 (CH3),
20.32 (CH3), 20.93 (CH3) (one Cq not apparent).
1H NMR (CDCl3): d = 9.25 (d, 4J = 0.9 Hz, 1 H), 8.62 (d, 3J = 5.7
Hz, 1 H), 7.91 (d, 3J = 7.4 Hz, 1 H), 7.79 (d, 3J = 7.4 Hz, 1 H), 7.67
Synthesis 2010, No. 6, 923–928 © Thieme Stuttgart · New York

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Azapyrrolo[3,2,1-jk]carbazoles and Azaindolo[3,2,1-jk]carbazoles
927
(d, 3J = 3.2 Hz, 1 H), 7.54 (t, 3J = 7.4 Hz, 1 H), 7.52 (d, 3J = 5.7 Hz,
1 H), 6.91 (d, 3J = 3.2 Hz, 1 H).
HRMS: m/z [M+] calcd for C16H9N3: 243.0797; found: 243.0797.
9H-Carbazole-1-carbonitrile (25)
13C NMR (CDCl3): d = 146.73 (CH), 144.25 (CH), 143.33 (Cq),
140.78 (Cq), 126.77 (Cq), 124.36 (CH), 122.38 (CH), 121.90 (CH),
121.50 (Cq), 118.28 (CH), 116.27 (Cq), 111.89 (CH), 106.87 (CH).
MS: m/z (%) = 192 (100) [M+], 164 (72), 138 (55), 114 (22), 96
(54), 83 (70), 63 (44), 50 (24).
Method 1: The pyrolysate obtained by FVP of 1-(2-nitrophenyl)-
1H-benzimidazole [16, 0.500 g (2.09 mmol), Tf = 850 °C, Ti = 160–
180 °C, P = 0.0034 Torr, t = 20 min] was subjected to dry flash
chromatography (silica gel, hexane–EtOAc) to give 25; yield: 0.26
g (64%); mp 189–190 °C (Lit.13 188–189 °C) (NMR data as below).
HRMS: m/z [M+] calcd for C13H8N2: 192.0688; found: 192.0690.
Method 2: The pyrolysate obtained by FVP of 1-(2-nitrophenyl)-
1H-indazole [17, 0.350 g (1.46 mmol), Tf = 850 °C, Ti = 250–270
°C, P = 0.013 Torr, t = 30 min] was subjected to dry flash chroma-
tography (silica gel, hexane–EtOAc) to give 25; yield: 0.16 g
(57%); mp 189–190 °C (Lit.13 188–189 °C).
1H NMR (CDCl3): d = 9.00 (br s, 1 H), 8.27 (dt, 3J = 7.7 Hz, 4J =
1.1 Hz, 1 H), 8.08 (ddd, 3J = 6.9 Hz, 4J = 1.7 Hz, 5J = 0.9 Hz, 1 H),
7.68 (dd, 3J = 7.7 Hz, 4J = 1.1 Hz, 1 H), 7.45–7.57 (m, 2 H), 7.29
(dd, 3J = 6.5 Hz, 4J = 1.4 Hz, 1 H), 7.25 (t, 3J = 7.7 Hz, 1 H).
Pyrido[3¢,2¢:4,5]pyrrolo[3,2,1-jk]carbazole (20)
FVP of 9-(3-nitropyridin-2-yl)-9H-carbazole [10, 0.500 g (1.73
mmol), Tf = 875 °C, Ti = 170 °C, P = 2.4 × 10–2 Torr, t = 40 min]
gave a pyrolysate that was purified by dry flash chromatography
(hexane–EtOAc) to give 20; yield: 0.356 g (85%); mp 149–150 °C.
1H NMR (CDCl3): d = 8.53 (dd, 3J = 5.1 Hz, 4J = 1.4 Hz, 1 H), 8.33
(dd, 3J = 7.8 Hz, 4J = 1.4 Hz, 1 H), 8.28 (dd, 3J = 7.7 Hz, 4J = 1.0
Hz, 1 H), 8.10 (d, 3J = 7.8 Hz, 1 H), 8.05 (d, 3J = 7.5 Hz, 1 H), 7.98
(d, 3J = 7.5 Hz, 1 H), 7.60 (m, 2 H), 7.39 (td, 3J = 7.7 Hz, 4J = 1.5
Hz, 1 H), 7.31 (dd, 3J = 7.8 Hz, 3J = 5.1 Hz, 1 H).
13C NMR (CDCl3): d = 149.92 (Cq), 145.11 (CH), 142.57 (Cq),
137.81 (Cq), 130.86 (CH), 129.95 (Cq), 127.13 (CH), 123.70 (Cq),
123.30 (CH), 122.74 (CH), 122.66 (CH) 120.21 (CH), 119.68 (CH),
118.94 (Cq), 116.91 (Cq), 115.49 (CH), 113.92 (CH).
13C NMR (CDCl3): d = 140.49 (Cq), 139.38 (Cq), 129.06 (CH),
127.18 (CH), 125.07 (CH), 124.23 (Cq), 122.42 (Cq), 120.55 (2
CH), 119.18 (CH), 117.25 (Cq), 111.20 (CH), 93.50 (Cq).
MS: m/z (%) = 192 (100) [M+], 164 (15), 138 (5), 96 (7).
3,4-Dimethyl-9H-carbazole-1-carbonitrile (30)
The pyrolysate obtained by FVP of 5,6-dimethyl-1-(2-nitrophenyl)-
1H-benzimidazole [26, (0.442 g (1.66 mmol), Tf = 850 °C, Ti = 160–
180 °C, P = 0.04 Torr, t = 40 min] was subjected to dry flash chro-
matography (silica gel, hexane–EtOAc) to give 30; yield: 0.215 g
(59%); mp 215 °C.
MS: m/z (%) = 242 (100) [M+], 214 (20), 188 (7), 167 (15), 139 (3),
121 (52), 93 (17), 81 (6).
HRMS: m/z [M+] calcd for C17H10N2: 242.0843; found: 242.0842.
1H NMR (CDCl3): d = 8.51 (br s, 1 H), 8.15 (d, 3J = 8.1 Hz, 1 H),
Pyrido[3¢,4¢:4,5]pyrrolo[3,2,1-jk]carbazole (21)
The pyrolysate obtained by FVP of 9-(3-nitropyridin-4-yl)-9H-car-
bazole [11, 0.492 g (1.70 mmol), Tf = 875 °C, Ti = 150–190 °C, P =
3.0 × 10–2 Torr, t = 60 min] was purified by dry flash chromatogra-
phy (hexane–EtOAc) to give 21; yield: 0.227 g (55%); mp 155–156
°C.
7.38–7.43 (m, 3 H), 7.30 (m, 1 H), 2.77 (m, 3 H), 2.40 (m, 3 H).
MS: m/z (%) = 220 (100) [M+], 205 (97), 194 (51), 180 (42), 73
(37).
HRMS: m/z [M+] calcd for C15H12N2: 220.09950; found:
220.09845.
1H NMR (CDCl3): d = 9.25 (s, 1 H), 8.63 (d, 3J = 5.6 Hz, 1 H), 8.02
(d, 3J = 7.8 Hz, 1 H), 7.95 (d, 3J = 7.5 Hz, 1 H), 7.93 (d, 3J = 7.5 Hz,
1 H), 7.73 (d, 3J = 7.8 Hz, 1 H), 7.63 (d, 3J = 5.6 Hz, 1 H), 7.54 (t,
3J = 7.5 Hz, 1 H), 7.50 (td, 3J = 7.8 Hz, 4J = 1.0 Hz, 1 H), 7.35 (td,
3J = 7.5 Hz, 4J = 1.0 Hz, 1 H).
13C NMR (CDCl3): d = 146.37 (CH), 144.39 (CH), 143.26 (Cq),
142.09 (Cq), 137.88 (Cq), 130.40 (Cq), 126.89 (CH), 125.81 (Cq),
123.87 (CH), 123.11 (CH), 122.78 (CH), 120.01 (CH), 119.76
(CH), 118.52 (Cq), 115.89 (Cq), 112.55 (CH), 107.22 (CH).
6-Methyl-9H-carbazole-1-carbonitrile (31)
The pyrolysate obtained by FVP of 1-(4-methyl-2-nitrophenyl)-1H-
benzimidazole [27, 26 mg (0.10 mmol), Tf = 850 °C, Ti = 150 °C,
P = 0.065 Torr, t = 15 min) gave 31; yield: 13 mg (60%); mp
185 °C.
1H NMR (CDCl3): d = 8.58 (s, 1 H), 8.16 (d, 3J = 7.5 Hz, 1 H), 8.05
(s, 1 H), 7.59 (dd, J = 7.6 Hz, J = 1.0 Hz, 1 H), 7.40–7.15 (m, 3
H), 2.47 (s, 3 H).
13C NMR (CDCl3): d (non-Cq signals only) = 129.03, 125.22,
128.68, 120.53, 119.12, 110.72, 18.55 (CH3).
3
4
MS: m/z (%) = 242 (100) [M+], 214 (14), 187 (5), 121 (17), 107 (17)
93 (11).
HRMS: m/z [M+] calcd for C17H10N2: 242.0843; found: 242.0847.
MS: m/z (%) = 206 (100) [M+], 205 (83), 177 (8), 151 (8), 103 (10).
Pyrido[2,3-b]pyrido[3¢,2¢:4,5]pyrrolo[3,2,1-hi]indole (22)
The pyrolysate obtained by FVP of 9-(3-nitropyridin-2-yl)-9H-py-
rido[2,3-b]indole [12, 0.073 g (0.25 mmol), Tf = 875 °C, Ti = 80–
120 °C, P = 4.0 × 10–2 Torr, t = 20 min] was purified by dry flash
chromatography (hexane–EtOAc) to give 22; yield: 0.37 g (60%);
mp 152–153 °C.
1H NMR (CDCl3): d = 8.62 (dd, 3J = 5.0 Hz, 4J = 1.6 Hz, 2 H), 8.35
(dd, 3J = 7.6 Hz, 4J = 1.6 Hz, 2 H), 8.02 (d, 3J = 7.5 Hz, 2 H), 7.61
(t, 3J = 7.5 Hz, 1 H), 7.80 (dd, 3J = 7.6 Hz, 3J = 5.0 Hz, 2 H).
HRMS: m/z [M+] calcd for C14H10N2: 206.08385; found:
206.08340.
3,4,6-Trimethyl-9H-carbazole-1-carbonitrile (32)
The pyrolysate obtained by FVP of 5,6-dimethyl-l-(4-methyl-2-ni-
trophenyl)-1H-benzimidazole [28, 55 mg (0.20 mmol), Tf = 850 °C,
Ti = 170–185 °C, P = 0.018 Torr, t = 15 min] gave 32; yield: 27 mg
(58%); mp 228 °C.
1H NMR (CDCl3): d = 8.42 (br s, 1 H), 7.92 (s, 1 H), 7.40–7.27 (m,
3 H), 2.78 (s, 3 H), 2.51 (s, 3 H), 2.38 (s, 3 H).
13C NMR (CDCl3): d = 150.16 (2 Cq), 146.63 (2 CH), 141.67 (Cq),
130.75 (2 CH), 123.69 (2 Cq), 123.67 (CH), 120.72 (2 CH), 117.93
(2 CH), 116.34 (2 Cq).
MS: m/z (%) = 234 (100) [M+], 233 (40), 220 (16), 219 (45), 109
(8).
MS: m/z (%) = 243 (30) [M+], 190 (72), 156 (100), 128 (26), 78
HRMS: m/z [M+] calcd for C16H14N2: 234.11515; found:
(15).
234.11490.
Synthesis 2010, No. 6, 923–928 © Thieme Stuttgart · New York

928
L. A. Crawford et al.
PAPER
9H-Pyrido[2,3-b]indole-8-carbonitrile (33)
(2) Wharton, S. I.; Henry, J. B.; McNab, H.; Mount, A. R. Chem.
Eur. J. 2009, 15, 5482.
(3) Palmer, B. D.; Smaill, J. B.; Boyd, M.; Boschelli, D. H.;
Doherty, A. M.; Hamby, J. M.; Khatana, S. S.; Kramer, J. B.;
Kraker, A. J.; Panek, R. L.; Lu, G. H.; Dahring, T. K.;
Winters, R. T.; Showalter, H. D. H.; Denny, W. A. J. Med.
Chem. 1998, 41, 5457.
(4) For a review, see: Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
(5) Rüchardt, C.; Meier, M.; Haaf, K.; Pakusch, J.; Wolber, E.
K. A.; Müller, B. Angew. Chem. Int. Ed. Engl. 1991, 30, 893.
(6) For example, see: Cadogan, J. I. G.; Hutchison, H. S.;
McNab, H. Tetrahedron 1992, 48, 7747.
The pyrolysate obtained by FVP of (3-nitropyridin-2-yl)-1H-benz-
imidazole [29, 303 mg (1.26 mmol), Tf = 850 °C, Ti = 180–200 °C,
P = 0.075 Torr, t = 40 min] gave 33; yield: 136 mg (56%).
1H NMR (DMSO-d6): d = 12.76 (br s, 1 H), 8.79 (dd, 3J = 4.7 Hz,
4J = 1.7 Hz, 1 H), 8.50–8.55 (m, 2 H), 7.90 (dd, 3J = 4.5 Hz, 4J = 1.7
Hz, 1 H), 7.40–7.27 (m, 2 H).
13C NMR (DMSO-d6):
d (CH signals only, from HSQC
spectrum) = 147.64 (CH), 131.06 (CH), 129.45 (CH), 126.60 (CH),
119.60 (CH), 116.34 (CH).
MS: m/z (%) = 193 (100) [M+], 166 (46), 164 (33), 139 (46), 138
(21), 88 (17).
HRMS: m/z [M+] calcd for C12H7N3: 193.06345; found: 193.06431.
(7) Suzuki, T.; Kinoshita, A.; Kawada, H.; Nakada, M. Synlett
2003, 570.
(8) For example, see: Guertler, C. F.; Blechert, S.; Steckhan, E.
Synlett 1994, 141.
Acknowledgment
(9) Adachi, M.; Sugasawa, T. Synth. Commun. 1990, 20, 71.
(10) Khan, M. A.; Polya, J. B. J. Chem. Soc. C 1970, 85.
(11) Tsuge, O.; Samura, H. J. Heterocycl. Chem. 1971, 8, 707.
(12) McNab, H. Aldrichimica Acta 2004, 37, 19.
(13) Kusurkar, R. S.; Pati, U. G. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1986, 25, 1038.
We are grateful to The Engineering and Physical Sciences Research
Council (UK) for research studentships for L.A.C. and S.I.W.
References
(1) Crawford, L. A.; McNab, H.; Mount, A. R.; Wharton, S. I.
J. Org. Chem. 2008, 73, 6642.
Synthesis 2010, No. 6, 923–928 © Thieme Stuttgart · New York