First Suzuki-Miyaura type cross-coupling of ortho-azidobromobenzene with arylboronic acids and its application to the synthesis of fused aromatic indole-heterocycles

Article abstract of DOI:10.1016/j.tet.2007.07.068

A short synthesis of some fused indole-heterocycles has been achieved via Pd-catalyzed cross-coupling reactions between azido-2-bromobenzene and arylboronic acids and subsequent thermally induced nitrene insertion. Additionally, 4-amino-α-carboline, a versatile intermediate toward grossularine analogs has also been prepared by Suzuki-Miyaura cross-coupling of 4-pivaloylaminopyridine-3-boronic acid with 2-bromoaniline, followed by simple functional group transformations.

Full text of DOI:10.1016/j.tet.2007.07.068

Tetrahedron 63 (2007) 10320–10329
First Suzuki–Miyaura type cross-coupling of ortho-
azidobromobenzene with arylboronic acids and its application
to the synthesis of fused aromatic indole-heterocycles
a
Marc Pudlo, Dorottya Csanyi, Fabien Moreau, Gyorgy Hajos,
b
a
b
ꢀ
€
ꢀ
Zsuzsanna Riedlb and Janos Sapia,
*
a
´
FRE CNRS 2715 ‘Isolement, Structure, Transformations et Syntheꢁse de Substances Naturelles’, Faculte de Pharmacie, IFR 53
´
´
Biomolecules, Universite de Reims-Champagne-Ardenne, 51 rue de Cognacq-Jay, F-51096 Reims, France
bChemical Research Center, Institute of Biomolecular Chemistry, Hungarian Academy of Sciences, H-1525 Budapest,
PO Box 17, Hungary
Received 23 June 2007; revised 13 July 2007; accepted 18 July 2007
Available online 26 July 2007
Abstract—A short synthesis of some fused indole-heterocycles has been achieved via Pd-catalyzed cross-coupling reactions between azido-
2-bromobenzene and arylboronic acids and subsequent thermally induced nitrene insertion. Additionally, 4-amino-a-carboline, a versatile
intermediate toward grossularine analogs has also been prepared by Suzuki–Miyaura cross-coupling of 4-pivaloylaminopyridine-3-boronic
acid with 2-bromoaniline, followed by simple functional group transformations.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Indole nucleus is a ubiquitous structural unit of many biolog-
ically active alkaloids and pharmaceutical agents. Although
the synthesis of functionalized indole derivatives has been
well-documented1 but short, functional group tolerating pro-
cedures are always required in organic-pharmaceutical
chemistry. Among the diverse synthetic methods intramo-
lecular annulation of nitrene intermediates proved to be an
efficient approach for the preparation of indole-heterocycles
of biological interest.2 The recent introduction of organome-
tallic coupling reactions aiming at the formation of aryl–aryl
carbon bonds gave a new impetus to develop new ap-
proaches.3 In this field Hajos et al. have worked out a
valuable procedure combining the Suzuki–Miyaura
cross-coupling reaction4 implying (hetero)arylhalides and
o-pivaloylaminobenzene boronic acid with thermally
induced intramolecular nitrene insertion (Fig. 1).5 This
approach allowed the synthesis of antiplasmodial alkaloids
isocryptolepine,5a isoneocryptolepine,5b and that of 11H-
indolo[3,2-c]isoquinoline,5c indazolo[2,3-b]isoquinoline,5d
4H-pyridazino[4,5-b]indol-4-one,5e and 1H-pyridazino
[4,5-b]indole5f derivatives of biological importance.
Keywords: Indole-heterocycles; Azido-2-bromobenzene; Suzuki–Miyaura
cross-coupling; Nitrene insertion.
* Corresponding author. Tel.: +33 0326918022; fax: +33 0326918029;
e-mail: janos.sapi@univ-reims.fr
Figure 1. Combined Suzuki–Miyaura cross-coupling—nitrene insertion
approach toward fused indole-heterocycles.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.068

M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
10321
2-bromoaniline 10. Acid catalyzed N-Boc deprotection of
11 led to the corresponding aniline derivative 7, along
with varying amount of tert-butyl substituted derivative
12. The formation of such type of side-product results
from an intermediate tert-butyl cation trapped by the in-
dole nucleus.8 Unfortunately, the location of the tert-butyl
group remained uncertain due to the complexity of the
NMR spectra (atropisomerism) (Scheme 1).
Figure 2. Structures of targeted heterocyclic systems.
In light of the low yield and the formation of side-products
we undertook a more exhaustive study on acid-free depro-
tection of 11. Thus, treatment of 11 in boiling toluene in
the presence of silica gel smoothly provided amine 7 in
93% yield. Shorter reaction time (30 min) and even higher
yield (97%) were achieved by microwave-assisted deprotec-
tion using silica gel as solid support.
Recently, for pharmaceutical purposes we had to
prepare some functionalized pyrrolo[3,2-a]carbazole de-
rivatives. Although the aimed bis-indole ring system
had already been described6 we searched an alternative
phosphine-free pathway based on our before mentioned
combination.
The key step diazotation of 7, following the standard proce-
dure, afforded unfortunately a complex mixture of unidenti-
fied products. Owing to the acid sensitivity of the indole ring
we attempted several modifications (buffered system, low-
temperature nitrosation, two-phase reaction, etc.) in vain.
Herein, we disclose in detail the synthesis of the pyrrolo[3,2-
a]carbazole ring system 1 completed with that of some
heterocyclic analogs of carbazoles, using for the first time
o-azido-bromobenzene (2), a direct precursor of nitrene in
the Suzuki–Miyaura cross-coupling reaction. In addition,
we propose a new path based on the classical Suzuki
arylation reaction followed by functional group transforma-
tions and nitrene insertion for the synthesis of 4-amino-a-
carboline skeleton 3 (Fig. 2).
As 7 is presumably too fragile to acid medium we turned
our attention to the direct introduction of the nitrene pre-
cursor azide group. To this end we envisaged a direct
Suzuki–Miyaura cross-coupling between 1-azido-2-bro-
mobenzene (2) and 1H-indole-5-boronic acid (9) enabling
a shorter synthetic approach. A survey of the literature
showed that Suzuki–Miyaura type couplings had never
been reported with free azide function bearing partners.
This choice seemed to be risky, even if we hoped in a rapid
coupling reaction, faster than the decomposition of nitrene
moiety.9
2. Results and discussion
2.1. Synthesis of 3,10-dihydro-pyrrolo[3,2-a]carbazole
(1)
Initially, we examined the Suzuki–Miyaura cross-coupling
reaction between 5-bromoindole (4) and 2-(2,2-dimethyl-
propionylamino)phenyl boronic acid (5).7a In a mixture
of dimethoxyethane and 10% aqueous NaHCO3 solution
using tetrakis(triphenylphosphine)palladium, [Pd(Ph3P)4]
as catalyst coupling reaction smoothly gave diaryl com-
pound 6 in 66% yield. Contrary to expectations removal
of the pivaloyl protecting group proved to be troublesome.
Neither diluted acid nor base catalyzed hydrolysis af-
forded the required 2-(1H-indol-5-yl)-phenylamine (7).
To overcome the difficulties of deprotection Pd-catalyzed
cross-coupling of 4 was performed with N-Boc protected
2-aniline boronic acid 87b under the same conditions
(57%). Higher yield (66%) was obtained when 1H-in-
dole-5-boronic acid 97c was reacted with N-Boc protected
2-Azido-bromobenzene (2)10 was quantitatively prepared
from 2-bromoaniline following the standard procedure.
In order to determine the reactivity and thermal stability of 2
a preliminary cross-coupling was carried out under the stan-
dard conditions with simple benzene boronic acid (13). As
expected, the corresponding azido-diaryl compound 14
was isolated in 68% yield by chromatography. The presence
of the azide function was evidenced by intense IR absorp-
tions (2114 and 2123 cmꢀ1) and confirmed by NMR spectro-
scopic methods. Accordingly, it was pleasure to note that
cross-coupling of 2 with 1H-indole-5-boronic acid (9)
gave the expected azido-diaryl compound 15 even in higher
yield (88%) (Table 1).
Scheme 1. (i) Pd(Ph3P)4, 10% NaHCO3aq, DME, D, 6: 66%, 11: 57% (4+8) or 66% (9+10); (ii) H2SO4aq, EtOH, D, from 6: 7:0%, from 11: 7:41%+12:6%; (iii)
SiO2,toluene, D, 7: 93%; (iv) SiO2, microwave, 7: 97%.

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M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
Table 1. Synthesis of indole-heterocycles by Suzuki–Miyaura cross-coupling of 2 with arylboronic acids and subsequent nitrene insertion
(FG)
Br
(FG)
Pd(Ph3P)4
160 °C
Ar-B(OH)2
+
Ar
Ar
10% NaHCO3
DME, 100 °C
N3
N
H
N3
2
Ar–B(OH)2
(HO)2B
No.
1
Time
Coupling products (yields)
Time
0.5 h
Heterocycles (yields)
6 h
N
H
N3
13
26 (71%)
14 (68%)
NH
(HO)2B
N3
2
5 h
7 h
N
N
H
N
H
H
9
15 (88%)
1 (65%)
HN
N
H
16 (0-5%)a
S
N3
S
S
18 (40%)
(HO)2B
17
3
6 h
2 h
N
H
S
27 (85%)
NH2
19 (3%)
O
O
O
(HO)2B
20
4
5
3.5 h
4 h
N
H
N3
28 (55%)
21 (42%)
(HO)2B
CN
3 h
4 h
N
H
N3
CN
CN
22
29 (70%)
24 (46%)
(HO)2B
N3
CHO
CHO
6
2 h
4 h
N
H
25 (53%)
CHO
23
30 (51%)
a
Estimated by 1H NMR from the mother liquor.
1
Thermal decomposition of 15 at 150 ꢁC and consequent
insertion of nitrene intermediate gave the desired 3,10-di-
hydro-pyrrolo[3,2-a]carbazole (1) in 65% yield. The
sense of nitrene insertion was evidenced by the disap-
pearance of a fine one proton doublet (d¼7.65 ppm,
J¼1.4 Hz) attributed to H-4 in 15. In the H NMR spec-
trum of the mother liquor isomer pyrrolo[3,2-b]carbazole
16 as minor product could be deduced. Interestingly,
this isomer was observed as major product when the ni-
trene formation was carried out from the corresponding

M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
10323
nitro derivative with triethylphosphite by microwave
activation.11
meats or tobacco smoke is reported to take part in the more
prevalent carcinogenic and mutagenic heterocyclic aryl-
amines.22
2.2. Extension to the preparation of other heterocyclic
analogs of carbazole
From synthetic point of view, among the natural products
few total syntheses, only two for the grossularines and one
affording cryptotackieine have been reported. In the first
total synthesis of grossularines developed by Hibino
et al.23 the imidazo-pyrido[2,3-b]indole moiety was ob-
tained by Pd-catalyzed cross-coupling between 3-haloge-
nated indoles and metallated imidazoles, followed by
thermal electrocyclisation of the intermediate isocyanate.
Aryl appendages on the C-2 carbon were introduced by
Pd-catalyzed carbonylation and subsequent treatment by
aryllithiums.
After some successful couplings we intended to study the
scope and limitations of the direct Suzuki arylation with
o-azidobromobenzene. Under classical conditions coupling
of 1-azido-2-bromobenzene (2) with 2-thiophene boronic
acid (17) afforded the corresponding diaryl azide 18 in low
yield (40%). From the reaction mixture 2-bromoaniline
(2%) and 2-thiophenylaniline (19),12 were isolated by chro-
matography. Their formation may be explained by hydroly-
sis of the corresponding iminophosphorane probably
resulting from the reaction between the triphenylphosphine
ligand and the azide function.
Two formal syntheses have passed by the same type of tetra-
cyclic key structure. A linear one by Molina et al.24 using
3-acetyl-2-aminoindole, while the convergent approach of
Achab et al.25 was based on Pd-catalyzed cross-couplings
between functionalized pyridine and aniline derivatives.
Recently, Horne and co-workers have reported a nice, three-
step biomimetic synthesis of grossularine-1 from b-oxo-
tryptamine.26
Coupling with 2-furan boronic acid (20) smoothly gave the
expected bis-aryl derivative 21 without reduced by-products,
however, the isolated yield remained modest (42%) due to
the instability of 21 during the purification. Cross-coupling
of 2 with other functionalized phenyl boronic acids 22 and
23 smoothly afforded the corresponding bis-aryl nitrile 24
and carbaldehyde 25.
Substituted or fused a-carbolines have been prepared from
various starting materials. Thus, 2-(1H)pyrazinones27 or
N,N0-diaryl-carbodiimides28 afforded a-carbolines by intra-
molecular Diels–Alder reaction, followed by aromatization.
Thermally induced cyclization–extrusion process from pyr-
idyl-benzotriazoles29 or 2-amidinylindole-3-carbaldehydes30
proved to be efficient also. Appropriately substituted indole
derivatives led to a-carbolines by intramolecular cyclization
between the C-9a and N-131 or C-2 and C-332 positions.
a-Carbolines have also been prepared by a combination of
two Pd-catalyzed reactions involving amination of iodobenz-
ene, followed by biaryl coupling reaction.33
For the thermal decomposition of azides treatment in boiling
o-dichlorobenzene was generally applied. Thus thermolysis
of azides 14, 18, and 21 followed by insertion of nitrene in-
termediate provided carbazole 26,13 4H-thieno[3,2-b]indole
(27),11 and 4H-furo[3,2-b]indole (28)14 in good or accept-
able yields. Similarly, functionalized carbazoles 29 and
3011,15 were obtained by thermolysis of the corresponding
bis-aryl derivatives 24 and 25.
2.3. Synthesis of a pyrido[2,3-b]indole ring system 3
Pyrido[2,3-b]indole (a-carboline) system is a common
structural feature of some alkaloids as the cytotoxic grossu-
larines 1 and 2,16 the neuroprotector mescengricin17, and
cryptotackieine (Fig. 3).18
On the basis of the above mentioned results such a short path
using 1-azido-2-bromobenzene (2) andN-protected4-amino-
pyridine-3-boronic acid (31) seemed to be suitable for the
preparation of pyrido[2,3-b]indole 3 skeleton and for fur-
ther structure–biological activity studies.
Bibliographic survey evidenced that great attention has been
payed to the synthesis of more complex pyrido[2,3-b]indoles
due to their antiviral,19 antitumoral20 or GABA reception
modulating activities.21 2-Amino-a-carboline found in fried
Boronic acid 31 was prepared in 70% yield by n-BuLi–
TMEDA assisted ortho-lithiation of N-pivaloyl-4-
Figure 3. Structures of some a-carboline containing natural products.

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M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
aminopyridine 32, followed by lithium–boron transme-
tallation.34 Overall yield proved to be very sensitive
to reaction conditions especially to temperature: addi-
tion of n-BuLi–TMEDA35 at ꢀ78 ꢁC followed by treat-
ment at ꢀ10 ꢁC for 2 h seemed to be optimal for
lithiation while introduction of boronic acid required
slow addition of (n-BuO)3B at ꢀ65 ꢁC and warming
up to room temperature overnight. As pyridine boronic
acids are frequently suffered from protodeboronation
3. Conclusion
In conclusion, we have accomplished the first Pd-cata-
lyzed cross-couplings between 1-azido-2-bromobenzene
(2) and diverse arylboronic acids resulting in the corre-
sponding azido-bis-aryl derivatives. Thermal ring closure
of latters allowed a short synthesis of some indole annu-
lated aromatic polycycles. This two step Suzuki–Miyaura
coupling—nitrene insertion pathway may have wide appli-
cations for the synthesis of acid, oxydation, or nitrosation
sensitive functionalized indole-heterocycles of biological
interest.
a
preliminary coupling of 32 with bromobenzene
(33a) was tried (Scheme 2). We were pleased to find
that Suzuki coupling with bromobenzene (33a)
smoothly afforded the corresponding bis-aryl derivative
34a in 69% yield. However, coupling of 32 with 1-azi-
do-2-bromobenzene (2) under the classical conditions
gave no coupling product 34b. Despite many efforts
like changing catalysts, solvents, and bases or using
microwave-assisted activation only deboronated product
was isolated. This failure is probably due to the steric
hindrance of ortho substituents (azide vs. pivaloyla-
mino) around the coupling sites.36
During the scope and limitation studies we found that direct
coupling of 1-azido-2-bromobenzene (2) with 4-pivaloyla-
minopyridine boronic acid (31) failed, probably due to ster-
ical hindrance. However, the aimed 4-amino substituted
a-carboline ring system (3), a versatile intermediate toward
grossularine analogs, was smoothly prepared by Suzuki–
Miyaura coupling of 31 with 2-bromoanaline, followed by
simple functional group transformations.
4. Experimental
4.1. General
All solvents were of reagent grade and, when necessary,
were purified and dried by standard methods. Reactions
and products were routinely monitored by thin layer chroma-
tography (TLC) on silica gel (Kieselgel 60 F254, Merck).
Column chromatography purifications were performed on
CHROMAGELÒ Silice 60 ACC 70–200 mm silica gel. Melt-
ing points were determined on a Reichert Thermovar hot-
stage apparatus and are uncorrected.
UV spectra were recorded in methanol solution on a Unicam
8700 apparatus. IR spectra were measured with a Bomen
Hartman or on a Spectrum BX/RX (Perkin-Elmer) instru-
ment. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded on a Bruker AC 300 spectrometer using TMS
as internal standard. Couplings expressed as s, sl, d, t, m cor-
respond to singlet, large-singlet, doublet, triplet, and multi-
plet, respectively. Mass spectra were recorded on a MSQ
ThermoFinnigan apparatus using electronspray (ESI) or on
a GCT Waters apparatus using electronimpact (EI) ionzation
method. Microwave activated reactions were carried out on
a Discovery CEM (300 W) apparatus.
Scheme 2. (i) n-BuLi, TMEDA, ꢀ78 ꢁC, (BuO)3B, THF, 70%; (ii) o-R–
C6H4–Br, Pd(Ph3P)4, NaHCO3, DME, D, a: 69%, b: 0%, c: 76%, d: 42%;
(iii) (a) NaNO2, HClaq, 0 ꢁC; (b) NaN3, 0 ꢁC, b: 98%; (iv) dichlorobenzene,
D.
In view of this unsuccessful coupling we tried a more con-
ventional path using 32 and 2-bromonitrobenzene (33c).
Under the classical coupling conditions o,o0-disubstituted
diaryl derivative 34c was smoothly obtained but the tri-
valent phosphorous compounds (Ph3P, (EtO)3P) mediated
Cadogan type reductive transformation37 of the nitro group
to nitrene 35 remained unsuccessful. Ultimately, we at-
tempted the classical approach to nitrene 35 via the
corresponding diazo compound. Cross-coupling between
pyridine boronic acid 32 and non-protected o-bromoaniline
(33d) led to the diaryl derivative 34d in acceptable yield
(42%). Transformation of the amine function of 34d into
azide group followed the well-documented pathway
in almost quantitative yield. Heated in boiling o-dichloro-
benzene diaryl azide 34b was transformed into 4-pivaloyl-
amino-a-carboline (36) in 68% yield via the corresponding
nitrene 35.
4.1.1. General procedure for Suzuki–Miyaura couplings
(general method A). A solution of aryl bromide in degassed
dimethoxyethane (DME) (5 mL/mmol) was stirred at room
temperature with Pd(Ph3P)4 (3–6 mol %) for 20 min then
arylboronic acid (1.2 equiv) and 10% aqueous NaHCO3 or
Na2CO3 solution (2.4 equiv) were added and the reaction
mixture was refluxed under nitrogen. After completion of
the reaction (TLC monitoring) DME was partially evapo-
rated under reduced pressure, the mixture was poured on
ice-water and extracted with dichloromethane (4ꢂ15 mL/
mmol). The combined organic layers were dried (Na2SO4),
filtered over CeliteÒ, evaporated in vacuo, and the residue
was purified by column chromatography to give the corre-
sponding diaryl compound.

M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
10325
4.1.2. General procedure of the thermolysis—nitrene in-
4.2.3. 2-(1H-Indol-5-yl)phenylamine (7).
sertion (general method B). A solution of aryl azide in o-di-
chlorobenzene (10 mL/mmol) was heated under reflux until
the disappearance of the starting material (TLC monitoring).
After evaporation of the solvent under reduced pressure the
residue was purified by column chromatography to give the
corresponding compounds.
4.2.3.1. By acid catalyzed N-Boc group deprotection.
A solution of [2-(1H-indol-5-yl)-phenyl]-carbamic acid tert-
butylester (11) (200 mg, 0.65 mmol) in a mixture of 25%
H2SO4 (10 mL) and ethanol (7 mL) was refluxed until the
disappearance of the starting material. The reaction mixture
was poured on ice-water, basified with 25% NH4OH, and
extracted with CH2Cl2 (4ꢂ10 mL). The combined organic
layers were dried (Na2SO4), evaporated to dryness, and the
residue was purified by column chromatography (eluant: di-
chloromethane) to afford the title product 7 (56 mg, 41%)
and its tert-butyl substituted derivative 12 (10 mg, 6%).
Compound 7: white-yellowish powder; mp: 120–121 ꢁC
(ether); UV (MeOH) lmax¼206, 227, 249, 284 nm; IR
4.2. Synthesis of 3,10-dihydro-pyrrolo[3,2-a]carbazole
(1)
4.2.1. 2,2-Dimethyl-N-[2-(1H-indol-5-yl)phenyl]propion-
amide (6). General method A. 5-Bromoindole (4): 0.78 g
(3.98 mmol); 2-(2,2-dimethylpropionylamino)phenyl bo-
ronic acid (5): 0.97 g (4.39 mmol); DME: 20 mL;
Pd(Ph3P)4: 0.16 g (0.138 mmol); 10% Na2CO3 solution:
4.7 mL (4.4 mmol); time: 3.5 h; purification: column chro-
matography (eluant: dichloromethane). Yield: 0.771 g
(66%); white-yellowish powder; mp: 170–173 ꢁC (ether);
(KBr) n¼3413, 2943, 1611 cmꢀ1
;
1H NMR (CDCl3)
d¼3.61 (s, 2H, NH2), 6.51 (t, J¼2.1 Hz, 1H, H-3), 6.75
(dd, J¼8.0, 0.9 Hz, 1H, H-30), 6.85 (dt, J¼8.0, 0.9 Hz, 1H,
H-50), 7.14 (dt, J¼8.0, 0.9 Hz, 1H, H-40), 7.16 (d,
J¼2.1 Hz, 1H, H-2), 7.21 (dd, J¼8.0, 0.9 Hz, 1H, H-60),
7.25 (dd, J¼8.4, 1.1 Hz, 1H, H-6), 7.35 (d, J¼8.4 Hz, 1H,
H-7), 7.70 (d, J¼1.1 Hz, 1H, H-4), 8.21 (s, 1H, indole
NH) ppm; 13C NMR (CDCl3) d¼102.6 (C-3), 111.3 (C-7),
115.4 (C-30), 118.6 (C-50), 121.0 (C-4), 123.3 (C-6), 124.8
(C-2), 127.9 (C-40), 128.1 (C-10), 129.0 (C-3a), 130.9 (C-
60), 130.9 (C-5), 134.9 (C-7a), 143.7 (C-20) ppm; MS (EI,
1
IR (KBr) n¼3418, 2947, 1663 cmꢀ1; H NMR (CDCl3)
d¼1.11 (s, 9H, (CH3)3), 1.65 (s, NHCO), 6.62 (d,
J¼2.2 Hz, 1H, H-3), 7.15 (d, J¼8.3 Hz, 1H, H-7), 7.21 (dt,
J¼7.3, 1.2 Hz, 1H, H-50), 7.31–7.42 (m, 3H, H-2, H-30, H-
40), 7.51 (dd, J¼8.3, 1.2 Hz, 1H, H-6), 7.65 (d, J¼1.2 Hz,
1H, H-4), 7.72 (s, 1H, indole NH), 8.41 (dd, J¼7.3,
1.2 Hz, 1H, H-60) ppm; 13C NMR (CDCl3) d¼27.4
((CH3)3), 39.7 (C–(CH3)3), 102.6 (C-3), 111.6 (C-7),
120.5 (C-4), 121.5 (C-30), 123.1 (C-40), 123.7 (C-6), 125.3
(C-2), 127.6 (C-60), 128.4 (C-5), 129.2 (C-3a), 130.3
(C-50), 133.2 (C-10), 135.3 (C-7a), 135.5 (C-20), 176.5
(CO) ppm.
ꢃ
m/z, %)¼208 (M+ , 100), 180 (14), 152 (8). HREIMS calcd
for C14H12N2: 208.1000, found: 208.0976. Compound 12:
amorphous solid; UV (MeOH) lmax¼211, 225, 288 nm; IR
1
(KBr) n¼3410, 3366, 3064, 2921, 1621 cmꢀ1; H NMR
(DMSO-d6) d¼1.38 and 1.47 (s, 9H, C(CH3)3), 4.82 (sl,
2H, NH2), 6.20 (sl, 1H, H-3), 6.72 (dd, J¼7.4 Hz, 1H,
H-50), 6.82 (dd, J¼7.0 Hz, 1H, H-30), 7.02–7.15 (m, 3H),
7.18 and 7.42 (d, J¼8.3 Hz, 1H, H-30), 7.47–7.52 (m, 1H),
7.50 and 7.74 (sl, 1H), 10.81 and 10.95 (sl, 1H, indole
NH) ppm; 13C NMR (CDCl3) d¼30.1 (30.7), 31.5 (31.8),
96.9, 110.7 (111.5), 115.4 (115.5), 118.6 (120.2), 120.0
(122.3), 121.5 (122.6), 126.1 (126.6), 127.7 (127.8), 128.7
(129.3), 129.6 (130.6), 130.8 (130.9), 134.9 (136.3), 143.6
(143.7), 149.7 (signals in brackets correspond to the atro-
4.2.2. [2-(1H-Indol-5-yl)-phenyl]-carbamic acid tert-
butylester (11). From 4: general method A. 5-Bromoindole
(4): 1.70 g (6.25 mmol); 2-tert-butoxycarbonylamino phe-
nyl boronic acid (8): 1.60 g (9.93 mmol); DME: 50 mL;
Pd(Ph3P)4: 0.35 g (0.30 mmol); 10% Na2CO3 solution:
25 mL (23.6 mmol); time: 3 h; purification: column chroma-
tography (eluant: dichloromethane–hexane 3:2/20:1).
Yield: 1.05 g (57%).
ꢃ
pisomer) ppm; MS (EI, m/z, %)¼264 (M+ , 100), 249 (75),
233 (7), 219 (4), 207 (8).
From 9: general method A. 1H-indole-5-boronic acid (9):
1.30 g (8.07 mmol); 2-bromo-N-tert-butoxycarbonylani-
line (10): 1.88 g (6.90 mmol); DME: 40 mL; Pd(Ph3P)4:
0.35 g (0.30 mmol); 10% Na2CO3 solution: 20 mL
(19.4 mmol); time: 4.5 h; purification: column chromato-
graphy (eluant: dichloromethane–hexane 3:2/20:1).
Yield: 1.40 g (66%).
4.2.3.2. By thermal deprotection. A suspension of [2-
(1H-indol-5-yl)-phenyl]-carbamic acid tert-butylester 11
(150 mg, 0.487 mmol) and silica gel (200 mg) in toluene
(4 mL) was refluxed under stirring until the disappearance
of the starting material (4–5 h). After filtration the silica
gel was washed with CH2Cl2–MeOH 4:1 (5ꢂ15 mL), the
combined filtrate was evaporated and the residue was puri-
fied by column chromatography (eluant: dichloromethane)
to afford 7 (94 mg, 93%), as a pale-yellowish powder.
White-yellowish powder; mp: 172–174 ꢁC (ether); IR
(KBr) n¼3340, 2966, 1703 cmꢀ1
;
1H NMR (CDCl3)
d¼1.45 (s, 9H, (CH3)3), 6.61 (d, 1H, J¼1.2 Hz, H-3),
6.71 (s, 1H, NHCO), 7.12 (td, J¼7.4, 1.1 Hz, 1H, H-50),
7.15 (dd, J¼7.4, 1.1 Hz, 1H, H-60), 7.25 (m, 2H, H-7, H-
2), 7.32 (dt, J¼7.4, 1.1 Hz, 1H, H-40), 7.50 (d, J¼8.3 Hz,
1H, H-6), 7.62 (d, J¼1.1 Hz, 1H, H-4), 8.18 (d,
J¼7.4 Hz, 1H, H-60), 8.52 (s, 1H, indole NH) ppm; 13C
NMR (CDCl3) d¼28.3 ((CH3)3), 80.3 (C–(CH3)3), 102.7
(C-3), 111.6 (C-7), 119.2 (C-4), 121.4 (C-30), 122.7 (C-
40), 123.2 (C-6), 125.2 (C-2), 127.7 (C-60), 128.3 (C-5),
129.7 (C-3a), 130.7 (C-50), 132.5 (C-10), 135.2 (C-7a),
135.6 (C-20), 153.1 (CO) ppm; MS (m/z, %)¼309 (M+1,
4.2.3.3. By microwave-assisted deprotection. N-Boc
protected product 11 (150 mg, 0.487 mmol) evaporated to
silica gel (1.0 g) was irradiated with microwave (Discovery
CEM 300 W 70% power) by 5 min portions until the disap-
pearance of the starting material. The treatment followed the
above mentioned procedure.
4.2.4. 1-Azido-2-bromobenzene (2). To a solution of 2-bro-
moaniline (2.0 g, 11.6 mmol) in water (50 mL) and concen-
trated HCl (2 mL) was added dropwise an aqueous (10 mL)
solution of sodium nitrite (0.92 g, 13.2 mmol). The reaction
ꢃ
12), 308 (M+ , 23), 253, 208 (100).

10326
M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
mixture was stirred at 0 ꢁC for 1 h and then sodium azide
(0.89 g, 13.2 mmol) dissolved in water (10 mL) was added
dropwise. Stirring was maintained at 0 ꢁC for 1 h and then
the reaction mixture was allowed to warm up to room
temperature. After extraction with dichloromethane (3ꢂ
15 mL) the organic layers were dried (Na2SO4), filtered,
and evaporated to dryness. Yield: 2.25 g (98%); brownish
oil; IR (KBr) n¼3234, 3061, 2917, 2115, 1576, 1471,
135.1 (C-3a), 138.2 (C-9a) (*interchangeable carbons) ppm;
ꢃ
MS (EI, m/z, %)¼206 (M+ , 100).
4.3. Synthesis of some heterocyclic analogs of carbazole
4.3.1. 2-(2-Azidophenyl)thiophene (18). General method
A. 1-Azido-2-bromobenzene (2): 0.514 g (2.6 mmol); thio-
phene-2-boronic acid (17): 0.400 g (3.12 mmol); DME:
30 mL; Pd(Ph3P)4: 0.240 g (0.208 mmol); 10% NaHCO3 so-
lution: 4.8 mL (5.72 mmol); time: 6 h; purification: column
chromatography (eluant: petroleum ether). Yield: 0.214 g
(40%); brownish oil; UV (MeOH) lmax¼213, 248 nm; IR
(KBr) n¼3063, 2918, 2846, 2117, 2090, 1573, 1484, 1443,
1
1438 cmꢀ1; H NMR (CDCl3) d¼6.97 (ddd, J¼7.6, 7.7,
0.9 Hz, 1H, H-4), 7.11 (dd, J¼8.0, 0.9 Hz, 1H, H-6), 7.30
(ddd, J¼7.6, 8.0, 1.0 Hz, 1H, H-5), 7.51 (d, J¼7.7, 1.0 Hz,
1H, H-3) ppm; 13C NMR (CDCl3) d¼113.8 (C-2), 119.4
(C-6), 125.9 (C-4), 128.5 (C-5), 133.8 (C-3), 138.6 (C-1)
ꢃ
ppm; MS (EI, m/z, %)¼169 (M+ ꢀ28, 77).
1295, 1241 cmꢀ1; H NMR (CDCl3) d¼7.1 (dd, J¼4.8,
1
3.7 Hz, 1H, H-4), 7.18 (td, J¼7.9, 1.1 Hz, 1H, H-50), 7.25
(dd, J¼7.9, 1.1 Hz, 1H, H-30), 7.32 (td, J¼7.9, 1.4 Hz, 1H,
H-40), 7.38 (dd, J¼4.8, 1.0 Hz, 1H, H-5), 7.45 (dd, J¼3.7,
1.0 Hz, 1H, H-3), 7.55 (dd, J¼7.9, 1.4 Hz, 1H, H-60) ppm;
13C NMR (CDCl3) d¼119.0 (C-30), 122.6 (C-50), 122.8
(C-40), 126.1 (C-1), 126.2 (C-5), 126.8 (C-3), 127.2 (C-4),
128.6 (C-6), 130.1 (C-10), 139.0 (C-2) ppm; MS (EI, m/z,
4.2.5. 2-Azidobiphenyl (14). General method A. 1-Azido-2-
bromobenzene (2): 0.500 g (2.5 mmol); benzene boronic
acid (13): 0.366 g (3.0 mmol); DME: 15 mL; Pd(Ph3P)4:
0.233 g (0.202 mmol); 10% NaHCO3 solution: 5 mL
(6.0 mmol); time: 6 h; purification: column chromatography
(eluant: petroleum ether). Yield: 0.329 g (68%); yellow crys-
tals; mp: 45 ꢁC (petroleum ether); UV (MeOH) lmax¼206,
236, 256 nm; IR (KBr) n¼3057, 3022, 2916, 2114, 2088,
ꢃ
%)¼173 (M+ ꢀ28, 67).
1
1577, 1476, 1427, 1295 cmꢀ1; H NMR (CDCl3) d¼7.21
4.3.2. 2-(2-Azidophenyl)furan (21). General method A.
1-Azido-2-bromobenzene (2): 0.486 g (2.45 mmol); furan-
2-boronic acid (20): 0.330 g (2.95 mmol); DME: 15 mL;
Pd(Ph3P)4: 0.226 g (0.196 mmol); 10% NaHCO3 solution:
4.9 mL (5.88 mmol); time: 3.5 h; purification: column chro-
matography (eluant: dichloromethane). Yield: 0.191 g
(42%); yellowish oil; UV (MeOH) lmax¼202, 250, 256,
287 nm; IR (NaCl) n¼2916, 2846, 2123, 2088, 1564,
(t, J¼6.6 Hz, 1H, H-4), 7.26 (d, J¼6.6 Hz, 1H, H-3), 7.34
(d, J¼7.6 Hz, 1H, H-6), 7.39 (dd, J¼7.6, 6.6 Hz, 1H, H-5),
7.39 (t, J¼7.7 Hz, 1H, H-40), 7.44 (d, J¼7.7 Hz, 2H, H-20),
7.44 (t, J¼7.7 Hz, 2H, H-30) ppm; 13C NMR (CDCl3)
d¼118.7 (C-3), 124.9 (C-4), 127.5 (C-40), 128.1 (C-20),
128.7 (C-5), 129.4 (C-30), 131.2 (C-6), 133.7 (C-2), 137.1
ꢃ
(C-1), 138.1(C-10) ppm; MS(EI, m/z, %)¼167(M+ ꢀ28, 56).
1480, 1436, 1375, 1296, 1212, 1146 cmꢀ1 1H NMR
;
4.2.6. 5-(2-Azidophenyl)-1H-indole (15). General method
A. 1-Azido-2-bromobenzene (2): 0.250 g (1.26 mmol);
1H-indole-5-boronic acid (9): 0.250 g (1.55 mmol); DME:
13 mL; Pd(Ph3P)4: 0.175 g (0.152 mmol); 10% Na2CO3 so-
lution: 4.0 mL (3.77 mmol); time: 5 h; purification: column
chromatography (eluant: heptane–dichloromethane 7:3).
Yield: 0.261 g (88%); viscous salmon oil; UV (MeOH)
(CDCl3) d¼6.50 (dd, J¼3.3, 1.7 Hz, 1H, H-4), 7.07 (d,
J¼3.3 Hz, 1H, H-3), 7.18 (dd, J¼7.6, 7.3 Hz, 1H, H-50),
7.21 (d, J¼8.1 Hz, 1H, H-30), 7.29 (dd, J¼8.1, 7.3 Hz, 1H,
H-40), 7.47 (d, J¼1.7 Hz, 1H, H-5), 7.84 (d, J¼7.6 Hz, 1H,
H-60) ppm; 13C NMR (CDCl3) d¼110.4 (C-5), 111.7
(C-4), 118.8 (C-30), 122.4 (C-20), 124.9 (C-50), 126.8
(C-60), 128.0 (C-4), 135.0 (C-10), 141.8 (C-5), 149.6
ꢃ
ꢃ
lmax¼205, 244 nm; IR (KBr) n¼3452, 2110, 1627 cmꢀ1
;
(C-2) ppm; MS (EI, m/z, %)¼185 (M+ , 11), 157 (M+ ꢀ28,
75); HREIMS calcd for C10H7NO3: 185.0589, found:
185.0993.
1H NMR (CDCl3) d¼6.61 (t, J¼2.6 Hz, 1H, H-3), 7.15–
7.41 (m, 7H), 7.65 (d, J¼1.1 Hz, 1H, H-4), 8.05 (s, 1H,
NH) ppm; 13C NMR (CDCl3) d¼103.0 (C-3), 110.5 (C-7),
118.6 (C-30), 121.5 (C-50), 123.7 (C-4), 124.8 (C-2), 124.9
(C-6), 127.7 (C-10), 128.0 (C-40), 130.0 (C-3a), 131.7 (C-
60), 135.0 (C-7a), 135.1 (C-5), 137.2 (C-20) ppm; MS (EI,
4.3.3. 20-Azidobiphenyl-4-carbonitrile (24). General
method A. 1-Azido-2-bromobenzene (2): 0.198 g
(1.00 mmol); 4-cyanophenyl boronic acid (22): 0.176 g
(1.21 mmol); DME: 5 mL; Pd(Ph3P)4: 0.093 g (0.08 mmol);
10% NaHCO3 solution: 2.0 mL (2.4 mmol); time: 3 h; puri-
fication: column chromatography (eluant: petroleum ether–
dichloromethane 1:1). Yield: 0.101 g (46%); yellowish
crystals; mp: 51–53 ꢁC (petroleum ether); UV (MeOH)
lmax¼207, 248, 270 nm; IR (KBr) n¼3462, 3366, 3207,
3057, 2916, 2837, 2220, 2123, 2088, 1916, 1797, 1604,
1577, 1507, 1480, 1441, 1397, 1296 cmꢀ1; 1H NMR (CDCl3)
d¼7.24 (dd, J¼7.6, 6.5 Hz, 1H, H-50), 7.28 (d, J¼7.6 Hz, 1H,
H-30), 7.32 (d, J¼7.6 Hz, 1H, H-60), 7.46 (t, J¼7.6, 6.5 Hz,
1H, H-40), 7.56 (d, J¼6.6 Hz, 2H, H-3), 7.71 (d, J¼6.6 Hz,
2H, H-2) ppm; 13C NMR (CDCl3) d¼111.1 (C-4), 118.8
(C-30), 118.8 (CN), 125.1 (C-50), 129.8 (C-40), 130.2 (C-3),
130.9 (C-60), 131.5 (C-10), 131.8 (C-2), 137.1 (C-20), 142.8
ꢃ
m/z, %)¼234 (M+ ꢀ28, 77).
4.2.7. 3,10-Dihydro-pyrrolo[3,2-a]carbazole (1). General
method B. 15: (330 mg, 1.41 mmol); o-dichlorobenzene:
15 mL; time: 7 h; purification: column chromatography (el-
uant: dichloromethane). Yield: 0.190 g (65%); white pow-
der; mp: 155–158 ꢁC; UV (MeOH) lmax¼205, 249, 279,
303, 330 nm; IR (KBr) n¼3408, 3048, 1634, 1460,1387,
1
1356, 1310, 1229 cmꢀ1; H NMR (DMSO-d6) d¼6.82 (d,
1H, J¼2.4 Hz, H-1), 7.15 (t, 1H, J¼7.3 Hz, H-7), 7.20
(d, 1H, J¼8.1 Hz, H-5), 7.23 (t, 1H, J¼8.3 Hz, H-8), 7.39
(dd, 1H, J¼2.4, 2.7 Hz, H-2), 7.54 (d, 1H, J¼8.1 Hz, H-4),
7.83 (d, 1H, J¼8.3 Hz, H-9), 8.05 (d, 1H, J¼7.3 Hz, H-6),
11.35 (sl, 1H, NH), 11.55 (sl, 1H, NH) ppm; 13C NMR
(CDCl3) d¼99.1 (C-1), 104.4 (C-4), 110.6 (C-5b), 114.6
(C-5*), 114.9 (C-6*), 115.0 (C-8*), 119.2 (C-7), 119.4 (C-
5a), 122.6 (C-9), 123.5 (C-2), 124.7 (C-10b), 132.8 (C-10a),
ꢃ
ꢃ
(C-1) ppm; MS (EI, m/z, %)¼220 (M+ , 10), 192 (M+ ꢀ28,
54); HREIMS calcd for C13H8N4: 220.0749, found:
220.0774.

M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
10327
4.3.4. 20-Azidobiphenyl-4-carbaldehyde (25). General
method A. 1-Azido-2-bromobenzene (2): 0.198 g
(1.00 mmol); 4-formylphenyl boronic acid (23): 0.180 g
(1.20 mmol); DME: 5 mL; Pd(Ph3P)4: 0.093 g (0.08 mmol);
10% NaHCO3 solution: 2.0 mL (2.4 mmol); time: 2 h; puri-
fication: column chromatography (eluant: petroleum ether–
dichloromethane 1:1). Yield: 0.118 g (53%); yellowish
J¼6.7, 2.8 Hz, 1H, H-6), 7.38 (dd, J¼6.7, 2.3 Hz, H-5),
7.47 (dd, J¼2.1 Hz, 1H, H-2), 7.59 (sl, 1H, NH), 7.72 (dd,
J¼7.6, 2.8 Hz, H-8) ppm; 13C NMR (CDCl3) d¼99.4 (C-
3), 112.2 (C-5), 114.5 (C-8a), 116.2 (C-8), 119.8 (C-7),
121.7 (C-6), 129.9 (C-8b), 138.9 (C-4a), 142.4 (C-3a),
145.8 (C-2) ppm; MS (EI, m/z, %)¼158 (M+1, 21), 157
ꢃ
(M+ , 12).
crystals; mp: <40 ꢁC (petroleum ether); UV (MeOH) lmax
¼
207, 256, 284 nm; IR (KBr) n¼3392, 3339, 2916, 2837,
4.3.8. 9H-Carbazole-2-carbonitrile (29). General method B.
20-Azidobiphenyl-4-carbonitrile (24): 0.130 g (0.59 mmol);
o-dichlorobenzene: 2.5 mL; time: 4 h; purification: column
chromatography (eluant: petroleum ether–dichloromethane
5:5/dichloromethane). Yield: 79 mg (70%); yellowish
crystals; mp: 120–122 ꢁC; UV (MeOH) lmax¼205, 222,
245, 305, 345 nm; IR (KBr) n¼3515, 3401, 3269, 3048,
2740, 2555, 2123, 2088, 1683, 1604, 1577, 1507, 1476,
1445, 1410, 1384, 1296, 1212 cmꢀ1 1H NMR (CDCl3)
;
d¼7.24 (dd, J¼7.1, 6.7 Hz, 1H, H-50), 7.28 (d, J¼6.8 Hz,
1H, H-30), 7.36 (d, J¼6.7 Hz, 1H, H-60), 7.45 (dd, J¼7.1,
6.8 Hz, 1H, H-40), 7.63 (d, J¼7.9 Hz, 2H, H-2), 7.94 (d,
J¼7.9 Hz, 2H, H-3), 10.06 (s, 1H, CHO) ppm; 13C NMR
(CDCl3) d¼118.8 (C-30), 125.1 (C-50), 129.4 (C-3), 129.6
(C-40), 130.1 (C-2), 131.0 (C-60), 132.2 (C-1), 135.2 (C-4),
137.2 (C-20), 144.3 (C-1), 191.9 (CHO) ppm; MS (EI, m/z,
1
2220, 1626, 1608, 1454, 1436, 1322, 1287, 1243 cmꢀ1; H
NMR (CDCl3) d¼7.30 (t, J¼7.7 Hz 1H, H-6), 7.46–7.55
(m, 3H, H-7, H-8, H-3), 7.75 (s, 1H, H-1), 8.09 (d,
J¼8.1 Hz, 1H, H-4), 8.12 (d, J¼7.7 Hz, 1H, H-5), 8.51 (sl,
1H, NH) ppm; 13C NMR (CDCl3) d¼107.8 (C-2), 111.1 (C-
8), 114.8 (C-1), 120.2 (CN), 120.3 (C-6), 120.9 (C-4), 121.1
(C-5), 122.0 (C-4b), 122.5 (C-3), 126.7 (C-4a), 127.8 (C-7),
138.2 (C-8a), 140.6 (C-9a) ppm; MS (EI, m/z, %)¼192
ꢃ
ꢃ
%)¼223 (M+ , 12), 195 (M+ ꢀ28, 44); HREIMS calcd for
C13H9N3O: 223.0796, found: 223.0746.
4.3.5. 9H-Carbazole (26). General method B. 2-Azido-
biphenyl (14): 130 mg (0.666 mmol); o-dichlorobenzene:
5 mL; time: 0.5 h; purification: column chromatography (el-
uant: petroleum ether–dichloromethane 8:2). Yield: 79 mg
(71%); yellow powder; mp: 240–243 ꢁC; UV (MeOH)
lmax¼210, 233, 257, 298 nm; IR (KBr) n¼3410, 3040,
2951, 2916, 2846, 1621, 1599, 1489, 1445, 1392, 1322,
ꢃ
(M+ , 19); HREIMS calcd for C13H8N2: 192.0687, found:
192.0680.
4.3.9. 9H-Carbazole-2-carbaldehyde (30). General
method B. 20-Azidobiphenyl-4-carbaldehyde (25): 0.160 g
(0.717 mmol); o-dichlorobenzene: 2.5 mL; time: 4 h; purifi-
cation: column chromatography (eluant: petroleum ether–
dichloromethane 5:5/dichloromethane). Yield: 71 mg
(51%); yellow crystals; mp: 150–152 ꢁC; UV (MeOH)
lmax¼194, 206, 251, 319, 366 nm; IR (KBr) n¼3374,
3330, 3031, 2846, 2740, 2460, 1921, 1877, 1744, 1683,
1665, 1621, 1498, 1441, 1344, 1322, 1274, 1243 cmꢀ1; 1H
NMR (CDCl3) d¼3.85 (s, 1H, NH), 7.26 (t, J¼7.9 Hz, 1H,
H-6), 7.50 (t, J¼7.9 Hz, 1H, H-7), 7.50 (d, J¼7.9 Hz, 1H,
H-8), 7.72 (d, J¼8.0 Hz, 1H, H-3), 7.97 (s, 1H, H-1), 8.12
(d, J¼7.9 Hz, 1H, H-5), 8.18 (d, J¼8.0 Hz, 1H, H-4),
10.07 (s, 1H, CHO) ppm; 13C NMR (CDCl3) d¼111.1
(C-7), 111.9 (C-1), 120.15 (C-6), 120.55 (C-4), 121.3
(C-5), 121.5 (C-3), 122.3 (C-4b), 127.8 (C-8), 128.5
(C-4a), 133.9 (C-2), 139.0 (C-9a), 141.2 (C-8a), 192.6
1
1203, 1137 cmꢀ1; H NMR (DMSO-d6) d¼4.12 (sl, 1H,
NH), 7.17 (t, J¼7.7 Hz, 2H, H-3), 7.40 (t, J¼7.7 Hz, 2H,
H-2), 7.51 (d, J¼7.7 Hz, 2H, H-1), 8.11 (d, J¼7.7 Hz, 2H,
H-4) ppm; 13C NMR (DMSO-d6) d¼111.2 (C-1), 118.9
(C-3), 120.5 (C-4), 122.8 (C-4a), 140.0 (C-8a) ppm; MS
ꢃ
(ESI, m/z, %)¼168 (M+H+ , 12); MS (EI, m/z, %)¼167
ꢃ
(M+ , 24); HREIMS calcd for C12H9N: 167.0735, found:
167.0731.
4.3.6. 4H-Thieno[3,2-b]indole (27). General method B.
2-(2-Azidophenyl)thiophene (18): 0.104 g (0.47 mmol);
o-dichlorobenzene: 5 mL; time: 2 h; purification: column
chromatography (eluant: petroleum ether–dichloromethane
8:2). Yield: 70 mg (85%); brown powder; mp: 115 ꢁC; UV
(MeOH) lmax¼192, 194, 204, 229, 244, 302, 312 nm; IR
ꢃ
1
(KBr) n¼3392, 2916, 2493, 2123, 1647, 1613 cmꢀ1; H
(CHO) ppm; MS (EI, m/z, %)¼195 (M+ , 17); HREIMS
NMR (CDCl3) d¼7.05 (d, J¼5.1 Hz, 1H, H-3), 7.15 (t, J¼
7.6 Hz, 1H, H-7), 7.25 (t, J¼7.7 Hz, 1H, H-6), 7.35 (d,
J¼5.1 Hz, 1H, H-2), 7.45 (d, J¼7.7 Hz, 1H, H-5), 7.75 (d,
J¼7.6 Hz, 1H, H-8), 8.02 (s, 1H, NH) ppm; 13C NMR
(CDCl3) d¼111.5 (C-3), 111.9 (C-5), 117.9 (C-8b), 118.8
(C-8), 119.8 (C-7), 122.0 (C-8a), 122.8 (C-6), 126.9 (C-2),
141.1 (C-4a), 142.9 (C-3a) ppm; MS (EI, m/z, %)¼173
calcd for C13H9NO: 195.0684, found: 195.0688.
4.4. Synthesis of the pyrido[2,3-b]indole ring system 3
4.4.1. 4-Pivaloylaminopyridine boronic acid (31). A
2.5 M solution of n-BuLi in hexane (17.5 mL, 43.8 mmol)
was added dropwise at ꢀ78 ꢁC to a mixture of 2,2-dimethyl-
N-(pyridin-4-yl)propionamide (32) (3.0 g, 16.8 mmol) and
TMEDA (6.6 mL, 43.8 mmol) suspended in dry THF
(70 mL). The reaction mixture was stirred at ꢀ78 ꢁC for
15 min and warmed up to ꢀ10 ꢁC and maintained at this
temperature for 2 h. After formation of the lithium derivative
a solution of tributylborate (7.7 g, 33.6 mmol) in dry THF
(20 mL) was added dropwise to the cooled (ꢀ78 ꢁC) reac-
tion mixture. After 2 h stirring at ꢀ78 ꢁC the reaction mix-
ture was allowed to warm up to room temperature during
overnight. To the mixture 4% NaOH solution (84 mL) was
carefully added and than extracted with ethylacetate
(100 mL). After separation the aqueous layer was acidified
ꢃ
(M+ , 21); HREIMS calcd for C10H7NS: 173.0299, found:
173.0292.
4.3.7. 4H-Furo[3,2-b]indole (28). General method B.
2-(2-Azidophenyl)furan (21): 0.100 g (0.54 mmol); o-
dichlorobenzene: 2 mL; time: 4 h; purification: column
chromatography (eluant: petroleum ether–dichloromethane
7:3/5:5). Yield: 46 mg (55%); brown oil; UV (MeOH)
lmax¼240, 297, 305 nm; IR (KBr) n¼3392, 3310, 3048,
2916, 1463, 1436, 1392, 1309, 1278, 1243, 1155,
1
1133 cmꢀ1; H NMR (CDCl3) d¼6.57 (d, J¼2.1 Hz, 1H,
H-3), 7.19 (ddd, J¼7.6, 6.7, 2.3 Hz, 1H, H-7), 7.20 (td,

10328
M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
to pH¼6 by careful addition of 30% HCl at 5 ꢁC. The mix-
ture was extracted with dichloromethane (10ꢂ30 mL), the
combined organic layers were dried (Na2SO4), filtered,
and evaporated to dryness under reduced pressure. The res-
idue was triturated with ether to obtain a gray-white solid 32
(2.63 g, 70%); mp: >350 ꢁC (ether); IR (KBr) n¼3450,
Pd(Ph3P)4: 0.069 g (0.06 mmol); 10% NaHCO3 solution:
1.39 mL (1.65 mmol); time: 8 h; purification: column chro-
matography (eluant: dichloromethane–heptane 8:2). Yield:
0.102 g (42%); brownish oil; UV (MeOH) lmax¼205,
242 nm; IR (KBr) n¼3401, 3330, 3198, 2966, 1692, 1591,
1
1573, 1498, 1401, 1304 cmꢀ1; H NMR (CDCl3) d¼1.11
2956, 2870, 1704, 1616, 1490 cmꢀ1
;
1H NMR (CDCl3,
and 1.32 (s, 9H, (CH3)3), 3.68 (sl, 2H, NH2), 6.87 (dd,
J¼6.6 Hz, 1H, H-30), 6.93 (dd, J¼7.25, 6.6 Hz, 1H, H-50),
7.09 (d, J¼7.25 Hz, 1H, H-60), 7.28 (t, J¼6.6 Hz, 1H, H-
40), 7.52 (d, J¼5.2 Hz, 0.8H, H-5a), 7.62 (sl, 0.4H, NHb),
7.99 (sl, 0.6H, NHa), 8.34 (d, J¼5.4 Hz, 0.4H, H-5b), 8.45
(s, 1H, H-2), 8.48 (d, J¼5.2 Hz, 0.6H, H-6a), 8.55 (d,
J¼5.4 Hz, 0.4H, H-6b) [a and b correspond to atropisomers]
ppm; 13C NMR (CDCl3) d¼27.0 and 27.4 (CH3), 40.0 (C–
C(CH3)3), 113.5 (C-50), 113.6 and 114.0 (C-5), 115.7 (C-
30), 123.6 (C-3), 130.4 (C-40), 131.3 (C-60), 143.0 (C-20),
143.8 (C-4), 150.6 and 150.5 (C-2), 150.9 (C-6), 177.3
CD3OD) d¼1.36 (s, 9H, (CH3)3), 7.40 (s, 1H, H-2), 8.17
(d, J¼6.5 Hz, 1H, H-5), 8.31 (sl, 1H, NH), 8.55 (d,
J¼6.5 Hz, 1H, H-6) ppm; 13C NMR (CDCl3, CD3OD)
d¼26.5 (CH3), 40.4 (C–C(CH3)3), 112.9 (C-5), 121.1 (C-
3), 147.5 (C-6), 156.0 (C-2), 156.8 (C-4), 175.4 (CO)
ppm; MS (ESI, m/z, %)¼223 (M+1, 65).
4.4.2. 2,2-Dimethyl-N-(3-phenylpyridin-4-yl)propion-
amide (34a). General method A. Bromobenzene (33a):
0.152 g (0.965 mmol); 4-pivaloylaminopyridine boronic
acid (31): 0.300 g (1.35 mmol); DME: 10 mL; Pd(Ph3P)4:
0.089 g (0.077 mmol); 10% NaHCO3 solution: 1.8 mL
(2.12 mmol); time: 10 h; purification: column chromato-
graphy (eluant: dichloromethane–methanol 95:5). Yield:
0.171 g (69%); brownish solid; mp: 80 ꢁC; UV (MeOH)
lmax¼208, 228, 249 nm; IR (KBr) n¼3216, 3145, 3057,
3022, 2960, 1687, 1577, 1502, 1472, 1401 cmꢀ1; 1H NMR
(CDCl3) d¼1.11 (s, 9H, (CH3)3), 7.39 (d, J¼7.3 Hz, 2H,
H-20), 7.47–7.59 (m, 3H, H-30, H-40), 7.71 (sl, NH), 8.43
(s, 1H, H-2), 8.44 (d, J¼5.8 Hz, 1H, H-5), 8.53 (d,
J¼5.8 Hz, 1H, H-6) ppm; 13C NMR (CDCl3) d¼27.1
(CH3), 40.1 (C–C(CH3)3), 113.3 (C-5), 126.2 (C-10), 128.5
(C-40), 132.1 (C-30), 134.1 (C-3), 142.1 (C-4), 150.0 (C-6),
150.2 (C-2), 176.9 (CO) ppm; MS (ESI, m/z, %)¼254
ꢃ
(CO) ppm; MS (EI, m/z, %)¼269 (M+ , 11); HREIMS calcd
for C16H19N3O: 269.1528, found: 269.1523.
4.4.5. 2,2-Dimethyl-N-[3-(2-azidophenyl)pyridin-4-yl]-
propionamide (34b). To a solution of 2,2-dimethyl-N-[3-
(2-aminophenyl)pyridin-4-yl]propionamide (34d) (0.100 g,
0.37 mmol) in 5% HCl (2.5 mL) was added dropwise at
0 ꢁC a solution of sodium nitrite (0.028 g, 0.41 mmol) in wa-
ter (0.5 mL). The reaction mixture was stirred at 0 ꢁC for 1 h
and then sodium azide (0.026 g, 0.41 mmol) dissolved in
water (0.5 mL) was added dropwise and stirring continued
for 1 h. After careful treatment with 5% sodium hydroxide
(pH¼10) the reaction mixture was extracted with dichloro-
methane (4ꢂ10 mL). The combined organic layers were
dried (Na2SO4), filtered, and evaporated to dryness. Yield:
0.116 g (98%); pink powder; mp: 110 ꢁC; UV (MeOH)
lmax¼213, 248 nm; IR (KBr) n¼3418, 2960, 2114, 1692,
ꢃ
(M+ , 25); HREIMS calcd for C16H18N2O: 254.1419, found:
254.1403.
1
4.4.3. 2,2-Dimethyl-N-[3-(2-nitrophenyl)pyridin-4-yl]-
propionamide (34c). General method A. 1-Bromo-2-
nitrobenzene (33c): 0.152 g (0.75 mmol); 4-pivaloylamino-
pyridine boronic acid (31): 0.200 g (0.91 mmol); DME:
8 mL; Pd(Ph3P)4: 0.069 g (0.06 mmol); 10% NaHCO3 solu-
tion: 1.39 mL (1.65 mmol); time: 10 h; purification: column
chromatography (eluant: dichloromethane–heptane 8:2).
Yield: 0.170 g (76%); yellowish solid; mp: 75 ꢁC; UV
(MeOH) lmax¼207, 221, 246 nm; IR (KBr) n¼3427, 3331,
1568, 1494, 1397 cmꢀ1; H NMR (CDCl3) d¼1.11 (s, 9H,
(CH3)3), 7.27–7.60 (m, 4H, H-30, H-40, H-50, H-60), 8.35 (s,
1H, H-2), 8.37 (d, J¼5.8 Hz, 1H, H-5), 8.55 (d, J¼5.8 Hz,
1H, H-6) ppm; 13C NMR (CDCl3) d¼27.1 (CH3), 40.0 (C–
C(CH3)3), 113.6 (C-5), 118.8 (C-30), 122.8 (C-20), 125.7
(C-50), 125.8 (C-10), 130.9 (C-60), 131.1 (C-40), 138.8
(C-3), 142.5 (C-4), 150.5 (C-2), 150.6 (C-6), 176.7 (CO)
ꢃ
ppm; MS (EI, m/z, %)¼295 (M+ , 11), 276 (89); HREIMS
calcd for C16H17N5O: 295.1419, found: 295.1423.
3057, 2960, 1696, 1573, 1524, 1498 cmꢀ1 1H NMR
;
(CDCl3) d¼1.06 (s, 9H, (CH3)3), 7.20 (sl, 1H, NH), 7.42 (td,
J¼7.5, 1.2 Hz, 0.5H, H-50a), 7.46 (dd, J¼7.5, 1.2 Hz, 0.5H,
H-0a), 7.49 (dd, J¼7.8, 1 Hz, 0.5H, H-30b), 7.56 (td, J¼7.5,
1.2 Hz, 0.5H, H-40a), 7.68 (td, J¼7.8, 1.1 Hz, 0.5H, H-40b),
7.72 (td, J¼7.8, 1 Hz, 0.5H, H-50b), 7.79 (dd, J¼7.5, 1.2 Hz,
0.5H, H-60a), 8.12 (dd, J¼7.8, 1.1 Hz, 0.5H, H-60b), 8.31 (s,
1H, H-2), 8.32 (d, J¼5.8 Hz, 1H, H-5), 8.59 (d, J¼5.8 Hz,
H-6) [a and b correspond to atropisomers] ppm; 13C NMR
(CDCl3) d¼26.9 (CH3), 39.8 (C–C(CH3)3), 114.0 (C-5),
122.8 (C-3), 128.2 and 128.3 (C-30), 130.4 (C-60), 131.7 and
131.9 (C-40), 132.7 and 133.4 (C-50), 142.5 (C-4), 148.7
(C-2), 150.0 (C-20), 151.1 (C-6), 176.5 (CO) ppm; MS (EI,
4.4.6. 2,2-Dimethyl-N-(9H-pyrido[2,3-b]indol-4-yl)pro-
pionamide (36). General method B. 2,2-Dimethyl-N-[3-
(2-azidophenyl) pyridin-4-yl]propionamide (34b): 0.230 g,
(0.78 mmol); o-dichlorobenzene: 5 mL; time: 5 h; purifica-
tion: column chromatography (eluant: cyclohexane–ethyl-
acetate 5:5). Yield: 0.141 g (68%); yellowish solid; mp:
190–193 ꢁC; UV (MeOH) lmax¼216, 248, 299 nm; IR
(KBr) n¼3311, 3142, 3069, 2957, 2908, 2844, 1668, 1608,
1588, 1496, 1456 cmꢀ1
;
1H NMR (CDCl3, CD3OD)
d¼1.50 (s, 9H, (CH3)3), 7.33 (dd, J¼7.9, 7.3 Hz, 1H,
H-60), 7.50 (dd, J¼8.0, 7.3 Hz, 1H, H-70), 7.58 (d, J¼8.0 Hz,
1H, H-80), 7.85 (d, J¼7.9 Hz, 1H, H-50), 8.13 (d,
J¼7.8 Hz, 1H, H-3), 8.34 (d, J¼7.8 Hz, 1H, H-2), 8.41 (sl,
1H, NH) ppm; 13C NMR (CDCl3, CD3OD d¼27.4 (CH3),
40.0 (C–C(CH3)3), 106.2 (C-3), 111.6 (C-8), 118.8 (C-4a),
118.9 (C-4b), 120.0 (C-7), 120.3 (C-5), 126.0 (C-6), 137.9
(C-4), 140.8 (C-8a), 146.2 (C-2), 152.3 (C-9a), 177.3 (CO)
ꢃ
m/z, %)¼299 (M+ , 24); HREIMS calcd for C16H17N3O3:
299.1270, found: 299.1234.
4.4.4. 2,2-Dimethyl-N-[3-(2-aminophenyl)pyridin-4-yl]-
propionamide (34d). General method A. 2-Bromonaniline
(33d): 0.129 g (0.75 mmol); 4-pivaloylaminopyridine bo-
ronic acid (31): 0.200 g (0.91 mmol); DME: 10 mL;
ꢃ
ppm; MS (m/z, %)¼268 (M+1, 25), 267 (M+ , 45); HREIMS
calcd for C16H17N3O: 267.1372, found: 267.1367.

M. Pudlo et al. / Tetrahedron 63 (2007) 10320–10329
13. Commercially available product.
10329
Acknowledgements
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