Efficient synthesis of 2-substituted 7-azaindole derivatives via palladium-catalyzed coupling and C-N cyclization using 18-crown-6

Article abstract of DOI:10.1055/s-2007-983730

A practical and straightforward preparation of various novel 2-substituted 7-azaindole derivatives from 2-amino-3-iodopyridine by a two-step procedure is described that gives the desired compounds in good overall yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983730

PAPER
2149
Efficient Synthesis of 2-Substituted 7-Azaindole Derivatives via Palladium-
Catalyzed Coupling and C–N Cyclization Using 18-Crown-6
S
ynthesis of 2-Substitu
a
ted 7-Azai
r
D
e
c
rivatives os Carlos de Mattos, Sergio Alatorre-Santamaría, Vicente Gotor-Fernández, Vicente Gotor*
Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo,
33006 Oviedo, Spain
Fax +34(98)5103448; E-mail: vgs@fq.uniovi.es
Received 26 April 2007
lyzed Sonogashira coupling followed by cyclization to
Abstract: A practical and straightforward preparation of various
give various 2-substituted 7-azaindoles in high overall
yields.
novel 2-substituted 7-azaindole derivatives from 2-amino-3-io-
dopyridine by a two-step procedure is described that gives the de-
sired compounds in good overall yields.
In our initial attempts we focused our efforts on the prep-
Key words: alkynes, 7-azaindoles, 18-crown-6, heterocycles, pal- aration of 2-phenyl-1H-pyrrolo[2,3-b]pyridine (3a). We
ladium catalysis
applied a modified procedure from that described by Hou-
lihan and co-workers using commercially available 2-
amino-3-methylpyridine (1),7 which allowed the forma-
tion of the amide 2 with benzoic anhydride in quantitative
yield (Scheme 1). Cyclization of the amide 2 gave 3a in
low yield (25%). We decided to extend this methodology
to the preparation of 2-methyl-1H-pyrrolo[2,3-b]pyridine
employing acetic anhydride, but the use of butyllithium
led to the formation of side reaction products due to the
acidity of the hydrogens a to the carbonyl group. To con-
firm this behavior, we next reacted 1 with pivaloyl anhy-
dride, intramolecular cyclization led to 2-tert-butyl-1H-
pyrrolo[2,3-b]pyridine in 60% yield. Based on these re-
sults we questioned if this strategy could be of general val-
ue for the preparation of 2-substituted 7-azaindoles
without compound structure limitations.
The indole core is present in a wide variety of biologically
active natural and unnatural compounds with important
applications in medicinal chemistry due to their capability
of binding to many receptors with excellent affinities.1
Because of their wide range of applications, the prepara-
tion and functionalization of indoles is a major area of fo-
cus for organic synthetic chemists and numerous
approaches for the synthesis of their analogues have been
described during the last few decades.2 Although the 7-
azaindole (1H-pyrrolo[2,3-b]pyridine) nucleus is present
in a few natural products, these compounds have attracted
much attention due to their interesting physicochemical
properties as they are known as efficient fluorescent chro-
mophores,3 but mainly because of their pharmacological
activity.4
O
O
O
Numerous methods have been described for the synthesis
of 7-azaindoles.5 Among them, ring-closure reactions in
which a carbon–nitrogen bond is formed constitutes a
common approach; in this manner Clemo and Swan de-
scribed the first preparation of 2-substituted 7-azaindoles,
such as 2-methyl-7-azaindole and 2-ethyl-7-azaindole,
which were obtained from the corresponding amides un-
der drastic reaction conditions.6 Later, the Madelung syn-
thesis involving an intramolecular cyclization under much
milder conditions led to 2-phenyl-1H-pyrrolo[2,3-b]pyri-
dine, however, the isolated yield was poor.7 Since that
time, many other approaches have been developed for the
preparation of a limited number of 2-substituted 7-azain-
doles,8 and many of them require N-protection of the in-
termediate pyrrole nitrogen fragment in the cyclization
reactions to reach the desired 7-azaindoles in good
yields.9
Ph
O
Ph
Et3N, CH2Cl2
r.t.
N
N
Ph
N
1
NH2
Ac2O
Et3N
CH2Cl2
r.t.
H
n-BuLi
THF
–20 °C to r.t.
2
Ph
3a
N
N
H
n-BuLi
THF
O
side-reaction products
N
N
Me
H
4
Scheme 1 Initial attempts for the synthesis of 7-azaindoles
In this manner, we decided to investigate different ap-
proaches for the preparation of 2-phenyl-1H-pyrrolo[2,3-
b]pyridine (3a) that have previously been satisfactorily
employed for the synthesis of indole homologues. The
best results achieved in the synthesis of 3a could then be
extended to the preparation of other interesting 7-azain-
doles. Thus, we initially considered the sequence based on
the palladium-catalyzed Sonogashira coupling of an
alkyne to 2-amino-3-iodopyridine (5) for later study of the
Herein, we describe a simple and efficient synthesis by an
easy two-step sequence that involves a palladium-cata-
SYNTHESIS 2007, No. 14, pp 2149–2152
x
x.
x
x
.
2
0
0
7
Advanced online publication: 18.06.2007
DOI: 10.1055/s-2007-983730; Art ID: Z10607SS
© Georg Thieme Verlag Stuttgart · New York

2150
M. C. de Mattos et al.
PAPER
R
cyclization process. Phenylacetylene (6a) was used then
as a model alkyne and the reaction with 5 in the presence
of copper(I) iodide and dichlorobis(triphenylphos-
phine)palladium with triethylamine as base in tetrahydro-
furan, gave 2-amino-3-(phenylethynyl)pyridine (7a) in
near quantitative yield (Scheme 2).
t-BuOK
18-crown-6
R
N
H
toluene, 65 °C
overnight
N
N
NH2
7a–f
3a–f
Scheme 3
R
Table 2 Synthesis of 2-Substituted 1H-Pyrrolo[2,3-b]pyridine 3a–f
by Intramolecular Cyclization of 7a–f
CuI
PdCl2(PPh3)2
I
+
R
Et3N, THF
r.t., overnight
N
NH2
7a–f
Entry
Compound
Isolated yield (%)
N
NH2
5
6a–f
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
94
84
87
82
80
81
Scheme 2
Table 1 Preparation of 7a–f from 2-Amino-3-iodopyridine (5) by
Palladium-Catalyzed Sonogashira Coupling
Entry
Compound
R
Isolated yield (%)
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
Ph
97
83
88
89
81
83
Pr
In conclusion, we have developed a versatile and efficient
route for the preparation of 2-substituted 7-azaindoles,
most of which have not previously been described in the
literature, using a simple two-step synthesis that involves
a palladium-catalyzed coupling and followed by intramo-
lecular cyclization using catalytic amounts of 18-crown-6,
to give 2-substituted 1H-pyrrolo[2,3-b]pyridines in high
overall yields.
Bu
(CH2)4Me
i-Bu
Cy
The same reaction was extended to alkyl derivatives 6b–e
and also to a cycloalkyl structure 6f, all gave the corre-
sponding pyridine derivatives 7b–f in high yields
(Table 1).
Chemical reagents were purchased from Aldrich, Fluka, Lancaster,
or Prolabo, and were used without further purification. Solvents
were distilled from a desiccant under N2. Flash chromatography
was performed using silica gel 60 (230–240 mesh). Melting points
were taken on samples in open capillary tubes and are uncorrected.
IR spectra were recorded on using NaCl plates or KBr pellets in a
Perkin-Elmer 1720-X F7. 1H, 13C NMR, DEPT, and 1H–13C hetero-
nuclear experiments were obtained using AV-300 (1H, 300.13 MHz
and 13C, 75.5 MHz) or DPX 300 (1H, 300.13 MHz and 13C, 75.5
MHz) spectrometers. ESI+ using a HP1100 chromatograph mass de-
tector, or EI with a Finigan MAT 95 spectrometer were used to
record mass spectra (MS). Microanalyses were performed on a
Perkin-Elmer model 2400 instrument.
Different approaches were then used in the intramolecular
cyclization step, for example, we performed this process
using 7a as starting material in the presence of indium
bromide as catalyst in refluxing toluene, unfortunately no
reaction was observed.10 Next, the amino group was sub-
jected to mesyl monoprotection using pyridine as base in
tetrahydrofuran at room temperature so that the cycliza-
tion of the N-mesyl derivative could be attempted, howev-
er, in the presence of tetrabutylammonium fluoride in
refluxing tetrahydrofuran, only starting material was re-
covered.11 Using potassium tert-butoxide as base and N-
methylpyrrolidine (NMP) as solvent, we did not observe
the formation 2-phenyl-1H-pyrrolo[2,3-b]pyridine (3a)
either at room temperature or at 40 °C.8c,d At this point, we
decided to use 18-crown-6, due to its ability to form a po-
tassium complex in its cavity, which is more soluble in the
reaction media than the corresponding free salt and, more-
over, its use will increase the potential of the base. We car-
ried out the process in anhydrous toluene as solvent,
observing poor reactivity at room temperature, however,
when the reaction mixture was heated to 65 °C no starting
material was detected and the final product 3a was recov-
ered in 94% yield after flash chromatography (Scheme 3).
2-Amino-3-(alk-1-ynyl)pyridines 7a–f; General Procedure
To a suspension of 2-amino-3-iodopyridine (5, 250 mg, 1.14
mmol), CuI (11.0 mg, 0.057 mmol), and PdCl2(PPh3)2 (39.9 mg,
0.057 mmol) in anhyd THF (4.6 mL) under a N2 atmosphere were
added successively Et3N (0.48 mL, 3.41 mmol) and the alkyne 6a–
f (1.48 mmol), and the mixture was stirred overnight at r.t. The mix-
ture was diluted with Et2O (5 mL) and filtered through Celite, the
solvents were evaporated under reduced pressure, and the crude res-
idue purified by flash chromatography (silica gel, hexane to 40%
EtOAc–hexane) to afford the corresponding alkynes 7a–f (Table 1).
2-Amino-3-(phenylethynyl)pyridine (7a)
Eluent gradient: hexane to 40% EtOAc–hexane; white solid; yield:
97%; mp 121–123 °C; Rf = 0.18 (20% EtOAc–hexane).
IR (KBr): 3467, 3289, 3136, 1633, 1564, 1452, 1246 cm–1.
The cyclization step was later performed with alkynes 7b–
f observing in all cases high yields of the isolated 7-azain-
doles 3b–f (Table 2).
1H NMR (300 MHz, CDCl3): d = 5.20 (br s, 2 H), 6.68 (dd, J = 7.4,
5.1 Hz, 1 H), 7.38 (t, J = 3.0 Hz, 3 H), 7.52–7.55 (m, 2 H), 7.62–
7.65 (m, 1 H), 8.04 (d, J = 4.0 Hz, 1 H).
Synthesis 2007, No. 14, 2149–2152 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted 7-Azaindole Derivatives
2151
13C NMR (75 MHz, CDCl3): d = 77.1, 95.7, 103.5, 113.5, 122.4,
128.4 (2 C), 128.7, 131.5 (2 C), 140.2, 147.1, 158.4.
13C NMR (75 MHz, CDCl3): d = 21.9 (2 C), 28.0, 28.6, 76.6, 95.6,
104.0, 113.2, 139.6, 146.8, 158.9.
MS (ESI+, 60 eV): m/z (%) = 195 [(M + H)+, 100], 196 [(M + 2 H)2+,
MS (ESI+, 60 eV): m/z (%) = 175 [(M + H)+, 100], 176 [(M + 2 H)2+,
17].
20], 217 [(M + Na)+, 18].
Anal. Calcd for C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found: C,
80.39; H, 5.19; N, 14.42.
Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C,
75.82; H, 8.10; N, 16.08.
2-Amino-3-(pent-1-ynyl)pyridine (7b)
Eluent gradient: hexane to 40% EtOAc–hexane; colorless oil; yield:
2-Amino-3-(cyclohexylethynyl)pyridine (7f)
Eluent gradient: hexane to 40% EtOAc–hexane; white solid; yield:
83%; Rf = 0.28 (40% EtOAc–hexane).
83%; mp 75–77 °C; Rf = 0.24 (40% EtOAc–hexane).
IR (NaCl): 3472, 3297, 3164, 2962, 1604, 1571, 1453, 1222 cm–1.
IR (KBr): 3468, 3290, 3143, 2928, 2851, 1626, 1569, 1453, 1222
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.35–1.48 (m, 3 H), 1.51–1.58 (m,
3 H), 1.72–1.76 (m, 2 H), 1.86–1.90 (m, 2 H), 2.59–2.64 (m, 1 H),
5.10 (br s, 2 H), 6.56 (dd, J = 7.5, 5.0 Hz, 1 H), 7.46 (dd, J = 7.4, 1.7
Hz, 1 H), 7.94 (dd, J = 5.0, 1.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 24.7, 25.7 (2 C), 29.7, 32.6 (2 C),
75.6, 100.9, 104.0, 113.2, 139.5, 146.8, 158.8.
MS (ESI+, 60 eV): m/z (%) = 200 [M+, 100], 201 [(M + H)+, 19].
1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7.3 Hz, 3 H), 1.57–
1.69 (m, 2 H), 2.42 (t, J = 7.0 Hz, 2 H), 5.10 (br s, 2 H), 6.56 (dd,
J = 7.4, 5.0 Hz, 1 H), 7.45 (d, J = 7.4 Hz, 1 H), 7.96 (d, J = 4.6 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 13.5, 21.4, 22.1, 75.8, 96.5, 103.9,
113.2, 139.6, 146.9, 158.9.
MS (ESI+, 60 eV): m/z (%) = 161 [(M + H)+, 100], 162 [(M + 2 H)2+,
16], 183 [(M + Na)+, 11].
Anal. Calcd for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C,
74.99; H, 7.56; N, 17.45.
Anal. Calcd for C13H16N2: C, 77.96; H, 8.05; N, 13.99. Found: C,
77.98; H, 8.02; N, 14.00.
2-Amino-3-(hex-1-ynyl)pyridine (7c)
Eluent gradient: hexane to 40% EtOAc–hexane; colorless oil; yield:
2-Substituted 1H-Pyrrolo[2,3-b]pyridines 3a–f; General Proce-
dure
88%; Rf = 0.28 (40% EtOAc–hexane).
IR (NaCl): 3472, 3330, 3167, 2957, 1605, 1571, 1452, 1223 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.1 Hz, 3 H), 1.39–
1.63 (m, 4 H), 2.44 (t, J = 7.1 Hz, 2 H), 5.10 (br s, 2 H), 6.55 (dd,
J = 7.5, 5.0 Hz, 1 H), 7.44 (dd, J = 7.4, 2.0 Hz, 1 H), 7.95 (dd,
J = 5.0, 2.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.5, 19.1, 21.9, 30.6, 75.7, 96.6,
103.9, 113.1, 139.5, 146.8, 158.9.
MS (ESI+, 60 eV): m/z (%) = 175 [(M + H)+, 100], 176 [(M + 2 H)+,
To a soln of the pyridine 7a–f (0.86 mmol) in anhyd toluene (14
mL) were added successively t-BuOK (203 mg, 1.81 mmol) and 18-
crown-6 (22.8 mg, 0.086 mmol), and the mixture was stirred over-
night at 65 °C. The solvent was evaporated under reduced pressure
and the residue suspended in H2O (5 mL) and extracted with CH2Cl2
(3 × 5 mL). The organic phases were combined and dried (Na2SO4)
and the organic solvent was removed under reduced pressure. The
crude mixture was purified by flash chromatography (silica gel, 10–
60% EtOAc–hexane) to afford the corresponding 7-azaindoles 3a–
f (Table 2).
15].
2-Phenyl-1H-pyrrolo[2,3-b]pyridine (3a)
Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C,
75.79; H, 8.11; N, 16.10.
Eluent gradient: 10–60% EtOAc–hexane; white solid; yield: 94%;
mp 204–206 °C; Rf = 0.56 (60% EtOAc–hexane).
IR (KBr): 3163, 2362, 1870, 1588, 1541, 1458, 1282 cm–1.
2-Amino-3-(hept-1-ynyl)pyridine (7d)
Eluent gradient: hexane to 40% EtOAc–hexane; colorless oil; yield:
89%; Rf = 0.27 (40% EtOAc–hexane).
IR (NaCl): 3474, 3300, 3167, 2931, 1604, 1570, 1454, 1223 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.1 Hz, 3 H), 1.27–
1.46 (m, 4 H), 1.54–1.64 (m, 2 H), 2.42 (t, J = 7.1 Hz, 2 H), 5.15 (br
s, 2 H), 6.54 (dd, J = 7.5, 5.0 Hz, 1 H), 7.44 (dd, J = 7.4, 2.0 Hz, 1
H), 7.94 (dd, J = 5.1, 1.7 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 6.81 (s, 1 H), 7.12 (dd, J = 7.7, 4.8
Hz, 1 H), 7.39–7.45 (m, 1 H), 7.52–7.56 (m, 2 H), 7.91–8.00 (m, 3
H), 8.33 (d, J = 4.3 Hz, 1 H), 12.78 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 97.3, 116.2, 122.5, 125.9 (2 C),
128.1, 128.6, 128.9 (2 C), 132.4, 139.6, 141.8, 149.8.
MS (ESI+, 60 eV): m/z (%) = 195 [(M + H)+, 100], 196 [(M + 2 H)2+,
19], 217 [(M + Na)+, 13].
13C NMR (75 MHz, CDCl3): d = 13.8, 19.4, 22.0, 28.3, 31.0, 75.7,
96.7, 103.9, 113.1, 139.5, 146.8, 158.9.
Anal. Calcd for C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found: C,
80.42; H, 5.18; N, 14.40.
MS (ESI+, 60 eV): m/z (%) = 188 [M+, 100], 189 [(M + H)+, 19].
2-Propyl-1H-pyrrolo[2,3-b]pyridine (3b)
Anal. Calcd for C12H16N2: C, 76.55; H, 8.57; N, 14.88. Found: C,
76.55; H, 8.59; N, 14.86.
Eluent gradient: 10–60% EtOAc–hexane; white solid; yield: 84%;
mp 73–75 °C; Rf = 0.47 (60% EtOAc–hexane).
IR (KBr): 2958, 1587, 1545, 1412, 1276 cm–1.
2-Amino-3-(4-methylpent-1-ynyl)pyridine (7e)
Eluent gradient: hexane to 40% EtOAc–hexane; colorless oil; yield:
81%; Rf = 0.22 (40% EtOAc–hexane).
1H NMR (300 MHz, CDCl3): d = 1.07 (t, J = 7.5 Hz, 3 H), 1.83–
1.96 (m, 2 H), 2.89 (t, J = 7.5 Hz, 2 H), 6.20 (s, 1 H), 7.07 (dd,
J = 7.6, 4.8 Hz, 1 H), 7.87 (dd, J = 7.8, 1.5 Hz, 1 H), 8.24 (d, J = 4.1
Hz, 1 H), 12.30 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.3, 30.7, 97.1, 115.3,
121.8, 127.5, 140.1, 141.6, 149.1.
IR (NaCl): 3470, 3382, 3303, 3166, 2950, 1607, 1567, 1450, 1219
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.03 (d, J = 6.8 Hz, 6 H), 1.84–
1.97 (m, 1 H), 2.34 (d, J = 6.5 Hz, 2 H), 5.10 (br s, 2 H), 6.56 (t,
J = 5.4 Hz, 1 H), 7.46 (d, J = 7.4 Hz, 1 H), 7.96 (d, J = 3.7 Hz, 1 H).
MS (ESI+, 60 eV): m/z (%) = 161 [(M + H)+, 100], 162 [(M + 2 H)2+,
15], 183 [(M + Na)+, 38].
Synthesis 2007, No. 14, 2149–2152 © Thieme Stuttgart · New York

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M. C. de Mattos et al.
PAPER
Anal. Calcd for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C,
74.95; H, 7.56; N, 17.49.
Anal. Calcd for C13H16N2: C, 77.96; H, 8.05; N, 13.99. Found: C,
77.97; H, 8.05; N, 13.98.
2-Butyl-1H-pyrrolo[2,3-b]pyridine (3c)
Eluent gradient: 10–60% EtOAc–hexane; white solid; yield: 87%;
mp 48–49 °C; Rf = 0.37 (60% EtOAc–hexane).
Acknowledgment
Financial support of this work by the Principado de Asturias (IB-05-
109) is gratefully acknowledged. V.G.-F. thanks Spanish MEC for
a personal grant (Juan de la Cierva Program), S.A.-S. thanks Mexi-
can CONACYT for a pre-doctoral fellowship and M.C.M thanks
Brazilian Agency CAPES for a post-doctoral fellowship.
IR (KBr): 3472, 3297, 3164, 2930, 1588, 1544, 1416, 1278 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.01 (t, J = 7.4 Hz, 3 H), 1.44–
1.57 (m, 2 H), 1.82–1.92 (m, 2 H), 2.94 (t, J = 7.4 Hz, 2 H), 6.25 (s,
1 H), 7.08 (dd, J = 7.7, 4.8 Hz, 1 H), 7.88 (dd, J = 7.7, 1.4 Hz, 1 H),
8.26 (dd, J = 4.8, 1.4 Hz, 1 H), 12.70 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 22.4, 28.4, 31.1, 96.9, 115.2,
121.9, 127.5, 139.9, 141.9, 149.2.
References
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MS (ESI+, 60 eV): m/z (%) = 175 [(M + H)+, 100], 176 [(M + 2 H)2+,
18].
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Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C,
75.79; H, 8.11; N, 16.10.
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2-Pentyl-1H-pyrrolo[2,3-b]pyridine (3d)
Eluent gradient: 10–60% EtOAc–hexane; white solid; yield: 82%;
mp 83–85 °C; Rf = 0.52 (60% EtOAc–hexane).
IR (KBr): 2930, 1588, 1542, 1427, 1278 cm–1.
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(5) (a) Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y.
Tetrahedron 2006, 63, 1031. (b) Schirok, H.; Figueroa-
Pérez, S.; Thutewol, M.; Paulsen, H.; Kroh, W.; Klewer, D.
Synthesis 2007, 251. (c) Caldwell, J. J.; Cheung, K.-M.;
Collins, I. Tetrahedron Lett. 2007, 48, 1527.
(6) Clemo, G. R.; Swan, G. A. J. Chem. Soc. 1945, 603.
(7) Houlihan, W. J.; Parrino, V. A.; Uike, Y. J. Org. Chem.
1981, 46, 4511.
1H NMR (300 MHz, CDCl3): d = 0.99 (t, J = 7.1 Hz, 3 H), 1.40–
1.55 (m, 4 H), 1.89–1.99 (m, 2 H), 2.97 (t, J = 7.7 Hz, 2 H), 6.30 (br
s, 1 H), 7.15 (br s, 1 H), 7.94 (d, J = 6.2, 1 H), 8.32 (br s, 1 H), 13.05
(br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 22.4, 28.7, 28.8, 31.5, 96.8,
115.2, 122.0, 127.4, 139.7, 142.0, 149.1.
MS (ESI+, 60 eV): m/z (%) = 188 [M+, 100], 189 [(M + H)+, 18].
Anal. Calcd for C12H16N2: C, 76.55; H, 8.57; N, 14.88. Found: C,
76.58; H, 8.57; N, 14.85.
2-Isobutyl-1H-pyrrolo[2,3-b]pyridine (3e)
Eluent gradient: 10–60% EtOAc–hexane; white solid: yield: 80%;
mp 82–84 °C; Rf = 0.53 (60% EtOAc–hexane).
IR (KBr): 3215, 3128, 3081, 2958, 1609, 1588, 1420, 1281 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.06 (t, J = 6.8 Hz, 6 H), 2.13–
2.27 (m, 1 H), 2.78 (d, J = 7.1 Hz, 2 H), 6.25 (s, 1 H), 7.07 (dd,
J = 8.0, 4.8 Hz, 1 H), 7.87 (dd, J = 7.7, 1.4 Hz, 1 H), 8.23 (dd,
J = 4.8, 1.7 Hz, 1 H), 12.45 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.5 (2 C), 28.8, 38.2, 97.9, 115.3,
121.8, 127.5, 140.0, 140.8, 149.1.
MS (ESI+, 60 eV): m/z (%) = 175 [(M + H)+, 100], 176 [(M + 2 H)2+,
13].
Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C,
75.81; H, 8.13; N, 16.06.
(8) (a) Estel, L.; Marsais, F.; Quéguiner, G. J. Org. Chem. 1988,
53, 2740. (b) Davis, M. L.; Wakefield, B. J.; Wardell, J. A.
Tetrahedron 1992, 48, 939. (c) Rodríguez, A. L.; Koradin,
C.; Dohle, W.; Knochel, P. Angew. Chem. Int. Ed. 2000, 39,
2488. (d) Koradin, C.; Dohle, W.; Rodríguez, A. L.; Schmid,
B.; Knochel, P. Tetrahedron 2003, 59, 1571.
2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridine (3f)
Eluent gradient: 10–60% EtOAc–hexane; white solid; yield: 81%;
mp 170–172 °C; Rf = 0.38 (60% EtOAc–hexane).
(9) (a) Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L.
A.; Repke, D. B.; Souchet, M. Synthesis 1991, 871.
(b) Park, S. S.; Choi, J.-K.; Yum, E. K. Tetrahedron Lett.
1998, 39, 627. (c) Hong, C. S.; Seo, J. Y.; Yum, E. K.; Sung,
N.-D. Heterocycles 2004, 63, 631. (d) McLaughlin, M.;
Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307.
(10) Sakai, N.; Annaka, K.; Konakahara, T. Org. Lett. 2004, 6,
1527.
IR (KBr): 3126, 3071, 3015, 2922, 2849, 1609, 1587, 1423, 1277
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25–1.60 (m, 5 H), 1.64–1.95 (m,
3 H), 2.17–2.22 (m, 2 H), 2.83–2.93 (m, 1 H), 6.21 (s, 1 H), 7.06
(dd, J = 6.8, 4.8 Hz, 1 H), 7.87 (d, J = 7.7 Hz, 1 H), 8.24 (s, 1 H),
12.08 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 26.1, 26.3 (2 C), 32.7 (2 C), 37.8,
95.0, 115.3, 121.6, 127.6, 140.3, 146.9, 149.0.
MS (ESI+, 60 eV): m/z (%) = 200 [M+, 100], 201 [(M + H)+, 19].
(11) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata, A.;
Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
1999, 529.
Synthesis 2007, No. 14, 2149–2152 © Thieme Stuttgart · New York