Syntheses of Oxazolo[4,5-c]pyridine and 6-Azaindole

Article abstract of DOI:10.1002/jhet.5570450240

(Chemical Equation Presented) The preparation of oxazolo[4,5-c]pyridine and 6-azaindole from 4-bromo-3-pivaloylaminopyridine (8) is reported. The oxazolopyridine 2-tert-butyl-oxazolo[4,5-c]pyridine (9) was successfully prepared from 8 in 78% yield by a new base/TBAB promoted non-catalyzed microwave cyclisation strategy (10 min) or, alternatively, in 54% yield by conventional heating (48 hrs) and CuI catalysis. The 6-azaindole 2-phenyl-1-(trimethylacetyl) -6-azaindole (13) was prepared from 8 in a two step procedure, including a Sonogashira coupling reaction.

Full text of DOI:10.1002/jhet.5570450240

Mar-Apr 2008
559
Syntheses of Oxazolo[4,5-c]pyridine and 6-Azaindole
Freddy Tjosaas, Ivar Broendbo Kjerstad and Anne Fiksdahl*
Department of Chemistry, Norwegian University of Science and Technology, NTNU
N-7491 Trondheim, Norway
e-mail: Anne.Fiksdahl@chem.ntnu.no
Received September 12, 2007
O
base/TBAB, DMSO
MW, 10 min
78%
N
N
Br
N
or:
Oxazolo[4,5-c]pyridine
H
CuI-cat. 48 hrs. !
N
tBu
54%
O
H
Ph
Ph
N
N
i) Sonogashira
t-Bu
ii) KO-tBu
O
6-Azaindole
The preparation of oxazolo[4,5-c]pyridine and 6-azaindole from 4-bromo-3-pivaloylaminopyridine (8) is
reported. The oxazolopyridine 2-tert-butyl-oxazolo[4,5-c]pyridine (9) was successfully prepared from 8 in
78% yield by a new base/TBAB promoted non-catalyzed microwave cyclisation strategy (10 min) or,
alternatively, in 54% yield by conventional heating (48 hrs) and CuI catalysis. The 6-azaindole 2-phenyl-1-
(trimethylacetyl)-6-azaindole (13) was prepared from 8 in a two step procedure, including a Sonogashira
coupling reaction.
J. Heterocyclic Chem., 45, 559 (2008).
HO
F
F
INTRODUCTION
N
N
O
4
O
O
O
OMe
N
N
Pyridine-fused analogues of benzo-fused bis-
heterocycles may in general offer some advantages from a
medicinal chemistry point of view, since the pyridine
fragment may provide better water solubility by offering
an additional site for protonation or salt formation or it
might enhance intermolecular interactions by formation of
an additional hydrogen bond to target proteins. We have
studied the transformation of a pyridine substrate into
both oxazolopyridine and 6-azaindole, which are
N-analogues of benzoxazole and indole, respectively
(Figure 1).
OH
OH
H
H
F
H
N
N
O
1
2
3
O
n
5
6
O
HO2C
6; 7-alkyl R = Cl
7; 6-alkyl R = F
R
N
7
Figure 2. Benzoxazoles: biologically active natural products (1-3),
material science compounds (4,5), benoxaprofen (6) and flunoxaprofen
(7) pharmaceuticals.
O
N
O
N
The compounds pseudoteroxazole (1) and seco-
pseudoteroxazole (2) can be isolated from the coral
Pseudopterogorgia elisabethae and are active as
inhibitors of M. tuberculosis growth [1]. Nakijinol (3) was
isolated from a marine sponge in the Spongiidae family
[2]. The benzoxazole 4 has been reported to act as a
fluorescent probe for sensing magnesium cation [3], while
the polymer marketed as Zylon(R) (5), a benzobisoxazole,
shows excellent thermo-oxidative stabilities, mechanical
tenacity and optoelectronic properties and has been used
to make monolayer luminescense devices (Figure 2) [4].
The benzoxazoles benoxaprofen (6) and flunoxaprofen (7)
are non-steroidal anti-inflammatory drugs (NSAIDs) [5].
Benoxaprofen (6) has been withdrawn from the U.S. and
British markets due to increased fatality in elderly patients
N
Oxazolo[4,5-c]pyridine
Benzoxazole
N
N
N
H
H
6-Azaindole
Indole
Figure 1. Structures of benzoxazole, indole and corresponding N-
analogues.
Benzoxazoles
are
bis-heterocyclic
compounds
consisting of a benzene-fused oxazole ring skeleton. The
ring system is found in a range of natural and biologically
active compounds, see Figure 2.

560
F. Tjosaas, I. B. Kjerstad and A. Fiksdahl
Vol 45
[6]. There has however, not been any reported fatal
adverse effects of flunoxaprofen (7) [5].
Based on the fact that a number of 3-nitropyridines
have been readily available through an improved nitration
method [11a,b], an investigation of the chemistry of
nitropyridines is now in progress in our laboratories. 4-
Bromo-3-pivaloylaminopyridine (8) is readily available
from 3-nitropyridine in approximately 50% yield in a
three step procedure [11c] (Scheme 2).
While there are many examples of benzoxazoles in the
literature, the occurrence of the N-analogues, the
oxazolopyridines (see Figure 1) is far less common, even
though they may be important supplements, which can be
used for altering the properties of benzoxazoles.
The indoles constitute an important class of
heterocycles. Since the indole structure is present in a
wide number of naturally occurring and pharmaceutical
compounds, the indole chemistry is one of the most active
research fields in heterocyclic chemistry. The N-
analogues azaindoles, also called pyrrolopyridines, are
essential subunits in many pharmaceutically important
compounds as well. The synthesis of azaindoles has been
a great synthetic challenge for chemists [7]. Many
classical methods for indole synthesis can often not
effectively be applied to the synthesis of the
corresponding azaindoles (Figure 1). In recent years,
advances in organometallic chemistry have enabled a
number of novel and efficient methodologies for
azaindole formation.
RESULTS AND DISCUSSION
Oxazolo[4,5-c]pyridine. The oxazolopyridine 9 was
initially prepared according to a procedure developed for
Cu-catalysed benzoxazole formation between primary
amines and o-dihalobenzenes [12]. The bromoamide 8
[11] was refluxed in toluene under nitrogen atmosphere
with K2CO3, catalytic amounts of CuI, and N,N-
dimethylethylenediamine (DMEDA, Scheme 2, Method
A). The Cu-catalysed C-O cross-coupling of the
bromoamide 8 had taken place in 48 hours and 2-tert-
butyl-oxazolo[4,5-c]pyridine (9) was isolated by
chromatography in moderate yield (54%). The bis-
heterocycle 9 may thus be prepared from pyridine in five
steps.
However, we have experienced that microwave (MW)
irradiation has been successful for a number of reactions
[13,14]. A non-catalysed MW method, including modified
reaction conditions, was therefore tested for the
cyclisation of 8 in order to yield the bis-heterocycle 9
(Scheme 2, Method B). After 10 minutes MW irradiation
(800 W) of a DMSO solution of bromopyridineamide 8,
Cs2CO3 and tetrabutylammonium bromide (TBAB), the
desired cyclisation product 9 was isolated in 78% yield.
Thus, Cu-catalysis was not required for this 4-
bromopyridine substrate (8), since a general nucleophilic
aromatic substitution had taken place. This base [15] and
MW promoted cyclisation would be the method of choice
for the preparation of oxazolo[4,5-c]pyridines, since high
yields are obtained within few minutes. The results
demonstrate the general fact that 4-bromopyridines may
be displaced by good nucleophiles due to the electron-
deficient character of the pyridine moiety and the
stabilisation gained from the para pyridine N-atom. In
addition, the presence of the TBAB ammonium ion would
activate the substrate for 4-bromo-substitution. The results
are also in accordance with the general experience that
microwave-accelerated reactions often offer the great
advantage of enhanced reaction rates and yields. The
present method represents an alternative to a previously
reported general oxazolopyridine preparation method
[16], based on a two step synthesis including amide
formation (50-80% yield) of 3-amino-4-hydroxypyridine
and a carboxylic acid, followed by cyclodehydration (40-
90%) by an intramolecular triphenylphosphine
condensation. Our method avoids the difficult removal of
triphenylphosphonium oxide.
The Larock heteroannulation represents a simple
approach to indoles, involving the palladium catalysed
heteroannulation of alkynes using o-iodoaniline
derivatives, as shown in Scheme 1 [8]. The reaction is
highly regioselective when unsymmetrical alkynes are
used. The most sterically bulky group is attached next to
the nitrogen atom in the indole product. The reaction is
also tolerant with regards to the aniline moiety, which can
be both unsubstituted and substituted. The method is,
however, reported to be successful only with iodoanilines,
while bromoanilines were in general unreactive [8,9]. 3-
Amino-4-iodopyridines have also been reported to
undergo Larock heteroannulation [10].
Scheme 1
R3
5 mol % Pd(OAc)2
I
5 mol % PPh3
R2
R3
R2
NHR1
N
R1
LiCl
Base
100 °C, DMF
We wanted to explore the versatility of 4-bromo-3-
pivaloylaminopyridine (8) as a key substrate for the
formation of both pyridine-fused heterocycles; the
oxazolopyridine 2-tert-butyl-oxazolo[4,5-c]pyridine (9)
and 6-azaindoles, the 2-phenyl-1H-pyrrolo[2,3-c]pyrid-
ines (11 or 13). Product 9 would be synthesised by an
intramolecular displacement of the bromine atom with the
amide carbonyl oxygen to give cyclisation, and azaindoles
11, respectively, by the one-step Larock heteroannulation
reaction or, alternatively 13, by the Sonogashira coupling
reaction followed by cyclisation.

Mar-Apr 2008
Syntheses of oxazolo[4,5-c]pyridine and 6-azaindole
561
Scheme 2
Using an alternative step-wise strategy for the 6-
azaindole preparation, the bromoamide 8 was reacted with
phenylacetylene in a Sonogashira reaction (Scheme 4).
Using Pd(PPh3)4, PPh3 and CuI as catalysts and NaOtBu
as base, N-(4-(phenylethynyl)pyridin-3-yl)-2-dimethyl-
propanamide (12) was isolated after chromatography in
53% yield. The new 6-azaindole, 2-phenyl-1-(trimethyl-
acetyl)-6-azaindole (13), was prepared in 7% yield by
heating compound 12 with KOtBu in 1-methyl-2-pyrrol-
idinone (NMP) at 60 °C for 24 hours [20].
pyridine
Method A:
N2O5
nitration [11]
CuI, K2CO3, DMEDA
Br
N
toluene, 48 hrs. !
H
NO2
N
tBu
54%
O
N
O
N
N
Method B:
3 steps [11]
TBAB, Cs2CO3, DMSO
MW, 10 min
9
8
50%
78%
6-Azaindole. Acidic hydrolysis of bromoamide (8) [11]
afforded 3-amino-4-bromopyridine (10) (77%, Scheme 3).
Compound 10 may alternatively be prepared (76%) by
KOH/MeOH hydrolysis of 8 [17]. Product 10 has
previously been prepared by photolysis (15%) of 4-
azidopyridine in HBr [18].
The Larock heteroannulation reaction has in general only
been successful for iodoaniline [8,9] and 4-iodopyridine
[10] substrates. Two different approaches to successfully
replace the iodoaryl substrates with the much cheaper but
less reactive 2-bromo or 2-chloroaryl compounds would be
either to apply a more reactive and electron-rich Pd
catalytic system or, alternatively, to use more reactive aryl
halide substrates. Some activated catalytic systems have
been developed for the Larock cyclisation [19] and
represent the first approach; by the proper choice among a
series of ligands, base, solvent and concentration, 2-bromo-
and 2-chloroanilines were reactive in the Larock hetero-
annulation reaction to form indoles.
We wanted to study the second approach; whether the
electron deficient character of the pyridine ring would
make the bromoamine 10 reactive enough to prepare 2,3-
diphenyl-6-azaindole (11) by the general Larock
palladium catalyzed heteroannulation. This is based on
our experience with 4-bromopyridines, which are
sufficiently activated for other palladium catalyzed cross-
coupling reactions and give high yields (85-90%) of a
number of new coupling products [11].
The bromoamine 10 was therefore reacted with
diphenylacetylene with LiCl, K2CO3 and catalytic
amounts of Pd(OAc)2/PPh3 in DMF at 100 °C (Scheme 3).
No reaction had taken place after 20 hours. The 6-
azaindole 11 was not observed and substrate 10 was
recovered. Replacing LiCl with n-Bu4NCl was not
successful either. The general Larock heteroannulation
reaction conditions were thus not successful for the
electron-deficient bromopyridine 10.
Scheme 4
Ph
5 mol % Pd(PPh3)4
Br
H
10 mol % PPh3
10 mol % CuI
N
tBu
H
H
Ph
N
tBu
O
NaO-tBu
Et3N-CH3CN
53%
N
O
N
8
12
KO-tBu
GLC:quant.
NMP, 60 °C isol. 7%
Ph
tBu
N
N
O
13
The low yield of compound 13 may be due to instability
of the product. Full conversion and no traces of the
substrate or by-products were observed after 24 hours of
reaction time, as indicated both by TLC and GLC.
However, the product seemed to decompose during work-
up and chromatography. Special precautions and more
gentle treatment of the 6-azaindole 13 would potentially
afford higher yields.
In conclusion, two different cyclisation strategies have
been used for the preparation of, respectively, the
oxazolo[4,5-c]pyridine 9 and the 6-azaindole 13 from 4-
bromo-3-pivaloylaminopyridine (8). The oxazolopyridine
2-tert-butyl-oxazolo[4,5-c]pyridine (9) was successfully
prepared from 8 in 78% yield by a new base/TBAB
promoted microwave cyclisation strategy or, alternatively,
in 54% yield by conventional heating and CuI catalysis.
The preparation of the 6-azaindole 2-phenyl-1-(trimethyl-
acetyl)-6-azaindole (13) was not successful by the Larock
heteroannulation method, but the 6-azaindole 13 was
prepared from 8 by a two step procedure, including a
Sonogashira coupling reaction. The bis-heterocycles 9 and
13 may thus be prepared from pyridine in five and six
steps, respectively.
Scheme 3
Ph
Ph
Br
Br
Ph
H
5 mol % Pd(OAc)2
5 mol % PPh3
EXPERIMENTAL
N
tBu
NH2
Ph
O
N
H2SO4
reflux
77%
N
Chemicals CuI, Pd(PPh3)4, KO-tBu (Fluka), Cs2CO3, K2CO3,
PPh3, 25 %H2SO4 (Merck), N,N-dimethylethylenediamine
(DMEDA), diphenylacetylene, n-Bu4NBr (TBAB) (Aldrich),
N
N
LiCl/n-Bu4NCl
K2CO3
H
11
8
10
100 °C, DMF

562
F. Tjosaas, I. B. Kjerstad and A. Fiksdahl
Vol 45
LiCl (Kebo lab), Pd(OAc)2 (Strem Chemicals); Solvents: pro
1
13C nmr (100 MHz, CHCl3): δ 27.7 (C(CH3)), 40.1 (C(CH3)),
82.1 (py-C≡C), 100.4 (py-C≡C), 119.6 (C-4), 121.2 (C-1’),
124.9 (C-5), 128.9 (C-3’,5’), 129.9 (C-4’), 131.7 (C-2’,6’),
133.1 (C-3), 141.6 (C-2), 144.1 (C-6), 176.5 (C=O). Partial 13C
nmr assignments are based on HSQC; ms: m/z 278 (M+, 12%),
258 (11), 256 (11), 194 (11), 174 (24), 172 (25), 85 (34), 57
(100), 41 (44); HRMS: calcd for C18H18N2O; 278.1419, observed
278.1416.
analysi quality. H/ 13C nmr: Bruker Avance DPX 300 and 400
spectrometers, chemical shifts are reported in ppm downfield
from TMS. J values are given in Hz. ms: Finnigan MAT 95 XL
(EI/ 70 eV. ir: Nicolet 20SXC FT-IR spectrophotometer.
Microwave irradiation was performed in a household microwave
oven (Elram M8017NP-CF), modified with a reflux condenser,
at 800 W output. Flash chromatography: Silica (sds, 60 Å, 40-63
µm). 4-Bromo-3-pivaloylaminopyridine (8) was prepared
according to the literature [11]. All reactions were conducted
under nitrogen atmosphere unless otherwise noted.
1-(2,2-Dimethyl-1-oxopropyl)-2-phenyl-6-azaindole (13).
The amide (12) (160 mg, 0.58 mmol) and KO-tBu (80 mg, 0.7
mmol) were stirred in NMP (1-methyl-2-pyrrolidinone, 8 ml) for
24 hours at 60 °C. The reaction mixture was added an aqueous
NH4Cl solution (sat.), extracted with diethyl ether, dried and
concentrated in vacuo. The product was obtained by flash
chromatography (ethyl acetate/n-pentane 1:10) in 7% yield (11
2-tert-Butyloxazolo[4,5-c]pyridine (9) [16]. The title product
was preferentially prepared by Method B below:
Method A. CuI (8 mg, 0.04 mmol) and K2CO3 (110 mg, 0,78
mmol) was dissolved in toluene (13 ml) and heated to reflux (110
°C). Toluene (10 ml) was removed by distillation before a toluene
(3 mL) solution of bromoamide (8) (100 mg, 0.39 mmol) and
DMEDA (5 mg, 0.039 mmol) was added. The reaction was
refluxed for 48 hours before the reaction was cooled to room
temperature and the pH was adjusted to 11 with aqueous NH3
(25%). After extraction, drying and concentration in vacuo, the
crystalline product was obtained (37 mg, 54%) by flash
chromatography (ethyl acetate/n-pentane 1:5), pure by 1H nmr.
Method B. Bromopyridineamide (8, 50 mg, 0.195 mmol),
TBAB (63 mg, 0.195 mmol, 1 equiv.), Cs2CO3 (254 mg, 0.78
mmol, 4 equiv.) were dissolved in DMSO (18 ml) and irradiated
by MW (800 W) in 10 minutes. After addition of water (20 mL),
extraction by CH2Cl2 (2x20 mL), drying and concentration in
vacuo, the crystalline product was obtained (27 mg, 78%), pure
by 1H nmr; 1H nmr (300 MHz, d6-aceton): δ 1.51 (s, 9H,
C(CH3)3, 7.47 (d, 1H, J 5.0, H-4), 8.54 (d, 1H, J 5.0, H-5), 9.02
(s, 1H, H-7); 13C nmr (100 MHz, CHCl3): δ 28.6 (C(CH3)3), 34.6
(C(CH3)3, 106.5 (pyr-C5), 139.3 (pyr-C3), 142.4 (pyr-C2), 145.2
(pyr-C6), 156.2 (pyr-C4), 174.6 (O-C(tBu)=N); HRMS: calcd
for C10H12N2O; 176.0950, observed 176,9042.
1
mg, 0.036 mmol). The product was pure by H nmr; ir (KBr)
2967, 2925, 2854, 2360, 2342, 1649, 1629, 1416, 1217, 1123,
1
691 cm-1; H nmr (300 MHz, CDCl3): δ 1.33 (s, 9H, C(CH3),
6.58 (s, 1H, H-3), 6.85 (d, J 5.2, 1H, H-4), 7.38 (m, 5H, Ph),
8.10 (d, J 5.1, 1H, H-5), 8.39 (s, 1H, H-7); ms: m/z 278 (M+,
6%), 263 (34), 235 (14), 223 (13), 222 (40), 221 (59), 195 (23),
194 (100), 193 (86), 192 (10), 167 (17), 166 (12), 139 (10);
HRMS: calcd for C18H18N2O; 278.1419, observed 278.1415.
REFERENCES
[1] Rodriguez. A. D.; Ramirez. C.; Rodriguez. I. I.; Gonzalez. E.
Org. Lett. 1999, 1, 527.
[2] Kobayashi. J.; Madono. T.; Shigemori. H. Tetrahedron Lett.
1995, 36, 5589.
[3] Tanaka. K.; Kumagai. T.; Aoki. H.; Deguchi. M.; Iwata. S. J.
Org. Chem. 2001, 66, 7328.
[4] Wu. C. C.; Tsay. P. Y.; Cheng. H. Y.; Bai. S. J. J. Appl. Phys.
2004, 95, 417.
[5] Dong. J. Q.; Liu. J.; Smith. P. C. Biochem. Pharmacol. 2005,
70, 937.
3-Amino-4-bromopyridine (10) [17,18]. The bromoamide
(8) (1.5 g, 5.9 mmol) was dissolved in H2SO4 (25% aq, 100 ml)
and heated to reflux (120 °C) for 3 hours before cooling to room
temperature. The pH was adjusted to 11-12 with aqueous NH3
(25%), extracted with diethyl ether and concentrated in vacuo.
The crude product was purified by flash chromatography (4%
NEt3 in ethyl acetate/n-pentane 2:1,) yielding 800 mg (4.5 mmol,
77%) product, pure by 1H and 13C nmr; 1H nmr (300 MHz,
CDCl3): δ 4.12 (br s, 2H, NH2), 7.34 (d, 1H, J 5.1, H-5), 7.81 (d,
1H, J 5.1, H-6), 8.11 (s, 1H, H-2); 13C nmr (100 MHz, CHCl3): δ
117.9 (C-4), 127.4 (C-5), 137.4 (C-2), 139.6 (C-6), 141.5 (C-3);
HRMS: calcd for C5H5BrN2; 171.9636, observed 171.9639.
N-(4-(Phenylethynyl)pyridin-3-yl)-2,2-dimethylpropanam-
ide (12). Bromoamide (8) (1 g, 3.9 mmol), Pd(PPh3)4 (450 mg,
0.4 mmol), n-Bu4NI (2.15 g, 5.8 mmol), CuI (200 mg, 1.2
mmol) and phenylacetylene (400 mg, 4.3 mmol) was dissolved
in NEt3-CH3CN (25 mL, 1:5) and stirred at room temperature for
24 hours before filtering through celite and concentrating in
vacuo. The crude product was isolated by flash chromatography
(ethyl acetate/n-pentane 1:4) yielding 580 mg (2.07 mmol, 53%)
[6] Bakke. O. M.; Manocchia. M.; de Abajo. F.; Kaitin. K. I.;
Lasagna. L. Clin. Pharmacol. Ther. 1995, 58, 108.
[7] Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem. Soc. Rev. 2007, 36 1120.
[8] Larock. R. C.; Yum. E. K. J. Am. Chem. Soc. 1991, 113,
6689.
[9] Roesch, K. R.; Larock, R. C.. Org. Letters, 1999, 1, 1551.
[10] Lee, M. S.; Yum, E. K. Bull. Kor. Chem. Soc. 2002, 23, 535.
[11] a) Bakke, J. M.; Hegbom, I.; Øvreeide, K.; Aaby, K. Acta
Chem. Scand., 1994, 48, 1001. b) Bakke, J. M.; Ranes, E. Synthesis,
1997, 281. c) Stockmann. V.; Fiksdahl. A. Tetrahedron in prep.
[12] Altenhoff. G.; Glorius. F. Adv. Synth. Catal. 2004, 346, 1661.
[13] Holt, J.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem.
2006, 43, 787.
[14] Tjosås, F.; Fiksdahl,A. Tetrahedron, 2007, 63, 11893.
[15] Norman, M. H.; Minick, D. J.; Martin, G. E. J. Heterocycl.
Chem. 1993, 30, 771.
[16] Heuser. S.; Keenan. M.; Weichert. A. G. Tetrahedron Lett.
2005, 46, 9001.
[17] Iwaki, T; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1999, 1505-1510.
[18] Sawanishi, H.; Hirai, T.; Tsuchiya, T. Heterocycles 1982, 19,
1043.
1
product, pure by H and 13C nmr; ir: (KBr) 3403, 3048, 2953,
2868, 2359, 2215, 1689, 1550, 1512, 1492, 1422, 1302, 1153,
1025, 837, 756, 688 cm-1; 1H nmr (300 MHz, CDCl3): δ 1.38 (s,
9H, C(CH3)), 7.46 (m, 4H, H-5,3’,4’,5’), 7.55 (m, 2H, H-2’,6’),
8.22 (d, J 5.2, 1H, H-6), 8.35 (s, 1H, H-2), 9.73 (br s, 1H, NH);
[19] Shen, M; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.;
Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129.
[20] Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. Synlett
2005, 3121.