A practical, efficient synthesis of 5-amino-7-azaindole

Article abstract of DOI:10.1055/s-2005-872088

A much improved, workable synthesis of 5-amino-7-azaindole is described in 66% overall yield starting from 2-amino-5-nitropyridine. The key stage involves a microwave promoted heteroannulation reaction of a pyridine alkyne. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872088

PAPER
2503
A Practical, Efficient Synthesis of 5-Amino-7-azaindole
le E. Pearson,*a Santosh Nandanb
A
P
ractical, Ef
t
ficient
u
S
ynthesis of
a
5-Amino-7
r
-azaindo
t
a
AstraZeneca Plc., Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Fax +44(1625)513910; E-mail: stuart.pearson@astrazeneca.com
b
AstraZeneca Pvt. Ltd. (R&D), Bellary Road, Hebbal, Bangalore 560 024, India
Fax +91(80)23621214; E-mail: santosh.nandan@astrazeneca.com
Received 10 March 2005; revised 27 April 2005
Abstract: A much improved, workable synthesis of 5-amino-7-
azaindole is described in 66% overall yield starting from 2-amino-
5-nitropyridine. The key stage involves a microwave promoted het-
eroannulation reaction of a pyridine alkyne.
Key words: azaindoles, alkynes, copper, cyclizations, microwaves
Our ongoing research programme investigating the use of
4-anilinoquinazolines as potential anticancer agents led us
to consider compounds of type 1. These compounds
would be made from the reaction of an appropriately sub-
stituted 4-chloro-quinazoline 2 with 5-amino-7-azaindole
(3) (Scheme 1). However, the key intermediate 3 is not
easily accessible. There is only one previously reported
literature synthesis,1 giving the product in 21% overall
yield in 4 steps from 7-azaindoline (5). A recent patent ap-
plication by Bristol–Myers Squibb2 describes the intro-
duction of the 5-amino-7-azaindole moiety into a
molecule indirectly, involving lithiation and protecting
group chemistry. We herein report a much-improved syn-
thesis of the title compound from the readily available 2-
amino-5-nitropyridine.
Scheme 1 Retrosynthetic strategy
accomplished by a 2-step procedure; reaction with a mix-
ture of fuming HNO3 and concentrated H2SO4 at –5 °C
gives first 1-nitro-7-azaindole (6), which was rearranged
to the desired 5-nitro- compound 7 by treatment with con-
centrated H2SO4. These two stages required highly con-
centrated solutions (1 g/mL of substrate) and careful
monitoring of temperature otherwise yields were much re-
duced. Compound 7 was dehydrogenated with palladium
on carbon at very high temperature to give 5-nitro-7-aza-
indole (8), a bright orange compound with very poor sol-
ubility in most solvents. A very dilute solution of this
compound in EtOH was catalytically hydrogenated to
give 3. We found that this reaction gave a mixture of the
desired product, nitroso compound and hydrogenated aza-
indole.
The 1959 Robison procedure (Scheme 2) starts from 7-
azaindoline (5), which is not commercially available, and
has to be prepared by reduction of 7-azaindole (4). In our
hands, stoichiometric Raney Ni, 5 bar pressure of H2, ele-
vated temperature and an extended reaction time were re-
quired to effect this transformation. The nitration of 5 was
We first attempted to modify the Robison procedure
(Scheme 3). We found that reaction of 7-azaindoline with
ferric nitrate nonahydrate3 in refluxing EtOH gave selec-
Scheme 2 Original Robison synthesis of 5-amino-7-azaindole
SYNTHESIS 2005, No. 15, pp 2503–2506
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-872088; Art ID: P03505SS
© Georg Thieme Verlag Stuttgart · New York

2504
S. E. Pearson, S. Nandan
PAPER
Scheme 3 Modified route from 7-azaindole
tive nitration of the 5-position in one step. Isolation of the at 190 °C using NMP as solvent. Desilylation occurs un-
product 7 was messy and cumbersome; we found it was der the reaction conditions to give 8. The problems en-
somewhat unstable on silica. The dehydrogenation to give countered in purifying and isolating 8 were solved by
8 could be accomplished using MnO2; however, the insol- evaporating the reaction mixture directly onto diatoma-
ubility and low polarity of 8 made its isolation problemat- ceous earth; this was placed onto a short pad of silica and
ic. Dry-loading onto silica and repeated chromatography eluted with hot THF. This procedure removed copper res-
was necessary to obtain material of adequate purity for the idues and other insoluble impurities, which were found to
following step. The final reduction to 3 was found to pro- poison the hydrogenation catalyst in the next stage. The
ceed more reliably using 10% platinum on carbon with product containing fractions were combined, cooled and
THF as solvent; this gave a cleaner product with no over- hydrogenated directly under platinum on carbon catalysis
reduction observed.
to give 3.
This procedure allowed us to synthesise workable Silica chromatography (eluting with EtOAc–MeOH,
amounts of 3, but was still far from ideal. The purifica- 97:3) gave a pure sample of 3 as a colourless crystalline
tions at each stage were troublesome, and any attempt to solid in 75% yield based on 11. Pure samples of 3 were
carry through material without purification resulted in stored dry and in solution for months without decomposi-
dramatically reduced yields.
tion.
Indoles and azaindoles have been prepared by copper me- We found it expedient to use freshly prepared samples of
diated cyclisation of aminopyridines bearing an ortho- 3 without further purification in subsequent reactions. We
alkyne group4 although this methodology has not been were able to obtain our final products 1 in higher overall
previously used to prepare 3. We decided to adopt this ap- yield using this approach than we could by isolating 3.
proach (Scheme 4); our starting point was 2-amino-5-ni- However, crude unpurified samples of 3 were found to de-
tropyridine (9), which was iodinated in the 3-position with compose over several days, giving polymeric material.
a mixture of KI and KIO3 according to the procedure of
In summary, we now have an efficient practical route to 5-
amino-7-azaindole which can be carried out on multigram
Batkowski.5 A Sonogashira reaction of 10 with trimethyl-
silyl acetylene gave 11 in excellent yield. Cyclisation to
the azaindole was achieved with catalytic copper (I) io-
dide either with thermal heating (reflux, 16 h, using DMF
as solvent), or more conveniently with microwave irradi-
ation. The CEM Explorer and Emrys Optimiser micro-
scale6 giving high quality material in 66% overall yield
from 2-amino-5-nitropyridine.
All chemicals used were of reagent grade and used as supplied.
Evaporation of solvent was carried out using a rotary evaporator un-
wave synthesisers were both used for this procedure, and
gave comparable results. We found that microwave heat-
der reduced pressure (2–500 mbar) with a bath temperature of up to
95 °C. Chromatography was carried out on silica; TLC was carried
ing gave cleaner products and shorter reaction times; the
optimal reaction conditions being 30 minutes irradiation
out on silica gel plates (Merck, Art. 5554). In general, the course of
reactions was followed by TLC and/or analytical LC–MS. NMR
Scheme 4 Improved procedure from 2-amino-5-nitropyridine
Synthesis 2005, No. 15, 2503–2506 © Thieme Stuttgart · New York

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A Practical, Efficient Synthesis of 5-Amino-7-azaindole
2505
spectra were obtained on a Bruker DPX-400 spectrometer at 400
MHz using DMSO-d6 or CDCl3 as solvent; the following abbrevia-
tions have been used: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad; v, very. Chemical shifts are expressed in ppm
downfield from TMS, which was used as an internal standard.
HRMS data were recorded by Madeleine Vickers, using Time of
Flight (TOF), Electron Impact (EI+), or Electrospray (ES+) tech-
niques. Values for m/z are given; the mass ion quoted is [MH]+
which refers to the protonated mass ion; reference to M+ is to the
mass ion generated by loss of an electron.
pale orange solid (overall yield 950 mg, 51%); mp 279–281 °C
[Lit.1 280 °C].
1H NMR (400 MHz, DMSO-d6): d = 6.74 (dd, J = 3.5, 1.3 Hz, 1 H),
7.75 (dd, J = 3.5, 2.2 Hz, 1 H), 8.87 (d, J = 2.1 Hz, 1 H), 9.10 (br s,
1 H), 12.46 (br s, 1 H).
13C NMR (101 MHz, DMSO-d6): d = 103.1, 119.2, 125.0, 130.5,
138.9, 139.1, 150.6.
HRMS (TOF, ES+): m/z calcd [MH]+ for C7H5N3O2: 164.0460;
found: 164.0457.
Modified Route from 7-Azaindole
7-Azaindoline (5)
5-Amino-7-azaindole (3)
5-Nitro-7-azaindole (950 mg, 5.82 mmol) was dissolved in THF (50
mL), and the solution was degassed and purged with N2. Platinum
on activated carbon (10%, 250 mg) was added, and the mixture was
hydrogenated using a balloon filled with hydrogen for 5 h at r.t. The
mixture was purged with N2, and the catalyst removed by filtration.
The filtrate was evaporated to give 5-amino-7-azaindole as an off
white solid (620 mg, 80%); mp 118–121 °C [Lit.1 130.5–131.5 °C].
7-Azaindole (3.80 g, 32.2 mmol) was dissolved in EtOH (200 mL).
Raney nickel (32.2 mmol) was added and the mixture hydrogenated
at 90–95 °C for 48 h under 5 bar pressure of H2. The reaction mix-
ture was cooled and filtered through a bed of diatomaceous earth.
The diatomaceous earth was washed with EtOH. The combined fil-
trates were concentrated in vacuo. The residue was purified by flash
chromatography, eluting with 25–37% EtOAc in i-hexane to re-
move impurities, increasing to EtOAc then 5% MeOH in EtOAc to
elute the product. Evaporation of the appropriate fractions gave the
product as a white crystalline solid (3.0 g, 77%); mp 78–79 °C [Lit.7
78.5–79.5 °C].
1H NMR (400 MHz, DMSO-d6): d = 4.37 (br s, 2 H), 6.26 (dd, J =
3.3, 1.8 Hz, 1 H), 7.19 (d, J = 2.6 Hz, 1 H), 7.34 (dd, J = 3.3, 2.7 Hz,
1 H), 7.82 (d, J = 2.6 Hz, 1 H), 11.13 (br s, 1 H).
MS (ES+): m/z = 134.1.
1H NMR (400 MHz, DMSO-d6): d = 2.94 (t, J = 8.3 Hz, 2 H), 3.44
(td, J = 8.3, 0.9 Hz, 2 H), 6.25 (br s, 1 H), 6.39 (dd, J = 7.0, 5.3 Hz,
1 H), 7.23 (dd, J = 7.0, 1.3 Hz, 1 H), 7.67 (dd, J = 5.3, 1.3 Hz, 1 H).
Improved Procedure from 2-Amino-5-nitropyridine
2-Amino-3-iodo-5-nitropyridine (10)
2-Amino-5-nitropyridine (7.00 g, 50.0 mmol) was dissolved in
H2SO4 (2 M, 100 mL). Potassium iodate (4.28 g, 20 mmol) was add-
ed portionwise at r.t. with stirring. The solution was heated to 100
°C under reflux. Potassium iodide (8.00 g, 48.2 mmol) was added
dropwise over 1 h as a solution in water (20 mL). A brown solution
resulted, with solid iodine collecting in the reflux condensor. Heat-
ing at reflux was continued for 30 min and the mixture was cooled
to ambient temperature. The mixture was adjusted to pH 7 with the
careful addition of solid NaHCO3. The mixture was diluted with
water (200 mL) and CH2Cl2 (250 mL) was added. Solid sodium
thiosulfate was added with vigorous stirring until the iodine colora-
tion had been discharged. A significant amount of yellowish solid
remained out of solution; this was collected by filtration, washed
with water and dried to give a yellow solid (10.5 g). The CH2Cl2
fraction was filtered through a silicone-treated filter paper and evap-
orated to give a yellow solid (2.4 g). The solids were combined to
give 2-amino-3-iodo-5-nitropyridine (12.7 g, 95%); mp 228–231
°C [Lit.5 237 °C].
13C NMR (101 MHz, DMSO-d6): d = 27.4, 43.8, 112.4, 122.1,
131.1, 145.9, 165.4.
HRMS (TOF, EI+): m/z [M]+ calcd for C7H8N2: 120.0687; found:
120.0683.
5-Nitro-7-azaindoline (7)
7-Azaindoline (2.00 g, 16.7 mmol) was dissolved in EtOH (70 mL).
Ferric nitrate nonahydrate (8.33 g, 20.6 mmol) was added, and the
mixture stirred at ambient temperature for 1 h, increasing to 50 °C
for 2 h, then at reflux for 16 h. The mixture was cooled and filtered
through a pad of diatomaceous earth. The filtrate was evaporated
onto diatomaceous earth; this was loaded onto a silica column
which had been equilibrated with 25% EtOAc in i-hexane. The col-
umn was eluted with 25–50% EtOAc in i-hexane. Evaporation of
the appropriate fractions gave 5-nitro-7-azaindoline as a light
brown solid (950 mg, 35%); mp 155–160 °C [Lit.1 260.5–261.5 °C].
1H NMR (400 MHz, DMSO-d6): d = 3.26 (t, J = 7.9 Hz, 2 H), 4.14
(t, J = 7.9 Hz, 2 H), 8.66 (s, 1 H), 9.18 (s, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 7.60 (v br s, 2 H), 8.57 (d, J =
2.2 Hz, 1 H), 8.84 (d, J = 2.2 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): d = 23.9, 46.3, 128.4, 131.1,
143.6, 145.1, 157.2.
13C NMR (101 MHz, DMSO-d6): d = 75.4, 135.1, 142.0, 146.1,
162.6.
HRMS (TOF, EI+): m/z [M]+ calcd for C7H7N3O2: 165.0538; found:
165.0542.
HRMS (TOF, ES+): m/z [MH]+ calcd for C5H4N3O2I: 265.9427;
found: 265.9446.
5-Nitro-7-azaindole (8)
2-Amino-5-nitro-3-[(trimethylsilyl)ethynyl]pyridine (11)
5-Nitro-7-azaindoline (1.90 g, 11.5 mmol) was suspended in tolu-
ene (125 mL), and the mixture was heated to reflux. Manganese di-
oxide (3.0 g, 34.5 mmol) was added and the mixture was heated at
reflux. At intervals of 2 h and 4 h, manganese dioxide (3.0 g, 34.5
mmol) was added. After a total of 6 h at reflux, the mixture was fil-
tered hot through a pad of diatomaceous earth. The diatomaceous
earth was washed with MeOH–CH2Cl2 (1:1, 4 × 100 mL). The com-
bined filtrates were evaporated onto silica; this was loaded onto a
silica column, which had been equilibrated with CH2Cl2. The col-
umn was eluted with 0–2% MeOH in CH2Cl2. Evaporation of the
appropriate fractions gave the pure product (300 mg), together with
the material of inferior quality (1200 mg). Repeated chromatogra-
phy with the above solvent system gave 5-nitro-7-azaindole as a
2-Amino-3-iodo-5-nitropyridine (2.00 g, 7.55 mmol) was dissolved
in a mixture of Et3N (50 mL), THF (8 mL) and DMA (16 mL), and
the solution was degassed and purged with N2 (3 ×). Trimethylsilyl-
acetylene (1.60 mL, 11.3 mmol), copper(I) iodide (29 mg, 0.15
mmol) and bis(triphenylphosphino) palladium(II) chloride (106
mg, 0.15 mmol) were added. The mixture was degassed and purged
with N2 one more time, then stirred at ambient temperature for 16 h.
A yellow solution containing a white precipitate resulted; the pre-
cipitate was removed by filtration, and the filtrate was concentrated
in vacuo. The residue was redissolved in the minimum volume of
CH2Cl2, and loaded onto a silica column which had been equilibrat-
ed with 15% EtOAc in i-hexane. The column was eluted with 15%
EtOAc in i-hexane to remove impurities, increasing to 35% EtOAc
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2506
S. E. Pearson, S. Nandan
PAPER
in i-hexane to elute the product. The appropriate fractions were
evaporated, and the residue triturated with i-hexane to give 2-ami-
no-5-nitro-3-[(trimethylsilyl)ethynyl]pyridine as a yellow solid
(1.65 g, 93%); mp 200–202 °C.
13C NMR (101 MHz, CDCl3): d = 100.0, 115.1, 121.0, 126.1, 133.6,
136.8, 144.6.
HRMS (TOF, EI+): m/z [M]+ calcd for C7H7N3: 133.0640; found:
133.0640.
1H NMR (400 MHz, CDCl3): d = 0.29 (s, 9 H), 5.84 (br s, 2 H), 8.32
(d, J = 2.6 Hz, 1 H), 8.92 (d, J = 2.6 Hz, 1 H).
References
13C NMR (101 MHz, CDCl3): d = 0.0, 97.8, 102.7, 104.0, 135.4,
136.4, 146.0, 162.1.
(1) Robison, M. M.; Robison, B. L.; Butler, F. P. J. Am. Chem.
Soc. 1959, 81, 743.
(2) Bhide, R.; Ruel, R.; Thibeault, C.; L’heureux, A. PCT Int.
Appl., WO 2004009601, 2004.
HRMS (TOF, ES+): m/z [MH]+ calcd for C10H13N3O2Si: 236.0855;
found: 236.0851.
(3) Poirier, J.-M.; Vottero, C. Tetrahedron 1989, 45, 1415.
(4) (a) Park, S. S.; Choi, J.-K.; Yum, E. K.; Ha, D.-C.
Tetrahedron Lett. 1998, 39, 627. (b) Kumar, V.; Dority, J.
A.; Bacon, E. R.; Singh, B.; Lesher, G. Y. J. Org. Chem.
1992, 57, 6995. (c) Wensbo, D.; Eriksson, A.; Jeschke, T.;
Annby, U.; Gronowitz, S.; Cohen, L. A. Tetrahedron Lett.
1993, 34, 2823. (d) Xu, L.; Lewis, I. R.; Davidsen, S. K.;
Summers, J. B. Tetrahedron Lett. 1998, 39, 5159.
(e) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.;
Pérez, M.; García-Martín, M. A.; González, J. M. J. Org.
Chem. 1996, 61, 5804.
5-Amino-7-azaindole (3) from 11
2-Amino-5-nitro-3-[(trimethylsilyl)ethynyl]pyridine (700 mg, 2.98
mmol) and copper(I) iodide (114 mg, 0.60 mmol) were dissolved in
NMP (14 mL). The mixture was irradiated in an Emrys Optimiser
focused microwave at 190 °C for 30 min. The mixture was evapo-
rated (95 °C, 2 mbar) onto diatomaceous earth (5 g); the residue was
placed onto a short pad of silica in a sinter funnel, and eluted with
hot THF (ca 50 °C, 250 mL). The appropriate fractions (ca. 250 mL)
were combined, and purged with N2. Platinum on activated carbon
(10%, 200 mg) was added, and the mixture hydrogenated using a
burette filled with hydrogen for 6 h at ambient temperature. The
mixture was purged with N2, and the catalyst removed by filtration.
The filtrate was concentrated and the residue chromatographed with
0–3% MeOH in EtOAc. The product containing fractions were
evaporated, and the residue was triturated with Et2O to give 5-ami-
no-7-azaindole as a colourless crystalline solid (296 mg, 75%); mp
127–129 °C [Lit.1 130.5–131.5 °C].
(5) Batkowski, T. Rocz. Chem. 1969, 43, 1623; Chem. Abstr.
1969, 72, 21575.
(6) Compound synthesised on 10-g scale using this method by
GVK Biosciences Pvt. Ltd. 210, My Home Tycoon, 6-3-
1192, Kundan Bagh, Begumpet, Hyderabad – 500016, India.
(7) Taylor, E. C.; Macor, J. E.; Pont, J. L. Tetrahedron 1987, 43,
5145.
1H NMR (400 MHz, DMSO-d6): d = 4.59 (br s, 2 H), 6.14 (dd, J =
3.5, 2.0 Hz, 1 H), 7.07 (d, J = 2.5 Hz, 1 H), 7.21 (dd, J = 3.5, 2.4 Hz,
1 H), 7.69 (d, J = 2.5 Hz, 1 H), 11.00 (br s, 1 H).
Synthesis 2005, No. 15, 2503–2506 © Thieme Stuttgart · New York