Synthesis of Substituted Imidazo[1, 5-a]pyrimidines, 1H-pyrrolo[2, 3-b]pyridines and 3-methyl-3H-imidazo[4, 5-b]pyridines

Article abstract of DOI:10.2174/157017809787893000

Cyclization of in situ generated 5-aminoimidazoles with various malondialdehydes or 1, 3-diketones gave substituted imidazo[1, 5-a]pyrimidines. However, cyclization of 2-aminopyrroles and 5-amino-1-methylimidazoles resulted in condensations on a carbon at

Full text of DOI:10.2174/157017809787893000

Letters in Organic Chemistry, 2009, 6, 203-207
203
Synthesis of Substituted Imidazo[1,5-a]pyrimidines, 1H-pyrrolo[2,3-
b]pyridines and 3-methyl-3H-imidazo[4,5-b]pyridines
Jingshing Wu, Xuechao Xing and Gregory D. Cuny*
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital
and Harvard Medical School, 65 Landsdowne St., Cambridge, MA 02139, USA
Received July 31, 2008: Revised November 03, 2008: Accepted January 19, 2009
Abstract: Cyclization of in situ generated 5-aminoimidazoles with various malondialdehydes or 1,3-diketones gave
substituted imidazo[1,5-a]pyrimidines. However, cyclization of 2-aminopyrroles and 5-amino-1-methylimidazoles
resulted in condensations on a carbon atom of the heterocyclic ring instead of nitrogen generating 1H-pyrrolo[2,3-
b]pyridines (i.e. 7-azaindoles) and 3-methyl-3H-imidazo[4,5-b]pyridines, respectively. In these cases the addition of
pyrrolidine to the reaction mixture after the initial condensation between the amino group and one of the carbonyl groups
of the malondialdehydes or 1,3-diketones significantly increased the yields of 1H-pyrrolo[2,3-b]pyridines and 3-methyl-
3H-imidazo[4,5-b]pyridines.
Keywords: Imidazo[1,5-a]pyrimidines, 1H-pyrrolo[2,3-b]pyridines, 7-azaindoles, 3-methyl-3H-imidazo[4,5-b]pyridines, cycli-
zation.
Recently, dorsomorphin (1) was discovered as an inhibi-
tor of bone morphogenetic protein (BMP) induced SMAD
1/5/8 phosphorylation by BMP type 1 receptor kinases ALK
(activin receptor-like kinase)-2, -3, and -6 utilizing a pheno-
typic screen to identify compounds that perturb embryonic
dorsoventral axis formation, Fig. (1) [1]. SMADs are pro-
teins that are directly involved in the regulation of gene tran-
potential intermediate in the synthesis of 4. Herein we report
our efforts to prepare 5 that has resulted in methodology for
the cyclization of in situ generated 5-aminoimidazoles, 2-
aminopyrroles and 5-amino-1-methylimidazoles with various
malondialdehydes or 1,3-diketones yielding substituted imi-
dazo[1,5-a]pyrimidines [4], 1H-pyrrolo[2,3-b]pyridines [5]
and 3-methyl-3H-imidazo[4,5-b]pyridines [6], respectively.
HN
O
N
N
N
N
N
N
N
N
N
2
1
N
Fig. (1). BMP signaling inhibitors of SMAD 1/5/8 phosphorylation.
scription [2]. Furthermore, inhibitor 1 was shown to decrease
BMP-regulated hepatic hepcidin gene transcription, leading
to increased in vivo iron levels [1]. A structure-activity rela-
tionship (SAR) study of 1 yielded optimized compound 2
(LDN-193189 or DM-3189), which inhibits SMAD 1/5/8
phosphorylation with an EC50 = 4.9 nM [3].
In general, 5-aminoimidazoles can be unstable and diffi-
cult to isolate. However, 5-aminoimidazoles were readily
generated in situ from the corresponding 5-nitroimidazoles
in the presence of hydrogen (1 atm) and 5% Pd/C in metha-
nol for 1 h at ambient temperature. Once the reduction was
complete, addition of various malondialdehydes or 1,3-
diketones in a mixture of methanol and acetic acid resulted
in the generation of substituted imidazo[1,5-a]pyrimidines in
moderate to excellent yields after heating at reflux for 16 h
[7]. For example, reduction of 6 followed by treatment with
4-methoxyphenylmalondialdehyde gave 7a in 72% isolated
yield (Table 1, entry 1) [8]. In the case of 3-bromophenyl-
malondialdehyde the resulting product 7b was generated in
lower yields (entry 2). However, utilizing phenylmalondial-
dehyde and several 1,3-diketones the resulting substituted
In the course of further SAR exploration of 2, changing
the pyrazolo[1,5-a]pyrimidine (i.e. 3) to either an imi-
dazo[1,5-a]pyrimidine and a pyrrolo[1,2-a]pyrimidine (i.e. 4)
was envisioned Fig. (2). Derivative 5 was contemplated as a
*Address correspondence to this author at the Laboratory for Drug Discov-
ery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham &
Women’s Hospital and Harvard Medical School, 65 Landsdowne St., Cam-
bridge, MA 02139, USA; Tel: +1-617-768-8640; Fax: +1-617-768-8606;
E-mail: gcuny@rics.bwh.harvard.edu
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

204 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Wu et al.
CO2R
X
Ar
Ar
Ar
N
N
N
N
X
N
N
N
Ar
Ar
4, X = N or CH
5, X = N or CH
3
Fig. (2). Imidazo[1,5-a]pyrimidines (4 and 5, X = N) and pyrrolo[1,2-a]pyrimidines (4 and 5, X = CH).
Table 1. Preparation of imidazo[1,5-a]pyrimidines 7
R1
CO2Et
CO2Et
N
H2 (1 atm), 5% Pd/C,
MeOH, rt
R2
R1
N
HN
N
then
N
O2N
R1C(O)CHR2C(O)R1,
6
7
MeOH, AcOH, ꢀ
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
H
H
H
4-OMePh
7a
7b
7c
7d
7e
72
23
62
77
79
3-BrPh
Ph
Me
Me
H
Ph
imidazo[1,5-a]pyrimidines were obtained in good yields (en-
tries 3 - 5).
malondialdehydes also gave 7-azaindoles 9b and 9c, albeit in
better yields (entries 2 and 3). 1,3-Diketones reacted in a
similar manner to give 1H-pyrrolo[2,3-b]pyridines 9d and 9e
in moderate to good yields (entries 4 and 5) [10].
Next, the 2-nitropyrrole 8 was similarly reduced in situ
and then treated with phenylmalondialdehyde. However, the
corresponding pyrrolo[1,2-a]pyrimidine was not obtained.
Instead cyclization on the C-3 carbon gave the 1H-
pyrrolo[2,3-b]pyridine 9a in low yield (Table 2, entry 1) [9].
Likewise, 3-bromo- and 4-methoxy substituted phenyl-
The initial reaction of malondialdehydes and 1,3-
diketones with the in situ generated 5-aminoimidazoles or 2-
aminopyrroles presumably involves carboxyl condensation
of the aldehydes or ketones with the newly generated amino
Table 2. Preparation of 1H-pyrrolo[2,3-b]pyridine 9
CO2Me
CO2Me
H2 (1 atm), 5% Pd/C,
HN
MeOH, rt
HN
N
then
R1
O2N
R1C(O)CHR2C(O)R1,
additive, MeOH, AcOH, ꢀ
R1
8
R2
9
Entry
Additivea
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
---
H
Ph
9a
9b
9c
9d
9e
9a
9b
7
---
---
H
H
3-BrPh
20
59
29
83
31
42
4-OMePh
---
Me
Me
H
Ph
H
---
pyrrolidine
pyrrolidine
Ph
H
3-BrPh
a1.0 equivalent added 20 min after addition of malondialdehydes or 1,3-diketones.

Cyclization of In Situ Generated 5-aminoimidazoles, 2-aminopyrroles
Letters in Organic Chemistry, 2009, Vol. 6, No. 3 205
CO2Me
CO2Me
CO2Me
R3
R1 HN
N
R3
R1 HN
N
HN
N
O
H2N
R2
R2
10
12
11
CO2Me
HN
N
R3
R1
R2
9
Scheme 1. Use of pyrrolidine to increase yields of 1H-pyrrolo[2,3-b]pyridine.
groups. In the case of the imidazoles the second condensa-
tion with the heterocyclic nitrogen appears to be fairly rapid
leading to imidazo[1,5-a]pyrimidines. However, with the
pyrroles reaction at C-3 appears to be much slower possibly
leading to undesired side-reactions. Addition of a secondary
amine, like pyrrolidine, could intercept intermediate 11 gen-
erating 12, which may be more stable under the prolonged
reaction conditions resulting in increased yields of the de-
sired products 9 (Scheme 2). In order to test this concept, 1
equivalent of pyrrolidine was added to the reaction mixture
20 min after the addition of phenylmalondialdehydes. As a
result, 8 was converted into 9a and 9b in significantly
greater yields than without the addition of pyrrolidine (Table
2, entries 6 and 7). Interestingly, simultaneous addition of
the pyrrolidine with the malondialdehydes was detrimental
further supporting the hypothesized role of the secondary
amine as outlined in Scheme 1.
In the case of 13, where the imidazole nitrogen is substi-
tuted, cyclization takes place on carbon similar to the pyrrole
substrates resulting in formation of 3-methyl-3H-
imidazo[4,5-b]pyridines 14 (Table 3) [11]. Again, the addi-
tion of an equivalent of pyrrolidine 20 min after the addition
of the malondialdehydes or 1,3-diketones resulted in in-
creased yields. For example, in situ reduction of 13 followed
by treatment with 4-methoxyphenylmalondialdehyde gave 3-
methyl-3H-imidazo[4,5-b]pyridines 14e in 10% yield (Table
3, entry 8). However, addition of pyrrolidine resulted in a
four-fold increase in yield of 14e to a moderate 42% (entry
9) [10].
Table 3. Preparation of 3-methyl-3H-imidazo[4,5-b]pyridines 14
CO2Me
Me
CO2Me
N
H2 (1 atm), 5% Pd/C,
Me
N
MeOH, rt
N
N
N
then
R1
O2N
R1C(O)CHR2C(O)R1,
R1
R2
additive, MeOH, AcOH, ꢀ
13
14
Entry
Additivea
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
---
Me
Me
Me
Me
H
H
H
14a
14a
15b
14b
14c
14d
14d
14e
14e
4
pyrrolidine
---
17
36
53
28
12
30
10
42
Ph
Ph
Ph
pyrrolidine
pyrrolidine
---
H
3-BrPh
3-BrPh
pyrrolidine
---
H
H
4-OMePh
4-OMePh
pyrrolidine
H
a1.0 equivalent added 20 min after addition of malondialdehydes or 1,3-diketones.

206 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Wu et al.
MeO
CO2Et
N
a
b
H
H
N
N
CO2Et
CO2Et
O2N
N
N
N
N
15
6
7a
MeO
CO2Et
N
MeO
CO2Et
N
N
c
d
N
N
N
Br
16
17
N
MeO
N
e
N
N
18
N
Scheme 2. Synthesis of BMP signaling inhibitor analog 18. Reagents and conditions: (a) H2SO4, fuming HNO3 (1/1, v/v), 0 °C to 50 °C, 3 h,
59%; (b) H2 (1 atm), Pd/C (5%), MeOH, 1 h and then 4-MeOPhCH(CHO)2, AcOH, MeOH, reflux, 16 h, 71%; (c) NBS, CH2Cl2, 0.5 h, 93%;
(d) quinoline-4-boronic acid, Pd(PPh3)4, Na2CO3 (2.0 M), 1,4-dioxane, reflux, 16 h, 38%; (e) H2SO4 (40%, v/v), 110 °C, 4 h, 56%.
The methodology developed for the synthesis of imi-
dazo[1,5-a]pyrimidines was utilized to prepare the BMP sig-
naling inhibitor analog 18 (Scheme 2). Imidazole 15 was
regioselectively nitrated with fuming nitric acid to give 6
[12]. In situ reduction of the nitro group followed by con-
densation with 4-methoxyphenylmalondialdehyde gave imi-
dazo[1,5-a]pyrimidine 7a in 71% yield. Regioselective bro-
mination with N-bromosuccinimide (NBS) generated 16 [3].
A palladium-mediated coupling of bromide 16 with quino-
line-4-boronic acid produced 17 [3]. Finally, treatment of 17
with aqueous sulfuric acid (40%, v/v) at 110 °C for 4 h gave
18 [13] in 56% yield via ester hydrolysis followed by decar-
boxylation.
tional imidazo[1,5-a]pyrimidines, 1H-pyrrolo[2,3-b]pyridines
and 3-methyl-3H-imidazo[4,5-b]pyridines derivatives that
can be used for various applications, including screening for
biological activities.
ACKNOWLEDGEMENTS
Financial support was provided by the Harvard Neuro-
Discovery Center (XX and GDC), Partners Healthcare (XX
and GDC) and Harvard College’s Undergraduate Research
Program (JW).
REFERENCES AND NOTES
In conclusion, cyclization of in situ generated 5-
aminoimidazoles with various malondialdehydes or 1,3-
diketones gave substituted imidazo[1,5-a]pyrimidines. How-
ever, under similar reaction conditions cyclization of 2-
aminopyrroles and 5-amino-1-methylimidazoles resulted in
condensations on a carbon atom of the heterocyclic ring in-
stead of nitrogen generating 1H-pyrrolo[2,3-b]pyridines (i.e.
7-azaindoles) and 3-methyl-3H-imidazo[4,5-b]pyridines,
respectively. In these cases the addition of pyrrolidine to the
reaction mixture after the initial condensation between the
amino group and one of the carbonyl groups of the
malondialdehydes or 1,3-diketones significantly increase the
yields of 1H-pyrrolo[2,3-b]pyridines and 3-methyl-3H-
imidazo[4,5-b]pyridines. Furthermore, the protocol devel-
oped for the synthesis of imidazo[1,5-a]pyrimidines was
utilized to prepare a BMP signaling inhibitor analog. The
methods described herein will facilitate the synthesis of addi-
[1]
Yu, P.B.; Hong, C.C.; Sachidanandan, C.; Babitt, J.L.; Deng, D.Y.;
Hoyng, S.A.; Lin, H.Y.; Bloch, K.D.; Peterson, R.T. Nat. Chem.
Biol., 2008, 4, 33.
Ross, S.; Hill, C.S. Int. J. Biochem. Cell Biol., 2008, 40, 383.
Cuny, G.D.; Yu, P.B.; Laha, J.K.; Xing, X.; Liu, J.-F.; Lai, C.S.;
Deng, D.Y.; Sachidanandan, C.; Bloch, K.D.; Peterson, R.T.
Bioorg. Med. Chem. Lett., 2008, 18, 4388.
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Hajos, G.; Riedl, Z. Sci. Synth., 2002, 12, 613.
(a) Merour, J.-Y.; Joseph, B. Curr. Org. Chem., 2001, 5, 471; (b)
Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y. Tetrahedron,
2006, 63, 1031.
Yutilov, Y.M. Adv. Heterocycl. Chem., 2005, 89, 169.
For other examples of similar cyclizations see: (a) Chern, J.-W.;
Lee, C.-C.; Lin, S.-L.; Tung, C.-S. Chin. Pharm. J., 1996, 48, 37;
(b) Novinson, T.; O’Brien, D.E.; Robins, R.K. J. Heterocycl.
Chem., 1974, 11, 873; (c) Ochiai, E.; Sibata, M. Yakugaku Zasshi,
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[6]
[7]
[8]
General synthesis of imidazo[1,5-a]pyrimidines, exemplified for
the synthesis of 7a: A mixture of 6 (68 mg, 0.4 mmol), Pd/C (5%,
60 mg) and MeOH (16 mL) was stirred under argon for 5 min, then

Cyclization of In Situ Generated 5-aminoimidazoles, 2-aminopyrroles
Letters in Organic Chemistry, 2009, Vol. 6, No. 3 207
under H2 (1 atm) for 1h before removal of the catalyst by filtration
temperature, quenched with saturated NaHCO3 (~ 30 mL until pH
> 7) and extracted with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by chromatography on silica gel
using 9% MeOH in CH2Cl2 to give 9c, which was further purified
by washing with ethyl acetate leading to a yellow solid (84 mg,
59%). 1H NMR (500 MHz, DMSO-d6) ꢀ 12.23 (s, 1H), 8.74 (d, J =
2.0 Hz, 1H), 7.90 (m, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.24 (s, 1H),
7.08 (d, J = 9.0 Hz, 2H), 3.92 (s, 3H), 3.82 (s, 3H); 13C NMR (125
MHz, DMSO-d6) ꢀ 161.50, 159.13, 143.93, 143.17, 131.72, 130.65,
130.41, 129.85, 128.28 (2), 116.63, 114.63 (2), 107.31, 55.22,
52.11; HR MALDI/DHB: m/z: 283.1077 [M + H]+, calcd 283.1073.
For an examples of similar cyclizations see: Blache, Y.; Gueiffier,
A.; Chavignon, O.; Viols, H.; Teulade, J.C.; Chapat, J.P. Heterocy-
cles, 1994, 38, 1527.
through
Celite.
To
the
filtrate
was
added
2-(4-
methoxyphenyl)malondialdehyde (72 mg, 0.4 mmol) followed by
AcOH (3 mL). The resulting reaction mixture was heated at reflux
overnight, then allowed to cool to room temperature, quenched
with saturated NaHCO3 (~ 30 mL until pH > 7) and extracted with
ethyl acetate. The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by chromatog-
raphy on silica gel using 5% MeOH in CH2Cl2 to give 7a as a yel-
low solid (85 mg, 72%). 1H NMR (500 MHz, CDCl3) ꢀ 9.63 (dd, J
= 0.5, 2.5 Hz, 1H), 8.68 (d, J = 2.5 Hz, 1H), 7.84 (d, J = 0.5 Hz,
1H), 7.58 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 4.52 (q, J =
7.0 Hz, 2H), 3.89 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H); 13C NMR (125
MHz, DMSO-d6) ꢀ 159.95, 158.79, 149.13, 140.02, 128.34 (2),
127.56, 125.48, 124.66, 123.45, 121.22, 114.89 (2), 60.87, 55.32,
14.19; HR MALDI/DHB: m/z: 298.1186 [M + H]+, calcd 298.1181.
For other examples of similar cyclizations see: (a) Wesch, T.; Iaro-
shenko, V.O.; Groth, U. Synlett, 2008, 1459; (b) Semichenko, E.S.;
Root, E.V.; Pokrovskii, L.M.; Suboch, G.A. Russ. J. Org. Chem.,
43, 406; (c) Kurihara, T.; Tani, T.; Imai, H.; Nasu, K. Chem.
Pharm. Bull., 1980, 28, 2972.
General synthesis of 1H-pyrrolo[2,3-b]pyridines and 3-methyl-3H-
imidazo[4,5-b]pyridines, exemplified for the synthesis of 9c: A
mixture of 8 (86 mg, 0.5 mmol), Pd/C (5%, 20 mg) and MeOH (4
mL) was stirred under argon for 5 min, then under H2 (1 atm) for
1.5 h before removal of the catalyst by filtration through Celite. To
the filtrate was added 2-(4-methoxyphenyl)malondialdehyde (89
mg, 0.5 mmol) followed by AcOH (1 mL). The resulting reaction
mixture was stirred 1 d at reflux and then allowed to cool to room
[11]
[12]
[13]
Zimmermann, H.; Brueckner, D.; Henninger, K.; Rosentreter, U.;
Hendrix, M.; Heldenich, J.; Lang, D.; Radtke, M.; Paulsen, D.;
Kern, A. WO2006089664, 2006.
[9]
1H NMR (500 MHz, CDCl3) ꢀ 9.02 (d, J = 4.0 Hz, 1H), 8.98 (d, J =
7.0 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.32
(s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 4.5 Hz, 1H), 7.76-
7.72 (m, 1H), 7.62-7.58 (m, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.08 (d,
J = 9.0 Hz, 2H), 3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) ꢀ
160.65, 150.20, 149.50, 148.59, 138.63, 136.30, 129.98, 129.28,
128.31 (2), 127.99, 127.17, 126.63, 126.51, 126.09, 125.39, 125.07,
123.57, 121.36, 115.27 (2), 55.69; HR MALDI/DHB: m/z:
353.1396 [M + H]+, calcd 353.1392.
[10]