One-step construction of 2-substituted-4,6-diazaindoles from carboxylic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.04.080

Treatment of unprotected 5-amino-4-methylpyrimidine (2) with n-BuLi gave dianion 3. Direct condensation of the dianion with various carboxylic acid derivatives furnished a range of 2-substituted-4,6-diazaindoles in good yields in one step without the need

Full text of DOI:10.1016/j.tetlet.2009.04.080

Tetrahedron Letters 50 (2009) 3952–3954
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-step construction of 2-substituted-4,6-diazaindoles from carboxylic
acid derivatives
*
Jinhua J. Song , Zhulin Tan, Jonathan T. Reeves, Daniel R. Fandrick, Heewon Lee,
Nathan K. Yee, Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road/PO Box 368, Ridgefield, CT 06877-0368, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of unprotected 5-amino-4-methylpyrimidine (2) with n-BuLi gave dianion 3. Direct condensa-
tion of the dianion with various carboxylic acid derivatives furnished a range of 2-substituted-4,6-diaz-
aindoles in good yields in one step without the need for protecting groups or oxidation-state adjustment.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 20 March 2009
Revised 21 April 2009
Accepted 21 April 2009
Available online 3 May 2009
1. Introduction
extended to the construction of diazaindoles. In this Letter, we
wish to report that this strategy was indeed successful and 2-
The indole nucleus is one of the most important heterocycles
and constitutes an essential structural element for a large number
of biologically interesting molecules. The wide application of in-
doles in medical sciences has stimulated the development of
numerous methodologies for its synthesis.1 Substituting the car-
bon atoms at positions 4–7 in the indole ring with one or two
nitrogen atoms gives the so-called azaindoles or diazaindoles.
Azaindoles and diazaindoles are often employed as indole bioisos-
teres to modulate biological activities of drug molecules. However,
in contrast to indole synthesis, there is a very limited collection of
methods for the construction of azaindoles and diazaindoles. Fur-
thermore, most of the known methods require multiple steps
and/or harsh reaction conditions.2
Previously, we have reported a one-step method for the synthe-
sis of 2-substituted-6-azaindoles from carboxylic esters (Fig. 1).3
Dilithiation of 3-amino-4-picoline (1) with s-BuLi gave the corre-
sponding dianion which was allowed to condense with a range of
esters to furnish 2-substituted-6-azaindoles in one operation with-
out the need for a protecting group.4 The commercial availability of
3-amino-4-picoline and the ready availability of esters render this
method very practical. As part of our research program, we also
needed a method for making 4,6-diazaindole analogues. Only a
small number of scattering reports could be found in the literature
for the synthesis of this structural motif.5,6 For example, a few 4,6-
diazaindoles were synthesized via a sequence consisting of a
Sonogashira coupling followed by base-mediated cyclizations.
However, the overall transformation to diazaindoles from com-
mercially available materials required at least 4 synthetic steps.
To address this synthetic challenge, we wondered if the dianion
chemistry that we employed for 6-azaindole formation could be
substituted-4,6-diazaindoles could be constructed in one step via
condensation of carboxylic acid derivatives and the commercially
available 5-amino-4-methylpyrimidine.7
2. Results and discussion
On the basis of our experience with dilithiation of 3-amino-4-
picoline, we have started our study by treating 5-amino-4-methyl-
pyrimidine with a few strong bases. The extent of dilithiation was
measured by deuterium incorporation at the methyl group as
determined using 1H NMRs. It was found that the use of n-BuLi
was effective to give dianion 3 in 48% yield in THF (Table 1, entry
1).8 No significant side reaction was occurring with the pyrimidine
ring. The use of s-BuLi gave the dianion in a much lower yield (en-
try 2). Treatment of compound 2 with MeLi also afforded the dian-
ion in 47% yield in THF and 16% yield in DME (entries 3 and 4). LDA
gave only 12% yield of dianion intermediate (entry 5). LHMDS was
not basic enough to effect dilithiation (entry 6).
s-BuLi
N
rt, 3 h, THF
N
then esters
RCO2R1
N
H
R
H2N
6-azaindoles
1
One-Step
N
N
N
?
N
N
H
R
H2N
4,6-diazaindoles
2
* Corresponding author. Tel.: +1 203 791 6207; fax: +1 203 791 5927.
E-mail address: jeff.song@boehringer-ingelheim.com (J.J. Song).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.080

J. J. Song et al. / Tetrahedron Letters 50 (2009) 3952–3954
3953
Table 1
Table 2
Dilithiation of 5-amino-4-methylpyrimidine
One-step diazaindole formation via dianion of 5-amino-4-methylpyrimidine
N
N
N
Li
Li
MeOD
D
base
N
N
N
N
N
HN
Li
H2N
O
H2N
R
4
+
N
Li
N
3
N
H
2
R
Z
N
H
Entry
Base
Solvent
Temp (°C)
Time (h)
D-incorporation in 4a (%)
Z = OR1, SR1, Cl or NR1R2
1
2
3
4
5
6
n-BuLi
s-BuLi
MeLi
MeLi
LDA
THF
THF
THF
DME
THF
THF
À70 to 23
À70 to 23
À50 to 10
À20
3
3
18
2.5
3
48
20
47
16
12
0
Entry
1
Substrate
Product
Yield (%)
68a
À70 to 23
À70 to 23
N
LHMDS
3
O
O
O
O
Ph
Determined by 1H NMR.
a
N
N
H
Ph
Ph
Ph
OEt
6a
Having identified a procedure that allowed for the generation of
the key dianion intermediate 3, we proceeded to test its condensa-
tion reactions with carboxylic acid derivatives using ethyl benzo-
ate as the initial substrate. Ethyl benzoate was added into the
dianion at À40 °C. After 0.5 h at that temperature, the reaction
mixture was warmed to room temperature for 1 h. The reaction
was quenched with methanol and treated with aq HCl to complete
the cyclization/dehydration. Then the reaction mixture was neu-
tralized to pH 8 and extractive workup was carried out to give
the product mixture which was subjected to crystallization in
EtOAc to furnish compound 6a in 68% yield as a tan-colored solid
(Table 2, entry 1). Presumably, the reaction proceeded through a
number of transformations as indicated in Figure 2.
2
3
4
5
68a
68a
24a
67a
O
NMe(OMe)
Ph
Br
Cl
Br
N
O
N
OMe
N
H
6b
The new method was also applied to a variety of other carbox-
ylic acid derivatives. It is worth noting that t-butyl benzoate and
Weinreb amide of benzoic acid worked equally well to give com-
pound 6a in 68% yields (Table 2, entries 2 and 3). Even benzoyl
chloride could be condensed with this dianion to provide the de-
sired product 6a in 24% yield (entry 4). Reaction with methyl 3-
bromobenzoate gave 67% yield without the detection of the debro-
minated byproduct (entry 5). Enolizable esters such as methyl
hydrocinnamate and methyl butyrate gave 63% and 54% yields,
respectively (entries 6 and 7). Thioester was also successfully uti-
lized for this reaction (entry 8). The sterically demanding adaman-
tyl-substituted ester gave product 6e in 77% yield (entry 9). Finally
a lactone substrate was converted into compound 6f in 51% yield
(entry 10).
In conclusion, we have described a one-step method for an
expedient and facile access to a range of 2-substituted-4,6-diazain-
doles in good to moderate yields. Treatment of the unprotected 5-
amino-4-methylpyrimidine with n-BuLi generated dianion 3 which
was allowed to react with various esters, an amide, an acid chlo-
ride, and a thioester to give the corresponding diazaindole prod-
ucts in a single synthetic step. This method uses inexpensive
reagents and readily available starting materials. It does not re-
quire the use of protecting groups and is operationally simple.
We believe that this new method will prove to be useful for the
synthesis of diazaindole-containing compounds.
N
O
N
6
63b
N
H
6c
Ph
Ph
OMe
N
O
O
54b
47a
77a
N
7
8
9
N
H
6d
OMe
SMe
N
Ad
N
N
H
6e
CO2Et
N
O
β-Naphthyl
N
10
51b
O
N
H
HO
6f
a
Isolated yields by crystallization.
Isolated yields by chromatography.
b
solved in ca. 2 mL THF; ca. 0.5 mL rinse) was added and the result-
ing mixture was stirred at À40 °C for 0.5 h and warmed to rt for
1 h. Methanol (15 mL) was added in 5 min followed by HCl
(10 mL 6 N aq). The solution was stirred for 15 h at rt. The mixture
was neutralized with NaHCO3 (50 mL, pH 8). EtOAc (100 mL) and
water (50 mL) were added. Then organic layer was washed with
water (50 mL) three times. The crude product mixture was purified
by silica gel chromatography (CH2Cl2/MeOH) or crystallization
(EtOAc/hexanes) to give product in yields reported in Table 2. Cop-
ies of 1H and 13C NMR of isolated products are provided as Supple-
mentary data to demonstrate homogeneity of samples. Purities of
3. Experimental
3.1. General procedure
5-Amino-4-methylpyrimidine (1.09 g, 10 mmol) was dissolved
in anhydrous THF (50 mL) in a dry flask under nitrogen. The solu-
tion was cooled to À20 °C and a solution of n-BuLi (2.5 M in hex-
anes, 10 mL, 25 mmol) was added in 10 min. The solution was
kept at À20 °C for 30 min and then warmed to rt, stirred at that
temperature for 3 h, and cooled to À40 °C. Substrate (3 mmol, dis-

3954
J. J. Song et al. / Tetrahedron Letters 50 (2009) 3952–3954
3.1.5. 6-Adamantan-1-yl-5H-pyrrolo[3,2-d]pyrimidine (6e)
N
Ph
N
1H NMR (DMSO-d6, 400 MHz) d 11.63 (s, 1H), 8.71 (s, 2H), 6.30
(s, 1H), 2.05 (s, 3H), 1.97 (s, 6H), 1.74 (s, 6H). 13C NMR (DMSO-d6,
100 MHz) d 157.6, 149.8, 138.1, 127.1, 95.5, 41.2, 36.0, 34.0, 27.7.
HPLC: 100 area%. HRMS calcd for the [M+1]+: 254.1651, found:
254.1657.
N
PhCO2Et
Ph
LiO
Li
N
O
N
N
H
-40 o
C
N
HN
Li
HN
Li
5
3
4
N
Ph
N
3.1.6. 1-Naphthalen-2-yl-3-(5H-pyrrolo[3,2-d]pyrimidin-6-yl)-
propan-1-ol (6f)
N
H
6a
Figure 2. Proposed reaction pathway.
1H NMR (DMSO-d6, 400 MHz) d 11.71 (br s, 1H), 8.71 (s, 1H),
8.70 (s, 1H), 8.00–7.85 (m, 4H), 7.57–7.42 (m, 3H), 6.38 (s, 1H),
5.50 (d, J = 4.40 Hz, 1H), 4.78 (ddd, J = 7.20, 5.30, 5.30 Hz, 1H),
2.97–2.82 (m, 2H), 2.22–2.05 (m, 2H). 13C NMR (DMSO-d6,
100 MHz) d 150.3, 149.8, 149.1, 143.3, 137.9, 132.8, 132.2, 127.7,
127.6, 127.5, 127.2, 126.0, 125.5, 124.5, 124.0, 98.4, 71.5, 37.7,
24.6. HPLC: 100 area%. HRMS calcd for the [M+1]+: 304.1444,
found: 304.1454.
isolated products were also measured by HPLC. HPLC method: Tos-
m; wave-
ohass super-ODS column 4.6 mm  5 cm, particle size 2
l
length 220 nm; gradient 10% acetonitrile/water (with 0.05%
trifluoroacetic acid) to 90% in 3.5 min, hold 1.5 min; flow rate
2 mL/min at 25 °C.
Supplementary data
3.1.1. 6-Phenyl-5H-pyrrolo[3,2-d]pyrimidine (6a)
1H NMR (DMSO-d6, 400 MHz) d 12.31 (br s, 1H), 8.87 (s, 1H),
8.81 (s, 1H), 8.00 (d, J = 7.36 Hz, 2H), 7.54 (t, J = 7.32 Hz, 2H), 7.45
(m, 1H), 7.14 (s, 1H). 13C NMR (DMSO-d6, 100 MHz) d 150.5,
150.2, 144.9, 139.3, 130.6, 129.4, 129.1, 128.4, 126.2, 98.3. HPLC:
100 area%. HRMS calcd for the [M+1]+: 196.0869, found: 196.0873.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.080.
References and notes
1. For recent reviews on indole chemistry, see: (a) Humphrey, G. R.; Kuethe, J. T.
Chem. Rev. 2006, 106, 2875 and references cited therein; (b) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045 and references cited therein.
2. For recent reviews on azaindole synthesis, see: (a) Song, J. J.; Reeves, J. T.; Gallou,
F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120; (b)
Popowycz, F.; Merour, J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689.
3. Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.; Yee, N. K.; Senanayake, C. H. J. Org. Chem.
2005, 70, 6512.
4. For lateral carbolithiation-based indole and azaindole methods requiring the use
of protecting groups, see: (a) Smith, A. B., III; Visnick, M.; Haseltine, J. N.;
Sprengeler, P. A. Tetrahedron 1986, 42, 2957; (b) Hands, D.; Bishop, B.; Cameron,
M.; Edwards, J. S.; Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877.
5. For papers on synthesis of 4,6-diazaindoles, see: (a) Harcken, C.; Ward, Y.;
Thomson, D.; Riether, D. Synlett 2005, 3121; (b) Rodriguez, A. L.; Koradin, C.;
Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2488; (c) Cupps, T. L.;
Wise, D. S.; Townsend, L. B. J. Org. Chem. 1983, 48, 1060; (d) Norman, M. H.;
Chen, N.; Chen, Z.; Fotsch, C.; Hale, C.; Han, N.; Hurt, R.; Jenkins, T.; Kincaid, J.;
Liu, L.; Lu, Y.; Moreno, O.; Santora, V. J.; Sonnenberg, J. D.; Karbon, W. J. Med.
Chem. 2000, 43, 4288.
6. For papers on synthesis of other diazaindole isomers, see: (a) Ames, D. E.; Bull, D.
Tetrahedron 1982, 38, 383; (b) Ames, D. E.; Brohi, M. I. J. Chem. Soc., Perkin Trans.
1 1980, 1384; (c) Vierfond, J. M.; Mettey, Y.; Mascrier-Demagny, L.; Miocque, M.
Tetrahedron Lett. 1981, 22, 1219; (d) Crooks, P. A.; Robinson, B. Can. J. Chem.
1969, 47, 2061; (e) Klutchko, S.; Hansen, H. V.; Meltzer, R. I. J. Org. Chem. 1965,
30, 3454.
7. 5-Amino-4-methylpyrimidine is commercially available in multi-kilogram
quantities from several vendors.
8. For reviews on lateral lithiation reactions, see: (a) Clark, R. D.; Johangir, A. In
Organic Reactions; John Wiley & Sons: New York, 1995; Vol. 47; (b) Snieckus, V.
Chem. Rev. 1990, 90, 879; (c) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306.
3.1.2. 6-(3-Bromophenyl)-5H-pyrrolo[3,2-d]pyrimidine (6b)
1H NMR (DMSO-d6, 400 MHz) d 12.38 (br s, 1H), 8.90 (s, 1H),
8.82 (s, 1H), 8.24 (s, 1H), 8.01 (d, J = 7.80 Hz, 1H), 7.63 (d,
J = 7.96 Hz, 1H), 7.49 (t, J = 7.88 Hz, 1H), 7.24 (s, 1H). 13C NMR
(DMSO-d6, 100 MHz) d 150.6, 149.9, 143.0, 139.7, 132.9, 131.9,
131.2, 128.5, 128.4, 126.2, 125.2, 122.5, 99.4. HPLC: 100 area%.
HRMS calcd for the [M+1]+: 273.9974, found: 273.9989.
3.1.3. 6-Phenethyl-5H-pyrrolo[3,2-d]pyrimidine (6c)
1H NMR (DMSO-d6, 400 MHz) d 11.78 (br s, 1H), 8.74 (s, 1H),
8.70 (s, 1H), 7.27 (m, 4H), 7.18 (m, 1H), 6.36 (s, 1H), 3.12 (m,
2H), 3.05 (m, 2H). 13C NMR (DMSO-d6, 100 MHz) d 150.2, 149.9,
148.4, 140.7, 138.1, 128.3, 128.2, 127.1, 126.0, 98.8, 34.0, 29.7.
HPLC: 98.9 area%. HRMS calcd for the [M+1]+: 224.1182, found:
224.1190.
3.1.4. 6-Propyl-5H-pyrrolo[3,2-d]pyrimidine (6d) (known
compound5a
)
1H NMR (DMSO-d6, 400 MHz) d 11.70 (br s, 1H), 8.72 (s, 1H),
8.71 (s, 1H), 6.35 (d, J = 1.00 Hz, 1H), 2.79 (t, J = 7.52 Hz, 2H), 1.74
(m, 2H), 0.94 (t, J = 7.32 Hz, 3H). 13C NMR (DMSO-d6, 100 MHz) d
150.3, 149.8, 149.1, 146.6, 137.9, 127.2, 98.5, 29.9, 21.6, 13.6. HPLC:
100 area%. HRMS calcd for the [M+1]+: 162.1025, found: 162.1030.