A general and efficient synthesis of azaindoles and diazaindoles

Article abstract of DOI:10.1055/s-2005-922753

The DBU-mediated cyclization of ortho-(Boc-amino)alkynyl pyridines, -pyridazines, -pyrimidines and -pyrazines efficiently generates azaindoles and diazaindoles, respectively. The reaction proceeds under mild conditions and in high yields. A variety of fun

Full text of DOI:10.1055/s-2005-922753

LETTER
3121
A General and Efficient Synthesis of Azaindoles and Diazaindoles
Synthesis of
Aza
h
s
and
D
r
iazaind
ioles stian Harcken, Yancey Ward, David Thomson, Doris Riether*
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/P.O. Box 368, Ridgefield,
Connecticut 06877, USA
Fax +1(203)7916072; E-mail: driether@rdg.boehringer-ingelheim.com
Received 30 August 2005
variable and moderate yields were observed. This is likely
due to the difficult isolation of the polar azaindole prod-
ucts from the reaction mixture. For example, extraction
with ethyl acetate or dichloromethane results in a large
amount of NMP remaining in the organic layer, while oth-
er extraction circumvents this problem, but requires many
extractions to isolate the product in good yield. Addition-
ally, the strong basic conditions caused side reactions to
occur when certain functional groups were present. There-
fore, it was desirable to develop a synthetic method that
enabled the cyclization of ortho-(Boc-amino)alkynyl
pyridines and diazines using a milder base in a more con-
venient solvent.
Abstract: The DBU-mediated cyclization of ortho-(Boc-ami-
no)alkynyl pyridines, -pyridazines, -pyrimidines and -pyrazines
efficiently generates azaindoles and diazaindoles, respectively. The
reaction proceeds under mild conditions and in high yields. A
variety of functional groups are tolerated.
Key words: azaindole, diazaindoles, cyclization, heterocycles,
alkynes
Azaindoles (pyrrolopyridines) and related heteroaromatic
ring systems are common moieties in pharmaceutically
important molecules. A limited number of synthetic
routes to access azaindoles are described in the literature.
The Madelung indole synthesis has been applied in the
preparation of 4-, 5- and 6-azaindoles1 as well as 4,6-di-
azaindoles (pyrrolopyrimidines).2 The 4-, 5-, 6- and 7-
azaindole isomers have been generated either by the cy-
clization of ortho-nitro-alkenylpyridines3 or the palladi-
um-catalyzed heteroannulation of internal alkynes with
ortho-aminoiodopyridines.4 Recently, the addition of the
dianion of 3-amino-4-picoline to carboxylic esters has
been reported for the synthesis of 6-azaindoles.5
Recently, an example was described in the literature using
DBU in the base-mediated cyclization of an ortho-(Boc-
amino)alkynyl pyridine in the synthesis of a 5-azain-
dole.17 In this example the reaction is run in DMF and the
Boc group is retained on the indole nitrogen atom. This
result inspired us to use DBU as a base. Furthermore,
many azaindoles and diazaindoles can be precipitated
from methanol–water mixtures. The presence of base in
an aqueous medium should also lead to Boc-deprotection
of the N-Boc-azaindole cyclization product. Therefore,
we investigated the DBU-mediated cyclization of
ortho-(Boc-amino)alkynyl pyridines and diazines 1 in
MeOH–water (Scheme 1). To our delight, this reaction
occurred smoothly yielding the desired N-deprotected
azaindoles and diazaindoles 2 in good yield. Additionally,
the work up consisted simply of removal of methanol and
addition of water to precipitate the product with crude
purities >95%.
However, the most general method used for the synthesis
of azaindoles is the cyclization of ortho-amino-alkynyl
pyridines. Historically, this transformation has been per-
formed using either transition metal-mediated processes
or strong bases. The first copper-mediated cyclization of
ortho-amino-alkynyl anilines in the synthesis of an indole
was described in 1963.6 Since then, transition metal-
mediated conditions have been applied to the synthesis of
5-azaindoles,7,8 6-azaindoles,8 7-azaindoles,8,9 4,5-diaza-
indoles (pyrrolopyridazines),10 and 4,6-diazaindoles.11
These reactions have typically been run at high tempera-
tures (>100 °C) in DMF and generate product in moderate
yields.
R
N
R
N
DBU
MeOH/H2O
N
H
BocHN
Alternatively, strong bases have been employed: cycliza-
tions to give 4- or 5-azaindoles have been performed with
NaOEt in EtOH;12 4-azaindoles have been generated us-
ing NaNH2 in DMF,13 and 4,7-diazaindoles have been cy-
clized using methylamine.14 More recently, t-BuOK or
KH in NMP has been used to synthesize various azain-
doles and diazaindoles.15,16 This last method has a more
general scope regarding the pattern of ring substitution
and functional group tolerability. However, in our hands,
or
or
R
65–85 °C
1–18 h
N,N
R
N,N
N
BocHN
H
2
1
Scheme 1 DBU-mediated cyclization of ortho-(Boc-amino)alkynyl
pyridines, -pyridazines, -pyrimidines and -pyrazines (1) efficiently
generates azaindoles and diazaindoles (2), respectively.
Mechanistically, the process likely involves the de-
protonation of the carbamate nitrogen in 3, cyclization to
give N-Boc azaindole 4 and subsequent cleavage of the
SYNLETT 2005, No. 20, pp 3121–3125
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922753; Art ID: S08305ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.1
2
.2
0
0
5

3122
C. Harcken et al.
LETTER
carbamate group with hydroxide ion to give azaindole 6.
This mechanism is supported by the fact that treatment of
N-Boc azaindole 4 with aqueous DBU rapidly generates 6
(Scheme 2). Aniline 5 does not cyclize under these condi-
tions, indicating that the carbamate is required for the
cyclization step.
DBU
MeOH/H2O (3:1)
N
N
N
65 °C, 3 h
Boc
BocHN
3
4
To evaluate the scope and limitations of this methodolo-
gy, the synthesis of various heteroaromatic ring systems
was investigated (Table 1).
Boc-protection18 of ortho-iodo-substituted and ortho-
bromo-substituted aminopyridines and ortho-bromo-
substituted or ortho-chloro-substituted aminopyridazines,
-aminopyrimidines and -aminopyrazines followed by
Sonogashira coupling19 with terminal alkynes were per-
formed as described in the literature. These substrates
N
N
N
H
H2N
5
6
Scheme 2 Reaction mechanism
Table 1 Synthesis of Azaindole and Diazaindole Isomers
Substrate
Product
Conditions (temp, time)
Isolated yield (%)a
91
65 °C, 3 h
N
N
H
N
BocHN
8
7
9
65 °C, 12 h
86
85
N
N
N
H
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
BocHN
10
65 °C, 3 h
85 °C, 14 h
65 °C, 1 h
65 °C, 1 h
65 °C, 1 h
65 °C, 1 h
N
N
N
H
12
14
11
13
15
17
19
21
62
98
86
97
90
N
H
N
N
N
N
N
N
N
H
16
18
N
N
N
N
N
H
N
N
N
N
H
N
20
22
N
N
N
N
N
H
a Yields are not optimized.
Synlett 2005, No. 20, 3121–3125 © Thieme Stuttgart · New York

LETTER
Synthesis of Azaindoles and Diazaindoles
3123
were then subjected to the cyclization conditions. The py- pyridines such as 23, 25, and 27 containing an unprotected
ridine isomers 7, 9, and 11 cyclized readily giving 6-aza- hydroxy group cyclized giving the hydroxyalkyl sub-
indole 8, 5-azaindole 10, and 4-azaindole 12 respectively, stituted azaindoles 24, 26, and 28 in good yields.
in good yields (85–91%).20 The reactions were complete
after 3–12 hours at 65 °C. 2-(Boc-amino)pyridine 13
required an extended reaction time (14 h) at a higher
temperature (85 °C) to achieve complete conversion to 7-
With an increase in steric demand, a slight decrease in
reaction rate was observed, e.g. sterically demanding
substrate 27 required a reaction time of 15 hours at 85 °C
to afford complete conversion. The same was found for
azaindole 14 (62% isolated yield). (Boc-amino)-substitut-
aryl-substituted alkynes 29 and 31. Exploring additional
ed pyridazines 15 and 17, pyrimidine 19, and pyrazine 21
functional groups, we also found that free amines are tol-
erated. Thus, aniline 31 was converted to azaindole 32
without any significant side reactions. We were also
pleased to find, that in accordance with our mechanistic
rationale, carbamate protecting groups on basic nitrogens
such as in 33 are retained under the cyclization conditions.
were subjected to the same conditions. The corresponding
diazaindoles, pyrrolopyridazines 16 and 18, pyrrolopyri-
midine 20, and pyrrolopyrazine 22, were isolated in excel-
lent yields (86–98%). It should be noted that various
pyridines with additional substituents on the pyridine ring
cyclize under the same conditions.21
In conclusion, we have developed a simple, efficient, and
To further assess the tolerance of functional groups to the
general synthesis of all azaindole isomers and numerous
reaction conditions, 3-(Boc-amino)-4-iodopyridine was
diazaindole isomers via the cyclization of ortho-(Boc-
coupled with selected terminal alkynes yielding function-
amino)alkynyl pyridines and diazines using DBU in aque-
alized substrates (Table 2). 3-(Boc-amino)-4-alkynyl
ous methanol. In general, the reaction has proceeded to
Table 2 Synthesis of 2-Substituted 6-Azaindoles
Substrate
Product
Condition (temp, time)
65 °C, 4 h
Isolated yield (%)a
79
HO
HO
N
N
H
N
BocHN
24
23
65 °C, 4 h
72
71
HO
HO
N
N
N
BocHN
H
25
26
HO
85 °C, 15 h
HO
N
N
H
28
30
N
BocHN
27
85 °C, 12 h
66
88
N
N
H
N
BocHN
29
H2N
85 °C, 18 h
H2N
N
N
H
32
N
BocHN
31
65 °C, 1 h
78
BocHN
BocHN
N
N
H
N
BocHN
34
33
a Yields are not optimized.
Synlett 2005, No. 20, 3121–3125 © Thieme Stuttgart · New York

3124
C. Harcken et al.
LETTER
Data for Alkynes.
completion in high yield at 65 °C within a few hours. The
cyclization products have been precipitated from the reac-
tion mixture and the products have not required purifica-
tion by chromatography. Furthermore, we have shown
that various functional groups are tolerated.
Compound 7: prepared from (4-iodopyridin-3-yl)carbamic
acid tert-butyl ester.23 1H NMR (400 MHz, CDCl3): d = 9.35
(s, 1 H), 8.20 (d, J = 5.06 Hz, 1 H), 7.19 (d, J = 5.06 Hz, 1
H), 7.06 (s, 1 H), 2.51 (t, J = 7.07 Hz, 2 H), 1.72 (qt, J = 7.07
Hz, J = 7.33 Hz, 2 H), 1.55 (s, 9 H), 1.09 (t, J = 7.33 Hz, 3
H).
This methodology represents the most general method for
the synthesis of azaindoles and diazaindoles described in
the literature to date. We believe that this methodology
will find many applications in the synthesis of compounds
containing this class of heterocycles.
Compound 9: 1H NMR data are in accordance with data
reported in the literature.7
Compound 11: prepared from (2-bromopyridin-3-
yl)carbamic acid tert-butyl ester.22 1H NMR (400 MHz,
CDCl3): d = 8.42 (d, J = 9.08 Hz, 1 H), 8.19 (dd J = 1.39 Hz,
J = 4.67 Hz, 1 H), 7.18 (dd, J = 4.67 Hz, J = 8.57 Hz, 1 H),
2.53 (t, J = 7.08 Hz, 2 H), 1.74 (qt, J = 7.33 Hz, J = 7.08 Hz,
2 H), 1.54 (s, 9 H), 1.10 (t, J = 7.33 Hz, 3 H).
References
Compound 13: prepared from (3-iodopyridin-2-yl)carbamic
acid tert-butyl ester.24 1H NMR (400 MHz, CDCl3): d = 8.36
(dd, J = 5.05 Hz, J = 1.77 Hz, 1 H), 7.60 (dd, J = 7.58 Hz,
1.77 Hz, 1 H), 7.57 (s, 1 H), 6.90 (dd, J = 7.58 Hz, J = 5.05
Hz, 1 H), 2.49 (t, J = 7.07 Hz, 2 H), 1.69 (qt, J = 7.33 Hz,
J = 7.07 Hz, 2 H), 1.54 (s, 9 H), 1.09 (t, J = 7.33 Hz, 3 H).
Compound 15: 1H NMR (400 MHz, CDCl3): d = 9.74 (br s,
1 H), 9.29 (br s, 1 H), 6.90 (s, 1 H), 2.99 (t, J = 7.58 Hz, 2
H), 1.69 (m, 11 H), 0.99 (t, J = 7.33 Hz, 3 H).
(1) Hands, D.; Sishop, B.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877.
(2) Modnikova, G. A.; Titkova, R. M.; Glushkov, R. G.;
Sokolova, A. S.; Silin, V. A.; Chernov, V. A. Pharm. Chem.
J. 1988, 22, 135.
(3) Kuzmich, D.; Mulrooney, C. Synthesis 2003, 1671.
(4) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39,
5355.
(5) Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.; Yee, N. K.;
Senanayake, C. H. J. Org. Chem. 2005, 70, 6512.
(6) Castro, C. E.; Stevens, R. D. J. Org. Chem. 1963, 28, 2163.
(7) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B.
Tetrahedron Lett. 1998, 39, 5159.
(8) Mazéas, D.; Guillaumet, G.; Viaud, M.-C. Heterocycles
1999, 50, 1065.
(9) Kumar, V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G.
Y. J. Org. Chem. 1992, 57, 6995.
(10) Ames, D. E.; Bull, D. Tetrahedron 1982, 38, 383.
(11) 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.
Compound 17: 1H NMR (400 MHz, CDCl3): d = 8.97 (br s,
1 H), 7.92 (br s, 1 H), 6.74 (s, 1 H), 2.99 (t, J = 7.58 Hz, 2
H), 1.69 (qt, J = 7.58 Hz, J = 7.58 Hz, 2 H), 1.63 (s, 9 H),
1.01 (t, J = 7.58 Hz, 3 H).
Compound 19: 1H NMR (400 MHz, CDCl3): d = 9.41 (s, 1
H), 8.73 (s, 1 H), 6.96 (br s, 1 H), 2.49 (t, J = 7.08 Hz, 2 H),
1.66 (qt, J = 7.33 Hz, J = 7.08 Hz, 2 H), 1.48 (s, 9 H), 1.03
(t, J = 7.33 Hz, 3 H).
Compound 21: 1H NMR (400 MHz, CDCl3): d = 8.34 (br s,
1 H), 8.24 (br s, 1 H), 6.46 (br s, 1 H), 2.96 (t, J = 7.58 Hz, 2
H), 1.69 (qt, J = 7.58 Hz, J = 7.34 Hz, 2 H), 1.62 (s, 9 H),
0.99 (t, J = 7.34 Hz, 3 H).
Compound 23: 1H NMR (400 MHz, CDCl3): d = 9.32 (s, 1
H), 8.14 (d, J = 5.03 Hz, 1 H), 7.16 (d, J = 4.80 Hz, 1 H),
6.97 (s, 1 H), 4.53 (s, 2 H), 1.46 (s, 9 H).
(12) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Yamanaka, H. Chem.
Pharm. Bull. 1987, 35, 1823.
(13) Brière, J.-F.; Dupas, G.; Quéguiner, G.; Bourguignon, J.
Heterocycles 2000, 52, 1371.
(14) Ames, D. E.; Brohi, M. I. J. Chem. Soc., Perkin Trans. 1
1980, 1384.
(15) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.;
Knochel, P. Tetrahedron 2003, 59, 1571.
Compound 25: 1H NMR (400 MHz, CDCl3): d = 9.26 (br s,
1 H), 8.12 (d, J = 5.05 Hz, 1 H), 7.25 (s, 1 H), 7.11 (d,
J = 5.05 Hz, 1 H), 3.79 (t, J = 5.71 Hz, 2 H), 2.60 (t, J = 6.95
Hz, 2 H), 1.85 (tt, J = 6.95 Hz, J = 5.71 Hz, 2 H), 1.48 (s, 9
H).
Compound 27: 1H NMR (400 MHz, CDCl3): d = 9.28 (s, 1
H), 8.14 (d, J = 5.05 Hz, 1 H), 7.13 (d, J = 5.05 Hz, 1 H),
6.98 (s, 1 H), 3.41 (s, 1 H), 1.60 (s, 6 H), 1.46 (s, 9 H).
Compound 29: 1H NMR (400 MHz, CDCl3): d = 9.35 (s, 1
H), 8.21 (d, J = 5.05 Hz, 1 H), 7.25–7.52 (m, 6 H), 7.04 (br
s, 1 H), 1.49 (s, 9 H).
(16) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P.
Angew. Chem. Int. Ed. 2000, 39, 2488.
(17) Choi-Sledeski, Y. M.; Kearney, R.; Poli, G.; Pauls, H.;
Gardner, C.; Gong, D.; Becker, M.; Davis, R.; Spada, A.;
Liang, G.; Chu, V.; Brown, K.; Collussi, D.; Leadley, R. Jr.;
Rebello, S.; Moxey, P.; Morgan, S.; Bentley, R.; Kasiewski,
C.; Maignan, S.; Guilloteau, J.-P.; Mikol, V. J. Med. Chem.
2003, 46, 681.
(18) Kelly, T. A.; Patel, U. R. J. Org. Chem. 1995, 60, 1875.
(19) General Procedure for the Sonogashira Coupling.
To a solution of ortho-(Boc-amino)halogeno pyridine or
diazine (1 mmol) in anhyd DMF (1 mL) and Et3N (3 mL)
was added copper iodide (0.10 mmol), Pd(PPh3)2Cl2 (0.05
mmol) and the alkyne (1 mmol) under argon and the reaction
stirred at r.t. for 15 h. The reaction was diluted with EtOAc
(10 mL), washed with sat. aq NH4Cl solution (2 × 5 mL) and
the combined aqueous layers were extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed with
brine (5 mL), dried over MgSO4 and concentrated. Column
chromatography (hexane–EtOAc) yielded ortho-(Boc-
amino)alkynyl pyridines or diazines in 37–99% yield.
Compound 31: 1H NMR (400 MHz, CDCl3): d = 8.85 (s, 1
H), 8.10 (d, J = 5.05 Hz, 1 H), 7.32 (d, J = 5.05 Hz, 1 H),
7.23 (d, J = 8.85 Hz, 2 H), 6.57 (s, J = 8.85 Hz, 2 H), 1.45 (s,
9 H).
Compound 33: 1H NMR (400 MHz, CDCl3): d = 9.41 (s, 1
H), 8.22 (d, J = 5.06 Hz, 1 H), 7.20 (d, J = 5.06 Hz, 1 H),
7.04 (s, 1 H), 4.86 (s, 1 H), 4.22 (d, J = 5.56 Hz, 2 H), 1.56
(s, 9 H), 1.48 (s, 9 H).
(20) Typical Procedure for the Cyclization.
To a solution of ortho-(Boc-amino)alkynyl pyridine or
diazine (1 mmol) in MeOH–H2O (5 mL, 3:1) was added
DBU (5 mmol) and the reaction heated to 65–85 °C for 1–14
h. Then, MeOH was removed under vacuum and the solution
cooled in an ice-water bath; H2O was added dropwise to
precipitate the azaindole or diazaindole. Compounds 16, 18,
28, and 30 did not solidify from aqueous solution. In these
cases the H2O–DBU mixture was decanted from the oil. The
Synlett 2005, No. 20, 3121–3125 © Thieme Stuttgart · New York

LETTER
oil is then dissolved in MeOH and the precipitation
Synthesis of Azaindoles and Diazaindoles
3125
98.08, 29.75, 21.46, 12.33. HRMS (APCI): m/z calcd for
C9H12N3 [M + 1]: 162.1025; found: 162.1031.
procedure repeated. Compound 28 was purified by
chromatography. The precipitate was collected by filtration,
washed with H2O and dried to give the desired products
(>95% purity). Yields 62%–97%.
Compound 22: mp (MeOH–H2O) 156 °C. 1H NMR (400
MHz, CDCl3): d = 10.26 (br s, 1 H), 8.36 (br s, 1 H), 8.08 (br
s, 1 H), 6.40 (s, 1 H), 2.81 (t, J = 7.58 Hz, 2 H), 1.79 (qt,
Data for Azaindoles and Diazaindoles.
J = 7.58 Hz, J = 7.34 Hz, 2 H), 0.99 (t, J = 7.34 Hz, 3 H). 13
NMR (100 MHz, MeOH-d4): d = 149.67, 143.79, 141.70,
C
Compound 8: mp (MeOH–H2O) 158 °C. 1H NMR (400
MHz CDCl3): d = 8.71 (s, 1 H), 8.20 (d, J = 5.31 Hz, 1 H),
7.43 (d, J = 5.31 Hz, 1 H), 6.28 (s, 1 H), 2.80 (t, J = 7.58 Hz,
2 H), 1.81 (qt, J = 7.58 Hz, J = 7.33 Hz, 2 H), 1.03 (t,
J = 7.33 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 145.22,
137.99, 134.03, 133.50, 132.73, 99.02, 30.45, 22.36, 13.90.
HRMS (APCI): m/z calcd for C10H13N2 [M + 1]: 161.1073;
found: 161.1075.
137.77, 136.53, 98.67, 31.67, 23.26, 14.09. HRMS (APCI):
m/z calcd for C9H12N3 [M + 1]: 162.1025; found: 162.1031.
Compound 24: mp (MeOH–H2O) 185 °C. 1H NMR (400
MHz, MeOH-d4): d = 8.60 (s, 1 H), 8.00 (d, J = 5.56 Hz, 1
H), 7.43 (d, J = 5.81 Hz, 1 H), 6.44 (s, 1 H), 4.79 (s, 2 H).
HRMS (APCI): m/z calcd for C8H9N2O [M + 1]: 149.0709;
found: 149.0711.
Compound 10: 1H NMR data are in accordance with data
reported in the literature.25
Compound 26: mp (MeOH–H2O) 161 °C. 1H NMR (400
MHz, MeOH-d4): d = 8.52 (s, 1 H), 7.96 (d, J = 5.56 Hz, 1
H), 7.44 (d, J = 5.56 Hz, 1 H), 6.29 (s, 1 H), 3.62 (t, J = 6.32
Hz, 2 H), 2.90 (t, J = 7.71 Hz, 2 H), 1.98 (tt, J = 6.32 Hz,
J = 7.71 Hz, 2 H). HRMS (APCI): m/z calcd for C10H13N2O
[M + 1]: 177.1022; found: 177.1026.
Compound 12: mp (MeOH–H2O) 123 °C. 1H NMR (400
MHz, CDCl3): d = 10.43 (s, 1 H), 8.40 (dd, J = 1.26 Hz, 4.80
Hz, 1 H), 7.59 (d J = 8.08 Hz, 1 H), 7.02 (dd, J = 4.80 Hz,
8.08 Hz, 1 H), 6.44 (s, 1 H), 2.80 (t, J = 7.58 Hz, 2 H), 1.76
(qt, J = 7.33 Hz, J = 7.58 Hz, 2 H), 0.98 (t, J = 7.33 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 147.27, 145.08, 141.98,
129.39, 117.72, 115.63, 99.68, 30.70, 22.37, 13.85. HRMS
(APCI): m/z calcd for C10H13N2 [M + 1]: 161.1073; found:
161.1076.
Compound 28: oil. 1H NMR (400 MHz, MeOH-d4): d = 8.60
(s, 1 H), 8.01 (d, J = 5.56 Hz, 1 H), 7.50 (d, J = 5.65 Hz, 1
H), 6.43 (s, 1 H), 1.57 (s, 6 H). HRMS (APCI): m/z calcd for
C10H11N2 [M – H2O + 1]: 159.0916; found: 159.0917.
Compound 30: mp (MeOH–H2O) 205 °C. 1H NMR (400
MHz, CDCl3): d = 8.92 (s, 1 H), 8.14 (d, J = 5.56 Hz, 1 H),
7.80 (d, J = 7.96 Hz, 2 H), 7.50 (d, J = 5.31 Hz, 1 H), 7.41
(dd, J = 7.58 Hz, J = 7.58 Hz, 2 H), 7.33 (dd, J = 6.81 Hz,
J = 6.81 Hz, 2 H), 6.79 (s, 1 H). HRMS (APCI): m/z calcd
for C13H11N2 [M + 1]: 195.0916; found: 195.0921.
Compound 32: mp (MeOH–H2O) 188 °C. 1H NMR (400
MHz, CDCl3): d = 8.76 (s, 1 H), 8.22 (d, J = 5.56 Hz, 1 H),
7.53 (d, J = 8.59 Hz, 2 H), 7.46 (d, J = 5.30 Hz, 1 H), 6.77
(d, J = 8.33 Hz, 2 H), 6.65 (s, 1 H), 3.49 (br s, 2 H). HRMS
(APCI): m/z calcd for C13H12N3 [M + 1]: 210.1031; found:
210.1034.
Compound 14: mp (MeOH–H2O) 65 °C. 1H NMR (400
MHz, CDCl3): d = 12.37 (s, 1 H), 8.21 (d, J = 4.55 Hz, 1 H),
7.83 (dd, J = 7.83 Hz, J = 1.26 Hz, 1 H), 7.03 (dd, J = 7.83
Hz, J = 4.80 Hz, 1 H), 6.20 (s, 1 H), 2.86 (t, J = 7.58 Hz, 2
H), 1.86 (qt, J = 7.58 Hz, J = 7.33 Hz, 2 H), 1.04 (t, J = 7.33
Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 149.33, 141.78,
140.18, 127.63, 122.00, 115.38, 97.17, 30.84, 22.46, 13.99.
HRMS (APCI): m/z calcd for C10H13N2 [M + 1]: 161.1073;
found: 161.1073.
Compound 16: mp (MeOH–H2O) 154 °C. 1H NMR (400
MHz, CDCl3): d = 9.46 (br s, 1 H), 9.28 (br s, 1 H), 6.35 (s,
1 H), 2.89 (t, J = 7.46 Hz, 2 H), 1.81 (qt, J = 7.45 Hz,
J = 7.33 Hz, 2 H), 0.95 (t, J = 7.33 Hz, 3 H). 13C NMR (100
MHz, MeOH-d4): d = 148.43, 145.51, 137.86, 133.96,
126.91, 99.78, 30.95, 23.37, 14.09. HRMS (APCI): m/z
calcd for C9H12N3 [M + 1]: 162.1025; found: 162.1032.
Compound 18: mp (MeOH–H2O) 177 °C. 1H NMR (400
MHz, CDCl3): d = 10.02 (br s, 1 H), 8.83 (br s, 1 H), 7.44 (br
s, 1 H), 6.64 (s, 1 H), 2.81 (t, J = 7.46 Hz, 2 H), 1.79 (qt,
Compound 34: mp (MeOH–H2O) 64 °C. 1H NMR (400
MHz, CDCl3): d = 8.75 (s, 1 H), 8.22 (d, J = 5.56 Hz, 1 H),
7.45 (dd, J = 5.56 Hz, J = 1.01 Hz, 1 H), 6.33 (s, 1 H), 5.15
(s, 1 H), 4.41 (d, J = 6.06 Hz, 2 H), 1.49 (s, 9 H). HRMS
(APCI): m/z calcd for C13H18N3O2 [M + 1]: 248.1393; found:
248.1384.
(21) Unpublished results: pyridines and diazines with
substituents such as NMe2, OMe, or CN are well tolerated in
this reaction.
(22) Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.;
Strosberg, A. M. J. Med. Chem. 1988, 31, 2136.
(23) Crous, R.; Dywer, C.; Holzapfel, C. W. Heterocycles 1999,
51, 721.
J = 7.46 Hz, J = 7.34 Hz, 2 H), 0.97 (t, J = 7.34 Hz, 3 H). 13
NMR (100 MHz, MeOH-d4): d = 151.68, 149.60, 130.76,
107.23, 97.11, 29.69, 21.40, 12.47. HRMS (APCI): m/z
calcd for C9H12N3 [M + 1]: 162.1025; found: 162.1032.
Compound 20: mp (MeOH–H2O) 176 °C. 1H NMR (400
C
MHz, CDCl3): d = 8.87 (s, 1 H), 8.63 (s, 1 H), 6.39 (s, 1 H),
2.79 (t, J = 7.46 Hz, 2 H), 1.75 (qt, J = 7.46 Hz, J = 7.46 Hz,
2 H), 0.95 (t, J = 7.46 Hz, 3 H). 13C NMR (100 MHz,
MeOH-d4): d = 151.10, 150.11, 148.43, 137.04, 127.43,
(24) Park, S. S.; Choi, J.-K.; Yum, E. K.; Ha, D.-C. Tetrahedron
Lett. 1998, 39, 627.
(25) Estel, L.; Marsais, F.; Queguiner, G. J. Org. Chem. 1988, 53,
2740.
Synlett 2005, No. 20, 3121–3125 © Thieme Stuttgart · New York