A versatile synthesis of 7-azaindoles

Article abstract of DOI:10.1055/s-2005-865243

1,3-Disubstituted 7-azaindoles were synthesized from 2,6-dichloropyridine using DoM and intramolecular aromatic substitution after epoxide opening by an amine. Even the sterically demanding adamantylamine may be incorporated leading to derivatives which a

Full text of DOI:10.1055/s-2005-865243

LETTER
1255
A Versatile Synthesis of 7-Azaindoles
A
V
ersatile Synthe
a
sis of 7-A
z
r
aindole
s
tmut Schirok*
Bayer HealthCare AG, Pharma Research, 42096 Wuppertal, Germany
Fax +49(202)364624; E-mail: hartmut.schirok@bayerhealthcare.com
Received 11 March 2005
Dedicated to Professor Lutz F. Tietze
with LDA, the addition to ketones like acetone, acetophe-
none, or trifluoroacetone occurred smoothly (Scheme 2),
and the desired tertiary alcohols 5 could be easily separat-
ed from unconsumed starting material by column filtra-
Abstract: 1,3-Disubstituted 7-azaindoles were synthesized from
2,6-dichloropyridine using DoM and intramolecular aromatic
substitution after epoxide opening by an amine. Even the sterically
demanding adamantylamine may be incorporated leading to deriv-
atives which are not accessible by alkylation of the parent com- tion due to their higher polarity. In agreement with
pound.
repeated reports in the literature, we detected small
amounts of the regioisomeric adducts resulting from lithi-
ation at the 4-position. In the course of our investigations
it turned out to be unnecessary to separate the regioiso-
mers, since the minor component leads to a polar, unpro-
ductive intermediate in the last step of the sequence. The
dehydration of 5 yielding a-substituted styrene deriva-
tives 6 was performed in a mixture of acetic and sulfuric
acid (3:1) at 130 °C for 30 minutes. The elimination prod-
ucts were isolated after basic work-up and did not need
further purification. Unfortunately, 5c failed to dehydrate
due to the strong electron-withdrawing effect of the tri-
fluoromethyl group. Even after heating in concentrated
sulfuric acid to 120 °C for 14 hours we recovered the
alcohol 5c almost quantitatively. With other reagents like
thionyl chloride, thionyl chloride/pyridine11 or Burgess’
reagent we were also unsuccessful, demonstrating that
this approach is not applicable for the synthesis of 3-
trifluoromethyl 7-azaindole.
Key words: azaindoles, pyridines, metalations, nucleophilic aro-
matic substitutions, ring closure
In nature 7-azaindoles (1H-pyrrolo[2,3-b]pyridines) ap-
pear only as a substructure in a small number of alkaloids.
However, much interest in this heterocyclic moiety has
arisen in recent pharmacological programs, wherein it
serves as bioisoster of indole or purine.1 Numerous publi-
cations on its synthesis and derivatization reflect the
increasing attention paid to this heterocyclic system.2,3
In connection with a medicinal chemistry program, we re-
quired a practical synthesis of 1,3-substituted azaindoles
of the general formula 1 (Scheme 1). Inspired by two re-
ports on the synthesis of indoles from 2-(2-chlorophe-
nyl)oxiranes4 and 2-(2-bromophenyl)oxiranes,5 we
decided to develop a new azaindole synthesis based on the
retrosynthetic analysis depicted in Scheme 1. An amine
should open the epoxide 2 to an amino alcohol, which ex-
pels the adjacent halogen by intramolecular nucleophilic
aromatic substitution. Subsequent dehydration should
yield the desired heterocycle 1. We planned to start with
2,6-dichloropyridine (4) for the synthesis of oxiranes 2.
The directed ortho metalation (DoM) of 4 should allow its
functionalization in the 3-position.6
The epoxides 2 were generated from the alkenes by oxida-
tion with MCPBA in dichloromethane, and were essen-
tially pure after basic extraction.
In the final step of the sequence the epoxides were reacted
with primary amines leading to the 7-azaindoles. The
transformation was performed in 1-butanol at 100–120 °C
(Scheme 3). Mechanistically, a domino12 epoxide-open-
ing-cyclization, and dehydration take place:
The lithiation7 of fluoro- and chloropyridines8 has been
thoroughly studied by Quéguiner9 and Schlosser.10 In our
hands, after deprotonation of 2,6-dichloropyridine (4)
The amine 3 attacks the oxirane 2 at the sterically less hin-
dered position, and an 1,2-aminoalcohol 7 is generated.
Scheme 1 Retrosynthesis.
SYNLETT 2005, No. 8, pp 1255–1258
1
7.
0
5.
2
0
0
5
Advanced online publication: 21.04.2005
DOI: 10.1055/s-2005-865243; Art ID: G08305ST
© Georg Thieme Verlag Stuttgart · New York

1256
H. Schirok
LETTER
Scheme 2 Synthesis of epoxides 2. Reagents and conditions: a) LDA, THF, –78 °C, then R1COMe, –78 °C → r.t.; b) H2SO4–AcOH (1:3),
130 °C; c) MCPBA, CH2Cl2, r.t.
The subsequent intramolecular nucleophilic aromatic sub-
stitution leads to the annellated system 8. The speed of the
reaction is determined by the steric hindrance of the amine
3. With linear amines like butyl- or allylamine it was com-
plete within three to five hours, whilst a-branched amines
like cyclopentylamine required heating overnight. Conse-
quently, using a-trisubstituted amines like tert-amylamine
or adamantylamine the reaction required heating for sev-
eral days to obtain the azaindoles in high yields. The inter-
mediate tertiary alcohol 8 can be isolated. However, it is
very prone to aromatization yielding 1, and therefore we
normally ran the sequence to completion. In most of the
examples, only a small portion of 8 spontaneously col-
lapsed to 1 and the addition of hydrochloric acid was
needed to catalyze the dehydration. The target compounds
were isolated in medium to high yields (Figure 1), demon-
strating the high versatility of our approach.
Scheme 3 Mechanism for the 7-azaindole formation.
The synthesis of the epoxides 2 via the styrenes 6 proved
to be facile since only one purification step was needed in
the 3-step sequence. However, we were interested in a
shorter approach. As depicted in Scheme 4, the reaction of
Figure 1 Synthesized 1,3-disubstituted 7-azaindoles; reaction time in parentheses.
Synlett 2005, No. 8, 1255–1258 © Thieme Stuttgart · New York

LETTER
A Versatile Synthesis of 7-Azaindoles
1257
the deprotonated pyridine 4 with chloroacetone 9 should with a-chloroketones after directed ortho metalation
yield the oxirane 2a in a single step. In our hands, we iso- (DoM). Thorough purification of the intermediates is not
lated the desired compound in 60% purity. Since the ac- necessary due to the robustness of the final reaction in the
companying compound was unreacted starting material, sequence. Its simplicity and broad substrate tolerance al-
which should not interfere in the subsequent step, we used lows a combinatorial access to the target compounds.
the crude product without purification. The reaction with
benzylamine gave 1-benzyl-3-methyl-7-azaindole (1c) in
50% overall yield.
2-(2,6-Dichloropyridin-3-yl)propan-2-ol (5a); Typical
Procedure
To a freshly prepared solution of LDA (89.2 mmol) in THF at
–78 °C, 2,6-dichloropyridine (12.0 g, 81.1 mmol) in THF (20 mL)
was added. After stirring for 2 h at this temperature acetone
(8.94 mL, 122 mmol) was added. The mixture was stirred for an ad-
ditional 2 h and then slowly warmed to r.t. The mixture was poured
into ice water and extracted twice with tert-butylmethyl ether. The
combined organic layers were washed with brine and dried over so-
dium sulfate. The solvent was removed under reduced pressure and
the residue was purified by column chromatography (CH2Cl2, then
CH2Cl2–MeOH, 50:1) to yield 11.8 g (71%) of the title compound
as a yellow oil.
Scheme 4 Two-step synthesis of 7-azaindoles from 2,6-dichloropy-
ridine. Reagents and conditions: a) LDA, THF, –78 °C, then 9; b)
BnNH2, 1-butanol, 120 °C, then HCl (aq), 50% overall yield.
1H NMR (400 MHz, DMSO-d6): d = 1.59 (s, 6 H), 5.58 (s, 1 H),
7.57 (d, J = 8.3 Hz, 1 H), 8.23 (d, J = 8.3 Hz, 1 H).
We were also interested in the regioselectivity of the cy-
clization step for 2,4-dichloropyridine derivatives 11
(Scheme 5). The styrene 10 was prepared from 5a in three
steps comprising N-oxidation (54%), elimination (96%),
2,6-Dichloro-3-isopropenylpyridine (6a)
Tertiary alcohol 5a (1.20 g, 5.82 mmol) was dissolved in AcOH
and chlorination (38%). An alternative route towards 10 (6.0 mL) and concd H2SO4 (2.0 mL) was added. The mixture was
heated to reflux for 30 min. It was poured into ice water, basified
started with the oxidation of 2,6-dichloropyridine (4;
69%)13 and reaction with acetone after deprotonation
with concd NaOH solution and extracted with CH2Cl2. The organic
layer was dried over sodium sulfate and evaporated to yield 868 mg
(57%) to yield the same product as isolated from the oxi-
dation of 5a. The epoxidation of 10 was significantly
slower than for the dichloro derivative 6, and 11 was iso-
(79%) of the title compound as a yellow oil.
1H NMR (300 MHz, DMSO-d6): d = 2.06 (dd, J = 1.3, 0.9 Hz, 3 H),
5.08 (m, 1 H), 5.38 (dq, 1.5, 1.3 Hz, 1 H), 7.56 (d, J = 7.9 Hz, 1 H),
lated in 71% yield. Its cyclization with benzylamine re-
7.82 (d, J = 7.9 Hz, 1 H).
sulted in the formation of the two regioisomers 12 and 13
(Scheme 5) in a 1:1.1 ratio. The lack of regioselectivity
demonstrates that the same strategy can be applied to the
synthesis of the regioisomeric 5-azaindoles (1H-pyrro-
13C NMR (125 MHz, DMSO-d6): d = 22.6, 118.7, 123.8, 137.5,
140.6, 142.1, 146.7, 147.5.
HRMS: m/z calcd for C8H7Cl2N: 186.9956; found: 186.9956.
lo[3,2-c]pyridines) starting with 4-chloro- or 4-fluoropy-
2,6-Dichloro-3-(2-methyloxiran-2-yl)pyridine (2a)
ridine. Further work in this area is currently underway.
Styrene 6a (4.10 g, 21.8 mmol) was dissolved in CH2Cl2 (120 mL)
and MCPBA (70%, 10.8 g, 43.6 mmol) was added in portions. The
reaction was stirred at r.t. for 20 h, then diluted with CH2Cl2 and
extracted three times with a cold 1 N NaOH solution. The organic
layer was dried over sodium sulfate and the solvent was evaporated
to yield the epoxide (3.6 g, 81%) as a light yellow oil.
In conclusion, a highly efficient synthesis of 7-azaindoles
was developed. Starting from readily available 2,6-
dichloropyridine 4, the epoxides 2 can be synthesized in
three steps via styrenes 6 or in a single transformation
Scheme 5 Regioselectivity of the cyclization. Reagents and conditions: a) 1. H2O2, CF3CO2H, reflux, 2. H2SO4–AcOH (1:3), 130 °C, 3.
POCl3, CHCl3, reflux; b) MCPBA, CH2Cl2, reflux; c) BnNH2, 1-butanol, 120 °C.
Synlett 2005, No. 8, 1255–1258 © Thieme Stuttgart · New York

1258
H. Schirok
LETTER
1H NMR (300 MHz, DMSO-d6): d = 1.59 (s, 3 H), 2.85 (d,
J = 4.9 Hz, 1 H), 3.07 (d, J = 4.9 Hz, 1 H), 7.59 (d, J = 7.9 Hz, 1 H),
7.94 (d, J = 7.9 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 21.4, 53.8, 56.1, 123.7, 135.2,
141.0, 147.2, 148.0.
B. P.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2004, 14,
3245. (i) Oh, S.-J.; Choe, Y.-S.; Chi, D.-Y.; Ryu, E. K.; Saji,
H.; Choe, Y. S.; Chi, D. Y.; Kim, S. E.; Lee, J.; Kim, B.-T.
Bioorg. Med. Chem. 2004, 12, 5505. (j) Wang, S.; Wan, N.
C.; Harrison, J.; Miller, W.; Chuckowree, I.; Sohal, S.;
Hancox, T. C.; Baker, S.; Folkes, A.; Wilson, F.; Thompson,
D.; Cocks, S.; Farmer, H.; Boyce, A.; Freathy, C.;
Broadbridge, J.; Scott, J.; Depledge, P.; Faint, R.; Mistry, P.;
Charlton, P. J. Med. Chem. 2004, 47, 1339. (k) Hilmy, K.
M. H. Arch. Pharm. 2004, 337, 15.
HRMS: m/z calcd for C8H7Cl2NO: 202.9905; found: 202.9895.
1-Benzyl-6-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridine (1c)
Epoxide 2a (120 mg, 0.59 mmol) and benzylamine (126 mg,
1.18 mmol) were heated to 110 °C in 1-butanol (0.5 mL) for 3 h.
Subsequently, 4 N HCl (1 mL) was added, and the mixture was
stirred at r.t. for 4 h). The mixture was basified with 1 N NaOH and
extracted three times with CH2Cl2. The combined organic layers
were dried over sodium sulfate and the solvent was evaporated. The
crude product was purified by preparative HPLC to yield 100 mg
(66%) of the title compound.
1H NMR (400 MHz, DMSO-d6): d = 2.25 (s, 3 H), 5.37 (s, 2 H),
7.13 (d, J = 8.1 Hz, 1 H), 7.20 (d, J = 7.1 Hz, 2 H), 7.24–7.33 (m, 3
H), 7.38 (s, 1 H), 8.01 (d, J = 8.1 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.37, 46.9, 108.9, 114.7,
119.2, 126.8, 127.1, 127.3, 128.5, 130.2, 138.0, 143.1, 146.0.
(2) (a) Desarbre, E.; Coudret, S.; Meheust, C.; Mérour, J.-Y.
Tetrahedron 1997, 53, 3637. (b) Park, S. S.; Choi, J.-K.;
Yum, E. K. Tetrahedron Lett. 1998, 39, 627.
(c) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39,
5355. (d) Alvarez, M.; Fernández, D.; Joule, J. A. Synthesis
1999, 615. (e) Chi, S. M.; Choi, J.-K.; Yum, E. K.; Chi, D.
Y. Tetrahedron Lett. 2000, 41, 919. (f) Allegretti, M.;
Arcadi, A.; Marinelli, F.; Nicolini, L. Synlett 2001, 609.
(g) Konradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.;
Knochel, P. Tetrahedron 2003, 59, 1571. (h) Thibault, C.;
L’Heureux, A.; Bhide, R. V.; Ruel, R. Org. Lett. 2003, 5,
5023. (i) Hong, C. S.; Seo, J. Y.; Yum, E. K.; Sung, N.-D.
Heterocycles 2004, 63, 631. (j) L’Heureux, A.; Thibault, C.;
Ruel, R. Tetrahedron Lett. 2004, 45, 2317. (k) Cottineau,
B.; O’Shea, D. F. Tetrahedron Lett. 2005, 46, 1935.
(l) Debenham, S. D.; Chan, A.; Liu, K.; Price, K.; Wood, H.
B. Tetrahedron Lett. 2005, 46, 2283.
HRMS: m/z calcd for C15H13ClN2: 256.0767; found: 256.0770.
6-Chloro-1-cyclopentyl-3-phenyl-1H-pyrrolo[2,3-b]pyridine
(1j)
The compound was prepared analogously to 1c from 2b.
(3) For a review see: Mérour, J.-Y.; Joseph, B. Curr. Org.
Chem. 2001, 5, 471.
(4) Tambute, A. C. R. Seances Acad. Sci., Ser. C 1974, 278,
1239.
(5) (a) Fleming, I.; Woolias, M. J. Chem. Soc., Perkin Trans. 1
1979, 827. (b) Fleming, I.; Woolias, M. J. Chem. Soc.,
Perkin Trans. 1 1979, 829.
(6) (a) Radinov, R.; Chanev, C.; Haimova, M. J. Org. Chem.
1991, 56, 4793. For reviews of the DoM technique see:
(b) Snieckus, V. Chem. Rev. 1990, 90, 879. (c) Clayden, J.
Organolithiums: Selectivity for Synthesis; Pergamon:
Oxford, 2002.
1H NMR (400 MHz, DMSO-d6): d = 1.67–1.80 (m, 2 H), 1.86–2.00
(m, 4 H), 2.11–2.22 (m, 2 H), 5.16 (quint, J = 7.4 Hz, 1 H), 7.22 (d,
J = 8.3 Hz, 1 H), 7.28 (t, J = 7.3 Hz, 1 H), 7.45 (t, J = 7.3 Hz, 2 H),
7.73 (d, J = 7.3 Hz, 2 H), 8.08 (s, 1 H), 8.33 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 23.6, 32.1, 54.7, 114.3, 115.9,
116.5, 124.3, 126.0, 126.3, 128.8, 131.0, 134.0, 143.1, 146.5.
HRMS: m/z calcd for C18H17ClN2: 296.1080; found: 296.1069.
References
(7) For a recent report on the deprotonation with lithium
magnesates see: Awad, H.; Mongin, F.; Trécourt, F.;
Quéguiner, G.; Marsais, F. Tetrahedron Lett. 2004, 45,
7873.
(8) Mongin, F.; Quéguiner, G. Tetrahedron 2001, 57, 4059.
(9) (a) Güngör, T.; Marsais, F.; Quéguiner, G. J. Organomet.
Chem. 1981, 215, 139. (b) Mallet, M.; Branger, G.; Marsais,
F.; Quéguiner, G. J. Organomet. Chem. 1990, 382, 319.
(c) See also: Mallet, M. J. Organomet. Chem. 1991, 406, 49.
(10) (a) Mongin, F.; Tognini, A.; Cottet, F.; Schlosser, M.
Tetrahedron Lett. 1998, 39, 1749. (b) Schlosser, M.; Rausis,
T. Eur. J. Org. Chem. 2004, 1018.
(1) For recent publications see: (a) Ujjainwalla, F.; Walsh, T. F.
Tetrahedron Lett. 2001, 42, 6441. (b) Routier, S.; Ayerbe,
N.; Mérour, J.-Y.; Coudert, G.; Bailly, C.; Pierré, A.;
Pfeiffer, B.; Caignard, D.-H.; Renard, P. Tetrahedron 2002,
58, 6621. (c) Sanderson, P. E. J.; Stanton, M. G.; Dorsey, B.
D.; Lyle, T. A.; McDonough, C.; Sanders, W. M.; Savage, K.
L.; Naylor-Olsen, A. M.; Krueger, J. A.; Lewis, S. D.; Lucas,
B. J.; Lynch, J. J.; Yan, Y. Bioorg. Med. Chem. Lett. 2003,
13, 795. (d) Kuo, G.-H.; Prouty, C.; DeAngelis, A.; Shen,
L.; O’Neill, D. J.; Shah, C.; Connolly, P. J.; Murray, W. V.;
Conway, B. R.; Cheung, P.; Westover, L.; Xu, J. Z.; Look,
R. A.; Demarest, K. T.; Emanuel, S.; Middleton, S. A.;
Jolliffe, L.; Beavers, M. P.; Chen, X. J. Med. Chem. 2003,
46, 4021. (e) Wang, T.; Zhang, Z.; Wallace, O. B.;
(11) Rodrigues, I.; Bonnet-Delpon, D.; Bégué, J.-P. J. Org.
Chem. 2001, 66, 2098.
(12) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131; Angew. Chem. 1993, 105, 137. (b) Tietze, L.
F. Chem. Rev. 1996, 96, 115. (c) Tietze, L. F.; Haunert, F. In
Stimulating Concepts in Chemistry; Vögtle, F.; Stoddart, J.
F.; Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2000, 39.
(13) D’Andrea, S. V.; Bonner, D.; Bronson, J. J.; Clark, J.;
Denbleyker, K.; Fung-Tomc, J.; Hoeft, S. E.; Hudyma, T.
W.; Matiskella, J. D.; Miller, R. F.; Misco, P. F.; Pucci, M.;
Sterzycki, R.; Tsai, Y.; Ueda, Y.; Wichtowski, J. A.; Singh,
J.; Kissick, T. P.; North, J. T.; Pullockaran, A.; Humora, M.;
Boyhan, B.; Vu, T.; Fritz, A.; Heikes, J.; Fox, R.; Godfrey,
J. D.; Perrone, R.; Kaplan, M.; Kronenthal, D.; Mueller, R.
H. Tetrahedron 2000, 56, 5687.
Deshpande, M.; Fang, H.; Yang, Z.; Zadjura, L. M.;
Tweedie, D. L.; Huang, S.; Zhao, F.; Ranadive, S.;
Robinson, B. S.; Gong, Y.-F.; Riccardi, K.; Spicer, T. P.;
Deminie, C.; Rose, R.; Wang, H.-G. H.; Blair, W. S.; Shi, P.-
Y.; Lin, P.-f.; Colonno, R. J.; Meanwell, N. A. J. Med.
Chem. 2003, 46, 4236. (f) Hugon, B.; Pfeiffer, B.; Renard,
P.; Prudhomme, M. Tetrahedron Lett. 2003, 44, 4607.
(g) Larraya, C.; Guillard, J.; Renard, P.; Audinot, V.; Boutin,
J. A.; Delagrange, P.; Bennejean, C.; Viaud-Massuard, M.-
C. Eur. J. Med. Chem. 2004, 515. (h) Zhang, H.-C.; Ye, H.;
Conway, B. R.; Derian, C. K.; Addo, M. F.; Kuo, G.-H.;
Hecker, L. R.; Croll, D. R.; Li, J.; Westover, L.; Xu, J. Z.;
Look, R.; Demarest, K. T.; Andrade-Gordon, P.; Damiano,
Synlett 2005, No. 8, 1255–1258 © Thieme Stuttgart · New York