Palladium-catalysed functionalisation at 4- and 6- position of the 7-azaindole system

Article abstract of DOI:10.1055/s-2001-13366

The synthesis of 4- and 6-substituted-7 azaindales through palladium-catalysed coupling reactions of the corresponding halosubstituted-7-azaindoles is described.

Full text of DOI:10.1055/s-2001-13366

LETTER
609
Palladium-Catalysed Functionalisation at 4- and 6- Position of the 7-Azaindole
System
a
b*
b
a
Marcello Allegretti, Antonio Arcadi, Fabio Marinelli, Luca Nicolini
a
Dompé Research Center, località Campo di Pile, I-67100 L’Aquila, Italy
b
Dipartimento di Chimica Ingegneria Chimica e Materiali della Facoltà di Scienze, Università de L’Aquila, Via Vetoio, Coppito Due,
I-67100 L’Aquila, Italy
Fax +39 0862 433753; E-mail: arcadi@univaq.it
Received 2 February 20001
Abstract: The synthesis of 4- and 6-substituted-7-azaindoles
through palladium-catalysed coupling reactions of the correspond-
ing halosubstituted-7-azaindoles is described.
Key words: 7-azaindoles, palladium catalysis, coupling reactions
The presence of the 7-azaindole moiety in the structure of
1
various drugs, such as anti-inflammatory and anti-
2
Scheme 1 i = ArB(OH)2 2a-f, KF, dioxane, Pd (dba) , P(t-Bu) ,
2 3 3
psychotic agents, corticotropin-releasing hormone recep-
1
00 °C
3
4
tor antagonists, etc. has motivated considerable synthet-
ic efforts toward functionalised azaindoles derivatives.
Among others, tropyl 7-azaindol-3-ylcarboxyamides have
Although in the last years the use of aryl/heteroaryl chlo-
rides in palladium-catalysed reactions has broadened
5
been evaluated as antitussive agents active on different
6
neuropeptide-driven reflexes. However, the structure-ac-
16
enormously, in our hands 1a,b, in contrast to Suzuki
tivity relationship studies in these series of pharmaceuti-
cally relevant compounds have been hardly limited by the
lack of a general strategy for the heteroaromatic ring func-
tionalisation.
coupling, were virtually inert towards Sonogashira/Heck
reactions (i.e 1b was quantitatively recovered after 24 h
reaction with 2-methyl-3-butyn-2-ol 2i in refluxing diox-
ane in the presence of Pd(PhCN) Cl /P(t-Bu) /CuI/HN(i-
2
2
3
1
7
Recently, palladium-catalysed heteroannulations of Pr)
system; 1b was also recovered (90%) after 12 h re-
2
2
-amino-3-iodopyridine derivatives with internal alkynes, action with styrene 2h in refluxing dioxane in the pres-
7
18
based on modified synthetic procedures for indoles, have ence of Pd
(dba) /P(t-Bu) /Cs CO ). This drawback can
3 3 2 3
2
been useful for the preparation of 2,3-disubstituted 7-aza- be overcome by using 6-bromo-7-azaindole 1c or the
8
19
indoles derivatives. Moreover, functionalisation at the 4-iodo-1-acetyl-7-azaindole 1d as viable substrates for
- and 3-position of 5-and 7-azaindole derivatives9 Pd-catalysed reactions. Indeed, 1c (Scheme 2) gave effi-
2
through palladium-mediated coupling reactions has been ciently the Sonogashira coupling derivative 3i (Table, en-
reported. Nevertheless, reports on the functionalisation at try 9) and afforded the alkene 3j in moderate yield (Table,
the 4 and 6-position of 7-azaindole derivatives, in partic- entry 10). Besides, bromide 1c gave better results than the
1
0
ular, are very limited in the literature although the syn- corresponding chloride 1b in the coupling reaction with
thesis of compounds bearing different substituents at thiophene-3-boronic acid 2f (Table, entries 8,9).
these positions has become a major achievement for me-
dicinal chemistry studies.
Herein, we report the facile functionalisation at the 4- and
6
-postion of the 7-azaindole system, which is based on
palladium-catalysed coupling reactions of the correspond-
ing 4- and 6-halo-7-azaindoles. We assumed that the
choice of a halide as leaving group is a key point to obtain
fruitful results for the introduction of a functionalised car-
bon-side chain into these heteroaromatics. Indeed, the
economically attractive 4- and 6- chloro-7-azaindoles1
0,11
1
a,b undergo palladium-catalysed coupling with the aryl/
1
2
heteroaryl boronic acids 2a-f, to afford the 4- and 6-sub-
stituted-7-azaindoles 3a-h (40-94% yield) (Scheme 1
1
3
Scheme 2 i = 3,3-diethoxy-1-propyne, dioxane, PdCl (PhCN) ,
2
2
and Table entries 1-7). The palladium-catalysed coupling
P(t-Bu) , CuI, piperidine, 100 °C, ii = Styrene, dioxane, Pd (dba) ,
3
2
3
of 1a,b is chemoselective and the formation of P(t-Bu) , Cs CO , 120 °C.
3
2
3
1
4
N-arylated products which may derive from C-N bond
1
5
cross-coupling were not observed.
Synlett 2001 No. 5, 609–612 ISSN 0936-5214 © Thieme Stuttgart · New York

6
10
M. Allegretti et al.
LETTER
The most reactive iodide 1d afforded the Sonogashira
coupling derivative 3k at r.t., as well as the ester 3l
Table Palladium-catalysed Synthesis of 4 and 6-substituted-7-aza-
indoles 3
a
2
0
(
Scheme 3; Table, entries 12, 14). Under the carbonyla-
tive basic conditions the acetyl group at the N-1 atom of
the 7-azaindole system was readily removed.
Scheme 3 i = 2-Methyl-3-butyn-2-ol, dioxane, PdCl2, dppf, CuI,
Et N, r.t. ii = CH OH, CO, Pd(PPh ) , Et N, 60 °C.
3
3
3
4
3
Furthermore, the Heck reaction of 1d with a Michael ac-
ceptor was investigated. The reaction of 1d with methyl
2
1
acrylate in DMF in the presence of K CO /KOAc as
2
3
bases and a catalytic amount of Pd(OAc) gave the Micha-
2
el adduct 3m (58% yield) as the only product. Probably,
under these reaction conditions the removal of the N-1
protective group of 1d is very fast. The nature of the base
strongly affects the reaction course. Indeed, using Et N as
3
2
2
base in the presence of the catalytic system Pd(OAc) /
2
P(o-tol) , a mixture of the palladium-catalysed coupling
3
derivatives 3n (38%) and 3o (45% yield) has been ob-
tained. The formation of 3o could also be accomplished
through a one-pot palladium-catalysed coupling/N-1
acetyl cleavage procedure (CH OH was added to the reac-
3
tion mixture after the disappearance of 1d) in a moderate
overall yield (44%) (Scheme 4).
Scheme 4 i = Methyl acrylate, DMF, Pd(Oac) , KOAc, K CO ,
2
2
3
7
0 °C
ii = Methyl acrylate, DMF, Pd(Oac) , P(o-tol) , Et N, 80 °C
2
3
3
iii = MeOH, 80 °C
Synlett 2001, No. 5, 609–612 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Palladium-Catalysed Functionalisation
611
Table continued
(3) Hodge, C.N.; Aldrich, P.E.; Wasserman, Z. R.; Fernandez
C.H.; Nemeth, G.A.; Arvanitis, A.; Cheeseman, R.S.;
Chorvat, R.J.; Ciganek, E.; Christos, T.E.; Gilligan, P.J.;
Krenitsky, P.; Scholfied, E.; Strucely, P. J. Med. Chem. 1999,
42, 819.
(
4) Marot, C.; Chavatte, P.; Morin-Allory, L.; Viaud, M.C.;
Guilaumet, G.; Renard, P., Lesieur, D.; Michel, A. J. Med.
Chem. 1998, 41, 4453; Beattie, D.E.; Crossley, R.; Curran,
A.C.W.; Hill, D.G.; Lawrence, A.E. J. Med. Chem. 1977, 20,
7
18; Verbiscar, A.J. J. Med. Chem. 1972, 15, 149.
5) Mantovanini, M.; Melillo, G.; Daffonchio, L. US Patent
750536 (applicant DOMPE SPA) 1998.
6) Melillo, G.; Porzio, S.; Fiorentino, S.; Caselli, GF. Regulatory
Peptides 1999, 80, 151.
(
(
(
5
7) Larock, R.C.; Yum, E.K.; Refvik, M.D. J. Org. Chem. 1988,
6
1
3, 7652; Larock, R.C.; Yum, E.K. J. Am. Chem. Soc. 1991,
13, 6689.
(
8) Rodriguez, A.L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem. Int. Ed. 2000, 39, 2488; Kang, S.K.; Park, S.S.; Kim,
S.S.; Choi, J.-K.; Yum, E.K. Tetrahedron Lett. 1999, 40,
4379; Mazeas, D.; Guillaumet, G.; Viaud, M.-C. Heterocycles
1999, 50, 1065; Park, S.S.; Choi, J.-K.; Yum, E.K.
Tetrahedron Lett. 1998, 39, 627; Ujjainwalla, F.; Warner, D.
Tetrahedron Lett. 1998, 39, 5355; Wensbo, D.; Annby, U.;
Gronowitz, S.; Cohen, L.A. Tetrahedron Lett. 1993, 34, 627;
Jeschke, T.; Wensbo, D.; Annby, U.; Gronowitz, S.; Cohen,
L.A. Tetrahedron Lett. 1993, 34, 6471; Kumar, V.; Dority,
J.A.; Bacon, E.R.; Singh, B.; Lesher, G.Y. J. Org. Chem.
1992, 57, 6995.
a
b
Yields refer to single runs and are given for isolated products. The
reaction was carried out at 100 °C in dioxane under nitrogen at-
mosphere
KF:Pd (dba)3 CHCl : P(t-Bu ) = 1:2:3.3:0.015:0.045; The reaction
was carried out at 100 °C in dioxane under nitrogen atmosphere
using the following molar ratios: 1c:2g: piperidine: Pd(Cl) (PhCN) :
CuI: P(tBu) = 1:1.5:5:0.015:0.030:0.045. The reaction was carried
out at 100 °C in dioxane under nitrogen atmosphere using the follo-
wing molar ratios: 1c:2h: Cs CO : Pd (dba) CHCl3: P(t-
Bu ) = 1:2:5:0.015:0.045. The reaction was carried out at r.t. in
dioxane under nitrogen atmosphere using the following molar ratios:
using
the
following
molar
ratios:
1:2:
c
2
3
3
2
2
d
3
2
3
2
3
e
3
f
1
d:2i: Et N: Pd(Cl) : CuI: dppf = 1:2:5:0.04:0.02:0.04. The reac-
3
2
(9) Chi, S.M.; Choi, J.-K.; Yum, E.K.; Chi, D.Y. Tetrahedron
Lett. 2000, 41, 919; Alvarez, M.; Fernàndez, D.; Joule, J.A.
Synthesis 1999, 615.
10) Clark, B.A.J; Parrick, J. J. Chem. Soc., Perkin Trans. 1 1974,
2270; Schneller, S.W.; Luo, J.-K. J. Org. Chem. 1980, 45,
4045-4048.
tion was carried out at 70 °C in dioxane under nitrogen atmosphere
using the following molar ratios: 1d:2i: Et N: PdCl (PPh ) :
CuI = 1:2:5:0.02:0.04. The reaction was carried out at 60 °C in
CH OH/Et N under CO atmosphere in the presence of Pd(PPh )
(
3
2
3 2
g
(
3
3
3 4
h
molar ratios 1d: Pd(PPh ) = 1:0.05). The reaction was carried out
3 4
at 80 °C in Et N/DMF under nitrogen atmosphere using the follo-
wing molar ratios: 1d:2j: Pd(OAc) : P(o-tol) = 1:2:0.05:0.1.
3
(11) Minakata, S.; Komatsu, M.; Ohshiro, Y. Synthesis 1992, 661.
12) Littke, A.F.; Dai, C.M.; Fu, G.C. J. Am. Chem. Soc. 2000, 122,
2
3
(
4020; Wolfe, J.P.; Buchwald, S.L. Angew. Chem. Int. Ed.
1999, 38, 2413.
In conclusion, we have developed a new synthesis of (13) A typical procedure is as follows: To a mixture of 4-chloro-7-
azaindole 1b (0.100 g, 0.63 mmol) in dioxane (3 mL), KF
4
- and 6-substituted-7-azaindoles through palladium-ca-
(0.220 g, 2.1 mmol), 3-methoxyphenylboronic acid 2c (0.192
talysed reactions. This methodology provides a powerful
tool for the preparation of a wide range of functionalised
4
g, 1.26 mmol), Pd (dba) CHCl (0.010 g, 0.009 mmol) and
2
3
3
P(t-Bu) (0.057 g, 0.028 mmol) were added. The reaction
3
- and 6-substituted azaindoles and allows a rapid in-
mixture was gently purged with nitrogen and stirred at 100 °C
for 4 h. After the reaction the mixture was cooled to room
temperature and submitted to chromatographic separation
eluting with a 70/30 (v/v) n-hexane/ethyl acetate to give 3d
crease in molecular complexity.
Acknowledgement
(
7
0.133 g, 94% yield): mp = 139-140 °C; IR (KBr) 3140, 1595,
-
1 1
70, 720, 680 cm ; H NMR (CDCl ) 3.81 (s, 3H), 6.68 (d,
This work was supported by the Ministero dell’Università e della
Ricerca Scientifica e Tecnologica (MURST-ROMA) and Consiglio
Nazionale delle Ricerche (C.N.R.-ROMA).
3
J = 3.5 Hz, 1H), 6.97 (m, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.32
1
3
(
(
m, 4H), 8.37 (d, J = 5.1 Hz, 1H), 11.66 (bs, 1H); C NMR
CDCl3) 55.3, 100.3, 114.1, 114.8, 118.8, 121.0, 125.6,
1
28.7, 129.8, 140.2, 142.2, 142.5, 148.9, 159.9; MS m/e: 224
+
References and Notes
(M , 100).
(
14) Lam, P.Y.S.; Clark, C.G.; Saubern, S.; Adams, J.; Averill,
K.M.; Chan, D.M.T.; Combs, A. Synlett 2000, 674 and
references therein.
15) Mederski, W.W.K.R.; Lefort, M.; Germann, M.; Kux, D.
Tetrahedron 1999, 55, 12757.
(
1) Henry, J.R.; Rupert, K.C.; Dodd, J.H.; Turchi, I.J.; Wadswort,
S.A.; Cavender, D.E; Fahmy, B.; Olini, G.C.; Davis, J.E.;
Pellegrino-Gensey, J.L.; Schafer, P.H.; Siekierka, J.J. J. Med.
Chem. 1998, 41, 4196; Henry, J.R.; Dodd, J.H. Tetrahedron
Lett. 1998, 39, 8763.
(
(
16) Gong, Y.; Pauls, H.W. Synlett 2000, 829; Zapf, A.; Beller, M.
Chem. Eur. J. 2000, 6, 1830; Ehrentraut, E.; Zapf, A.; Beller,
M. Synlett 2000, 1589; Zhang, C.; Trudell, M.L. Tetrahedron
Lett. 2000, 41, 595; Bei, X.; Turner, H.W.; Weinberg, W.H.;
Guram, A.S. J. Org. Chem. 1999, 64, 6797; Parrot, I.;
Rival, Y.; Wermuth, C.G. Synthesis 1999, 1163; Littke, A.F.;
(
2) Kulagowski, J.J.; Broughton, H.B.; Curtis, N.R.; Mawer, I.M.;
Ridgill, M.P.; Baker, R.; Emms, F.; Freedman, S.B.;
Marwood, R.; Patel, S.; Ragan, C.I.; Leeson, P.D. J. Med.
Chem. 1996, 39, 1941; Baker, R.; Kulagowski, J.J.; Curtis,
N.R.; Leeson, P.D.; Ridgill, M.P.; Smith, A.I. US Patent
5,576,319, and references therein.
Synlett 2001, No. 5, 609–612 ISSN 0936-5214 © Thieme Stuttgart · New York

6
12
M. Allegretti et al.
LETTER
(20) Selected data for 3k-l; 3k: mp = 103-105 °C; IR (KBr)
Fu, G.C. Angew. Chem. Int. Ed. 1999, 38, 2411; Stürmer, R.
Angew. Chem. Int. Ed. 1999, 38, 3307 and references therein.
-
1 1
3300, 1720, 1590, 720, 670 cm ; H NMR (CDCl ) 1.69
3
(
17) Hundertmark, T.; Littke, A.F.; Buchwald, S.L.; Fu, G.C. Org.
Lett. 2000, 2, 1729; Menicagli, R.; Samaritani, S.; Gori, S.
Tetrahedron Lett. 1999, 40, 8419.
(s, 6H), 3.04 (s, 3H), 6.69 (d, J = 4.1 Hz, 1H), 7.17 (d, J = 5.0
Hz, 1H), 7.98 (d, J = 4.1 Hz, 1H), 8.28 (d, J = 5.0 Hz, 1H);
1
3
C NMR (CDCl ) 25.8, 31.3, 65.6, 77.8, 84.0, 101.2, 105.0,
3
+
(
18) Littke, A.F.; Fu, G.C. J. Org. Chem. 1999, 64, 10.
19) Compound 1d has been prepared from bromo- and
chloropyridines as described in: Corcoran, R.C.; Bang, S.H.
Tetrahedron Lett. 1990, 31, 6757; mp = 143-144 °C; IR (KBr)
120.7, 123.6, 124.7, 125.7, 143.5, 169.2; MS m/e: 242 (M ,
(
41), 200 (85), 185(100), 157(40), 143(15). 3l: mp = 172-
-
1 1
173 °C; IR (KBr) 3120, 1740, 1600 cm ; H NMR (CDCl )
3
4.02 (s, 3H), 7.07 (d, J = 3.5 Hz, 1H), 7.54 (d, J = 3.5 Hz,
1H), 7.75 (d, J = 5.0 Hz, 1H), 8.44 (d, J = 5.0 Hz, 1H), 10.28
-
1 1
1
720 cm ; H NMR (CDCl ) 3.02 (s, 3H), 6.50 (d, J = 4.1
3
1
3
Hz, 1H), 7.58 (d, J = 5.1 Hz, 1H), 7.97 (d, J = 5.1 Hz, 1H),
(bs, 1H); C NMR (CDCl ) 53.3, 103.0, 117.5, 120.2, 128.8,
3
1
3
+
8
1
7
.02 (d, J = 4.1 Hz, 1H); C NMR (CDCl ) 25.8, 99.1, 108.3,
130.0, 143.0, 167.9; MS m/e: 176 (M , 100), 145(41),
3
+
25.7, 127.9, 129.2, 143.5, 145.7, 168.9; MS m/e: 287 (M ,
117(68).
0), 244 (100).
(21) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P.
Synlett 1996, 568.
(
22) Terpko, M.O.; Heck, R.F. J. Am. Chem. Soc. 1979, 101, 5281.
Article Identifier:
437-2096,E;2001,0,05,0609,0612,ftx,en;G02401ST.pdf
1
Synlett 2001, No. 5, 609–612 ISSN 0936-5214 © Thieme Stuttgart · New York