Synthesis and Reactivity of 7-Azaindoles (1H-Pyrrolo (2,3-b) Pyridine)

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Synthesis and Reactivity of 7-Azaindoles (1H-Pyrrolo(2,3-b)pyridine)
Article in Current Organic Chemistry · May 2001

DOI: 10.2174/1385272013375427
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Current Organic Chemistry, 2001, 5, 471-506 471
Synthesis and Reactivity of 7-Azaindoles (1H-Pyrrolo[2,3-b]pyridine)
Jean-Yves Mérour* and Benoît Joseph
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans BP

6759, 45067 Orléans Cedex 2, France
Abstract: The results of research into the chemistry of 7-azaindole during the last twenty
years are presented. New synthetic methods for the 7-azaindole structures are developed
including palladium-catalysed cross-coupling reactions. Reactivity of 3-formyl-, 3-
halogeno- and 2-lithio-7-azaindole derivatives is reported. Functionalisation of the
pyridine ring via the N-oxide is also described. In the last part, biological activity of
various 7-azaindole derivatives is briefly indicated.
1.0 INTRODUCTION This review take into account the preceding one [8]. We
decided to disregard in the present report, the synthesis and
Azaindoles have fueled considerable synthetic interest the reactivity of condensed 7-azaindole systems as well as
primarly as bioisosters for indoles. Although naturally studies on fully hydrogenated azaindoles.
occuring 7-azaindoles are relatively scarce compared to
indoles, we can mentionned for example Variolins which The 7-azaindole 1 contains one nitrogen atom in the five-
were isolated from Antartic sponge Kirkpatrickia varialosa. membered pyrrole ring and one nitrogen atom in the six-
These alkaloids were shown to be active against P388 membered pyridine ring.
murine leukemia cells and among them, Variolin B was
found to be the most active derivative [1, 2].
H2N
N N
N H
N 1
O
OH OH OCH3
Theoretical study on azaindoles was carried out using a

SCF-CI π-electron semiempirical method calculations and
N
N N N showed that the nitrogen atom of pyridine ring behaves as a
N N π and σ acceptor whereas pyrrole ring acts as a π donor and
H2N H2N σ acceptor [9]. A more recent study using ab initio approach
indicated that lower negative charges were preferred on the
Variolin B Variolin D nitrogen pyrrolo atom; the carbon atom in position-3 was
found to have the highest electron density [10].
The properties of some 7-azaindoles with respect to 7-Azaindole 1 has also been the subject of intense
plants have been studied. 7-Azaindole-3-acetic acid investigation by fluorescence spectroscopy. At room
stimulates the vacuolation of protoplasms in the roots of temperature, proton transfer reactions leading to tautomers of
Allium cepa [3]. For its part, 7-azatryptophan inhibits the 1 are very fast; no dimeric emissions can be observed. At
growth of Nicotiana tabacum and Daucus carota cells [4]. lower temperature, emissions from the dimer appear (Scheme
3- and 6-Substituted 7-azaindole derivatives have been tested 1) [11]. The energy barriers associated with the tautomerism
as potential agrochemicals [5]. Biological activities were have been determined in different solvent (i.e. EACT 4.8
also observed with enzyms or bacteria. Thus, 7-azaindole kcal/mole in ethanol) [12].
binds to the enzyme Erm (methyltransferase family) which
conferes resistance to antibiotics [6]. 7-Azatryptophan
decreased the Tetrahymena pyriformis growth [7]. 7-
Azaindoles have also enjoyed widespread application as N
N
potential pharmaceutical agents. hν
H H 2
N N
N N
H
Address correspondence to this author at the Institut de Chimie Organique
et Analytique, BP 6759, Université d'Orléans, 45067 Orléans, France;
E-mail: jean-yves.merour@univ-orleans.fr Scheme 1.
1385-2728/01 $20.00+.00 © 2001 Bentham Science Publishers Ltd.

472 Current Organic Chemistry, 2001, Vol. 5, No. 5 Mérour and Joseph
1 + CH3OH
N N N N
H
H H
O
CH3
H
+ H3 C O CH3O +
N H N N
N H
H
Scheme 2.
Petrich examined the tautomerisation of 7-azaindole 1 in 2.0 SYNTHESIS OF 7-AZAINDOLES

methanol and ethanol [13]. In the excited site,
tautomerisation occurs readily and constitutes the major 7-Azaindoles have been the target of extensive synthetic
route of non radiative relaxation. Compared to the rate efforts as a consequence of their potent pharmacological
constant for reaction in methanol or ethanol the decay rate activities. The most general method for the construction of
constant is decreased by a factor of 2.7 for reaction in MeOD this ring system involves pyrrolo annelation into a
and EtOD; the tautomerisation reaction which is mediated preformed pyridine ring. However available routes to 7-
by at least one molecule of solvent might occur by concerted azaindoles such as Madelung [17, 18] or Fischer [19, 20]
transfer of the two hydrogens (Scheme 2) [14]. type syntheses are often limited mainly due to their narrow
scope compared to their use in indole field.
CH3
C6H5N(Na)CH3 a: R = CH3
R b: R= C6H5
18-60% c: R = 4-pyridinyl
N NH N N
H
O R 3-a-c
2 a-c
Scheme 3.
Pyrrolopyridines are commonly compared to indole; but 2.1 From 2-Aminopyridine Derivatives
there are a number of differences in the physical and chemical
properties; for example 7-azaindoles are stronger bases than Wibberley has described the synthesis of 2-substituted 7-
indoles, pK a = 4.59 for 1 [15]. azaindoles 3a-c from amides 2a-c (Scheme 3) [20].
The gas phase basicities of 1- and 7-methyl-7-azaindoles Rasmussen and Mahadevan [21], then Meade and
were obtained by ion cyclotron resonance techniques and ab Beauchamp [22] have described a modified Madelung and
initio calculations at the STO 3G level. The 7-methyl-7- extended Reissert synthetic route to give 6-methyl-7-
azaindole is more basic than 1-methyl counterpart in the gas azaindole 6 (Scheme 4). The usual procedure using the
phase [16]. condensation of triethyl orthoformate onto 4 gave the
expected imidate in 74% yield but on a large scale secondary
The properties of 7-azaindoles were governed by the product was obtained in large amount. This difficulty was
involvement in their condensed bicyclic system of two N- avoided by treatment of the 3,6-dimethyl-2-aminopyridine 4
heteroatomic rings with opposite π-electron effects: pyridine with a mixture of PCl5 and N-methylformanilide in
with a deficient of π-electrons and pyrrole with an excess of chloroform at reflux. Cyclisation of pyridine 5 in N-
π-electrons. methylaniline in the presence of sodium hydride afforded 6
(yield not reported, Scheme 4).
PCl5
NaH
C6H5N(CHO)CH3 CH3
CH3 C6H5NHCH3
CHCl3 reflux
C6 H5
87% H3C N N N N
H3C N NH2 H3C N H
CH3
6
4 5
Scheme 4.
Synthesis and Reactivity of 7-Azaindoles Current Organic Chemistry, 2001, Vol. 5, No. 5 473
1) s-BuLi, THF -40oC Et3N, MsCl

CH3
2) DMF, -40oC, 5 min rt, 5 min
OH
91%
85% N N N
N NHBoc N
Boc Boc
7 8 9
Scheme 5.
The lithiation of heteroatomic derivatives and more were added to afford 3-substituted 2-tert-butoxycarbonyl-
particularly of pyridine systems has been extensively studied aminopyridines 14 (Scheme 7). Generation of the new
notably by the Quéguiner's group [23]. The Madelung type dianions from 14 with n-BuLi followed by addition of DMF
synthesis has been considerably improved: better yields or methyl or phenyl Weinreb amides gave after hydrolysis 2-
and/or tolerance for functionalised groups on the pyridine substituted or 2,3-disubstituted 7-azaindoles 15 [25].
ring are now reported.
In the preceding synthesis, azaindolineazaindole
Functionalisation of the methyl group of 2-tert- derivative 17 and aminoalcohol 16 have been isolated as the
butoxycarbonylamino-3-methylpyridine 7 was performed by two major impurities during the synthesis of 7-azaindole 1.
directed ortho lithiation in the presence of 2 eq of s-butyl The alcohol can be considered as a product resulting from an
lithium (s-Buli) at -40°C followed by addition of N,N- aldol reaction between two molecules of the intermediate
dimethylformamide (DMF) to afford the alcohol 8 in 85% aldehyde in the synthesis of 1 (Scheme 8).
yield (Scheme 5). The intermediate alcohol was stable under
O H
Li
CH3 n-Buli 2.5 eq 5.5 M HCl
THF, 0oC DMF ∆, 8 h
OLi 12 1
65%
N NH N N N NHPiv (2 steps)
R
O R 13
11 R = t-Butoxy
7 R = t-Butoxy 12 R = t-Bu
10 R = t-Bu
Scheme 6.
usual conditions of dehydration but underwent facile Addition of ester 18 on the dilithium salt 11 led to the
elimination with mesyl chloride and triethylamine in keto intermediate 19 which undergoes an intramolecular
dichloromethane at room temperature to afford the N-tert- cyclisation in acidic conditions to afford 20 in 10% yield.
butoxycarbonyl-7-azaindole 9 in 91% yield [24]. The 7-azaindole derivative 20 so obtained showed
1) n-Buli, -20oC
R1 R1 R1
THF 1) n-BuLi, THF 5.5 M HCl
2) R 1X 2) R2CON(CH3)R3 R2 1 h, 45oC
7 R2
69-84% R3 = CH3, OCH3 OH 39-84%
NHBoc N N N
N (2 steps) N H
Boc
14 1 R1=R2=H
15 R1 = CH3, CH2C 6H5, allyl
R2= H, CH3, C6H5
Scheme 7.
Similarly, treatment of 7 or 2-tert-butylcarbonylamino-3- H

N
methylpyridine 10 with 2.5 eq of n-Buli in THF at 0°C,
N
gave a dark solution of the corresponding dilithio H+ NH
intermediates 11 or 12. Addition of N,N-dimethylformamide
on 12 gave the aldehyde 13. Final cyclisation was performed OH N N
H N
with 5.5 M HCl at reflux to give 1 in an overall yield of NH2
65% (Scheme 6).
16 17
In the case of the dilithio intermediate 11, various
electrophiles such as iodomethane, 1-chloro-3-iodopropane Scheme 8.
R
N
N N R
H3COOC (CH2) 2 N NR O N 10% HCl
18
11 10%
N N
H
20 R = 4-ClC6H4
N NHBoc
19
Scheme 9.
pharmacological properties on the dopaminergic system Refinements of this mechanism show that the
(Scheme 9) [26]. monolithiated species is rather the enamine B, which
cyclises faster in the presence of an excess of LDA (Scheme
The tert-butyloxycarbonyl (Boc) and tert-butylcarbonyl 12) [28].
(Piv) protecting groups are not necessary to lithiate the
methyl group of 3-picoline. Thus, monolithiation of 3- 3-Ethylpyridine reacted similarly to afford 3-methyl-2-
methylpyridine 21 followed by addition of benzonitrile, then phenyl-7-azaindole 15a in 25% yield. 3-tert-Butyl-7-
H H
CH3 LDA, THF C6 H5
C 6H5 CN excess LDA H2O
C 6H5 3b
NLi
N N N N
Li H Li
21
Scheme 10.
thermolysis and work up afforded the 2-phenyl-7-azaindole azaindole 22 was obtained in 90% yield if the reaction was
3b [27]. However, reaction yields are only moderate even carried out with 2,2-dimethylpropanenitrile instead of
under forcing conditions (63% after heating at 100°C for 36 benzonitrile [27].
C6 H5 C 6H5
LDA, THF N N
C6H5CN N Li N H2O
H
Li
21
3b
2 LDA, THF Li H2O

C 6H5CN
C 6H5 C6H5
N N
N Li N Li
H
Li
A
Scheme 11.
h); better yields under milder conditions are observed (90%) Quéquiner’s group has developed an one-pot reaction
when an excess of LDA is used (2 eq) (Scheme 10). between 2-amino-3-iodopyridine and enolates under SRN1
conditions to afford the corresponding 1,2-disubstituted 7-
Such improvement was attributed to formation of a azaindoles (Scheme 13) [29, 30]. Thus, 3-iodo-2-tert-
dilithiated intermediate A as illustrated in the Scheme 11. butylcarbonylaminopyridine 23 treated with an excess of
excess
LDA
N N
NHLi
N Li
B
Scheme 12.
nitrogen atom and protonation of this pyridine nitrogen atom

CH3 in the acidic medium explain these poor results.
CH3 Heterogeneous catalysed Fischer reaction of acetaldehyde

C 6H5 CH3 or acetone and 2-pyridinylhydrazine 26 in the presence of
N N N CH3 alumina and fluorinated aluminium oxide afforded 7-
H N H azaindole 1 or 2-methyl-7-azaindole 3a in low yields
15a 22 (Scheme 14) [31].
In the same way, 7-azatryptamine 29 was prepared from

lactam α-enamine 27 and 2-pyridinylhydrazine 26 via
tricyclic derivative 28 (Scheme 15) [19].
ketone enolate (2-propanone or pinacolone) in anhydrous
liquid ammonia under UV illumination gave the keto More recently in the search of new ligands of
derivative 24 or 25 via quantitative and selective benzodiazepine receptors, the synthesis of compound 31 was
substitution of iodine. In the dark, no reaction was observed. carried out via a Fischer reaction between 26 and ketone 30.
Hydrolysis of the pivaloylamino moiety, cyclisation and The [3,3] sigmatropic rearrangement was effective under
dehydration were simultaneously achieved under acidic thermically conditions (160°C for 9 h, 71% overall yield)
conditions (3N HCl) to lead in good yield to 2-substituted (Scheme 16) [32, 33].
7-azaindole 3a or 22 after acidic workup.
O
excess
R O
I HCl
hν , NH3 R
R
N NHPiv N N
N NHPiv H
24 R=CH3 80% 3a R = CH3 80%
23 22 R = t-Bu 90%
25 R=t-Bu 99%
Scheme 13.
2.2 Fischer Type Reactions 2.3 Diels-Alder Reactions
Fischer reaction is one of the main method for the Generation of the pyridine ring and pyrrole ring can be
synthesis of indole derivatives. In the case of the 7-azaindole observed from 1,2,4-triazines through an intramolecular
H
N Al 2O3
NH2 CH3COCH3
250-400oC
+ or
N R
CH3CHO
N N
26 H
1 R = H 15%
3a R = CH3 35%
Scheme 14.
nucleus, the Fischer indolisation of pyridylhydrazones either inverse electron demand Diels-Alder reaction followed by an
fails or gives the desired compounds in low yields. oxidation reaction of the 7-azaindoline ring obtained [34].
Deactivation of the pyridine ring by the inductive effect of the Reaction of 4-aminobutyne with triazolo compound 32 gave
NH2
n NH
26 + HN ZnCl2
N
32-85% N N
N O H
O N H
29
28
27 n = 1,2
Scheme 15.
O HN
N COC6H5 1) ∆
N
2) NH2 NH2, ∆
26 +
71%
N
H N
H
31
30
Scheme 16.
33. The latter heated at refluxing bromobenzene gave 34. triazolopyridine 37, obtained by diazotation reaction of
Final aromatisation with DDQ afforded6-(4-chlorophenyl)-7- nitroderivative 36. Photochemical reaction of 37 was carried
azaindole 35. No yields were reported (Scheme 17). out using a medium-pressure mercury lamp (125 W) and
4-ClH4C6
N N N
N C6 H5 Br
N X
H2N(CH2) 2 C CH 156oC
HN X
4-ClH4C6 N SO2CH3
4-ClH4 C6 N N
H
32
33
34 X-X = CH2-CH2
DDQ, rt
35 X-X = CH = CH
Scheme 17.
However, this synthetic procedure applied to the preparation gave the corresponding azacarbolines in 93% yield as a
of more elaborated 7-azaindole was limited by the high mixture of isomers 38 and 39. 6-Isopropoxy-9-methoxy-α-
temperatures required for the Diels-Alder reaction. In all carboline was further oxidised with ceric ammonium nitrate
cases, significant decomposition of the starting materials was to give the quinone. The mild conditions provided
observed. compounds not accessible by the thermal route (Scheme 18).
An alternative route was developed by Parrick and Similarly, compounds 42-43 were prepared from triazolo
coworkers [35]. Methoxycarbolines 38-39 were prepared by derivatives 40-41 by Bisagni and coworkers (Scheme 19)
application of photo-Graebe-Ullmann reaction to [36].
H3CO
CH3
CH3
N O
N H CH3
O CH3
H 38 (84%)
N N 1) H2, Pd N
2) diazotation
N hν
66%
O2N N N CH3
(2 steps) O
OCH3
CH3
36
H3CO OCH3
37
N N
H
39 (9%)
Scheme 18.
N Amounts of cyclised products were improved when lithium

chloride was added in the medium. The reaction was also
N
R2 performed with various protecting groups on nitrogen atom
N N
R2 in position-2. Reactions of pivaloyl 23 or acyl substituted 2-
R1 amino-3-iodopyridine 46c (R= Ac) as starting materials gave
hν only coupling products 48. Tert-butyloxycarbonyl group
N CH3 provided in similar amount 47b and 48b. Coupling
H3C N H reactions using 4-methoxybenzyl or 4-methoxyphenyl as
R1
protective group led to an improved yield of desired cyclised
42 R1 = H, R 2 = CH3 34% products 47f or 47g.
40 R1 = H, R2 = CH3
41 R1 = CN, R2 = H 43 R1 = CN, R2 = H 38%
From derivative 47e, a large number of 3-methyl-2-
Scheme 19. substituted 7-azaindoles such as 49-52 have been prepared as
reported in Scheme 22 [39].
In the same way, 2,3-disubstituted 7-azaindole 53 with

2.4 Palladium-Catalysed Reaction
an hydroxyethyl chain was prepared in good yield from 46e.
Bond formation between sp2 carbons is now routinely For the condensation of 5-substituted 2-amino-3-
done using palladium (0) complexes as catalyst [37]. Several iodopyridines 54 with 4-trimethyl (or triethyl) silyl-3-butyn-
research groups have developed palladium-catalysed 7- 1-ol, dichlorobis(triphenylphosphine)palladium (II) was a
azaindole syntheses. Thus, a Stille reaction between 3- better catalyst than palladium acetate, and LiCl was an
triflyoxy-2-nitropyridine 44 and 1-ethoxy-2- essential reagent with respect to accomplishing good
tributylstannylethene in the presence of regioselectivity and improved yield (Scheme 23) [40].
dichlorobis(triphenylphosphine)palladium (II) and Heteroalkylation of the silylalkyne was also highly
tetraethylammonium chloride in acetonitrile gave a mixture regioselective (compounds 55). In all cases, the silyl group
of E and Z isomers of 45 in 88% yield. Hydrogenation of 45 was found in position-2, indicating a high regioselectivity
over Raney nickel followed by an acidic cyclisation at reflux for the nucleophilic attack of the nitrogen atom.
of methanol afforded 7-azaindole 1 in 70% two steps yield
Using this synthetic approach, 7-azaindolin-3-ones 58
(Scheme 20) [38].
have been prepared in two steps in our laboratory (Scheme
Pd(PPh3 )2Cl2
(Et) 4NCl 1) H2 , Raney Ni, CH3OH
OTf OC2H5
CH3CN reflux 2) HCl, CH3OH reflux
SnBu3 1
+
H5C2 O 88% 70%
N NO2 N NO2
44 45 (E/Z 14:74)
Scheme 20.
Yum has reported a convenient and simple approach to 3- 24). Palladium-catalysed heteroannulation between 3-iodo-2-
methyl-2-trimethylsilyl-7-azaindole 47 via palladium- pivaloyl or 2-benzenesulfonylaminopyridine 23 or 56 and
catalysed heteroannulation reaction of 1- methoxyallene afforded derivatives 57 in 65-80% yield. Final
trimethylsilylpropyne with 2-amino-3-iodopyridine ozonolysis reaction on 57 afforded 7-azaindolin-3-ones 58
derivatives 23 or 46 (Scheme 21) [39]. Reaction of 2-amino- [41].
3-iodopyridine derivatives 46a (R= H) with 1-
trimethylsilylpropyne in the presence of palladium acetate In the search of new potent cAMP Phosphodiesterase III
and quaternary ammonium chlorides provided around 40% of inhibitors, 7-azaindole derivative 61 has been prepared from
cyclised products 47a and 20% of coupling product 48a. substituted 3-iodo-2-aminopyridine 59 and
CH3 CH3
Pd(OAc) 2
CH3 (R1) 4NCl or LiCl
I KOAc, DMF
+ Si(CH3) 3 +
N N NHR
N NHR
Si(CH3) 3 R
R1 = CH3, C2H5 48 (0-47%)
47 (27-91%)
23 R = Piv
46 a R = H b R=Boc c R=COCH3 d R= C6H5 e R = CH2C6 H5
f R = 4-CH3OC6H4 g R = 4-CH3OC6H5CH2
Scheme 21.
CH3
TFA, CH2Cl2
H 49 R = CH2 C6H5
86% N
N
R
CH3
ClI, CCl4
I 50 R = CH2 C6H5
CH3 88%
N N
R
Si(CH3) 3
N I
N CH3
CH2 C6H5 Pd(OAc)2
KOAc, DMF
47e 51 R = CH2 C6H5
73%
N N
R
CH3
Na, NH3 Si(CH3)3 47a

81% N N
H
Scheme 22.
OH
Pd(OAc)2
Na 2CO3, DMF
46e + (CH3)3 Si CH2CH2OSi(CH3) 3 Si(CH3) 3
41%
N N
CH2C6 H5
53
OH
LiCl
R I Pd(dppf)Cl2 R
Na2CO3, DM F
+ (C2H5) 3Si CH2CH2OH Si(C2H5) 3
N NH2 N N
H
54 R = CH3 , COOCH3 , Cl 55
Scheme 23.
O
Pd(PPh3) 2Cl2
I Na 2CO3, CH3CN O3, (CH3) 2S
+ O OCH3 OCH3
65-80% 25-54%
CH3 N N N N
N NHR
R R
23 R = Piv 58
57
56 R = SO2 C6H5
Scheme 24.
trimethylsilylacetylene. The reaction was carried out in the 60 was effective at reflux of DMF to provide desired
presence of dichlorobis(triphenylphosphine)palladium (II) in compound 61 and desilylated by-product 62 in fair yields
THF to give 60 in 96% yield. Intramolecular cyclisation of (Scheme 25) [42].
N N N H
R CuI, DMF
reflux
+
H3C N NH2 H3C N N H3C N NH2
H
59 R = I 61 (40%)
62 (35%)
Si(CH3) 3
Pd(PPh3 )2 Cl2
60 R = C C-Si(CH3)3 CuI, Et3N, THF
96%
Scheme 25.
An alternative Suzuki methodology was investigated in Hemetsberger’s reaction [44] is routinely used in indole
view to improve the yield of 61 (Scheme 26). Coupling chemistry but scarcely in 7-azaindole series. Using this
reaction between 59 and 2-ethoxyvinylborane 63 in the approach, Molina has recently reported a synthetic pathway
presence of a catalytic amount of tetrakis(triphenylphosphine) of ethyl 4-methoxy-7-azaindole-2-carboxylate 69 (Scheme
palladium (0) in THF was performed to give the vinylether 28) [45]. 3-Formylpyridine 67 was stirred with ethyl
intermediate 64. Without further purification, the latter was azidoacetate in the presence of sodium methoxide at -15°C to
hydrolysed with 2N HCl for 48 h to give the 7-azaindole 61 provide vinylazide 68 in 61% yield. At toluene reflux,
in 78% [42]. intramolecular cyclisation of 68 occurred to afford 7-azaindole
C 2H5O N OC 2H5 N
O 1) Pd (PPh3) 4
59 + 2) NaOH, THF, ∆
B H 2N HCl
O N
H3C N NH2 H3C N H
63 64 61 (78%)
Scheme 26.
2.5 Miscellaneous Syntheses derivative 69 in good yield. The latter was further used as
starting material for the multistep synthesis of variolin
MAP kinase p38 enzyme has recently attracted much derivatives. Thus, protection of 69 with a SEM group (94%
interest as a potential target for anti-inflammatory drugs. yield) followed by a reduction with LiAlH4 and final
Thus, compound 66 (RWJ 68534) having a 7-azaindole oxidation with manganese dioxide in dichloromethane gave
skeleton has proven to be a highly selective inhibitor of p38 the aldehyde 70 in fair yield. Condensation of 70 with ethyl
enzym and was prepared according to a variation of the azidoacetate provided vinylazide 71 in 76% yield which was
Bischler-Möhlau indole synthesis using an unsymmetrical submitted to a Staudinger reaction with triphenylphosphine
benzoin derivative as starting material (Scheme 27) [43]. to afford the iminophosphorane 72 in 82% yield.
Deprotection of the SEM group using tetrabutylammonium
Reaction between 65 and 4-methoxy-2,6-diaminopyridine fluoride-SiO2 system under microwave heating, cleanly
in the presence of 5 eq of sulfuric acid in dimethoxyethane at removed it in 70% yield without affecting the
reflux gave 66 in 53% yield. Traces of the regioisomer, with iminophosphorane moiety. The last step was the aza-Wittig
the pyridinyl substituent in position-2, was observed. reaction with aromatic isocyanates in THF at room
F OCH3
t-Bu(CH3) 2SiO OCH3
H2SO4
+ DME
53% F
N O H2N N NH2
H2N N N
65 H
66 (RWJ 68534)
Scheme 27.
OCH3
OCH3 OCH3 xylene
N3CH2COOC2 H5
COOC2H5 reflux
CHO C2 H5ONa, -15oC R
67%
N N
N3
N N R'
68 69 R= COOEt R' = H 67%
67 1) NaH, SEM Cl, DMF
2) LiAlH4, THF reflux
70 R=CHO R' = SEM 52% 3) MnO2, CH2Cl2, rt
N3CH2COOC2H5
76%
C2H5ONa, -15oC
OCH3
OCH3
OCH3
1) TBAF
2) RNCO
N PPh3
N COOC2H5 63%
(2 steps) N N COOC 2H5 82%
N N COOC2H5
N
RNH SEM N
P(C6 H5 )3 SEM N3
73 72 71
Scheme 28.
temperature to directly afford the desired pyrimido annelation In 1975, Brodrick reported the synthesis of 7-azaindole
compounds 73 in high yields. derivatives where the key step was the reaction of 2-
aminopyrrole 76 with ethyl ethoxymethylenemalonate
followed by intramolecular cyclisation in diphenyl ether
2.6 From Pyrrole [47]. The pyridone derivative obtained was converted in two
steps to the 7-azaindole. In order to prepare NADH models
If most of the syntheses of 7-azaindole have pyridine with high reactivity and good enantioselectivity, Quéguiner
derivatives as starting materials, some preparations requiring has described the synthesis of 3,5-disubstituted 7-azaindoles
pyrrole moiety have been reported (Scheme 29) [46]. Thus, 79 from the same 2-aminopyrrole 76 and the sodium salt of
compound 75 was prepared in low yield from 3,3-dimethoxy-2-formylpropanenitrile 77 (Scheme 30) [48].
methylvinylketone and 1-phenyl-2-aminopyrrole 74. The overall yield for the synthesis was 35-40% yield
(method A). An improved one pot procedure (method B,
CH3 80%) has been developed where enamine 78 was not isolated
and the pH kept under rigorous control (pH >9).
NH2 + COCH3
N 23% According to the method described below, new
N N
C6H5 antagonist 82 of the corticotropin-releasing hormone receptor
C6H5
75 which has clinically beneficial properties in anxiety and
74
depression, has been prepared from 2-aminopyrrole 80 and
Scheme 29.
NC
NC NC
CN C2H5NH3+Cl- CN C2 H5ONa
NH2
AcOH N
OK NHC2H5
method A C 2H5
78 76
H3CO CN
H+
H3CO ONa
1) C2 H5 NH3+ Cl- 77
NC 2) KOH
CN
CN 3) 77
NC
80%
OK
method B N N
C 2H5
79
Scheme 30.
NC
O O
CH3 R
NH2
1) AcOH, C2 H5 OH NH2
Br NC N
CN 2) t-BuOK, C2H5OH C2H5OH, HCl
+ Br
78% H3 C N N
OK Br
H3C CH3
H3C CH3
80
CH3
H3C
81 R = CN H+ , ∆
82 R = H 66%
Scheme 31.
acetylacetone (Scheme 31) [49]. In acidic medium, both 2.7 Electrocyclic Ring Closure
compounds reacted to give 7-azaindole 81. Hydrolysis and
final decarboxylation afforded 82 in 66% yield. Molina has reported a new access to 7-azaindole skeleton
through a consecutive aza-Wittig reaction-electrocyclic ring
In the same report was also described the introduction of closure-intramolecular amination process (Scheme 32) [50].
chloro and morpholino substituents in position-4 of the 7- Condensation of ethyl azidoacetate on aldehyde 85 in the
azaindole ring via the preparation of N-oxide to give presence of sodium ethoxide in ethanol at -12°C led to the
compounds 83 and 84 in moderate yields. azide which was transformed into iminophosphorane 86 in
71% overall yield. The latter was reacted with several
aliphatic or aromatic isocyanates in toluene at reflux to give
O
pyridine derivatives 87 (76-86% yield). Compounds 87
stirred in nitrobenzene at reflux gave the corresponding 7-
Cl N CN azaindole derivatives 88. Pyridine moiety of 87 was the
CN
result of electrocyclic ring closure of the intermediate
carbodiimide followed by [1,3] proton shift.
N H3C N N
H3C N Br
Br
3.0 REACTIVITY OF 7-AZAINDOLE DERIVATIVES
Three relevant papers by Robison and coworkers in

83 (29%) 84 (44%) 1955-59 described the reactivity of 7-azaindole with
CH3 CH3 electrophilic reagents and its fundamental reactions [17, 51,
H3C H3C
52].
H 1) N3 CH2COOC2H5
C2 H5ONa COOC 2H5
O 2) PPh3
71% N=PPh3
(2 steps)
86
85
R-N=C=O
76-86%
toluene, ∆
C 6H5
C6H5NO2 , ∆
H5 C2OOC N N
70-87%
R H5 C2OOC N NHR
88 R=C6H5, 4-H3CC6 H4 87
Scheme 32.
R-Br Ar O
1 acetone
44-53% 1 +
N N 68-83% N
N
Br H
Br
R O
89
R = β-D-glucopyranosyl 90
Ar
β-D-galactopyranosyl
α-D-arabinopyranosyl
Scheme 33.
3.1 N-Alkylation N-Alkylations of anionic 7-azaindoles, obtained from 1, 6

and 93 by addition of NaH, KOH, K2CO3 or n-Buli in
In unsymmetrical heterocycle systems with more than aprotic solvent (THF, DMF, DMSO…) were performed with
one available alkylation site, the knowledge of factors alkyl or aryl halides to give various N-substituted
governing site selectivity is crucial. Unionised 7-azaindole 1 compounds 96-99 (Scheme 36) [59-62]. The N-alkylation
afforded N-alkylation on the pyridine ring by heating. Under was irreversible and under kinetic control [63] and such
more vigorous conditions, dialkylation was first observed conditions are widely used in organic synthesis. 7-Azaindole
followed by monodealkylation with the consequent 1 is more reactive than isomers 4-, 5- or 6-azaindoles toward
formation of the more stable pyrrole N-alkylated product. N-alkylation; that may be correlated to the acidity of the N-
Thus, glycosylation of 7-azaindole 1 with 7-pyridine protonated conjugate acid (pKa = 4.59) [15].
acetobromoglucose, galactose and arabinose afforded
compounds 89 in 44-53% yield (Scheme 33) [53]. In the same way, amino protecting groups were
Treatment of 1 with bromoketone in acetone afforded introduced at the pyrrole nitrogen of 1 and 100 to afford N-
pyridinium salt 90 (Scheme 33) [54]. protected 7-azaindoles 101-102 in good yields (Scheme 37)
[64, 65].
Beauchamp has also reported the synthesis of dimer 91 as
salt from 7-azaindole using NbCl5 [55]. N-Acetyl-7-azaindoles 103 by treatment with
(C5H5)2TiCH 2ClAl(CH 3)2 afforded N-isopropenyl-7-
azaindoles 104 in 41-56% yield (Scheme 38) [66].
Michael type addition of 7-azaindole was also

investigated. Thus, treatment of 2-phenyl-7-azaindole 3b and
N N
H acrylonitrile in the presence of Triton B afforded N-
cyanoethyl-2-phenyl-7-azaindole105 in 78% yield (Scheme
N 39) [20]. Michael type addition has been also reported
between 1 and dehydroalanine derivative 106. The N-
CH3
N alkylated derivative 107 was then obtained in 93% yield
[67].
91
Methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate
108 has also proved to be efficient alkylating agent on the
potassium anion of 1 to afford derivative 109 in 92% yield
In an other report [56], a solution of 7-azaindole 1 with (Scheme 40) [68].
malonic derivatives stirred at 160°C for 5 min afforded
tricyclic derivatives 92 in 65-75% yield (Scheme 34).
NO2 NO2
H3CO CH3
R-CH(COOR') 2 N toluene, ∆
1 N + N
65-75% 67%
N N H3CO CH3 N N
O O H
CH3
R = alkyl, CH2C6 H5, aryl R
93 94
Scheme 34.
Nevertheless, N-methyl alkylation of the pyrrole ring of 1) AlCl 3, CS 2

93 occurred in neutral conditions with DMF dimethyl acetal O 2) OH-, H2O
to give 94 in 67% yield (Scheme 35) [57]. When compound 1 +
1 was treated with ethylene oxide in the presence of 71% N N
aluminium chloride (AlCl3) in carbon disulfide, N-(2-
hydroxyethyl)-7-azaindole 95 was obtained in 71% yield 95
(Scheme 35) [58]. OH
Scheme 35.
Br
O CHO
NO2
NaH, DMF K2CO3 , RX, CH3CN
or KOH, DMSO 93
1 29-91%
89% N
N N
N
R
CH2CH2OC 6H4-CHO 97
96
R = a: CH2 CH2Br b: CH2CH2COOC2H5
c: CH2 CH(OH)CH2 OH
NaH, DMSO
C6H5CH2 Cl
AlCl3, TMSCN N N
O 81%
C6H5COCl N N
1 H3C N H H3C N
NC
11%
O 6 CH2C6 H5
99
98
Scheme 36.
Br Br
n-BuLi, THF n-BuLi, THF
t-Bu(CH3) 2SiCl
1 RX
41-94% 58-82% N
N N N N N
H
Si(CH3) 2t-Bu R
102
101 100
R = a: TBDM S b: MEM
c: Boc d: Ts
Scheme 37.
R R
(C5 H5 )2TiCH2ClAl(CH3) 2
41-56%
N N N N
CH3 CH3
O
103 a R = H, b R=C 6H5 104
Scheme 38.
CH2=CHCN
Triton B, CH3CN
C 6H5 C6H5
N 78% N
N H N
3b 105
CN
COOCH3
K2CO3, CH3CN
1 +
N(COOt-Bu) 2 93%
N N
106
H3COOC
N(COOt-Bu) 2
107
Scheme 39.
Cl N
N
K2CO3, CH3 CN COOCH3
1 + Cl
COOCH3 92%
NH
Cl N
Cl
108 109
Scheme 40.
N-Vinylation of 1 was also described by Reisch. Thus, 3.2 Glycosylation

reaction between 7-azaindole 1 and propiolic acid ethyl ester
in the presence of palladium catalyst in triethylamine afforded 7-Deazapurine 2',3'-dideoxynucleoside triphosphates are
exclusively E-acrylate derivative 110 (no yield was reported) potent inhibitors of HIV reverse transcriptase as their purine
(Scheme 41) [69]. counterparts. The synthesis and the activity of the analogue
1,7-dideaza-2',3'-dideoxyribonucleoside has been reported
Pd(PPh3 )2 Cl2 but with only marginal activity for the triphosphate
Et3N, 90oC derivative [71]. Direct glycosylation of N-anion of 4-nitro-7-
1 + COOC 2H5
azaindole 113, generated under solid-liquid phase-transfer
N N
conditions with potassium carbonate and cryptand (tris[2-(2-
methoxyethoxy)ethyl]amine, TDA-1) with 2,3-
COOC2 H5 dideoxyribofuranosyl chloride 114 afforded nucleosides 115
in 38% yield as a mixture of anomers (α/β 0.8:1) (Scheme
110 43) [72].
Scheme 41.
The glycosylation reaction between the
Russian researchers have investigated the condensation of bromomagnesium salt of 7-azaindole 1 and 2,3,5-tri O-
bromomagnesium salt of 2-methyl-7-indole 3a on diethyl benzyl-D-arabinofuranose116 in dichloromethane followed
oxalate in different solvents [70]. N-Acylation occurred in
CH3
111
N N
C2 H5M gBr
C2 H5OH COCOOC2 H5
73%
H5C2 O OC2H5
CH3 + COCOOC2H5
64%
N N O O
CH3 112
MgBr THF
N N
H
Scheme 42.
73% yield (111) in ethanol. In THF, C-acyl derivative 112 by acidic cyclisation gave C-glycoside 117 in 80% two steps
was isolated as the major compound (Scheme 42). yield as a mixture of anomers (α/β 87:12, Scheme 44) [73].
NO2 NO2
NO2
K2 CO3, CH3CN
O N
Cl TDA-1 N N
+ t-Bu(CH3)2 SiO N
N O
N H t-Bu(CH3 )2SiO
114 O
113 t-Bu(CH3 )2SiO
115α (17%) 115β (21%)
Scheme 43.
BnO
O
N
BnO
NH 117α
1) CH2Cl2, rt OBn
O 2) 1.75 M HCl, CH2Cl2, rt
OH
+ BnO +
80% H
N (2 steps) N
N
MgBr BnO OBn N
O
113 116 BnO
117β
BnO OBn
α/β 87:12
Scheme 44.
It should noted that the same reaction performed in THF Bromination of 7-azaindole occurred in good yields using
gave predominantly the N-glycoside. bromine [51] or NBS as reagent (Scheme 46). Using NBS,
3-bromo-2-bromomethyl-7-azaindole 120 was obtained in
N-(Tert-butyldimethylsilyl)-7-azaindole 101 was allowed good yield from 3a [74]. Treatment of 121 with bromine
to react with 2,3,5-tri-O-benzyl-D-ribofuranosyl fluoride 118
O
N N
N BnO Si(CH3) 2t-Bu
Si(CH3 )2t-Bu BnO OBn 119β

101 BF 3.Et2O
+
+ EtCN, -78oC 62% α/β 74:26
O EtNO2, -15o C 80% α/β 18:82
F
N
BnO
O
BnO OBn N
BnO Si(CH3) 2t-Bu
118
BnO OBn 119α
Scheme 45.
.
in the presence of BF3 Et2O in such organic solvents as gave 3-bromo derivative 122 in 69% yield [75].
propanenitrile and nitroethane to give C-glycosides 119 as a
mixture of anomers [64]. α-Selectivity increased when the 1) protection
Br
reaction was performed in propanenitrile at -78°C. In 2) NBS/CCl 4
nitromethane at -15°C, the β-isomer was predominant CH3
N 3) NBS, CCl4
(Scheme 45). N H (PhCO2) 2 N N Br
82% CO2CH3
3a 120
3.3 Electrophilic Attack at Carbon C 3
CH3
CH3 Br
As described for the indole nucleus, the C3 atom of 7- NC
azaindole is susceptible to be substituted by electrophilic NC
Br2
reagents. Thus, a great variety of classical electrophilic
N 69%
reagents has been displayed such as bromine, chlorine, Cl N
Cl N N
iodine, nitric acid, anhydride acetic,… to obtain 3- CH2C6H5
CH2C6 H5
121
substituted 7-azaindoles. 122
Scheme 46.
3.3.1 Halogenation
Cl
I 1) ClI, pyridine
2) Boc 2O, DMAP
dioxane NCS, CHCl 3, rt
1
92% from 1 99%
N N N N
H
Boc
124 123
Scheme 47.
Chloration of 1 using N-chlorosuccinimide as reagent at addition of trimethylstannylchloride [65]. Conversion was

room temperature gave 123 in high yield [5]. Similarly, highly efficient with TBDMS group (99% yield), while the
iodation [20, 76] of 1 was performed with iodine yield from N-Boc derivative was insufficient. In the case of
monochloride (ClI) in pyridine to give unstable 3-iodo tosyl group, lithiation on the arylsulfonyl ring was observed
derivative which was immediately converted to its N-Boc leading to the distannyl derivative in 22% yield. 1-Tert-
derivative 124 (Scheme 47). butyldimethylsilyl-3-trimethylstannyl-7-azaindole 126a was
chosen to investigate optimum coupling conditions with 2-
Several reports in the literature have demonstrated the bromopyridine. The best conditions were obtained in the
utility of these synthons. Metalation of 3-halo-7-azaindole presence of palladium tetrakis(triphenylphosphine)palladium
OH
Br O
n-BuLi (2 eq) Li 0oC, 3 h
THF, -5oC 57%
N N
H N N
N N H
100
Li 125
Scheme 48.
with n-BuLi gave access to various 3-substituted derivatives. (0) with lithium chloride in refluxing THF. The TBDMS
Lithium-bromine exchange on derivative 100 followed by group has the further advantage that simple extraction into
addition of ethylene oxide afforded alcohol 125 in 57% yield dilute acid was sufficient to remove it. Final compound 127
(Scheme 48) [58]. was obtained in 45% yield (Scheme 49).
Br Sn(CH3)3 N
1) 2-bromopyridine
1) t-BuLi, THF, -90oC
Pd(PPh3 )4, LiCl, THF
2) (CH3) 3SnCl 2) HCl
126a
10-99% 45%
N N N N N
N H
R R
126
102 R = a: TBDMS c: Boc 127
b: MEM d: Ts
Scheme 49.
N-Protected 3-bromo-7-azaindole derivatives 102 were Few years ago, a non-nucleoside inhibitor of reverse
converted into the corresponding 3-trimethylstannyl transcriptase 128 (analogue of nevirapine) was prepared from
derivatives 126 by treatment with tert-BuLi followed by N-tert-butyloxycarbonyl-3-trimethylstannyl-7-azaindole
H3C O
N
O
H3C
TfO N N
SnBu3 N N
n-BuLi, THF,
C2H5 N
-78oC, Bu3 SnCl
N
124 Pd(PPh3) 2Cl2
C 2H5
19% N N DMF, 110oC N
Boc
126c 7%
N N 128
H
Scheme 50.
NO2 NO2
HNO3
HNO3, H2SO4, 0oC CF 3COOH, 0o C
48% N 60%
N N N N
H H N H
O O O
131 129 130
NO2 NO2
HNO3
CF3COOH, 0oC
+
N 71%
H3C N N H3C N N
H H3C N H H
O O
O
132 134
133
Scheme 51.
126c. The low yield of the cross-coupling reaction was 3.3.3 Acylation
largely due to the difficulties of purification (Scheme 50)
[76]. According to the experimental conditions used, the
orientation of acylation (N- or C-acylation) was governed. C-
Acylation [79] in position-3 of 1 was performed in the
O 1) Ac 2O
CH3
AlCl3, CS 2
2) H2O Ac 2O, AcOH
1
90% 90% N
N N N
H
O
H3 C
135 135
Scheme 52.
3.3.2 Nitration presence of acetic anhydride and AlCl3 to give 135. N-

Acylation of 1 was carried out with a mixture of acetic
7-azaindole 1 was nitrated in position-3 using nitric acid anhydride and acetic acid at reflux to afford 103a (Scheme
[52, 60]. Nitration of N-oxide 129, obtained by treatment of 52).
1 with mCPBA [77], with HNO3 in trifluoroacetic acid at
0°C gave the 4-nitro derivative 130 in good yield [78]. Friedel-Crafts reaction between 136 and acid chloride 137
Nitration of 129 in sulfuric acid afforded this time the 3-nitro in the presence of AlCl3 provided potent serotoninergic
isomer 131 (Scheme 51). This result indicates that such antagonist 138 in 31% yield (Scheme 53) [80].
conditions the directive influence of the pyrrole ring nitrogen
on the electrophilic substitution exceeds that of the N-oxide. In the same way, reaction of bromoacetyl bromide with 1
It should be noted that the nitration of N-oxide-6-methyl-7- in the presence of AlCl3 in carbon disulphide afforded 3-
azaindole 132 gave a mixture of 3- and 4-nitro derivatives bromoacetyl-7-azaindole 139 in 75% yield [79]. This α-
133 and 134 in 71% yield (ratio 2:3) [71]. Deoxygenation of bromoketone treated with piperidine derivative afforded the
N-oxides with phosphorus trichloride led to the corresponding amide 140, skeletal framework of alkaloid
corresponding 7-azaindoles. family (Scheme 54). No yields were reported [81].
N
O CH3
N AlCl3, CS 2, rt
+ O CH3
N N 31%
N N
CH3 Cl
CH3
137 138
136
Scheme 53.
O R1 O
HN
R2
Br N N
CH3CN, Et3 N reflux
N N N N
N H R1 N
H H R1
R2 R2
139 140
O
75% AlCl3, CS2
Br
Br
Scheme 54.
3.3.4 Sulfur and Seleno Derivatives derivative was also obtained [83]. Robinson has prepared 3-
formyl-7-azaindole 143 in 55% yield from azagramine 142
Sulfur dichloride reacted with 7-azaindole 1 to give bis- [17]. The same yield (50%) was observed by reaction of 1
3,3'-thio-7-azaindole 141 (Scheme 55). The substitution of with hexamethylene tetramine in acidic medium [84].
sulfur by selenium led to bis-3,3'-seleno-7-azaindole. Contrary to 1, N-alkyl 7-azaindoles 136 and 144b-d easily
Nucleophilic attack at the C 3 carbon atom by diethyl selenite underwent Vilsmeier-Haack reaction to give 3-formyl
generated from selenium dioxide and ethanol afforded the derivatives 145 in 62-85% yield (Scheme 56) [80].
seleno derivative [82].
Several of reports in the literature reveal the importance of
CH2Cl 2 3-formyl 7-azaindoles in the synthesis of new derivatives
S
1 + SCl2 [83]. Nucleophilic addition of methyl magnesium bromide
44% N N on 3-formyl-7-azaindole 143 was performed to provide
N N secondary alcohol 146 in 77% yield [79]. Protection of the
H H
nitrogen atom of 143 with a Boc group followed by sodium
141 borohydride reduction afforded primary alcohol 147 in a
global yield of 59% [85].
Scheme 55.
Kato has described oxidation of N-alkyl or allyl 3-formyl-
7-azaindole 145 (Scheme 57) [80]. Oxidation of N-alkyl
3.4 3-Formyl-7-Azaindole derivatives 145a-c was performed with potassium
permanganate in a mixture of water/acetone to give acids
7-Azaindole 1 was not easily formylated under normal 148a-c in 40-62% yield. For N-allyl derivative 145d, the
Vilmeier-Haack reaction conditions since the 1-formyl oxidation was carried out with sodium cyanide and
CH3 H
O
N
CH3 N4(CH2) 6 N4(CH2) 6
propionic acid acetic acid
1 143
55% 50%
N N N
N H H
143
142
H
O
R = a: CH3
POCl 3, DMF b: C2H5
62-85% c: CH2CH2OAc
N N N
N d: CH2CH=CH2
R R
136 (R=CH3), 144b-d 145
Scheme 56.
159 in 93% yield (Scheme 60) [88]. The latter was engaged
HO in peptide coupling reaction to afford potent antiallergenic
CH3
OH agent 160. Interestingly, when the initial condensation was
performed at higher temperature, double decarboxylation
occurred to give 3-vinyl-7-azaindole 161 in 77% yield
(Scheme 60) [82, 89].
N N
H N N
Boc 3-Formyl-7-azaindole 143 was easily alkylated on the
146 (77%) nitrogen atom using potassium carbonate as base in
147 acetonitrile [90]. N-substituted derivatives 162 were obtained
in 61-74% yield. Intramolecular Heck reaction on 162 was
performed in the presence of tetrakis(triphenylphosphine)
palladium (0) as catalyst to afford the corresponding
manganese dioxide followed by alkaline hydrolysis to give tetracyclic derivatives 163-164. The yield obtained for the
148d. Coupling reaction of 148 with amine by the DCC- six-membered ring was higher than for the five membered
HOBt method gave serotoninergic antagonists 149. ring (Scheme 61). Compound 165 was cyclised into 166
according to a free-radical mechanism [91]. In patent
For our part, we have also oxidised the aldehyde group of literature, the formation in low yield of compound 168 from
N-phenylsulfonyl-3-formyl-7-azaindole 150 with sodium ester 167 has been reported [92].
chlorite to afford acid 151 in 95% yield (Scheme 58) [86].
Esterification of 151 led to ester 152. Lithiation in position- Amidification of 151, prepared from the corresponding
2 of 152 then addition of iodomethane afforded 153 in 77% aldehyde reported in Scheme 58, with 2-iodoaniline at room
yield. The latter was lithiated on the 2-methyl position and temperature in dichloromethane in the presence of EDCI (1-
quenched with benzyl bromide. Acid hydrolysis of the ester [3-dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride)
group was carried out in the presence of boron tribromide to and DMAP (4-dimethylaminopyridine) afforded the
provide acid 154 in 68% two steps yield. Intramolecular corresponding amide (Scheme 62) [93]. The latter was then
cyclisation of 154 with trifluoroacetic anhydride gave protected with a Boc group to give derivative 169 in 79%
tetracyclic derivative 155 in 62% yield. yield (two steps). Intramolecular Heck reaction was
performed in the presence of palladium acetate as catalyst and
Henry reaction on aldehyde 156 was also reported to give silver carbonate to afford tetracyclic derivative 170 in 72%
nitrovinyl 157 in 51% yield [87]. Final reduction resulted in yield. The formation of triflate 171 was carried out with
the formation of analogue of melatonine 158 (Scheme 59). triflic anhydride in dichloromethane and pyridine at room
temperature. The latter was then submitted to Stille and
Condensation of aldehyde 143 with malonic acid in Suzuki reactions.
piperidine and pyridine at 40°C afforded α,β-ethylenic acid
CH3
N
CH3
H HO N
O
O O NH
NH2
KMnO4, H2O
acetone HOBt, DCC
40-62% 26-76%
N N N N N
N
R R R
149a-c
145a-c 148a-c
R = a: CH3, b: CH2CH3, c: CH2CH2 OAc

CH3
CH3 N
N
H O O
NH2
O OH NH
1) MnO2, NaCN
CH3OH, AcOH HOBt, DCC
2) NaOH 33%
N N N N N
N H2O, C2H5OH
78%
145d 148d 149d

Scheme 57.
H RO
O CH3 O
O O
NaClO2, NH2 SO3H LDA, CH3I
dioxane, H2O THF, -78oC
95% CH3
N N 77%
N N N
N
SO2C 6H5 SO2C 6H5 SO2 C6H5
151 R = OH 1) LDA, THF, -78oC

CH3OH, H+ 68% C6H5CH2Br
91%
152 R = OCH3 2) BBr3 , CH2Cl2
HO
O
(CH3CO) 2O
BF3, Et2 O C6 H5
O C 2H4Cl2 , rt
N N
SO2C6H5
N N 154
SO2C 6H5
155
Scheme 58.
H NO2
NHAc
O
CH3NO2 1) NaBH4, SiO2
CH3O CHCl 3, i-PrOH
NH4OAc CH3O CH3O
2) H2 , Raney Ni
51% CH3OH
N N N
H N H 22% N
N
(2 steps) H
158
156 157
Scheme 59.
O H
COOH N
CH2 (COOH)2
N
piperidine, pyridine
RNH2
40oC, 40 h EDCl N
143
C6H5
20%
93% N N N N
H H H5C 6
160
CH2(COOH) 2
piperidine, pyridine
reflux, 24 h
143
77%
N N
H
161
Scheme 60.
H H
O
2-BrC 6H4CH2CH2OTs O
or 2-BrC6H4CH2Br Pd(PPh3) 4
K2 CO3, CH3CN KOAc, DMF
143 Br
61-74% N N N
N
n
n
162 163 n= 1 25%

164 n= 2 90%
H H
O O
Bu3 SnH CH3O
CH3O Br C6 H6
75% N
N N N
166
165
O 1) BrCH2CH2CH2OH O
1) oxidation OR OR
2) NCS
2) SOCl2 3) HCl, (C2H5) 2O
3) ROH/CH3Li 4) K2 CO3
143 O
N N <5% N N
H
167 168
R= CH2 N C4H9
Scheme 61.
O O Boc
O
OH I
1) 2-iodoaniline N Pd(OAc) 2, PPh3 NH
EDCl, DMAP Ag2 CO3, DMF
2) Boc 2O, DMAP
100oC
N 79%
N N N 72% N
(2 steps) N
SO2C6H5 SO2C 6H5 SO2C6H5
151 169 170
79% Tf 2O, pyridine

CH2Cl2, rt
TfO
N
N N
SO2C6H5
171
Scheme 62.
3.5 7-Azaindolinones obtained with a sulfonyl protecting group (40-60%). N-

oxidation of the nitrogen atom of the pyridine ring was not
7-Azaindolinones 173 were obtained in 30-60% yield by observed. Introduction of a 2-hydroxy substituent on the 7-
Baeyer-Villiger oxidation of N-substituted 3-formyl-7- azaindolinone was sometimes observed.
azaindole 172 (Scheme 63) [94]. The best yield was
H R4
R4 O O
m-CPBA a R = COCH3 R4 , R6 = H
CH2Cl2 , 0oC b R = SO2 C6H5 R4 , R6 = H
c R = SO2C6H5 R4 = H R6 = Cl
30-60%
R6 N N d R = SO2 C6H5 R4 = Cl R6 = H
R6 N N
R
R
172 173
Scheme 63.
Aldolisation reactions of 7-azaindolinone 173b with 2-ketomalonate gave the corresponding ethylenic ester 178
aromatic aldehydes afforded the ethylenic ketones 174 in 60- with satisfactory yields.
88% yield [95]. The ketones 174 were engaged in inverse
electron-demand Diels-Alder reaction with ethoxyvinyl ether Horner-Emmons reaction conditions applied to 173b
in the presence of ytterbium salt as catalyst to afford pyrano with diethyl phosphonoacetonitrile in the presence of sodium
derivatives 175 in high yields as a mixture of diastereomers. hydride gave access to 2-(7-azaindol-3-yl)acetonitrile 179.
δ-Carbolines 176 were then prepared by treatment with Final catalytic hydrogenation afforded 7-azatryptamine 180
hydroxylamine (Scheme 64) [96]. (Scheme 65) [97].
O OC 2H5
O
R-C6H4CHO OC 2H5 O
piperidine
Yb(fod) 3 ∆
N N 60-88%
N C 6H4R 89-97%
N N C 6H4R
SO2 C6H5 N
SO2C 6H5 SO2 C6H5
173b
174 175
58-74% NH2OH,HCl
R = 4-CH3, 4-H3CO, 4-Cl, 4-NO2,
2-NO2, 2-COOCH3
N C 6H4R
N
SO2 C6H5
176
Scheme 64.
It should be noted that aldolisation reaction between 2- 3.6 N-amination

amino-3-formylpyridine and 173b led directly to tetracyclic
structure 177a (X= N) in 55% yield. The use of 2-formyl-3- Two approaches have been developed to reach N-amino
nitrobenzene instead of 2-amino-3-formylpyridine gave 7-azaindoles. First, treatment of 1 with sulfamic acid in basic
derivative 177b (X= CH) after catalytic hydrogenation [94]. medium afforded N-amino-7-azaindole 181 in 62% yield
In the case of ketones, only activated derivative such diethyl [98]. The latter gave access to new related structures for the
X
N
O
COOC2H5
N N
N N COOC2H5
SO2C6H5 H
178
177a X = N
177b X = CH
NH2
CN
(C 2H5O)2P(O)CH2CN H2, Pd
NaH, THF C2 H5 OH
173b
60% 51%
N N N
N
SO2C6 H5 SO2C6H5
180
179
Scheme 65.
treatment of infective diseases. Thus, reductive amination benzenesulfonyl-7-azaindole188, a regiospecific metallation

between 181 and ethanal afforded N-ethyl derivative 182 in in position-2 may occur [100]. The lithio derivative,
96% yield. Condensation of 182 with generated in situ, was quenched with electrophiles such as
diethylethoxymethylenemalonate (EEMM) gave 183 in 77% I2, ICH3, CO2, DMF, trimethylsilyl chloride,
yield. Finally, intramolecular cyclisation occurred in trimethylstannyl chloride and aromatic aldehydes to afford 2-
dowtherm to furnish tricyclic derivative 184 in low yield substituted 7-azaindoles 189 (33-94% yield). Addition of
(Scheme 66). TMEDA in the medium increases the yield of 2-
NH2SO3H NaBH4
KOH,DMF CH3CHO, CH3OH EEMM COOC2H5
62% 96% 77%
N N N N
N N COOC 2H5
NH2 NHC 2H5 N
H5C 2
183
15% ∆
N N COOC 2H5
N
H5C2
184
Scheme 66.
N-Amino derivatives were also prepared via trimethylsilyl and trimethylstannyl derivatives 189d and
rearrangement of 2-hydroxy-2-(3-pyridinyl)acetic hydrazides 189e (Scheme 68).
[99]. Under mesylation condition, compound 185 led to the
formation of O- and C-sulfonylated 7-azaindoles 186 and 187 This anionic methodology has proven to be quite
in 8% and 46% yield respectively (Scheme 67). versatile for the synthesis of 7-azaolivacin derivative [100].
2-Lithio-7-azaindole in THF at -25°C was condensed with
functionalised aldehyde 190 to afford alcohol 191. Oxidation
4.0 REACTIONS IN POSITION-2 of 191 according to Swern procedure followed by addition of
methyl magnesium bromide afforded lactone 192 in 90%
The preparation of 2-substituted 7-azaindole has emerged yield. Final Dibal reduction then alkaline cyclisation (14%)
as an extremely powerful synthetic method. From N- gave desired tetracyclic derivative 193 (Scheme 69).
C 6H5 C6 H5
Et 3N
N CH3SO2Cl SO2CH3
OSO2CH3 + O
OH H
N N N N
N
N N N
O O
O N
185
186 (8%) 187 (46%)
Scheme 67.
LDA, -20oC
THF, TMEDA E+
Li E
N N N N
N N
SO2C 6H5 SO2 C6H5 SO2C6 H5
188 189
a E = CHO 33%
b E = CH3 94%
c E = COOH 60%
d E = Si(CH3) 3 69%
e E = Sn (CH3) 3 70%
Scheme 68.
OCH3
N LDA, -25oC
188 + 60%
OHC OCH3 N N OH CON(C 2H5)2
SO2C6 H5
CON(C 2H5) 2
190 191
1) Swern oxidation
63% 2) CH3MgCl
3) AcOH
4) SiO2
H3CO
N O
O OCH3
1) Dibal
2) OH-
N N CH3 N
14%
N CH3 SO2C6H5
N
SO2 C6H5
192
193
Scheme 69.
Stille reaction between trimethylstannyl derivative 189e decrease of the energy of the HOMO of the diene. 2-Vinyl-7-
and 3-iodo-2-pivalylaminopyridine 23 has been also reported azaindole 195 was prepared in two steps from 188 [89].
and gave access to 2-heteroaryl-7-azaindole 193 in good Regioselective lithiation of 188 and quenching with iodine
yields (Scheme 70) [100]. provided iododerivative 194 in 83% yield. Palladium
catalysed coupling reaction between 194 and vinyltributyltin
The Diels-Alder reactions of 2- or 3-vinyl-7-azaindoles afforded 195 in 80% yield (Scheme 71). Vinyl derivative 195
represent an interesting methodology for the syntheses of was engaged in Diels-Alder reactions with dimethylacetylene
azacarbazoles. The reactivity of these vinyl derivatives is dicarboxylate (DMAD) to afford a mixture of compounds
lower than the corresponding indole derivatives due to a fully and partially aromatised. The mixture treated with
PivNH
Pd(PPh3 )2Cl2
I N
BnEt 3N Cl-, CH3CN
Sn(CH3) 3 +
N N N NHPiv 65% N
N
SO2C 6H5 SO2C6H5
23 193
189e
Scheme 70.
SnBu3
1) LDA, THF, -22oC Pd(PPh3 )4
2) I 2, -22oC LiCl, DMF, 90oC
188 I
83% N 80% N
N N
SO2C 6H5 SO2C6 H5
195
194
1) DMAD
20% C2H4Cl2 , 90oC
CH3 (2 steps)
H3C 2) DDQ
N
toluene, 110oC
H3COOC COOCH3
N O
O 1) TBAF, THF, reflux
2) CH3I, NaH
3) H2NCH2CH2N(CH3) 2
31%
(3 steps) N N
N N SO2C6H5
CH3 196
197
Scheme 71.
DDQ at refluxing toluene afforded 196 in 20% two-step 194. The low reactivity of 199 due to the presence of the
yield. From the latter, potential cytotoxic agent 197 was ester group afforded the fully aromatised cycloadduct 200 in
prepared in three steps. 17% yield and dimer 201 in 20% yield (Scheme 72) [89].
Similarly, compound 198 was prepared from 3-vinyl-7- A temporary protecting group on the nitrogen atom can
azaindole 161 according to the methodology described be used to lithiate in position-2; 7-azaindole-2-carboxylic
below. This compound exhibits significant cytotoxic acid 202 has been prepared using this methodology (Scheme
activity [89]. 73) [101]. This synthetic approach gave the final 7-azaindole
derivative with a free NH. Recently Alvarez, reported the
synthesis of deoxyvariolin B using key intermediate 203
O [102].
CH3
N N
N
N CH3 5.0 7-AZAGRAMINE AND 7-AZATRYPTOPHANE
O
CH3 DERIVATIVES
198
7-Azagramine 142 is an useful starting material due to
the easy displacement of the trimethyl amino group after
Diels-Alder reaction with DMAD as dienophile was also quaternisation with iodomethame or dimethylsulfate.
performed with diene 199, prepared from 2-iodo derivative According to Mannich reaction, 7-azagramine 142 was
N
COOCH3
N
Pd(OAc)2, Et3 N DMAD H3 COOC COOCH3 H5C 6O2 S
DMF, 90oC toluene, 110oC
194 COOCH3 +
56% N N COOCH3 OCH3
SO2C6H5 N O
N
N N
199 H5C 6O2S
SO2C 6H5 COOCH3
200 (17%) 201 (20%)
Scheme 72.
1) t-BuLi, -78oC
2) CO2, -78oC
n-BuLi, THF, -78oC 3) H+
1 COOH
CO2 41% from 1
N N N N
H
COOLi
202
O
1) N
N CHO
O
2) DHP, H+
3) NH2NH2 OTHP
38% from 1 N
N H
H2N
203
Scheme 73.
prepared from 1, formaldehyde and dimethylamine occurs multiply in most proteins. So 7-azatryptophan as an
hydrochloride. Treatment of 142 with iodomethane led to alternative probe has a single exponential fluorescence decay
the quaternary Mannich base 204 (Scheme 74) [17, 103, (780 ps in water, pH 7) and the location of its absorption
104]. and emission spectra permit it to be detected unambiguously
CH3 CH3
I-
N +N CH3
HCHO CH3 CH3
(CH3) 2NH, HCl CH3I
1
N N N
H N H
142 204
Scheme 74.
Potent D4 receptor antagonists 206 [105] were readily [107, 108]. 7-Azatryptophan has been incorporated into β-
prepared in good yields by the displacement of 142 with 2,4- galactosidase by in vivo methods as fluorescent probes [107].
disubstituted morpholines 205 in refluxing toluene (Scheme The first known biological activity of 7-azatryptophan was
75). the inhibition of tetrahymena pyriformis growth factor
through inhibition of tryptophan metabolism. Some reports
Mercaptoaminoacid (cysteine or homocysteine) were also described the synthesis of 7-azatryptophan derivatives [108,
used with 142 or 204 to afford derivatives 207, 208 in fair 109]. The racemic 7-azatryptophan was synthesised several
yields [103, 105, 106]. years ago from 7-azagramine [17]. Asymmetric alkylation of
glycine derivatives have received considerable attention with
The difficulty in using tryptophan as an optical probe of a variety of chiral auxiliaries to provide aminoacids of known
protein structure and dynamics are well known; tryptophan configuration in high optical purity. First synthesis of (-) 7-
has an intrinsic non-exponential fluorescence decay and its azatryptophan [85] was reported via the alkylation of (1R,
R
HN toluene N X
142 + R > 65% N
X O
O N
H
206
205
X = CH2, O R = H, 4-Cl, 4-H3CO, 3-Cl
Scheme 75.
HOOC
NH2
HOOC
NH2
S S
N N N
H 207 N 208
H
4R) camphorimine of tert-butyl glycinate 210 with the N- Martinez described a diastereoselective method using
tert-butoxycarbonyl-3-iodomethyl-7-azaindole 209, obtained diastereoselective alkylation and protonation
from 3-formyl-7-azaindole 143 in 4 steps (Scheme 76). (deracemisation) (Scheme 77) [110]. 7-Azatryptophan 214
Alkylation of imine 210 was effective in a solution of was quantitatively obtained from the racemic mixture 213
KHMDS in HMPA at -100°C and furnished derivative 211 (95% yield). Schiff base 215 was prepared from 214 in 81%
in 27% yield with a diastereomeric ratio better than 98. The yield, using chiral auxiliary (S,S,S)-2-hydroxypinan-3-one in
camphor auxiliary was removed in the presence of toluene with a catalytic amount of BF3.Et 2O. Diastereomers
hydroxylamine chloride and the Boc group cleaved with were easily separated if the nitrogen atom was protected as
trifluoroacetic acid to give the (-) R-7-azatryptophan 212. Boc derivative. Schiff base was deprotonated with KHMDS
H3 C CH3
H3C CH3
210
COOt-Bu
1) Boc 2O NCH2COOt-Bu
I H3C
2) NaBH4
3) PPh, CCl4 KHMDS, THF H N
H3C
143
4) NaI, acetone HMPA, -100oC
25% 27%
N N N N
(4 steps)
Boc Boc 211
209
1) NH OH
47% 2) CF 2COOH
3
COOH
H
H2 N
N N
H 212
Scheme 76.
NH2 COOCH3
1) CH3OH, ClSi(CH3) 3
N
COOH 2) 2-hydroxypinan-2-one OH
BF 3.Et2O, toluene
81% CH3
N N N
N (2 steps) H
H
214 (D,L) 215
1) Boc 2O, CH2Cl2
76% 2) 2 eq KHMDS, -80oC
(2 steps) 3) NH Cl
95% 12 N HCl 4
NHCOCH3 COOCH3
COOC2H5 N
COOC 2H5 OH
CH3
N N N
N H
H 213 216
Scheme 77.
NH2
CH3
CN
N
CH3 KCN, (CH3) 2SO4 H2, Raney Ni
N N N
N N H N H
H
217 29
142
H N N
N N
H N N
CH3 H
H3COOC CH3
219 218
Scheme 78.
(2 eq) at -80°C; the protonation was carried out with a The only known chlorination of 7-azaindole 1 was
saturated ammonium chloride solution to afford 216 in a performed on position-4 by reaction of its N-oxide with
diastereoisomeric excess of only 66%. phosphorus oxychloride [77]. The reactivity of the pyridine
ring was enhanced by transformation into its N-oxide [71,
The best method to obtain (R) or (S) 7-azatryptophan is 78]. Halogen, cyano and thiocyanato groups have been
treatment of the racemic N-acetyl 7-azatryptophan with the introduced onto position-6 of 7-azaindole via a Reissert-
enzyme Aspergillus genus acylase which afford (S) 7- Henze salt. Thus 7-azaindole N-oxide was treated with acid
azatryptophan in 45% yield. (R) isomer was obtained by halides in THF to give 6-halo-7-azaindole derivatives 220
hydrolysis in acidic medium of the separated (R) N-acetyl-7- and 221 in 57-60% yield [112]. Benzoyl groups on nitrogen
azatryptophan [110]. atom were readily removed by basic treatment to afford 222
and 223. The halogenation reactions were completely
Urögdi described the synthesis of analogue of vinpocetine regioselective except if trichloroacetyl chloride was employed
219 in 6 steps from 7-azagramine 142 via derivatives 217 as acid chloride. HMDS was used as a base to trap hydrogen
and 29 and the formation of key intermediate 218 (Scheme halide (Scheme 79).
78) [111].
Treatment of 129 with trimethylsilyl cyanide in refluxing
THF was unproductive; but addition of benzoyl chloride
6.0 FUNCTIONALISATION OF THE PYRIDINE accelerated substitution by cyanide anion even at room
RING temperature so cyano derivative 224 was obtained (39%
yield) with chloro derivative 220 (51% yield) (Scheme 80).
The direct functionalisation of the pyridine is not easy Interestingly, in the case with methyl chloroformate as the
with nucleophilic reagent since the pyrrole ring deactivates acylating agent, cyanation did not proceed at all and only
the pyridine ring. Position-4 and 6 are the more favourable chloro derivative 225 was isolated. In the same way,
position from charge distribution. 6-Substituted 7-azaindoles trimethylsilyl cyanide was allowed to react with 129 to give
have been generally prepared through ring closure of pyridine 6-iodo-7-azaindole 226 in 23% yield [112].
derivatives including the functional group.
HMDS, rt 1M NaOH
C6H5COX CH3OH
N N X N N 99% N
H X N H
O COC6H5
129 220 X = Cl 60% 222 X = Cl

221 X = Br 57% 223 X = Br
Scheme 79.
(CH3) 3SiCN, rt (CH3 )3 SiCN, rt

ClCOOCH3 C 6H5COCl
129 +
77%
Cl N N N Cl N N
NC N
COOCH3 COC6H5 COC 6H5
(CH3) 3SiI
225 23% ClCOOCH3
HMDS, rt 224 (39%) 220 (51%)
I N N
COOCH3
226
Scheme 80.
Chemical transformations of 6-halo-7-azaindoles have dichlorobis(triphenylphosphine)palladium (II) gave the

been studied by Minakata [82]. The displacement of bromine ethynyl derivative 228 in 79% yield. Desilylation and
atom of 223 in position-6 by 35% aqueous ammoniac deacetylation reactions of the latter occurred with 1N sodium
solution, (or ethylenediamine or diethylenetriamine) was hydroxide to give acetylenic derivative 229 (Scheme 82).
performed at 200°C in a sealed tube to afford 6-amino Iodo derivative 226 was coupled with gaseous acetylene to
derivative 227 (Scheme 81). afford diethynylated derivative 230 in 72% yield [82].
In 7-azaindoline series [113, 114], aminolysis of 231 in

NH3, 200oC
the presence of morpholine, piperidine or pyrrolidineafforded
N 80% 6-amino 7-azaindoline derivatives. In the case of
Br N H2N N N
H H benzylamine as nucleophile, 7-azaindole derivative 232 was
223 227 obtained in 81% yield (Scheme 83).
Scheme 81. Treatment of 4-chloro-7-azaindole 233 with aniline at

180°C for 3 hours provided the unexpected 4-amino-5-
Palladium-catalysed cross-coupling reaction between N- azaindole 234 in 84% yield [78, 115]. The structure of 234
benzoyl-6-bromo-7-azaindole 221 and trimethylsilylacetylene has been determined by X-ray analysis. 4-Hydroxy-7-
in the presence of copper iodide (I) and azaindole afforded the same compound using a mixture of
Si(CH3) 3
Pd(PPh3) 2Cl2
1 N NaOH, rt
221
79% N 95%
N N N
H
(CH3) 3Si COC6H5
228 229
1) H H
Pd(PPh3) 2Cl 2
2) 1 N NaOH
226 N N
72%
(2 steps) N N
H H
230
Scheme 82.
CH3 CH3
NC NC
C6H5CH2NH2
81%
Cl N N
H5C6 CH2NH N N
CH2C6 H5 CH2C6 H5
231
232
Scheme 83.
N(CH3)2 Cl NHC6 H5
(CH3) 2NH, HCl, 180oC C6H5NH2 , 180oC N

68% 84%
N N N N
N H H
233 C 6H5
235 234
NHC6H5 NHC6H5 NHC6H5
H+
NC 6H5
N N NH C H NH N N H
H N 6 5 2 H
NHC 6H5 NHC6H5

H
N
NC6H5 NHC6 H5
N NH2 N
C6 H5
Scheme 84.
aniline and phosphorus pentoxide. This rearrangement has the amide function was performed with borane-
been extended to substituted anilines and to primary tetrahydrofuran complex and the resulting 7-azaindoline was
alkylamines; secondary alkylamines and N-methylaniline led oxidised with manganese triacetate in acetic acid at 75°C to
to normal substitution products without rearrangement such give 5-bromo-7-azaindole 238 in a 50% overall yield. The 5-
as 235. A proposed mechanism for this rearrangement was bromo derivative was treated with sodium methoxide in the
depicted on Scheme 84. The mechanism involves the presence of copper (1) bromide in a mixture of DMF and
generation of a Schiff base intermediate. methanol to provide 5-methoxy derivative 239 in 72% yield.
This derivative was subjected to a Vilsmeier-Haack reaction
Nevertheless using an other approach 4-amino-7- to afford aldehyde 156 in 41% yield.
azaindole was obtained from 4-nitro-7-azaindole [78].
Using pyridinium perbromide or NBS in tert-butanol
In order to obtain 5-methoxy-7-azaanalogues of afforded only 3,3-dibromo-2-oxo-7-azaindoline [116-118]. 7-
melatonin, Guillaumet and co-workers prepared 156 from 1 Azaoxindole 242 has been also obtained from 240 via a
in five steps (Scheme 85) [87]. Halogenation of 7-azaindole 1 cleavage of the N-N bond of 241 (Scheme 86) [99].
with bromine in a mixture of tert-butanol and water at room
temperature provided tribromo derivative 236 in 85% yield. 7-Azaisatin was first obtained by treatment of 7-
Treatment with zinc in acetic acid furnished azaoxindole with nitrous acid followed by hydrolysis of the
monobrominated derivative 237 in 94% yield. Reduction of intermediate oxime [118]. An other route for its preparation
Br
Br Br Br 1) BH3, THF Br
Br 2, t-BuOH, rt Zn, AcOH 2) Mn(OAc) 3
1 O O
85% 94% 50%
N N N N
N H N H
H
236 237 238
72% CH3ONa,DMF
H
O
CH3O CH3 O
POCl 3, DMF
41% N
N N
N H H
239
156
Scheme 85.
OH
H
N Et3 N, CH3 SO2Cl
N Li, NH3
O O
46% 70%
O O N N N
N N H
N
240 242
O
241
Scheme 86.
from 7-azaindole has been reported by Parrick and coworkers 246 was carried out by the reaction of 136 with bromine in
[119]. Oxidation of 7-azaindole with CrO3 as oxidant in the dichloromethane (94% yield) (Scheme 88). Oxidation of 246
presence of bromine afforded 5-bromo-7-isatine 243 [120]. with NBS in DMSO was carried out at 60°C for 6 h under
Alkylation with substituted benzyl chloride gave 244 which ambient pressure and then under reduced pressure to remove
finally gave access to 245, the first non peptide antagonist of the generated hydrogen bromide; 7-azaisatin 247 was
Bombesin antagonist and gastrin releasing peptide (Scheme obtained with 90% yield. N-Ethyl and N-benzyl-7-azaisatin
87). have been also prepared according this procedure [121].
O
Br O
Cl
Cl O
O NH
N HN
Br N (NH4) 2CO3
Br
Cl KCN, C 2H5OH O
O O
N N N
H N
Cl
243 Cl
244
Cl
Cl
245
Scheme 87.
N-Methyl-7-azaindole 136 was obtained in 95% yield A plausible mechanism for this transformation was
from the reaction of iodomethane with the sodium salt of 1 illustrated in Scheme 89.
in dimethylacetamide. The synthesis of 3-bromo derivative
Br O
NaH, CH3I
CH3CON(CH3) 2 Br2 , CH2Cl2 NBS, DMSO
1 O
95% 94% 90%
N N N N N
N
CH3 CH3 CH3
136 246 247
Scheme 88.
Br
Br Br Br CH3
NBS, DMSO DMSO S CH3

Br O
N N N
N N N
CH3 CH3 CH3
O Br
Br
H2O
O O
-HBr
N N N
N
CH3 CH3
Scheme 89.
7.0 PHARMACOLOGICAL PROPERTIES OF system and shown affinity for serotonin receptor [125].
DIFFERENT 7-AZAINDOLE DERIVATIVES Compound 251 was a potential dopaminergic D4 ligand
[26]. Carboxylic acid 252 was reported as a potential
In this last part, we reported some examples of thrombin inhibitor [126].
pharmacological active 7-azaindole derivatives recently
described in the literature. Anti-inflammatory properties of 7- Hypolipidemic agent 255 has been prepared in two steps
azaindoles have been already reviewed [122]. Bis indole 248 from 253 (Scheme 90) [127].
has been reported to inhibit protein kinase C [123].
Compound 256 was reported as an inhibitor of
cholesterol biosynthesis [128]. For derivative 257 a
H hypolipidemic activity was demonstrated [59]. Compound
N
O O 258 was evaluated against methicillin-resistant
Staphylococcus Aureus [129]. 259 acted on cardiac sodium
channels [130].
N Enzyme inhibition was found for 260 [104]. Various

N N
pharmacological properties were reported for 261 [131], 262
CH3 CH3 [60], and 263 [132]. Compound 264 obtained from 7-
248
azaindoleacetonitrile 217 decreased the smooth muscle
proliferation [133].
Compound 249 was described as a renin inhibitor [124].
7-Azaindole derivative 250 was active in nervous central
H3C
CH3
O OH
NH OH N N
HN
N
N O NH
N H N N
250
249
H3 CO
COOH
N N
H N N
H
251 252
N N
NaH, DMF
Br(CH2) 4Br 1) H2 , Ni
CH3
N 2) R-N=C=O
N O NH
79% N R= H3C CH3
N 78% CH3
CH3
NC NC H3C NH
CH3
253 CH3
254
CH3
255
Scheme 90.
H
COOC2 H5 N N
N O O
O
OH S
OH
N N 257
CH3
H3C
256
Cl
O S N N N N
S N
N CH(C6H5) 2
H
N N OH
H
COO
Cl 259
O
258
N CH2 C6H5
NH2
S O N
N N
N N
N N OH CH2 CH2C6H5
H HO
261
260
Ar
NC
NO2 N
S
N
H
N N
OH N
N H
N N
H
OH
262
263 264
8.0 CONCLUSION [3] Pilet, P. E. C. R. Acad. Sci. Ser. C 1971, 273, 2253.
New significant improvements have been obtained in the [4] Widholm, J. M. Biochem. Biophys. Acta 1972, 261, 44.
synthesis of 7-azaindole derivatives notably by the [5] Minakata, S., Hamada, T., Komatsu, M., Tsuboi, H.,
development of palladium catalysed reactions and anionic Kikuta, H., Osshiro, Y. J. Agric. Food Chem. 1997, 45 ,
condensation reactions. The interchange between sp2 carbon 2345.
and sp2 nitrogen atom modifies the chemical reactivity of 7-
azaindole derivatives compared to their indole counterpart [6] Philip, J. H., Jürgen, D., Jeffrey, M. S., David, J., Michele,
but the biological activity is anticipated to be quite similar. K., Michael, T., David, J. A., Andrew, P., Vicki, N., Ping,
Z., Rachel, H., Michael, C., Bruce, B., Leonard, K.,
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Synthesis and Reactivity of 7-Azaindoles (1H-Pyrrolo (2,3-b) Pyridine)

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Synthesis and Reactivity of 7-Azaindoles (1H-Pyrrolo(2,3-b)pyridine)

Article in Current Organic Chemistry · May 2001

Jean YVES Merour Benoît Joseph

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Synthesis and Reactivity of 7-Azaindoles (1H-Pyrrolo[2,3-b]pyridine)

Jean-Yves Mérour* and Benoît Joseph

Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans BP

Theoretical study on azaindoles was carried out using a

1385-2728/01 $20.00+.00 © 2001 Bentham Science Publishers Ltd.

Petrich examined the tautomerisation of 7-azaindole 1 in 2.0 SYNTHESIS OF 7-AZAINDOLES

1) s-BuLi, THF -40oC Et3N, MsCl

Similarly, treatment of 7 or 2-tert-butylcarbonylamino-3- H

2 LDA, THF Li H2O

nitrogen atom and protonation of this pyridine nitrogen atom

CH3 Heterogeneous catalysed Fischer reaction of acetaldehyde

In the same way, 7-azatryptamine 29 was prepared from

2.2 Fischer Type Reactions 2.3 Diels-Alder Reactions

N Amounts of cyclised products were improved when lithium

In the same way, 2,3-disubstituted 7-azaindole 53 with

Na, NH3 Si(CH3)3 47a

Three relevant papers by Robison and coworkers in

3.1 N-Alkylation N-Alkylations of anionic 7-azaindoles, obtained from 1, 6

Michael type addition of 7-azaindole was also

Nevertheless, N-methyl alkylation of the pyrrole ring of 1) AlCl 3, CS 2

N-Vinylation of 1 was also described by Reisch. Thus, 3.2 Glycosylation

115α (17%) 115β (21%)

Si(CH3 )2t-Bu BnO OBn 119β

Chloration of 1 using N-chlorosuccinimide as reagent at addition of trimethylstannylchloride [65]. Conversion was

3.3.2 Nitration presence of acetic anhydride and AlCl3 to give 135. N-

136 (R=CH3), 144b-d 145

R = a: CH3, b: CH2CH3, c: CH2CH2 OAc

145d 148d 149d

151 R = OH 1) LDA, THF, -78oC

162 163 n= 1 25%

79% Tf 2O, pyridine

3.5 7-Azaindolinones obtained with a sulfonyl protecting group (40-60%). N-

It should be noted that aldolisation reaction between 2- 3.6 N-amination

treatment of infective diseases. Thus, reductive amination benzenesulfonyl-7-azaindole188, a regiospecific metallation

200 (17%) 201 (20%)

X = CH2, O R = H, 4-Cl, 4-H3CO, 3-Cl

129 220 X = Cl 60% 222 X = Cl

(CH3) 3SiCN, rt (CH3 )3 SiCN, rt

Chemical transformations of 6-halo-7-azaindoles have dichlorobis(triphenylphosphine)palladium (II) gave the

In 7-azaindoline series [113, 114], aminolysis of 231 in

Scheme 81. Treatment of 4-chloro-7-azaindole 233 with aniline at

(CH3) 2NH, HCl, 180oC C6H5NH2 , 180oC N

NHC6H5 NHC6H5 NHC6H5

NHC 6H5 NHC6H5

NBS, DMSO DMSO S CH3

N Enzyme inhibition was found for 260 [104]. Various

REFERENCES [7] Kidder, G. W., Dewey, V. C. Biochem. Biophys. Acta

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