Synthesis of 4-(cyclic dialkylamino)-7-azaindoles by microwave heating of 4-halo-7-azaindoles and cyclic secondary amines

Article abstract of DOI:10.1016/j.tetlet.2007.01.003

Nucleophilic aromatic substitution of 4-chloro- and 4-fluoro-7-azaindoles with cyclic secondary amines under microwave heating gave a straightforward and rapid synthesis of 4-(cyclic dialkylamino)-7-azaindoles. 4-Fluoro-7-azaindoles showed a greater reactivity towards S_NAr reactions under these conditions than 4-chloro-7-azaindole.

Full text of DOI:10.1016/j.tetlet.2007.01.003

Tetrahedron Letters 48 (2007) 1527–1529
Synthesis of 4-(cyclic dialkylamino)-7-azaindoles
by microwave heating of 4-halo-7-azaindoles
and cyclic secondary amines
John J. Caldwell, Kwai-Ming Cheung and Ian Collins*
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK
Received 5 December 2006; revised 20 December 2006; accepted 4 January 2007
Available online 7 January 2007
Abstract—Nucleophilic aromatic substitution of 4-chloro- and 4-fluoro-7-azaindoles with cyclic secondary amines under microwave
heating gave a straightforward and rapid synthesis of 4-(cyclic dialkylamino)-7-azaindoles. 4-Fluoro-7-azaindoles showed a greater
reactivity towards SNAr reactions under these conditions than 4-chloro-7-azaindole.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, palladium-catalysed cross-coupling of 1 and
primary anilines has been demonstrated, leading to good
yields of 4-anilino-7-azaindoles.11 A similar cross-
coupling of allylamine with 1 has also been reported.12
Many compounds of potential pharmaceutical interest
contain the 7-azaindole (1H-pyrrolo[2,3-b]pyridine)
motif,1–6 including examples of simple 4-N- or 4-O-
substituted compounds.4,7,8 As part of a drug discovery
research program, we required a method for the prepa-
ration of 4-(cyclic dialkylamino)-7-azaindoles. The most
direct route, involving the nucleophilic aromatic substi-
tution of a 4-halo-7-azaindole with appropriate amines
(Scheme 1), has received only sporadic attention and
requires quite drastic reaction conditions.9,10 For exam-
ple, heating a neat mixture of 4-chloro-7-azaindole 19
with a five-fold excess of dimethylamine hydrochloride
or other simple dialkylamines at 180 °C provided the
nucleophilic displacement products.9,10 However, simi-
lar conditions using primary alkylamines or anilines
gave only the 4-amino-5-azaindole (1H-pyrrolo[3,2-c]-
pyridine) products of displacement–rearrangement.9
Improvements in reactivity are commonly seen for SNAr
reactions when a fluoride leaving group is employed in
the place of a chloride.13 The rate determining step of
the SNAr mechanism is the initial addition of the nucle-
ophile to the aromatic carbon, and the greater electro-
negativity of fluorine relative to chlorine accelerates
this by increasing the positive charge on the reactive aro-
matic carbon. A concise synthesis of 4-fluoro-7-azain-
dole 2 has been described,12 and we therefore chose to
compare the reactivity of 4-chloro- and 4-fluoro-7-
azaindoles 1 and 2. We anticipated that high tempera-
tures might still be necessary and thus looked to micro-
wave heating as a convenient means of achieving this,
which was also compatible with a parallel synthesis ap-
proach.14 The benefits of microwave heating for acceler-
ating thermal SNAr reactions of heteroaromatic halides
has been demonstrated.15–18
2. Results and discussion
4-Chloro-7-azaindole 1 was prepared from 7-azaindole
by the literature procedure.10 To obtain 4-fluoro-7-
azaindole 2 we initially used a modification of the pub-
lished methodology12 (Scheme 2), obtaining 1-triisoprop-
yl-4-bromo-7-azaindole 3 in 3 steps from 7-azaindole.
While the original procedure for conversion of 3 to
Scheme 1.
*
Corresponding author. Fax: +44 208 722 4205; e-mail: Ian.Collins@
icr.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.003

1528
J. J. Caldwell et al. / Tetrahedron Letters 48 (2007) 1527–1529
Table 1. Temperature dependence of the reaction of 1 and 2 with
morpholinea
Temperatureb (°C)
Timec (h) for complete
conversion to 7a
1, X = Cl
2, X = F
12
4.5
2.0
1.5
120
140
160
180
n.d.d
n.d.
7
2.5
a Compound 1 or 2, morpholine (5 equiv), Et3N (5 equiv), NMP
(0.4 M).
b Internal reaction vessel temperature (Biotage Initiator 60 microwave
reactor).
c Time required for >95% conversion of 1 or 2 as determined by HPLC
analysis of the reaction mixture at 30 min intervals.
d n.d. = not determined.
Scheme 2. Reagents and conditions: (i) AcCl, NaI, MeCN, reflux; (ii)
2 M NaOH, THF, 40 °C; (iii) NaH, TIPSCl, THF, reflux; (iv) n-BuLi,
Et2O, À78 °C then FN(SO2Ph)2, THF, À78 °C; and (v) TBAF, THF,
rt.
fluoride 4 involved reaction with tert-butyllithium, we
found that this reagent could be replaced with n-butylli-
thium provided the lithiation step was carried out in diethyl
ether, to give 4 in a comparable yield (66%). The use of
THF as the solvent gave no metalation, although this
solvent was required for the addition of the electrophilic
fluorine source (N-fluorobenzenesulfonimide) which was
otherwise insoluble in diethyl ether. The synthesis of 4
and 2 via the 4-iodo derivative 6 was also investigated.
Trans-halogenation19,20 of 1 was achieved using sodium
iodide and acetyl chloride to generate 4-iodo-7-azain-
dole 521 after hydrolysis of the N-acetylated intermedi-
ate. Protection of 5 as the N-triisopropylsilyl derivative
6 was followed by metalation with n-butyllithium and
quenching with N-fluorobenzenesulfonimide to give 4.
The yield of this transformation was similar to that
starting from the corresponding bromide. The synthesis
of 4 and 2 via iodide 6 provides an alternative route to
these interesting synthetic intermediates.12,22
Scheme 3. Reagents and conditions: (i) 1, amine (5 equiv), Et3N
(5 equiv), NMP, microwave 180 °C, 3 h; and (ii) 2 or 4, amine
(5 equiv), Et3N (5 equiv), NMP, microwave 160 °C, 2 h.
Table 2. SNAr reactions of 1, 2 and 4 with cyclic secondary amines
under the conditions shown in Scheme 3
Product
Yielda from
1
2
4
The temperature dependence of the reactions of 1 and 2
with excess morpholine under microwave irradiation
was investigated (Table 1). In both cases, the desired
4-morpholino substitution product 7a was formed. The
4-fluoro substrate 2 showed a moderate enhanced reac-
tivity over chloride 1. It is therefore possible that use of
the fluoride would be beneficial for the reactions of more
complex, temperature sensitive amines. It is noteworthy
that 4-fluoro-7-azaindole 2 is more stable and less reac-
tive to substitution than 4-fluoropyridine,23 presumably
as a result of the presence of the fused electron-rich pyr-
role ring in the bicycle. The lowest temperatures that
gave >95% reaction in 2–3 h were chosen for each sub-
strate (1: 180 °C, 3 h; 2 and 4: 160 °C, 2 h) and a range
of simple cyclic secondary amines were investigated
(Scheme 3, Table 2). The behaviour of the silyl-pro-
tected intermediate 4 was studied since the high temper-
atures and generation of fluoride ion during the
7a
7b
7c
7d
7e
7f
59 (57b)
53e
65
65
62
54
n.d.
61c
61
63
43
43
51
n.d.
56d
56
74
55
59 (32d)
n.d.f
20 (24d)
7g
a Isolated yields of purified material homogeneous by 1H NMR and
HPLC analysis (>95%).
b Et3N omitted.
c 6 equiv of amine used.
d 2 equiv of amine used.
e 4 h reaction time.
f n.d. = not determined.
substitution reaction were anticipated to give concomi-
tant N-desilylation.

J. J. Caldwell et al. / Tetrahedron Letters 48 (2007) 1527–1529
1529
In most cases, moderate to good yields of the required
References and notes
4-amino-7-azaindoles 7a–g were obtained after ion
exchange and/or chromatographic purification. Substi-
tuted piperidines, pyrrolidine and less nucleophilic cyclic
amines such as morpholine and N-methylpiperazine
were effectively incorporated. No significant differences
were observed in the yields for conversion of 1, 2 or 4,
but lower temperature and shorter reaction times were
adequate for the reaction of fluorides 2 and 4. In the
case of the reaction of morpholine with 4, a good yield
of 7a was obtained using only 2 equiv of the amine.
However, this did not translate to the reaction of 4-benz-
ylpiperidine to give 7e, where 5 equiv of the amine were
necessary. The reaction of 1 with morpholine was un-
affected by the inclusion or omission of triethylamine.
The reaction of Boc-protected piperazine with 4 was
attempted to investigate if the method was compatible
with this temperature-labile protecting group, and low
but reproducible yields of the N-Boc-protected 4-piper-
azinyl-7-azaindole were obtained. Although compounds
7a–g are structurally simple, with the exception of 7g24
this is to our knowledge the first time their synthesis
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A solution of 2 (0.020 g, 0.153 mmol), morpholine
(0.080 mL, 0.915 mmol) and Et3N (0.128 mL, 0.915
mmol) in NMP (0.5 mL) was heated in a Biotage Initia-
tor 60 microwave reactor at 160 °C for 2 h. Purification
by ion exchange on an SCX-2 Isolute column, eluting
with MeOH then 2 M NH3–MeOH, followed by pre-
parative TLC (EtOAc) gave 7a (0.019 g, 0.094 mmol,
1
61%). H NMR (500 MHz, CDCl3) d 3.48–3.50 (4H,
m), 3.93–3.95 (4H, m), 6.46 (1H, d, J 5.5 Hz), 6.49
(1H, d, J 3.5 Hz), 7.22 (1H, d, J 3.5 Hz), 8.15 (1H, d,
J 5.5 Hz), 10.40 (1H, br, s); 13C NMR (125 MHz,
CDCl3) d 49.7, 66.8, 100.1, 101.8, 110.5, 121.9, 144.1,
150.1, 151.7; m/z (ES+) 204 (M+H+).
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We thank Dr. T. McHardy for preliminary experiments
on the reactivity of 1. This work was supported by Can-
cer Research UK [CUK] Grant No. C309/A2187. Addi-
tional funding was received from Astex Therapeutics
Ltd (J.J.C.).