Total syntheses of 6- and 7-azaindole derived GnRH antagonists

Article abstract of DOI:10.1016/S0040-4039(01)01322-3

The palladium(0)-catalyzed heteroannulation of a triethylsilyl alkyne and an ortho-aminoiodopyridine derivative is used as the key step in a highly convergent route to 6- and 7-azaindoles of biological interest.

Full text of DOI:10.1016/S0040-4039(01)01322-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6441–6445
Total syntheses of 6- and 7-azaindole derived GnRH antagonists
Feroze Ujjainwalla* and Thomas F. Walsh
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
Received 29 June 2001; accepted 18 July 2001
Abstract—The palladium(0)-catalyzed heteroannulation of a triethylsilyl alkyne and an ortho-aminoiodopyridine derivative is used
as the key step in a highly convergent route to 6- and 7-azaindoles of biological interest. © 2001 Elsevier Science Ltd. All rights
reserved.
In a series of recent reports, we have described the
biological activities and the syntheses of a variety of
potent GnRH antagonists of the 2-arylindole class.1
Initially, these structures were prepared via the Fisher
indole method,1,2 but then, ultimately, we were drawn to
the elegant approach of Larock.3,4 During the evolution
of this medicinal chemistry effort, we became intrigued
at the biological implication of replacing the indole core
in one of our more promising lead designs (1),5 with a
6- or 7-azaindole template (2; Fig. 1).
doles. At the onset of our studies, we discovered that this
method had indeed been applied to azaindole synthesis,
but with only moderate success on relatively simple
systems.6 In spite of the limited literature precedent, we
discovered that this transformation could be prepara-
tively useful if Pd(dppf)Cl2 was adopted as the catalyst
of choice, and our preliminary results in this area were
published recently.7
In this report, we describe the synthetic application of this
strategy to more sophisticated azaindole systems such as
compound2. Disconnectionof2viatheLarocktransform
affords aminopyridine 3 and known alkyne 4 (Scheme 1).3
We reasoned that Larock’s method of indole synthesis
may be directly applicable to the preparation of azain-
H
N
N
H
N
N
O
N
N
H
O
N
N
N
H
1
2
Pd0
H
N
N
OBn
I
MeO2C
O
N
+
N
N
H
N
NH2
3
SiEt3
4
2
Electrophilic Aromatic
Substitution
Figure 1.
MeO2C
N
NH2
5
Keywords: palladium; heteroannulation; azaindole; 2-aminopyridines.
* Corresponding author. Tel.: 732 594 1719; fax: 732 594 2210;
Scheme 1. Retrosynthetic analysis of 7-azaindole 2.
e-mail: feroze ujjainwalla@merck.com
–
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01322-3

6442
F. Ujjainwalla, T. F. Walsh / Tetrahedron Letters 42 (2001) 6441–6445
lective, and moreover, the harsh nature of the reaction
conditions would likely be incompatible with our resi-
dent ester functionality.8 Instead, we focused our atten-
tion to the research of Wachi and Terada who had
shown that benzoxazine derivatives of 3-substituted
pyridine-N-oxides could be rearranged exclusively to
2-amino-5-substituted pyridines.9 Accordingly, benzox-
azine 8 was prepared via the literature route which
involved reaction of salicylamide with acetone in the
presence of sulfuric acid,10 followed by chlorination
with phosphorous pentachloride in phosphorous oxy-
chloride.9 In our hands, formation of benzoxazine 7
under the published conditions proved troublesome,
with yields ranging from 26 to 37% depending on the
reaction scale (literature yield 47%). However, if the
reaction was conducted in neat 2,2-dimethoxypropane
in the presence of a catalytic amount of pyridinium
toluene-4-sulfonate (PPTS), the desired adduct could be
obtained in near quantitative yield after recrystalliza-
tion (Scheme 2).
The synthesis of fragment 3 is shown below (Schemes
2–4). Although the Chichibabin reaction was a tempt-
ing and potentially expedient entry to systems such as
5, investigation of the chemical literature revealed that
installation of the amino group would not be regiose-
O
O
HN
H2N
HO
i
O
6
7
ii
Cl
O
N
8
Pyridine N-oxide 11 was also prepared in two steps
involving a one-pot base-catalyzed double enolization-
double alkylation sequence, followed by N-oxidation of
the pyridine (Scheme 3).
Scheme 2. Reagents and conditions: (i) 2,2-dimethoxypropane,
PPTS, 83°C, 15 h, 97%; (ii) PCl5, POCl3, 50°C, 3 h, 50%.
Reaction of compounds 8 and 11 (2 equiv.) in
dichloromethane (DCM) at reflux according to the
Wachi and Terada procedure gave the rearranged com-
pound 12 in only 18% yield (Scheme 4). However, we
discovered that reaction of 8 and 11 (1 equiv.) in
1,2-dichloroethane (1,2-DCE) at reflux for 3 days
resulted in the complete consumption of starting mate-
rials to provide 12 in 84% yield. This is in marked
contrast to the findings of Wachi and Terada who
stipulate that 2 equiv. of N-oxide are essential for
successful rearrangement, the second equiv. serving as a
scavenger for HCl. In our case, HCl is probably liber-
ated from the reaction mixture because of the higher
boiling point of 1,2-DCE. Regioselectivity in this step is
presumably derived from an unfavorable steric interac-
tion between the 3-substituent of the pyridine and the
gem-dimethyl moiety of the benzoxazine during the
proposed [2,3]-sigmatropic rearrangement. Acid cata-
lyzed hydrolysis7 and subsequent re-esterification of 13
afforded amino ester 14 in 88% overall yield. Elec-
trophilic aromatic iodination under the influence of
silver(I)-assisted catalysis furnished the requisite iodide
3 as a stable colorless solid.
i
EtO2C
EtO2C
N
N
9
10
ii
EtO2C
N
O
11
Scheme 3. Reagents and conditions: (i) KHMDS, MeI, rt, 12
h, 83%; (ii) m-CPBA, NaHCO3, CHCl3, H2O, rt, 12 h, 92%.
O
O
EtO2C
i
8
+
11
N
N
12
ii
Palladium(0)-catalyzed heteroannulation of alkyne 4
with aminoiodopyridine 3 under the original Larock
conditions [Pd(OAc)2, PPh3, LiCl, Na2CO3, DMF,
100°C] gave the desired 7-azaindole 15 in low yield
(ꢀ10%) together with significant recovery of 3.4 How-
ever, use of the Pd(dppf)Cl2/LiCl/Na2CO3 reagent sys-
tem resulted in complete consumption of 3 to provide
15 in 95% yield (Scheme 5). [NB. We have observed on
a number of occasions that the yield of azaindole
product is generally maximized, if the LiCl additive is
pre-dried at 100°C, under high vacuum, for approxi-
I
iv
MeO2C
RO2C
N
NH2
N
NH2
X = H (13)
X = Me (14)
3
iii
Scheme 4. Reagents and conditions: (i) 1,2-DCE, 82°C, 3
days, 84%; (ii) conc. HCl, 100°C, 8 h, 88%; (iii) conc. H2SO4,
MeOH, 65°C, 15 h, 100%; (iv) I2, AgCO2CF3, MeOH, rt, 15
h, 62%.

F. Ujjainwalla, T. F. Walsh / Tetrahedron Letters 42 (2001) 6441–6445
6443
3
4
+
H
N
N
i
O
N
N
N
H
OBn
MeO2C
18
N
N
X
Pd0
H
X = SiEt3 (15)
X = I (16)
ii
OBn
N
I
iii
+
O
N
NH2
SiEt3
OBn
MeO2C
19
4
N
N
H
17
Scheme 6. Retrosynthetic analysis of 6-azaindole 18.
iv-xiii
Our synthesis of 19 began with 2-chloro-5-nitropy-
ridine, which was commercially available (Scheme 7).
Addition of diethyl malonate, proceeded smoothly,
but mono-decarboxylation under either neutral or
basic conditions could not be controlled, instead
yielding the a-picoline. Addition of the unsymmetrical
t-butyl methyl malonate and subsequent acid-cata-
lyzed decarboxylation furnished the desired ester (21)
in good overall yield.12 Two fold tandem enolization-
alkylation gave the gem-dimethylcarboxylate 22. Nitro
group reduction, acylation, base-catalyzed ester
hydrolysis and amide formation provided diamide 26
in greater than 90% overall yield, without the purifi-
cation of any intermediates. Directed ortho-lithiation
with t-BuLi under kinetic control, followed by an
iodine quench, afforded 27 as the sole regioisomer.13
Hydrolysis of the sterically less hindered pivaloyl
amide functionality furnished the target aminopy-
ridine 19.
H
N
N
O
N
N
N
H
2
Scheme 5. Reagents and conditions: (i) Pd(dppf)Cl2·CH2Cl2,
LiCl, Na2CO3, DMF, 100°C 15 h, 95%; (ii) ICl, AgBF4,
MeOH/THF, rt, 1 h, 84%; (iii) 3,5-dimethylbenzeneboronic
acid, Pd(dppf)Cl2·CH2Cl2, 1N Na2CO3, EtOH, toluene,
85°C 15 h, >99%; (iv) KOH, MeOH, 65°C, o/n; (v) iso-
quinuclidine·HCl, PyBOP, NEt3, CH2Cl2, rt, 4 h, 86% (two
steps); (vi) (BOC)2O, DMAP, K2CO3, CH2Cl2, rt, 5 h, 84%;
(vii) H2 (50 psig), Pd(OH)2/C, EtOH, AcOH, rt, 3 days,
92%; (viii) Zn(N3)2·2Py, PPh3, imidazole, DEAD, CH2Cl2,
0°C to rt, 15 h; (ix) H2 (50 psig), Pd(OH)2/C, EtOH, rt, 15
h, 83% (two steps); (x) 2,4-dintrobenzenesulfonyl chloride,
sat. aq. NaHCO3, CH2Cl2, rt, 0.5 h, 79%; (xi) 4-(2-hydroxy-
ethyl)pyridine, DEAD, benzene, rt, 1 h; (xii) n-PrNH2,
CH2Cl2, rt, 0.25 h, 90% (two steps); (xiii) TFA, CH2Cl2, rt,
6 h, 95%.
As before, palladium-catalyzed heteroannulation of 4
with 19 using the Pd(dppf)Cl2/LiCl/Na2CO3 reagent
combination gave a good yield of the desired 6-azain-
dole (28; Scheme 7). Surprisingly, initial attempts to
convert the triethylsilyl group to the requisite iodide
29 under a variety of conditions were unsuccessful.
Ultimately, we found that exposure of 28 to IPy2BF4
in the presence of triflic acid provided 29 in quantita-
tive yield.14 Suzuki–Miyaura cross-coupling with 3,5-
dimethylbenzeneboronic acid proceeded without
incident to afford 2-aryl-6-azaindole 30. The remain-
der of the synthetic sequence to the final 6-azaindole
target 18 was realized according to the literature
route (Scheme 8).3
mately 1–2 h prior to use in the reaction.7] Func-
tional group interconversion to the iodide,11 followed
by palladium(0)-catalyzed arylation with 3,5-dimethyl-
benzeneboronic acid, afforded the desired 2-aryl-7-
azaindole 17 in 80% overall yield. Elaboration of 17
to 2 was accomplished in 10 steps according to a
general strategy previously reported.3
The 7-azaindole 2 was found to be a very potent
GnRH antagonist relative to the indole congener 1,
‘throwing down the gauntlet’ for a 6-azaindole vari-
ant, i.e. structure 18. Again we proceeded by way of
the reliable and versatile Larock methodology which
revealed aminopyridine 19 as our initial synthetic
target (Scheme 6).
In conclusion, the foregoing results have highlighted
the viability of the Larock strategy for the construc-
tion of challenging azaindole systems. The biological
activity of these and other related structures will be
reported in due course.

6444
F. Ujjainwalla, T. F. Walsh / Tetrahedron Letters 42 (2001) 6441–6445
t
CO2 Bu
19
4
Cl
+
i
MeO2C
N
i
N
NO2
NO2
20
ii
N
OBn
O
ii
N
N
X
MeO2C
iii
H
MeO2C
N
N
N
N
NO2
X = SiEt3 (28)
X = I (29)
NO2
22
21
iv
iii
MeO2C
v
N
OBn
MeO2
NH
O
O
N
NH2
N
H
23
24
30
vi
iv-xi
HO2C
N
H
N
vii
N
N
NH
O
O
N
NH
O
N
N
N
H
O
26
25
18
viii
Scheme 8. Reagents and conditions: (i) Pd(dppf)Cl2·CH2Cl2,
LiCl, Na2CO3, DMF, 100°C, 15 h, 62%; (ii) IPy2BF4, TfOH,
CH2Cl2, rt, 1.5 h, 98%; (iii) Pd(dppf)Cl2·CH2Cl2, 3,5-
dimethylbenzeneboronic acid, 1N Na2CO3, EtOH, toluene,
90°C, 15 h, >99%; (iv) (BOC)2O, DMAP, K2CO3, CH2Cl2, rt,
1 h, 89%; (v) H2 (50 psig), Pd(OH)2/C, EtOH, AcOH, rt, 2
days, 84%; (vi) Zn(N3)2·2Py, PPh3, imidazole, DEAD,
CH2Cl2, rt, 15 h; (vii) H2 (50 psig), Pd(OH)2/C, EtOH, rt, 1.5
h, 80% (two steps); (viii) 2,4-dintrobenzenesulfonyl chloride,
sat. aq. NaHCO3, CH2Cl2, rt, 0.5 h, 90%; (ix) 4-(2-hydrox-
yethyl)pyridine, DEAD, benzene, rt, 1 h; (x) n-PrNH2,
CH2Cl2, rt, 0.25 h, 60% (two steps); (xi) TFA, CH2Cl2, rt, 6
h, 97%.
N
I
ix
N
I
O
N
NH
O
N
NH2
O
27
19
Scheme 7. Reagents and conditions: (i) NaH/t-butyl methyl
malonate, DMF, rt, 5 h; (ii) TFA, DCM, rt, 2 h, 69%; (iii)
NaH, MeI, DMF, −20 to 0°C, 15 h, 76%; (iv) Pd/C, H2, (50
psig), MeOH, 0.75 h; (v) pivaloyl chloride, NEt3, THF/Et2O
(1:1), 0°C to rt, 0.75 h; (vi) 2.5N NaOH, MeOH, 50°C, o/n;
(vii) isoquinuclidine·HCl, PyBOP, NEt3, CH2Cl2, rt, 15 h,
81% (four steps); (viii) (a) t-BuLi, THF, −78 to −45°C, 6 h;
(b) I2, THF, −78 to −10°C, 69% (91% based on recovered 26);
(ix) 24% aqueous H2SO4, 95°C, 3.5 h, 78%.
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