A novel method to enable SNAr reaction of aminopyrrolopyrazoles

Article abstract of DOI:10.1016/j.tetlet.2011.01.148

Here we report mild, environmentally-friendly reaction conditions which enable the addition-elimination S_NAr reaction between weakly reactive substrates - an aminopyrrolopyrazole template and several substituted pyrimidines. The method was developed during our efforts to synthesize a series of novel P21-activated kinase (PAK) inhibitors.

Full text of DOI:10.1016/j.tetlet.2011.01.148

Tetrahedron Letters 52 (2011) 1692–1696
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel method to enable SNAr reaction of aminopyrrolopyrazoles
⇑
Chuangxing Guo , Liming Dong, Joseph Marakovits, Susan Kephart
Oncology Medicinal Chemistry, Pfizer PharmaTherapeutics R&D, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Here we report mild, environmentally-friendly reaction conditions which enable the addition–elimina-
tion SNAr reaction between weakly reactive substrates—an aminopyrrolopyrazole template and several
substituted pyrimidines. The method was developed during our efforts to synthesize a series of novel
P21-activated kinase (PAK) inhibitors.
Received 18 August 2010
Revised 27 January 2011
Accepted 31 January 2011
Available online 4 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Compound 1 (Scheme 1) is a P21-Activated Kinase (PAK) inhib-
itor which is potent (Ki/EC50 ꢀ30 nM), soluble, and metabolically
stable. The main shortcoming of compound 1 is its low oral bio-
availability likely due to high efflux.1 In order to reduce efflux,
one of our strategies was to replace the amide on the pyrazole with
aminopyrimidine. The amidopyrazole motif, required for binding
to the hinge region of the PAK protein, may also bind to certain ef-
flux transporters (e.g., MDR).2 While maintaining PAK hinge bind-
ing, the proposed alteration to the amidopyrazole may weaken the
binding to the efflux transporter, and, therefore, reduce the efflux
of PAK inhibitors.
Our strategy was to form the heterocycle-aminopyrazole C–N
bond at the end of the synthesis, enabling quick access to many di-
versely-substituted pyrimidines (Scheme 1). Similar C–N bonds
have been formed by palladium-catalyzed Buchwald couplings,3,4
but we were concerned about regioselectivity in the presence of
an unprotected pyrazole NH.5 Instead, we investigated SNAr condi-
tions to form this bond. Published examples of SNAr reactions be-
tween aminopyrazoles and chloropyrimidines require high
temperatures;6 basic catalysis using either trialkyl amines7,8 or
inorganic salts;9 acidic catalysis using HCl/dioxane,5,10 hydrochlo-
ride salts,11 or phenol as solvent;12 or some combination of these
factors. Microwave irradiation at very high temperatures has been
used to couple aminopyrazoles with less-reactive chloroheterocy-
cles under basic conditions.13 An interesting variation uses BOP
to directly activate pyrimidin-4-ones to nucleophilic attack with-
out a chlorination step.14 The resulting HOBt ethers undergo SNAr
reaction with a variety of amines, including anilines, though cou-
plings with aminoheterocycles were not reported.
An aminopyrrolopyrazole 6A (Table 1) with the phenylethyl-
amine head group was prepared in three steps from the protected
aminopyrrolopyrazole core.1 We expected the SNAr displacement
to be a challenge because this aminopyrazole is only moderately
nucleophilic, and many of the chloropyrimidine coupling partners
had only modest reactivity. Furthermore, the phenylethylamine
head group is not stable under high temperatures (>120 °C, either
basic or acidic conditions). The model system shown in Table 1 was
used to evaluate SNAr displacement conditions.
Heating 4-chloro-6-ethylpyrimidine (5a), the aminopyrazole
(6A), and triethylamine at 140 °C in isopropanol yielded only a
H
H
N
PAK Lead 1
MW: 446
LogD: 1.77
Solubility: 395 M
PAK4 Ki: 0.030µM
HLM ER: 0.39
N
O
Cl
H
N
N
N
N
N
SNAr
HN
N
N
N
µ
+
HN
HN
O
N
N
H2N
N
CACO2: AB 0.1; BA/AB 326
2
4
3
N
Scheme 1.
⇑
Corresponding author. Tel.: +1 858 622 5927.
E-mail address: alex.guo@pfizer.com (C. Guo).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.148

C. Guo et al. / Tetrahedron Letters 52 (2011) 1692–1696
1693
Table 1
Model system for evaluation of reaction conditions
H
H
N
O
N
O
N
N
Cl
N
H
N
N
N
HN
O
SNAr
HN
N
N
HN
N
N
+
+
HN
N
HN
conditions
N
N
H2N
O
7
5a
6A
acylated product 7'
N
Conditions
Basic
Reaction conditions
Et3N/DMF, wave, 180 °C
Et3N/iPrOH, wave, 140 °C
Et3N/NMP, wave, 200 °C
TMG/DMF, 50–100 °C
NH4Cl, 25–100 °C
Observations
l
l
l
Decomp., no product
Decomp., trace of product
Decomp., no product
Decomp., no product
Decomp., no product
Decomp., no product
Decomp., no product
Decomp., no product
No solvent, 140–180 °C
Silver salt
AgBF4/NMP,
lwave, 150 °C
Ag2CO3/NMP,
l
wave, 100 °C
Pd
Acidic
Xantphos/Pd(OAc)2/Cs2CO3/dioxane/ 80 °C
HCl/dioxane/iPrOH, 140 °C
1:1 HOAc/dioxane, lwave, 200°C
3 equiv HOAc/dioxane, lwave, 200 °C
TFA, 100 °C
Undesired regioisomer-addition to pyrazole ring N
Decomp. trace of product
Decomp. trace of product
70 + ꢀ5% product
70 + trace product
Me3CCO2H, neat, 100–160 °C
1:1 HOAc/H2O, 100 °C
70 + trace product
ꢀ50% (33%) product + trace 70
trace of product 7 and significant decomposition of the starting
materials. Changing the solvent to DMF or NMP led only to decom-
position, and changing the base strength from strong (tetramethyl-
guanidine, TMG) to weak (aminopyrazole 6A alone) to buffered
(ammonium chloride) had no effect. Likewise, varying the reaction
temperature and heat source (50–180 °C, microwave vs thermal
heating) provided no improvement. Addition of silver salts (to acti-
vate the chloropyrimidine) only led to more decomposition.
Slightly better results were obtained using acidic conditions. Heat-
ing in the presence of excess HCl, TFA, or acetic acid in the organic
solvent (or acid itself as solvent) gave trace amounts of the desired
product 7. Attempts to drive the reaction to completion by raising
the temperature led to decomposition or, when using TFA or acetic
acid, acylation of the aminopyrrolopyrazole. Since some of the de-
sired product 7 was formed in the acetic acid reactions, they were
the focus of further optimization. To avoid the acyl aminopyrro-
lopyrazole side product 70, reaction conditions were changed to
suppress the acylation. Reducing the concentration of acetic acid
(from co-solvent down to only 3 equiv) led to a slight increase in
product yield (ꢀ5%). Replacing acetic acid with the more sterically
hindered pivalic acid (Me3CCO2H) did not prevent acylation. We
hypothesized that an ethylidyneoxonium intermediate (formed
from acetic acid under elevated temperature) might be the precur-
sor to the acyl side products 70, and that water might be able to
scavenge that reactive species. Indeed, substituting water for
dioxane as a co-solvent minimized the formation of the side prod-
uct, affording an improved yield of the desired product 7 (50% by
LC–MS, 33% isolated yield after preparative HPLC purification). In
contrast, palladium-catalyzed coupling afforded regioisomeric
products resulting from addition to the pyrazole ring nitrogens
rather than to the exocyclic primary amine. Shen et al.5 report sig-
nificant variation in the regioselectivity of Buchwald-type reac-
tions of aminopyrazoles depending on the combination of a
catalyst, ligand, and base. Many combinations were selective for
addition to the ring nitrogens.
The substrates of interest here are not very reactive so the
addition step may be the rate-determining step. Basic conditions
do not activate the chloropyrimidine (3), which by itself is not
electrophilic enough to undergo the addition of the weakly
nucleophilic aminopyrazole (4). A silver cation may activate aryl-
halide (3) via its strong coordination with the halide, but causes
decomposition of the aminopyrazole (4) at the elevated temper-
ature required for the reaction. Weak acids, such as acetic acid
(pKa = 4.75), are especially effective in facilitating the addition
step between these two partners: the chloropyrimidine is acti-
vated by protonation (3–30), while a substantial fraction of the
weakly basic aminopyrazole (estimate pKa of 4 is ꢀ4.8)15 re-
mains as the more reactive free base. In contrast, stronger acids
such as hydrochloric acid or TFA fully protonate the aminopyrz-
ole, and, therefore, hinder the addition step. When hydrochloric
acid solution is used as the reaction solvent, the excess nucleo-
philic anions may accelerate the acid-catalyzed decomposition
of the substrate, particularly at elevated temperatures. Aqueous
acetic acid appears to be an optimal solvent to promote the
SNAr reaction between the chloropyrimidine and the amino-
pyrazole.
Table 2 illustrates the broad scope of the SNAr reaction in aque-
ous acetic acid. A number of diverse pyrimidine analogs (7–30)
were successfully prepared from aminopyrrolopyrazole intermedi-
ates 6A–C.1 Most of the 4-chloropyrimidine reagents (5a–s) re-
acted to give a moderate yield of product after isolation by
preparative HPLC. The actual conversion is likely better, but the
product molecules are highly soluble in water, so significant loss
of the product could occur during work-up. The SNAr conditions
are mild enough that sensitive functional groups, such as cyano
(h, i), heteroarylfluoride (e, j, k, f) and benzylchloride (r, s) survive
the reaction—no hydrolysis products were observed. At the same
time, the method is effective at activating the less electrophilic
chloropyrimidines to SNAr displacement. For example, pyrimidines
e and j are deactivated by alkyoxy groups, but afford yields of the
desired products comparable to b, k, or o, which lack the alkoxy
groups.
The SNAr reaction mechanism consists of two steps, an addition
followed by an elimination as shown in Scheme 2.

1694
C. Guo et al. / Tetrahedron Letters 52 (2011) 1692–1696
Basic conditions:
Acidic conditions:
H
N
Cl
N
N
N
3
Cl
N
H2N
4
N
H
N
N
3
H+
Cl
N
N
HXR
H2N
addition
4
N
[X=O (solvent) or N(4)]
H
N
N+
H
N
N
3'
addition
+
NH2
N
-
Cl
XR
H
N
N
N
N
H
+
OH2
NH2
N
Cl
H
N
N
N
N
H
H
N
NH
Cl
N
N
N
N
NH
Cl
H
base
N
elimination
N
H
N
H
elimination
N
N
H
N
N
N
HN
N
HN
2
N
N
2'
N+
H
Scheme 2. Proposed mechanism of SNAr reactions.
A significant side reaction is hydrolysis of the starting chloro-
pyrimidines to hydroxypyrimidines. Adding a second equivalent
of chloropyrimidine improved the yield in certain cases (9, 17),
but in most other cases, excess chloropyrimidine just led to more
hydroxypyrimidine side-product, complicating purification. The
optimal stoichiometry for chloropyrimidine was found to be
1.5 equiv. Lower reaction temperatures were also found to mini-
mize chloropyrimidine hydrolysis. Many of the SNAr reactions take
place at 25 °C in aqueous acetic acid with good yields in most of the
cases (20, 24–28). Those substrates which are poorly soluble in
aqueous acetic acid solution at 25 °C were run at higher tempera-
tures (30, 50 °C) or in glacial acetic acid (28, at 25 °C).
The scope of the SNAr conditions was further evaluated. The
chlorothienopyrimidine 5f was tested for its reactivity toward
several aminoheteroarenes, including 2-aminopyridine (pKa 6.67),
2-aminothioazole (pKa 3.2), 2-aminoimidazole (pKa 8.6), 3-amino-
triazole (pKa 4.17), 3-aminopyrazole (pKa 4.8), and 4-aminopyra-
zole (pKa 4.1).16 Under the standard SNAr conditions (1:1 acetic
acid/water, 100 °C, 1 h), only 3-aminopyrazole reacts with chloro-
pyrimidine 5f to give the desired SNAr product (72% isolated yield).
The acetic acid seems optimal for promoting SNAr reaction of
3-aminopyrazole, again indicating the importance of matching
the acidity of the acid catalyst and the basicity of the substrate
aminoheteroarene as discussed above.
General conditions1: Chloropyrimidine 5 (0.45 mmol) and ami-
nopyrazole 6 (0.30 mmol) were mixed in 1:1 acetic acid/water
solution (1.4 mL) or in glacial acetic acid (1.4 mL) and stirred at
100 °C in an oil bath for 1 h (or 50 °C for 4 h or 25 °C for 18 h).
The mixture was neutralized by the addition of ice-cold 5% NaOH
solution (10 mL) and extracted with methylene chloride (3 ꢁ 25 mL).
Combined organic layers were dried and concentrated. The residue
was further purified by normal phase flash chromatography
(Biotage, for cPropylphenyl analogs R = C) or reversed phase pre-
parative HPLC (analogs with free amines R = A or B), affording
the desired aminopyrimidines (7–30).
In summary, new, mild displacement conditions to enable SNAr
reactions of aminopyrazoles have been established which mini-
mize side product formation. As a result, we were able to synthe-
size a number of novel PAK inhibitors. The new aqueous acetic
acid SNAr conditions provide chemists an additional effective
method for C–N bond formation between modestly electrophilic
chloropyrimidines and weakly nucleophilic aminoarenes. The
new method uses acetic acid and water as the reaction solvents,
which are inexpensive and friendly to environment.

C. Guo et al. / Tetrahedron Letters 52 (2011) 1692–1696
1695
Table 2
Scope of aqueous acetic acid SNAr reaction
H
H
N
O
R
O
R
N
HOAc-H2O
N
N
N
N
HeteroAr-Cl
+
25-100oC,
1-18h
5a-s
6A-C
HN
H2N
7-30
HeteroAr
A
B
C
R =
or
or
HN
O
(S)
(S)
HN
N
N
HeteroAr:
a
b
c
d
e
f
g
N
N
j
F
F
N
N
N
N
N
N
N
N
S
N
N
S
S
N
N
N
N
Et
N
N
OEt
h
i
l
k
n
m
O
F
F
N
S
S
N
N
N
N
N
N
CN
CN
N
N
N
N
O
N
o
F
p
q
r
s
S
O
N
S
N
N
N
N
Cl
Cl
N
N
N
N
N
Compd ID
HeteroAr
R
Conditions
Standard
2 equiv Heteroar Cl
Standard
Standard
Standard
2 equiv HeteroAr Cl
Standard
Standard
Isolated yield (%)
7
9
a
d
e
f
h
d
g
c
l
d
r
o
b
j
k
c
i
n
m
n
p
q
r
A
A
A
A
B
B
C
C
C
C
C
C
A
A
A
A
B
B
C
C
C
C
C
C
33
73
33
32
53
81.80
41
11
13
15
17
19
21
23
25
27
29
8
10
12
14
16
18
20
22
24
26
28
30
43
Standard
39.30
33.5 (84.4)
75.80
25
28
32
25
28
21
48
56
65
79.20
76.40
75.80
41
100 °C, 1 h (25 °C, 18 h)
100% HOAc, 25 °C, 18 h
Standard
Standard
Standard
Standard
Standard
Standard
Standard
25 °C, 18 h
Standard
25 °C, 18h
25 °C, 18 h
100% HOAc, 25 °C, 18 h
50 °C, 4 h
s
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