Synthesis of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines from 4,6-dichloropyrimidine-5-carboxaldehyde: Insights into selectivity and reactivity

Article abstract of DOI:10.1055/s-0033-1338862

Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5- carboxaldehyde with both aromatic and aliphatic hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective, high-yielding, and operationally simple manner are presented. For aromatic hydrazines, the reaction is performed at a high temperature in the absence of an external base. For aliphatic hydrazines, the reaction proceeds at room temperature in the presence of an external base. The observed selectivity and reactivity trends are rationalized through consideration of the proposed reaction mechanism. The 1-substituted 4-chloropyrazolo[3,4-d]pyrimidine products serve as versatile synthetic intermediates, through further functionalization of the 4-chloride moiety, enabling the rapid generation of a structurally diverse array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338862

PAPER
▌1791
paper
Synthesis of 1,4-Disubstituted Pyrazolo[3,4-d]pyrimidines from 4,6-Dichloro-
pyrimidine-5-carboxaldehyde: Insights into Selectivity and Reactivity
Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
Christie Morrill,* Suresh Babu, Neil G. Almstead, Young-Choon Moon*
PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA
Fax +1(908)2220567; E-mail: cmorrill@ptcbio.com; E-mail: ymoon@ptcbio.com
Received: 28.03.2013; Accepted: 06.05.2013
Dedicated to Prof. Scott E. Denmark on the occasion of his 60th birthday
As pyrazolo[3,4-d]pyrimidines are ubiquitous in the phar-
Abstract: Strategies for carrying out the reaction of 4,6-dichloro-
maceutical industry, a number of different strategies have
pyrimidine-5-carboxaldehyde with both aromatic and aliphatic hy-
been employed for their synthesis. Most of these strate-
gies, however, can be categorized into two disconnections
drazines to generate 1-substituted 4-chloropyrazolo[3,4-
d]pyrimidines in a selective, high-yielding, and operationally sim-
ple manner are presented. For aromatic hydrazines, the reaction is (Scheme 1). The most commonly cited synthetic route in-
performed at a high temperature in the absence of an external base.
For aliphatic hydrazines, the reaction proceeds at room temperature
in the presence of an external base. The observed selectivity and
onto a 5-amino-4-cyanopyrazole, which in turn is synthe-
reactivity trends are rationalized through consideration of the
proposed reaction mechanism. The 1-substituted 4-chloropyrazo-
volves generation of the pyrazolo[3,4-d]pyrimidine ring
system through the annulation of a carbonyl compound
sized from 2-(ethoxymethylene)malononitrile and a hy-
drazine (route A),1a,3,5,7–9,12a or some variation
lo[3,4-d]pyrimidine products serve as versatile synthetic intermedi-
ates, through further functionalization of the 4-chloride moiety,
thereof.1c,2,11a,14–16 The second most common synthetic
enabling the rapid generation of a structurally diverse array of 1,4-
disubstituted pyrazolo[3,4-d]pyrimidines.
route reverses the construction order of the two rings by
adding a hydrazine onto an existing 4-chloropyrimidine-
5-carboxaldehyde through a combined condensation/
nucleophilic aromatic substitution reaction (route
B).3,4,6,7,10,12,13,17 In these cases the pyrimidine starting ma-
terial is generally purchased or synthesized from another
commercially available pyrimidine. Less common syn-
thetic routes include a Diels–Alder reaction between 5-
amino-1-phenyl-4-pyrazolecarboxylic acid and 1,3,5-tri-
azines,18 the cyclization of 4-aminopyrimidine-5-carbox-
aldehyde oximes,19 and the reaction of 5-(benzoyl-
amino)pyrazoles with nitriles.20
Key words: condensation, hydrazines, hydrazones, nucleophilic
aromatic substitution, pyrazolo[3,4-d]pyrimidines
Pyrazolo[3,4-d]pyrimidines have attracted much attention
in drug discovery programs. Because of their structural re-
semblance to purine nucleobases, they are ideally suited
to selectively interact with a diverse array of pharmaceu-
tically relevant targets. For example, pyrazolo[3,4-d]py-
rimidine substrates have been established as inhibitors of
PDE9 (Alzheimer’s disease, diabetes),1 Src (osteoporo-
sis),2 p38α (inflammatory and autoimmune diseases),3
MRP4 (resistance to anticancer drugs),4 and ADA (isch-
emia);5 as well as antagonists of adenosine A2A (Parkin-
son’s disease)6 and adenosine A3 (inflammation,
regulation of cell growth).7 They have demonstrated both
anticonvulsant8 and antibacterial9 activities. They have
also been extensively exploited as inhibitors of oncogenic
kinases, including Bcr,10 Abl,10,11 mTOR,12 PI3K,12e–f,13
Src,2,11b,14 EGF-R,15 and CDK.16 Pyrazolo[3,4-d]pyrimi-
dines serve as excellent core structures for drug analogues
because they offer multiple options for diversification,
through functionalization of the 1-, 2-, 3-, 4-, or 6-position
(Figure 1).
NC
route A
NC
NC
N
OEt
N
carbonyl
compound
H2N
NH2
N
R
HN
N
N
R
N
O
R
route B
N
H
NH2
HN
N
Cl
R
Scheme 1 Common methods to form pyrazolo[3,4-d]pyrimidines
Recent interest in our laboratories has focused on the gen-
eration of a structurally diverse library of 1,4-disubstitut-
ed pyrazolo[3,4-d]pyrimidines. The most efficient
strategy to obtain these compounds would be to utilize
route B (Scheme 1), performing the direct condensation of
commercially available 4,6-dichloropyrimidine-5-car-
boxaldehyde (1) with various substituted hydrazines
(Scheme 2). An array of 1-substituted 4-chloropyrazo-
lo[3,4-d]pyrimidines (4) would thus be generated, which
could undergo subsequent diversification at the 4-position
4
3
N
2
N
6
N1
N
R
Figure 1 1-Substituted pyrazolo[3,4-d]pyrimidines
SYNTHESIS 2013, 45, 1791–1806
Advanced online publication: 06.06.2013
DOI: 10.1055/s-0033-1338862; Art ID: SS-2013-C0248-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1792
C. Morrill et al.
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H
N
Cl
N
Cl
N
Cl
N
O
Cl
N
N
R
NH2
N
N
HN
N
N R
H
+
+
+
N
H
N
N
R
N
Cl
Cl
R
1
2
3
4
5
Scheme 2 Direct condensation of 1 with 2
through displacement of the 4-chloro substituent. Where- functionalization of 4 to generate a variety of 1,4-disubsti-
as application of route A (Scheme 1) toward the formation tuted pyrazolo[3,4-d]pyrimidines.
of key intermediate 4 would necessitate multiple synthetic
steps, usage of route B could potentially generate 4 in a
Reactions Involving Aromatic Hydrazines
single step.
Our initial efforts were directed toward the reaction of
carboxaldehyde 1 with arylhydrazines 2a–d. We applied
the same reaction conditions that had been reported in the
This proposed synthetic route is advantageous in terms of
its simplicity. However, the requisite condensation reac-
tion faces selectivity issues. Desired product 4 is generally
observed to be the major product of this reac-
literature for the direct condensation of 1 with arylhydra-
zines.17a None of these experiments yielded selective reac-
tion,3,4,10,12,13,17a–c but several other products are possible,
tions (Table 1, entries 1–4). The major products were
namely hydrazone 3 and 2-substituted pyrazolo[3,4-d]py-
rimidine 5 (Scheme 2). Indeed all three products were ob-
served in our early attempts to condense carboxaldehyde
1 with various arylhydrazines (vide infra). Although
pyrazolo[3,4-d]pyrimidines 4 and 5, with the formation of
small quantities of hydrazone 3. A clear electronic trend
was observed. Electron-rich hydrazines like 2a strongly
favored the formation of 4 (entry 1), whereas electron-
product mixtures have been previously reported in the lit-
deficient hydrazines like 2d favored the formation of 5
erature for condensation reactions involving 117a or relat-
(entry 4). Performing these same reactions in the absence
ed pyrimidine substrates,10,17c the development of
of triethylamine led to dramatically different results: hy-
methods for achieving selectivity remains challenging.
Our efforts in this area led us to establish strategies to se-
lectively generate 4 in high yield, which we reported in a
drazone 3 was the predominant product in all cases (en-
tries 5–8).
recent communication.21 Herein, we present additional in- These observations prompted us to consider the reaction
sights into both the scope of this reaction and the factors mechanism, suspecting that it would provide insight into
that influence its selectivity. We also describe the further developing a strategy to achieve product selectivity. The
Table 1 Initial Reactions of 1 with Arylhydrazinesa
H
N
Cl
N
Cl
N
Cl
O
Cl
N
N
R
NH2
Et3N
N
N
N
N R
N
H
+
HN
+
+
N
H
THF, 65 °C, 1 h
N
N
R
N
Cl
Cl
R
1
2b
3
4
5
Entry
R
Et3N (equiv)
1 (%)c
3 (%)c
4 (%)c
5 (%)c
1
2
3
4
5
6
7
8
4-MeOC6H4 (a)
Ph (b)
2.1
2.1
2.1
2.1
0
ND
ND
2
ND
2
91
63
9
35
4-ClC6H4 (c)
4-F3CC6H4 (d)
4-MeOC6H4 (a)
Ph (b)
7
40
51
9
9
8
74
3
92
96
98
79
5
ND
ND
ND
ND
0
4
ND
ND
ND
4-ClC6H4 (c)
4-F3CC6H4 (d)
0
2
0
21
a Reaction conditions: 0.2 M, 1.05 equiv of 2, 0.3–0.6 mmol scale.
b HCl salt.
c Determined from relative 1H NMR ratios in the crude reaction mixture. ND = not detected.
Synthesis 2013, 45, 1791–1806
© Georg Thieme Verlag Stuttgart · New York

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Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
1793
H
N
H
N
H
N
Cl
N
R
O
Cl
R
H
N
H
N
H
N
Cl
Cl
N
N
Cl
O
i
3
N
N
Cl
Cl
O
N
R
4
N
H
path B
N
N
H
1 + 2
Cl
NH2
N
N
N
R
N
NH2
ii
iii
H
R
Cl
O
Cl
N
O
Cl
N
H
R
N
H
N
Cl
H
N
R
R
N
NH
N
N
NH
HN
v
iv
5
H
Scheme 3 Possible reaction pathways
presence of two different electrophilic sites on 1 and two Scheme 3. For each possible pathway, product formation
different nucleophilic sites on 2 results in three possible is dependent upon the productive collapse of a tetrahedral
reaction pathways (Scheme 3). Initial condensation with intermediate, either i, ii, or iv, whose formation is revers-
the aldehyde moiety of 1 can only proceed with the exter- ible. One would expect the productive collapse of i to be
nal nitrogen of 2, reversibly generating tetrahedral inter- facilitated by acidic conditions, therefore advancing path
mediate i, which then eliminates water to form hydrazone A. Basic conditions, on the other hand, should instead ac-
3 (path A). Hydrazone 3 can be isolated as such, or it can celerate the productive collapse of ii and iv, promoting
cyclize to form 4. Initial displacement of the chloro sub- both paths B and C.
stituent of 1, on the other hand, can occur with either ni-
Returning to our goal of developing strategies to selec-
trogen of 2, reversibly generating either ii (path B) or iv
tively synthesize 4, we postulated that our observations
(path C), which in turn form iii or v, followed by 4 or 5,
regarding the effect of an external base on the preferred
respectively.
Table 2 Resubjection of 3 to Original Reaction Conditionsa
Product 5 can only form if 2 displaces the chloro substit-
uent of 1 prior to the condensation process (Scheme 3,
path C), whereas product 4 can be generated through ei-
ther the initial condensation of 2 with the aldehyde (path
A) or initial chloride displacement (path B). We therefore
needed to determine which pathway was generating 4 in
the examples shown in entries 1–4 of Table 1. Was 2 ini-
tially condensing with the aldehyde or displacing the chlo-
ride? To answer this question, hydrazones 3a–d were
isolated and resubjected to the original reaction conditions
(Table 2). Within the original reaction time of one hour,
cyclization to form 4 was not observed with any of the
hydrazones (Table 2, entries 1–4). Even with a prolonged
reaction time, only small quantities of 4 were observed
(entries 5–8). These results indicate that at 65 °C in the
presence of an external base, 4 does not readily form via
cyclization of hydrazone 3 (Scheme 3, path A). Although
3 itself does form to a small extent under these reaction
conditions (Table 1, entries 2–4), it does not cyclize. Prod-
uct 4 must therefore arise primarily through initial chlo-
ride displacement by 2 (Scheme 3, path B).
H
N
Cl
N
Cl
N
N
R
Et3N (2.1 equiv)
THF, 65 °C
N
N
N
H
N
R
Cl
3
4
Entry
R
Time (h)
3 (%)b
4 (%)b
1
2
3
4
5
6
7
8
4-MeOC6H4 (a)
Ph (b)
1
1
>99
>99
>99
>99
88
ND
ND
ND
ND
12
5
4-ClC6H4 (c)
4-F3CC6H4 (d)
4-MeOC6H4 (a)
Ph (b)
1
1
24
24
24
24
95
4-ClC6H4 (c)
4-F3CC6H4 (d)
96
4
99
1
a Reaction conditions: 0.2 M, 1.05 equiv of HCl, 1 equiv of H2O, 0.3
mmol scale.
The results given in Table 1 suggest that the preferred re-
action pathway is dictated by the presence or absence of
an external base. We believe that this observation is con-
sistent with the reaction mechanisms illustrated in
b Determined from relative 1H NMR ratios in the crude reaction mix-
ture. ND = not detected.
© Georg Thieme Verlag Stuttgart · New York
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C. Morrill et al.
PAPER
Table 3 Optimized Conversion of 1 into 3a
reaction pathway could be exploited. Performing the con-
densation in the presence of an external base inherently
leads to product mixtures, as it facilitates reaction through
both paths B and C (Scheme 3). However, carrying out the
reaction in the absence of an external base promotes only
path A and thus generates a single product, hydrazone 3.
Although 3 did not readily cyclize to form 4 in the exam-
ples presented in Tables 1 and 2, a subsequent cyclization
H
N
Cl
O
Cl
R
Cl
N
N
R
NH2
DMF
N
H
HN
+
N
H
r.t., 1–2 h
R
N
Cl
2b
1
3
reaction, utilizing alternative reaction conditions, might Entry
Isolated yield (%)
allow conversion of 3 into 4. While this strategy would re-
sult in a two-step procedure, selectivity issues would be
completely precluded.
1
2-MeOC6H4 (e)
4-MeOC6H4 (a)
4-MeC6H4 (f)
Ph (b)
93
87
92
97
94
92
89
93
96
99
92
85
88
91
2
Our next task was to optimize the synthesis and isolation
of hydrazone 3. Having established reaction conditions to
selectively generate 3 from 1 and 2 at 65 °C (Table 1, en-
tries 5–8), we screened additional solvents at room tem-
perature. Nucleophilic solvents such as isopropyl alcohol
were not compatible with 1, as they readily displaced the
chloro substituents. The conversion of 1 into 3 did pro-
ceed cleanly in THF, 1,4-dioxane, acetonitrile, acetic acid,
and DMF. The reaction was the most efficient in DMF,
exhibiting essentially quantitative conversion within two
hours. Either the free base or the HCl salt of 2 was a viable
starting material, but for electron-deficient hydrazines
such as 2d, reactions involving the HCl salt progressed
more slowly. Adding cold aqueous sodium bicarbonate to
the crude reaction mixture and filtering the resultant pre-
cipitate led to the isolation of 3. Purification via column
chromatography was not necessary. Table 3 shows the
conversion of 1 into aromatic hydrazones 3a–o using our
optimized reaction conditions.21 The reaction worked ef-
ficiently for electron-rich substrates (entries 1–3), elec-
tron-deficient substrates (entries 6–10), sterically
hindered substrates (entries 1, 6, and 11), and heteroaro-
matic substrates (entries 12–15).
3
4
5
4-FC6H4 (g)
6
2-ClC6H4 (h)
3-ClC6H4 (i)
7
8
4-ClC6H4 (c)
4-BrC6H4 (j)
4-F3CC6H4 (d)
1-naphthyl (k)
2-pyridyl (l)
9
10c
11
12d
13d
14d
15d
2-quinoxalyl (m)
2-benzo[d]oxazolyl (n)
4-(5-methylthieno[2,3-d]pyrimidyl) (o) 98
a Reaction conditions: 0.3–1 M, 1.05 equiv of 1, 0.5–3 mmol scale.
b HCl salt, unless otherwise noted.
c Free base of 2 was used.
d Bis-HCl salt of 2 was generated in situ using 2 equiv of 4 M HCl in
1,4-dioxane.
With hydrazones 3a–o in hand, we needed to identify re-
action conditions under which they would efficiently cy-
clize to form 4a–o. Hydrazones like 3 tend to resist
cyclization, presumably because they exist in the E-con-
figuration.17a,22 Heating at elevated temperatures can
sometimes facilitate the process.17a Even prolonged heat-
ing of 3 at 65 °C in the presence of triethylamine was in-
sufficient to substantially effect cyclization to form 4
(Table 2, entries 5–8). Performing the cyclization of 3a in
the absence of triethylamine, however, led to vastly im-
proved conversion (Table 4, entry 1). Unfortunately we
also observed a small amount of side product 6a, which
presumably resulted from a reaction between 4a and an
equivalent of unreacted 3a. Performing the reaction in
acetonitrile led to increased consumption of 3a, but a sig-
nificantly greater amount of 6a formed as well (entry 2).
A similar scenario was observed at 80 °C (entry 3). It was
thus clear that, although this cyclization occurred at tem-
peratures as low as 65 °C, higher temperatures were nec-
essary in order to increase the cyclization rate such that all
of 3a would cyclize before reacting with 4a. At 140 °C, 3a
was completely consumed within 20 minutes, and only a
small amount of 6a formed (entry 4). Formation of 6a
could be further suppressed by either reducing the concen-
tration (entry 5) or further increasing the temperature (en-
tries 6, 7).23
The reactions of hydrazones 3b–d were evaluated next.
The cyclization proceeded more slowly as the phenyl sub-
stituent of 3 became less electron-rich. For example, after
20 minutes at 140 °C, all of 3a had been consumed (Table
4, entry 4), 19% of 3b remained (entry 8), 52% of 3c re-
mained (entry 11), and 86% of 3d remained (entry 14).
Complete conversion of 3 into 4, without formation of 6,
was again achieved by increasing the temperature (entries
8–16). A temperature of 180 °C was sufficient to effect
the quantitative conversion of 3 into 4 within 20 minutes
for every substrate except 3d, which required a tempera-
ture of 200 °C (entries 15, 16).
After establishing the optimal conditions to convert 3a–d
into 4a–d, this cyclization reaction was performed with a
variety of other aromatic hydrazones (Table 5).21 For the
sake of simplicity, these reactions were performed at 200
°C, since most substrates cyclized within 20 minutes at
Synthesis 2013, 45, 1791–1806
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
1795
Table 4 Optimization of the Cyclization of 3 to Form 4a
Reactions Involving Aliphatic Hydrazines
R
Having developed an efficient two-step procedure to se-
lectively synthesize 4 from 1 and various aromatic hydra-
zines, the reaction of 1 with aliphatic hydrazines was
investigated. Unlike the aromatic hydrazines (Table 1, en-
tries 1–4), aliphatic substrates selectively generated 4 in
high yield in the presence of an external base (Table
6).21,24 Essentially quantitative conversion to 4 was ob-
served within one hour at room temperature, and isomeric
product 5 was not detected. Products 4p–t were cleanly
isolated by removing the solvent in vacuo, following an
aqueous workup, without the use of column chromatogra-
phy. We observed significantly higher yields than those
reported in the literature for similar reactions.17a This im-
provement in yield may exist because our reactions were
carried out at room temperature instead of 65 °C, as some
product decomposition could occur at elevated tempera-
tures.25
N
N
H
N
Cl
N
N
N
N
Cl
N
N
R
N
+
N
N
H
N
H
Cl
N
R
N
R
Cl
N
3
4
6
Cl
Entry R
Temp Time
3
4
6
(°C)b
(h)
(%)c
(%)c
(%)c
1d
2
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
Ph (b)
65
65
24
47
16
48
16
5
68
67
5
24
16
3
80
ND
ND
ND
ND
ND
19
33
4
140
140
160
180
140
160
180
140
160
180
140
180
200
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
95
5e
6
>99
98
ND
2
Table 5 Optimized Cyclization of 3 to Form 4a
7
>99
76
ND
5
H
Cl
8
N
Cl
N
N
R
200 °C
20 min
9
Ph (b)
ND
ND
52
97
3
N
N
N
H
N
10
Ph (b)
>99
47
ND
1
N
Cl
R
11
12
13
14
15
16
4-ClC6H4 (c)
4-ClC6H4 (c)
4-ClC6H4 (c)
4-F3CC6H4 (d)
4-F3CC6H4 (d)
4-F3CC6H4 (d)
3
4
7
91
2
Entry
R
Isolated yield (%)
ND
86
>99
10
ND
4
1
2b
3
2-MeOC6H4 (e)
4-MeOC6H4 (a)
4-MeC6H4 (f)
Ph (b)
85
97
98
91
99
94
92
97
86
96
92
90
92
92
10
90
ND
ND
ND
>99
4b
5
a Reaction conditions: 0.2 M in MeCN unless otherwise noted, 0.1–
0.9 mmol scale.
4-FC6H4 (g)
b Microwave heating was used in all cases except for entries 1–3.
c Determined from relative 1H NMR ratios in the crude reaction mix-
ture. ND = not detected.
6c
7
2-ClC6H4 (h)
3-ClC6H4 (i)
4-ClC6H4 (c)
4-BrC6H4 (j)
4-F3CC6H4 (d)
1-naphthyl (k)
2-pyridyl (l)
2-quinoxalyl (m)
d 0.2 M in THF.
8b
9
e 0.02 M in MeCN.
this temperature, regardless of their electronic properties.
Acceptable solvents for this process included THF, 1,4-
dioxane, and acetonitrile. Both microwave and conven-
tional heating (sealed tube) were evaluated, and no differ-
ence was observed between the two methods in terms of
the reaction efficiency. 1,4-Dioxane was utilized for reac-
tions involving conventional heating, due to its higher
boiling point. Acetonitrile, on the other hand, was the pre-
ferred solvent for the microwave reactions, because it
reached 200 °C more readily in our microwave reactor
compared to THF or 1,4-dioxane. Pyrazolo[3,4-d]pyrimi-
dine products 4a–o were isolated by adding cold aqueous
sodium bicarbonate and filtering the resultant precipitate.
Purification via column chromatography was not neces-
sary.
10b
11
12d
13
14
15
2-benzo[d]oxazolyl (n)
4-(5-methylthieno[2,3-d]pyrimidyl) (o) 90
a Reaction conditions: 0.5 M in 1,4-dioxane using conventional heat-
ing (sealed tube) unless otherwise noted, 0.5 mmol scale.
b Reaction conditions: 0.5 M in MeCN using microwave heating, 0.5
mmol scale.
c Reaction time: 40 min.
d Product 4 was isolated as the HCl salt.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1791–1806

1796
C. Morrill et al.
PAPER
Table 6 Reactions of 1 with Aliphatic Hydrazinesa
complicated, as it appears that all reaction pathways
shown in Scheme 3 are operative. We suggest that this re-
duced selectivity exists because the two nitrogen atoms of
aromatic hydrazines are competitive nucleophiles. Initial
reaction at the internal nitrogen of 2 initiates path B, while
initial reaction at the external nitrogen leads to both paths
A and C.
Cl
N
Cl
N
O
NH2
Et3N
N
HN
+
N
H
N
THF, r.t., 1 h
N
R
Cl
R
1
2
4
Entry
R
Et3N
Isolated
Despite the inherent lack of selectivity that exists for aro-
matic hydrazines in the presence of an external base, a
clear electronic trend is evident in entries 1–4 of Table 1
and warrants an explanation. Electron-rich hydrazines
like 2a favor reaction through path B (Scheme 3). Elec-
tron-deficient hydrazines like 2d show the opposite selec-
tivity, with path C being preferred. Path B and path C
proceed through tetrahedral intermediates ii and iv, re-
spectively, which presumably exist as an equilibrium mix-
ture. In this scenario, the product distribution would be
dictated by the position of the equilibrium. Considering
the structures of ii and iv, one would expect ii to be fa-
vored if R is electron-donating and disfavored if R is elec-
tron-withdrawing, whereas iv should not be significantly
affected by the electronic nature of the R group. This in-
terpretation supports the results presented in entries 1–4 of
Table 1. With electron-rich 2a, ii is favored and thus 4
forms selectively (Table 1, entry 1). With electron-defi-
cient 2d, ii is disfavored, and thus 5 is the major product
(Table 1, entry 4). The above discussions provide a ratio-
nale to explain our observations, which can serve as a pre-
dictive model for other systems. However, further
mechanistic studies are required in order to more fully de-
termine the operative reaction pathways.
(equiv)
yield (%)
1
H (p)
1
1
1
2
3
74
92
81
84
95
2b
3
Me (q)
CH2CH2OH (r)
cyclohexyl (s)
Bn (t)
4c
5d
a Reaction conditions: 0.3–0.8 M, 1.05 equiv of 2, 0.5–0.8 mmol scale.
b i-Pr2NEt was used instead of Et3N.
c HCl salt of 2 was used.
d Bis-HCl salt of 2 was used.
The reactions described in Table 6 could proceed via ei-
ther path A or path B (Scheme 3). To determine whether
or not path A was operative in these cases, isolated hydra-
zones 3s and 3t were stirred with two equivalents of trieth-
ylamine in THF at room temperature, and subsequent
1
examination of the crude reaction mixture by H NMR
analysis revealed no formation of 4s or 4t. These observa-
tions suggest that the reactions shown in Table 6 must pro-
ceed through path B, analogous to the reactions shown in
entries 1–4 of Table 1. This interpretation is consistent
with our earlier postulation that reactions between 1 and 2
initially undergo chloride displacement by 2 when an ex-
ternal base is present.
Some additional studies were performed to determine if
the selectivity that was inherent in reactions involving al-
iphatic hydrazines would hold if the internal hydrazine ni-
trogen atom was less reactive than those of hydrazines
2q–t. The internal nitrogen atom of aliphatic hydrazine 2u
is sterically hindered with a bulky tert-butyl group. At 65
°C, the reaction of 2u with 1 resulted in a nearly 1:1 mix-
ture of 4u and 5u (Table 7, entry 1). Selectivity toward 4u
improved somewhat at lower temperatures (entries 2, 3),
but 5u still formed. In the case of hydrazine 2v, the inter-
nal nitrogen is sterically unencumbered, but it is rendered
electron-deficient through an electron-withdrawing triflu-
oroethyl substituent. At 65 °C, the reaction of 2v with 1
led to a mixture of 4v and 5v, with 5v being the major
product (entry 4). This result is similar to that obtained
with electron-deficient arylhydrazines 2c and 2d (Table 1,
entries 3, 4) and is consistent with our hypothesis regard-
ing intermediate ii being disfavored by an electron-with-
drawing R group (vide supra). Lowering the reaction
temperature did not significantly alter the product selec-
tivity in this case (Table 7, entry 5).27 As with the aromatic
hydrazines, product selectivity toward 4 could be
achieved with hydrazines 2u and 2v by instead perform-
ing their reactions with 1 as two-step procedures carried
out in the absence of an external base (Scheme 4).
Discussion of the Reaction Mechanism
The difference in product selectivity between aliphatic
and aromatic hydrazines in the presence of an external
base is striking. Aliphatic substrates selectively generate
4 (Table 6), proceeding exclusively through path B
(Scheme 3). Aromatic substrates, on the other hand, gen-
erate mixtures of 3, 4, and 5 (Table 1, entries 1–4); with 3
resulting from path A, 4 resulting from path B, and 5 re-
sulting from path C. The high selectivity with which ali-
phatic hydrazines 2q–t react with 1 could be attributed to
the reactivity difference between the two nitrogen atoms
of 2q–t. It has been previously observed that the internal
nitrogen of methylhydrazine (2q) is more nucleophilic
than the external nitrogen.26 A similar situation likely ex-
ists for hydrazines 2r–t. If the internal nitrogen atom of 2
serves as the predominant nucleophile in the reaction with
1, then intermediate ii (Scheme 3) will form preferentially
over iv. Assuming that productive collapse of ii is rapid in
the presence of an external base, then path B will be the
sole reaction pathway, ensuring the selective formation of
4. With aromatic hydrazines the situation becomes more
Synthesis 2013, 45, 1791–1806
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
1797
Table 7 Reactions of 1 with 2u and 2va
Arylhydrazines 2a–d were used to evaluate the efficiency
of a one-pot, high temperature reaction with 1 in the ab-
sence of an external base (Table 8). As expected, these re-
Cl
Cl
Cl
O
NH2
N
N
actions
demonstrated
high
selectivity
toward
Et3N
THF
+
HN
N
N
R
N
H
+
pyrazolo[3,4-d]pyrimidine 4 over 5. A slight excess of 1
was employed in these reactions, as excess 2 could dis-
place the 4-chloro substituent of 4 and thus generate by-
products. The primary issue for these reactions was that
the in situ generated water partially hydrolyzed the 4-
chloro substituent of 4, generating by-product 7. When 1
and 2a were subjected to the previously optimized cycli-
zation conditions (Table 5), 35% conversion to by-prod-
uct 7a was observed (Table 8, entry 1). Production of 7a
could be significantly reduced by decreasing the concen-
tration (entry 2). Further suppression of 7a was accom-
plished by shortening the reaction time (entries 3–5). By
employing a reaction time of only one minute, chloride
hydrolysis could be reduced to <5%, while maintaining
quantitative cyclization of 3, with both 2a and 2b (entries
5, 6).
N
N
N
N
R
N
Cl
R
1
2
4
5
Entry
R
Temp Time
1
4
5
(°C)
(h)
(%)b
(%)b (%)b
1
2
3
4
5
t-Bu (u)
t-Bu (u)
t-Bu (u)
65
r.t.
0
1
1
7
1
1
ND
2
54
70
85
36
33
46
28
11
64
63
4
CH2CF3 (v)
CH2CF3 (v)
65
r.t.
ND
4
a Reaction conditions: 0.2 M, 1.05 equiv of 2, 2.1 equiv of Et3N, 0.2
mmol scale. HCl salt of 2u was used. 2v was used as a 70 wt% solu-
tion in H2O.
b Determined from relative 1H NMR ratios in the crude reaction mix-
ture. ND = not detected.
Electron-deficient products 4c and 4d were both slower to
form and more sensitive to hydrolysis. These reactions
needed more time to reach completion and required a
higher level of dilution in order to suppress chloride hy-
drolysis (Table 8, entries 7–13). For these more challeng-
ing substrates, we investigated the options of minimizing
the presence of HCl or water. For example, using 2d in its
free base form, as opposed to the HCl salt, significantly
suppressed the hydrolysis process (entries 14, 15). These
results suggest that chloride hydrolysis is promoted by ac-
id. Alternatively, it was found that performing the reaction
of 1 with 2c in the presence of magnesium sulfate could
minimize the formation of 7c (entries 16, 17).30 The opti-
mized one-pot reactions of 1 with 2a–d were performed
on a preparative scale as well (Table 9). Products 4a–d
were isolated in good yield after adding cold aqueous so-
dium bicarbonate to the crude reaction mixture and filter-
ing the resultant precipitate. This method of purification
was adequate to remove the small quantities of by-product
7 from the reactions involving 2a and 2b, but not from
those of 2c and 2d.
One-Pot Reactions Involving Arylhydrazines
Thus far we had established efficient procedures to selec-
tively react 1 with 2 to obtain 1-substituted 4-chloropyr-
azolo[3,4-d]pyrimidines (4), using either aromatic or
aliphatic hydrazines. Reactions with most aliphatic hydra-
zines could achieve selectivity through a single-step reac-
tion. Aromatic hydrazines, however, required a two-step
procedure. We wondered if this transformation could in-
stead be carried out as a one-pot reaction. Several litera-
ture procedures describe single-step, high temperature
reactions of other heteroaromatic chlorocarboxaldehydes
with substituted hydrazines, performed in the absence of
an external base. These procedures selectively generated
the desired pyrazolo-quinoline,28 -naphthyridine,29 or
-pyrazole28a isomers, analogous to 4, in a single step.
However, none of these products contained a sensitive
substituent comparable to the 4-chloride of 4.
H
HCl
Cl
N
Cl
N
O
Cl
N
N
THF
100 °C, 1 h
NH2
N
DMF
HN
N
N
H
+
(1)
N
H
r.t., 2 h
(microwave)
N
N
Cl
Cl
91%
isolated yield
98%
isolated yield
1
3u
4u
2u
H
Cl
N
CF3
Cl
N
O
MeCN
Cl
N
NH2
200 °C, 5 min
DMF
N
HN
N
N
H
+
(2)
CF3
N
H
N
CF3
r.t., 2 h
(microwave)
N
Cl
N
Cl
66%
isolated yield
90%
isolated yield
1
3v
4v
2v
Scheme 4 Two-step reactions of 1 with 2u and 2v
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1791–1806

1798
C. Morrill et al.
PAPER
Comparing the one-pot procedure (Table 9) to the two-
step procedure (Tables 3 and 5) for reactions involving
aromatic hydrazines, there are advantages and disadvan-
tages to each. The one-pot procedure is operationally sim-
pler, but it suffers from substrate-dependent sensitivity to
both concentration and reaction time. These issues would
become especially important if larger scale reactions were
desired. The two-step procedure requires an additional
isolation step, but it is clearly more robust and is still quite
facile. We suggest that for small scale reactions, in which
4 will undergo a subsequent transformation, the one-pot
procedure is the method of choice. If large quantities of 4
are desired in highly pure form, then we recommend the
usage of the two-step synthesis.
Further Functionalization of the 4-Position
Finally, we demonstrated the utility of 4-chloropyrazo-
lo[3,4-d]pyrimidine 4 as a key intermediate to generate a
variety of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines.
Due to the highly reactive nature of the 4-chloro substitu-
ent, it is possible to further functionalize the 4-position of
4 through nucleophilic aromatic substitution reactions.
The one-pot procedures presented in Table 9 were com-
bined with the subsequent addition of a nucleophile, gen-
erating pyrazolo[3,4-d]pyrimidines 8 and 9 using two-
step, one-pot reactions (Scheme 5).31 This procedure was
not only successful with amines (equation 1), but unacti-
vated 1-methylindole was also able to displace the chlo-
ride (equation 2).
Additional examples of functionalization at the 4-position
of 4 can be readily demonstrated using isolated 4 as the
Table 8 Optimization of One-Pot Reactions of 1 with 2a–da
H
Cl
N
OH
N
N
Cl
N
O
Cl
N
N
R
NH2
200 °C
N
N
N
H
HN
+
+
N
N
N
H
N
N
R
Cl
Cl
R
R
1
2b
3
4
7
Entry
R
Time (min)
Conc. (M)
3 (%)c
4 (%)c
7 (%)c
1
2
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
4-MeOC6H4 (a)
Ph (b)
20
20
10
5
0.5
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.01
0.2
0.2
0.01
0.2
0.1
0.1
0.1
ND
ND
ND
ND
ND
ND
9
65
83
92
94
97
98
77
66
76
98
65
53
97
96
98
95
97
35
17
8
3
4
6
5
1
3
6
1
2
7
4-ClC6H4 (c)
4-ClC6H4 (c)
4-ClC6H4 (c)
4-ClC6H4 (c)
4-F3CC6H4 (d)
4-F3CC6H4 (d)
4-F3CC6H4 (d)
4-F3CC6H4 (d)
4-F3CC6H4 (d)
4-ClC6H4 (c)
4-ClC6H4 (c)
1
14
34
24
2
8
3
ND
ND
ND
25
9
3
10
11
12
13
14d
15d
16e
17e,f
3
3
10
47
3
15
15
15
15
3
ND
ND
ND
ND
ND
ND
4
2
5
5
3
a Reactions were performed in MeCN unless otherwise noted; heating was performed using a microwave reactor; 1.05 equiv of 1, 0.2 mmol scale.
b HCl salt unless otherwise noted.
c Determined from relative 1H NMR ratios in the crude reaction mixture. ND = not detected.
d Free base of 2 was used.
e MgSO4 (3 equiv) was used.
f Reaction was performed in THF with 1 equiv of i-Pr2NEt.
Synthesis 2013, 45, 1791–1806
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
1799
of 4t has been phosphonated.33 Compounds 4b and 4q
have undergone both cyanation (with potassium cya-
nide)34 and aroylation (with aromatic aldehydes)35 at the
4-position. Despite the highly electrophilic nature of the
4-chloride of 4, this position can even be rendered nucleo-
philic. For example, the 4-position of 4b has been lithiated
and subsequently added to aldehydes and ketones.36
Table 9 Optimized One-Pot Reactions of 1 with 2a–da
Cl
Cl
O
NH2
200 °C
N
HN
+
N
H
N
N
R
N
N
Cl
2b
4
R
1
Entry
R
Conditions
Isolated yield
(%)
In summary, we have developed efficient procedures to
selectively convert 4,6-dichloropyrimidine-5-carboxalde-
hyde (1) and various hydrazines into 1-substituted 4-chlo-
ropyrazolo[3,4-d]pyrimidines (4), using either aromatic
or aliphatic hydrazines. Each hydrazine class has a dis-
tinct set of requisite reaction conditions to achieve selec-
tivity. For aromatic substrates, the key is to carry out the
reaction in the absence of an external base. This reaction
can be performed as either a two-step procedure or a one-
pot process. Aliphatic hydrazines, on the other hand, gen-
erally exhibit high selectivity toward 4 in the presence of
an external base. The observations that we have docu-
mented have been rationalized within the proposed reac-
tion mechanism, establishing a model that can be utilized
to predict the optimal conditions needed to effect selective
reactions between other combinations of 4-chloropyrimi-
dine-5-carboxaldehydes and substituted hydrazines. Fi-
nally, all of the protocols reported herein are operationally
simple, high-yielding, and involve reaction conditions
that are mild enough to preserve the 4-chloro substituent
of 4. The highly reactive nature of this 4-chloride can be
exploited through further functionalization at the 4-posi-
tion. Thus 4 serves as a highly versatile synthetic interme-
diate, capable of rapidly generating a structurally diverse
array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines.
1
4-MeOC6H4 (a)
Ph (b)
MeCN (0.2 M), 1 min
MeCN (0.2 M), 1 min
THF (0.1 M), 5 min
MeCN (0.1 M), 15 min
87
2
95
3c
4e
4-ClC6H4 (c)
4-F3CC6H4 (d)
86d
95d
a Heating was performed using a microwave reactor, 1.05 equiv of 1,
0.5 mmol scale.
b HCl salt unless otherwise noted.
c MgSO4 (3 equiv), i-Pr2NEt (1 equiv).
d 1H NMR analysis of 4 shows the presence of 3 mol% of 7.
e Free base of 2 was used.
starting material. As illustrated in Scheme 6,31 the 4-chlo-
ro substituent of 4c was directly displaced with alkoxides
(equations 1 and 2) or Grignard reagents (equation 3). 4c
also underwent Suzuki cross-coupling reactions (equation
4). In all of these cases, the 4-chloride of 4c was selective-
ly displaced over the chloro substituent on the 1-phenyl
moiety, providing an additional opportunity for selective
functionalization of these molecules. Many other exam-
ples of further functionalization at the 4-position of 4 can
be found in the literature. The 4-chloride of 4b has been
transformed into various sulfur moieties.32 The 4-chloride
O
N
HCl
Cl
N
O
1. MeCN, 200 °C, 1 min
NH2
(microwave)
N
HN
(1)
N
H
N
+
2. morpholine (1.2 equiv)
i-Pr2NEt (3.2 equiv)
r.t., 30 min
N
N
Cl
1
8
78%
isolated yield
OMe
2a
OMe
Me
N
NH2
Cl
N
O
1. MeCN, 200 °C, 15 min
(microwave)
HN
N
N
H
N
(2)
+
2. 1-methylindole (3 equiv)
200 °C, 2 h
(microwave)
N
N
Cl
1
9
CF3
2d
40%
isolated yield
CF3
Scheme 5 Further functionalization of 4 via one-pot reactions
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1791–1806

1800
C. Morrill et al.
PAPER
magnetic stir bar located inside of the reaction vessel and a rotating
magnetic plate located below the floor of the microwave cavity.
Cl
N
O
Purification of 1: 4,6-Dichloropyrimidine-5-carboxaldehyde (1)
was not stable at room temperature for extended periods of time.
Carboxaldehyde 1 obtained from commercial sources was a yellow-
orange solid that was contaminated with its monohydrolyzed deriv-
ative, 4-chloro-6-hydroxypyrimidine-5-carboxaldehyde (5–10
mol% by 1H NMR, DMSO-d6), along with other minor impurities.
Within days, the amount of this impurity had increased, and over
time the bis-hydrolyzed derivative, 4,6-dihydroxypyrimidine-5-car-
boxaldehyde, was also detected. For the studies described herein,
commercially purchased 1 (Aldrich or Matrix Scientific) was ini-
tially purified by silica gel chromatography (0 to 10% EtOAc gra-
dient in hexanes) to obtain a white solid (which usually contained
faint yellow portions) whose sole impurity was 4-chloro-6-hy-
droxypyrimidine-5-carboxaldehyde in <5 mol% by 1H NMR
(DMSO-d6). This material was stored in the refrigerator when not in
use and maintained its integrity for several months.
N
i-PrOH (2 equiv)
N
N
t-AmONa (2 equiv)
N
N
(1)
N
N
THF, 0 °C to r.t., 16 h
83%
isolated yield
4c
10
Cl
Cl
Cl
N
O
N
phenol (2 equiv)
t-AmONa (2 equiv)
N
N
N
N
(2)
N
N
THF, 0 °C to r.t., 16 h
87%
isolated yield
4c
11
Conversion of 1 into 3a–o and 3u–v; 4,6-Dichloro-5-{[2-(4-
methoxyphenyl)hydrazono]methyl}pyrimidine (3a); Typical
Procedure A
Cl
Cl
Cl
N
To a 50 mL round-bottomed flask was added 1 (97%, 500 mg, 2.74
mmol), 4-methoxyphenylhydrazine hydrochloride (2a; 456 mg,
2.61 mmol), and DMF (10 mL). The reaction was allowed to stir un-
der a N2 atmosphere at r.t. for 1 h. Ice (5 g) was added with stirring,
followed by a solution of NaHCO3 (330 mg, 3.9 mmol) in H2O (5
mL). The resultant precipitate was filtered, washed with H2O, and
dried at 40–50 °C under vacuum overnight to obtain 3a; yield: 678
mg (87%); yellow powder; mp 114–115 °C.
Me
N
N
N
MeMgBr (2 equiv)
N
N
(3)
N
N
THF, 0 °C to r.t., 17 h
82%
isolated yield
4c
12
Cl
1H NMR (500 MHz, DMSO-d6): δ = 11.01 (s, 1 H), 8.70 (s, 1 H),
Cl
7.96 (s, 1 H), 7.01–7.10 (m, 2 H), 6.84–6.94 (m, 2 H), 3.70 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 157.5, 153.9, 153.7, 137.9,
126.5, 125.4, 114.7, 113.6, 55.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H10Cl2N4O: 297.0304;
Cl
N
PhB(OH)2 (1.1 equiv)
K2CO3 (3 equiv)
PdCl2(dppf) (9%)
N
N
N
N
N
(4)
N
found: 297.0301 (100), 301.0240 (10), 299.0270 (64), 261 (60).
N
THF, 170 °C, 10 min
(microwave)
4,6-Dichloro-5-[(2-phenylhydrazono)methyl]pyrimidine (3b)
Yield (Procedure A): 678 mg (97%); yellow powder; mp 152–
153 °C.
1H NMR (500 MHz, DMSO-d6): δ = 11.15 (s, 1 H), 8.75 (s, 1 H),
8.04 (s, 1 H), 7.23–7.32 (m, 2 H), 7.11 (d, J = 7.57 Hz, 2 H), 6.86
(t, J = 7.25 Hz, 1 H).
4c
13
63%
isolated yield
Cl
Cl
Scheme 6 Further functionalization of 4c
13C NMR (126 MHz, DMSO-d6): δ = 157.9, 154.5, 144.1, 129.3,
127.0, 126.4, 120.4, 112.5.
HRMS (ESI): m/z [M + H]+ calcd for C11H8Cl2N4: 267.0199;
found: 267.0194 (100), 271.0137 (10), 269.0165 (60), 231 (98).
1H and 13C NMR spectra were recorded on a Bruker 500 MHz NMR
spectrometer. Flash column chromatography was performed on a
CombiFlash Companion system (Isco, Inc.) with Silicycle pre-
packed silica gel cartridges. HRMS (ESI positive) analyses were
performed on an LTQ Orbitrap Discovery mass spectrometer. An-
hydrous solvents were purchased from Acros and used without fur-
ther purification. All commercially available reagents (Aldrich,
Acros, Matrix Scientific) were purchased and used without further
purification unless otherwise noted.
4,6-Dichloro-5-{[2-(4-chlorophenyl)hydrazono]methyl}pyrimi-
dine (3c)
Yield (Procedure A): 734 mg (93%); yellow powder; mp 167–
168 °C.
1H NMR (500 MHz, DMSO-d6): δ = 11.24 (s, 1 H), 8.76 (s, 1 H),
8.04 (s, 1 H), 7.27–7.35 (m, 2 H), 7.04–7.15 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 158.1, 154.7, 143.1, 129.2,
128.0, 126.2, 123.7, 114.0.
HRMS (ESI): m/z [M + H]+ calcd for C11H7Cl3N4: 300.9809; found:
300.9804 (100), 306.9709 (3), 304.9746 (31), 302.9775 (92), 265
(64).
Microwave Irradiation Experiments: Microwave irradiation exper-
iments were performed in sealed vessels using a Biotage Initiator 60
microwave reactor, which utilized a continuous focused microwave
power delivery system with operator-selectable power output from
0 to 400 W. The reaction temperature was continuously monitored
by measuring the outer temperature of the reaction vessel with a cal-
ibrated infrared temperature control mounted on the side of the re-
action vessel. Reactions generally reached their target temperature
within 2 min upon initiation of the irradiation process, and they re-
mained within five degrees of that temperature throughout the des-
ignated reaction time. All reactions were performed using a stirring
option, which was accomplished through use of a Teflon-coated
4,6-Dichloro-5-({2-[4-(trifluoromethyl)phenyl]hydrazo-
no}methyl)pyrimidine (3d)
Yield (Procedure A): 862 mg (99%); yellow powder; mp 159–
160 °C.
1H NMR (500 MHz, DMSO-d6): δ = 11.48 (s, 1 H), 8.80 (s, 1 H),
8.12 (s, 1 H), 7.61 (d, J = 8.51 Hz, 2 H), 7.23 (d, J = 8.51 Hz, 2 H).
Synthesis 2013, 45, 1791–1806
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PAPER
Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
1801
13C NMR (126 MHz, DMSO-d6): δ = 158.4, 155.1, 147.2, 129.8,
126.6 (q, J = 3.78 Hz), 126.0, 124.8 (q, J = 271.90 Hz), 120.1 (q,
J = 32.34 Hz), 112.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H7Cl3N4: 300.9809;
found: 300.9803 (100), 306.9716 (3), 304.9744 (31), 302.9774
(94), 265 (73).
HRMS (ESI): m/z [M + H]+ calcd for C12H7Cl2F3N4: 335.0073;
found: 335.0066 (100), 338.9996 (10), 337.0036 (68), 299 (40).
5-{[2-(4-Bromophenyl)hydrazono]methyl}-4,6-dichloropyrimi-
dine (3j)
Yield (Procedure A): 495 (96%); yellow powder; mp 161–162 °C.
4,6-Dichloro-5-{[2-(2-methoxyphenyl)hydrazono]methyl}py-
rimidine (3e)
Yield (Procedure A): 413 mg (93%); yellow powder; mp 113–
114 °C.
1H NMR (500 MHz, DMSO-d6): δ = 10.67 (s, 1 H), 8.74 (s, 1 H),
8.41 (d, J = 1.26 Hz, 1 H), 7.39 (dd, J = 1.58, 7.88 Hz, 1 H), 6.99
(dd, J = 1.42, 8.04 Hz, 1 H), 6.91 (dt, J = 1.10, 7.65 Hz, 1 H), 6.81–
6.88 (m, 1 H), 3.86 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 157.9, 154.4, 145.6, 133.3,
128.7, 126.5, 121.3, 120.4, 112.4, 111.2, 55.6.
1H NMR (500 MHz, DMSO-d6): δ = 11.23 (s, 1 H), 8.76 (s, 1 H),
8.05 (d, J = 0.95 Hz, 1 H), 7.40–7.48 (m, 2 H), 7.01–7.09 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 158.1, 154.7, 143.4, 132.0,
128.1, 126.2, 114.5, 111.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H7BrCl2N4: 344.9304;
found: 344.9301 (60), 350.9214 (4), 348.9250 (47), 346.9275 (100),
311 (45).
4,6-Dichloro-5-{[2-(naphthalen-1-yl)hydrazono]methyl}pyrim-
idine (3k)
Yield (Procedure A): 290 mg (92%); brown powder; mp 159–160
°C.
HRMS (ESI): m/z [M + H]+ calcd for C12H10Cl2N4O: 297.0304;
found: 297.0296 (98), 301.0239 (13), 299.0267 (60), 291 (100).
1H NMR (500 MHz, DMSO-d6): δ = 11.33 (s, 1 H), 8.79 (s, 1 H),
8.53 (d, J = 0.63 Hz, 1 H), 8.27–8.37 (m, 1 H), 7.85–7.94 (m, 1 H),
7.50–7.59 (m, 3 H), 7.41–7.49 (m, 2 H).
4,6-Dichloro-5-[(2-p-tolylhydrazono)methyl]pyrimidine (3f)
Yield (Procedure A): 387 mg (92%); yellow powder; mp 145–146
°C.
13C NMR (126 MHz, DMSO-d6): δ = 158.2, 154.8, 139.3, 133.9,
129.9, 128.2, 126.6, 126.3, 126.0, 125.0, 121.5, 121.2, 120.2, 107.7.
1H NMR (500 MHz, DMSO-d6): δ = 11.05 (s, 1 H), 8.72 (s, 1 H),
7.99 (s, 1 H), 7.05–7.12 (m, 2 H), 6.98–7.04 (m, 2 H), 2.23 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H10Cl2N4: 317.0355;
found: 317.0351 (100), 321.0296 (10), 319.0323 (60), 281 (28).
13C NMR (126 MHz, DMSO-d6): δ = 157.7, 154.2, 141.8, 129.7,
129.1, 126.4, 126.1, 112.6, 20.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H10Cl2N4: 281.0355;
found: 281.0348 (93), 285.0288 (9), 283.0317 (69), 245 (100).
4,6-Dichloro-5-{[2-(pyridin-2-yl)hydrazono]methyl}pyrimi-
dine (3l)
Yield (Procedure A): 455 mg (85%); tan powder; mp 187–188 °C.
4,6-Dichloro-5-{[2-(4-fluorophenyl)hydrazono]methyl}pyrimi-
dine (3g)
Yield (Procedure A): 400 mg (94%); yellow powder; mp 150–
151 °C.
1H NMR (500 MHz, DMSO-d6): δ = 11.12 (s, 1 H), 8.73 (s, 1 H),
8.01 (d, J = 0.95 Hz, 1 H), 7.06–7.16 (m, 4 H).
13C NMR (126 MHz, DMSO-d6): δ = 157.9, 156.7 (d, J = 235.62
Hz), 154.4, 140.7 (d, J = 1.26 Hz), 126.9, 126.3, 115.9 (d, J = 23.94
Hz), 113.6 (d, J = 7.56 Hz).
1H NMR (500 MHz, DMSO-d6): δ = 11.54 (br s, 1 H), 8.79 (s, 1 H),
8.24 (s, 1 H), 8.14–8.20 (m, 1 H), 7.70 (ddd, J = 1.73, 7.09, 8.51 Hz,
1 H), 7.26 (d, J = 8.20 Hz, 1 H), 6.87 (ddd, J = 0.95, 5.04, 7.25 Hz,
1 H).
13C NMR (126 MHz, DMSO-d6): δ = 158.5, 156.2, 155.2, 147.7,
138.4, 129.8, 126.2, 116.3, 106.8.
HRMS (ESI): m/z [M + H]+ calcd for C10H7Cl2N5: 268.0151;
found: 268.0150 (100), 272.0090 (10), 270.0120 (64), 232 (2).
HRMS (ESI): m/z [M + H]+ calcd for C11H7Cl2FN4: 285.0105;
found: 285.0097 (100), 289.0042 (11), 287.0068 (68), 249 (76).
2-{2-[(4,6-Dichloropyrimidin-5-yl)methylene]hydrazinyl}qui-
noxaline (3m)
Yield (Procedure A): 282 mg (88%); orange powder; mp 222–223
°C.
1H NMR (500 MHz, DMSO-d6): δ = 12.27 (s, 1 H), 9.07 (s, 1 H),
8.86 (s, 1 H), 8.32–8.37 (m, 1 H), 7.96 (d, J = 8.20 Hz, 1 H), 7.69–
7.80 (m, 2 H), 7.53–7.63 (m, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 159.0, 155.9, 149.9, 140.5,
138.3, 136.0, 132.9, 130.6, 128.8, 126.5, 126.0, 125.8.
4,6-Dichloro-5-{[2-(2-chlorophenyl)hydrazono]methyl}pyrimi-
dine (3h)
Yield (Procedure A): 415 mg (92%); tan powder; mp 161–163 °C.
1H NMR (500 MHz, DMSO-d6): δ = 10.76 (s, 1 H), 8.79 (s, 1 H),
8.56 (d, J = 0.95 Hz, 1 H), 7.55 (dd, J = 1.26, 8.20 Hz, 1 H), 7.38
(dd, J = 1.26, 7.88 Hz, 1 H), 7.26–7.33 (m, 1 H), 6.89 (ddd,
J = 1.42, 7.25, 8.04 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H8Cl2N6: 319.0260;
found: 319.0259 (100), 323.0198 (10), 321.0230 (64), 315 (2).
13C NMR (126 MHz, DMSO-d6): δ = 158.5, 155.1, 140.5, 131.2,
129.6, 128.2, 126.2, 121.2, 116.8, 114.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H7Cl3N4: 300.9809;
found: 300.9803 (92), 306.9713 (3), 304.9746 (27), 302.9775
(100), 265 (79).
2-{2-[(4,6-Dichloropyrimidin-5-yl)methylene]hydrazinyl}ben-
zo[d]oxazole (3n)
Yield (Procedure A): 279 mg (91%); yellow powder; mp 207–
208 °C.
1H NMR (500 MHz, DMSO-d6): δ = 12.63 (br s, 1 H), 8.90 (s, 1 H),
8.37 (s, 1 H), 7.55 (d, J = 7.57 Hz, 1 H), 7.45 (br m, 1 H), 7.24 (t,
J = 7.57 Hz, 1 H), 7.15 (t, J = 7.57 Hz, 1 H).
4,6-Dichloro-5-{[2-(3-chlorophenyl)hydrazono]methyl}pyrimi-
dine (3i)
Yield (Procedure A): 400 mg (89%); bright yellow powder; mp
172–174 °C.
13C NMR (126 MHz, DMSO-d6): δ = 159.5, 159.2, 156.7, 147.5,
137.4, 126.1, 124.3, 122.0, 116.0, 109.6. Note that not all 13C peaks
are visible, and several are broad (see spectrum in the Supporting
Information). Product 3n likely exists as a mixture of rotamers.
1H NMR (500 MHz, DMSO-d6): δ = 11.28 (s, 1 H), 8.78 (s, 1 H),
8.05 (d, J = 0.95 Hz, 1 H), 7.29 (t, J = 8.04 Hz, 1 H), 7.10 (t,
J = 2.05 Hz, 1 H), 6.98–7.06 (m, 1 H), 6.88 (ddd, J = 0.79, 2.05,
7.88 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H7Cl2N5O: 308.0100;
found: 308.0099 (100), 312.0038 (10), 310.0069 (66), 304 (8).
13C NMR (126 MHz, DMSO-d6): δ = 158.2, 154.9, 145.6, 133.9,
131.0, 128.7, 126.1, 119.8, 111.8, 111.2.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1791–1806

1802
C. Morrill et al.
PAPER
4-{2-[(4,6-Dichloropyrimidin-5-yl)methylene]hydrazinyl}-5-
methylthieno[2,3-d]pyrimidine (3o)
4-Chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (4b)
Yield (Procedure B): 105 mg (91%); tan powder; mp 111–112 °C.
Yield (Procedure A): 330 mg (98%); yellow powder; mp 182–
184 °C.
1H NMR (500 MHz, DMSO-d6): δ = 11.69 (br s, 1 H), 8.91 (s, 1 H),
8.48 (s, 1 H), 7.90 (d, J = 3.47 Hz, 1 H), 7.21 (s, 1 H), 2.58 (s, 3 H).
13C NMR spectrum for 3o could not be obtained due to the highly
insoluble nature of this compound in DMSO-d6 and all other com-
mon NMR solvents.
Alternative One-Pot Synthesis of 4b: To a microwave vial was add-
ed 1 (97%, 95 mg, 0.52 mmol), phenylhydrazine hydrochloride (2b;
72 mg, 0.5 mmol), and MeCN (2.5 mL). The reaction mixture was
heated with stirring in a microwave reactor at 200 °C for 1 min; then
cooled to r.t. The crude mixture was cooled in an ice bath. A cold
solution of NaHCO3 (130 mg, 1.5 mmol) in H2O (8 mL) was added,
with stirring. The resultant precipitate was filtered, washed with
H2O, and dried at r.t. under a N2 flow to obtain 110 mg (95%) of 4b
as a yellow powder.
HRMS (ESI): m/z [M + H]+ calcd for C12H8Cl2N6S: 338.9981;
found: 338.9997 (100), 342.99 (13), 340.997 (34), 165 (24).
1H NMR (500 MHz, DMSO-d6): δ = 8.99 (s, 1 H), 8.77 (s, 1 H),
8.11–8.18 (m, 2 H), 7.60–7.66 (m, 2 H), 7.42–7.48 (m, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 155.4, 154.2, 152.6, 137.8,
134.0, 129.4, 127.4, 121.4, 114.7.
HRMS (ESI): m/z [M + H]+ calcd for C11H7ClN4: 231.0432;
5-[(2-tert-Butylhydrazono)methyl]-4,6-dichloropyrimidine (3u)
Yield (Procedure A): 590 mg (91%); white powder; mp 114–
115 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.65 (s, 1 H), 8.25 (br s, 1 H),
7.71 (s, 1 H), 1.20 (s, 9 H).
13C NMR (126 MHz, DMSO-d6): δ = 157.3, 153.6, 127.1, 123.4,
found: 231.0432 (100), 233.0402 (33), 204 (3).
4-Chloro-1-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine
(4c)
Yield (Procedure B): 129 mg (97%); tan powder; mp 130–131 °C.
53.6, 28.4.
HRMS (ESI): m/z [M + H]+ calcd for C9H12Cl2N4: 247.0512;
found: 247.0509 (100), 251.0454 (12), 249.0481 (72), 204 (1).
Alternative One-Pot Synthesis of 4c: To a microwave vial was add-
ed 4-chlorophenylhydrazine hydrochloride (2c; 90 mg, 0.5 mmol),
i-Pr2NEt (87 μL, 0.5 mmol), MgSO4 (181 mg, 1.5 mmol), and THF
(5 mL). The reaction mixture was stirred at r.t. for 10 min, and 1
(97%, 95 mg, 0.52 mmol) was then added. The reaction mixture was
heated with stirring in a microwave reactor at 200 °C for 5 min; then
cooled to r.t. The crude mixture was filtered through filter paper,
eluting with CH2Cl2. The solvent was removed in vacuo. MeCN (2
mL) was added, and the solution was cooled in an ice bath. A cold
solution of NaHCO3 (130 mg, 1.5 mmol) in H2O (8 mL) was added
with stirring. The resultant precipitate was filtered, washed with
H2O, and dried at r.t. under a N2 flow to obtain 117 mg (86%) of 4c
as a yellow powder, which also contained 3 mol% 7c by 1H NMR
analysis.
4,6-Dichloro-5-{[2-(2,2,2-trifluoroethyl)hydrazono]methyl}py-
rimidine (3v)
Compound 3v was synthesized according to Procedure A, from 1
(97%, 400 mg, 2.19 mmol) and 2,2,2-trifluoroethylhydrazine (2v;
70 wt% in H2O, 535 mg, 3.28 mmol) in DMF (2.2 mL) to obtain 396
mg of 3v as a yellow powder, which contained 1 wt% DMF by 1H
NMR (66% yield); mp 113–114 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.79 (br s, 1 H), 8.73 (s, 1 H),
7.80 (s, 1 H), 4.04 (q, J = 9.46 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 158.5, 155.2, 126.9, 126.8,
125.0 (q, J = 281.82 Hz), 50.0 (q, J = 31.50 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C7H5Cl2F3N4: 272.9916;
1H NMR (500 MHz, DMSO-d6): δ = 8.99 (s, 1 H), 8.76 (s, 1 H),
8.19 (d, J = 8.51 Hz, 2 H), 7.67 (d, J = 8.83 Hz, 2 H).
found: 272.9924 (100), 105 (22).
Conversion of 3a–o into 4a–o; 4-Chloro-1-(4-methoxyphenyl)-
1H-pyrazolo[3,4-d]pyrimidine (4a); Typical Procedure B
To a microwave vial was added 3a (149 mg, 0.5 mmol) and MeCN
(1 mL). The reaction mixture was heated with stirring in a micro-
wave reactor at 200 °C for 20 min; then cooled to r.t. A cold solution
of NaHCO3 (63 mg, 0.75 mmol) in H2O (4 mL) was added with stir-
ring. The resultant precipitate was filtered, washed with H2O, and
dried at r.t. under vacuum overnight to obtain 4a (Note: Isolation of
equally pure 4 could alternatively be accomplished by simply con-
centrating the crude reaction mixture in vacuo. The in situ generated
HCl, which was present in the crude reaction mixture, was generally
not observed to form a salt with 4 upon concentration and thus pre-
sumably evaporated); yield: 126 mg (97%); tan powder; mp 122–
123 °C.
13C NMR (126 MHz, DMSO-d6): δ = 155.5, 154.2, 152.6, 136.6,
134.3, 131.4, 129.4, 122.5, 114.8.
HRMS (ESI): m/z [M + H]+ calcd for C11H6Cl2N4: 265.0042;
found: 265.0041 (100), 268.9982 (11), 267.0013 (67), 197 (4).
4-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]py-
rimidine (4d)
Yield (Procedure B): 129 mg (96%); orange powder; mp 88–89 °C.
Alternative One-Pot Synthesis of 4d: To a microwave vial was add-
ed 1 (97%, 95 mg, 0.52 mmol), 4-(trifluoromethyl)phenylhydrazine
(2d; 88 mg, 0.5 mmol), and MeCN (5 mL). The reaction mixture
was heated with stirring in a microwave reactor at 200 °C for 15
min; then cooled to r.t. The crude mixture was cooled in an ice bath.
A cold solution of NaHCO3 (130 mg, 1.5 mmol) in H2O (8 mL) was
added, with stirring. The resultant precipitate was filtered, washed
with H2O, and dried at r.t. under a N2 flow to obtain 146 mg (95%)
of 4d as a yellow powder, which also contained 3 mol% 7d by 1H
NMR analysis.
1H NMR (500 MHz, DMSO-d6): δ = 9.02 (s, 1 H), 8.80 (s, 1 H),
8.43 (d, J = 8.51 Hz, 2 H), 7.96 (d, J = 8.51 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 155.7, 154.3, 153.1, 140.9,
134.9, 127.0 (q, J = 32.13 Hz), 126.7 (q, J = 3.78 Hz), 123.9 (q,
J = 272.16 Hz), 120.9, 115.1.
Alternative One-Pot Synthesis of 4a: To a microwave vial was add-
ed 1 (97%, 95 mg, 0.52 mmol), 4-methoxyphenylhydrazine hydro-
chloride (2a; 87 mg, 0.5 mmol), and MeCN (2.5 mL). The reaction
mixture was heated with stirring in a microwave reactor at 200 °C
for 1 min; then cooled to r.t. The crude reaction mixture was cooled
in an ice bath. A cold solution of NaHCO3 (130 mg, 1.5 mmol) in
H2O (8 mL) was added, with stirring. The resultant precipitate was
filtered, washed with H2O, and dried at r.t. under vacuum overnight
to obtain 113 mg (87%) of 4a as a tan powder.
1H NMR (500 MHz, DMSO-d6): δ = 8.95 (s, 1 H), 8.72 (s, 1 H),
7.96–8.02 (m, 2 H), 7.13–7.20 (m, 2 H), 3.84 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 158.4, 155.2, 154.1, 152.2,
133.4, 130.9, 123.3, 114.5, 114.3, 55.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H6ClF3N4: 299.0306;
found: 299.0304 (100), 301.0275 (30), 189 (6).
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN4O: 261.0538;
found: 261.0541 (100), 263.0511 (33), 234 (4).
4-Chloro-1-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
(4e)
Yield (Procedure B): 110 mg (85%); tan powder; mp 85–87 °C.
Synthesis 2013, 45, 1791–1806
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
1803
1H NMR (500 MHz, DMSO-d6): δ = 8.85 (s, 1 H), 8.70 (s, 1 H),
7.56–7.66 (m, 1 H), 7.49 (dd, J = 1.58, 7.57 Hz, 1 H), 7.32 (dd,
J = 0.95, 8.20 Hz, 1 H), 7.16 (dt, J = 1.26, 7.57 Hz, 1 H), 3.72 (s, 3
H).
13C NMR (126 MHz, DMSO-d6): δ = 155.2, 154.7, 153.9, 153.8,
133.4, 131.4, 128.9, 125.3, 120.6, 113.2, 112.9, 55.9.
1H NMR (500 MHz, DMSO-d6): δ = 8.86 (s, 1 H), 8.85 (s, 1 H),
8.21 (d, J = 8.20 Hz, 1 H), 8.13 (d, J = 8.20 Hz, 1 H), 7.76–7.81 (m,
1 H), 7.70–7.75 (m, 1 H), 7.63 (ddd, J = 0.95, 6.94, 8.20 Hz, 1 H),
7.52 (ddd, J = 1.10, 6.94, 8.35 Hz, 1 H), 7.41 (dd, J = 0.63, 8.51 Hz,
1 H).
13C NMR (126 MHz, DMSO-d6): δ = 155.4, 154.5, 154.1, 134.0,
133.8, 132.9, 130.1, 129.1, 128.3, 127.5, 126.9, 125.9, 125.4, 122.6,
113.6.
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN4O: 261.0538;
found: 261.0537 (100), 263.0508 (34), 246 (3).
HRMS (ESI): m/z [M + H]+ calcd for C15H9ClN4: 281.0589;
found: 281.0586 (100), 283.0558 (31), 218 (2).
4-Chloro-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidine (4f)
Yield (Procedure B): 120 mg (98%); yellow powder; mp 122–
124 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.98 (s, 1 H), 8.75 (s, 1 H),
7.98–8.07 (m, 2 H), 7.43 (d, J = 7.88 Hz, 2 H), 2.40 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 155.4, 154.1, 152.4, 136.9,
135.5, 133.8, 129.8, 121.3, 114.5, 20.6.
4-Chloro-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (4l)
Yield (Procedure B): 121 mg (90%); tan powder; mp 175–177 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.02 (s, 1 H), 8.81 (s, 1 H),
8.68 (d, J = 3.78 Hz, 1 H), 8.11–8.18 (m, 1 H), 8.06–8.11 (m, 1 H),
7.56 (dd, J = 6.78, 5.20 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 155.7, 154.1, 153.1, 149.8,
148.9, 139.2, 134.5, 123.4, 117.2, 114.7.
HRMS (ESI): m/z [M + H]+ calcd for C10H6ClN5: 232.0384;
found: 232.0381 (100), 234.0351 (33), 469 (1).
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN4: 245.0589;
found: 245.0588 (100), 247.0558 (33), 218 (4).
4-Chloro-1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidine
(4g)
Yield (Procedure B): 123 mg (99%); tan powder; mp 156–158 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.99 (s, 1 H), 8.78 (s, 1 H),
8.17 (dd, J = 4.89, 8.67 Hz, 2 H), 7.48 (t, J = 8.83 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 160.7 (d, J = 245.7 Hz),
155.4, 154.2, 152.5, 134.2 (d, J = 2.52 Hz), 134.0, 123.6 (d, J = 8.82
Hz), 116.3 (d, J = 23.94 Hz), 114.6.
2-(4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)quinoxaline
(4m)
Yield (Procedure B): 141 mg (92%); rose-colored powder; mp 220–
223 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.79 (s, 1 H), 9.15 (s, 1 H),
8.98 (s, 1 H), 8.23 (dd, J = 1.42, 8.35 Hz, 1 H), 8.16–8.21 (m, 1 H),
7.92–8.02 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 156.3, 155.7, 154.3, 144.7,
141.6, 140.5, 139.5, 135.9, 131.3, 130.2, 129.32, 129.25. Note that
not all 13C peaks are visible (see spectrum in the Supporting Infor-
mation). Product 4m was highly insoluble in DMSO-d6 and all other
common NMR solvents; thus the 13C spectrum could not be record-
ed at a concentration adequate to visualize all 13C peaks.
HRMS (ESI): m/z [M + H]+ calcd for C11H6ClFN4: 249.0338;
found: 249.0336 (100), 251.0307 (34), 197 (3).
4-Chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine
(4h)
Yield (Procedure B): 125 mg (94%); tan powder; mp 107–110 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.91 (s, 1 H), 8.81 (s, 1 H),
7.80 (dd, J = 1.42, 8.04 Hz, 1 H), 7.73 (dd, J = 1.73, 7.72 Hz, 1 H),
7.68 (dt, J = 1.73, 7.80 Hz, 1 H), 7.59–7.64 (m, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H7ClN6: 283.0493;
found: 283.0490 (100), 285.0461 (32), 267 (5).
13C NMR (126 MHz, DMSO-d6): δ = 155.6, 154.1, 154.0, 134.2,
134.1, 131.9, 131.0, 130.4, 130.2, 128.4, 113.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H6Cl2N4: 265.0042;
found: 265.0040 (100), 268.9983 (10), 267.0013 (65), 238 (3).
2-(4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzo[d]oxa-
zole (4n)
Yield (Procedure B): 124 mg (92%); yellow powder; mp 236–
239 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.18 (s, 1 H), 9.03 (s, 1 H),
7.85–7.94 (m, 2 H), 7.47–7.53 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 157.0, 154.61, 154.58, 151.6,
4-Chloro-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine
(4i)
Yield (Procedure B): 121 mg (92%); tan powder; mp 112–113 °C.
148.7, 140.1, 137.9, 125.61, 125.58, 119.9, 115.4, 111.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H6ClN5O: 272.0334;
found: 272.0332 (100), 274.0300 (33), 244 (5).
1H NMR (500 MHz, DMSO-d6): δ = 9.05 (s, 1 H), 8.82 (s, 1 H),
8.32 (t, J = 2.05 Hz, 1 H), 8.18 (ddd, J = 0.79, 1.97, 8.28 Hz, 1 H),
7.67 (t, J = 8.20 Hz, 1 H), 7.53 (ddd, J = 0.95, 2.05, 8.04 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 155.7, 154.3, 152.9, 139.0,
134.6, 133.7, 131.3, 127.1, 120.6, 119.5, 115.0.
HRMS (ESI): m/z [M + H]+ calcd for C11H6Cl2N4: 265.0042;
found: 265.0040 (100), 268.9982 (10), 267.0011 (65), 198 (4).
4-(4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-methylthie-
no[2,3-d]pyrimidine (4o)
Yield (Procedure B): 137 mg (90%); yellow powder; mp 185–
190 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.24 (s, 1 H), 8.96 (s, 1 H),
8.95 (s, 1 H), 7.84 (d, J = 1.26 Hz, 1 H), 1.84 (d, J = 1.26 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 172.1, 156.2, 155.0, 154.6,
1-(4-Bromophenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine
(4j)
Yield (Procedure B): 210 mg (86%); tan powder; mp 166–168 °C.
152.7, 150.0, 135.2, 128.7, 126.7, 125.6, 113.9, 15.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H7ClN6S: 303.0214;
1H NMR (500 MHz, DMSO-d6): δ = 9.02 (s, 1 H), 8.81 (s, 1 H),
8.15–8.19 (m, 2 H), 7.82–7.86 (m, 2 H).
found: 303.0224 (100), 305.019 (34), 105 (26).
13C NMR (126 MHz, DMSO-d6): δ = 155.6, 154.3, 152.7, 137.1,
134.5, 132.4, 122.9, 119.8, 114.9.
HRMS (ESI): m/z [M + H]+ calcd for C11H6BrClN4: 308.9537;
Conversion of 1 into 4p–t; 4-Chloro-1H-pyrazolo[3,4-d]pyrimi-
dine (4p); Typical Procedure C
To a 20 mL vial was added 1 (97%, 88 mg, 0.5 mmol), Et3N (0.070
mL, 0.5 mmol), and THF (1 mL). The reaction mixture was allowed
to stir at 0 °C for 10 min under a N2 atmosphere. To the solution was
added hydrazine monohydrate (2p; 0.026 mL, 0.525 mmol) in THF
found: 308.9533 (77), 312.9483 (24), 310.9510 (100), 197 (4).
4-Chloro-1-(naphthalen-1-yl)-1H-pyrazolo[3,4-d]pyrimidine
(4k)
Yield (Procedure B): 128 mg (92%); brown powder; mp 97–100 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1791–1806

1804
C. Morrill et al.
PAPER
(1 mL) dropwise. The reaction mixture was allowed to warm to r.t.
and stirred for 1 h. The solvent was removed in vacuo, and the res-
idue was partitioned between CH2Cl2 (6 mL) and H2O (10 mL). The
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 6 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo to obtain 4p; yield: 56 mg
(74%); dark yellow powder; mp 156–158 °C.
4-Chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimi-
dine (4v)
To a microwave vial was added 3v (110 mg, 0.4 mmol) and MeCN
(4 mL). The reaction mixture was heated with stirring in a micro-
wave reactor at 200 °C for 5 min; then cooled to r.t. The solvent was
removed in vacuo to obtain 85 mg (90%) of 4v as an orange oil,
which solidified upon storage in the refrigerator; mp 57–58 °C.
1H NMR (500 MHz, CDCl3): δ = 8.85 (s, 1 H), 8.28 (s, 1 H), 5.10
(q, J = 8.20 Hz, 2 H).
1H NMR (500 MHz, DMSO-d6): δ = 14.51 (br s, 1 H), 8.83 (s, 1 H),
8.45 (d, J = 0.95 Hz, 1 H).
13C NMR (126 MHz, CDCl3): δ = 155.4, 155.3, 154.6, 134.0, 122.7
(q, J = 280.56 Hz), 114.0, 48.3 (q, J = 36.54 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C7H4ClF3N4: 237.0149;
13C NMR (126 MHz, CDCl3): δ = 155.4, 155.1, 154.7, 133.8, 113.5.
HRMS (ESI): m/z [M + H]+ calcd for C5H3ClN4: 155.0119;
found: 155.0117 (100), 157.0088 (34), 149 (4).
found: 237.0156 (43), 239.0126 (14), 102 (48).
4-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (4q)
4-[1-(4-Methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-
yl]morpholine (8)
Yield (Procedure C): 78 mg (92%); yellow powder; mp 94–96 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.88 (s, 1 H), 8.48 (s, 1 H),
4.08 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 154.6, 153.5, 152.7, 131.8,
112.9, 34.3.
HRMS (ESI): m/z [M + H]+ calcd for C6H5ClN4: 169.0276;
found: 169.0274 (100), 171.0244 (32), 133 (13).
To a microwave vial was added 1 (97%, 95 mg, 0.52 mmol), 4-me-
thoxyphenylhydrazine hydrochloride (2a; 87 mg, 0.5 mmol), and
MeCN (2.5 mL). The reaction mixture was heated with stirring in a
microwave reactor at 200 °C for 1 min; then cooled to r.t. Morpho-
line (53 μL, 0.61 mmol) and i-Pr2NEt (280 μL, 1.6 mmol) were add-
ed, and the mixture was allowed to stir, open to air, at r.t. for 30 min.
H2O (6 mL) was added with stirring. The resultant precipitate was
filtered, washed with H2O, and dried at r.t. under vacuum overnight
to obtain 122 mg (78%) of 8 as a tan powder; mp 147–148 °C.
2-(4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol (4r)
Yield (Procedure C): 120 mg (81%); yellow powder; mp 91–93 °C.
1H NMR (500 MHz, CDCl3): δ = 8.47 (s, 1 H), 8.11 (s, 1 H), 7.92–
7.98 (m, 2 H), 7.02–7.09 (m, 2 H), 4.05 (t, J = 4.57 Hz, 4 H), 3.89–
3.93 (m, 4 H), 3.87 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 158.4, 157.2, 155.3, 153.9, 133.1,
131.9, 123.8, 114.3, 101.4, 66.5, 55.5, 45.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H17N5O2: 312.1455;
found: 312.1465 (100), 102 (6).
1H NMR (500 MHz, DMSO-d6): δ = 8.86 (s, 1 H), 8.49 (s, 1 H),
4.82 (br s, 1 H), 4.51 (t, J = 5.67 Hz, 2 H), 3.86 (t, J = 5.52 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 154.5, 153.5, 153.3, 132.0,
113.0, 59.1, 50.1.
HRMS (ESI): m/z [M + H]+ calcd for C7H7ClN4O: 199.0381;
found: 199.0380 (100), 201.0351 (34), 181 (13).
4-Chloro-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine (4s)
4-(1-Methyl-1H-indol-3-yl)-1-[4-(trifluoromethyl)phenyl]-1H-
pyrazolo[3,4-d]pyrimidine (9)
Yield (Procedure C): 100 mg (84%); tan powder; mp 56–57 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.85 (s, 1 H), 8.47 (s, 1 H),
4.72–4.88 (m, 1 H), 1.91–2.00 (m, 4 H), 1.87 (d, J = 13.24 Hz, 2 H),
1.64–1.75 (m, 1 H), 1.40–1.56 (m, 2 H), 1.27 (d, J = 12.93 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6): δ = 154.3, 153.5, 151.9, 131.7,
113.0, 56.6, 31.8, 24.82, 24.80.
HRMS (ESI): m/z [M + H]+ calcd for C11H13ClN4: 237.0902;
found: 237.0902 (100), 239.0873 (33), 155 (33).
To a microwave vial was added 1 (97%, 95 mg, 0.52 mmol), 4-(tri-
fluoromethyl)phenylhydrazine (2d; 88 mg, 0.5 mmol), and MeCN
(5 mL). The reaction mixture was heated with stirring in a micro-
wave reactor at 200 °C for 15 min; then cooled to r.t. 1-Methylin-
dole (187 μL, 1.5 mmol) was added, and the mixture was heated
with stirring in a microwave reactor at 200 °C for 2 h. The crude
product mixture was dry-loaded directly onto silica gel and purified
twice by silica gel chromatography (12 g then 4 g SiO2, 0 to 30%
EtOAc gradient in hexanes) to obtain 81 mg (40%) of 9 as a yellow
powder; mp 198–199 °C.
1-Benzyl-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (4t)
Yield (Procedure C): 175 mg (95%); tan powder; mp 72–74 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.09 (s, 1 H), 9.06 (s, 1 H),
8.82 (s, 1 H), 8.73–8.78 (m, 1 H), 8.56 (d, J = 8.51 Hz, 2 H), 7.95
(d, J = 8.83 Hz, 2 H), 7.55–7.61 (m, 1 H), 7.26–7.36 (m, 2 H), 3.96
(s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 157.4, 156.0, 153.2, 141.6,
137.4, 136.01, 135.97, 126.5 (q, J = 3.78 Hz), 126.2 (q, J = 32.76
Hz), 126.1, 124.1 (q, J = 272.16 Hz), 123.0, 122.9, 121.8, 120.6,
111.1, 110.6, 110.3, 33.3.
1H NMR (500 MHz, DMSO-d6): δ = 8.91 (s, 1 H), 8.53 (s, 1 H),
7.23–7.36 (m, 5 H), 5.70 (s, 2 H).
13C NMR (126 MHz, DMSO-d6): δ = 154.9, 153.8, 152.8, 136.2,
132.6, 128.6, 127.8, 127.7, 113.1, 50.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN4: 245.0589;
found: 245.0588 (100), 247.0559 (31), 197 (2).
1-tert-Butyl-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (4u)
To a microwave vial was added 3u (124 mg, 0.5 mmol) and THF (3
mL). The reaction mixture was heated with stirring in a microwave
reactor at 100 °C for 1 h; then cooled to r.t. The solvent was re-
moved in vacuo to obtain 103 mg (98%) of 4u as an orange oil,
which solidified upon storage in the refrigerator; mp 36–37 °C.
HRMS (ESI): m/z [M + H]+ calcd for C21H14F3N5: 394.1274;
found: 394.1285 (100), 102 (2).
1-(4-Chlorophenyl)-4-isopropoxy-1H-pyrazolo[3,4-d]pyrimi-
dine (10)
To a conical vial was added 4c (40 mg, 0.15 mmol), i-PrOH (23 μL,
0.3 mmol), and THF (0.75 mL). The reaction mixture was allowed
to stir, open to air, in an ice bath for 5 min, after which t-AmONa
(2.5 M in THF, 120 μL, 0.3 mmol) was added. The reaction was al-
lowed to reach r.t. and stirred for 16 h. The crude reaction mixture
was transferred to a separatory funnel, and CH2Cl2 (10 mL), sat. aq
NH4Cl (10 mL) and brine (5 mL) were added. The layers were sep-
arated, and the aqueous layer was extracted with CH2Cl2 (2 × 10
mL). The combined organic layers were dried (Na2SO4), and the
1H NMR (500 MHz, DMSO-d6): δ = 8.84 (s, 1 H), 8.40 (s, 1 H),
1.75 (s, 9 H).
13C NMR (126 MHz, DMSO-d6): δ = 153.6, 153.4, 152.3, 130.5,
114.1, 61.0, 28.7.
HRMS (ESI): m/z [M + H]+ calcd for C9H11ClN4: 211.0745;
found: 211.0746 (55), 213.0717 (20), 155 (100).
Synthesis 2013, 45, 1791–1806
© Georg Thieme Verlag Stuttgart · New York

PAPER
Selective Synthesis of 4-Chloropyrazolo[3,4-d]pyrimidines
1805
crude material was purified by silica gel chromatography (4 g SiO2,
0 to 10% EtOAc gradient in hexanes) to obtain 36 mg (83%) of 10
as a white powder; mp 145–146 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.71 (s, 1 H), 8.49 (s, 1 H),
8.21–8.27 (m, 2 H), 7.62–7.68 (m, 2 H), 5.63 (sept, J = 6.20 Hz, 1
H), 1.43 (d, J = 6.31 Hz, 6 H).
Acknowledgment
The authors wish to thank Dr. Ramil Baiazitov (PTC Therapeutics,
Inc.) and Prof. Scott E. Denmark (University of Illinois, Urbana-
Champaign) for helpful discussions and Jane Yang (PTC Therapeu-
tics, Inc.) for analytical support.
13C NMR (126 MHz, DMSO-d6): δ = 163.0, 156.1, 154.3, 137.3,
133.5, 130.7, 129.3, 122.2, 103.9, 70.6, 21.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H13ClN4O: 289.0851;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
found: 289.0861 (10), 291.083 (3), 247 (100).
References
1-(4-Chlorophenyl)-4-phenoxy-1H-pyrazolo[3,4-d]pyrimidine
(11)
(1) (a) Meng, F.; Hou, J.; Shao, Y. X.; Wu, P. Y.; Huang, M.;
Zhu, X.; Cai, Y.; Li, Z.; Xu, J.; Liu, P.; Luo, H. B.; Wan, Y.;
Ke, H. J. Med. Chem. 2012, 55, 8549. (b) Verhoest, P. R.;
Fonseca, K. R.; Hou, X.; Proulx-LaFrance, C.; Corman, M.;
Helal, C. J.; Claffey, M. M.; Tuttle, J. B.; Coffman, K. J.;
Liu, S.; Nelson, F.; Kleiman, R. J.; Menniti, F. S.; Schmidt,
C. J.; Vanase-Frawley, M.; Liras, S. J. Med. Chem. 2012, 55,
9045. (c) Claffey, M. M.; Helal, C. J.; Verhoest, P. R.; Kang,
Z.; Fors, K. S.; Jung, S.; Zhong, J.; Bundesmann, M. W.;
Hou, X.; Lui, S.; Kleiman, R. J.; Vanase-Frawley, M.;
Schmidt, A. W.; Menniti, F.; Schmidt, C. J.; Hoffman, W.
E.; Hajos, M.; McDowell, L.; O’Conner, R. E.; MacDougall-
Murphy, M.; Fonseca, K. R.; Becker, S. L.; Nelson, F. R.;
Liras, S. J. Med. Chem. 2012, 55, 9055.
A procedure analogous to that employed for 10 using sodium phen-
oxide as the nucleophile was carried out. The crude material was pu-
rified by silica gel chromatography (4 g SiO2, 0 to 10% EtOAc
gradient in hexanes) to obtain 42 mg (87%) of 11 as a pale yellow
powder; mp 188–189 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.69 (s, 1 H), 8.50 (s, 1 H),
8.23–8.29 (m, 2 H), 7.65–7.71 (m, 2 H), 7.53 (t, J = 7.88 Hz, 2 H),
7.34–7.41 (m, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 163.3, 156.0, 154.8, 151.8,
137.1, 133.6, 131.0, 129.9, 129.4, 126.3, 122.5, 122.0, 103.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H11ClN4O: 323.0694;
found: 323.0706 (100), 325.067 (32), 102 (13).
(2) Manetti, F.; Santucci, A.; Locatelli, G. A.; Maga, G.;
Spreafico, A.; Serchi, T.; Orlandini, M.; Bernardini, G.;
Caradonna, N. P.; Spallarossa, A.; Brullo, C.; Schenone, S.;
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McIntyre, K. W.; Gillooly, K.; Doweyko, A. M.; Sack, J. S.;
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(5) Settimo, F. D.; Primofiore, G.; Motta, C. L.; Taliani, S.;
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Stamford, A. W.; Tulshian, D.; Ongini, E.; Hunter, J.;
Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.;
Lachowicz, J.; Ng, K.; Feng, K. I. Bioorg. Med. Chem. Lett.
2007, 17, 1376. (b) Harris, J. M.; Neustadt, B. R.; Zhang, H.;
Lachowicz, J.; Cohen-Williams, M.; Varty, G.; Hao, J.;
Stamford, A. W. Bioorg. Med. Chem. Lett. 2011, 21, 2497.
(7) Baraldi, P. G.; Bovero, A.; Fruttarolo, F.; Romagnoli, R.;
Tabrizi, M. A.; Preti, D.; Varani, K.; Borea, P. A.; Moorman,
A. R. Bioorg. Med. Chem. 2003, 11, 4161.
(8) Kelley, J. L.; Davis, R. G.; McLean, E. W.; Glen, R. C.;
Soroko, F. E.; Cooper, B. R. J. Med. Chem. 1995, 38, 3884.
(9) Burch, H. A. J. Med. Chem. 1968, 11, 79.
(10) Deng, X.; Okram, B.; Ding, Q.; Zhang, J.; Choi, Y.; Adrián,
F. J.; Wojciechowski, A.; Zhang, G.; Che, J.; Bursulaya, B.;
Cowan-Jacob, S. W.; Rummel, G.; Sim, T.; Gray, N. S.
J. Med. Chem. 2010, 53, 6934.
1-(4-Chlorophenyl)-4-methyl-1H-pyrazolo[3,4-d]pyrimidine
(12)
To a conical vial was added 4c (40 mg, 0.15 mmol) and THF (0.75
mL). The solution was allowed to stir, open to air, in an ice bath for
5 min, after which MeMgBr (1 M in THF, 300 μL, 0.3 mmol) was
added. The reaction mixture was allowed to reach r.t. and stirred for
17 h. The crude reaction mixture was transferred to a separatory
funnel, and CH2Cl2 (10 mL), sat. aq NH4Cl (10 mL), and brine (5
mL) were added. The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (2 × 10 mL). The combined organic lay-
ers were dried (Na2SO4), and the crude material was purified by sil-
ica gel chromatography (4 g SiO2, 0 to 30% EtOAc gradient in
hexanes) to obtain 30 mg (82%) of 12 as a yellow powder; mp 145–
146 °C.
1H NMR (500 MHz, DMSO-d6): δ = 8.98 (s, 1 H), 8.77 (s, 1 H),
8.23–8.29 (m, 2 H), 7.61–7.68 (m, 2 H), 2.82 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): δ = 164.1, 155.5, 151.8, 137.2,
135.4, 130.6, 129.3, 122.0, 115.2, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN4: 245.0589;
found: 245.0600 (100), 247.057 (32), 218 (2).
1-(4-Chlorophenyl)-4-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(13)
To a microwave vial was added 4c (40 mg, 0.15 mmol), phenylbo-
ronic acid (20 mg, 0.16 mmol), K2CO3 (62 mg, 0.45 mmol),
PdCl2(dppf) (10 mg, 0.014 mmol), THF (2.2 mL), and H2O (10 μL).
The reaction mixture was heated with stirring in a microwave reac-
tor at 170 °C for 10 min. The crude reaction mixture was passed
through a small silica gel plug eluting with EtOAc, and the crude
material was purified by silica gel chromatography (4 g SiO2, 0 to
10% EtOAc gradient in hexanes) to obtain 29 mg (63%) of 13 as a
white powder; mp 165–166 °C.
1H NMR (500 MHz, DMSO-d6): δ = 9.21 (s, 1 H), 9.03 (s, 1 H),
8.35 (dd, J = 1.73, 7.72 Hz, 2 H), 8.31 (d, J = 9.14 Hz, 2 H), 7.63–
7.73 (m, 5 H).
13C NMR (126 MHz, DMSO-d6): δ = 160.1, 155.7, 153.2, 137.1,
135.8, 135.6, 131.9, 130.9, 129.4, 129.3, 129.1, 122.5, 112.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H11ClN4: 307.0745;
found: 307.0758 (100), 309.073 (31), 102 (4).
(11) (a) Manetti, F.; Brullo, C.; Magnani, M.; Mosci, F.; Chelli,
B.; Crespan, E.; Schenone, S.; Naldini, A.; Bruno, O.;
Trincavelli, M. L.; Maga, G.; Carraro, F.; Martini, C.;
Bondavalli, F.; Botta, M. J. Med. Chem. 2008, 51, 1252.
(b) Radi, M.; Dreassi, E.; Brullo, C.; Crespan, E.; Tintori, C.;
Bernardo, V.; Valoti, M.; Zamperini, C.; Daigl, H.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1791–1806

1806
C. Morrill et al.
PAPER
Musumeci, F.; Carraro, F.; Naldini, A.; Filippi, I.; Maga, G.;
Schenone, S.; Botta, M. J. Med. Chem. 2011, 54, 2610.
(23) We considered the possibility of 6 serving as an intermediate
capable of converting to 4 at elevated temperatures. To test
this hypothesis, isolated 6a was heated at 180 °C in MeCN
for 20 min, in both the presence and the absence of 1 equiv
of HCl (4 M in 1,4-dioxane). In both cases, formation of 4a
was not observed (1H NMR of the crude reaction mixture).
In both cases, 6a did, however, undergo 70–80% conversion
to a new product, identified by both UPLC/MS and 1H NMR
(taken of the crude reaction mixture) as 4-chloro-6-{(4-
methoxyphenyl)[1-(4-methoxyphenyl)-1H-pyrazolo[3,4-
d]pyrimidin-4-yl]amino}pyrimidine-5-carbonitrile.
(24) We also investigated the corresponding reactions of 2q–t in
the absence of an external base. In cases where 2 was an HCl
salt (2s and 2t), exclusive formation of hydrazone 3 was
observed. When 2 was used in its free base form (2q and 2r),
a mixture of 1 and 4 (ca. 1:2) was observed, along with
several unidentified minor byproducts. When 2.1 equiv of
2q and 2r were used instead of 1.05 equiv, 4 was formed
quantitatively. In the latter case 2q and 2r presumably
functioned as the external base, thus leading to similar
results as those obtained in Table 6.
(12) (a) Richard, D. J.; Verheijen, J. C.; Curran, K.; Kaplan, J.;
Toral-Barza, L.; Hollander, I.; Lucas, J.; Yu, K.; Zask, A.
Bioorg. Med. Chem. Lett. 2009, 19, 6830. (b) Zask, A.;
Verheijen, J. C.; Curran, K.; Kaplan, J.; Richard, D. J.;
Nowak, P.; Malwitz, D. J.; Brooijmans, N.; Bard, J.;
Svenson, K.; Lucas, J.; Toral-Barza, L.; Zhang, W. G.;
Hollander, I.; Gibbons, J. J.; Abraham, R. T.; Ayral-
Kaloustian, S.; Mansour, T. S.; Yu, K. J. Med. Chem. 2009,
52, 5013. (c) Nowak, P.; Cole, D. C.; Brooijmans, N.;
Bursavich, M. G.; Curran, K. J.; Ellingboe, J. W.; Gibbons,
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Synthesis 2013, 45, 1791–1806
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