A scalable approach to diaminopyrazoles using flow chemistry

Article abstract of DOI:10.1016/j.tetlet.2012.05.152

This Letter reports on how the combination of microwave and continuous flow chemistry facilitated the convenient preparation of aminopyrazoles from commercial aryl halides. The method was applied to a variety of substrates with good to excellent yields an

Full text of DOI:10.1016/j.tetlet.2012.05.152

Tetrahedron Letters 53 (2012) 4498–4501
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A scalable approach to diaminopyrazoles using flow chemistry
⇑
Noel S. Wilson , Augustine T. Osuma, Jennifer A. Van Camp, Xiangdong Xu
Medicinal Chemistry Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6113, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter reports on how the combination of microwave and continuous flow chemistry facilitated the
convenient preparation of aminopyrazoles from commercial aryl halides. The method was applied to a
variety of substrates with good to excellent yields and further extended toward the complete flow syn-
thesis of 5,7-dimethyl-3-phenylpyrazolo[1,5-a]pyrimidin-2-amine.
Received 9 March 2012
Revised 29 May 2012
Accepted 30 May 2012
Available online 21 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Flow chemistry
Sequential flow process
Aminopyrazole
Pyrazolopyrimidine
Single mode microwave
The scale-up of single mode microwave reactions typically in-
volves the use of batch reactors and continuous flow systems.1,2
While useful, the use of large batch reactors for this purpose in-
volves the transfer of optimized chemistry from smaller single-
mode systems,3 and may result in the need for re-optimization.2
Continuous flow reactors offer many benefits including eliminating
the need for re-optimization of time and temperature that is typi-
cally required for scale-up.4 Further, their increased safety benefits
(e.g. small amounts of reagents in the reactor, reaction scalability,
and precise control of reaction variables)5 attracted our interest.
Several groups have demonstrated the utility of accelerating or-
ganic reactions in a continuous flow reactor with microwave irra-
diation;6 however, our in-house observations have shown that
these systems are limited in their heating capabilities due to the
short resonance times when using small single mode microwaves.7
To overcome this inadequate heating capability, lower flow rates
can be employed to maximize resonance time in the microwave;
however, this limits the overall throughput of the system. More re-
cently, it has been reported that microwave processes can be
scaled using continuous flow systems equipped with conventional
heating modules.8
we initiated our own internal investigation into scaling up sin-
gle-mode microwave processes using commercial meso-flow
systems.
Fused heterocyclic derivatives such as pyrazolo[1,5-a]pyrimi-
din-2-amine 1 continue to play a major role in many ‘small mole-
cule’ drug discovery programs and as a result pyrazolo[1,5-
a]pyrimidine derivatives have recently been identified as kinase
inhibitors and as CNS therapeutic agents.9,10 Synthetic methodol-
ogy for the generation of these scaffolds has been described previ-
ously.11 In one approach, the diamino-pyrazole 3 was reacted with
diketones 4 (or a corresponding equivalent such as 5) under micro-
wave irradiation to afford pyrazolo[1,5-a]pyrimidin-2-amines.
Although the transformation of 3 to 1 proceeded with good yields,
the microwave approach has limitations when larger quantities of
material are required to prosecute structural–activity relationships
(SAR) and in vivo evaluation of desirable analogs. We describe
herein a convenient and scalable approach to substituted diamin-
Pump A
Waste
S
S
Reagent A
In our need to efficiently prepare multi-gram quantities of a
variety of aminopyrazole and pyrazolopyrimidine derivatives we
sought to develop a scalable process utilizing conventional chem-
istry methods and/or microwave. Our initial efforts were accompa-
nied by undesired longer reaction protocols and the lack of
scalability with single-mode microwave technology. To this end
BPR
S
System
Solvent
Heat
Exchanger
Reagent B
Tube Reactor
Collect
&
Heater
BPR = back pressure regulator
S = switch
⇑
Corresponding author. Tel.: +1 847 935 2256; fax: +1 847 938 2756.
E-mail address: noel.wilson@abbott.com (N.S. Wilson).
Figure 1. Schematic representation of the flow apparatus.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.152

N. S. Wilson et al. / Tetrahedron Letters 53 (2012) 4498–4501
4499
Table 1
Optimization of flow reaction conditions for the formation of diaminopyrazoles
NH2
NH2
N
NH2NH2.H2O
N
HN
R
R
N
Entry
Method
Solvent
Rt (min)
Temp (°C)
Equiv hydrazine hydrate
Conversion (%)
1
2
3
4
5
6
7
8
Microwave
Microwave
Flow
Flow
Flow
Flow
Flow
Flow
Flow
EtOH
nBuOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
15
15
14
10
5
1
5
5
140
140
140
140
140
140
140
140
140
120
100
5
5
5
5
5
5
2
1
1
1
1
<20
60
100
100
99
95
96
93
97
9
10
11
10
10
10
Flow
Flow
92
84
Table 2
Optimization of solvent conditions for the formation of diaminopyrazoles using 2-(4-
nitrophenyl)malononitrile and 1 equiv of hydrazine hydrate under microwave
irradiation at 140 °C for 10 min and continuous flow at 140 °C for 10 min
NH2
N
NH2NH2.H2O
N
HN
NO2
NO2
NH2
N
Entry
Method
Solvent
Conversion (%)
1
2
3
4
5
6
7
8
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
Flow
EtOH
MeOH
Dioxane
1:0.5 MeOH/Dioxane
1:1 MeOH/Dioxane
0.75:1 MeOH/Dioxane
0.5:1 MeOH/Dioxane
0.5:1 MeOH/Dioxane
50
24
80
28
81
91
100
100
Figure 2. Dark precipitate observed in coils when 2-(4-nitrophenyl)malononitrile is
treated with 1 equiv of hydrazine hydrate in ethanol as solvent.
We have found that a variety of aryl malononitriles in a 2:1
mixture of dioxane/methanol, are easily converted into their corre-
sponding aminopyrazoles in good to excellent yield by treatment
with 1 equiv of hydrazine hydrate in flow at 140 °C and a reso-
nance time of 10 min (Table 3). Interestingly aliphatic and benzyl
malononitriles did not undergo cyclization and only starting mate-
rial was obtained. However increasing the equivalents of hydrazine
hydrate to five did provide the corresponding benzylpyrazole, al-
beit in 16% conversion (Table 3, entry 9). The continuous flow
methodology can be extended to synthesize other heterocyclic
compounds. Cyclization of methyl 2-cyano-2-phenylacetate and
3-oxo-2-phenylpropanenitrile with 1 equiv of hydrazine hydrate
successfully afforded 5-amino-4-phenyl-1H-pyrazol-3(2H)-one
and 4-phenyl-1H-pyrazol-5-amine, respectively (Table 3, entries
10 and 11). Furthermore, additional structural diversity can be
achieved by reacting phenyl malononitrile with other nucleophiles,
such as benzamidine (Table 3, entry 12). To our surprise, reacting
hydroxylamine with 2-phenylmalononitrile did not yield the de-
sired cyclized product (Table 3, entry 13).
Additionally, we have expanded the scope of the flow process
for the generation of a pyrazolo[1,5-a]pyrimidin-2-amine deriva-
tive (Scheme 1). Our goal was to develop a two step continuous
flow process that does not require a work-up step after formation
of the aminopyrazole. To this end, the aminopyrazole along with
excess acetylacetone were pumped into a second flow reactor to
perform the next synthetic transformation. Our initial results indi-
cated that this sequential flow process is amenable to the forma-
opyrazoles and extensions toward the development of a continu-
ous flow process of 5,7-dimethyl-3-phenylpyrazolo[1,5-a]pyridin-
2-amine.
A commercially available continuous-flow unit, the Unqisis
Flowsyn,12 was used for all flow reactions. The reagents were
pre-dissolved, pumped through a static T-mixer, and heated in a
PTFE coil reactor (14 mL) or stainless steel coil reactor (20 mL)
via an aluminum heating block. The exiting reaction mixture was
passed through a heat exchanger followed by a 100 psi rated back-
pressure regulator and collected. The configuration is depicted in
Figure 1.
Our preliminary results when transferring optimized, single-
mode batch microwave conditions to a continuous flow unit were
comparable with only solvent manipulation (Table 1, entries 2 and
3). However, superior yields were obtained using continuous flow
versus irradiation with a single-mode microwave (Table 1, entry 3).
The equivalents of hydrazine hydrate were reduced without com-
promising the overall % conversion to product by increasing the
overall resonance time to 10 min (Table 1, entries 5 and 9). When
2-(4-nitrophenyl)malononitrile was treated with 1 equiv of hydra-
zine hydrate in ethanol a dark precipitate was observed in coils
(Fig. 2). A single-mode microwave was used to quickly scan sol-
vents for reactivity and solubility (Table 2). We found that a 2:1
mixture of dioxane/methanol was the optimum solvent for conver-
sion of 2-(4-nitrophenyl)malononitrile to the corresponding ami-
nopyrazole (Table 2, entries 7 and 8).

4500
N. S. Wilson et al. / Tetrahedron Letters 53 (2012) 4498–4501
Table 3
NC
CN
NH2NH2
BuOH
HN
H2N
N
NC
N
CN
X
Ph
Results from reacting various malononitriles with 1 equiv of nucleophile under
continuous flow
NaH
Pd(PPh3)2 Cl2
NH2
Ph
Ph
3
X = Br, I
Entry Starting material
Nucleophile Product
Conversion
(%)
(isolated
yield)
2
R1
O
R1
N
4
O
R3
R2
R3
N
R2
EtOH
NH2
N
Or
R3
NH2
N
Ph
O
5
1
NH2NH2ÁH2O
100(94)
N
R1
1 R1, R2, R3 = H, Me
N
R2
H2N
N
N
H
ortho—97
(42)
meta—100
(95)
para—100
(94)
NH2
Scheme 1. Methodology for the generation of diaminopyrazole and pyrazolo[1,5-
a]pyrimidine derivatives.
N
2
NH2NH2ÁH2O
N
H
H2N
N
N
N
ortho—100
(81)
meta—100
(88)
para—100
(97)
NH2
N
F
NH2
NH2
N
3
NH2NH2ÁH2O
N
F
N
HN
H2N
N
H
N
ortho—89
(26)
meta—100
(99)
para—100
(92)
140 oC, 10 min.
1 equiv.
NH2
N
NH2NH2.H2O
O
XS
O
O
4
NH2NH2ÁH2O
N
OMe
N
H2N
H
NH2
N
N
N
H2N
N
NH
O2N
O2N
N
5
NH2NH2ÁH2O
100 (99)
140 oC, 20 min.
N
H2N
Cl
NH2
Cl
Scheme 2. Flow synthesis of 5,7-dimethyl-3-phenylpyrazolo[1,5-a]pyrimidin-2-
amine.
N
N
NH
F3C
F3C
H2N
6
NH2NH2ÁH2O
NH2NH2ÁH2O
NH2NH2ÁH2O
93 (33)
N
N
H2N
NH2
N
In summary, we have developed a process that allows the con-
trolled continuous flow synthesis of aminopyrazoles in good to
excellent yields. The versatility of this flow process can be further
extended to the complete flow synthesis of 5,7-dimethyl-3-phen-
ylpyrazolo[1,5-a]pyridin-2-amine.
N
N
7
8
0
0
HN
N
NH2
N
N
N
H2N
H
N
Acknowledgments
N
NH2
0
9
NH2NH2ÁH2O
NH2NH2ÁH2O
N
We thank Dr. Stevan Djuric and Dr. Anil Vasudevan for helpful
discussions and project support.
16a
F
N
H
F
H2N
N
O
O
O
References and notes
10
96 (83)
NH
N
H
1. (a) Strauss, C. R. Org. Process Res. Dev. 2009, 13, 915–923; (b) Kremsner, J. M.;
Stadler, A.; Kappe, C. O. Top. Curr. Chem. 2006, 266, 233–278; (c) Ondruschka,
B.; Bonrath, W.; Stuerga, D. In Microwaves in Organic Synthesis; Loupy, A., Ed.,
2nd ed.; Wiley-VCH: Weinheim, 2006; (d) Roberts, B. A.; Strauss, C. R. Acc.
Chem. Res. 2005, 38, 653–661.
2. Lehmann, H.; LaVecchia, L. Org. Process Res. Dev. 2010, 14, 650–656.
3. Schmink, J. R.; Kormos, C. M.; Devine, W. G.; Leadbeater, N. E. Org. Process Res.
Dev. 2010, 14, 205–214.
H2N
N
N
O
11
NH2NH2ÁH2O
100 (85)
N
N
H
H2N
H2N
N
4. Bergamelli, F.; Iannelli, M.; Marafie, J. A.; Moseley, J. D. Org. Process Res. Dev.
2010, 14, 926–930.
N
NH
12
13
70 (62)
5. (a) Stazi, F.; Cancogni, D.; Turco, L.; Westerduin, P.; Bacchi, S. Tetrahedron Lett.
2010, 51, 5385–5387; (b) Palmieri, A.; Ley, S. V.; Hammond, K.; Polyzos, A.;
Baxendale, I. R. Tetrahedron Lett. 2009, 50, 3287–3289; (c) Malet-Sanz, L.;
Madrzak, J.; Holvey, R. S.; Underwood, T. Tetrahedron Lett. 2009, 50, 7263–7267.
6. (a) Venturoni, F.; Nikbin, N.; Ley, S. V.; Baxendale, I. R. Org. Biol. Chem. 2010, 8,
1798; (b) Baxendale, I. R.; Hayward, J. J.; Ley, S. V. Comb. Chem. HTS 2007, 10,
802–836; (c) Wilson, N. S.; Sarko, C. R.; Roth, G. P. Org. Process Res. Dev. 2004, 8,
535–538; (d) Bergamelli, F.; Iannelli, M.; Marafie, J. A.; Moseley, J. D. Org.
Process Res. Dev. 2010, 14, 926–930; (e) Benali, O.; Deal, M.; Farrant, E.;
Tapolczay, D.; Wheeler, R. Org. Process Res. Dev. 2008, 12, 1007; (f) Mennecke,
K.; Cecilia, R.; Glasnov, T. N.; Gruhl, S.; Vogt, C.; Feldhoff, A.; Vargas, M. A. L.;
Kappe, C. O.; Kunzand, U.; Kirschning, A. Adv. Synth. Catal. 2008, 350, 717; (g)
Solodenko, W.; Mennecke, K.; Vogt, C.; Gruhl, S.; Kirschning, A. Synthesis 2006,
1873; (h) Jachuck, R. J. J.; Selvaraj, D. K.; Varma, R. S. Green Chem. 2006, 8, 29.
7. Wilson, N.S. 4th Annual Unqisis Flow Chemistry Symposium, British Consulate,
Cambridge, MA, November 15, 2010, unpublished results.
N
NH2
N
N
H2N
NH2
N
NH2OH
0
O
H2N
N
a
5.0 equiv of hydrazine hydrate were used.
tion of both the aminopyrazole as well as 5,7-dimethyl-3-phen-
ylpyrazolo[1,5-a]pyridin-2-amine (Scheme 2). The scope and
limitations of these reactions are currently under detailed investi-
gation and will be reported in due course.

N. S. Wilson et al. / Tetrahedron Letters 53 (2012) 4498–4501
4501
8. (a) Castellano, S.; Tamborini, L.; Viviano, M.; Pinto, A.; Sbardella, G.; Conti, P. J.
Org. Chem. 2010, 75, 7439–7442; (b) Bagley, M. C.; Fusillo, V.; Jenkins, R. L.;
Lubinu, M. C.; Mason, C. Org. Biomol. Chem. 2010, 8, 2245–2251.
10. Jimenez, J.-M.; Knegtel, R.; Charrier, J.-D.; Stamos, D.; Li, P.; Come, J.; Aronov, A.
WO 2006/052913 A1.
11. Zvilichovsky, G.; David, M. J. Chem. Soc., Perkin Trans. 1 1983, 11.
12. Uniqsis Inc homepage: http://www.uniqsis.com/.
9. He, L.; Gilligan, P.; Chorvat, R.; Arvanitis, A. U.S. 6358,950 B.1.