A one-pot process for the regioselective synthesis of 1,3,4-trisubstituted-1H-pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2008.11.099

This Letter reports a facile and regioselective one-pot synthesis of 1,3,4-trisubstituted-1H-pyrazoles. It comprises a three-step telescoped sequence, which has been utilised in the production of a variety of differentially substituted pyrazoles.

Full text of DOI:10.1016/j.tetlet.2008.11.099

Tetrahedron Letters 50 (2009) 696–699
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A one-pot process for the regioselective synthesis
of 1,3,4-trisubstituted-1H-pyrazoles
*
Steven A. Raw , Andrew T. Turner
Process Research and Development, AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter reports a facile and regioselective one-pot synthesis of 1,3,4-trisubstituted-1H-pyrazoles. It
comprises a three-step telescoped sequence, which has been utilised in the production of a variety of dif-
ferentially substituted pyrazoles.
Received 6 October 2008
Revised 18 November 2008
Accepted 26 November 2008
Available online 30 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
As part of a current research programme, we required a robust
and safe process to provide significant quantities of 1,3-dimethyl-
1H-pyrazole-4-carbaldehyde 1 (Fig. 1). This important building
block 1 has found use in the preparation of several pharmacologi-
cally active agents.1 Furthermore, this general 1,3,4-substituted
pyrazole motif is also an important constituent in several classes
of pharmaceutically active compounds.2
Ideally, we required a short, regioselective synthesis of pyra-
zoles of type 2 (e.g., Alk = Et) or 4 (which in turn would give access
to 1) that would be amenable to scale-up and avoided the use of
Vilsmeier–Haack type chemistry. As discussed, none of the pub-
lished methods satisfied those requirements, which led us to de-
vise a novel approach to the construction of such pyrazoles,
targeting ring-formation at the C4–C5 bond (Scheme 1).6
Me
R
3
4
1 R = CHO
CO2Et
2 R = CO2Alk
2 N
5
4 H
Me
3
N 1
Me
3 R = CH2OH
4 R = CN
FGI
5
1
2/3/4
2
1
N
O
N
Figure 1.
Me
5
Although a few syntheses of this compound have been reported
in the literature,3 these methods all have significant drawbacks. In
some, the desired compound 1 is produced in low yield, as a regio-
isomeric mixture or, indeed, as a by-product.3a,e Those prepara-
tions that do give good yields and selectivity3b–d employ the
Vilsmeier reagent or the Vilsmeier–Haack reaction to construct
the heterocyclic system. Over and above the toxicity of the re-
agents and intermediates involved, the practicalities of this chem-
istry proved prohibitive: in our hands, the reaction mixtures were
thick, immobile gels which produced significant exotherms, both
during reaction and upon quenching.
Similarly, reported syntheses of the corresponding ester-substi-
tuted pyrazoles 24 also suffer from drawbacks: product mix-
tures,4a,c,d diazotization steps,4b,d relatively high step-count or
expensive raw materials.4e This also applies to the corresponding
pyrazole acid 10.4d,e
H
H2N
OEt
NH
Me
H2N
+
N
Me
O
O
O
8
7
6
Scheme 1.
In this approach, a key intramolecular Knoevenagel-type con-
densation would allow incorporation of the C5 carbon into the
molecule as a formyl moiety (it is C5 that is often introduced via
Vilsmeier-type chemistry). Hydrazone 5 would be derived from
ethyl acetoacetate 6 and the known 1-formyl-1-methylhydrazine
7,7 accessed in turn from commercially available methylhydrazine
8.
In a wider context, the most prevalent approach to substituted
pyrazoles is the reaction of hydrazine-derivatives with 1,3-dike-
tones (comprising C3–C5 using the numbering above).8 Given the
importance of the pyrazole sub-unit in pharmaceutically active
compounds, this classical method still attracts current industrial
research interest.9 Our proposed approach is complimentary to this
Lastly, the nitrile 4 has been reported as an isolated compound
just once,5 again as a regioisomeric mixture.
* Corresponding author. Tel.: +44 (0) 1625 232848.
E-mail address: steven.raw@astrazeneca.com (S.A. Raw).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.099

S. A. Raw, A. T. Turner / Tetrahedron Letters 50 (2009) 696–699
697
Table 1
(with the C3–C5 unit being assembled in the ring-forming step)
and would represent a useful tool in the heterocyclic synthetic
arsenal.
1,3,4-Trisubstituted pyrazoles10,12
Entry
b-Keto ester
Pyrazole
CO2Et
Yield (%)
41
We have shown that, in the forward direction, synthesis of 2 can
be telescoped into one stage (Scheme 2): reaction of methylhydr-
azine 8 with ethyl formate gives 1-formyl-1-methylhydrazine 7
(accompanied by the regioisomer in a ratio of ꢀ6.5:1, desired to
undesired). Addition of ethyl acetoacetate 6 allows formation of
hydrazone 5 and pyrazolone 9. Finally, we were pleased to observe
that base-induced cyclisation gave the desired pyrazole ester 2,
accompanied only by the corresponding acid 10, thus proving
our retrosynthetic rationale.
O
1
N
CO2Et
N
Me
CO2Et
CO2Et
O
2
3
35
49
N
CO2Et
N
Me
H
H
H
H2N
N
O
O
H2N
NH
Me
Me
N
H
O
N
Me
O
N
+
EtOCHO
EtOH,
reflux
CO2Et
CO2Et
N
7
8
~6 : 1
Me
OEt
CO2Et
Reflux
O
O
4
5
6
30
6
N
N
Me
CO2Et
H
Me
Me
CO2Et
EtO2C
N
O
O
Me
N
H
N
31 (+29% acid)
32 (+14% acid)
N
O
N
EtO2C
CO2Et
N
9
Me
5
Me
CO2Et
O
O
O
EtONa/EtOH
OEt
OEt
O
O
O
N
CO2Et
Me
Me
OH
N
Me
CONEt2
+
N
N
N
Me
N
Me
2
O
O
O
7
8
42
N
10
NEt2
N
Me
41%, 98% (w/w)
7%, 99% (w/w)
O
Scheme 2.
H
N
O
46
An operationally simple isolation of ester 2 was also developed:
the reaction mixture was partitioned between t-butyl methyl ether
(MTBE) and water to remove water-soluble by-products (including
pyrazolone 9 and acid 10). The organic solvent is then swapped
from MTBE to n-heptane by distillation and product 2 crystallises
from the solution on cooling, and is isolated in 41% yield, 98%
(w/w).10 Furthermore, simply acidifying the aqueous extract to
pH 4 causes crystallisation of acid 10, which can be isolated in
7% yield, 99% (w/w), if so desired.11
Though relatively low yields of 2 are obtained, this is an opera-
tionally simple three-step telescope, coupled with straightforward
isolation of the product. The pyrazole produced is of high quality
and, importantly, is regioisomerically pure.
N
H
N
N
Me
Me
CN
NH2
42a
N
9
N
N
Me
Me
a
Hydrazone formation was carried out in AcOH. The mixture was diluted with
IMS and basified with conc. NaOH to carry out the cyclisation step.
Having established the methodology for the production of 2, we
were keen to explore its applicability to the regioselective synthe-
sis of other 1,3,4-trisubstituted-1H-pyrazoles. To this end, several
b-keto esters were exposed to the reaction sequence outlined in
Scheme 1. The results are summarised in Table 1.
As can be seen, in terms of the ketone, primary alkyl (entries
1–3) and secondary alkyl (entry 4) substituents work well in this
methodology. More complex ester substituents (entries 5 and 6)
are also tolerated, though these are accompanied by significant
hydrolysis of the side chain ester. As well as b-ketoesters, both
secondary (entry 8) and tertiary (entry 7) b-ketoamides work well
in this methodology, with aryl- and alkyl-amide functionalities
being tolerated. Finally, b-ketonitrile equivalents, such as 3-amin-
ocrotonitrile, also take part in this chemistry (entry 9), though
these required slightly different reaction conditions to give opti-
mum yield. We also have some evidence that alcoholysis or hydro-
lysis of the nitrile moiety occurs under these reaction conditions.
Unfortunately, other esters are not tolerated in this chemistry.
For instance, when benzyl acetoacetate was employed, complete
transesterification to the ethyl ester of the pyrazole product was

698
S. A. Raw, A. T. Turner / Tetrahedron Letters 50 (2009) 696–699
observed. Also, arylketones are conspicuous by their absence from
the results shown in Table 1, the resonance deactivation of the
carbonyl attenuating their reaction with the relatively unreactive
1-formyl-1-methyl hydrazine under a variety of conditions.
In an effort to address the non-participation of arylketones in
this methodology, we also examined the reaction of substituted
ethyl ynoates 11 with 1-formyl-1-methylhydrazine 7 (Scheme 3).
Disappointingly, though the desired pyrazoles were indeed ob-
tained, the yields were much lower than those seen with b-keto-
esters. It is, however, encouraging that some of the desired
pyrazoles were observed and optimisation of reaction conditions
to allow efficient participation of conjugated alkynes in this type
of chemistry is ongoing within our laboratories, to be reported in
due course.
Acknowledgements
The authors would like to acknowledge Dr. Leigh Ferris (PR & D,
AstraZeneca) and Dr. Barry Hayter (Medicinal Chemistry, AstraZen-
eca) for investigation of Vilsmeier-based approaches to 1.
References and notes
1. (a) For example, Devasagayaraj, A.; Jin, H.; Lui, Q.; Marinelli, B.; Samala, L.; Shi.
Z.-C.; Tunoori, A.; Wang, Y.; Wu, W.; Zhang, C.; Haiming, Z. Int. Patent WO
2007/089335; Chem. Abstr. 2007, 147, 258033.; (b) Boulet, S. L.; Clark, B. P.;
Fairhurst, J.; Gallagher, P. T.; Johansson, A. M.; Whatton, M. A.; Wood, V. A. Int.
Patent WO 2005/092885; Chem. Abstr. 2005, 143, 367217.; (c) Damour, D.;
Hardy, J.-C.; Mignani, S. Int. Patent WO 97/25327; Chem. Abstr. 1997, 127,
176438.; (d) Aloup, J.-C.; Audiau, F.; Barreau, M.; Damour, D.; Genevois-Borella,
A.; Jimonet, P.; Mignani, S.; Ribeill, Y. Int. Patent WO 95/26350; Chem. Abstr.
1995, 124, 146198.
2. (a) For example, Mansfield, D.; Reick, H.; Coqueron, P.-Y.; Desbordes, P.; Villier,
A.; Grosjean-Cournoyer, M.-C.; Genix, P. Int. Patent WO 2006/108791; Chem.
Abstr. 2006, 145, 438609.; (b) Hu, Y.; Xu, B.; Liao, Y.; Nawoschik, K.; Liu, Y.;
Sandrasagra, A.; Fathi, R.; Yang, Z. Int. Patent WO 2006/183751; Chem. Abstr.
2006, 145, 249201.; (c) Ewing, W. R.; Li, J.; Sulsky, R. B.; Hernandez, A. S. U.S.
Patent 2006/079562; Chem. Abstr. 2006, 144, 390925.; (d) Erion, M. D.; Van
Poelje, P. D. U.S. Patent US 6756,360, 2004; Chem. Abstr. 2004, 141, 71536.; (e)
Momose, Y.; Sakai, N.; Maekawa, T.; Hazami, M.; Kawamura, T.; Sera, M. Int.
Patent WO 2004/039365; Chem. Abstr. 2004, 140, 406802.; (f) McKee, T. D.;
Suto, R. K.; Tibbitts, T.; Sowadski, J. Int. Patent WO 2003/074497; Chem. Abstr.
2003, 139, 286330.; (g) Bohme, A.; Boireau, A.; Canton, T.; Pratt, J., Stultzman,
J.-M. Int. Patent WO 2000/054772; Chem. Abstr. 2000, 133, 247292.
3. (a) Park, M.-S.; Park, H.-J.; Park, K. H.; Lee, K.-I. Synth. Commun. 2004, 34, 1541–
1550; (b) Ishii, T.; Tomitani, K.; Shimotori, H.; Tanaka, Y.; Ishikawa, K. Japanese
Patent 01-168674, 1989; Chem. Abstr. 1989, 112, 35853.; (c) Ishii, T.; Tomitani,
K.; Shimotori, H.; Tanaka, Y.; Ishikawa, K. Japanese Patent 01-168673, 1989;
Chem. Abstr. 1989, 112, 35852.; (d) Ishii, T.; Tomitani, K.; Shimotori, H.; Tanaka,
Y.; Ishikawa, K. Japanese Patent 01-168672, 1989; Chem. Abstr. 1989, 112,
35851.; (e) Wijnberger, C.; Habraken, C. L. J. Heterocycl. Chem. 1969, 6, 545.
4. (a) Hishiwaki, N.; Matsushima, K.; Chatani, M.; Tamura, M.; Ariga, M. Synlett
2004, 703–707; (b) Yamamoto, S.; Morimoto, K.; Sato, T. J. Heterocycl. Chem.
1991, 28, 1545–1547; (c) Menozzi, G.; Mosti, L.; Schenone, P. J. Heterocycl.
Chem. 1987, 24, 1669–1675; (d) Huppatz, J. L. Aust. J. Chem. 1983, 36,
135–147; (e) Bajnati, A.; Hubert-Habart, M. Bull. Soc. Chim. Fr. 1988, 3, 540–
547.
H
H2N
N
Me
O
R
CO2Et
CO2Et
H
7
EtOH
Reflux
EtONa
Reflux
R
N
+
N
Me
N
O
N
R
CO2Et
Me
11a R=Me
11b R=Ph
2 R=Me, 18%
R=Ph, 8%
Scheme 3.
Finally, we have also demonstrated that ester 2 can indeed be
converted easily to the target aldehyde 1 (Scheme 4). As shown,
simple functional group interconversion gave access first to the
alcohol 3, then to aldehyde 1 in good yields. For our purposes,
these steps were telescoped into a single stage, which gave 1 in
78% overall yield.13
5. Press, J. B.; Eudy, N. H.; Morton, G. O. J. Org. Chem. 1983, 48, 4605–4611.
6. We found some precedence for this type of cyclisation in the production of
pyrazolo[1,5-a]indole and quinoline systems, in which the N-carbonyl and
N-alkyl substituents of the hydrazone are contained in a cyclic motif, see:
Winters, G.; Odasso, G.; Conti, M.; Tarzia, G.; Galliani, G. Eur. J. Med. Chem. 1984,
19, 215–218; A similar mechanism has also been implicated in the production
of a minor pyrazolo[5,1,a]indole by-product, see: Toja, E.; Omodei-Sale, A.;
Nathansohn, G. Tetrahedron Lett. 1979, 31, 2921–2924.
O
Me
Me
O
OH
N
N
2 M LiAlH4 in THF
THF, RT
N
Me
3
N
7. Pedersen, C. T. Acta Chem. Scand. 1964, 18, 2199–2200.
8. Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem. 1966, 6, 347–429.
9. For example, see: Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675. It should
be noted that, even in this methodology, the use of methylhydrazine gives poor
regioselectivity at best.
Me
2
88%, 87% (w/w)
10. Typical laboratory-scale procedure for 2: To a cooled solution (0–5 °C) of
methylhydrazine (660 mmol, 35.0 mL) in IMS (215 mL) was added ethyl
formate (688 mmol, 55.5 mL) dropwise so that the temperature remained
below 10 °C. Once the addition was complete, the solution was heated to reflux
for 4 h. To the colourless solution was then added ethyl acetoacetate
(550 mmol, 70.0 mL) and reflux continued for a further 4 h. The resulting
MnO2,THF,
reflux
H
Me
O
yellow solution was cooled to ꢀ55 °C and
a solution of 21 wt % sodium
Telescope (ref. 13)
78%, 99% (w/w)
ethoxide in IMS (550 mmol, 205.4 mL) was added dropwise so that a gentle
reflux was maintained. Once addition was complete, reflux was maintained for
45 min. The suspension was then cooled to rt and diluted with 3 M ammonium
chloride (360 mL) and brine (360 mL). The resulting solution was extracted
with MTBE (2 Â 360 and 1 Â 180 mL). The combined organics were washed
with saturated brine (180 mL) diluted with water (180 mL). The MTBE solution
was concentrated by distillation to ꢀ400 mL, then n-heptane (1200 mL) was
added. Distillation was continued until the head temperature was constant at
97–99 °C and the volume in the vessel was 380 mL. The solution was allowed
to cool to ambient temperature, then in an ice/water bath to 3–5 °C. The
precipitated solid was collected by filtration, washed with cold n-heptane
(2 Â 80 mL) and dried in vacuo at ambient temperature to give the desired
pyrazole ester 2 (38.32 g, 98 wt %, 223 mmol, 41% yield), as an off-white
crystalline solid. The spectroscopic data for this material match those reported,
see Ref. 4c.
N
N
Me
1
93%, 98% (w/w)
Scheme 4.
In summary, we have developed a robust 3-step, 1-stage pro-
cess for the synthesis of 1,3,4-trisubstituted-1H-pyrazoles which
exploits a novel C4–C5 disconnection strategy and readily available
raw materials. The chemistry is operationally simple and obviates
the need to employ Vilsmeier-type chemistry. To demonstrate its
synthetic utility, this methodology has been successfully applied
to produce a range of pyrazoles (Table 1).
11. Acid 10 has been shown to undergo the reduction–oxidation chemistry applied
to ester 2 equally well.
12. All compounds gave satisfactory spectroscopic data.
13. Typical laboratory-scale procedure for 1: To a solution of pyrazole ester 2
(204 mmol, 35.0 g) in THF (209 mL) at 0–3 °C was added a solution of 2.0 M
LiAlH4 in THF (204 mmol, 102 mL) dropwise so that the temperature remained
below 10 °C. Once the addition was complete, the mixture was stirred at 0–3 °C

S. A. Raw, A. T. Turner / Tetrahedron Letters 50 (2009) 696–699
699
for 1 h, then warmed to ambient temperature. After a total of 3 h, the mixture
was cooled in water bath, and water (7.0 mL) was added dropwise
thickness of Whatman GF/B paper in a split Buchner funnel). The cake was
washed with THF (3 Â 80 mL). The combined THF solution was concentrated
by distillation to ꢀ100 mL, then n-heptane (200 mL) was added. Distillation
was continued until the head temperature was constant at 97–99 °C and the
volume in the vessel was 160 mL. The solution was allowed to cool to 45 °C,
which caused precipitation of the product as an oil which then crystallised. The
mixture was then cooled in an ice/water bath to 3–5 °C. The solid was collected
by filtration, washed with cold n-heptane (2 Â 30 mL) and dried in vacuo at
ambient temperature to give the desired pyrazole aldehyde 1 (19.82 g, 99 wt %,
158 mmol, 78% yield), as a white crystalline solid. The spectroscopic data for
this material match those reported, see Ref. 3e.
a
[CAUTION—vigorous effervescence!] over 10 min. This was followed by
dropwise addition of 1 M sodium hydroxide (7.0 mL) over 10 min, then more
water (7.0 mL) over 1 min. Vigorous stirring was employed to maintain
mobility. Harborlite-800 filter aid (30 g) was added to the mixture and the
solid residues were removed by filtration. The cake was washed with THF
(3 Â 70 mL). To the combined organic solution (containing 3) was added
manganese dioxide [85%, activated <5 lm, Aldrich cat. 217646] (1020 mmol,
102.3 g) and the mixture heated to reflux. After 6 h, the mixture was cooled to
room temperature and the solid residues were removed by filtration (double-