A four-step tandem synthesis of 3,5-diaroyl-4-arylpyrazoles from 1,3-diaryl-propane-1,3-diketones

Article abstract of DOI:10.1016/j.tetlet.2017.09.050

A novel four-step tandem procedure was developed for efficient synthesis of 3,5-diaroyl-4-arylpyrazoles by simply stirring the mixture of 1,3-diarylpropane-1,3-diketones, TsN₃, aqueous MeNH₂ and Na₂CO₃ in DMF at 85 °C for 3 h.

Full text of DOI:10.1016/j.tetlet.2017.09.050

Accepted Manuscript
A Four-Step Tandem Synthesis of 3,5-Diaroyl-4-arylpyrazoles from 1,3-Diaryl-
propane-1,3-diketones
Jianlan Zhang, Wenwen Chen, Dayun Huang, Xiaobao Zeng, Xinyan Wang,
Yuefei Hu
PII:
S0040-4039(17)31177-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.050
TETL 49320
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 August 2017
15 September 2017
18 September 2017
Please cite this article as: Zhang, J., Chen, W., Huang, D., Zeng, X., Wang, X., Hu, Y., AFour-StepTandemSynthesis
of 3,5-Diaroyl-4-arylpyrazoles from 1,3-Diaryl-propane-1,3-diketones, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.09.050
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A Four-Step Tandem Synthesis of 3,5-Diaroyl-4-
arylpyrazoles
diketones
Leave this area blank for abstract info.
from
1,3-Diaryl-propane-1,3-
Jianlan Zhang,a Wenwen Chen,a Dayun Huang,a Xiaobao Zeng,a Xinyan Wang,a* Yuefei Hua*
Ar
O
O
TsN , aq. MeNH , DMF
2
3
O
O
o
Na CO (0.2 eq), 85 C, 3 h
2
3
Ar
Ar
Ar
Ar
Eighteen products in
43-95% yields
N
NH

1
Tetrahedron Letters
journal homepage: www.els evier.com
A Four-Step Tandem Synthesis of 3,5-Diaroyl-4-arylpyrazoles from 1,3-Diaryl-
propane-1,3-diketones
Jianlan Zhang,a Wenwen Chen,a Dayun Huang,a Xiaobao Zeng,a Xinyan Wang,a* Yuefei Hua*
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing
100084, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel four-step tandem procedure was developed for efficient synthesis of 3,5-diaroyl-4-
arylpyrazoles by simply stirring the mixture of 1,3-diarylpropane-1,3-diketones, TsN3, aqueous
MeNH2 and Na2CO3 in DMF at 85 oC for 3 h.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
tandem synthesis
pyrazole
1,3-diketone
diazo compound
1,3-dipolar cycloaddition
Pyrazoles are an important heterocyclic family due to their
wide spectrum of biological properties.[1] As shown in Figure 1,
both structures of celecoxib (A)[2a] and crizotinib (B)[2b] contain a
pyrazole unit. The former is used as a COX-2 selective
nonsteroidal anti-inflammatory drug and the latter is an anti-
cancer drug for treatment of some non-small cell lung carcinoma.
Recently, 3,4,5-trisubstituted pyrazoles C[3a] were reported as
potent inhibitors of carbonic anhydrase isoforms and D[3b]
demonstrated the antiproliferative activities.
is the condensation between hydrazines and 1,3-dicarbonyls; the
other is 1,3-dipolar cycloaddition between diazo compounds and
alkynes.
R2
R2
4
R1
R3
R3
R3
R2
R1
1,3-dipolar
cycloaddition
3
O
5
O
condensation
+
+
N
N
R
H2NHN
R
R1CH N2
NH2
N
Scheme 1. Two practical methods for the synthesis of pyrazoles.
Cl
CF3
O
Me
The 1,3-dipolar cycloaddition usually has higher regioselec-
tivity and is more suitable for the synthesis of 3,4,5-trisubstituted
pyrazoles because two substituents (R2 and R3) conveniently
come from the alkynes. However, this method seriously suffered
from the limited scope of alkynes. As shown in Scheme 2,
although alkenes are excellent dipolarophiles for most 1,3-dipolar
cycloadditions, only a few of them bearing a good leaving group
(such as NO2 or Br) can be used as alternatives of alkynes for
such purpose.[5] When the normal alkenes were used, at least one
more step for aromatization was required.[6]
N
N
N
Me
Cl
F
N
A
SO2NH2
B
N
H
O
O
O
O
NH
NH
S
HO
Ph
Ph
N
N
N
N
Ph
N
N
SO2NH2
SO2NH2
R2
R2
L
R
R3
R3
R1CH N2
C
R
D
Figure 1. Some bioactive pyrazole derivatives.
R2
R2
R1
R3
R3
R1
Pyrazole scaffold is a five-membered heterocycle containing
two nitrogen atoms. A number of methods have been developed
for the synthesis of pyrazole derivatives and two practical
methods were mainly employed.[1d,4] As shown in Scheme 1, one
aromatization
N NH
N NH
Scheme 2. 1,3-Dipolar cycloaddition with different alkenes.

2
Tetrahedron
However, several interesting 1,3-dipolar cycloadditions[6,7]
(entry 2), but it still was not acceptable. Considering MeNH2 is
not a good base for enolization of 1a, the second base was used.
Compared to the amines (entries 3-6) and alkali hydroxides
(entry 7), the alkali carbonates (entries 8-10) gave the best results.
The highest yield of 4a was obtained in the presence of 0.2 equiv
of Na2CO3 (entry 10).
between aldehydes/ketones and diazo compounds drew our
attention, in which the carbonyl group was in situ converted into
enol or enamine in the presence of a base, such as a secondary
amine or a carbonate. It was interesting to observe that 1,3-
diphenylpropane-1,3-dione (1a) were converted into 3,5-
dibenzoyl-4-phenylpyrazole (4a) in two separated steps, but with
low efficiency (Scheme 3).[6] Herein, we would like to report that
the same conversion can be completed in one step with high
efficiency. Further experiments proved that this is a general four-
step tandem procedure, by which a series of 3,5-diaroyl-4-aryl-
pyrazoles 4 were synthesized efficiently by simply stirring the
mixture of 1,3-diarylpropane-1,3-diones 1, TsN3, aqueous
MeNH2 and Na2CO3 in DMF at 85 oC for 3 h.
Table 1. Conditional tests for the tandem synthesis of 4a.a
Ph
O
O
TsN3, 40% aq. MeNH2
O
O
DMF, base, temperature, 3 h
Ph
Ph
Ph
Ph
12-93%
N
NH
1a, 2.4 equiv
4a
entry
base
(equiv)
temp
(oC)
time
(h)
4a
yield (%)b
N2
TsN3
Ph
Ph
1
2
3
----
----
rt
3
3
3
3
3
3
3
3
3
3
8
3
3
3
12
42
50
68
71
80
83
85
91
93
93
90
88
93
by Regiz diazo-transfer
Ph
Ph
85
85
85
85
85
85
85
85
85
75
95
85
85
O
O
previous report
O
O
Et3N (0.2)
1a
2a
4
5
DABCO (0.2)
pyrolidine (0.2)
DBU (0.2)
TsN3, aq. MeNH2, Na2CO3
DMF, 85 oC, 3 h, 93%
this work
6
K2CO3
7
KOH (0.2)
Ar
O
O
1a, K2CO3, MeOH
rt, 2 d, 26%
8
Cs2CO3 (0.2)
K2CO3 (0.2)
Na2CO3 (0.2)
Na2CO3 (0.2)
Na2CO3 (0.2)
Na2CO3 (0.1)
Na2CO3 (0.3)
Ph
9
N2
Ph
Ph
N NH
O
10
11
12
13
14
3a
4a
Scheme 3. Synthesis of 3,5-dibenzoyl-4-phenylpyrazole (4a).
In fact, the previous reported two-step procedure[6] for the
conversion of 1a into 4a involved three well-studied reactions: (a)
Regitz diazo-transfer of 1a; (b) C–C bond cleavage of 2a; and (c)
1,3-dipolar cycloaddition between 1a and 3a. Investigation
showed that they are all base-catalyzed reactions and the best
catalyst for each reaction is tertiary amines,[8] alkali
hydroxides[9,10] and alkali carbonates,[7a,11] respectively.
Unfortunately, these three reactions have not become a tandem
reaction because no one base or bases could be shared efficiently
by each of them. For example, the previous conversion of 2a into
4a actually is a two-step tandem reaction including a formation
of 3a by C–C bond cleavage of 2a. It had a low efficiency just
because K2CO3 is not an efficient base for C–C bond cleavage of
2a. Luckily, we recently found that the compound 3a could be
obtained in almost quantitative yield when the mixture of
substrate 1a and TsN3 was treated by aqueous MeNH2 in DMF.[12]
As shown in Scheme 4, since the diazo compound 2a was
confirmed to be an intermediate, this procedure offered a highly
efficient two-step tandem synthesis of 3a from 1a.
a The solution of 1a (1.2 mmol), TsN3 (0.5 mmol), aq. MeNH2
(40%, w/w, 0.6 mmol) and a base in DMF (2 mL) was stirred
under the given temperatures and times. b Isolated yields.
To generalize this tandem reaction, different substrates were
tested. As shown in Scheme 5, all tested substrates 1a-1r gave
the desired products 4a-4r smoothly under the optimized
conditions.[14] The steric effects were clearly observed in the
group of products 4b-4d, in which the ortho-substituents (4b) led
Ar
O
O
TsN3, 40% aq. MeNH2, DMF
O
O
Na2CO3 (0.2 eq), 85 oC, 3 h
Ar
43-95%
Ar
Ar
Ar
N
NH
1a-1r
(2.4 equiv)
4a-4r
Me
Me
Me
4d, 91%
F
4a, 93%a
Cl
4b, 54%
4c, 83%
Br
4e, 88%
TsN3, 40% aq. MeNH2 (w/w)
Ph
Ph
Ph
Cl
DMF, rt, 25 min
94%
N2
O
O
O
Cl
4g, 87%
Br
1a
3a
4j, 72%
Cl
4i, 79%
4f, 81%
4h, 89%
N2
Regiz
diazo-transfer
C C bond
cleavage
OMe
Ph
Me
Me
Ph
2a
O
But
O
OMe
OMe
4k, 87%
4l, 43%
4m, 95%
4n, 82%
Scheme 4. Two-step tandem synthesis of 3a from 1a.
O
O
OMe
OMe
S
This result also strongly implied that the pyrazole 4a may be
synthesized by this procedure when excess 1a is employed. Thus,
we were encouraged to test the tandem synthesis of 4a from 1a as
shown in Table 1. To our disappointment, the desired 4a was
obtained in 12% yield when the mixture of 1a (2.4 equiv), TsN3
and aq. MeNH2 (40%, w/w) was stirred at room temperature for 3
4p, 89%
4q, 80%
4r, 81%
4o,
78%
OMe
aThe isolated yields were obtained for all products.
Scheme 5. Tandem synthesis of the desired products 4a-4r.
o
h (entry 1). The yield of 4a was significantly improved at 85 C

3
to lower yields and longer reaction times. Their electronic effects
were completely same as the synthesis of α-diazoketones 3.[12]
The product 4r was synthesized smoothly from the
corresponding heteroaryl substrates 1r. In a 3-gram scale
synthesis, 4a was obtained in 95% yield after purification by a
flash chromatography. However, the strong electron-withdrawing
group substituted 1,3-diaryl-1,3-diketones and 1,3-dialkyl-1,3-
diketones proved to be unsuitable substrates for this tandem
synthesis, because the former usually are inaccessible
substrates[13] and the later can not be converted into the
corresponding α-diazoketones.[12] As shown in Figure 2, the
structure of the product 4e was confirmed by single crystal X-ray
diffraction analysis.[15]
References and notes
1. For selected reviews: (a) Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman
New J. Chem. 2017, 41, 16–41. (b) Khan, M. F.; Alam, M. M.; Verma,
G.; Akhtar, W.; Akhter, M.; Shaquiquzzaman, M. Eur. J. Med. Chem.
2016, 120, 170–201. (c) Pérez-Fernández, R.; Goya, P.; Elguero, J.
Arkivoc 2014, ii, 233–293. (d) Schmidt, A.; Dreger, A. Curr. Org. Chem.
2011, 15, 1423–1463.
2. (a) McCormack, P. L. Drugs 2011, 71, 2457–2489. (b) Forde, P. M.;
Rudin, C. M. Expert Opin. Pharmacother. 2012, 13, 1195–1201.
3. (a) Balseven, H.; İşgör, M. M.; Mert, S.; Alım, Z.; Beydemir, S.; Ok, S.;
Kasımoğulları, R. Bioorg. Med. Chem. 2013, 21, 21–27. (b) Mert, S.;
Yağlıoğlu, A. Ş.; Demirtas, I.; Kasımoğulları, R. Med. Chem. Res. 2014,
23, 1278–1289.
4. For a review, see: Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-
Fuentes, A. Chem. Rev. 2011, 111, 6984–7034.
5. For selected references, see: (a) Kumar, R.; Namboothiri, I. N. N. Org.
Lett. 2011, 13, 4016–4019. (b) Xie, J.-W.; Wang, Z.; Yang, W.-J.; Kong,
L.-C.; Xu, D.-C. Org. Biomol. Chem. 2009, 7, 4352–4354.
6. For selected reference, see: Sachse, A.; Penkova, L.; Noël, G.; Dechert,
S.; Varzatskii, O. A.; Fritsky, I. O.; Meyer, F. Synthesis 2008, 800–806.
7. (a) Shu, W.-M.; Zheng, K.-L.; Ma, J.-R.; Sun, H.-Y.; Wang, M.; Wu, A.-
X. Org. Lett. 2015, 17, 1914–1917. (c) Wang, L.; Huang, J.; Gong, X.;
Wang, J. Chem.–Eur. J. 2013, 19, 7555–7560.
8. For selected reviews, see: (a) Regitz, M. Synthesis 1972, 351−373. (b)
−749.
Regitz, M. Angew. Chem. Int. Ed. 1967, 6, 733
Figure 2. The structure of 4e.
9. Al2O3-catalyzed C–C bond cleavage, see: (a) Qian, Y.; Shanahan, C. S.;
Doyle, M. P. Eur. J. Org. Chem. 2013, 6032–6037. (b) Korneev, S.;
Richter, C. Synthesis 1995, 1248−1250.
Based on the above results, a possible pathway was proposed
for this tandem reaction. As shown in Scheme 6, the substrate 1
initially carried out a MeNH2-catalyzed Regitz diazo-transfer to
give product 2. A MeNH2-mediated C–C bond cleavage of 2 then
occurred to form product 3. Meanwhile, the excess substrate 1
was enolized in presence of Na2CO3 to yield reactive specie 5.
Finally, the target product 4 was produced by a dipolar
cycloaddition between 3 and 5. Since 1 was used twice as a
substrate to form the intermediate 3 and the reactive specie 5,
respectively, this procedure actually is a four-step tandem
procedure.
10. Alkali hydroxide-catalyzed C–C bond cleavage, see: (a) Abid, I.;
Gosselin, P.; Mathé-Allainmat, M.; Abid, S.; Dujardin, G.; Gaulon-
Nourry, C. J. Org. Chem. 2015, 80, 9980−9988. (b) Lancou, A.; Haroun,
H.; Kundu, U. K.; Legros, F.; Zimmermann, N.; Mathé-Allainmat, M.;
Lebreton, J.; Dujardin, G.; Gaulon-Nourry, C.; Gosselin, P. Tetrahedron
2012, 68, 9652−9657. (c) Abu-Elfotoh, A.-M.; Nguyen, D. P. T.;
Chanthamath, S.; Phomkeona, K.; Shibatomi, K.; Iwasa, S. Adv. Synth.
Catal. 2012, 354, 3435–3439. (d) Zhdanova, O. V.; Korneev, S. M.;
Nikolaev, V. A. Russ. J. Org. Chem. 2004, 40, 316–328. (e)
Branderhorst, H. M.; Kemmink, J.; Liskamp, R. M. J.; Pieters, R. J.
Tetrahedron Lett. 2002, 43, 9601–9603. (f) Doyle, M. P.; Winchester, W.
R.; Protopopova, M. N.; Kazala, A. P.; Westrum, L. J. Org. Synth. 1996,
73, 13. (g) Regitz, M.; Hocker, J.; Liedhegener, A. Org. Prep. Proced.
Int. 1969, 1, 99–104.
MeNH -promoted
2
C-C bond cleavage
O
O
O
N
2
Ar
Ar
Ar
11. (a) Shu, W.-M.; Ma, J.-R.; Zheng, K.-L.; Sun, H.-Y.; Wang, M.; Yang,
Y.; Wu, A.-X. Tetrahedron 2014, 70, 9321–9329.
3
2
N
2
Ar
O
O
1,3-dipolar
cycloaddition
MeNH -catalyzed
2
Regitz diazo-transfer
12. Zhang, J.; Chen, W.; Huang, D.; Zeng, X.; Wang, X.; Hu, Y. J. Org.
Chem. 2017, 82, 9171–9174.
TsN
O
3
Ar
Ar
N
NH
13. 13 An only procedure for the synthesis of 1,3-di(4-nitrophenyl)-1,3-
diketone, see: Zawadiak, J.; Mrzyczek, M. Spectrochim. Acta. A 2012,
96, 815–819.
Na CO -induced
3
4
2
O
ONa O
enolization
Ar
Ar
Ar
Ar
14. A typical procedure for preparation of 3,5-dibenzoyl-4-phenyl-
pyrazole (4a). To a stirred solution of 1,3-diphenylpropane-1,3-dione
(1a, 269 mg, 1.2 mmol) and Na2CO3 (10.6 mg, 0.1 mmol) in DMF (2 mL)
was added tosyl azide (98.6 mg, 0.5 mmol) and MeNH2 (40% aqueous
solution, 46.6 mg, 0.6 mmol) successively. After the mixture was stirred
at 85 oC (oil bath) for 3 h (monitored by TLC), it was quenched with
water. The resultant mixture was extracted with CH2Cl2 and the
combined layers were dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue was purified by a flash
chromatography [silica gel, 15% EtOAc in petroleum ether (60–90 oC)]
to give 164 mg (93%) of product 4a as a white solid, mp 148−150 oC
(lit.[6] 154 oC). 1H NMR (400 MHz) δ 12.3 (s, 1H), 7.78 (bs, 4H),
7.41−7.39 (m, 2H), 7.26−7.23 (m, 4H), 7.15−7.12 (m, 2H), 7.07−7.02 (m,
3H); 13C NMR (100 MHz) δ 133.0, 130.6, 130.4, 130.0, 128.0, 127.7,
127.6, 127.4.
1
5
Scheme 6. A proposed pathway for the tandem synthesis of 4.
In conclusion, a novel method was developed for the synthesis
of 3,5-diaroyl-4-arylpyrazoles by simply stirring the mixture of
1,3-diarylpropane-1,3-diones, TsN3, aqueous MeNH2 and
Na2CO3 in DMF at 85 oC for 3 h. It was a novel four-step tandem
reaction, in which the 1,3-diarylpropane-1,3-diketone was used
twice as a substrate. Although both aqueous MeNH2 and Na2CO3
were used as bases, each of them has its specific duties and
responsibilities without interferences.
The products 4b−4r were prepared by the similar procedure.
Acknowledgments
15. CCDC 1565073 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
We gratefully acknowledge financial support from NNSFC
(Nos. 21372142 and 21472107).

4
Tetrahedron
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5
Highlights
1.
A tandem method for synthesis of 3,4,5-
trisubstituted pyrazoles was developed.
2. It was performed by simply stirring the
mixture of all reactants together.
3. Two bases were used, but each of them has
its specific duties and responsibilities.
4. A novel four-step tandem pathway was
proposed.