N-Alkylhydrazones of aliphatic ketones in the synthesis of 1,3,4-trisubstituted non-symmetric pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2014.02.058

Reactions of N-alkylhydrazones of aliphatic ketones with the Vilsmeier-Haack reagent (DMF-POCl₃) were evaluated as a promising approach toward the synthesis of trisubstituted non-symmetric pyrazoles. It was found that either 1,3,4-trialkylpyrazoles or 1,3-dialkylpyrazole-4-carbaldehydes could be obtained in these transformations in high yields (72-83%), in a regioselective manner.

Full text of DOI:10.1016/j.tetlet.2014.02.058

Accepted Manuscript
N-Alkylhydrazones of aliphatic ketones in the synthesis of 1,3,4-trisubstituted
non-symmetric pyrazoles
Sergey P. Ivonin, Bohdan B. Kurpil, Eduard B. Rusanov, Oleksandr O.
Grygorenko, Dmitry M. Volochnyuk
PII:
S0040-4039(14)00300-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.02.058
TETL 44245
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
27 November 2013
23 January 2014
12 February 2014
Please cite this article as: Ivonin, S.P., Kurpil, B.B., Rusanov, E.B., Grygorenko, O.O., Volochnyuk, D.M., N-
Alkylhydrazones of aliphatic ketones in the synthesis of 1,3,4-trisubstituted non-symmetric pyrazoles, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.02.058
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N-Alkylhydrazones of aliphatic ketones in
the synthesis of 1,3,4-trisubstituted non-
symmetric pyrazoles
Sergey P. Ivonin, Bohdan B. Kurpil’, Eduard B. Rusanov, Oleksandr O. Grygorenko,* Dmitry M. Volochnyuk
R'
R''
NHR
DMF
N
X
X
N
N
or
?
POCl3
N
N
R'
R''
R
R
R, R', R'' = Alkyl
X = [R'/R'' - CH2] or CHO

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
N-Alkylhydrazones of aliphatic ketones in the synthesis of 1,3,4-trisubstituted non-
symmetric pyrazoles
Sergey P. Ivonin,a Bohdan B. Kurpil’,a Eduard B. Rusanov,a Oleksandr O. Grygorenko,b, ∗ Dmitry M.
Volochnyuka
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
bNational Taras Shevchenko University of Kyiv, Volodymyrska Street, 64, Kyiv 01601, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Reactions of N-alkylhydrazones of aliphatic ketones with the Vilsmeier–Haack reagent (DMF–
POCl3) were evaluated as a promising approach toward the synthesis of trisubstituted non-
symmetric pyrazoles. It was found that either 1,3,4-trialkylpyrazoles or 1,3-dialkylpyrazole-4-
carbaldehydes could be obtained in these transformations in high yields (72–83%), in a
regioselective manner.
Received in revised form
Accepted
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoles
Aliphatic hydrazones
Regioselectivity
CCNN +C heterocyclization
Vilsmeier–Haack reaction
Pyrazoles are an important class of heterocycles widely used
in various areas of chemistry and related sciences. They represent
an attractive chemotype for medicinal chemistry; more than 90
marketed drugs registered on the DrugBank database contain a
pyrazole moiety.1 The most recognized approach to the
construction of a pyrazole ring relies on its [3+2] disconnection,
leading to a CCC bis-electrophile and an NN binucleophile as the
starting building blocks (Scheme 1).2 This method, however,
suffers from regioselectivity problems when applied to the
synthesis of non-symmetric polysubstituted pyrazoles. One of the
alternative approaches relies on the [4+1] disconnection of the
pyrazole moiety, which corresponds to the reaction of a CCNN
binucleophile with a C-electrophilic reagent. This method was
used for the preparation of 1,3,4-trisubstituted pyrazoles with an
N-aryl substituent; it relied on the cyclization of N-aryl
hydrazones under Vilsmeier–Haack conditions (DMF–POCl3)
pronounced nucleophilic centers susceptible to electrophilic
attack. It is known, for example, that N,N-dimethylhydrazones
are acylated at the N1 atom of the hydrazone moiety in the
presence of weak bases (e.g. amines).7 The direction of the
reaction can be changed to C-acylation if the hydrazone is first
deprotonated with a strong base such as LDA.8
R2
R3
R2
R3
R2
R3
[4+1]
[3+2]
C C
C
C
C
N
N
C
N
N
N
R1
N
R1
R1
Scheme 1. Selected retrosynthetic approaches to pyrazoles
R
R'
O
Ar
Ar
(Scheme 2).3–5 This approach was extented to N-acyl hydrazones
4
NH
NH
DMF
DMF
POCl3
N
N
N
N
and semicarbazides, which allowed for the preparation of N-acyl
and N-unsubstituted pyrazoles.4,5 Recent trends in drug
discovery, however, show an attempt to move away from
molecules rich in aromatic rings toward sp3-enriched, low-
molecular weight, hydrophilic compounds.6 In this respect,
extension of the [4+1] approach toward the pyrazoles mentioned
above to N-alkylhydrazones of aliphatic ketones is of interest.
N
N
POCl3
R'
R
Ar
Ar
Scheme 2. Cyclization of N-aryl hydrazones of aliphatic ketones
under Vilsmeier–Haack conditions
In this work, we have studied the formylation of N-
alkylhydrazones of aliphatic ketones under Vilsmeier–Haack
conditions, as a potential regioselective approach to trisubstituted
non-symmetric pyrazoles. It should be noted that only a few
Unlike their N-aryl and N-acyl-substituted counterparts, which
normally act as C-nucleophiles in reactions with electrophilic
agents, N-alkylhydrazones of aliphatic ketones possess three
———
∗ Corresponding author. Tel.: +38-044-239-3315; fax: +38-044-573-2643; e-mail: gregor@univ.kiev.ua

2
Tetrahedron Letters
isolated examples of analogous transformations have been
R
N
R
N
aq. OH-
(work-up)
NHR
N+
described in the literature, including reactions with N-
alkylhydrazones of α,β-unsaturated ketones,9 α,α-dichloro- and
α,α-difluoroketones,10 and acetone.11 Several examples of the
formylation of N-alkylhydrazones of aliphatic ketones with N,N-
dimethylformamide dimethyl acetal leading to the formation of
trisubstituted pyrazoles have also been described.12
DMF
N
N
CHO
N
POCl3
1a-c
DMF
4a-c
9a-c
2a-c
R
POCl
N
N
NHR
HN+
R
CHO
It was found that the reaction of acetone N-alkylhydrazones
1a–c with the Vilsmeier–Haack reagent, followed by aqueous
alkaline work-up resulted in the formation of mixtures of
pyrazoles 2a–c and 3a–c (Scheme 3).13 The nature of the R group
in the starting hydrazone 1 did not have any great impact on the
reaction outcome. The ratio of the products depended mainly on
the reaction temperature: whereas at 20 °C, 3a was the main
product obtained from 1a (yields: 21% of 2a, 41% of 3a), at –20
°C, it was 2a which had formed predominantly (73% of 2a, 10%
of 3a). The formation of small quantities of 3 at –20 °C was
observed in all the cases studied, however, this was not a
problem since the products could be easily separated by
distillation. The structure of 3a was confirmed by X-ray
diffraction studies (Figure 1).14
+
-Me2NH2
N
N
N
R
N
5a-c
DMF
N
8a-c
DMF
POCl
3a-c
POCl
R
R
NHR
HN+
N
N
aq. OH-
(work-up)
N
N
+
-Me2NH2
N
N+
N+
O
6a-
7a-c
2a-c
Scheme 4. Plausible mechanisms for the formation of products 2a–c
and 3a–c
R
R
N
O
NH
O
DMF
N
N-alkylhydrazones of 2-butanone (e.g. 1d) have an additional
regioselectivity problem related to the possibility of electrophilic
attack at either the α-CH3 or the α-CH2 moiety. It was found that
under the conditions described above, the pyrazole 8d arising
from the initial attack of the formylating reagent at the α-CH2
group of the hydrazone was the major product formed from 1d
(74%); only a minor amount of the alternative product 2d was
isolated (15%) (Scheme 5, Table 1).15 This can be explained by
the higher thermodynamic stability of ene-hydrazine tautomer 10
(which leads to the formation of 8) as compared to 11 (which
gives 2). In contrast, reaction with hydrazone 1e led to the
formation of aldehyde 2e (76%), which can be explained by the
increased steric effect provided by the isopropyl group. These
results are in accordance with the literature data on the
N
N
N
R
+
POCl3
N
N
R
1a, R = Me
1b, R = iPr
1c, R = tBu
2a, 72%
2b, 78%
2c, 83%
3a, 12%
3b, 8%
3c, 7%
Scheme 3. Reaction of acetone N-alkylhydrazones 1a–c with the
Vilsmeier–Haack reagent
corresponding
N-arylhydrazones.4
As
expected,
N-
alkylhydrazone 1g, without an α-CH2 moiety, gave only the
product 2g (73%) (Scheme 6), whereas the example without an
α-CH3 group (1f) gave only 8f (81%).
(only for
R' = Me)
NHR
NHR
NHR
HN
HN
N
R''
R''
R''
R'
R'
10
11
1d-f
DMF
POCl3
DMF
POCl3
Figure 1. X-ray crystal structure of 3a (ball-and-stick representation)
A plausible mechanism for the formation of the products 2a–c
and 3a–c is given in Scheme 4. Reaction of 1a–c with the
Vilsmeier–Haack reagent can result in either N- or C-attack to
give intermediates 4a–c or 5a–c, respectively. The intermediates
5a–c are able to further react with the electrophile to provide
vinamidinium salts 6a–c, which can undergo cyclization to give
pyrazole derivatives 7a–c. Formation of pyrazoles 8a–c by
intramolecular cyclization of 5a–c, followed by subsequent
reaction of 8a–c with the Vilsmeier–Haack reagent is unlikely,
since formylation of pyrazoles usually occurs at elevated reaction
temperatures. Hydrolysis of compounds 4a–c and 7a–c results in
the formation of 2a–c and 9a–c, respectively. Compounds 9a–c
can undergo hydrazone exchange to give pyrazoles 3a–c. It
should be noted that compound 9a was prepared by an alternative
synthesis, and it was not reactive towards formylation under the
conditions described above, however, it did react with aldehyde
2a to give 3a.
RHN NH+
NHR
R''
R'
R''
HN+
R'
O
R''
R''
N
N
N+
N
N
N
N
R
R
2d-f
8d-f
Scheme 5. Reactions of hydrazones 1d–f with DMF–POCl3
Table 1. Reactions of hydrazones 1d–f under Vilsmeier–Haack
formylation conditions according to Scheme 5
Entry Hydrazone
R
R′
R′′
Products (yield, %)
1
2
3
1d
1e
1f
Me
Me
Me
Me
Me
Me
iPr
2d (15%),16 8d (74%)
2e (76%)
(CH2)4
8f (81%)

3
NH
O
Perumal, P. T.; Sridhar, R. Synth. Commun. 2003, 33, 1483–1488.
(e) Rathelot, P.; Azas, N.; El-Kashef, H.; Delmas, F.; Giorgio, C.
D.; Timon-David, P.; Maldonado, J.; Vanelle, P. Eur. J. Med.
Chem. 2002, 37, 671–679.
N
DMF
N
POCl3
73%
N
2g
1g
4.
5.
Lebedev, A. V.; Lebedeva, A. B.; Sheludyakov, V. D.; Kovaleva,
E. A.; Ustinova, O. L.; Kozhevnikov, I. B. Russ. J. Gen. Chem.
2005, 75, 412–416.
Scheme 6. Reaction of hydrazone 1g with DMF–POCl3
(a) Bratenko М. К.; Chernyak I. N.; Vovk M. V. Russ. J. Org.
Chem. 1997, 33, 1368–1370. (b) Baraldi, P. G.; Cacciari, B.;
Spalluto, G.; Romagnoli, R.; Braccioli, G.; Zaid, A. N.; Pineda de
las Infantas, M. J. Synthesis 1997, 1140–1142. (c) Chaitanya, M.
V. S. R. K.; Dubey, P. K. Heterocycl. Commun. 2013, 19, 49–55.
Nadin, A.; Hattotuwagama, C.; Churcher, I. Angew. Chem. Int. Ed.
2012, 51, 1114 – 1122.
N-Alkylhydrazones 1h,i derived from Boc-protected 4-
piperidone were also introduced into the reaction with the
Vilsmeier–Haack reagent. As a result, fused Boc-protected
pyrazoles 12h,i were formed, which were used in the
deprotection step without purification or characterization. The
target pyrazolopiperidines 13h,i were synthesized in 79–83%
overall yields (Scheme 7).17 Therefore, this method was
compatible with functionalized substrates containing a Boc-
protected secondary amino function.
6.
7.
(a) Sharma, S. D.; Pandhi, S. B. J. Org. Chem. 1990, 55, 2196–
2200. (b) Lerche, H.; Wanninger, G.; Severin, T. Synthesis 1982,
1111–1112.
8.
9.
Enders, D.; Pathak, V. N.; Weuster, P. Chem. Ber. 1992, 125,
515–524.
Bagley, S. W.; Southers, J. A.; Cabral, S.; Rose, C. R.;
Bernhardson, D. J.; Edmonds, D. J.; Polivkova, J.; Yang, X.;
Kung, D. W.; Griffith, D. A.; Bader, S. J. J. Org. Chem. 2012, 77,
1497–1506.
O
10. Hölscher, I. Eur. Pat. 2008996, 2008; Chem. Abstr. 2009, 150,
98309.
11. One isolated example of analogous transformations involving
N
3
DMF, POCl
O
N
NHR
N
R
work-up
O
N
N
acetone N-methylhydrazone was described in
a
short
, R = Me
1h
, R = iPr
1i
communication by our group, see: Ivonin, S. P. Chem. Heterocycl.
Compd. 2011, 47, 1048–1049.
12h
12i
O
HCl
12. (a) Orwat, M. J.; Pinto, D. J. P.; Smith II, L. M.; Srivastava, S.;
Corte, J. R. WO2013/55984, 2013; Chem. Abstr. 2013, 158,
590118. (b) Kennedy, L. J. Synlett 2008, 600–604. (c) Hanau, C.
E.; Hegde, S. G.; Wu, K. K.; Nacro, K.; Liu, S.; Buchler, I. P.;
Meyers, M. J.; Graneto, M, J.; Mershon, S. M. PCT Int. Pat.
WO 2004/58176, 2004; Chem. Abstr. 2004, 141,123620.
. 2HCl
N
N
R
HN
, 79% in 2 steps
13h
, 83% in 2 steps
13i
13. General procedure for the reaction of N-alkylhydrazones 1a–c
with the Vilsmeier–Haack reagent: POCl3 (0.1 mol) was added
dropwise to DMF (20 mL) at 0 °C. After 1 h, the mixture was
cooled to –20 °C, and a solution of N-alkylhydrazone (0.05 mol)
in DMF (10 mL) was added dropwise at –20 °C. The mixture was
stirred at –20 °C for 3 h and at 80 °C for 2 h, then cooled to
ambient temperature and poured onto ice (100 g). The resulting
mixture was made alkaline with 30% aq NaOH (to pH = 9–10).
The product was extracted with CHCl3 (3×200 mL). The combined
organic extracts were separated and dried over Na2SO4. The
solvent was removed under reduced pressure, and the residue was
distilled in vacuo.
Scheme 7. Synthesis of pyrazolopiperidines
In conclusion, reactions of N-alkylhydrazones of aliphatic
ketones with the Vilsmeier–Haack reagent result in the formation
of 1,3,4-trisubsituted non-symmetric pyrazoles depending on the
substitution pattern in the starting compounds. In particular,
substrates possessing a sterically accessible α-CH2 group form
1,3,4-trialkylpyrazoles. Hydrazones with an α-CH3 group and
sterically hindered or no α-CH2 moiety lead to the formation of
1,3-dialkylpyrazole-4-carbaldehydes. In the case of acetone N-
alkylhydrazones, by-products arising from initial N-attack of the
formylating reagent were observed.
14. Final atomic coordinates, geometrical parameters and
crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2
1EZ,
UK
(e-mail:
deposit@ccdc.cam.ac.uk;
fax:
Supplementary Material
+44 1223 336033) and are available on request quoting the
deposition number CCDC 973531.
15. General procedure for the reaction of N-alkylhydrazones 1d–h
with the Vilsmeier–Haack reagent: POCl3 (0.1 mol) was added
dropwise to DMF (20 mL) at 0 °C. After 1 h, a solution of N-
alkylhydrazone (0.05 mol) in DMF (10 mL) was added dropwise
at –5°C. The mixture was stirred at –5 to 0 °C for 2 h and at 80 °C
for 30 min, and then treated as described above for the reaction of
hydrazones 1a–c.
Supplementary material is available for this article including
compound characterization data.
References and notes
16. Instead of the aldehyde 2d, the corresponding carboxylic acid 14
was characterized, which was formed upon oxidation of 2d with
KMnO4 (see Table S1 of the supplementary material).
1.
2.
Knox, C.; Law, V.; Jewison, T.; Liu, P.; Ly, S.; Frolkis, A.; Pon,
A.; Banco, K.; Mak, C.; Neveu, V.; Djoumbou, Y.; Eisner, R.;
Guo, A. C.; Wishart, D. S. Nucleic Acids Res. 2011, 39, D1035–
1041.
17. General procedure for synthesis of 4,5,6,7-tetrahydro-2H-
pyrazolo[4,3-c]pyridines 13h,i: Boc-protected pyrazolopiperidines
12h,i (0.01 mol) were refluxed with 6 M aq HCl (20 mL) for 0.5 h.
The solvent was removed under reduced pressure, and the residue
was dried in vacuo to give 13h,i.
(a) Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes,
A. Chem. Rev. 2011, 111, 6984–7034. (b) Fustero, S.; Simón-
Fuentes, A.; Sanz-Cervera, J. F. Org. Proc. Prep. Int. 2009, 41,
253–290. (c) Abdel-Wahab, B. F.; Khidre, R. E.; Farahat, A. A.
Arkivoc 2011, 196–245. (d) Dang, T. T.; Dang, T. T.; Langer, P.
Synlett 2011, 2633–2342.
3.
See, for example: (a) Abu-Zaied, M. A.; El-Telbani, E. M.;
Nawwar, G. A. M.; Elgemeie, G. H. Eur. J. Med. Chem. 2011, 46,
229–235. (b) Kumar, A.; Prakash, O.; Kinger, M.; Singh, S. P.
Can. J. Chem. 2006, 84, 438–442. (c) Sridhar, R.; Sivaprasad, G.;
Perumal, P. T. J. Heterocycl. Chem. 2004, 41, 405–408. (d)