Reaction of hydrazones derived from electron-deficient ketones with Vilsmeier-Haack reagent

Article abstract of DOI:10.1515/hc-2014-0176

Reaction of hydrazones derived from ketones bearing an acceptor substituent adjacent to the carbonyl group (α,α,α-trifluoroacetone and ethyl pyruvate) with Vilsmeier-Haack reagent was studied. In most cases, the method allows for regioselective preparatio

Full text of DOI:10.1515/hc-2014-0176

Heterocycl. Commun. 2014; 20(6): 351–354
SReergeaycP.tIvioonnin, BoofhdhanyBd. Kruarpzil’o, Onleekssanddr Oe.rGirvygeordenkfor*oanmd Dmeiltrey Mc.tVroolonch-nyuk
deficient ketones with Vilsmeier-Haack reagent
Abstract: Reaction of hydrazones derived from ketones our ongoing interest in such transformations [12–14], we
bearing an acceptor substituent adjacent to the carbonyl have turned our attention to the reaction of hydrazones
group (α,α,α-trifluoroacetone and ethyl pyruvate) with 1a–d (Figure 1) derived from ketones bearing an acceptor
Vilsmeier-Haack reagent was studied. In most cases, the substituent adjacent to the carbonyl group (i.e., α,α,α-
method allows for regioselective preparation of 1,3-disub- trifluoroacetone, ethyl pyruvate, and butanedione) with
stituted pyrazole-4-carbaldehydes – the products of initial Vilsmeier-Haack reagent. It should be noted that only
C-electrophilic attack, although in one case, the product N-aryl hydrazones 1e and 1f derived from ethyl pyruvate
resulting from concurrent N- and C-attacks of the electro- and 1-phenylpropane-1,2-dione were studied in the lit-
phile at the hydrazone moiety is observed. Under analo- erature previously in analogous transformations [15–20];
gous conditions, the reaction of N-arylhydrazone derived in this case, a formation of aldehydes 2e,f was observed
from butanedione leads to the formation of 3-chloro-3-(1- (Scheme 3).
arylpyrazol-3-yl)acrylaldehyde – the product of double
formylation at both ketone and hydrazone moieties of the
starting material.
Results and discussion
Keywords: electrophilic substitution; hydrazones pyra-
zoles; regioselectivity.
Since the reaction of N-arylhydrazones of ethyl pyruvate
(1e) with DMF-POCl3 has been described in the literature,
we first checked if the method is amendable for their
aliphatic counterpart 1a. We have shown previously [12]
that the reactivity of N-alkylhydrazones toward Vilsmeier-
Haack reagent often contradicts regularities observed
for their N-aryl analogues. Nevertheless, in the case of
1a, it was found that the reaction proceeded in expected
manner, leading to the formation of aldehyde 2a in a 71%
DOI 10.1515/hc-2014-0176
Received October 21, 2014; accepted October 28, 2014
Introduction
Non-symmetric polysubstituted pyrazoles are challenging yield (Scheme 4).
targets for regioselective synthesis because the classical
Because the building blocks of the type 2a look prom-
method, which relies on the use of CCC bis-electrophile ising in terms of lead-oriented synthesis [21], we have
and NN bis-nucleophile as the starting building blocks demonstrated their bifunctional reactivity by some rep-
(Scheme 1) [1–3], often leads to mixtures of isomers. resentative transformations (Scheme 5). In particular,
One of the possible alternative approaches relies on the mild alkaline hydrolysis of 2a gave carboxylic acid 3a in
reaction of CCNN bis-nucleophile (e.g., hydrazone of an 94% yield. Oxidation of 2a led to the formation of carbox-
enolizable ketone) with Vilsmeier-Haack reagent (DMF- ylic acid 4a (68%). Finally, reaction of 2a with hydrazine
POCl3) acting as C-electrophile [4–11]. This reaction can hydrate resulted in the construction of pyrazolo[3,4-d]
lead to several types of products resulting from the initial pyridazine ring system of the compounds 5a (85%).
attack of the electrophilic reagent at either α(α′)-carbon
In the reaction with Vilsmeier-Haack reagent, hydra-
or nitrogen atom of the hydrazone (Scheme 2). As a part of zone 1b gave the product 6b in 82% yield (Scheme 6). It
should be noted that we have observed compounds of
the type 6b only as minor products in the reactions of
*Corresponding author: Oleksandr O. Grygorenko, National
N-alkylhydrazones with Vilsmeier-Haack reagent previ-
Taras Shevchenko University of Kyiv, Volodymyrska Street, 64,
ously [13]. Formation of 6b can be explained by concur-
Kyiv 01601, Ukraine, e-mail: gregor@univ.kiev.ua
rent attack of the electrophile at the nitrogen atom of
Sergey P. Ivonin, Bohdan B. Kurpil’ and Dmitry M. Volochnyuk:
Institute of Organic Chemistry, National Academy of Sciences of
Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
the corresponding enhydrazine form 7b. This can be
explained by a stronger electron-withdrawing effect of the
Brought to you by | University of California
Authenticated
Download Date | 1/4/15 3:45 PM

ꢀꢀꢀꢁ
352ꢀ
ꢀS.P. Ivonin et al.: Hydrazone formylation
R2
R3
O
O
O
R3
R2
N
O
O
O
R3
R2
[3+2]
[4+1]
OH
OEt
HO
OEt
NaOH
94%
KMnO4
68%
N
C
N
N
R1
N
N
N
N
R1
N
R1
N
N
N
3a
2a
4a
Scheme 1ꢂ
85%
N
N2H4 H2O
NH
O
R1
R1
R2
R3
N
R3
O
O
NH
N
N
DMF
N
N
N
or
or
N
R2
N
R3
N
R3
R2
POCl3
R1
and other products
R1
5a
(for R2 = H)
resulting from N-attack
Scheme 5ꢂ
Scheme 2ꢂ
H
N
N
N+
N
O
work-up
N
N
N
F
O
F
F
O
F
F3C
F3C
F3C
Br
F
8b
EtO
F
1b
N
DMF
N
N
N
HN
Ph
or
HN
HN
N
POCl 3
H
NH
NH
H
N
+HN
+HN
1a
1b
1c
1d
DMF
HN
N
CF3
N
CF3
POCl 3
Figure 1ꢂHydrazones 1a–d studied in this work.
CF3
7b
N+
+
-Me2NH2
O
O
O
X
N
N
N
DMF
8b
work-up
X
N
N
N
POCl 3
55–96%
N
N
HN
Ar
N
CF3
6b: 82%
CF3
CF3
2b
N+
Ar
O
N
O
N
1e: X = OR
1f: X = Ph
2e: X = OR
2f: X = Ph
Scheme 6ꢂ
Scheme 3ꢂ
F
F
F
O
F
O
O
O
OEt
F
F
DMF
DMF
EtO
N
N
POCl3
79%
POCl 3
71%
HN
Ph
1c
N
N
N
HN
N
Ph
1a
2a
2c
Scheme 4ꢂ
Scheme 7ꢂ
trifluoromethyl group as compared with ethoxycarbonyl, decreased nucleophilicity of nitrogen atom of the hydra-
which lowers the C-nucleophilicity of 7b. The product 8b zone moiety in 1c, due to the effect of the phenyl substitu-
resulting from this attack undergoes hydrazone exchange ent, prevented N-attack of the electrophile.
with the product of formal C-attack 2b to give 6b.
An unexpected product 9d (62%) was obtained in
Unlike 1b, N-phenylhydrazone 1c was transformed the reaction of hydrazone 1d with the Vilsmeier-Haack
to the product of C-attack of the electrophile 2c (79%) reagent (Scheme 8). Obviously, in this case, chlorofor-
upon treatment with DMF-POCl3 (Scheme 7). Obviously, mylation at the ketone moiety resulting from the initial
Brought to you by | University of California
Authenticated
Download Date | 1/4/15 3:45 PM

ꢁꢀꢀꢀ
S.P. Ivonin et al.: Hydrazone formylationꢂ
ꢂ353
O
Cl
C-electrophilic attack at both ketone and hydrazone moi-
eties of the starting compound. This result is contrary to
the literature data for N-arylhydrazones of 1-phenylpro-
pane-1,2-dione (giving the expected 1,3-disubstituted
pyrazole-4-carbaldehyde), because analogous reaction is
impossible in that case.
OH
N+
DMF
N
N
N
POCl 3
HN
Ar
HN
Ar
HN
Ar
10d
1d: Ar = 4-BrC6H4
Cl
Cl
N
N+
N+
DMF
POCl 3
NH+
NH
Experimental
HN
Ar
HN
Ar
12d
11d
Solvents were purified according to the standard procedures. Hydra-
zones1a–dwere prepared usingreported procedures[13, 14]. Analytical
TLC was performed using Polychrom SI F254 plates. Column chroma-
tography was performed using Kieselgel Merck 60 (230–400 mesh) as
the stationary phase. 1H NMR and 13C NMR spectra were recorded on a
Varian Gemini 2000 spectrometer at 400 and 100 MHz, respectively.
Elemental analyses (C, H, N, S, Cl, Br) were conducted at the Labo-
ratory of Organic Analysis, Institute of Organic Chemistry, National
Academy of Sciences of Ukraine. Electrospray ionization mass spectra
were recorded on an Agilent 1200 LCMSD SL instrument.
+
-Me2NH2
Cl
N+
Cl
N
O
work-up
N
N
N
Ar
Ar 9d: 62%
Scheme 8ꢂ
General procedure for the reaction of hydrazones 1 with
Vilsmeier-Haack reagent
attack at α′-CH3 group occurs first; the intermediate 10d
thus obtained undergoes second electrophilic attack to
give 11d. Because 11d is a dication, it does not react with
an additional mole of Vilsmeier-Haack reagent but under-
goes cyclization to pyrazole 12d, which is transformed
into aldehyde 9d upon workup.
POCl3 (0.1 mol) was added dropwise to DMF (20 mL) at 0°C. Afer 1 h,
a solution of hydrazone 1 (0.05 mol) in DMF (10 mL) was added drop-
wise at 0°C. The mixture was stirred at 0°C for 1 h and at 80°C for 1 h,
then cooled to ambient temperature and poured onto ice (100 g). The
resultant precipitate was filtered to give the product 2a, 2c, 6b, or 9d.
Ethyl 4-formyl-1-methyl-1H-pyrazole-3-carboxylate (2a):ꢀYield
71%; mp 107–108°C; 1H NMR (CDCl3): δ 10.39 (s, 1H), 7.98 (s, 1H), 4.49
(q, J ꢀ= ꢀ 7.2 Hz, 2H), 4.03 (s, 3H), 1.45 (t, J ꢀ= ꢀ 7.2 Hz, 3H); 13C NMR (DMSO-
d6): δ 185.6, 160.9, 142.4, 134.3, 123.6, 60.8, 39.8, 13.9; MS: m/z 183
(MH+). Anal. Calcd for C8H10N2O3: C, 52.74; H, 5.53; N, 15.38. Found: C,
52.97; H, 5.26; N, 15.50.
Conclusions
In most cases, reaction of hydrazones derived from
ketones bearing an acceptor substituent adjacent to the
carbonyl group (e.g., COOR, CF3, C(O)R) with Vilsmeier-
Haack reagent is a powerful method for the preparation
of the corresponding 1,3-disubstituted pyrazole-4-car-
baldehydes, resulting from initial C-electrophilic attack.
In particular, both N-alkyl- and N-arylhydrazones derived
from pyruvic acid esters give 1-substituted 4-formylpyra-
zole-3-carboxylates, which are promising bifunctional
building blocks for organic synthesis. The reactions of
N-arylhydrazones of α,α,α-trifluoroacetone also lead to
1-aryl-3-trifluoromethylpyrazole-4-carbaldehydes. On the
contrary, the corresponding N-alkylhydrazones are prone
to both N- and C-formylation. This behavior is obviously
related to the strong inductive electron-withdrawing
effect of the trifluoromethyl group. Finally, treatment of
N-arylhydrazones of butanedione gives the pyrazole-
1-Phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehydeꢀ(2c):ꢀ
Yield 79%; mp 105–106°C; 1H NMR (CDCl3): δ 10.05 (s, 1H), 8.51 (s, 1H),
7.72 (d, J ꢀ= ꢀ 7.6 Hz, 2H), 7.53 (t, J ꢀ= ꢀ 7.6 Hz, 2H), 7.44 (t, J ꢀ= ꢀ 7.6 Hz, 1H); 13
C
NMR (DMSO”-d6): δ 182.4, 140.5 (q, J ꢀ= ꢀ 37.5Hz), 137.9, 135.5, 129.6, 128.4,
122.2, 121.7, 119.7; 19F NMR (75 MHz): δ -62.08; MS: m/z 241 (MH+). Anal.
Calcd for C11H7F3N2O: C, 55.01; H, 2.94; N, 11.66. Found: 55.16; H, 3.08;
N, 11.47.
(E)-N-methyl-N′-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
methylene)formohydrazide (6b):ꢀYield 82%; mp 143–144°C; 1H
NMR (CDCl3): δ 8.70 (s, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 3.97 (s, 3H), 3.25
(s, 3H); 13C NMR (DMSO-d6): δ 164.5, 137.9 (q, J ꢀ= ꢀ 37.5 Hz), 132.9, 132.5,
123.6, 120.1, 39.9, 27.1; 19F NMR (75 MHz): δ -61.28; MS: m/z 235 (MH+).
Anal. Calcd for C8H9F3N4: C, 41.03; H, 3.87; N, 23.92. Found: C, 40.83;
H, 3.99; N, 24.06.
3-(1-(4-Bromophenyl)-1H-pyrazol-3-yl)-3-chloroacrylaldehyde
1
(9d):ꢀYield 62%; mp 109–110°C; H NMR (DMSO-d6): δ 9.98 (s, 1H),
derived β-chlorovinyl aldehydes resulting from double 9.32 (s, 1H), 7.88 (d, J ꢀ= ꢀ 9.0 Hz, 2H), 7.74 (d, J ꢀ= ꢀ 9.0 Hz, 2H), 6.54 (d, J ꢀ= ꢀ
Brought to you by | University of California
Authenticated
Download Date | 1/4/15 3:45 PM

ꢀꢀꢀꢁ
354ꢀ ꢀS.P. Ivonin et al.: Hydrazone formylation
1.8 Hz, 1H), 6.00 (d, J ꢀ= ꢀ 1.8 Hz, 1H); 13C NMR (DMSO-d6), δ 183.8, 148.7,
137.3, 135.7, 132.5, 129.0, 122.2, 121.1, 121.0, 120.5; MS: m/z 312 (MH+).
Anal. Calcd for C12H8BrClN2O: C, 46.26; H, 2.59; N, 8.99; (Br+Cl) 37.03.
Found: C, 46.15; H, 2.52; N, 9.04; (Br+Cl) 36.73.
6-methyl-2-oxo-2H-pyran-3-yl)pyrazoles. Can. J. Chem. 2006,
84, 438–442.
[6] Sridhar, R.; Sivaprasad, G; Perumal, P. T. An efficient synthesis
of 1H-pyrazole-4-carboxylic acid esters with Vilsmeier reagent
under neat conditions. J. Heterocycl. Chem. 2004, 41, 405–408.
[7] Perumal, P. T.; Sridhar, R. Synthesis of novel 1-h-pyrazole-
4-carboxylic acid esters by conventional and microwave
assisted Vilsmeier cyclization of hydrazones. Synth. Commun.
2003, 33, 1483–1488.
[8] Rathelot, P.; Azas, N.; El-Kashef, H.; Delmas, F.; Giorgio, C. D.;
Timon-David, P.; Maldonado, J.; Vanelle, P. 1,3-Diphenylpyra-
zoles: synthesis and antiparasitic activities of azomethine
derivatives. Eur. J. Med. Chem. 2002, 37, 671–679.
[9] Lebedev, A. V.; Lebedeva, A. B.; Sheludyakov, V. D.;
Kovaleva, E. A.; Ustinova, O. L.; Kozhevnikov, I. B. Vilsmeier
formylation of hydrazones and semicarbazones derived from
alkyl, benzyl, and cycloalkyl methyl ketones. Russ. J. Gen.
Chem. 2005, 75, 412–416.
[10] Bratenko, M. K.; Chernyak, I. N.; Vovk, M. V. Polyfunctional
pyrazoles. Russ. J. Org. Chem. 1997, 33, 1368–1370.
[11] Chaitanya, M. V. S. R. K.; Dubey, P. K. A simple and efficient
synthesis of novel naphthyridine-1H-pyrazole-4-carboxylic acid
esters/carbaldehydes using Vilsmeier-Haack reagent. Hetero-
cycl. Commun. 2013, 19, 49–55.
[12] Ivonin, S. P. Novel method for the synthesis of 4-formyl-
1,3-dimethylpyrazole. Chem. Heterocycl. Comp. 2011, 47,
1048–1049.
4-Formyl-1-methyl-1H-pyrazole-3-carboxylic acid (3a):ꢀNaOH
(0.40 g, 0.01 mol) was dissolved in MeOH (20 mL), then pyrazole 2a
(1.82 g, 0.01 mol) was added. The resulting solution was stirred at
room temperature for 1 h, then concentrated, diluted with water (20
mL), and acidified to pHꢀ= ꢀ3. The resultant precipitate was filtered and
dried on air to give the product 3a (1.45 g): Yield 94%; mp 215–217°C;
1H NMR (DMSO-d6): δ 13.46 (br s, 1H), 10.22 (s, 1H), 8.44 (s, 1H), 3.95
(s, 3H); 13C NMR (DMSO-d6): δ 186.1, 162.4, 143.4, 134.2, 123.6, 39.5; MS:
m/z 155 (MH+). Anal. Calcd for C6H6N2O3: C, 46.76; H, 3.92; N, 18.18.
Found: C, 46.94; H, 3.76; N, 17.95.
3-(Ethoxycarbonyl)-1-methyl-1H-pyrazole-4-carboxylic acid (4a):ꢀ
To a mixture of pyrazole 2a (1.82 g, 0.01 mol) and water (20 mL),
KMnO4 (1.58 g, 0.01 mol) was added at room temperature upon stir-
ring. The resulting mixture was stirred at room temperature for 3 h.
Then the solid was filtered off and washed with water (3ꢀ× ꢀ10 mL). The
combined filtrates were acidified to pHꢀ= ꢀ3, and the precipitate formed
was filtered to give carboxylic acid 4a (1.34 g): Yield 68%; mp 188–
1
189°C; H NMR (DMSO-d6): δ 12.6 (br s, 1H), 8.28 (s, 1H), 4.28 (q, J ꢀ= ꢀ
7.2 Hz, 2H), 3.89 (s, 3H), 1.27 (t, J ꢀ= ꢀ 7.2 Hz, 3H); 13C NMR (DMSO-d6): δ
162.6, 162.5, 143.0, 135.7, 114.7, 61.1, 39.2, 13.9; MS: m/z 198 (MH+). Anal.
Calcd for C8H10N2O4: C, 48.49; H, 5.09; N, 14.14. Found: C, 48.74; H,
4.82; N, 14.07.
[13] 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 Lett. 2014, 55, 2187–2189.
2-Methyl-2H-pyrazolo[3,4-d]pyridazin-7(6H)-one (5a):ꢀA solution
of pyrazole 2 (1.82 g, 0.01 mol) and hydrazine hydrate (0.01 mol) in
i-PrOH (10 mL) was stirred under reflux for 2 h. Then the mixture was
concentrated, and the residue was crystalized from MeOH to give the
[14] Ivonin, S. P.; Kurpil’, B. B.; Grygorenko, O. O.; Volochnyuk, D. M.
Reaction of hydrazones derived from active methylene com-
pounds with Vilsmeier-Haack reagent. Monatch. Chem. 2014,
DOI: 10.1007/s00706-014-1293-7 [Epub ahead of print].
[15] Baraldi, P. G.; Cacciari, B.; Spalluto, G.; Romagnoli, R.; Bracci-
oli, G.; Zaid, M. J.; Pineda de las Infantas, M. J. A new synthetic
approach to indazole synthesis. Synthesis 1997, 1140–1142.
[16] Perumal, P. T.; Sridhar, R.; Etti, S.; Ponnuswamy, M. N.;
Shanmugam, G.; Mathivanan, N.; Prabavathy, V. R. Design,
synthesis and anti-microbial activity of 1H-pyrazole carboxy-
lates. Bioorg. Med. Chem. Lett. 2004, 14, 6035–6040.
[17] Sridhar, R.; Perumal, P. T. A new protocol to synthesize
1,4-dihydropyridines by using 3,4,5-trifluorobenzeneboronic
acid as a catalyst in ionic liquid: synthesis of novel 4-(3-car-
boxyl-1H-pyrazol-4-yl)-1,4-dihydropyridines. Tetrahedron 2005,
61, 2465–2470.
[18] Matiichuk, V. S.; Potopnyk, M. A.; Obushak, N. D. Molecular
design of pyrazolo[3,4-d]pyridazines. Russ. J. Org. Chem.
2008, 44, 1352–1361.
[19] Bratenko, M. K.; Barus, M. M.; Vovk, M. V. Polyfunctional
pyrazoles. 5. Preparative synthesis of 1-aryl-4-formylpyra-
zole-3-carboxylic acids. Chem. Heterocycl. Comp. 2009, 45,
1464–1468.
1
product 5 (1.27 g): Yield 85%; mp 280–282°C; H NMR (DMSO-d6), δ
13.24 (br s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 4.15 (s, 3H); 13C NMR (DMSO-
d6), δ 156.5, 141.8, 133.0, 128.1, 118.5, 40.1; MS: m/z 151 (MH+). Anal.
Calcd for C6H6N4O: C, 48.00; H, 4.03; N, 37.32. Found: C, 47.78; H, 4.30;
N, 37.26.
References
[1] Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A.
From 2000 to mid-2010: a fruitful decade for the synthesis of
pyrazoles. Chem. Rev. 2011, 111, 6984–7034.
[2] Fustero, S.; Simón-Fuentes, A.; Sanz-Cervera, J. F. Recent
advances in the synthesis of pyrazoles. A review. Org. Proc.
Prep. Int. 2009, 41, 253–290.
[3] Abdel-Wahab, B. F.; Khidre, R. E.; Farahat, A. A. Pyrazole-3(4)-
carbaldehydes: synthesis, reactions and biological activity.
Arkivoc 2011, 196–245.
[4] Abu-Zaied, M. A.; El-Telbani, E. M.; Nawwar, G. A. M.;
Elgemeie, G. H. Synthesis and in vitro anti-tumor activity of
new oxadiazole thioglycosides. Eur. J. Med. Chem. 2011, 46,
229–235.
[5] Kumar, A.; Prakash, O.; Kinger, M.; Singh, S. P. Synthesis
of some new 1-aryl-4-formyl-3-(4-hydroxy-6-methyl-2-
oxo-2H-pyran-3-yl)pyrazoles using the Vilsmeier-Haack
reaction – isolation of the key intermediate 1-aryl-3-(4-hydroxy-
[20] Bratenko, M. K.; Chornous, V. A.; Vovk, M. V. Polyfunctional
pyrazoles. 2. 1-Aryl-3-benzoyl-4-formyl- and 4-carboxypyra-
zoles. Chem. Heterocycl. Comp. 2001, 37, 467–469.
[21] Nadin, A.; Hattotuwagama, C.; Churcher, I. Lead-oriented
synthesis: a new opportunity for synthetic chemistry. Angew.
Chem. Int. Ed. 2012, 51, 1114–1122.
Brought to you by | University of California
Authenticated
Download Date | 1/4/15 3:45 PM