Cyclocondensation between fatty acid hydrazides and 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones: Introducing a trifluoromethylated head onto fatty acid moieties

Article abstract of DOI:10.1080/00397911.2017.1364769

This paper reports the regioselective synthesis of new trifluoromethylated lipid derivatives, namely, 1-(5-hydroxy-5-trifluoromethyl-3-alkyl-4,5-dihydro-1H-pyrazol-1-yl)alkan-1-ones, through cyclocondensation reactions between a series of fatty hydrazides (palmitoyl, stearoyl, and oleoyl hydrazides) obtained from fatty acids from renewable resources (1,1,1-trifluoro-4-alkoxy-3-alken-2-ones [F₃CC(O)CH?C(R¹)OR, where R¹ = H and R?Et; R¹ = –(CH₂)₆CH₃, –(CH₂)₆CH₃, –(CH₂)₈CH₃, –(CH₂)₉CH₃, –(CH₂)₁₀CH₃, –(CH₂)₁₂CH₃, –(CH₂)₂Ph], and R?Me). Experimental observations showed that the lipophilic characteristic of 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazoles (5–7) prevent the acid catalyzed dehydration to aromatization of 1H-pyrazole ring, although in some cyclocondensations a proportion of the aromatic derivative 1-(5-trifluoromethyl-3-alkyl-1H-pyrazol-1-yl)alkan-1-one was obtained. All products were characterized using multinuclear (¹H, ¹³C, ¹⁹F) NMR spectroscopy.

Full text of DOI:10.1080/00397911.2017.1364769

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Cyclocondensation between fatty acid hydrazides
and 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones:
Introducing a trifluoromethylated head onto fatty
acid moieties
Wystan K. O. Teixeira, Helena A. Gonçalves, Débora L. de Mello, Sidnei
Moura, Darlene C. Flores & Alex F. C. Flores
To cite this article: Wystan K. O. Teixeira, Helena A. Gonçalves, Débora L. de Mello, Sidnei
Moura, Darlene C. Flores & Alex F. C. Flores (2017): Cyclocondensation between fatty acid
hydrazides and 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones: Introducing a trifluoromethylated head onto
fatty acid moieties, Synthetic Communications, DOI: 10.1080/00397911.2017.1364769
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1364769
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Date: 11 August 2017, At: 07:37

Cyclocondensation between fatty acid hydrazides and 1,1,1-
trifluoro-4-alkoxy-3-alken-2-ones: Introducing a
trifluoromethylated head onto fatty acid moieties
Wystan K. O. Teixeira
Escola de Química e Alimentos, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil
Helena A. Gonçalves
Escola de Química e Alimentos, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil
Débora L. de Mello
Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
Sidnei Moura
Instituto de Biotecnologia, Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
Darlene C. Flores
Escola de Química e Alimentos, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil
Alex F. C. Flores
Escola de Química e Alimentos, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil
Address correspondence to Alex F. C. Flores
1

Supplemental data (full experimental details and characterization of title compounds) for this
article can be access on the publisher’s website. <TQ: The publisher’s website will be a live
link.>
ABSTRACT
This paper reports the regioselective synthesis of new trifluoromethylated lipid
derivatives, namely, 1-(5-hydroxy-5-trifluoromethyl-3-alkyl-4,5-dihydro-1H-pyrazol-1-yl)alkan-
1
-ones, via cyclocondensation reactions between a series of fatty hydrazides (palmitoyl, stearoyl,
and oleoyl hydrazides) obtained from fatty acids from renewable resources (1,1,1-trifluoro-4-
1
1
1
alkoxy-3-alken-2-ones [F
3
CC(O)CH=C(R )OR, where R = H and R = Et; R = -(CH
2
)
6
CH , -
3
(
CH CH , -(CH CH , -(CH
2
)
6
3
2
)
8
3
2
)
9
CH , -(CH , -(CH , -(CH Ph]; and R = Me).
3
2
)
10CH
3
2
)
12CH
3
2 2
)
Experimental observations showed that the lipophilic characteristic of 5-hydroxy-5-
trifluoromethyl-4,5-dihydro-1H-pyrazoles (5–7) prevent the acid catalyzed dehydration to
aromatization of 1H-pyrazole ring, although in some cyclocondensations a proportion of the
aromatic derivative 1-(5-trifluoromethyl-3-alkyl-1H-pyrazol-1-yl)alkan-1-one was obtained. All
1
13
19
products were characterized using multinuclear ( H, Cꢀ, Fꢀ) NMR spectroscopy.
GRAPHICAL ABSTRACT
KEYWORDS: [3 + 2] cyclocondensation, 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones, 5-hydroxy-
5
-trifluoromethyl-4,5-dihydro-1H-pyrazoles, fatty hydrazides
2

Introduction
Cyclocondensation between CF -containing dieletrophiles, such as 4,4,4-trifluoro-1-
3
aryl/heteroaryl-1,3-butanediones, 1,1,1-trifluoro-2,4-alkenones, and 1,1,1-trifluoro-4-methoxy-3-
alken-2-ones, and hydrazines has largely been used to synthesize trifluoromethyl-substituted 1H-
pyrazole derivatives. Several research groups have reported results on mechanistic aspects of
such reactions, involving the regio-selectivity and stability of intermediates such as
hydrazone/enaminone and 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazoles.[1–6] Singh,[7]
Elguero,[8] and Norris conducted systematic studies of cyclocondensation between hydrazines
and 4,4,4-trifluoro-1-aryl/heteroaryl-1,3-butanediones, 4,4-difluoro-1-phenyl-1,3-butanedione,
[9]
1
,1,1-trifluoro-2,4-pentanedione, and 1,1,1,5,5,5-hexafluoropentanedione. Each author
concluded that the orientation of the first attack of the nucleophilic nitrogen depends on the
substituent in the hydrazine, but not as a kinetic parameter to reactivity, but rather mainly due to
the thermodynamic stability of 3,5-dihydroxypyrazolidines in equilibrium and posterior imine
bond formation. This approach was revisited by Singh and Elguero,[10] who studied reactions
between aryl and heteroarylhydrazines and 1-aryl-4,4,4-trifluoro-2,3-butanediones under neutral
and acidic conditions, however, they did not mention the pH of the reaction solutions used. The
authors were able to synthesize and isolate a wide range of 3- and 5-trifluoromethyl-1H-
pyrazoles, and concluded that the synthetic approach is tunable on three parameters: the pH
conditions, i.e., using neutral (without the addition of acid) or acidic media; and the electron-
withdrawing effect of the substituent on the hydrazine moiety and on the phenyl ring of the 1,3-
butanedione. Volkova[11] reported reactions between 4,4,4-trifluoro-1-(thien-2-yl)-1,3-
butanedione and hydrazines, and initially demonstrated that a trifluoromethyl-substituted
carbonyl can be attacked by molecules of water or alcohol solvents presented in a reaction
3

medium, which changes the reactivity of electrophilic carbonyls; the reactions were conducted in
ethyl ether, leading to 5-hydroxy-3-(thien-2-yl)-5-trifluoromethyl-4,5-dihydro-1H-pyrazole,
which can then be subjected to dehydration to form the respective tautomerizable 3(5)-(thien-2-
yl)-5(3)-trifluoromethyl-1H-pyrazole. Ros and Pons[12] reacted 2-hydroxyethylhydrazine with
4
,4,4-trifluoro-1-(pyridin-2-yl)-1,3-butanedione in ethanol, and were able to tune the results by
controlling the reaction temperature; however, they obtained only the 1,5-regioisomer as 5-
hydroxy-1-(2-hydroxyethyl)-3-(pyridin-2-yl)-5-trifluoromethyl-4,5-dihydro-1H-pyrazole when
reactions were conducted at 0°C for 7hꢀ or as 2-[3-(pyridin-2-yl)-5-trifluoromethyl-1H-pyrazol-
1
-yl]ethanol when reactions were conducted at 25°C for 15hꢀ. Scheme 1 summarizes these
results.
Dinucleophilic hydrazides or hydrazide-like compounds have been systematically
employed in reactions with CF -containing dieletrophiles to synthesize 1H-pyrazoles and
3
polyheterocyclic systems with desirable biological or electronic properties.[13–19] However, none
of the cited studies described the production of regioisomers 1H-pyrazoles.
The reactivities of hydrazides and hydrazide-like nitrogens are well differentiated, so that
the first nucleophilic attack is always from an unsubstituted nitrogen, leading to an imine bond,
hydrazone (semicarbazone, thiosemicarbazone), and then a cyclization product via hemiaminal
moiety formation; ultimately, this forms stable 5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-
pyrazole derivatives, as shown in Scheme 2.
Moreover, renewable resources are increasingly being used in the production of useful
chemicals. For example, vegetable oils and carbohydrates can be used as feedstocks for the
manufacture of a variety of sustainable materials and products, including fine chemicals and
polymeric materials.[20] Since the 1950sꢀ, oleochemistry has grown into a major field, both at
4

research institutes and in industries. A large variety of products based on fats and oils have been
developed, including biodiesel, surfactants, emollients, biodegradable mineral oil replacements
for lubricants, polymer supplies, and fine chemicals.[21–23]
In this context, we decided to apply the cyclocondensation [3 + 2] between 1,1,1-
trifluoro-4-alkoxyalk-3-en-2-ones and fatty hydrazides to obtain a series of new oleochemicals.
Specifically, we used a large set of 1,1,1-trifluoro-4-alkoxyalk-3-en-2-ones (1a-g), mostly
derived from unbranched, long-chain 2-alkenones, with ecofriendly palmitic, stearic, and oleic
fatty hydrazides. Cyclocondensation between 4-etoxy-1,1,1-trifluorobut-3-en-2-one and the
series of fatty hydrazides is a synthetic approach to introduce an unbranched trifluoromethylated
head to a natural fatty moiety, leading to new, interesting hybrid oleochemicals.
Results and discussion
A series of 1,1,1-trifluoro-4-methoxyalk-3-en-2-ones (1b-g) were obtained via
trifluoroacetylation of the respective dimethoxy acetal derivatives.[24] The 4-ethoxy-1,1,1-
trifluorobut-3-en-2-one (1a) was obtained from ethyl vinyl ether trifluoroacetylation, as
described previously.[25] The fatty hydrazides were obtained by hydrazinolysis of the respective
fatty methyl alkanoates, as described previously.[26] This step was the most challenging in the
proposed route. Although there were no problems with the saturated esters, the process of
reduction of oleic acid derivatives competes for the hydrazine hydrate of the medium (for the
reduction of the double bond), and so it is necessary to strictly control the temperature and
reaction time. Higher temperatures or longer reaction periods lead to a mixture of hydrazides 3
and 4; on the other hand, we could not obtain the pure oleyl hydrazide without it containing some
amount of methyl oleate (see the spectra for compound 7, Supplementary Material).
5

The reaction conditions for synthesizing 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-
1
H-pyrazoles were adapted from a method already described in the literature, in which
cyclocondensation was carried out in methanol under BF
conducted cyclocondensation between 1a and palmitoyl hydrazide (2) at a 1:1 molar ratio in
0mLꢀ ethanol, a reasonably ecofriendly solvent that solubilizes hydrazides. The reaction mixture
3
.OEt
catalysis.[27] Initially, we
2
1
was stirred at 25–50°C for 24hꢀ and monitored by TLC; the reaction proceeded without
consuming dielectrophile 1a. Cyclocondensation occurred only at ethanol reflux for 24hꢀ even
without adding a catalyst, leading to 5-hydroxy-5-trifluoromethyl-1-palmitoyl-4,5-dihydro-1H-
pyrazole (5a), which precipitated out at 80% yield. Changing the reaction solvent did not
improve its performance. Adding 10 wt.% BF
3
.OEt inꢀ EtOH did not change the reaction results;
2
in fact, the product obtained under these conditions had to be recrystallized after precipitation in
the reaction medium. Table 1 summarizes the reaction conditions optimized for
cyclocondensation to obtain 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazoles.
Next, we verified whether the same conditions could be used with dielectrophilic precursors with
a long-chain substituent. A 1:1 mixture of 1,1,1-trifluoro-4-methoxypentadec-3-en-2-one (1e)
and palmitoyl hydrazide (2) in EtOH was stirred at 80°C for 24hꢀ, leading to 5-hydroxy-5-
trifluoromethyl-1-palmitoyl-3-undecyl-4,5-dihydro-1H-pyrazole (5e) at 78% yield. The reaction
conditions shown in Table 1 (entry 4) were extended to cyclocondensations between series 1a-g
and fatty hydrazides to afford the respective 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-
1
H-pyrazoles 5–7 (Scheme 3).
The structure of each product was assigned based on NMR spectroscopy and LC-MS/MS
1
data. The H NMR spectra for 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazole 5–7
showed a general feature, displaying the signals as doublets with characteristic geminal coupling
6

constant of 19Hzꢀ related to diastereotopic hydrogens at C-4 on the 1H-pyrazole ring at 3.07 and
3
.21ppmꢀ (Figure 1).
Signals due to diasterotopic hydrogens from 5a appeared to be more deshielded at
.19ppmꢀ, as doublets of multiplets, and at 3.35ppmꢀ, as doublets of doublets. This demonstrated
3
that alkyl substituents at the 3-position of the 1H-pyrazole ring have a shielding effect on
hydrogen nuclei. Further, the multiplicity of the more shielded signal indicated coupling with
fluorine nuclei in the trifluoromethyl group with 4JHF ~1.6Hzꢀ, approximately the same value of
the 3JHH between H-3 and H-4. In this spectrum, it was also possible to observe the signals of
diastereotopic -hydrogens to the carbonyl of the hydrazide portion as doublets of multiplets
1
3
between 2.6–2.8ppmꢀ (Figure 1). The Cꢀ NMR spectra showed the characteristic signals for
each derivative series. In general, the quartet related to the CF group displayed at about δ
23ppmꢀ with JCF 288Hzꢀ, that related to C-5 of the 1H-pyrazole ring was at about δ 90ppmꢀ with
3
1
3JCF 34Hzꢀ, the singlet signal related to the carboxyl group was at about δ 176ppmꢀ, and a cluster
of overlapping signals related to the long methylene chain was observed between 22 and 35ppmꢀ.
Some attempts were made to dehydrate/aromatize the 1-(3-heptyl-5-hydroxy-5-
trifluoromethyl-4,5-dihydro-1H-pyrazol-1-yl)hexadecan-1-one (5b), using a mild method that
would not also cause hydrolysis of the alkanoyl moiety from the 1H-pyrazole ring.[13,15] We were
unable to completely convert 4,5-dihydro-1H-pyrazole derivatives 5–7 into their respective
1
dehydrated/aromatized derivatives. Figure 2 shows the H NMR spectra of the mixture obtained
after a conventional sulfuric acid dehydration of compound 5b at 25°C.
Experimental
7

The 1,1,1-trifluoro-4-methoxy-3-alken-2-ones (1a-g) were synthesized according to
previous procedures developed in our laboratory.[24] 1H, Cꢀ and Fꢀ spectra were acquired at
13
19
3
05Kꢀ on a Bruker Ascend Avance III 400 spectrometer using a 5mmꢀ dual probe. Chemical
shifts (δ) are reported in ppm from tetramethylsilane (TMS), and coupling constants (J) are given
in Hz. Compounds 5–8 were dissolved in acetonitrile (Merck, USA), 50% (v/v) with deionized
water and 0.1% formic acid. The dissolved compounds were infused individually into the ESI
−
1
source using a syringe pump (Harvard Apparatus) at a flow rate of 150 μL min . ESI( + )-MS
were acquired using a hybrid high-resolution and high-accuracy (5 μL/L) microTof (Q-TOF)
mass spectrometer (Bruker® Scientific). Cone voltages were set to + 3500Vꢀ and + 40Vꢀ,
respectively, with a desolvation temperature of 100°C. Diagnostic ions were identified by
comparing experimental to theoretical ESI( + )-MS/MS.
General procedure for 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-
pyrazole synthesis
A solution of 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones (1a-g) (3 mmol) and NH
3 mmol) in 10mLꢀ EtOH was stirred at 80°C until complete dissolution, and the resulting
mixture was stirred for 16hꢀ. After the reaction was completed, the mixture was cooled and the
H-pyrazole derivative product was precipitated out, filtered off, and washed with cooled EtOH
2
NH .HCl
2
(
1
and water. Products were analyzed without further purification. Spectroscopic data are shown in
the Supplementary Information.
1
-(5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)hexadecan-1-one (5a) was
1
): δ 6.94 (t, 3JHH 1.5Hzꢀ,
),
obtained (80%) as a yellowish wax (EtOH). H NMR (400MHzꢀ, CDCl
3
1
H, H3), 3.35 (m, 2JHH 19.5Hzꢀ, 1H, H4b), 3.17 (d, 2JHH 19.5Hzꢀ, 1H, H4a), 2.71 (m, 2H, αCH
2
8

.68 (q, 3JHH 7.5Hzꢀ, 2H, βCH
NMR(100MHzꢀ CDCl
), 1.41–1.17 (m, 22H, CH
), 0.89 (t, 3JHH 7.1Hzꢀ, 6H, CH
); Cꢀ
13
1
2
2
3
), 90.0 (q, 2JCF
3
): δ 176.2 (CO), 144.4 (C3), 123.3 (q, JCF 287.1Hzꢀ, CF
3
1
9
3
8
4.5Hzꢀ, C5), 44.7 (C4), 22.9–35.1 (CH
2
), 14.0 (CH
3
); Fꢀ NMR (376.5MHzꢀ CDCl ) δ ppm: –
3
-1
-1
1.8 (s). C20
H
36
F
3
N
2
O
2
calcd. mass 393.2729gꢀ.mol . Found: 393.2844gꢀ.mol .
1
-(3-heptyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-1-yl)hexadecan-1-one
1
): δ 3.21 (d, 2JHH
), 2.35 (t, 3JHH 7.75Hzꢀ,
). 13Cꢀ NMR
); 91.2 (q, 2JCF
(
5b) was obtained (80%) as a yellow wax (EtOH). H NMR (400MHzꢀ, CDCl
3
1
8.9Hzꢀ, 1H, H4b), 3.07 (d, 2JHH 19.1Hzꢀ, 1H, H4a), 2.64 (m, 2H, αCH
H, αCH ), 1.63 (m, 4H, βCH ), 1.40–1.21 (m, 31H, CH
2
2
2
2
2
), 0.89 (m, 6H, CH
3
(100MHzꢀ, CDCl
3
): δ 175.8 (CO), 157.7 (C3), 123.4 (q, JCF 287.6Hzꢀ, CF
3
1
9
3
8
4.1Hzꢀ, C5), 45.3 (C4), 22.6–34.7 (CH
2
), 14.0 (CH
3
); Fꢀ NMR (376.5MHzꢀ CDCl ) δ ppm: –
3
-1
-1
1.8 (s). C27
H
50
F
3
N
2
O
2
calcd. mass 491.3819gꢀ.mol . Found: 491.3952gꢀ.mol .
Cyclocondensation between 1,1,1-trifluoro-4-alkoxy-3-alken-2-one
1
and fatty
hydrazides 2–4 is an efficient method to synthesize 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-
dihydro-1H-pyrazoles at good yields and purity. The results demonstrate the efficiency and
versatility
of
1,1,1-trifluoro-4-alkoxy-3-alken-2-one
precursors
to
introduce
a
trifluoromethylated head into natural fatty acid moieties, producing a new class of lipophilic
compounds with gelling and lubricant characteristics. Our data also endorse the high
thermodynamic stability of the hemiketal/aminal C-5 moiety produced during [CCC + NN]
cyclocondensation between hydrazides and perfluoroalkyl-substituted 1,3-dielectrophiles.
Acknowledgments
The authors are grateful for financial support from Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq, Universal Grant 6577818477962764-01) and
9

Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS). Fellowships
from CAPES (W.K.O. Teixeira, H.A. Gonçalves, and D.L. de Mello) are also acknowledged.
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25] Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S. Chem. Lett. 1976, 409–502.
26] Rauf, A.; Sharma, S.; Gangal, S. Arkivoc 2007, 137–147.
27] Beck, P.; Santos, J. M.; Kuhn, B. L.; Moreira, D. N.; Flores, A. F. C.; Martins, M. A. P.;
D’oca, M. G. M.; Piovesan, L. A. J. Braz. Chem. Soc. 2012, 23, 2122–2127.
1
1

Table 1. Optimization of reaction conditions for cyclocondensation between 1a and palmitoyl
hydrazide.
Entry
Solvent
Solvent volume
Temperature (°C)
Time (h)
Yield (%)
(mL)
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
MeCN
MeCN
AcOH
iPrOH
5
50
50
50
80
80
65
80
80
50
80
16
24
24
24
24
24
24
36
12
24
-a
-a
10
20
10
10
10
10
10
10
10
-a
80
65b
53c
45c
82
-d
1
0
75
aRecovery of starting reagents.
bWith 10 wt.% BF
3
2
.EtO . Yield after recrystallization from MeOH.
c
1
Conversion measured by H NMR.
dMixture of products: N’-acetyl palmitoyl hydrazide, 5a, and reactants.
1
2

1
Figure 1. Parallel between H NMR spectra of 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-
1
1
H-pyrazoles 5a and 5b, with projections showing the dihedral angles between the H nuclei and
the other substituents of the pyrazole ring.
1
3

1
3
Figure 2. Cꢀ{H} NMR spectrum of a mixture of 5b and 1-(3-heptyl-5-trifluoromethyl-1H-
pyrazol-1-yl)hexadecan-1-one, obtained via dehydration/aromatization of 4,5-dihydro-1H-
pyrazole 5b with sulfuric acid.
1
4

Scheme 1. Synthesis of trifluoromethyl-1H-pyrazoles from trifluoromethyl--diketones and
hydrazines.
1
5

Scheme 2. Synthesis of trifluoromethyl-1H-pyrazoles from trifluoromethyl--diketones,
hydrazides, and hydrazide-like nitrogens.
1
6

Scheme 3. Synthesis of 1-acyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazole 5–7
derivatives.
1
7