Efficient trifluoromethylation of C(sp2)-H functionalized α-oxoketene dithioacetals: a route to the regioselective synthesis of functionalized trifluoromethylated pyrazoles

Article abstract of DOI:10.1039/c7ra01130j

An operationally simple approach for the regioselective construction of diversely substituted trifluoromethylated pyrazoles via nucleophilic trifluoromethylation of iodo-substituted α-oxoketene dithioacetals is described. X-ray crystallographic studies confirmed the trifluoromethylation as well as formation of a regioselective cyclized product. Furthermore, trifluoromethylated pyrazoles bearing thiomethyl groups may allow further functionalization and are of considerable interest in medicinal chemistry.

Full text of DOI:10.1039/c7ra01130j

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Efficient trifluoromethylation of C(sp2)–H
functionalized a-oxoketene dithioacetals: a route
to the regioselective synthesis of functionalized
trifluoromethylated pyrazoles†
Cite this: RSC Adv., 2017, 7, 10150
a
b
c
d
a
*
N. Sharma, N. Kumari, T. S. Chundawat, S. Kumar and S. Bhagat
An operationally simple approach for the regioselective construction of diversely substituted
trifluoromethylated pyrazoles via nucleophilic trifluoromethylation of iodo-substituted a-oxoketene
dithioacetals is described. X-ray crystallographic studies confirmed the trifluoromethylation as well as
formation of a regioselective cyclized product. Furthermore, trifluoromethylated pyrazoles bearing
thiomethyl groups may allow further functionalization and are of considerable interest in medicinal
chemistry.
Received 25th January 2017
Accepted 30th January 2017
DOI: 10.1039/c7ra01130j
rsc.li/rsc-advances
Organouorine compounds, particularly triuoromethylated a-Iodinated ketene dithioacetals, to our knowledge, have been
molecules have generated considerable attention in the eld of reported to be synthesized by iododecarboxylation which suffers
organic chemistry due to their wide range of applications in from low efficiency and undesired side reactions.10 Furthermore,
material sciences as well as in pharmaceutical & agrochemical there are no reports on the utilization of these iodofunctional-
industries.1,2 The interesting medicinal properties that the tri- ized oxoketene dithioacetals in organic transformation reac-
uoromethyl group imparts are anticipated due to an increase tions. In view of these reported limitations and our ongoing
in lipophilicity and metabolic stability.3,4 As naturally occurring efforts to explore oxoketene dithioacetals for construction of
triuoromethylated compounds are not reported in the litera- N-heterocycles,11 we envisioned that the development of efficient
ture, tremendous research efforts from synthetic organic iodination strategy as well as triuoromethylation protocol of
chemists are focused on the development of an efficient route these a-iodo substituted dithioacetals would allow for a new
for selective introduction of the triuoromethyl group onto access to multisubstituted triuoromethylated oxoketene
aromatic and heteroaromatic ring systems under mild and dithioacetals under mild reaction conditions. Moreover, elabo-
selective reaction conditions.5–7
rations on these triuoromethylated synthons in cyclization
Functionalized a-oxoketene dithioacetals have emerged as reactions resulted in regioselective construction of biologically
versatile intermediates for the synthesis of various heterocyclic important functionalized triuoromethylated pyrazoles.12,13
compounds in the eld of organic synthesis.8 Among them, a- Here it should be noted that there are only few reports of tri-
halogenated oxoketene dithioacetals are of special interest due uoromethylations of C(sp2)–H bond of oxoketene dithioace-
to their diverse applications as synthons in metal catalysed tals14 which are suffering from drawbacks such as use of oxidant,
reactions.9 Despite their wide scope, synthetic utility of a-halo- ligands and additives as well as longer reaction hours. Adding to
genated oxoketene dithioacetals has not been well documented. this, using similar reaction conditions triuoromethylated pyr-
azoles of completely different regioselectivity were obtained as
compared to compounds reported by Yu et al.14a (Scheme 1).
aOrganic Synthesis Research Laboratory, Department of Chemistry, A. R. S. D. College,
University of Delhi, New Delhi-110021, India. E-mail: sunitabhagat28@gmail.com
bInstitute of Nuclear Medicine & Allied Sciences, Defence Research & Development
Organization, Brig. SK Mazumdar Marg, Delhi-110054, India
cDepartment of Applied Sciences, The Northcap University (formerly ITM University),
Gurgaon-122001, Haryana, India
dPhysical Chemistry Division, CSIR-National Chemical Laboratory, Dr Homi Bhabha
Road, Pune-411008, India
† Electronic supplementary information (ESI) available: Copies of 1H, 13C NMR &
HRMS data for target compounds. X-ray crystallographic data of compounds 3l
with CCDC no. 1051488 and 4i with CCDC no. 1051460. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c7ra01130j
Scheme 1 Functionalization of a-iodinated oxoketene dithioacetals.
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To probe the viability of the designed strategy, a-oxoketene (Table 1, entry 6). CuI was essential to the reaction because
dithioacetals15 were subjected to rst direct C(sp2)–H iodination when KI was used in place of CuI or in absence of CuI desired
using N-iodosuccinimide as environmental friendly iodine product was not formed (Table 1, entries 7 & 8). By screening
source to get the desired compounds 2a–l in excellent yields. with polar organic solvents, such as n-BuOH, t-BuOH and PEG-
1
Formation of products was conrmed on the basis of H NMR 400 there was no formation of desired product 3f (Table 1,
and 13C NMR data. Disappearance of peak of vinylic proton at entries 9–11).
d 6.4–6.8 due to substitution by iodine with co-presence of peak
at d 94–100 due to vinylic C–I conrmed the presence of iodine scope of the reaction was explored considering both the yield
atom at a position. and variety of substituents at a-iodo oxoketene dithioacetals
With the optimized conditions in hand (Table 1, entry 3), the
Encouraged by the versatility of a-oxoketene dithioacetals to (Table 2). The results shown in Table 2 suggested that the
rapidly undergo substitution reactions,8e a-iodo substituted reaction of a-iodo oxoketene dithioacetals 2b–g bearing elec-
oxoketene dithioacetals were subjected to undergo tri- tron withdrawing substituents at both -m and -p positions could
uoromethylation reactions using relatively inexpensive, afford a-triuoromethylated oxoketene dithioacetals 3a–g in
convenient but underutilized methyl uorosulfonyl diuor- good yields (entry 2–7).
oacetate (FSO2CF2COOMe)16 as reagent through transition
For substrates with electron releasing group on aromatic
metal catalysed cross coupling reaction in the presence of CuI. ring, effective conversion was observed only with –pCH3 as
To identify the optimal conditions for the reaction, a-iodo substituent (entry 8).
oxoketene dithioacetal 2f was subjected to transition metal
However, a-iodo oxoketene dithioacetals substituted with
catalysed triuoromethylation using methyl uorosulfonyl –OCH3 at -o or -p positions were proven ineffective. This may be
diuoroacetate (FSO2CF2COOMe) and different reagents by anticipated due to inability of nucleophilic substitution reac-
varying solvents to yield 3f. When 1.5 eq. of FSO2CF2COOMe tion to take place due to increased electron density at vinylic
ꢀ
and 1.2 eq. of CuI were used in DMF as solvent at 60 C, 40% position through conjugation. Cyclopropyl substituted a-tri-
yield of product 3f was observed (Table 1, entry 1). An increase uoromethylated oxoketene dithioacetals were obtained in 86%
of temperature to 80 ꢀC resulted in the increase of yield to 60% yield (entry 9). Furthermore, when a heteroaromatic nucleus
(Table 1, entry 2). From the Table 1 it is clear that yield of was introduced in substrates 2j–l, the reaction provided the
desired compound 3f was maximum i.e. 86% when the reaction desired products 3j–l in good to excellent yields (entries 10–12).
was heated at 90 C (Table 1, entry 3). However no change in Structural assignments have been made on the basis of 1H
ꢀ
yield was observed when reaction temperature was increased NMR, 13C NMR and HRMS data. In 13C NMR data of compounds
from 90 ꢀC to 110 ꢀC (Table 1, entry 4). It should be noted that 3a–l, disappearance of peak at d 94–100 with simultaneous
increase in equivalents of FSO2CF2COOMe and CuI to 2 eq. did appearance of peaks at d 122 and d 119 which corresponds to
not had any effect on yield of 3f (Table 1, entry 5). An exami- vinylic carbon as well as carbon atom of –CF3 group was
nation of other copper source such as Cu(OAc)2 was not effective observed. HRMS data of each compound showed M+1 peak. The
for this transformation and deiodination of 2f was observed structure of the product 3l was determined by single crystal X-
ray diffraction (Fig. 1). The structures of the other products
were concluded by analogy.
Table 1 Optimization of reaction conditionsa
Finally, we demonstrated the further applicability of a-tri-
uoromethylated oxoketene dithioacetals 3a–l in cyclization
reactions, regioselective construction of aromatic/heteroaromatic
multisubstituted 1H-pyrazoles 4a–l was achieved in 72–83% yield
by cyclization with hydrazine hydrate (Table 3). Formation of the
regioselective cyclized product was conrmed on the basis of 1H
NMR and X-ray crystallographic studies of 4i (Fig. 2). Structural
Entry Source of CF3
Reagent Solvent Temp (ꢀC) Yieldb (%)
assignments of 4a–l have been made on the basis of IR, 1H NMR,
13C NMR, 19F NMR and HRMS data. IR spectra of the products
revealed absorption peaks for secondary amino groups (in the
region 3170–3460 cm1) while no peak for ketocarbonyl group
around 1670–1690 was observed which conrmed that –C]O
was utilized in cyclization reaction. In the 1H NMR spectra,
disappearance of one of the characteristic peak of –SMe group
with appearance of upeld shi of –NH protons as broad singlet
at d 7.8–9.3 ppm as compared to –NH protons of literature re-
ported compound 5 (ref. 14a) which appeared at d 11.9–12.2 ppm
supported the formation of cyclized pyrazole ring of 4(a–l)
1
FSO2CF2COOMe CuI
DMF
DMF
DMF
DMF
DMF
60
80
90
110
90
90
90
90
40
60
86
86
86c
—
—
—
—
—
—
2
3
4
5
FSO2CF2COOMe CuI
FSO2CF2COOMe CuI
FSO2CF2COOMe CuI
FSO2CF2COOMe CuI
6
FSO2CF2COOMe Cu(OAc)2 DMF
7
8
FSO2CF2COOMe KI
FSO2CF2COOMe
DMF
DMF
n-BuOH 90
t-BuOH 90
PEG-400 90
—
9
10
11
FSO2CF2COOMe CuI
FSO2CF2COOMe CuI
FSO2CF2COOMe CuI
a
Reactions were performed using 2f (1 mmol), 1.5 equiv. of regioselectively instead of compound 5. Disappearance of peaks
in 13C NMR for carbonyl carbon at d 175.5–195.5 ppm and –SCH3
FSO2CF2COOMe, 1.2 equiv. of reagent 3 h unless otherwise stated.
b
c
Isolated yield. Reaction were performed using FSO2CF2COOMe
carbon at 14.2–14.9 ppm conrms that the cyclized product was
formed. Appearance of a singlet at d À53.0–55.0 in 19F NMR data
(2eq.), catalyst (2eq.).
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Table 2 Synthesis of trifluoromethylated a-oxoketene dithioacetalsa
Entry
1
Substrate 2
Product 3
Yieldb (%)
80%
Fig. 1 ORTEP drawings of compound 3l.
2
3
4
5
85%
84%
86%
86%
Table
3 Regioselective synthesis of aromatic/heteroaromatic tri-
fluoromethylated 1H-pyrazolesa
6
7
85%
83%
8
9
82%
86%
a
Unless otherwise specied, reactions were performed using 1 equiv. of
3, 1.2 equiv. of NH2NH2$H2O in EtOH.
conrmed the presence of –CF3 group in the desired cyclized
compound.
10
11
85%
84%
In conclusion, we have developed a mild, ligand free
approach for the triuoromethylation of readily synthesized a-
iodo oxoketene dithioacetals in excellent yields. The reaction
was well tolerant towards a wide variety of substituents. The
simplicity and generality of this method makes it attractive
for the introduction of CF3 group into functionally diverse
a-iodo substituted oxoketene dithioacetals. The resultant tri-
uoromethylated synthons were further utilized as bifunctional
building blocks in cyclocondensation reaction for the exclusive
regioselective synthesis of valuable triuoromethylated
12
93%
a
Reactions were performed using 2a–l (1 mmol), 1.5 equiv. of
FSO2CF2COOMe, 1.2 equiv. of CuI 2–3 h. b Isolated yield.
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