Copper-Catalyzed Double C-H Alkylation of Aldehyde-Derived N,N-Dialkylhydrazones with Polyhalomethanes: Flexible Access to 4-Functionalized Pyrazoles

Article abstract of DOI:10.1021/acscatal.6b02439

Here, 4-functionalized pyrazoles have been made accessible in a single step from readily available aldehyde-derived N,N-dialkyl hydrazones and functionalized polyhalomethane derivatives. The process is believed to follow copper-catalyzed cascade C(sp²)-H haloalkylation/C(sp³)-H cyclization/aromatization reaction sequences.

Full text of DOI:10.1021/acscatal.6b02439

Letter
pubs.acs.org/acscatalysis
Copper-Catalyzed Double C−H Alkylation of Aldehyde-Derived
N,N‑Dialkylhydrazones with Polyhalomethanes: Flexible Access to
4‑Functionalized Pyrazoles
Alexis Prieto, Didier Bouyssi,* and Nuno Monteiro*
́ ́ ́
Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS), CNRS UMR 5246, Univ Lyon, Universite Claude
Bernard Lyon 1, F-69622 Villeurbanne, France
S
* Supporting Information
ABSTRACT: Here, 4-functionalized pyrazoles have been made accessible in a single
step from readily available aldehyde-derived N,N-dialkyl hydrazones and functionalized
polyhalomethane derivatives. The process is believed to follow copper-catalyzed cascade
C(sp2)−H haloalkylation/C(sp3)−H cyclization/aromatization reaction sequences.
KEYWORDS: copper, halomethanes, homogeneous catalysis, hydrazones, pyrazoles
Scheme 1. Transition-Metal-Catalyzed Double C−H Bond
Functionalization of N,N-Dialkylhydrazones as a Strategy
Toward Pyrazoles via C−C Bond Formation: (a)
Dehydrogenative Cyclization of Acetophenone-Derived
Hydrazones and (b) Tandem Haloalkylation/Cyclization of
Aldehyde-Derived Hydrazones
yrazoles are fascinating, highly essential heterocyclic
Pcompounds utilized extensively in various areas of the
chemical industry, notably as pharmaceuticals and agro-
chemicals, as well as coloring agents.1 Among other important
applications, they can act as ligands in coordination
compounds2 and serve as units in supramolecular architec-
tures.3 In view of the functional diversity of pyrazoles, the
development of new practical strategies to rapidly construct
such aza-heterocycles with diverse substitution patterns is
highly desirable. Among the conventional approaches devel-
oped over the past decades for the construction of the pyrazole
skeleton,4 the most commonly used include the cyclo-
condensation of hydrazine derivatives with 1,3-disubstituted
three-carbon units, including 1,3-diketones and α,β-unsaturated
ketones, and the [3 + 2] cycloadditions of nitrogen-based 1,3-
dipoles with alkynes or alkenes. However, such procedures
often suffer from regioselectivity issues, which greatly reduces
their attractiveness. Hydrazones are important, easily available
intermediates in synthetic organic chemistry involved in a
plethora of applications5 that also include the synthesis of
functionalized pyrazoles.6 In this area, the development of
efficient and practical methods involving transition-metal-
catalyzed intramolecular C−C or C−N bond formation
through direct double functionalization of C−H bonds has
been the recent target of synthetic chemists.7 A notable
illustration of this type of approach was given by Ge and co-
workers,7c who reported, in 2013, an elegant copper-catalyzed
dehydrogenative cyclization of acetophenone-derived N,N-
dialkylhydrazones by a double C(sp3)−H bond functionaliza-
tion (Scheme 1a). An interesting feature of the process pertains
to a direct functionalization at the sp3-hybridized carbon atom
α to the terminal hydrazone amino group.8 However, despite its
simplicity and high synthetic efficiency, the process was found
to not be suitable to deliver C4-substituted pyrazoles.
Aldehyde-derived N,N-disubstituted hydrazones are partic-
ularly attractive as umpolung carbonyl reagents, because of the
presence of the electron-releasing amino component that
activates the azomethine (CHN) carbon atom position
toward electrophilic substitution,9 thereby enabling introduc-
tion of a functional group through direct C(sp2)−H bond
functionalization. The past few years have witnessed intense
renewed activity in this research area, with contributions from
our own group10 and others.11 Efficient catalytic radical
Received: August 26, 2016
Revised: September 20, 2016
© XXXX American Chemical Society
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Letter
reactions using transition metals (Cu, Pd, Au, Ir) have been
developed that allow the installation of a wide range of new
Table 1. Selected Optimization Experiments for the Cu-
Catalyzed Trichloromethylation/Cyclization of Hydrazone
functional groups (e.g., CF3,10a,b,11a CF2CO2Et,
a
1a with CCl4
10c,d,11a,c
CF2CONR2
PO(OEt)211d), and thereby create new
opportunities for practical applications of these valuable
synthetic intermediates. For instance, we have demonstrated10d
the Cu-catalyzed C(sp2)−H alkylation of N,N-dialkylhydra-
zones (1) with difluoromethyl bromides (BrCF2R) that yields
difluoroalkylated hydrazones as useful precursors toward α,α-
difluorocarbonyl compounds.10c The transformation was
suggested to be initiated by a radical/SET pathway involving
the formation of an electrophilic haloalkyl radical that can add
to the CN bond of the hydrazone.12 As part of our ongoing
efforts to devise new applications of this methodology, it was
envisioned that other nonfluorinated polyhalomethanes (i.e.,
CCl4, R−CCl3) may participate in the process13 and open up
direct access to hitherto unknown polyhalomethylated N,N-
dialkylhydrazones (2) as expectedly reactive synthetic inter-
mediates having high potential for further elaboration.14 As we
began exploring this possibility using CCl4 as a CCl3-transfer
reagent, we made an interesting discovery: the reaction resulted
in direct formation of a pyrazole derivative having incorporated
a Cl atom at the C-4 position (3, R4 = Cl) (Scheme 1b). Such
unexpected reaction, whereby two new C−C bonds are formed
in sequence, appeared very promising as a novel, practical, and
convergent access to polysubstituted pyrazoles from simple,
readily available starting materials, while allowing flexible
attachment of chemical handles at the C-4 position that can
further help to create diversity. Herein, we disclose our
preliminary investigations regarding the scope and limitations
of the method, and we provide some mechanistic insight into
plausible reaction pathways.
Initial studies focused on the trichloroalkylation of p-
trifluoromethylbenzaldehyde N,N-dimethylhydrazone 1a using
CCl4 as a solvent and reagent in the presence of a base (i.e.,
Et3N, DIPEA, KOAc, or K2CO3), and a copper catalyst
combined with a nitrogen-based bidentate ligand (i.e., Tmeda,
Bipy, or Phen) (see Table 1). Preliminary experiments
established the following conditions as being optimal in
affording the corresponding 4-chloropyrazole 3a in satisfying
yield (70%, 19F NMR spectroscopy): 10 mol % CuCl (or CuI)/
Phen, Et3N (4 equiv), 80 °C, 2 h (see Table 1, entries 4 and 5).
Importantly, the reaction would not proceed in the absence of
catalyst under otherwise identical conditions (Table 1, entry 7).
Also important was the fact that CCl4 does not need to be used
as a solvent. Indeed, the same reaction could be performed, for
instance, in 1,4-dioxane in the presence of only 5 equiv of CCl4,
which gave pyrazole 3a in identical yield (Table 1, entry 15).
Other solvents (i.e., DCE, MeCN, or THF) proved less
effective (Table 1, entries 12−14).
b
time
(h)
yield
(%)
entry
cat
ligand
base
solvent
CCl4
1
2
CuCl
CuCl
CuCl
CuCl
CuI
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
24
24
24
2
57
47
70
69
70
65
0
Tmeda
Bipy
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
DCE
3
4
Phen
Phen
Phen
5
2
6
CuCl2
2
7
2
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
2
0
9
DIPEA
KOAc
K2CO3
Et3N
2
38
29
0
10
11
12
13
14
15
16
2
2
c
2
31
33
60
70
58
c
Et3N
MeCN
2
c
Et3N
THF
2
c
Et3N
1,4-dioxane
1,4-dioxane
2
d
Et3N
2
a
Reaction conditions: 1a (0.3 mmol), base (4 equiv), 10 mol % copper
salt, 10 mol % ligand (Tmeda = tetramethylethylenediamine, Bipy =
2,2′-bipyridine, Phen = 1,10-phenanthroline) in 2.0 mL of solvent at
b
80 °C. Determined by 19F NMR spectroscopy, using α,α,α-
c
d
trifluorotoluene as an internal standard. 5 equiv of CCl4. 2 equiv
of CCl4.
a
Table 2. Scope of Organic Polyhalides
b
entry
R−CX3
CCl4
product
yield (%)
1
2
3
4
5
6
7
R = Cl (3a)
70 (47)
CCl3Br
R = Cl (3a)
48 (−)
43 (21)
84 (66)
93 (72)
CBr4
R = Br (3b)
R = CN (3c)
R = CO2Et (3d)
R = COPh (3e)
R = F (3f)
CCl3CN
CCl3CO2Et
CCl3COPh
CCl3F
c
With suitable reaction conditions in hand, we began to
examine the scope of the reaction. We envisioned that many
organic halides other than CCl4 may prove to be suitable
reacting partners and open access to pyrazoles featuring a
diversity of functional groups at the C-4 position, having
potential for further derivatization reactions. Therefore, we
investigated the reaction of our model substrate 1a with a series
of polyhalogenated methanes (see Table 2). It is noteworthy
that bromotrichloromethane (CCl3Br) could not be used with
similar success in the production of 4-chloropyrazole 3a (Table
2, compare entries 1 and 2). A comparable reactivity was
observed with tetrabromomethane (CBr4), which furnished the
corresponding 4-bromopyrazole 3b in only moderate yield
45 (42 )
NR
a
Reaction conditions: 1a (0.5 mmol), R−CX3 (5.0 equiv), Et3N (4
equiv), 10 mol % CuCl/Phen in 3.0 mL of 1,4-dioxane at 80 °C for 2
b
h. Determined by 19F NMR spectroscopy using α,α,α-trifluoroto-
luene as an internal standard. Isolated yields are indicated in
parentheses. The isolated product contained about 7% of inseparable
c
impurities.
(Table 2, entry 3). A series of functionalized trichloromethanes
was then tested. Gratifyingly, trichloroacetonitrile (CCl3CN)
and ethyl trichloroacetate (CCl3CO2Et) participated efficiently
in the process, giving the desired pyrazoles, having incorporated
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Letter
a cyano (3c) or ester group (3d) in good isolated yields (66%
and 72%, respectively; see Table 2, entries 4 and 5).
Trichloroacetophenone (PhCOCCl3) also yielded the corre-
sponding functionalized pyrazole (3e), albeit in moderate yield
(Table 2, entry 6). Finally, we were attracted by the possibility
of accessing a C4-fluorinated pyrazole (3f). Disappointingly,
however, the reaction was not applicable to trichlorofluoro-
methane (CCl3F) (Table 2, entry 7).
which may also serve as useful reaction handles for further
elaborations. We then further explored the substrate scope,
with regard to substitution pattern at the terminal hydrazone
amino group that would enable installation of substituents at
the C-5 position of the pyrazole ring (Scheme 3). Interestingly,
a
Scheme 3. Scope of Hydrazine Precursors
Next, we investigated the effect of substituents on the aryl
moiety of various benzaldehyde N,N-dimethylhydrazones
(Scheme 2). Relatively good yields were generally achieved
a
Scheme 2. Scope of Aldehyde Precursors
a
Reaction conditions: 1 (0.5 mmol), R4−CCl3 (5.0 equiv), Et3N (4
equiv), CuCl (10 mol %), and Phen (10 mol %) in 3.0 mL of 1,4-
dioxane at 80 °C for 2 h. Isolated yields are given. The product
b
contained about 8% of inseparable impurities.
hydrazones bearing cyclic amino groups, i.e., 1-piperidinyl, 4-
morpholinyl, and 1-homopiperidyl participated in the cycliza-
tion process, giving the desired pyrazolo-annelated products
(3x−y, 3z, and 3aa, respectively) in moderate to good yields.
An X-ray structure was obtained for 3x, confirming its chemical
structure.15
Importantly, the cost-effectiveness and mildness of the
method created scale-up opportunities. For instance, a 10
mmol preparative-scale synthesis of 4-cyanopyrazole 3y could
be achieved without further optimization while still maintaining
a high isolated yield of 73%, thus demonstrating the robustness
of our protocol (see Scheme 4).
A preliminary investigation into the mechanism of the
reaction was then conducted. The possibility of a radical/SET-
initiated pathway similar to that previously postulated for
difluoroalkylation reactions of hydrazones was first inves-
tigated.10c,d,11c Interestingly, addition of radical scavenger
2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO, 5 equiv) to the
a
Reaction conditions: 1 (0.5 mmol), R2−CCl3 (5.0 equiv), Et3N (4
equiv), CuCl (10 mol %), and Phen (10 mol %) in 3.0 mL of 1,4-
dioxane at 80 °C for 2 h. Isolated yields are given.
Scheme 4. Gram-Scale Experiment
with para- and meta-substituted aryls regardless of the electron-
donating or electron-withdrawing nature of substituents (3g−
3u). Again, the nature of the substituent incorporated at the C-
4 position influenced the yield, best results being achieved with
a CN or CO2Et group, compared to chlorine. As illustrated by
3v, even sterically hindered ortho-substituted aryls were
tolerated to some extent. Notably, the reaction displayed
good tolerance toward a variety of functional groups, including
cyano, carboxylic ester, acetyl, N,N-dimethylamino, and halide
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standard reaction of 1a with CCl3CO2Et totally inhibited the
formation of 3a (Scheme 5a). In addition, when butylated
Aromatization to the pyrazole (3) would finally occur via the
elimination of HCl.17
In summary, we have developed a cost-efficient, scalable
protocol for the preparation of 4-functionalized pyrazoles based
on readily available aldehyde-derived N,N-dialkylhydrazones,
functionalized polyhalomethanes, and copper salt catalyst. The
reaction exhibits a broad substrate scope and excellent
functional-group tolerance, and it allows flexible attachment
of chemical handles at the C-4 position that may be used for
further chemistry. The process is believed to follow a cascade
copper-catalyzed C−H haloalkylation/C−H cyclization/aroma-
tization reaction sequence, whereby two new C−C bonds are
formed. Further studies into the scope and limitations, as well
as the mechanistic understanding of this reaction, are currently
underway in our laboratories.
Scheme 5. Mechanism Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b02439.
hydroxytoluene (BHT, 5.0 equiv) was used as a radical
scavenger in this reaction, 3a was produced in a significantly
diminished yield (47%). Interestingly, a BHT-CCl2CO2Et
adduct was also isolated in the form of the cyclohexadienone
4 (33% yield based on BHT) (Scheme 5b). Moreover, the
presence of 1 equiv of the electron transfer scavenger p-
dinitrobenzene (DNB) had also a dramatic deleterious effect,
leading to inhibition of the reaction (Scheme 5c).
In light of the above observations, and on the basis of
previous reports, a cascade copper-catalyzed haloalkylation/
cyclization/aromatization sequence may be proposed as a
plausible reaction pathway (see Scheme 6). This mechanism
Experimental procedures including characterization and
NMR spectra for all new compounds (PDF)
X-ray data for compound 3x (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: didier.bouyssi@univ-lyon1.fr.
*E-mail: nuno.monteiro@univ-lyon1.fr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 6. Possible Mechanistic Pathway
■
This research was assisted financially by a grant to A.P. from the
French Ministry of Higher Education and Research (MESR).
We thank G. Pilet (Laboratoire des Multimater
́
iaux et
Interfaces, Universite
analysis.
́
Lyon 1) for the X-ray crystallographic
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