Palladium-Catalyzed C(sp2)-H Alkylation of Aldehyde-Derived Hydrazones with Functionalized Difluoromethyl Bromides

Article abstract of DOI:10.1002/anie.201510334

A palladium-catalyzed C(sp²)-H difluoromethylation of aldehyde-derived hydrazones using bromodifluoromethylated compounds to afford the corresponding functionalized difluoromethylketone hydrazones has been established. It is proposed that a radical/SET mechanism proceeding via a difluoroalkyl radical may be involved in the catalytic cycle. Applications of the methodology to the synthesis of α,α-difluoro-β-ketoesters and α,α-difluoroketones (RCOCF₂H) have been illustrated.

Full text of DOI:10.1002/anie.201510334

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International Edition: DOI: 10.1002/anie.201510334
German Edition: DOI: 10.1002/ange.201510334
Homogeneous Catalysis
2
À
Palladium-Catalyzed C(sp ) H Alkylation of Aldehyde-Derived
Hydrazones with Functionalized Difluoromethyl Bromides
Alexis Prieto, Romain Melot, Didier Bouyssi,* and Nuno Monteiro*
2
me 1a).[5] Our current efforts are now focusing on the
À
Abstract: A palladium-catalyzed C(sp ) H difluoromethyla-
tion of aldehyde-derived hydrazones using bromodifluorome-
thylated compounds to afford the corresponding functional-
ized difluoromethylketone hydrazones has been established. It
is proposed that a radical/SET mechanism proceeding via
a difluoroalkyl radical may be involved in the catalytic cycle.
Applications of the methodology to the synthesis of a,a-
difluoro-b-ketoesters and a,a-difluoroketones (RCOCF2H)
have been illustrated.
discovery of efficient protocols for the direct introduction of
functionalized difluoromethylene (CF2) groups. The CF2
moiety has attracted significant attention in recent years
with applications arising in various areas, including medicinal
chemistry. For instance, the difluoromethylene moiety (CF2R,
CF2H) has been recognized as a potential bioisostere of
hydroxy or thiol groups, as well as a carbonyl group. The
benefits include increased acidity of proximate functional
groups and conformational changes.[6] Compared to trifluoro-
2
À
A
ldehyde-derived hydrazones are important, readily avail-
methylation, C(sp ) CF2 bond-forming reactions have been
able reagents in synthetic organic chemistry and involved in
a plethora of applications.[1] They are notably attractive as
umpolung carbonyl reagents because of the presence of the
electron-releasing amino component which activates the
much less explored and new methods are therefore highly
desirable. For this purpose, it is of interest to note that while
there is still a lack of readily available, broadly useful
electrophilic hypervalent(III) iodine CF2-transfer reagents,[7]
various functionalized halodifluoromethylated compounds
=
azomethine (CH N) carbon atom position towards electro-
philic substitution.[2] Given the unique properties that fluo-
[Hal CF2 FG with FG = CO2Et, CONR2, PO(OEt)2,
SO2Ph] have been recently shown to be convenient reagents
to access difluoromethylated compounds by transition metal
catalyzed (or mediated) coupling reactions, and notably those
involving palladium.[8–17] Only a limited number of palladium-
catalyzed difluoromethylation processes with functionalized
difluoromethyl halides have been reported so far. Reports in
the late 80ꢀs by the groups of Chen[10] and Burton[11]
established the palladium(0)-induced addition of fluoroalkyl
iodides to alkenes as a SET-initiated radical process[12]
involving a difluoromethyl radical, thus leading to the
corresponding iododifluoromethylated adducts. More
recently in 2014, Wang and co-workers[13] described a palla-
dium-catalyzed aryldifluoromethylation process which
affords difluoromethylated oxindole derivatives from N-
arylacrylamides and ICF2SO2Ph. A difluoromethyl radical
triggered by palladium(0) supposedly initiates the reaction. In
2012, the group of Reutrakul[14] reported the Heck-type
coupling of BrCF2SO2Ph with either styrenes or vinyl ethers
and the mechanism is proposed to follow the well-known
Heck catalytic cycle. In the same paper, the authors also
À
À
rine substitution can impart on molecules,[3] we recently
2
À
became interested in the development of methods for C(sp )
H electrophilic fluoroalkylation of aldehyde-derived hydra-
zones, thus anticipating that this would expand their applica-
tion to potentially useful organofluorine molecules for
biological investigations.[4] In 2013, we reported a very mild
protocol for introducing a trifluoromethyl (CF3) group onto
the azomethine position of N,N-disubstituted aldehyde-
derived hydrazones. The process relies on the use of a hyper-
valent iodine CF3-transfer reagent which supposedly acts as
a trifluoromethyl radical source in the presence of a copper
salt by a single-electron transfer (SET) mechanism (Sche-
À
described the C H difluoromethylation of various hetero-
aromatic compounds.[15] Efficient Heck-type protocols appli-
cable to a wide range of fluoroalkyl bromides, including
BrCF2CO2Et and acetamide derivatives, were proposed by
Zhang and co-workers in 2015, with some evidence for
a radical/SET mechanism which proceeds by free fluoroalkyl
radicals.[16] Previously, the palladium-catalyzed difluorome-
thylation of aryl boronic acids with BrCF2PO(OEt)2 had been
investigated by the same group.[17a] A SET-initiated radical
À
Scheme 1. Transition metal catalyzed C H fluoroalkylation of hydra-
zones.
[*] A. Prieto, R. Melot, Dr. D. Bouyssi, Dr. N. Monteiro
UniversitØ Lyon 1, Institut de Chimie et Biochimie MolØculaires et
SupramolØculaires, CNRS UMR 5246, CPE Lyon
43, Boulevard du 11 Novembre 1918, 69622 Villeurbanne (France)
E-mail: Bouyssi@univ-lyon1.fr
À
oxidative addition of the C Br bond was suggested to be
involved in the palladium catalytic cycle. Subsequently,
Monteiro@univ-lyon1.fr
difluoroallylation,[17b] difluoropropargylation,[17c] and hetero-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510334.
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aryldifluoromethylation[17d] of organoborons were reported
by this group.
In this context, we reasoned that since oxidative addition
of bromodifluoromethyl reagents to palladium is feasible,
selected reaction conditions. The use of monodentate phos-
phine ligands led essentially to no conversion (entries 1–4).
The bidentate diphenylphosphine ligand Xantphos, known as
an efficient ligand for reductive elimination from fluoroalkyl
then electrophilic palladation of aldehyde-derived hydra-
palladium(II)
complexes,
also
proved
ineffective
zones with the resulting FG CF2Pd Br complex might
(entry 9).[17a,19] However, we were pleased to discover that
the related tBuXantphos, bearing bulkier tert-butyl groups on
the P atoms, was an extremely efficient ligand for promoting
the reaction, thus affording the desired difluorinated product
3a in an excellent 93% yield as determined by 19F NMR
spectroscopy (entry 10). Among other bidentate ligands
tested (entries 5–8), only rac-binap and the ferrocenyl-based
ligand dppf showed potent activity, but proved far less
efficient compared to tBuXantphos. Note that essentially no
reaction was observed in the absence of a ligand (entry 12).
Other combinations of bases (tBuOK, K2CO3, K3PO4, Et3N)
and solvents (MeCN, toluene, DMF, DMSO) were also
examined but did not lead to any significant improvement.[20]
With the optimized reaction conditions in hand, the scope
of the coupling reaction was then examined (Scheme 2). First
we investigated the effect of varying the nature of the
terminal amino group of the p-nitrobenzaldehyde-derived
II
À
represent a possible alternative strategy to the desired
difluoromethylated aldehyde-derived hydrazones (Sche-
me 1b). To the best of our knowledge, there is only one
2
À
precedent for the palladium-catalyzed C(sp ) H functional-
ization of hydrazones and it was reported by Hartwig and co-
workers[18] in 2006. The report concerned the coupling of aryl
bromides with N-tert-butylhydrazones to afford the corre-
sponding aryl ketones upon hydrolysis. The reaction is
believed to occur by a catalytic mechanism similar to that
proposed for the arylation of ketones. Herein we report the
development of a palladium-catalyzed coupling of aldehyde
hydrazones with halodifluoromethylated reagents which
affords difluoromethylketone hydrazones.
Preliminary studies have focused on the reaction of the
p-nitrobenzaldehyde-derived N,N-dimethylhydrazone 1a as
a
model substrate with ethyl bromodifluoroacetate
(BrCF2CO2Et; 2; Table 1). The latter reagent is particularly
attractive as it is practical, inexpensive, and provides a con-
venient functional handle for further elaboration or increase
in molecular complexity. The reaction was initially evaluated
at 808C using 1,4-dioxane as the solvent, AcOK as the base,
and a catalytic amount [Pd2(dba)3] as a source of palladium-
(0). Several phosphorus ligands were thus screened under the
Table 1: Selected optimization experiments for difluoromethylation of
the 4-nitrobenzaldehyde-derived N,N-dimethylhydrazone 1a with 2.[a]
Entry
Ligand (mol%)
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
tBu3P·HBF4 (10)
tBuXPhos (10)
RuPhos (10)
DavePhos (10)
rac-binap (5)
dppf (5)
tBu-dppf (5)
DPEPhos (5)
Xantphos (5)
tBuXantphos (5)
tBuXantphos (10)
none
24
24
24
24
24
24
24
24
24
2
trace
5
trace
trace
16
29
trace
trace
trace
93 (76)[c]
63
9
10
11
12
2
2
6
[a] Reaction conditions: 1a (0.3 mmol), 2 (2.0 equiv), AcOK (2 equiv),
[Pd2dba3] (2.5 mol%). and ligand in 1.0 mL solvent. [b] Determined by
19F NMR spectroscopy using a,a,a-trifluorotoluene as an internal
standard. [c] Yield of the isolated product. binap=2,2’-bis(diphenyl-
phosphanyl)-1,1’-binaphthyl, DavePhos=2-dicyclohexylphosphanyl-2’-
(N,N-dimethylamino)biphenyl, dba=dibenzylideneacetone, DPE-
Phos=bis(2-diphenylphosphinophenyl)ether, dppf=1,1’-bis(diphenyl-
phosphino)ferrocene, Ruphos=2-dicyclohexylphosphino-2’,6’-diiso-
propoxybiphenyl, Xantphos=9,9-dimethyl-4,5-bis(diphenylphosphino)-
xanthene.
Scheme 2. Scope of the palladium-catalyzed difluoromethylation of
aldehyde hydrazones with BrCF2CO2Et. Reaction conditions:
1 (0.5 mmol), 2 (1.0 mmol), AcOK (1.0 mmol), [Pd2(dba)3]
(0.0125 mmol), and tBuXantphos (0.025 mmol) in 1.5 mL 1,4-dioxane
at 808C. Yields (%) were determined by 19F NMR analysis of the crude
reaction mixture using a,a,a-trifluorotoluene as an internal standard.
Yield of the isolated product is given within parentheses. [a] 89% yield
of isolated product based on recovered starting material. [b] N.D.=not
determined; the products are contaminated with unreacted starting
material (see the Supporting Information).
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hydrazones. While the dibenzylhydrazone still furnished the
The mechanistic details of the catalytic coupling reaction
expected product 3b, albeit in moderate yield, the much less
electron-donating diphenylhydrazone resulted in essentially
no reaction (3c). Hydrazones bearing cyclic amino groups,
that is, 1-piperidinyl and 4-morpholinyl, participated effi-
ciently in the coupling reaction giving the desired products 3d
and 3e, respectively, in high yields. Most interestingly, the
monosubstituted N-methylhydrazone yielded the ring-fluori-
nated 4,4-difluoropyrazol-5-one 3 f as the sole product, which
presumably originates from spontaneous lactamization of the
amino ester coupling product.[22] Next we investigated the
effect of substituents on the aryl moiety of various benzalde-
hyde-derived N,N-dimethylhydrazones. Good results were
obtained with para- and meta-substituted aryls. Notably,
substrates with electron-withdrawing para substituents
afforded the products 3g–m in higher yields than those
bearing electron-donating substituents (3o–r). However,
sterically hindered ortho-substituted aryls afforded the
desired coupling product in low yield (3u). The reaction
tolerated a wide range of substituents/functional groups,
including nitro, cyano, carboxylic ester, formyl, acetyl, and
halide (Cl, Br), thus offering opportunities for further
diversification. However, the presence of a vinyl substituent
on the aryl moiety (3t) led only to decomposition of the
substrate. Importantly, several heterocyclic aldehyde-derived
hydrazones [i.e. pyridinyl, quinolinyl, and pyrazolyl (3v–3x)]
proved suitable substrates for the transformation wherein the
heterocyclic ring was untouched. An ethyl glyoxylate hydra-
zone participated also efficiently in the reaction (3y).
Unfortunately, as illustrated with 3z, aliphatic aldehyde-
derived hydrazones proved to be more challenging substrates
for this reaction, thus giving only small amounts of the desired
product under the standard reaction conditions. Finally, the
robustness of this transformation was further demonstrated
by performing the synthesis of 3m on a 2.5 mmol scale (64%
yield).[23] Importantly, the scope of the reaction coupling
partners was not restricted to ethyl bromodifluoroacetate 2
(Scheme 3). Indeed, the coupling reaction of 1a with the
remain unclear at the present stage. However, given the
known propensity of Pd0 species to promote the formation of
difluoromethyl radicals from fluoroalkyl halides through
SET,[10–13,16,17] the possibility of a radical/SET pathway that
would initiate the catalytic reaction was briefly explored. Our
standard coupling reaction of 1a with 2 (93% yield) was thus
repeated in the presence of the radical scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO; 1.0 equiv). Interest-
ingly, formation of coupling product 3a was completely
inhibited, and the TEMPO–CF2CO2Et adduct 8[24] was
formed in 31% yield as estimated by 19F NMR spectroscopy
(Scheme 4a). The reaction was also conducted in the presence
Scheme 4. Preliminary mechanistic studies. a) Inhibition experiment
using TEMPO. b) Radical clock experiment with a-cyclopropylstyrene.
of 2,6-di-tert-butyl-4-methylphenol (BHT; 1.0 equiv) which
again led to inhibition of the coupling process. Moreover,
repeating the reaction in the presence of 5 mol% of the
electron transfer scavenger p-dinitrobenzene (1:1 ratio with
respect to the metal) caused a dramatic drop in the reaction
yield (25%). Finally, we performed a radical clock experi-
ment using a-cyclopropylstyrene (9) as a radical trapping
agent.[25] When 9 was reacted with 2, formation of the known
ring-expanded product 10 was observed (18% yield as
estimated by 19F NMR spectroscopy), thus confirming that
a free CF2CO2Et radical can be generated under our standard
reaction conditions (Scheme 4b).[16b]
bromodifluoroacetamide
4,[17b]
or
even
2-(bromo-
difluoromethyl)benzo[d]oxazole (6),[17d] was made possible
with some modifications of the reaction conditions (potas-
sium phosphate as the base in DMF at 1208C) to afford the
desired coupling products 5 and 7, respectively.
These preliminary experiments seem to confirm that
a radical/SET pathway may initiate the coupling reaction.
Furthermore, deuterium-labeling studies showed no primary
kinetic isotope effect (KIE; kH/kD = 1.14) in the experiment
using
a deuterated benzaldehyde-derived N,N-dimethyl-
hydrazone (1n-d) thus indicating that cleavage of the
À
azomethine C H bond is not involved in the rate-determining
step of the process.[20] A plausible mechanism is depicted in
Scheme 5 and takes into account the previous observations.
The process would begin with single-electron transfer from
the Pd0 metal complex to the fluoroalkyl bromide to form the
PdIBr complex A and difluoroalkyl radical intermediate B,
with subsequent recombination of these two species to give
the regular PdII oxidative addition adduct C.[26] Subsequent
electrophilic palladation of the hydrazone, followed by
deprotonation of the resulting cationic intermediate D
would generate the azomethinyl PdII complex E. Finally,
reductive elimination would form the coupling product and
Scheme 3. Scope of coupling partners. DMF=N,N-dimethylform-
amide.
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Scheme 7. Elaboration of the hydrazone products 3.
ation at 608C to afford the corresponding b-ketoester 11 in
75% yield upon isolation (Scheme 7). a,a-Difluoro-b-
ketoesters are particularly attractive as precursors of optically
active fluorinated b-hydroxy esters which are important
building blocks for the synthesis of various organofluorine
compounds, notably bioactive fluorinated peptides.[28] Inter-
estingly, it was also established that further microwave
irradiation at a more elevated temperature (2008C) allows
subsequent deethoxycarbonylation of the difluoro keto-
esters[29] to afford the corresponding a,a-difluoro ketones
(RCOCF2H). This transformation was illustrated by the one-
pot, two-step synthesis[30] of the difluorinated pyrazolyl-
ethanone 12 (62% yield), on account of the important role
played by fluorinated pyrazoles in medicinal and agro
chemistry.[31] Overall, these valuable a,a-difluoro carbonyl
derivatives are made accessible in three steps from simple
aldehydes.[32]
Scheme 5. SET-initiated mechanism involving electrophilic palladation.
Scheme 6. SET-initiated mechanism involving electrophilic radical
In summary, we have developed a practical procedure for
the synthesis of hitherto unknown a,a-difluoroketone hydra-
zones based on the coupling of readily available (hetero)-
aromatic aldehyde-derived hydrazones with halodifluorome-
thylated reagents under palladium catalysis. In addition,
applications of the methodology to functional-group trans-
formations have been illustrated, notably through the
straightforward conversion of aldehydes, via their hydrazones,
into a,a-difluoro-b-ketoesters and a,a-difluoroketones. We
have also shown that 4,4-difluoropyrazol-5-one derivatives
are directly accessible from N-monosubstituted hydrazones,
although the transformation would require further optimiza-
tion. Further studies into the scope and limitations as well as
the mechanistic understanding of this reaction are currently
underway in our laboratories and will be reported as events
merit.
addition.
recycle the active Pd0 catalytic species. However, other
mechanistic pathways that would involve addition of B
across the C N bond of the hydrazone as a key step and
result in the formation of the aminyl radical F, cannot be ruled
out at this stage (Scheme 6). In this case, H-elimination would
then proceed by two possible pathways. The radical F may be
oxidized by PdI to the cationic intermediate G, thereby
regenerating the active Pd0 species. Subsequent deprotona-
=
=
tion would restore the C N bond of the hydrazone moiety to
yield the final product. Alternatively, F may be trapped by PdI
to give the PdII complex H. The C N bond would then be
=
restored by b-hydride elimination.[27] It is noteworthy that no
TEMPO–hydrazone adduct was detected in the trapping
experiment. Although conclusive evidence is still pending,
detection of reaction intermediates by positive ion electro-
spray mass spectrometry revealed molecular ions at m/z 685.1
and 727.3, with the predicted isotope pattern resulting from
the palladium atom, and they are attributed to the [(tBu-
Xantphos)PdBr]+ and [(tBuXantphos)PdCF2CO2Et]+ cat-
ions, respectively, thereby providing evidence for difluoro-
alkyl palladium intermediates.[20]
Experimental Section
Preparation of the difluoropropanoate hydrazones 3: In a glass tube
equipped with a magnetic stir bar, the selected hydrazone (0.5 mmol),
dry potassium acetate (98.2 mg, 1.0 mmol), and ethyl 2-bromo-2,2-
difluoroacetate (128.2 mL, 1.0 mmol) were successively added to
a suspension of [Pd2dba3] (11.5 mg, 2.5 mol%) and tBuXantPhos
(12.5 mg, 5 mol%) in 1,4-dioxane (1.5 mL). The reactor was flushed
with argon, sealed, and heated at 808C for 2 h. The reaction mixture
was then cooled to room temperature and concentrated in vacuo. The
residue was purified by flash chromatography (silica gel, appropriate
mixture of n-pentane/ethyl acetate) to afford the corresponding
difluoropropanoate hydrazone.
The hitherto unknown hydrazones 3 are compounds with
great potential for further synthetic manipulation, notably as
intermediates for different classes of a,a-difluoro carbonyl
derivatives. For instance, the carbonyl function of 3n could be
restored by simple acidic treatment under microwave irradi-
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[17] a) Z. Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang, X. Zhang, Angew.
Acknowledgments
Chem. Int. Ed. 2014, 53, 1669; Angew. Chem. 2014, 126, 1695. It is
noteworthy that other functionalized difluoroalkyl halides, for
example, BrCF2CO2Et and acetamide derivatives, participated
in the reaction but required copper iodide as a cocatalyst; b) Q.-
Q. Min, Z. Yin, Z. Feng, W.-H. Guo, X. Zhang, J. Am. Chem.
Soc. 2014, 136, 1230; c) Y.-B. Yu, G.-Z. He, X. Zhang, Angew.
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4822.
This research was supported financially by a grant to A.P.
from the French Ministry of Higher Education and Research
(MESR). We thank G. Pilet (Laboratoire des multimatØriaux
et interfaces, UniversitØ Lyon 1) for the X-ray crystallo-
graphic analysis, and C. Duchamp for mass spectrometry
analyses.
[18] A. Takemiya, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 14800.
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Keywords: fluorine · homogeneous catalysis · hydrazones ·
palladium · reaction mechanisms
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1885–1889
Angew. Chem. 2016, 128, 1917–1921
[20] See the Supporting Information for details.
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À
[15] For another recent report on the palladium-catalyzed C H
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Received: November 6, 2015
Published online: December 16, 2015
Angew. Chem. Int. Ed. 2016, 55, 1885 –1889
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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