Copper-Catalyzed Reaction of Trifluoromethylketones with Aldehydes via a Copper Difluoroenolate

Article abstract of DOI:10.1002/anie.201508266

A copper-catalyzed reaction of easily accessible α,α,α-trifluoromethylketones with various aldehydes affords difluoro-methylene compounds in the presence of diboron and NaOtBu. The key process of the reaction is the formation of a copper difluoroenolate by 1,2-addition of a borylcopper intermediate to α,α,α-trifluoromethylketones and subsequent β-fluoride elimination. Mechanistic studies including the isolation and characterization of a possible anionic copper alkoxide intermediate are also described.

Full text of DOI:10.1002/anie.201508266

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Communications
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International Edition: DOI: 10.1002/anie.201508266
German Edition: DOI: 10.1002/ange.201508266
Aldol Reaction
Copper-Catalyzed Reaction of Trifluoromethylketones with Aldehydes
via a Copper Difluoroenolate
Ryohei Doi, Masato Ohashi, and Sensuke Ogoshi*
Abstract: A copper-catalyzed reaction of easily accessible
a,a,a-trifluoromethylketones with various aldehydes affords
difluoro-methylene compounds in the presence of diboron and
NaOtBu. The key process of the reaction is the formation of
a copper difluoroenolate by 1,2-addition of a borylcopper
intermediate to a,a,a-trifluoromethylketones and subsequent
b-fluoride elimination. Mechanistic studies including the iso-
lation and characterization of a possible anionic copper
alkoxide intermediate are also described.
Scheme 1. a) The CÀC bond formation of a nickel difluoroenolate with
b. [Ni]=[Ni(dcpe)][FB(C F ) ]. b) Retrosynthetic analysis of the
2
6
5 3
difluoroenolate A (M, m=metal).
D
ifluoroenolates are powerful synthetic tools for preparing
difluoro-methylene compounds which are important inter-
[
1]
mediates or products in medicinal chemistry. Several pro-
tocols to generate difluoroenolates by the Reformatsky
reaction using relatively expensive a-bromo-a,a-difluorocar-
bonyl compounds and other stepwise procedures have been
phenyl)imidazole-2-ylidene, pin = 2,3-dimethyl-2,3-butane-
diolate] to an aldehyde generates an a-borylated copper
[
7,8]
alkoxide in situ.
Inspired by this reaction, we conducted
the reaction of [(IPr)CuBpin] with 1a to observe the copper
alkoxide 4a/CuIPr in a 32% yield (Scheme 2). The molecular
[
2–4]
reported.
Herein, we disclose the copper-catalyzed reac-
tions of trifluoromethylketones with aldehydes via a copper
difluoroenolate which enables direct transformation of tri-
fluoroacetic acid derivatives into difluoro-methylene com-
pounds. A possible reaction path concerning the reactivity
and equilibrium of difluoroenolate is also discussed based on
the mechanistic studies.
We have previously reported a novel synthetic method of
a nickel difluoroenolate [(PhCOCF )Ni(dcpe)][FB(C F ) ]
2
6
5 3
[
dcpe = 1,2-bis(dicyclohexylphosphino)ethane] by B(C F ) -
6 5 3
promoted CÀF bond activation of a,a,a-trifluoroacetophe-
[5]
Scheme 2. Reaction of [(IPr)CuBpin] with 1a via formation of the
copper difluoroenolate D. Molecular structure of 4a/CuIPr. THF=te-
trahydrofuran. Thermal ellipsoids are shown at 30% probability and
hydrogen atoms were omitted for clarity.
none (1a), which is coordinated to nickel(0) (Scheme 1a).
Furthermore, a rapid CÀC bond-forming reaction of the
nickel difluoroenolate with 4-tolualdehyde (2b) occurred
quantitatively to afford the aldol product 3ab/[Ni]. However,
B(C F ) could not be regenerated because of the stability of
6
5 3
the BÀF bond of which formation was the driving force
behind the CÀF bond-cleavage step. Another efficient
method for cleaving a CÀF bond is b-fluoride elimination,
which is known to proceed under relatively mild reaction
conditions. With this strategy in mind, the retrosynthetic
analysis suggested the a-metallated alkoxide B as a synthon of
a difluoroenolate (A; Scheme 1b). Sadighi reported that the
structure of 4a/CuIPr was confirmed by X-ray crystallogra-
[
9]
phy. This result suggests the formation of the difluoroeno-
late D via the intermediate C. Motivated by this outcome, we
attempted the reaction of 1a with the aldehyde 2b in the
presence of a catalytic amount of CuCl, IPr, and NaOtBu, and
1.5 equivalents of bis(pinacolato)diboron (B pin ), and it
[
6]
2
2
afforded a trace amount of the coupling product 3ab/Bpin
along with a 4% yield of the homoadduct 4a/Bpin (see
1
,2-addition of [(IPr)CuBpin] [IPr= 1,3-bis(2’,6’-diisopropyl-
[10]
Table S1 in the Supporting Information). By increasing the
amount of NaOtBu to 0.6 and 1.5 equivalents, the yield of
[
*] R. Doi, Prof. Dr. M. Ohashi, Prof. Dr. S. Ogoshi
Department of Applied Chemistry, Faculty of Engineering
Osaka University, Suita, Osaka 565-0871 (Japan)
E-mail: ogoshi@chem.eng.osaka-u.ac.jp
Homepage: http://www.chem.eng.osaka-u.ac.jp/~ogoshi-lab/en/
index.html
3
ab/Bpin was improved to 32 and 56%, respectively. Next,
several auxiliary ligands were screened. Various phosphine
ligands were tested, however the yields were compatible to
that obtained in the absence of a ligand. Contrary to these
results, nitrogen-based ligands such as 1,10-phenanthroline
(
(
Phen), 2,2’-bipyridine, and 4,7-diphenyl-1,10-phenanthroline
bathophenanthroline, BPhen) improved the yields to 81–
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201508266.
82%. The choice of an inorganic base was also crucial:
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a reaction using LiOtBu resulted in a lower yield and KOtBu
gave a trace amount of 3ab/Bpin. The reaction even
proceeded at 308C, and no reaction occurred in the absence
of copper catalyst.
The catalyst loadings could be reduced to 1 mol%, and
with these reaction conditions the corresponding alcohol
product 3ab was isolated in an 82% yield (Table 1). Then, we
reduced under the same reaction conditions. The bulky
ketone 1s afforded the corresponding product 3sb in a 37%
yield even at 608C. The cyclohexyl trifluoromethyl ketone 1o
reacted with 2b to yield coupling product 3ob in an 85%
yield. Although NMR analysis of crude reaction mixtures
indicated full conversions of aldehydes, the formation of some
unidentified by-products was observed, and possibly account
for decreased yields. Ethyl trifluoroacetate could not be
applied under the reaction conditions.
[
a]
Table 1: Substrate scope.
To gain deeper insights into the reaction mechanism,
a mixture of CuCl and Phen was treated with excess NaOtBu
in [D ]THF. NMR analysis of the reaction mixture indicated
8
the formation of a complex bearing two tBuO groups relative
to Phen. In fact, [(L)Na][Cu(OtBu) ] (5, where L = Phen or
2
BPhen) was successfully isolated from the reaction of CuCl,
[11]
ligand, and 2 equivalents of NaOtBu (Scheme 3).
The
Scheme 3. Formation of the complexes 5.
crystal structures of 5 were determined by X-ray crystallog-
raphy (for 5b see Figure 1; and, for 5a see the Supporting
[
9]
Information). The complexes formed dimers through coor-
dination of tBuO groups to sodium atoms. The copper atoms
[
a] Yields of isolated purified products. n.d.=not detected. [b] Reaction
was conducted at 608C. [c] Reaction time was 24 h.
Figure 1. The molecular structure of complex 5b.Thermal ellipsoids are
shown at 50% probability and hydrogen atoms were omitted for clarity.
Selected bond lengths [Š]: Cu1–O1 1.820(3), Cu1–O2 1.819(3), Na1–
O1 2.241(3), Na1–O3 2.208(3), Na1–N1 2.417(3), Na1–N2 2.470(3),
angles [8]: O1-Cu1-O2 170.14(10), O1-Na1-O3 118.15(11), O1-Na1-N1
explored the substrate scope of this reaction. The reaction was
affected by the steric hindrance of benzaldehydes (3ac, 3ad,
3
ae). The reactions of benzaldehydes bearing an electron-
donating methoxy (2 f) and an N,N-dimethylamino group
9
1
6.29(10), O1-Na1-N2 129.19(10), O3-Na1-N1 124.59(11), O3-Na1-N2
09.95(11), N1-Na1-N2 67.26(10).
(
(
2g) gave the corresponding products 3af (56%) and 3ag
64%). Functional groups such as ester (3ah), fluorine and
bromine attached to the aromatic ring (3ai, 3aj), Bpin (3ak),
and acetal (3al) survived under the reaction conditions. 2-
Thiophenecarboxaldehyde and 1-naphthaldehyde also gave
the desired products 3am and 3an, respectively. Contrary to
aromatic aldehydes, aliphatic aldehydes such as 2o and 2p
could not be applied to these reaction conditions. We next
examined the scope of the trifluoromethyl ketone. The
reactions of trifluoroacetophenones bearing an electron-
donating methoxy, N,N-dimethylamino group and an elec-
adopted a two-coordinate linear structure while the confor-
mation of the sodium atoms could be described as a distorted
tetrahedral coordinated by either Phen or BPhen and two
tBuO groups. It is noteworthy that 5a acts as a catalyst in our
system.
In the catalytic reaction, the addition of a difluoroenolate
to either a trifluoromethylketone (1) or aldehyde (2) could
occur. We monitored the reaction, by NMR spectroscopy, in
the absence of an aldehyde and observed the sodium alkoxide
of homoadduct 4a/Na in a 55% yield along with some
unidentified products (Scheme 4). It merits note that 4a/Bpin
tron-withdrawing CF group afforded the desired products
3
3
fb, 3gb, and 3qb in moderate yields. The reaction of 1r,
bearing chlorine at the 4-position of the benzene ring,
afforded the product 3rb, and the CÀCl bond was not
11
was not detected even though B NMR analysis revealed the
3
42
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Scheme 4. Generation, reactivity, and equilibrium of 4a/Na. Reaction
conditions: a) 5 mol% CuCl/Phen, 1 equiv B pin , 1 equiv NaOtBu,
2
2
[
D ]THF, RT, 30 min. b) 0.27 mmol aldehyde 2b, RT, 12 h. Yield is
8
based on 2b. c) 0.2 mmol imine 6, RT 5 h, then NaOHaq. Yield of the
isolated product is given. d) Excess iPrOH, RT, 5 min. Yield is based
on 1a. e) 0.2 mmol benzoyl chloride, RT, 9 h. Yield is based on benzoyl
chloride.
Figure 2. A possible reaction mechanism.
difluoroenolate H. In this step, NaOtBu would act as
a promoter of b-fluoride elimination since the b-fluoride
elimination of a fluoroalkyl copper complex is promoted by
[
6k]
existence of a considerable amount of residual B pin . These
the addition of sodium salt. The reaction of H with 2 gives
the alkoxide I, which reacts with B pin to generate the cross-
2
2
observations indicate the sluggish transmetallation of 4a/Na
2
2
[12]
with B pin under the catalytic reaction conditions. The
adduct 3/Bpin. The enolate H also can react with 1 to form
the alkoxide J which is in equilibrium between 4/Na and 5a in
the presence of NaOtBu. The selective formation of 3 could
be rationalized by the equilibrium and the difference in
basicity between I and J. The alkoxide I is sufficiently basic to
give a thermodynamically stable borate ester of cross-adduct
3/Bpin, while the reaction of J with B pin is much slower,
2
2
addition of the aldehyde 2b resulted in the formation of the
cross-adduct 3ab/Bpin in a high yield even at room temper-
ature (Scheme 4). An analogous reaction with N-(4-methyl-
benzylidene)-4-methylbenzenesulfonamide (6) afforded the
corresponding product 7 (Scheme 4). In contrast, protonolysis
of the reaction mixture did not afford PhCOCF H, but did
2
2
2
afford the alcohol 4a (Scheme 4). The alkoxide 4a/Na was
also trapped by the addition of benzoyl chloride to deliver the
ester 8 (Scheme 4). These observations indicate that in the
presence of anionic copper species like 5a, 4a/Na is in
equilibrium with the anionic enolate E which produces 3ab/
Bpin by a reaction with 2b. In fact, in the presence of
a catalytic amount of 5a and a stoichiometric amount of
B pin , the reaction of 2b with 4a/Na, which was generated by
probably because of the electron-withdrawing nature of five
fluorine atoms attached to the b-carbon atoms.
In summary, we have achieved the copper-catalyzed
reaction of trifluoromethylketone with aldehyde by CÀF
bond cleavage using B pin as a reductant in the presence of
2
2
NaOtBu. This novel methodology is a potential alternative to
the known procedures for synthesis of difluoro compounds by
circumventing the use of expensive mixed-halogen com-
pounds and lengthy procedures. Further exploration on the
improvement of yields, scope, and extension to an asymmetric
version are currently underway in our group. The catalytic
reaction was highly selective to give the cross-adducts,
although the copper difluoroenolate generated in situ reacts
with either trifluoromethylketone to give the homoadducts or
aldehyde to give the cross-adducts. The mechanistic inves-
tigation rationalized this high selectivity by revealing the
existence of an equilibrium between alkoxides of the homo-
adducts and those of cross-adducts, which more easily give the
thermodynamically stable borate ester rather than those of
homo-adducts.
2
2
treatment of 4a with NaH, yielded 3ab/Bpin quantitatively
Scheme 5). In this case, we confirmed formation of 1a by
(
Scheme 5. Copper-catalyzed reaction of 4a/Na with 2b in the presence
of B pin .
2
2
Acknowledgements
1
9
means of F NMR analysis. The reaction also proceeded in
the presence of 10 mol% of either CuCl/Phen or CuCl,
whereas the product was not obtained at all in the absence of
CuCl.
This work was supported by a Grant-in-Aid for Young
Scientist (A) (25708018) and Scientific Research on Innova-
tive Area “Molecular Activation Directed toward Straight-
forward Synthesis” (23105546) from MEXT, and ACT-C from
JST. R.D. is grateful for support as a JSPS Research Fellow.
A possible reaction mechanism is depicted in Figure 2.
First, the reaction of CuCl, Phen, and NaOtBu gives the
cuprate 5a. Reaction of 5a with B pin affords an anionic
2
2
borylcopper species F which reacts with 1 to give the
intermediate G. b-Fluoride elimination of G affords the
Keywords: aldol reaction · boron · CÀF activation · copper ·
synthetic methods
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How to cite: Angew. Chem. Int. Ed. 2016, 55, 341–344
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Received: September 4, 2015
Revised: September 15, 2015
Published online: October 30, 2015
3
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