Synthesis of Chiral α-CF3-Substituted Benzhydryls via Cross-Coupling Reaction of Aryltitanates

Article abstract of DOI:10.1021/acs.orglett.0c03673

We describe a highly efficient approach toward α-CF3-substituted benzhydryls thanks to the employment of organotitanium(IV) based nucleophiles. The use of commercially available anesthetic halothane as a cheap fluorinated building block in a sequential one-pot nickel-catalyzed enantioselective cross-coupling reaction of aryl titanates allowed for the synthesis of chiral α-CF3-substituted benzhydryls in good yields and excellent enantioselectivities. Alternatively, α-CF3-benzyl bromides could be employed under similar conditions to obtain the same family of compounds in higher yields and excellent selectivities. A benzhydryl moiety is a common motif in many biologically active compounds, and their enantioenriched fluorinated analogs should be of great interest in the search for novel drugs and agrochemicals.

Full text of DOI:10.1021/acs.orglett.0c03673

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Letter
Synthesis of Chiral α‑CF3‑Substituted Benzhydryls via Cross-
Coupling Reaction of Aryltitanates
Andrii Varenikov, Evgeny Shapiro, and Mark Gandelman*
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ABSTRACT: We describe a highly efficient approach toward α-
CF3-substituted benzhydryls thanks to the employment of
organotitanium(IV) based nucleophiles. The use of commercially
available anesthetic halothane as a cheap fluorinated building block
in a sequential one-pot nickel-catalyzed enantioselective cross-
coupling reaction of aryl titanates allowed for the synthesis of chiral
α-CF3-substituted benzhydryls in good yields and excellent
enantioselectivities. Alternatively, α-CF3-benzyl bromides could be
employed under similar conditions to obtain the same family of
compounds in higher yields and excellent selectivities. A benzhydryl
moiety is a common motif in many biologically active compounds,
and their enantioenriched fluorinated analogs should be of great
interest in the search for novel drugs and agrochemicals.
ite-selective fluorination has become a widespread
the synthesis of enantioenriched α-CF3-substituted benzhydr-
yls was in progress, Shen and co-workers reported an elegant
approach to the synthesis of such compounds via an
enantioconvergent nickel-catalyzed cross-coupling reaction of
racemic α-CF3-benzyl bromides with arylzincates, obtained in
situ from corresponding boronates (Scheme 1b).10b This work
represents the only reported approach for the enatioselective
catalytic synthesis of compounds of type 1. However, some
substantial limitations should be noted: the method is limited
to electron-poor electrophiles; a very high catalyst loading and
a large excess of the transmetalating reagent should be used;
additionally, utilization of butyllithium for the preparation of
intermediate arylboronates limits the choice of functional
groups installed in nucleophiles.
Recently we reported on the first utilization of titanium-
based nucleophiles in an asymmetric cross-coupling reaction.11
These reagents proved to be superior to their magnesium and
zinc counterparts in the enantioselective synthesis of α-CF3-
benzyl thioethers, being a compromise between a high
reactivity of organomagnesium species and a functional
group tolerance of a corresponding organozinc reagent.12 We
wanted to expand the success of these reagents to other
challenging transformations, such as a synthesis of α-CF3-
S
approach to alter features of a target compound.1 Along
with physical properties, fluorination significantly affects the
reactivity and stability of a molecule and nearby functional
groups.2 These phenomena are of great utility for the
agricultural and medicinal industries, as a tool for adjusting
activity, bioavailability, and metabolic stability of a compound.
Among other fluorinated moieties, the trifluoromethyl group is
widely employed as a bioisoster for ethyl3 and nitro4 groups, as
well as a substitute to a metabolically labile methyl group,5 or
to augment a lipophilicity of a target molecule. An increasingly
growing demand for trifluoromethyl-containing motifs con-
tinuously leads to the exploration of new reaction pathways,
including the use of alternative building CF3-installing blocks.
While the introduction of a trifluoromethyl group is not a
trivial task, the need to create a CF3-substituted stereogenic
center in an enantioselective fashion significantly increases the
complexity of this synthetic goal.6
Diarylmethanes is a widely encountered family of
pharmacophores, and its utilization in an enantiopure form is
especially important (Scheme 1a).7 Therefore, development of
asymmetric catalytic approaches to the synthesis of chiral 1,1-
diarylmethanes gain much attention in the organic commun-
ity.8 Remarkably, synthesis of the compounds of type 1,
bearing the biomedically relevant CF3 group at stereogenic
center, in an enantioselective fashion is not a straightforward
transformation9 and only a few methods have been presented
to date.10 The synthesis of the motif 1 in an enantioenriched
manner can be achieved via enantiospecific cross-coupling
reaction of α-CF3-benzyl tosylates10a or via recent elegant
fluoroarylation of gem-difluoroalkenes.10c While our work on
Received: November 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03673
© XXXX American Chemical Society
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over, substituents on the aromatic ring directly influence the
stability and reactivity of the radical 3 imposing difficulties on
the generality of the desired approach.17 Therefore, it imposes
a considerable problem on the utilization of stabilized radicals
of type 3.
Scheme 1. Synthesis of Chiral α-CF3-Substituted
Benzhydryls
We started investigation of the reaction from the choice of a
model starting material. Reacting α-CF3-4-chlorophenylbenzyl
bromide 2a with 3-MeOPhTi(OiPr)3 and t-BuONa in the
presence of a nickel precatalyst and bisoxazoline ligand L1, we
were pleased to find that the desired compound can be
obtained in an 85% yield and 97% ee (Scheme 3). However,
Scheme 3. Choice of a Model Electrophile
the use of 4-methoxy substituted electrophile 2b provided the
corresponding benzhydryl 1b in 3% yield only. As a
consequence of the relatively high stability of the radical,
which derived from 2b, the homocoupling of this electrophile
was the main product of the reaction. Thus, 2b was chosen as a
model substrate for the further optimization of the reaction
conditions.
benzhydryles. In this letter we report on the utilization of
aryltitanates in an enantioconvergent nickel-catalyzed cross-
coupling reaction for a synthesis of chiral α-CF3-substituted
benzhydryls. To our delight, organotitanium nucleophiles
proved to be very efficient reagents in this challenging
transformation, allowing a number of aforementioned limi-
tations and synthetic issues to be overcome. Notably, we
describe here the use of halothanean inexpensive commer-
cially available anestheticas a fluorinated building block for
the synthesis of α-CF3-diarylmethanes via sequential enantio-
selective one-pot cross-coupling reactions of aryl titanates.
Despite wide availability, the use of halothane as a CF3-
installing building block is not a common practice,13 while its
utilization in an enantioselective synthesis, to the best of our
knowledge, is unprecedented.
We have assumed that the proposed reaction follows the
Ni(I)/Ni(III) radical mechanistic pathway elucidated for such
type of cross-coupling processes by Fu and others.14 The
anticipated concept implies involvement of a substantially
stabilized α-CF3-benzyl radical 3 as a key reaction intermediate
(Scheme 2).15 While stabilization of the radical during cross-
couplings usually is a beneficial factor for the reaction
success,16 an excessive stabilization can significantly impair
the formation of the desired product. Presumably, this stability
could lead to side reactions, including substantial homocou-
pling (vide infra), instead of coordination to the Ni center with
the concomitant product-forming reductive elimination. More-
After an extensive search we found that a LiCl additive has a
prolific effect on the reaction outcome, increasing the yield up
to 41% (Table 1, entry 2). Along with a yield, the use of the
additive significantly increased the time required to reach a full
conversion. The reaction conditions could be simplified by
using lithium tert-butoxide instead of the t-BuONa/LiCl
system without a compromise on the reaction outcome
(entry 3).18 Diglyme could be employed as a solvent instead
of THF with a subtle improvement in the yield, although a
slight decrease in enantioselectivity was observed (entry 4).
Interestingly, the reaction performance can be improved by
using aryltitanium(tris-tert-butoxide) as a nucleophile and 2
equiv of LiCl in the absence of the alkoxide base to 61%,
although accompanied by high reaction time (entry 5).
Notably, the highest reactivity for arylmagnesium and arylzinc
reagents was also observed for the catalyst based on the ligand
L1. However, these organometallic nucleophiles were inferior
to the aryltitanate variant in the reaction with 2b (entries 6 and
7).19 The presence of the nickel precatalyst and ligand L1 are
both essential for the process (entries 8 and 9). Both air and
moisture have a deleterious effect on the process (entries 10
and 11). The reaction can be performed at 0 °C, although the
yield of 1b is decreased (entry 12). Lowering the catalyst
loading to 7% also diminishes the yield of 1b (entry 13).20
Notably, our approach significantly improves the efficiency
of the reaction of problematic electrophiles of type 2b (bearing
electron-donating substrates) compared to the previously
reported approach (61% yield, 97% ee vs 25% yield, 80% ee).10b
Scheme 2. Proposed Approach to the α-CF3-Substituted
Benzhydryls
B
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a b
,
Having a set of optimal conditions, we proceeded to the
investigation of the reaction scope. ArTi(OtBu)3/LiCl and
ArTi(OiPr)3/t-BuOLi systems performed similarly for most of
the studied substrates, although the reaction time of the former
system was significantly longer. Therefore, we employed the
ArTi(OiPr)3/t-BuOLi system, which allows completion of the
reaction for most of the targeted substrates within 12 h. A
variety of structurally and electronically diverse 1,1-diaryl-
2,2,2-trifluoroethanes can be obtained in excellent yields and
enantioselectivities (Scheme 4). Electrophiles bearing electron-
withdrawing groups generally provide corresponding products
in >90% yields. Gratifyingly, for electron-rich analogsthe
problematic substrates in a previous approachgood yields
were obtained with Ti(IV) nucleophiles. Even for very
electron-rich electrophiles, bearing multiple alkoxy substituents
(1da, 1ea), practical yields were achieved. Substituents
elsewhere on the aryl ring but in an ortho-position do not
interfere with the reaction. Among ortho-substituted variants
only starting materials, bearing a small substituent such as a
fluorine atom, provide the desired product in a synthetically
useful yield (1ja). Functional groups, such as esters, nitriles,
halogens, and boropinacols are well tolerated. 3-Thienyl (1ka)
or ferrocene-derived (1ma) electrophiles also can be efficiently
employed in the developed process.21
Table 1. Optimization of the Reaction Conditions
Yield of
1b (%)
ee
Entry
Variation
(%)
c
1
t-BuONa instead of t-BuOLi
t-BuONa, 2 equiv of LiCl as additives
none
Diglyme instead of THF
ArTi(OtBu)3 and 2 equiv of LiCl instead of
ArTi(OiPr)3 and t-BuOLi
3
n.d.
96
97
92
97
2
3
4
41
43
45
61
d
5
6
7
8
ArMgCl instead of ArTi(OiPr)3/t-BuOLi
ArZnI instead of ArTi(OiPr)3/t-BuOLi
No NiCl2·glyme
9
8
n.d.
n.d
−
−
−
95
94
96
traces
4
traces
16
9
No L1
10
11
12
13
Under air in a closed vial
0.1 equiv of H2O
0 °C instead of −13 °C
7% instead of 9% catalyst
20
26
a
b
Reactions performed on 0.0625 mmol scale. Determined by 19F
NMR vs internal standard. 2 h reaction time. 120 h reaction time;
n.d. − yield was not determined for reactions with a yield <10%.
c
d
The aryltitanium coupling partner can also be varied to a
great extent. Aromatic motifs bearing both electron-with-
drawing and electron-donating substituents can be introduced
a
Scheme 4. Scope of the Cross-Coupling Reaction of α-CF3-Benzyl Bromides with Aryltitanates
a
b
Reactions were performed on a 0.5 mmol scale in duplicate. Isolated yields. NMR yields (if applicable) are given in square brackets. Diglyme
c
d
e
instead of THF. −25 °C instead of −13 °C. 1,1,1-Trifluoro-2-bromo-4-phenylbutane as a starting material. The aryl titanate was prepared in situ,
starting from the corresponding aryl bromide or iodide; see SI for details.
C
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in high yields. Electron-rich aryl titanates provided products in
slightly higher yields than the corresponding electron-poor
counterparts. In the latter case yields were diminished in favor
of the formation of the homocoupled product. The
substitution pattern of the nucleophile favors meta- and para-
substituents, while low conversion and a poor mass balance
were observed for the ortho-substituted analogs.22 Esters,
nitriles, tertiary amines, (thio)ethers, bromides, protected
aldehydes, trifluoromethoxy, and silyl groups can be present
in the nucleophile structure leaving the catalytic process
unaffected.23
Scheme 6. Scope of a One-Pot Sequential Cross-Coupling
Reaction
a
The reaction can be easily scaled up to a gram scale. As such,
the compound 1ah was obtained in 91% yield and 98% ee on a
5 mmol scale (1.5 g of the starting benzyl bromide).
Additionally, the reaction is not limited to benzylic electro-
philes. Aliphatic α-CF3-alkyl bromides undergo an efficient
transformation under similar conditions, providing the product
4 in 91% yield and 95% ee. Moreover, aryltitanates can be
prepared in situ starting from the corresponding aryl iodides via
halogen−magnesium exchange with iPrMgCl·LiCl and further
transmetalation to Ti(OiPr)4 without significant effect on the
reaction outcome (1al and 1am; see SI for details).
Interestingly, benzyl chlorides also can be efficiently utilized
in the reaction, yet in somewhat lower yields. As such, α-CF3-
4-chlorobenzyl chloride 2a′ was converted to the correspond-
ing benzhydryl 1a under similar reaction conditions in a 79%
yield and 97% ee (Scheme 5).
a
Reactions were performed on 0.5 mmol scale in duplicate. Isolated
yields are given. NMR yields are given in square brackets.
Scheme 5. Cross-coupling of α-CF3-Benzyl Chlorides
selectivity of the reaction, giving rise to the formation of the
undesired symmetrical benzhydryl. The attempts to introduce
an aryl moiety bearing electron-poor substituents on the
second step increases amounts of product of formal
dechlorodefluorination. Thus, compounds containing two
electron-poor aryls are obtained only in moderate yields
(1h). Additionally, this approach allows for a facile creation of
deuterium-labeled analogues of this family of compounds
(1ba-D) using easy-to-prepare halothane-D (5-D).
In conclusion, we have developed a method for the
preparation of α-CF3-substituted benzhydryls via an enantio-
selective nickel-catalyzed cross-coupling reaction. The use of
an aryltitanate-based nucleophile enabled the synthesis of a
variety of a chiral 1,1-diaryl-2,2,2-trifluoroethanes starting from
α-CF3-benzyl bromides in high yields and excellent enantio-
selectivities. Remarkably, our approach allows this reaction to
be performed with electronically diverse electrophiles and
nucleophiles including those bearing electron-donating sub-
stituents. Alternatively, the same family of products can be
obtained under similar conditions as a one-pot two-step
sequence starting from a cheap, commercially available
anesthetic halothane in good yields and excellent enantiose-
lectivities. To the best of our knowledge, it represents the first
use of halothane as a CF3-group donor in asymmetric catalysis.
Mechanistic studies of aryltitanium involved asymmetric cross-
coupling reactions are underway in our laboratories.
The unexpectedly high reactivity of α-CF3-benzyl chlorides
led us to explore another approach toward synthesis of
compounds of family 1. We envisioned that starting from 1-
chloro-1-bromo-2,2,2-trifluoroethane, or halothanea cheap
commercially available anestheticit is possible to perform a
sequential one-pot cross-coupling reaction24 to prepare benzyl
chlorides in situ followed by their conversion to 1. If viable, the
use of such a starting material in the catalytic asymmetric
cross-coupling protocol would allow for the creation of α-CF3-
diarylmethanes through a rapid increase of a molecular
complexity.
Gratifyingly, halothane undergoes a smooth reaction to
provide the corresponding α-CF3-benzyl chloride in a nearly
quantitative yield under similar conditions. Moreover, both
steps can be performed as a one-pot sequence without addition
of extra amounts of the catalyst in the second step.25
Regarding the scope, we were pleased to see that this
strategy allows for the creation of a variety of enantioenriched
diarylmethanes (Scheme 6). The preparation of diaryltrifluoro-
ethanes bearing both electron-rich and electron-poor aromatic
motifs in any combination is feasible under the designed
protocol. Generally, high yields are obtained if aryl titanates
bearing electron-donating substituents are employed on each
reaction step (1b). However, the use of less electron-rich
coupling partners results in a yield decrease regardless of the
stage of employment. As such, the use of electron-poor
aryltitanates on the first step of the sequence affects the
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03673.
Experimental procedures, characterization data, nuclear
magnetic resonance and high performance liquid
chromatography spectra of new compounds (PDF)
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CCDC 2026395−2026396 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Mark Gandelman − Schulich Faculty of Chemistry, Technion -
Israel Institute of Technology, Haifa 3200008, Israel;
orcid.org/0000-0002-9651-2902; Email: chmark@
technion.ac.il
Authors
Andrii Varenikov − Schulich Faculty of Chemistry, Technion -
Israel Institute of Technology, Haifa 3200008, Israel;
orcid.org/0000-0001-9118-261X
Evgeny Shapiro − Schulich Faculty of Chemistry, Technion -
Israel Institute of Technology, Haifa 3200008, Israel
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the Israel
Science Foundation (Grant No. 1890_/15) and Israel
Innovation Authority (Grant No. 69747). We are grateful to
Dr. Natalia Fridman (Technion − Israel Institute of
Technology) for the X-ray analysis and structure solution of
compounds 1ca and 1ad.
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responsible for the improvement, allowing for more selective
transmetalation. See ref 16k for a similar effect.
(19) 1a was obtained in 56% yield (98% ee) and 60% yield (97% ee)
in the reaction of 2a with 3-methoxyphenylmagnesium bromide or 3-
methoxyphenylzinc iodide correspondingly.
(20) The reaction is proposed to proceed via Ni(I)/Ni(III) catalytic
cycle. No dynamic kinetic resolution of the electrophile was observed;
the ee of the product remains constant during the course of the
reaction. The reaction is interrupted with subequimolar amounts of
TEMPO and resumes once it is consumed.
(21) 2-Thienyl or 2-furyl-derived electrophiles under similar
conditions provided a complex mixture of products.
(22) ortho-Fluoro, -methyl, and -methoxy aryltitanium nucleophiles
provided products in poor yields and/or enantioselectivities.
(23) The use of heteroaromatic aryltitanates, such as 2-thienyl and
6-methoxy-3-pyridyl, was unsucessful.
(24) Jiang, X.; Kulbitski, K.; Nisnevich, G.; Gandelman, M.
Enantioselective assembly of tertiary stereocenters via multicompo-
nent chemoselective cross-coupling of geminal chloro(iodo)alkanes.
Chem. Sci. 2016, 7, 2762−2767.
(25) See Tables S1 and S2 for optimization of the reaction
conditions and influence of conditions on the reaction outcome for
the first and the second step of the cross-couipling reaction
correspondingly.
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(17) Fu et al. presented a nickel-catalyzed Negishi cross-coupling
reaction of aliphatic α-CF3-substituted electrophiles, yet the
corresponding benzylic electrophiles were not shown to be suitable
reaction partners. See refs 16k and 16l.
(18) While the exact reason of this improvement is currently under
investigation, we speculate that the increase in an ionic strength of a
solution due to the formation of soluble LiBr as a coproduct might be
F
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Org. Lett. XXXX, XXX, XXX−XXX