Stereoconvergent negishi arylations of racemic secondary alkyl electrophiles: Differentiating between a CF3 and an alkyl group

Article abstract of DOI:10.1021/jacs.5b04725

In this report, we establish that a readily available nickel/bis(oxazoline) catalyst accomplishes a wide array of enantioconvergent cross-couplings of arylzinc reagents with CF₃-substituted racemic secondary alkyl halides, a process that necessitates that the chiral catalyst be able to effectively distinguish between a CF₃ and an alkyl group in order to provide good ee. We further demonstrate that this method can be applied without modification to the catalytic asymmetric synthesis of other families of fluorinated organic compounds.

Full text of DOI:10.1021/jacs.5b04725

Communication
pubs.acs.org/JACS
Stereoconvergent Negishi Arylations of Racemic Secondary Alkyl
Electrophiles: Differentiating between a CF3 and an Alkyl Group
Yufan Liang and Gregory C. Fu*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
enantioselectivity in such a process, the catalyst must effectively
differentiate between a CF3 and an alkyl group,12,13 which was
ABSTRACT: In this report, we establish that a readily
available nickel/bis(oxazoline) catalyst accomplishes a
wide array of enantioconvergent cross-couplings of
arylzinc reagents with CF3-substituted racemic secondary
alkyl halides, a process that necessitates that the chiral
catalyst be able to effectively distinguish between a CF3
and an alkyl group in order to provide good ee. We further
demonstrate that this method can be applied without
modification to the catalytic asymmetric synthesis of other
families of fluorinated organic compounds.
not achieved in the only previous report of such a cross-
coupling.14
In this report, we establish that cross-couplings of CF3-
substituted racemic alkyl electrophiles can indeed be achieved
with good enantioselectivity, without the need for an additional
activating/directing group elsewhere in the molecule. Specifi-
cally, we establish that a nickel/bis(oxazoline) catalyst can
effect asymmetric Negishi arylations of secondary alkyl halides
(eq 2).
he incorporation of a trifluoromethyl (CF3) group in an
T
organic molecule can lead to substantially altered
properties, including biological activity, as compared to a
nonfluorinated compound.1 Whereas significant advances have
been described in the synthesis of molecules that contain an
Ar−CF3 bond,2 progress in the development of general
3
methods for the synthesis of compounds that include a Csp −
CF3 bond has been more limited, particularly in the case
wherein the carbon that bears the CF3 group is a tertiary
stereogenic center.3,4 Examples of catalytic asymmetric
reactions that generate the latter class of compounds include
the α-trifluoromethylation of aldehydes,5 the conjugate addition
to CF3-containing electron-deficient alkenes,6 the trifluorome-
thylation of allylic electrophiles,7 and the hydrogenation of
CF3-substituted alkenes;8 these methods often require a
suitable additional functional group (e.g., carbonyl, alkenyl, or
aryl substituent) to achieve the desired bond formation and
good enantioselectivity. The development of a general
approach that proceeds in high ee without the need for such
a functional group could thus complement existing strategies.
Recently, we have established that chiral nickel catalysts can
accomplish enantioconvergent cross-coupling reactions of a
number of racemic secondary electrophiles.9 These methods
have typically employed alkyl halides that either are activated
(e.g., benzylic or allylic) or include a directing group (e.g., a
carbonyl or a sulfonamide). In order to achieve the objective
outlined above, we decided to pursue the development of a
general method for the stereoconvergent cross-coupling of an
electrophile of type A (eq 1);10,11 to furnish good
The data in Table 1 illustrate the impact of various reaction
parameters on the efficiency of this stereoconvergent cross-
coupling.15 If either of the catalyst components (NiCl2·glyme
or bis(oxazoline) ligand 1, each of which is commercially
available and can be handled in air) is omitted, little or no
carbon−carbon bond formation is observed (entries 2 and 3).
Other ligands, including related bis(oxazolines), a pybox, and a
1,2-diamine,16 furnish lower ee’s and yields (entries 4−7). The
use of less of the organozinc nucleophile, a lower catalyst
loading, or THF (without diglyme) as the solvent results in no
erosion in enantioselectivity but in a modest loss in yield
(entries 8−10). At room temperature, side reactions such as
hydrodebromination and debromodefluorination become sig-
nificant (entry 11). This enantioconvergent Negishi arylation is
not highly water-sensitive: the addition of 0.1 equiv of water has
no deleterious effect on either ee or yield (entry 12).
Next, we explored the scope of this new method for the
catalytic enantioselective synthesis of stereogenic centers that
bear a CF3 substituent (Table 2).17 Although the use of an
ortho-substituted arylzinc reagent leads to a modest yield of the
desired cross-coupling product (entry 1), an array of meta- and
para-substituted nucleophiles, either electron-rich or electron-
poor, generally furnish very good ee’s and yields (entries 2−
11). Functional groups such as an aryl ether,18 an aryl halide
(Br, Cl, and F),19 an aryl thioether,20 and oxygen and nitrogen
Received: May 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b04725
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
With regard to the electrophilic coupling partner, the scope
of this method for enantioselective Negishi cross-couplings of
fluorinated secondary alkyl halides is also fairly broad (Table
3).21 It is worth noting that, in the case of entry 1, the catalyst
Table 1. Stereoconvergent Negishi Arylations of Fluorinated
Electrophiles: Effect of Reaction Parameters
a
Table 3. Stereoconvergent Negishi Arylations of Fluorinated
a
Electrophiles: Scope with Respect to the Electrophile
b
entry
variation from the “standard” conditions
ee (%)
yield (%)
1
none
95
−
−
89
<2
3
2
no NiCl2·glyme
no (S,S)-1
3
4
(S,S)-2, instead of (S,S)-1
(S,S)-3, instead of (S,S)-1
(R,R)-4, instead of (S,S)-1
(S,S)-5, instead of (S,S)-1
1.1 equiv of Ph−ZnCl
3.0% NiCl2·glyme, 3.9% (S,S)-1
THF only
33
40
−
11
95
94
95
86
26
27
<2
4
5
6
7
8
78
72
82
15
88
9
10
11
12
rt, instead of −20 °C
0.1 equiv of H2O added
95
a
b
All data are the average of two experiments. The yields were
determined through analysis by 19F NMR spectroscopy (with the aid
of an internal standard).
Table 2. Stereoconvergent Negishi Arylations of Fluorinated
a
Electrophiles: Scope with Respect to the Nucleophile
a
b
All data are the average of two experiments. Yield of purified
product.
must effectively differentiate between a CF3 and a CH3 group in
order to deliver the product in very good ee.12 A variety of
functional groups are compatible with the reaction conditions,
including a silyl ether, a primary alkyl chloride,22 a primary alkyl
bromide,23 a primary alkyl tosylate,24 an aryl ether,18 a ketone,
an aryl iodide,19 a carbamate, an ester, and a furan.
The choice of electrophile is not limited to alkyl bromides.
Thus, without modification we can apply to a racemic
secondary alkyl iodide the method that we have developed
for stereoconvergent cross-couplings of bromides (eq 3).25
Significantly, the method can also be applied to electrophiles
that bear an electron-withdrawing group other than CF3. Thus,
excellent enantioselectivity is observed with an array of
fluorinated substituents, including perfluoroalkyl, CF2Cl,
CF2COPh, and CF2CO2Et (eqs 4−7).26
In conclusion, we have developed a versatile stereo-
convergent Negishi arylation of racemic secondary alkyl halides
wherein a chiral nickel catalyst differentiates between a CF3 and
an alkyl substituent in order to deliver a high enantiomeric
excess. In contrast to many other catalytic asymmetric
processes that generate tertiary stereocenters that bear a CF3
substituent, this method does not require an extraneous
a
b
All data are the average of two experiments. Yield of purified
product.
heterocycles are compatible with the coupling conditions. On a
gram scale (1.34 g of product), the stereoconvergent Negishi
reaction illustrated in entry 2 of Table 2 proceeds in 96% ee
and 91% yield; it is noteworthy that this cross-coupling is not
especially air-sensitivewhen conducted in a capped vial under
air, the product is generated with similar efficiency (96% ee,
87% yield).
B
DOI: 10.1021/jacs.5b04725
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(3) For discussions and leading references, see: (a) Yang, X.; Wu, T.;
Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826−870. (b)
References 1b and 2b. (c) Liang, T.; Neumann, C. N.; Ritter, T.
Angew. Chem., Int. Ed. 2013, 52, 8214−8264. (d) Xu, J.; Liu, X.; Fu, Y.
Tetrahedron Lett. 2014, 55, 585−594.
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́
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12165.
(10) For examples of metal-catalyzed cross-coupling reactions of
CF3CH2OTs and CF3CH2I (primary alkyl electrophiles), see:
(a) Zhao, Y.; Hu, J. Angew. Chem., Int. Ed. 2012, 51, 1033−1036.
(b) Liang, A.; Li, X.; Liu, D.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Chem.
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(11) To the best of our knowledge, there are no examples of metal-
catalyzed cross-couplings of perfluorinated alkyl nucleophiles with
unactivated alkyl electrophiles, which could represent a complemen-
tary route to the products illustrated in eq 1.
(12) For an early example of an enantioselective reaction wherein
differentiation between a CF3 and a CH3 group is achieved, see: Feigl,
D. M.; Mosher, H. S. Chem. Commun. 1965, 615−616.
(13) For a recent review on the influence of fluorine in asymmetric
catalysis, see: Cahard, D.; Bizet, V. Chem. Soc. Rev. 2014, 43, 135−147.
(14) Liang, Y.; Fu, G. C. Angew. Chem., Int. Ed. 2015, 54, 9047−9051.
(15) Notes: (a) The method described in ref 14 is not effective for
the arylation process illustrated in Table 1, furnishing poor ee and
yield. (b) PhZnCl is generated from PhLi. If PhZnCl is produced
instead from PhMgCl, then the arylation proceeds in 95% ee and 81%
yield. Ph2Zn is not effective under these conditions, furnishing 88% ee
and a 9% yield.
(16) These families of ligands have previously been employed in
stereoconvergent nickel-catalyzed cross-couplings of alkyl electro-
philes: (a) Bis(oxazoline): Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 1264−1266. (b) Pybox: Reference 9a. (c) 1,2-Diamine: Saito,
B.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 6694−6695.
activating/directing group; furthermore, this approach is
effective at producing a variety of other enantiomerically
enriched fluorinated compounds under the same conditions.
From a practical perspective, it is noteworthy that both of the
catalyst components are commercially available and can be
handled in air and that the method is not particularly air- or
water-sensitive. Further studies of nickel-catalyzed cross-
couplings of alkyl electrophiles are underway.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b04725.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: gcfu@caltech.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences: R01-
GM62871) and the Gordon and Betty Moore Foundation
(Caltech Center for Catalysis and Chemical Synthesis). We
thank Dr. Allen G. Oliver (University of Notre Dame) and Dr.
Nathan D. Schley for assistance.
(17) Notes: (a) During the course of these couplings, we have not
observed kinetic resolution of the electrophile (<5% ee), consumption
of the cross-coupling product, or erosion in the ee of the product. (b)
In a preliminary study under our standard conditions, a thienylzinc, a
pyridylzinc, and an alkenylzinc reagent were not suitable cross-
coupling partners. (c) Hydrodebromination of the electrophile is the
predominant side reaction.
(18) For examples of the reactivity of aryl ethers in nickel-catalyzed
cross-couplings, see: Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.;
Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011,
111, 1346−1416.
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DOI: 10.1021/jacs.5b04725
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Journal of the American Chemical Society
Communication
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D
DOI: 10.1021/jacs.5b04725
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX