Nickel/bis(oxazoline)-catalyzed asymmetric negishi arylations of racemic secondary benzylic electrophiles to generate enantioenriched 1,1-diarylalkanes

Article abstract of DOI:10.1021/ja408561b

A tertiary stereogenic center that bears two different aryl substituents is found in a variety of bioactive compounds, including medicines such as Zoloft and Detrol. We have developed an efficient method for the synthesis of enantioenriched 1,1-diarylalkanes from readily available racemic benzylic alcohols. Formation of a benzylic mesylate (which is not isolated), followed by treatment with an arylzinc reagent, LiI, and a chiral nickel/bis(oxazoline) catalyst, furnishes the Negishi cross-coupling product in high ee and good yield. A wide array of functional groups (e.g., an aryl iodide, a thiophene, and an N-Boc-indole) are compatible with the mild reaction conditions. This method has been applied to a gram-scale synthesis of a precursor to Zoloft.

Full text of DOI:10.1021/ja408561b

Communication
pubs.acs.org/JACS
Nickel/Bis(oxazoline)-Catalyzed Asymmetric Negishi Arylations of
Racemic Secondary Benzylic Electrophiles to Generate
Enantioenriched 1,1-Diaryalkanes
Hien-Quang Do,‡,† E. R. R. Chandrashekar,† and Gregory C. Fu*,‡,†
‡Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
†Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: A tertiary stereogenic center that bears two
different aryl substituents is found in a variety of bioactive
compounds, including medicines such as Zoloft and
Detrol. We have developed an efficient method for the
synthesis of enantioenriched 1,1-diarylalkanes from readily
available racemic benzylic alcohols. Formation of a
benzylic mesylate (which is not isolated), followed by
treatment with an arylzinc reagent, LiI, and a chiral nickel/
bis(oxazoline) catalyst, furnishes the Negishi cross-
coupling product in high ee and good yield. A wide
array of functional groups (e.g., an aryl iodide, a thiophene,
and an N-Boc-indole) are compatible with the mild
reaction conditions. This method has been applied to a
gram-scale synthesis of a precursor to Zoloft.
ecause an array of bioactive compounds bear a tertiary
Bstereocenter with two aryl substituents, including medicines
such as Zoloft, Detrol, and Condylox,1 the development of
methods for the enantioselective synthesis of 1,1-diarylalkanes
more-reactive oxygen-based leaving groups is generally accom-
has been the focus of substantial effort. A variety of strategies that
plished under Brønsted-basic conditions, whereas their con-
version to alkyl halides is often achieved under Brønsted-acidic
exploit asymmetric catalysis have been pursued, such as the
hydrogenation of 1,1-diarylalkenes2 and the 1,4-addition of aryl
conditions. In 2012, we described a nickel/pybox-catalyzed
nucleophiles to α,β-unsaturated carbonyl compounds.3 An
alternative approach, the enantioconvergent cross-coupling of a
racemic benzylic electrophile with an arylmetal reagent, has not
yet been accomplished, although impressive progress has been
recorded in the stereoselective coupling of enantioenriched
benzylic electrophiles with aryl nucleophiles using an achiral
catalyst.4,5 Here, we describe nickel-catalyzed asymmetric
Negishi reactions of racemic benzylic electrophiles with arylzinc
reagents that generate a broad spectrum of 1,1-diarylalkanes in
good ee (eq 1).
enantioconvergent Negishi arylation of propargylic carbonates.6d
However, this method was not effective for a racemic benzylic
carbonate.
We next turned our attention to a different family of oxygen
leaving groups: readily accessible mesylates.10 Because benzylic
mesylates are highly reactive electrophiles,11 we chose to employ
them without isolation. As depicted in Table 1 (entry 1), under
the appropriate conditions, a nickel/bis(oxazoline) catalyst can
achieve the net arylation of a benzylic alcohol to generate a 1,1-
diarylalkane with high enantioselectivity and in good yield.
Essentially no carbon−carbon bond formation occurred in the
absence of NiBr2·diglyme (Table 1, entry 2), whereas a small
amount of the cross-coupling product was formed in the absence
of bis(oxazoline) ligand L (entry 3). Two families of ligands that
are useful for other asymmetric Negishi arylation reactions (1
and 2)12 were not useful under these conditions (<2% yield;
entries 4 and 5), and a commercially available 2,2′-linked
bis(oxazoline) (3) that is related to ligand L furnished somewhat
We have recently pursued the development of an array of
enantioconvergent cross-couplings of racemic alkyl electro-
philes.6,7 Most relevant to the objective described herein, we have
reported two nickel-catalyzed methods for asymmetric Negishi
reactions of benzylic halides with alkylzinc reagents.6a,8
Unfortunately, neither of these procedures proved effective
when an arylzinc was employed as the nucleophile.9
An ongoing challenge in the field of stereoconvergent cross-
coupling is the use of alkyl electrophiles that bear oxygen, rather
than halogen, leaving groups. The significance of this objective
arises in part from the fact that the conversion of alcohols to
Received: August 18, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Table 1. Influence of Reaction Parameters on the Catalytic
Asymmetric Synthesis of a 1,1-Diarylalkane
Table 2. Catalytic Asymmetric Synthesis of 1,1-Diarylalkanes
from Racemic Benzylic Alcohols: Scope with Respect to the
Alcohol
a
a
a
b
All data are the average of two experiments. The yields were
determined through GC analysis with the aid of a calibrated internal
standard.
lower ee but comparable yield (entry 6). The omission of LiI led
to a loss in enantioselectivity and yield (entry 7), whereas use of
LiBr instead provided very good ee but only a modest quantity of
the desired cross-coupling product (entry 8). When the
asymmetric Negishi arylation was conducted with less catalyst
or less nucleophile or at a higher temperature, inferior results
were obtained relative to the best conditions (entries 9−12 vs
entry 1).
With an effective method for the catalytic asymmetric
synthesis of a model 1,1-diarylalkane in hand, we examined the
scope with respect to the electrophile (Table 2). For alkyl
substituents (R) that range in size from methyl to cyclobutyl, the
Negishi arylations proceeded with consistently good enantiose-
lectivities (entries 1−6).13 Furthermore, asymmetric cross-
couplings could be achieved in the case of aryl substituents
(Ar) that are either electron-rich14 or -poor (e.g., entries 15−
24).15 A wide array of functional groups are compatible with the
cross-coupling conditions, including an olefin (entry 9), silyl
ether (entry 10), acetal (entry 11), alkyl ester (entry 12), ketone
(entry 13), nitrile (entry 14), aryl fluoride (entries 15 and 24),
aryl chloride (entry 16), aryl bromide (entry 17), aryl ether
(entries 19 and 21), aryl ester (entry 20), aryl amine (entry 23),
furan (entry 26), and thiophene (entries 27 and 28). On a gram
scale (1.40 g of product), the enantioconvergent Negishi
arylation illustrated in entry 2 proceeded in 95% ee and 89%
yield.
The scope is also fairly broad with respect to the nucleophile
(Table 3). Thus, an array of para- and meta-functionalized
arylzinc reagents are suitable cross-coupling partners (entries 1−
12), including one that bears an aryl iodide (entry 6).16
a
b
All data are the average of two experiments. Yield of purified
c
d
product. Reaction temperature: −35 °C. Nucleophile: (p-tolyl)ZnI.
e
Nucleophile: PhZnI.
B
dx.doi.org/10.1021/ja408561b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Catalytic Asymmetric Synthesis of 1,1-Diarylalkanes
from Racemic Benzylic Alcohols: Scope with Respect to the
a
Nucleophile
catalyst, followed by an intramolecular Friedel−Crafts reaction,
furnished tetralone B in good ee (92%) and 75% overall yield
from the alcohol.
In conclusion, we have developed a nickel-catalyzed stereo-
convergent Negishi cross-coupling of racemic benzylic electro-
philes with arylzinc reagents that affords valuable enantioen-
riched 1,1-diarylalkanes from readily available alcohols in high ee
and good yield. Carbon−carbon bond formation occurs under
mild conditions that are compatible with a range of functional
groups. This method represents an unusual example of the use of
an oxygen-based electrophile in an enantioconvergent, nickel-
catalyzed cross-coupling, although mechanistic studies are
consistent with the possibility that the species that undergoes
oxidative addition may be a benzylic iodide that is generated in
situ under the reaction conditions. Regardless, this process
provides a straightforward approach to enantioenriched 1,1-
diarylalkanes from benzylic alcohols, as exemplified by its
application to an asymmetric synthesis of (S)-sertraline tetralone,
a precursor of Zoloft. Ongoing studies are focused on the
development of additional nickel-catalyzed methods for cross-
coupling alkyl electrophiles, including enantioselective reactions
and mechanistic investigations.
a
b
All data are the average of two experiments. Yield of purified
c
d
product. Equiv of arylzinc reagent: 1.5. Benzylic alcohol coupling
partner: 1-phenylpropanol. Reaction temperature: −30 °C.
e
Furthermore, an indolylzinc reagent can be employed as the
nucleophile (entry 15).
As indicated in Table 1 (entry 7), under our optimized
asymmetric arylation conditions, the presence of LiI is important
for the formation of the desired 1,1-diarylalkane in high ee and
good yield. We hypothesize that a nucleophilic iodide reacts with
the benzylic mesylate to generate a benzylic iodide in situ, and
this is the electrophile that engages with the nickel catalyst in the
cross-coupling process.17 Indeed, we have determined that a
benzylic mesylate does react with LiI in CH2Cl2/THF at −45 °C
to generate a benzylic iodide. Furthermore, cross-couplings of a
benzylic mesylate and the corresponding benzylic iodide proceed
with similar ee and yield (eq 2).18
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
gcfu@caltech.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support has been provided by the NIH (National Institute of
General Medical Sciences: R01-GM62871) and Dr. Reddy’s
Laboratories (E.R.R.C.). We thank Dr. Scott C. Virgil (Caltech
Center for Catalysis and Chemical Synthesis, supported by the
Gordon and Betty Moore Foundation) and Dr. Nathan D. Schley
for assistance.
To illustrate the utility of this catalytic asymmetric method for
the formation of 1,1-diarylalkanes, we applied it to a gram-scale
synthesis of (S)-sertraline tetralone (B; eq 3), a precursor of
sertraline hydrochloride (Zoloft, a leading antidepressant
drug).1a,19 Thus, enantioconvergent Negishi arylation of racemic
benzylic alcohol A in the presence of 4.5% of the chiral nickel
REFERENCES
■
(1) For reviews and leading references, see: (a) Khouzam, H. R.; Ernes,
R.; Gill, T.; Roy, R. Compr. Ther. 2003, 29, 47. (b) Salvatore, S.; Serati,
M.; Bolis, P. Expert Opin. Pharmacother. 2008, 9, 1249. (c) Stayrook, K.
C
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R.; Carson, M. W.; Ma, Y. L.; Dodge, J. A. In Vitamin D; Feldman, D.,
Pike, J. W., Adams, J. S., Eds.; Elsevier: London, 2011; pp 1497−1508.
(2) For examples and leading references, see: (a) Woodmansee, D. H.;
Pfaltz, A. Chem. Commun. 2011, 47, 7912. (b) Tolstoy, P.; Engman, M.;
Paptchikhine, A.; Bergquist, J.; Church, T. L.; Leung, A. W.-M.;
Andersson, P. G. J. Am. Chem. Soc. 2009, 131, 8855; this reference
includes a discussion of other approaches to the synthesis of 1,1-
diarylalkanes.
(3) For example, see: Paquin, J.−F.; Defieber, C.; Stephenson, C. R. J.;
Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850.
(4) For recent reports and leading references, see: (a) Maity, P.;
Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. J.
Am. Chem. Soc. 2013, 135, 280. (b) Zhou, Q.; Srinivas, H. D.; Dasgupta,
S.; Watson, M. P. J. Am. Chem. Soc. 2013, 135, 3307. (c) Harris, M. R.;
Hanna, L. E.; Greene, M. A.; Moore, C. E.; Jarvo, E. R. J. Am. Chem. Soc.
2013, 135, 3303 (doubly benzylic electrophiles).
(5) For an example of an umpolung process that employs an
enantioenriched benzylic nucleophile, see: Imao, D.; Glasspoole, B. W.;
Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024.
(6) For recent examples and leading references, see: (a) Binder, J. T.;
Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 17003. (b) Choi, J.;
Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102. (c) Wilsily, A.; Tramutola,
F.; Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 5794.
(d) Oelke, A. J.; Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 2966.
(7) For a recent application in a total synthesis of a natural product
(carolacton), see: Schmidt, T.; Kirschning, A. Angew. Chem., Int. Ed.
2012, 51, 1063.
(8) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482.
(9) Under conditions described in ref 6a, the cross-coupling of a
benzylic halide with an arylzinc reagent proceeded in poor yield and
poor ee. See also footnote 6c in ref 8.
(10) For a previous example of a nickel-catalyzed cross-coupling of an
alkyl sulfonate, see: Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222.
(11) For leading references, see: (a) Kochi, J. K.; Hammond, G. S. J.
Am. Chem. Soc. 1953, 75, 3443. (b) Hammond, G. S.; Peloquin, J.; Fang,
F. T.; Kochi, J. K. J. Am. Chem. Soc. 1960, 82, 443. (c) Coates, R. M.;
Chen, J. P. Tetrahedron Lett. 1969, 10, 2705.
(12) For example, see: (a) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc.
2008, 130, 12645. (b) Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew.
Chem., Int. Ed. 2009, 48, 154. (c) Refs 6b and 6d.
(13) In a preliminary experiment under our standard conditions, a
highly hindered electrophile (R = isopropyl) was not a suitable cross-
coupling partner.
(14) Benzylic bromides and iodides wherein the aromatic group is
electron-rich can be highly reactive and therefore difficult to isolate.
(15) In preliminary experiments under our standard conditions, an
electrophile in which the aromatic group was hindered (o-tolyl) or very
electron-poor (cyano- or ester-substituted) was not a suitable cross-
coupling partner.
(16) For leading references to nickel-catalyzed cross-coupling
reactions of aryl electrophiles, including processes that involve C−O
bond cleavage: Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem.
2013, 19.
(17) For a suggestion of a tosylate-to-iodide substitution in an iron-
catalyzed cross-coupling reaction: Ito, S.; Fujiwara, Y.-i.; Nakamura, E.;
Nakamura, M. Org. Lett. 2009, 11, 4306.
(18) (a) The improved yield for the cross-coupling of the benzylic
iodide in the presence of LiI (eq 2) may be due to an increase in the
dielectric constant of the reaction medium or to nucleophilic activation
of the organozinc reagent. (b) Under otherwise identical conditions, a
benzylic bromide cross-coupled in comparable yield but slightly lower
ee, whereas a benzylic chloride was not a suitable electrophile. (c) In
preliminary studies, ZnPh2 was not an effective cross-coupling partner.
(19) Quallich, G. J. Chirality 2005, 17, S120.
D
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