Palladium-Catalyzed Negishi Coupling of α-CF3 Oxiranyl Zincate: Access to Chiral CF3-Substituted Benzylic Tertiary Alcohols

Article abstract of DOI:10.1021/jacs.7b06630

We report a Pd-catalyzed stereospecific α-arylation of optically pure 2,3-epoxy-1,1,1-trifluoropropane (TFPO). This method allows for the direct and reliable preparation of optically pure 2-CF₃-2-(hetero)aryloxiranes, which are precursors to many CF₃-substituted tertiary alcohols. The use of continuous-flow methods has allowed the deprotonation of TFPO and subsequent zincation at higher temperature compared to that under traditional batch conditions.

Full text of DOI:10.1021/jacs.7b06630

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Article
Palladium-Catalyzed Negishi Coupling of #-CF3 Oxiranyl Zincate:
Access to Chiral CF3-substituted Benzylic Tertiary Alcohols
Hu Zhang, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Jul 2017
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PalladiumꢀCatalyzed Negishi Coupling of αꢀCF3 Oxiranyl Zincate:
Access to Chiral CF3ꢀsubstituted Benzylic Tertiary Alcohols
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Hu Zhang, Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
ABSTRACT: We report a Pdꢀcatalyzed stereospecific αꢀarylation of optically pure 2,3ꢀepoxyꢀ1,1,1ꢀtrifluoropropane (TFPO). This
method allows for the direct and reliable preparation of optically pure 2ꢀCF3ꢀ2ꢀ(hetero)aryloxiranes, which are precursors to many
CF3ꢀsubstituted tertiary alcohols. The use of continuousꢀflow methods has allowed the deprotonation of TFPO and subsequent zinꢀ
cation at higher temperature compared to that under traditional batch conditions.
Introduction
in the case of αꢀCF3 oxiranyl zincates, since the strongly elecꢀ
tronꢀwithdrawing CF3 group further reduces the nucleophiliciꢀ
ty of the alkylzinc species. We hypothesized that a bulky biarꢀ
yldialkylphosphine ligand would promote the transmetallation
step by forming a coordinatively unsaturated L1Pd(Ar)X inꢀ
termediate, which should be less hindered and exhibit higher
reactivity toward transmetallation with the organozinc speꢀ
cies.9 Herein, we report the successful development of a highly
effective and general catalyst system for the Negishi coupling
of αꢀCF3 oxiranyl zincate with aryl bromides or chlorides to
access 2ꢀarylꢀ2ꢀtrifluoromethyloxiranes in essentially optically
pure form (>99% ee or >99:1 dr).
The strongly electronꢀwithdrawing trifluoromethyl (CF3)
group can dramatically affect the physical and biological
properties of compounds, such as lipophilicity and metabolic
stability.1 These unique effects have led to the prevalence of
CF3 group in synthetically prepared bioactive molecules.2 In
particular, chiral CF3ꢀsubstituted tertiary alcohols and their
derivatives are present in a diverse range of therapeutic drugs
(Scheme 1a). Yet, efficient and general methods for their
preparation in optically pure form are still limited. Previous
methods mostly rely on enantioselective addition of nucleoꢀ
philes to trifluoromethylketones or nucleophilic trifluoromethꢀ
ylation of prochiral ketones (Scheme 1b).3 Although high enꢀ
antioselectivities are often observed, these methods provide
access to only a few, specialized classes of CF3ꢀsubstituted
tertiary alcohols.
Result and discussion
We initially investigated a series of G3ꢀpalladacycle precataꢀ
lysts10 bearing various biaryldialkylphosphine ligands for the
Negishi coupling of 3a with αꢀCF3 oxiranyl zincate I (Table
1). Among the precatalysts evaluated11, the palladacycle based
on CPhos (P1), previously reported to be an excellent catalyst
in the Negishi coupling of secondary alkylzincs,12 was found
to be the only catalyst that promoted the formation of the deꢀ
sired coupling product 4a, albeit in trace yield (entry 1). Sigꢀ
nificant improvement was observed by adding one equivalent
LiCl, presumably by forming a more reactive highꢀorder alꢀ
The nucleophilic ringꢀopening of enantioenriched 2ꢀ
substituted 2ꢀtrifluoromethyloxiranes may provide an alternaꢀ
tive, more general, approach to the stereoselective synthesis of
chiral CF3ꢀsubstituted tertiary alcohols (Scheme 2a). The funcꢀ
tionalization of enantioenriched αꢀtrifluoromethyl oxiranyl
anion 2, which could be generated by stereoretentive metaꢀ
lation of optically pure 2,3ꢀepoxyꢀ1,1,1ꢀtrifluoropropane
(TFPO, 1), represents an attractive means of accessing these
intermediates since both enantiomers of 1 are readily accessiꢀ
ble from hydrolytic kinetic resolution of the racemic oxirane4.
In 2002, Uneyama and coworkers reported the stereoselective
trapping of 2 with a variety of electrophiles, including aldeꢀ
hydes and MeI, to give the 2ꢀalkylated epoxides.5 However,
the arylation of 2 proved challenging. The authors reported a
single example of a Negishi coupling between the zincated αꢀ
trifluoromethyl oxiranyl anion and an aryl iodide.6 In this case,
a modest yield was obtained despite the use of a high catalyst
loading and an excess of aryl iodide (The enantiomeric excess
of the product was not reported, Scheme 2b).
2−
kylzincate species RZnCl3 (II) (entry 2).13 A further imꢀ
provement in yield was observed when the amount of ZnCl2
was reduced to 0.6 equiv (entry 3), perhaps by favoring the
2−
formation of dialkylzincate R2ZnCl2 (III) as the dominant
alkylzinc spe cies.14 Based on the observation that αꢀCF3
oxiranyl zincate species are much less basic than typical orꢀ
ganozinc reagents,15 we hypothesized that a precatalyst bearꢀ
ing a more acidic anilino group would be more readily activatꢀ
ed via deprotonation. This led us to investigate the G5ꢀ
precatalyst (P2).16 Indeed, the use of P2 showed higher reacꢀ
tivity than P1 (entry 4). By comparison, less readily deprotoꢀ
nated G4ꢀprecatalyst P3 gave a much lower yield (entry 5).
Finally, using toluene as cosolvent and slow addition of a soꢀ
lution of the organozinc resulted in further improvement to
provide 4a in excellent yield (entry 6 and 7).
In contrast to the extensive progress in the Negishi coupling
of primary and secondary alkylzinc species,7 the coupling of
tertiary alkylzinc reagents is relatively rare.8 Problems in the
coupling of tertiary alkylzincs include the slow rate of
transmetallation of the bulky nucleophile and competitive βꢀ
hydride elimination. These challenges are further exacerbated
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Scheme 1. (a) Examples of CF3ꢀsubstituted tertiary alcohols and derivatives in pharmaceuticals (b) Enantioselective addiꢀ
tion to trifluoromethylketones or trifluoromethylation of ketones
1
2
3
4
5
6
7
(a)
CF3
NH
H
N
O
OH
CF3
O
Me
HN
O
Me
Me
Cl
N
O
Cl
CF3
S
N
O
O
O
N
CF3
8
9
F
CF3
Cl
Efavirenz
(antiretroviral)
HSD-16
(antidiabetic)
Fluralaner
(antiparasitic)
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(b)
CF3-substituted tertiary alcohols accessible from reported methods (ref. 3):
OH
O
Nu:
O
R
F3C OH
Ar
F3C OH
R
CF3
Nu
F3C OH
R
R
R
CF3
catalyst
NO2
Me
or
F3C OH
F3C OH
Ar
F3C OH
R
OH
O
−
OH
'CF3
'
Ar
O
CF3
Ar
Ar
R
catalyst
R
R
Scheme 2. (a) Synthesis of CF3ꢀsubstituted tertiary alcohols via αꢀCF3 oxiranyl anion (b) Negishi coupling of αꢀCF3 oxiranyl
zincate with aryl halides
The highly unstable nature of oxiranyl anions necessitates
their generation and subsequent electrophilic trapping at very
low temperatures under batch conditions (often below −90
°C). This is difficult to achieve using standard cryogenic
equipment and poses a major challenge for the scaleꢀup of
reactions. Recently, continuousꢀflow systems have been
shown to provide several advantages for reactions involving
thermally unstable intermediates.17 With more efficient mixing
and heat transfer, reactions under continuousꢀflow conditions
may be performed at considerably higher temperatures comꢀ
pared to batch conditions. Yoshida and coworkers reported the
development of continuousꢀflow systems for electrophilic
trapping of various oxiranyl anions at −78 to −48 °C.18 More
recently, we19 and the Knochel group20 independently develꢀ
oped systems for the deprotonation and zincation of aromatic
rings to form (hetero)aryl zincates in continuousꢀflow folꢀ
lowed by Negishi coupling. We sought to transfer the generaꢀ
tion of III into a continuousꢀflow system, aiming to increase
the reaction temperature and improve the scalability of the
process. We found that deprotonation of (S)ꢀ1 and subsequent
zincation could be conducted at −50 °C in continuousꢀflow
(Scheme 3). The organozincate III generated was added diꢀ
rectly into the batch reactor for Negishi coupling to provide 4a
in excellent yield.
Using this continuousꢀflow to batch system we explored the
substrate scope of this Negishi coupling reaction (Table 2).
Substrates bearing various electrophilic functional groups
successfully underwent crossꢀcoupling to provide the epoxides
in good yield (4b to 4e). Examples of acidic functional groups
such as an alcohol (4i), carbamate (4j), and sulfonamide (4k),
are compatible with this transformation. A variety of brominꢀ
ated or chlorinated heterocycles, including quinoline, pyridine,
azaindole, and benzothioazole, are also competent partners,
providing the epoxide product in moderate to good yield (4m
to 4r). We believe that the lower yields realized with subꢀ
strates 4j, 4n, 4o and 4q are mostly due to lower yielding
Negishi coupling reactions. The NMR yields with these subꢀ
strates, which were determined before purification, were also
lower compared to other substrates. We also note that, in genꢀ
eral,
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Table 1. Optimization of the Negishi couplinga
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entry
precat.
P1
ZnCl2 (equiv.)
alkylzinc
time (h)
solvent
THF
Yieldd of 4a
2%
1
2b
3
1.1
1.1
0.6
0.6
0.6
0.6
0.6
12
12
2
I
THF
13%
P1
II
THF
41%
P1
III
III
III
III
III
4
2
THF
69%
P2
5
2
THF
11%
P3
6
7c
2
THF/toluene
74%
90% (>99% eee)
P2
0.5
THF/toluene
P2
a
b
c
Reactions were conducted on 0.5 mmol scale, see SI for details of the experiments. 1 equivalent LiCl added. Slow addition of orꢀ
ganozinc solution over 30 minutes at 40 °C. d Yields were determined by 19F NMR analysis using α,α,αꢀtrifluoromethyltoluene as an inꢀ
ternal standard. e Enantiomeric excesses are determined by chiral HPLC.
Scheme 3. Continuousꢀflow to batch system
the transformation of pyridineꢀcontaining substrates is more
challenging and gives lower yields of product. Importantly, no
erosion in enantiopurity was ever observed during the course
of metalation and arylation; thus in all cases examined, the
products were isolated with >99% ee or >99:1 dr. The absoꢀ
lute configuration of the epoxide product was determined by
Xꢀray crystallographic analysis of 4g.
tosyl 2ꢀarylꢀ2ꢀCF3ꢀaziridine 7 was synthesized in two steps
and 75% yield from 4m. Chiral diol 8, a precursor to Mosher’s
acid,21 was prepared from bromobenzene (3s) and (S)ꢀ1 in two
steps and 70% yield with 1 mol% catalyst loading (Scheme
4b). HSDꢀ01622, a drug candidate for the treatment of typeꢀ2
diabetes, has been previously prepared from 3t in 37% yield
over five steps, four of which were used to prepare epoxide 4t.
The Negishi coupling of 3t with organozinc III afforded 4t in
a single step (68% isolated yield, >99:1 dr) (Scheme 4c), exꢀ
emplifying the potential utility and efficiency of this method
for the construction of medicinally relevant molecules.
As previously mentioned, the optically pure 2ꢀarylꢀ2ꢀ
trifluoromethyloxiranes obtained from this method represent
attractive substrates for ringꢀopening reactions with various
nucleophiles. To illustrate this point, optically pure amino
alcohol 5 and homopropargyl alcohol 6 were obtained in high
yield by the ringꢀopening of 4m with cyclopropylamine and
alkynyllithium, respectively (Scheme 4a). Additionally, Nꢀ
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Table 2. Substrate scopea
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a Reactions were conducted on 2 mmol scale. Yields are of isolated products and are the average of two runs. Enantiomeric excesses are
determined by chiral HPLC.
Scheme 4. Synthetic applications of the Negishi coupling of αꢀCF3 oxiranyl anion
a) Ring-opening of 4m with different nucleophiles
b) Formal asymmetric synthesis of Mosher's acid
F3C OH
H
N
1. Flow-Batch system
(S)-1 (1 equiv.)
NH2
P2 (1 mol%)
EtOH, 70 °C, 3 h
Me
N
F3C OH
THF/toluene, 45 °C
5
Br
OH
30 min
95% yield, >99% ee
2. H2O, dioxane
85 °C, 24 h
TMS
F3C OH
8
TMS
3s
Li
F3C
O
70% yield over two step
THF, rt, overnight
(3 equiv.)
>99% ee
Me
N
6
Me
N
ref. 21
92% yield, >99% ee
1. TsNH2, K2CO3 (cat.),
BnEt3NCl (cat.)
dioxane, 90 °C, 6 h
2. PPh3, DIAD, Et3N
THF, rt, 6 h
4m
>99% ee
F3C
NTs
OMe
OH
F3C
O
Me
N
7
Mosher's acid
75% yield over two steps
>99% ee
c) Concise synthesis of HSD-016
(ref. 22: 4 steps, <51% yield, 93:7 dr)
OH
O
F3C
Me
F3C
Me
Br
1. Flow-Batch system
(S)-1 (1.1 equiv.)
P2 (4 mol%)
THF/toluene, 40 °C
30 min
F
F
F
Me
Me
2. NaBH4, EtOH, rt, 5 h
N
N
N
N
N
N
S
S
CF3
S
CF3
CF3
O
O
O
O
O
O
68% yield, >99:1 dr
HSD-016
4t
3t
65% yield from 3t
>99:1 dr
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lective trifluoromethylation of ketones, see: (e) Yang, X.; Wu, T.;
Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826–870. For
asymmetric synthesis of αꢀCF3ꢀsubstituted αꢀhydroxy carboxylic acid
by 1,2ꢀmigration of CF3 group, see: (f) Wang, P.; Feng, L. W.; Wang,
L.; Li, J. F.; Liao, S.; Tang, Y. J. Am. Chem. Soc. 2015, 137, 4626–
4629.
(4) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307–1315.
(5) (a) Yamauchi, Y.; Katagiri, T.; Uneyama, K. Org. Lett. 2002,
4, 173–176; For a recent review on oxiranyl anions, see: (b) Capriati,
V.; Florio, S.; Luisi, R. Chem. Rev. 2008, 108, 1918–1942.
(6) Yamauchi, Y.; Kawate, T.; Katagiri, T.; Uneyama, K. Tetrahe-
dron 2003, 59, 9839–9847.
(7) For a recent review on Negishi coupling, see: Haas, D.; Hamꢀ
mann, J. M.; Greiner, R.; Knochel, P. ACS Catal. 2016, 6, 1540–
1552.
(8) For examples of Negishi coupling of tertiary alkylzinc with arꢀ
yl halides, see (a) Samann, C.; Dhayalan, V.; Schreiner, P. R.;
Knochel, P., Org. Lett. 2014, 16, 2418–2421; (b) Greszler, S. N.,
Halvorsen, G. T.; Voight, E. A. Org. Lett., 2017, 19, 2490–2493 and
references therein.
(9) For reviews on biaryldialkylphosphine ligands in Pdꢀcatalyzed
crossꢀcoupling reactions, see: (a) Surry, D. S.; Buchwald, S. L. An-
gew. Chem. Int. Ed. 2008, 47, 6338–6361; (b) Martin, R.; Buchwald,
S. L. Acc. Chem. Res. 2008, 41, 1461–1473; for biaryldialꢀ
kylphosphine ligands in Pdꢀcatalyzed Negishi coupling reactions, see:
(c) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028–13032; (d) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 7532–7533; (e) Yang, Y.; Oldenhuis, N. J.; Buchwald, S. L.,
Angew. Chem. Int. Ed. 2013, 52, 615–619.
(10) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci.,
2013, 4, 916–920
(11) See supporting information for a list of palladacycle precataꢀ
lysts examined.
(12) Yang, Y.; Niedermann, K.; Han, C.; Buchwald, S. L. Org.
Lett. 2014, 16, 4638–4641.
(13) Achonduh, G. T.; Hadei, N.; Valente, C.; Avola, S.; O'Brien,
C. J.; Organ, M. G. Chem. Commun. 2010, 46, 4109–4111.
(14) Two distinct peaks were observed in 19F NMR when racemic
TFPO was used, indicating the formation of two diastereomers of
dialkylzincate. Only one peak was observed when enantiopure TFPO
was used. See SI for the spectra.
(15) The αꢀCF3 oxiranyl zincate I could not be effectively
quenched by water.
(16) For the first report on this class of precatalyst, see: Bruno, N.
C.; Niljianskul, N.; Buchwald, S. L., J. Org. Chem. 2014, 79, 4161–
4166.
(17) (a) Wirth, T. Microreactors in organic synthesis and cataly-
sis. Wiley–VCH: Weinheim, 2008; (b) Noel, T.; Buchwald, S. L.,
Chem Soc Rev 2011, 40, 5010–5029; (c) Wegner, J.; Ceylan, S.;
Kirschning, A. Adv. Synth. Catal. 2012, 354, 17–57; (d) Hessel, V.;
Kralisch, D.; Kockmann, N.; Noel, T.; Wang, Q. Chemsuschem 2013,
6, 746–789; (e) Pastre, J. C.; Browne, D. L.; Ley, S. V. Chem. Soc.
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R. J.; Myers, R. M. Angew. Chem. Int. Ed. 2015, 54, 3449–3464; (g)
Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed. 2015,
54, 6688–6728; (h) Ley, S. V.; Fitzpatrick, D. E.; Myers, R. M.; Batꢀ
tilocchio, C.; Ingham, R. J. Angew. Chem. Int. Ed. 2015, 54, 10122–
10136; (i) Kobayashi, S. Chem-Asian J. 2016, 11, 425–436.
(18) Nagaki, A.; Takizawa, E.; Yoshida, J. J. Am. Chem. Soc.
2009, 131, 1654–1655.
(19) Roesner, S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2016, 55,
10463–10467.
(20) (a) Becker, M. R.; Knochel, P. Org. Lett. 2016, 18, 1462–
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1
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7
8
Conclusion
In summary, we have developed an efficient Pdꢀcatalyzed
arylation of TFPO by using a highꢀorder dialkylzincate and a
precatalyst that is effectively activated by the weakly basic
zincate. A continuousꢀflow to batch system has also been deꢀ
veloped. This threeꢀstep process allows for the generation of
αꢀCF3 oxiranyl zincate at much higher temperature compared
to the batch conditions. This method demonstrates excellent
compatibility with functional groups and reliably provides 2ꢀ
arylꢀ2ꢀtrifluoromethyloxiranes in exceptionally high enantioꢀ
meric excess. With the rich chemistry of epoxides, this process
constitutes a general approach to various CF3ꢀsubstituted terꢀ
tiary alcohols and related molecules.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data for all comꢀ
pounds (PDF)
Crystallographic data for 4g (CIF)
AUTHOR INFORMATION
Corresponding Author
* sbuchwal@mit.edu
Notes
The authors declare the following competing financial interest(s):
MIT has or has filed patents on ligands that are described in the
paper from which SLB and former/current coworkers receive
royalty payments.
ACKNOWLEDGMENT
We acknowledge Novartis International AG for supporting this
work. We thank the National Science Foundation (CHEꢀ0946721)
for funding the Xꢀray facility at MIT. We thank Dr. Peter Mueller
for Xꢀray crystallographic. We thank Dr. Yiming Wang, Dr.
Nicholas White, and Dr. Christine Nguyen for assistance with the
preparation of this manuscript. We are grateful to Drs. Gerhard
Penn and Benjamin Martin (Novartis) for helpful comments. We
thank Sigma Aldrich for a gift of CPhos.
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