Enantioselective Formation of CF3-Bearing All-Carbon Quaternary Stereocenters via C-H Functionalization of Methanol: Iridium Catalyzed Allene Hydrohydroxymethylation

Article abstract of DOI:10.1021/jacs.7b04374

Using an iridium catalyst modified by PhanePhos, CF₃-allenes react with methanol to form branched products of hydrohydroxymethylation as single regioisomers with excellent levels of enantiomeric enrichment. This hydrogen autotransfer process enables catalytic enantioselective formation of acyclic CF₃-bearing all-carbon quaternary stereocenters in the absence of stoichiometric metals or byproducts.

Full text of DOI:10.1021/jacs.7b04374

Communication
pubs.acs.org/JACS
Enantioselective Formation of CF3‑Bearing All-Carbon Quaternary
Stereocenters via C−H Functionalization of Methanol: Iridium
Catalyzed Allene Hydrohydroxymethylation
Michael Holmes, Khoa D. Nguyen, Leyah A. Schwartz, Tom Luong, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
Scheme 1. Catalytic Enantioselective Formation of Acyclic
CF3-Bearing All-Carbon Quaternary Stereocenters
ABSTRACT: Using an iridium catalyst modified by
PhanePhos, CF3-allenes react with methanol to form
branched products of hydrohydroxymethylation as single
regioisomers with excellent levels of enantiomeric enrich-
ment. This hydrogen autotransfer process enables catalytic
enantioselective formation of acyclic CF3-bearing all-
carbon quaternary stereocenters in the absence of
stoichiometric metals or byproducts.
he catalytic enantioselective formation of all-carbon
T
quaternary stereocenters remains a formidable challenge
in chemical synthesis.1−3 In this context, the enantioselective
formation of acyclic CF3-bearing all-carbon quaternary centers is
especially daunting.4−7 As established in seminal work by
Shibata,4a methods capable of delivering this motif are restricted
to conjugate additions of β,β-disubstituted enones4a,b,e,g,h or
nitroolefins4c,d,f,i−k and two isolated reports of asymmetric allyl5a
and propargyl5b substitution. In connection with ongoing studies
of alcohol mediated C−C coupling via hydrogen autotransfer,8
we recently developed catalytic enantioselective methods for the
formation of acyclic all-carbon quaternary stereocenters that
utilize vinyl epoxides3a,b,d and 1,3-dienes3c as pronucleophiles.
Attempts to adapt this technology to the formation of acyclic
CF3-bearing stereocenters via ruthenium catalyzed CF3-allene-
paraformaldehyde reductive coupling mediated by 2-propanol
failed to deliver highly enantiomerically enriched adducts.9
The unique efficacy of iridium(I)-PhanePhos10 complexes in
recently developed methanol mediated hydrohydroxymethyla-
tions of 2-substituted-1,3-dienes,3c along with the availability of
improved protocols for the preparation of CF3-allenes,11
motivated our continued efforts toward this elusive bond
formation. Here, expanding upon the use of methanol as a C1-
feedstock in metal catalyzed C−C coupling,12−14 we report that
iridium-PhanePhos complexes promote the methanol-mediated
hydrohydroxymethylation of CF3-allenes to form highly
enantiomerically enriched adducts with complete branched-
regioselectivity (Scheme 1). Thus, catalytic enantioselective
formation of acyclic CF3-bearing all-carbon quaternary stereo-
centers is achieved in the absence of stoichiometric metals or
byproducts.
reaction was highly substrate dependent with significant variation
in isolated yield and enantioselectivity. Furthermore, all other
chiral ligands that were evaluated failed to deliver products of C−
C coupling. These circumstances led us to explore the influence
of alternate reaction parameters. As illustrated in the
optimization of the methanol-mediated hydrohydroxymethyla-
tion of CF3-allene 1i to form 2i, several interesting trends
emerged (Table 1). For CF3-allene 1i and other allenes bearing
electron deficient aryl moieties, changing the precatalyst from
[Ir(cod)Cl]2 to Ir(cod)(acac) resulted in higher levels of
enantiomeric enrichment, but with lower conversion (Table 1,
entries 1 and 2). A modest increase in reaction temperature
improved the isolated yield of 2i without compromising
enantioselectivity (Table 1, entry 3). The addition of water
(500 mol %) increased enantioselectivity, but led to competing
transfer hydrogenation of 1i (Table 1, entry 4). Tetrabutylam-
monium iodide (TBAI) (10 mol %) suppresses competing
transfer hydrogenation and increases enantioselectivity to a small
extent (Table 1, entry 5). Using water (500 mol %) and TBAI
(10 mol %) in concert, the neopentyl alcohol 2i could be
obtained in 81% yield and 90% ee (Table 1, entry 6). Exchanging
acetone for ethyl acetate as solvent improved enantioselectivity
but diminished yield (Table 1, entry 7).
Taking into account the aforesaid influence of the indicated
reaction parameters, the conversion of 1,1-disubstituted CF3-
allenes 1a−1o to neopentyl alcohols 2a−2o was explored (Table
2). Two general sets of conditions emerged. In the coupling of
CF3-allenes 1a−1f and 1k, which incorporate electron rich,
electron neutral or slightly electron deficient aryl moieties, use of
Given the singular effectiveness of iridium(I)-PhanePhos in
asymmetric diene hydrohydroxymethylation,3c these conditions
were applied to the coupling of methanol with 1,1-disubstituted
CF3-allenes 1a−1o. Although the desired coupling products 2a−
2o were generated with complete branched regioselectivity, the
Received: April 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b04374
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Influence of Various Reaction Parameters in the
Optimization of the Enantioselective Iridium-Catalyzed C−C
Coupling of CF3-Allene 1i with Methanol To Form Alcohol
Table 2. Enantioselective Iridium-Catalyzed Coupling of
Methanol with CF3-Allenes 1a−1o To Form Higher Alcohols
a
2a−2o
a
2i
entry
lr(l)Ln
additive (mol %)
T (°C) yield (%) ee (%)
1
2
3
4
5
6
[lr(cod)CI]2
lr(cod)(acac)
lr(cod)(acac)
lr(cod)(acac)
lr(cod)(acac)
lr(cod)(acac)
Ir(cod)(acac)
70
70
80
80
80
80
80
56
14
79
56
79
81
72
64
79
79
89
84
90
94
H2O (500 mol %)
TBAI (10 mol %)
H2O/TBAI
b
7
H2O/TBAI
a
Yields of material isolated by silica gel chromatography. Enantiose-
lectivities were determined by chiral stationary phase HPLC analysis.
EtOAc solvent.
b
the iridium catalyst derived from [Ir(cod)Cl]2 and (R)-
PhanePhos in acetone solvent at 70 °C was optimal. For CF3-
allenes bearing highly electron deficient aryl moieties, the
precatalyst Ir(cod)(acac) in ethyl acetate solvent at 80 °C was
preferred. Under both sets of conditions, TBAI and H2O were
frequently required to enhance enantioselectivity. By tailoring
reaction conditions in this manner, alcohols 2a−2o with CF3-
bearing all-carbon quaternary stereocenters could be formed
with uniformly high levels of enantioselectivity and as single
regioisomers. Alkyl substituted CF3-allenes engage in efficient
methanol-mediated hydrohydroxymethylation, but enantiose-
lectivities were lower (<50% ee). The absolute stereochemical
assignment of adducts 2a−2o is based on single crystal X-ray
diffraction analysis of 2b and 2f. Attempted use of higher alcohols
led to regio- and enantioselective transfer hydrogenation of the
internal allene π-bond (ca. 40% ee).
To demonstrate how adducts 2a−2o can be used in chemical
synthesis, alcohol 2a was subjected to a series of functional group
manipulations. Conversion of alcohol 2a to the corresponding p-
toluenesulfonate followed by exposure to sodium cyanide in
DMSO at 150 °C provided the nitrile 3, representing a
remarkable example of an SN2 reaction at a highly congested
neopentyl center (eq 1). Jones oxidation of alcohol 2a followed
by Fischer esterification provides the β,γ-unsaturated methyl
ester 4 (eq 2). Finally, conversion of alcohol 2a to the benzoate
followed by oxidative cleavage15 of the vinyl moiety delivers the
chiral α-stereogenic carboxylic acid 5 (eq 3).
As exemplified in methanol-mediated transfer hydrogenations
of C−C π-bonds,16 the reversible and highly endothermic nature
of methanol dehydrogenation (ΔH(MeOH) = +20 kcal/mol vs
ΔH(EtOH) = +16 kcal/mol)17 can be overcome by linking
dehydrogenation to an exothermic process. Methanol dehydro-
genation also poses a significant challenge in the hydro-
hydroxymethylation of π-unsaturated reactants and invariably
represents the rate-limiting step.3c,14 However, as the present
allene-methanol C−C couplings involve formation of a highly
congested CF3-bearing all-carbon quaternary stereocenter, it was
unclear whether methanol dehydrogenation or carbonyl addition
would be rate-limiting. To gain further insight into the catalytic
mechanism, CF3-allene 1a was subjected to d4-methanol under
otherwise standard conditions (Scheme 2, eq 4). The product,
a
Yields of material isolated by silica gel chromatography. Enantiose-
lectivities were determined by chiral stationary phase HPLC analysis.
b
c
[Ir(cod)Cl]2, 70 °C, Me2CO. Ir(cod)(acac), TBAI (10 mol %), 80
d
e
f
°C, EtOAc. TBAI (10 mol %). H2O (200 mol %). H2O (500 mol
%). See Supporting Information for further experimental details.
deuterio-2a, completely retains deuterium at the carbinol position
(Ha, Hb = >95% H), suggesting deuterio-2a is kinetically inert
with respect to dehydrogenation due to coordination of the
homoallylic olefin to iridium, blocking the adjacent coordination
site required for β-hydride elimination. Although deuterium is
not incorporated at the vinylic terminus of deuterio-2a (Hd, He =
2
2
<5% H), a significant quantity of deuterium appears at the
2
internal vinylic position (Hc = 58% H). Unlike related diene-
methanol C−C couplings,3c this data suggests the hydro-
metalation event is a completely regioselective process.
Incomplete incorporation of deuterium at the internal vinylic
B
DOI: 10.1021/jacs.7b04374
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Journal of the American Chemical Society
Communication
we propose that carbonyl addition occurs from an allyliridium-
(III) intermediate (Scheme 2, bottom).
To summarize, CF3-bearing all-carbon quaternary stereo-
centers are exceptionally difficult to prepare in enantiomerically
enriched form, with existing protocols for their construction
largely restricted to conjugate additions to β,β-disubstituted CF3-
enones and nitroolefins.4 Here, we demonstrate that iridium
complexes modified by PhanePhos catalyze the methanol-
mediated hydrohydroxymethylation of CF3-allenes to generate
this structural motif in a completely regioselective and highly
enantioselective fashion in the absence of stoichiometric metals
or byproducts. Future studies will focus on the development of
related C−C bond forming transfer hydrogenations for the
conversion of abundant feedstocks to value-added products.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b04374.
■
S
Experimental procedures and spectral data; HPLC traces
corresponding to racemic and enantiomerically enriched
samples (PDF)
Scheme 2. General Catalytic Mechanism and Deuterium
Labelling Studies
a
X-ray diffraction data for 2b (CIF)
X-ray diffraction data for 2f (CIF)
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
■
ORCID
Michael J. Krische: 0000-0001-8418-9709
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for partial
support of this research.
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Journal of the American Chemical Society
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DOI: 10.1021/jacs.7b04374
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