Catalytic, enantioselective 1,2-difluorination of cinnamamides

Article abstract of DOI:10.1021/acs.orglett.9b00938

The enantio- and diastereoselective synthesis of 1,2-difluorides via chiral aryl iodide-catalyzed difluorination of cinnamamides is reported. The method uses HF-pyridine as a fluoride source and mCPBA as a stoichiometric oxidant to turn over catalyst, and

Full text of DOI:10.1021/acs.orglett.9b00938

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic, Enantioselective 1,2-Difluorination of Cinnamamides
Moriana K. Haj, Steven M. Banik, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: The enantio- and diastereoselective synthesis of
1,2-difluorides via chiral aryl iodide-catalyzed difluorination of
cinnamamides is reported. The method uses HF-pyridine as a
fluoride source and mCPBA as a stoichiometric oxidant to turn
over catalyst, and affords compounds containing vicinal, fluoride-
bearing stereocenters. Selectivity for 1,2-difluorination versus a
rearrangement pathway resulting in 1,1-difluorination is enforced
through anchimeric assistance from a N-tert-butyl amide
substituent.
Scheme 1. Product Selectivity in Aryl Iodide-Catalyzed
Difluorination of Cinnamamides
he stereocontrolled introduction of fluorine atoms into
Torganic molecules is a long-standing challenge in
synthetic chemistry driven, to a significant extent, by the
beneficial properties fluorination can impart to the physical
and biological properties of organic molecules.1 Due to their
known preference for adopting gauche conformations, vicinal
difluorides represent a particularly interesting subset of
organofluorine compounds.2 The direct, enantioselective 1,2-
difluorination of alkenes represents a most appealing approach
to this class of compounds, but no general methods have yet
been identified for accomplishing such a transformation.3
Reported examples of enantiocontrolled synthesis of vicinal
difluorides most often involve deoxyfluorination of 1,2-
fluoroalcohols derived from stereodefined epoxides or diols.4
However, these reactions are prone to competitive elimination
pathways and are often low-yielding.5 New methods for direct,
enantioselective vicinal difluorination could enable a more
thorough exploration of the gauche effect on molecular
structure and function.
There has been remarkable progress over the past decade in
the development of enantioselective alkene difunctionalization
reactions using hypervalent iodine reagents and catalysts.6 In
that context, the Gilmour lab and our group recently
developed catalytic variants of the alkene 1,2-difluorination
first reported by Hara.3n,6g,h Our system engaged HF-pyridine
as a nucleophilic fluoride source and meta-chloroperbenzoic
acid (mCPBA) as the stoichiometric oxidant,7 and included a
single example of an enantioselective variant in the 1,2-
difluorination of trisubstituted cinnamamide 2q catalyzed by
chiral aryl iodide 1a (Scheme 1).8 However, in subsequent
work, we found that the scope of that reaction was severely
limited due to competing rearrangement pathways. Here, we
address that selectivity challenge through a systematic study of
the factors influencing product distribution, leading to the
development of a protocol for the highly chemo- and
enantioselective 1,2-difluorination of trisubstituted cinnama-
mide substrates. These reactions provide versatile synthetic
building blocks bearing contiguous secondary and tertiary
fluorine-bearing stereocenters. Concurrent with our efforts,
Gilmour and co-workers reported a complementary method
Received: March 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00938
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Letter
a
Table 1. Optimization of the 1,2-Difluorination Reaction
a
Unless noted otherwise, reactions were conducted on a 1.00 mmol
scale and isolated yields of 3 are listed. Reported ratios of 1,2-
difluoride to 1,1-difluoride were determined by 19F NMR analysis of
b
crude product mixtures. Reaction conducted on 0.10 mmol scale,
with yields of 1,2-difluoride determined by 1H NMR against an
internal standard.
for the enantioselective 1,2-difluorination of simple, electron-
deficient styrenes.9
Styrenyl substrates are susceptible to rearrangement path-
ways under electrophilic fluorination conditions, thereby
affording 1,1-difluorinated products.10,11 For example, in the
attempted difluorination of trisubstituted cinnamamide 2a
catalyzed by aryl iodide 1b, a mixture of 1,2- and 1,1-difluoride
products was obtained unselectively (Scheme 1A). Product
partitioning is proposed to arise from the initial fluoroiodina-
tion adduct A, which can undergo aryl iodide displacement
either by the amide carbonyl oxygen or by the aryl group
(Scheme 1B).6g,j The basis for enantioinduction is likely
common to both pathways and was explored computationally
in a recent collaborative study.11e We hypothesized that the
amide anchimeric assistance pathway leading to the 1,2-
product might be enhanced through judicious introduction of
N-substituents, since substitution has been demonstrated to
lower the strain energy in small rings in specific cases.12
We evaluated a series of N-substituted amides as model
substrates for the enantioselective 1,2-difluorination reaction
with catalyst 1b (Table 1). While tertiary amide derivatives of
2 displayed poor reactivity, secondary amides underwent
reaction more efficiently than the primary amide 2a. Thus, the
difluorination of N-methyl amide 2b (entry 2) proceeded with
improved yield and enantioselectivity, although without any
change in product ratio. Decreasing the HF-pyridine
concentration led to a modest improvement in selectivity for
the 1,2-product 3b, with optimal yields obtained using 5.6
equiv (entry 3). The dependence of product ratio on HF-
pyridine loading might be attributable to attenuation of amide
nucleophilicity by hydrogen bonding between the amide and
HF.13 Increasing the size of the secondary amide N-substituent
resulted in increased selectivity for formation of 1,2-difluoride
products (entries 3−7), with the N-tert-butyl amide 2f
affording the desired 1,2-difluoride 3f almost exclusively
(entry 7). Notably, the reaction of 2f proceeded with
significantly diminished chemoselectivity when 11 equiv of
HF-pyridine were used (entry 8).14
Figure 1. (A) Scope of the enantioselective 1,2-difluorination of N-
tert-butyl cinnamamides. Reactions were conducted on 1.00 mmol
scale with 5.6 equiv of HF-pyridine. Ratios of 1,2-difluoride to 1,1-
difluoride were determined by 19F NMR analysis of crude product
mixtures. Isolated yields of diastereomerically pure 1,2-difluoride are
reported unless otherwise noted. The relative and absolute
configurations of all 1,2-difluorination products were assigned by
analogy to those of 3q (ref 16). a Reaction conducted with 2.8 equiv
of HF-pyridine. b Reaction conducted on 0.20 mmol scale with 2.8
equiv of HF-pyridine and added pyridine (pyr/HF = 1:4.5). The
1
reported yield was determined by H NMR using nitrobenzene as an
internal standard. (B) Hammett plot of σ+ values of the aryl
substituents in 2f and 2h−j versus the product ratio (log(1,2:1,1))
obtained for each substrate.
Under the optimized conditions, a variety of tert-butyl
cinnamamide derivatives were found to undergo highly
diastereo- and enantioselective formation of the corresponding
1,2-difluorination products (Figure 1A).15 Substrates bearing
electron-withdrawing and mildly electron-donating substitu-
ents (2g−i) were particularly effective. The electron-rich
cinnamamide 2j underwent reaction with only modest
chemoselectivity to generate a 2.2:1.0 ratio of the desired
1,2-difluoride to the 1,1-difluoride, with the 1,2-difluoride
isolated in 40% yield and 98% e.e. This result is nonetheless
notable because it overturns the overwhelming selectivity for
1,1-difluoride observed for the analogous primary amide
substrate (see Supporting Information). A further increase in
chemoselectivity for the 1,2-product was obtained by
increasing the ratio of pyridine to HF from 1:9 to 1:4.5.
Although we have not performed a systematic investigation of
B
DOI: 10.1021/acs.orglett.9b00938
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Letter
substituent σ+ constants and log(3:4) for substrates 2f and
2h−j (Figure 1B). The α-alkyl substituent of the cinnamamide
could also be varied (Figure 1A). Substrate 2l, which bears an
ethyl substituent at the α-position of the cinnamamide,
undergoes 1,2-difluorination exclusively. Indene 2m, which is
not susceptible to an aryl migration pathway, afforded 3m in
moderate yield and enantioselectivity. Nonstyrenyl unsaturated
amides display poor reactivity under the reaction conditions.
We sought to elucidate the basis for the significant impact of
the amide N-substituent on product ratio. A strong linear free-
energy correlation was observed between the 1,2- vs 1,1-
product ratios and the Charton values (ν) of the amide N-
substituents for 2a−f (Figure 2A), indicating that the effect is
primarily steric in nature.17 Larger substituents thus appear to
enhance amide anchimeric assistance relative to aryl migration,
thereby favoring the 1,2-difluorination pathway.
The electronic effect of the amide N-substituent on the
competition between the aryl migration and amide trapping
pathways was probed by examining substrates bearing
fluorinated N-substituents (2n−p). Substrates bearing elec-
tron-withdrawing N-alkyl substituents underwent difluorina-
tion with lower product selectivity for the 1,2-difluoride
(Figure 2B, top). The experimentally measured infrared
stretching frequencies of the amide carbonyls of 2c and 2n−
p correlate to ln(3:4) (Figure 2B, bottom). As might be
anticipated, decreased nucleophilicity of the amide oxygen
disfavors anchimeric assistance relative to phenonium ion
formation.
The products of the difluorination reaction can be
derivatized to access versatile, enantioenriched vicinal
difluoride building blocks (Scheme 2). Treatment of 3f with
a solution of hydrogen bromide in acetic acid resulted in
efficient cleavage of the tert-butyl group to afford primary
amide 3a. The arene of 3f can be degraded oxidatively to give
carboxylic acid 5, thereby providing a 1,4-dicarbonyl bearing a
second functional handle off the stereodefined difluoride
framework.
In conclusion, we have developed a catalytic, enantiose-
lective 1,2-difluorination of cinnamamides. The competing 1,1-
difluorination resulting from phenonium rearrangement was
suppressed through enhancement of anchimeric assistance by a
proximal tert-butyl amide. The resulting products and their
derivatives may serve as versatile building blocks for the
preparation of 1,2-difluoride-containing compounds, enabling
further study of this interesting motif. Efforts are underway to
extend the scope of this methodology to other enantioselective
fluorofunctionalization reactions.
Figure 2. (A) Plot of Charton values (ν) for amide N-substituents of
2a−f versus the product ratio (ln(1,2:1,1)) obtained for each
substrate. (B) Plot of amide carbonyl stretching absorptions for 2c
and 2n−p versus the product ratio (ln(1,2:1,1)) obtained for each
substrate. Reactions were conducted on a 1.00 mmol scale. Reported
ratios of 1,2-difluoride to 1,1-difluoride were determined by 19F NMR
analysis of the crude mixture.
Scheme 2. Product Derivatization
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00938.
Experimental procedures and characterization data
(PDF)
the effect of the reaction medium on product distribution,
Gilmour and co-workers have demonstrated clearly that 1,2:1,1
product ratios are dependent on amine concentrations in
difluorinations of electron-deficient styrenes.9 Chemoselectiv-
ity for 1,2- vs 1,1-difluorination was observed to be correlated
directly to the nucleophilicity of the arene, as evidenced by the
positive linear correlation (ρ+ = 4.34) between the Hammett
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jacobsen@chemistry.harvard.edu.
ORCID
Eric N. Jacobsen: 0000-0001-7952-3661
C
DOI: 10.1021/acs.orglett.9b00938
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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Synlett 1998, 1998, 495.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (GM043214) and by an
NSF predoctoral fellowship to S.M.B. We thank Dr. Adam
Trotta (Harvard University) for helpful discussions.
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acetic acid to afford the primary amide product 3q (see Supporting
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DOI: 10.1021/acs.orglett.9b00938
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