Asymmetric fluorination of enamides: Access to α-fluoroimines using an anionic chiral phase-transfer catalyst

Article abstract of DOI:10.1021/ja303959p

The use of a BINOL-derived phosphate as a chiral anionic phase-transfer catalyst in a nonpolar solvent allows the enantioselective fluorination of enamides using Selectfluor as the fluorinating reagent. We demonstrate that a wide range of stable and synthetically versatile α-(fluoro)benzoylimines can be readily accessed with high enantioselectivity. These compounds have the potential to be readily elaborated into a range of highly stereodefined β-fluoroamines, compounds that constitute highly valuable building blocks of particular importance in the synthesis of pharmaceuticals.

Full text of DOI:10.1021/ja303959p

Communication
pubs.acs.org/JACS
Asymmetric Fluorination of Enamides: Access to α-Fluoroimines
Using an Anionic Chiral Phase-Transfer Catalyst
Robert J. Phipps, Kenichi Hiramatsu, and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: The use of a BINOL-derived phosphate as
a chiral anionic phase-transfer catalyst in a nonpolar
solvent allows the enantioselective fluorination of
enamides using Selectfluor as the fluorinating reagent.
We demonstrate that a wide range of stable and
synthetically versatile α-(fluoro)benzoylimines can be
readily accessed with high enantioselectivity. These
compounds have the potential to be readily elaborated
into a range of highly stereodefined β-fluoroamines,
compounds that constitute highly valuable building blocks
of particular importance in the synthesis of pharmaceut-
icals.
he prevalence of fluorine atoms in pharmaceutical agents1
has driven the development of new methods for the
T
these compounds as nucleophiles in our fluorination process
(eq 2).11 The success of this class of substrates as nucleophiles
in a number of enantioselective phosphoric acid-catalyzed
reactions was encouraging.12 We were particularly encouraged
by the reported stability of N-carbobenzyloxy (Cbz) ketimines,
which made us optimistic that an α-fluoroimine may be stable
and isolable, in line with our goal.11b,12f We commenced our
studies by examining the fluorination of several ene−
carbamates based on 2-methyltetralone (Table 1).
After 8h of reaction, the Cbz ene−carbamate 1a was
fluorinated to a very low degree in the absence of a catalyst
(entry 1). Addition of our phase-transfer catalyst C8-TRIP
resulted in complete conversion to the fluorinated product in
the same amount of time (entry 2). The α-fluoroimine product
was stable and isolable, and the obtained product enantiose-
lectivity of 55% was highly encouraging. The analogous methyl
carbamate resulted in a similarly high yield but lower
enantioselectivity (entry 3). Fluorination of N-acetylenamide
1c was also clearly accelerated by our phase-transfer catalyst but
resulted in a disappointingly low enantioselectivity (3% ee;
entries 4 and 5). However, by progressing to the N-
benzoylenamide 1d, we were delighted to discover that the
desired product could be obtained with excellent efficiency and
selectivity (91% yield, 90% ee; entry 6). Notably, after the same
reaction time in the absence of catalyst, only a 6% yield of
fluorinated product was obtained (entry 7).
enantioselective2,3 introduction of fluorine into small molecules
that may constitute basic building blocks for elaboration into
biologically relevant molecules. In this context, the chiral β-
fluoroamine motif is one of remarkable utility; the presence of a
β-fluorine is well established to lower the pKa of the amine
nitrogen, impacting binding, metabolism, and other pharmaco-
logical properties.1b,4 Nevertheless, there are few direct
methods for the asymmetric synthesis of β-fluoroamines.
Those that do exist often proceed through processes in
which introduction of the fluorine is not itself asymmetric5 or
through α-fluorocarbonyl compounds generated by enantiose-
lective fluorination of ketones and aldehydes.6 Organocatalysis
has provided a number of elegant protocols for this asymmetric
α-fluorination reaction, including cinchona alkaloid-mediated
transformations3b,7 and those based on enamine catalysis.8 We
noted that the latter highly successful organocatalyic methods
proceed via α-fluoroimine intermediates that are subsequently
hydrolyzed for the necessary release of the secondary amine
catalyst. We speculated that a methodology, distinct from
enamine catalysis, in which an enantioenriched α-fluoroimine
could be isolated would be highly versatile. These products
could be elaborated through a number of well-precedented
pathways to a wide variety of enantioenriched β-fluoroamines.9
Our laboratory has recently reported the enantioselective
fluorocyclization of olefins using a cationic fluorinating agent,
Selectfluor, and anionic phase-transfer catalysts based on chiral
phosphoric acids, specifically TRIP and C8-TRIP (eq 1).10 As a
powerful application of this new strategy we sought to apply
this concept to the enantioselective synthesis of α-fluoroimines.
Specifically, enamides and ene−carbamates have seen much
recent use in asymmetric synthesis, and we sought to employ
While the reaction was found to tolerate a number of apolar
solvents, the highest enantioselectivity was obtained in hexane
Received: March 5, 2012
Published: May 11, 2012
© 2012 American Chemical Society
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Communication
Table 1. Optimization of the Enamide Fluorination Reaction
a
b,c
entry
R
catalyst
solvent, time
% yield 2
% ee 2
d
1
2
CO2Bn (1a)
none
toluene, 8 h
toluene, 8 h
toluene, 8 h
toluene, 8 h
toluene, 8 h
toluene, 8 h
toluene, 8 h
PhF, 24 h
14
−
CO2Bn
(S)-C8-TRIP
(S)-C8-TRIP
none
77
75
55 (R)
22 (R)
−
3
CO2Me (1b)
d
4
Ac (1c)
Ac
16
5
(S)-C8-TRIP
(S)-C8-TRIP
none
84
91
3
6
Bz (1d)
Bz
90 (R)
d
7
6
−
8
Bz
(S)-C8-TRIP
(S)-C8-TRIP
(S)-C8-TRIP
(S)-TRIP
87
85
88
83
83
13
90 (R)
94 (R)
96 (R)
92 (R)
92 (R)
11 (R)
9
Bz
cyclohexane, 24 h
hexane, 24 h
toluene, 24 h
hexane, 24 h
10
11
12
Bz
Bz
Bz
(S)-TRIP
e
13
Bz
(S)-TRIP
hexane, 24 h
a
b
c
Isolated yields after chromatography on silica gel, unless otherwise indicated. Determined by HPLC. Absolute configurations (in parentheses)
d
were determined by hydrolysis and comparison of optical rotation with ref 13. 1H NMR yield using 1,2-dimethoxyethane as an internal standard.
e
Reaction was run in the absence of Na2CO3.
(entries 8−10). To evaluate the commercially available
phosphoric acid catalyst TRIP in our process, we compared
this catalyst with C8-TRIP in two cases. In toluene, the
enantioselectivity with the two catalysts was found to be similar
(entries 6 and 11), but in hexane, C8-TRIP was superior
(entries 10 and 12). In the absence of an inorganic base, the
fluorination proceeded to very low conversion with poor
selectivity (entry 13). We speculate that the parent phosphoric
acid is a very poor catalyst and that, in accordance with our
proposal, the phosphate is required in order to undergo anion
exchange with the Selectfluor reagent.
delivered stable products with high enantiomeric excesses (2q−
s). In addition, a benzosuberone-derived enamide was also
amenable to our reaction (2t), and in two of the above cases,
using 3-hexanol as an additive again led to improved selectivity.
To assess the effectiveness of our reaction on a substrate with a
Table 2. Exploration of the Scope of Substituted Enamides
Having established the optimum conditions, we next
examined the scope of the transformation. Gratifyingly, a
range of cyclic enamides provided high yields of stable α-
(fluoro)benzoylimines with high selectivities in this process
(Table 2). Substitution on the enamide functionality was well-
tolerated, as methyl, allyl, phenyl, and benzyl groups all gave
high enantioselectivity, leading to products bearing a variety of
diversely substituted quaternary fluorinated stereocenters
(entries 1−3 and 6). In addition, these stereocenters bear a
vicinal imine that is stable enough to isolate but poised to
undergo a variety of further diastereoselective transformations.
Indanone-derived enamides participated readily, and we used
this scaffold to demonstrate that substrates with a variety of
electronic characters are well-tolerated (entries 5−11). In the
case of entry 4, in which the originally obtained enantiose-
lectivity was lower (81% ee), we observed a beneficial effect of
running the reaction in the presence of 5 equiv of 3-hexanol,
which led to improved selectivity (94% ee).15 The 2-
phenylcyclohexanone-derived enamide 1o gave slightly reduced
but still synthetically useful enantioselectivity, with the versatile
fluorinated enamide 2o being isolated (entry 12). However, the
corresponding 2-methylcyclohexanone-derived enamide re-
vealed the present limitation (18% ee).16
a
b
Isolated yields after chromatography on silica gel. Determined by
c
HPLC. The absolute configurations of 2d and 2h were determined by
comparison of the optical rotations of their hydrolysis products with
refs 13 and 14, and that of 2o was determined by X-ray
crystallography; absolute configurations of all the other compounds
d
We next turned our attention to enamides bearing no
substitution (Table 3). Anticipating that product stability or
racemization via tautomerization could be problematic, we were
pleasantly surprised to find that tetralone-derived enamides
were tentatively assigned by analogy. Toluene was used as the
e
solvent. Reaction was run in the presence of 5 equiv of 3-hexanol.
f
g
h
(S)-TRIP was used as the catalyst. Reaction time was 48 h. See the
Supporting Information for details.
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Journal of the American Chemical Society
Communication
a b
,
Table 3. Fluorination of Unsubstituted Enamides
Scheme 2. Reduction of 2q without Racemization
ene−carbamates with N-acylimines12f,h and nitrosobenzene12e
to provide a tentative rationalization of the absolute stereo-
chemistry that we observed experimentally.19 Utilizing the
bifunctional nature of this class of catalysts, we anticipate that
the phosphate anion is able to form an ion pair with the
Selectfluor reagent on one oxygen atom while simultaneously
activating the enamide through hydrogen bonding with the
second. The enamide would reside so as to put the bulk of the
tetralone in an “open” quadrant, with the amide group
occupying a “closed” quadrant (Figure 1). We speculate that
a
b
Isolated yields after chromatography on silica gel. ee’s were
c
determined by HPLC. Reaction was run in the presence of 5 equiv
of 3-hexanol.
pre-existing stereocenter, racemic flavanone-derived enamide
1u was synthesized. Fluorination of this heterocyclic substrate
resulted in an approximately equal ratio of separable anti and
syn diastereomers, both with excellent enantioselectivity (93
and 99% ee; Table 3), although the instability of the syn
diastereomer compromised the final isolated yield. This
example illustrates the high selectivity of our catalytic system,
regardless of the nature of an existing stereocenter.
To test the limits of our fluorination reaction, we applied it to
chloro- and bromo-substituted enamides 1v and 1w. While
there have been several reports on the catalytic asymmetric
synthesis of geminal chlorofluoro compounds, compatible
substrates have to date remained limited to activated methylene
compounds, such as β-keto esters, and aldehydes.17 Reports of
chiral geminal fluorobromo compounds remain sparse, most
likely because their asymmetric synthesis is challenging.18
Accordingly, the extension of our methodology to encompass
these classes of product (Scheme 1) is a testament to the future
potential of this strategy for asymmetric fluorination: the
geminal fluorochloro product 2v was obtained in 95% ee and
the novel chiral bromofluoro compound 2w in 83% ee.
Figure 1. Mechanistic proposal for observed absolute stereochemistry.
the high tolerance of our reaction toward substitution on the
enamide (Figure 1, R1) as well as an existing stereocenter at the
3-position (Table 3, 2u) may reflect the fact that these
positions point away from the catalyst and thus have no effect
on catalyst−substrate binding.20 The remarkably high selectiv-
ity obtained with benzamide compared with other acyl groups
is a focus of current investigation.
In summary, we have extended our concept of anionic phase-
transfer catalysis10,21 to encompass the enantioselective
fluorination of cyclic enamides. The scope of this trans-
formation is broad, and we have demonstrated the effectiveness
of the reaction on five-, six-, and seven-membered rings as well
as heterocyclic rings. Our future work will focus on gaining
insight into the factors controlling the selectivity and, more
generally, opening new avenues for this mode of catalysis.
Scheme 1. Fluorination of Halo-Substituted Enamides
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and compound characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
■
Finally, to demonstrate the surprisingly robust nature of
product 2q and in general the ready further transformation of
our products, we showed that 2q tolerates reduction with
lithium aluminum hydride without any loss of stereochemical
integrity (Scheme 2).
The extensive previous efforts directed toward understanding
the mechanism of BINOL-derived phosphoric acid-catalyzed
reactions allow us to advance a plausible hypothesis as to the
origin of the observed enantioselectivities. We have employed
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank University of California, Berkeley and Amgen for
financial support. R.J.P. is grateful to the European Commission
for a Marie Curie International Outgoing Fellowship. K.H.
gratefully acknowledges support from Asubio Pharma Co., Ltd.
́
the model of Simon and Goodman regarding the reactions of
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Journal of the American Chemical Society
Communication
in undesirable solubilization of the Selectfluor reagent. Investigations
into the reasons for this improvement are underway.
(16) Enamide 1p derived from 2-methylcyclohexanone gave
fluorinated benzoylimine 2p in 18% ee:
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