A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates

Article abstract of DOI:10.1021/ja302552e

A Ru-catalyzed direct thermal trifluoromethylation and perfluoroalkylation of N-acyloxazolidinones has been developed. The reaction is experimentally simple and requires inexpensive reagents while providing good yields of products with good levels of stereocontrol. Preliminary studies have shown notable compatibility with functional groups, aromatics, and certain heteroaromatic substituents. The described method provides a useful alternative for the synthesis of fluorinated materials in an experimentally convenient manner.

Full text of DOI:10.1021/ja302552e

Communication
pubs.acs.org/JACS
A Simple Method for Asymmetric Trifluoromethylation of N-Acyl
Oxazolidinones via Ru-Catalyzed Radical Addition to Zirconium
Enolates
Aaron T. Herrmann, Lindsay L. Smith, and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States
S
* Supporting Information
highlighted.8c,10Although direct extension of this type of
ABSTRACT: A Ru-catalyzed direct thermal trifluorome-
thylation and perfluoroalkylation of N-acyloxazolidinones
has been developed. The reaction is experimentally simple
and requires inexpensive reagents while providing good
yields of products with good levels of stereocontrol.
Preliminary studies have shown notable compatibility with
functional groups, aromatics, and certain heteroaromatic
substituents. The described method provides a useful
alternative for the synthesis of fluorinated materials in an
experimentally convenient manner.
reactivity to fluoroalkylation reactions has proven to be highly
challenging, we have succeeded in reaching this goal by
enlisting in situ generated zirconium enolates (eq 1). The
development of this protocol highlighting operational simplicity
in the direct α-fluoroalkylation of N-acyl oxazolidinones is
described herein.11
he growing appreciation of unique physical and chemical
Early attempts to extend the chloroalkylation reaction of
titanium enolates to fluoroalkylations concentrated on screen-
ing a range of transition metal catalysts, including those that
have been previously used in Kharasch-type additions of
iodoperfluoroalkanes to olefins. Typical examples include
[Ph3P]3RuCl2,12 Ru3(CO)12,13 Fe3(CO)12,13 and Co2(CO)8;13
however, in no instance any amount of fluoroalkylation product
was detected. After exhausting our options with titanium
enolates, we explored other metal halides potentially capable of
effecting soft enolizations (SmBr3, BiCl3, InCl3, Yb(OTf)3,
VOCl3, VCl3, VCl4, ZrCl4, HfCl4).14 In contrast to our
expectations, it was the group IVa metal halides, ZrCl4 and
HfCl4,15 that proved to be uniquely competent in the
fluoroalkylation reactions.
Once these metal halides had been identified, a number of
transition metal redox catalysts for the generation of
perfluoroalkyl radicals were examined (Table 1). Among
these, ruthenium catalysts emerged as the most promising
(entries 7−11), with Ru[Ph3P]3Cl2, the catalyst used in the
original chloroalkylation of titanium enolates, being the most
effective. The ruthenium-catalyzed perfluoropropylation of N-
acyl oxazolidinone 1, which served as a benchmark reaction,
was characterized by a clean transformation to 2 using only a
moderate excess (5 equiv) of n-C3F7I (entry 11). The side
products were comprised of only the α,β-unsaturated imide as a
result of HF elimination from 2 (12%) and the cleaved
oxazolidinone auxiliary (11%),16 which together accounted for
the majority of the remaining mass balance. Similar outcomes
were observed with hafnium enolates derived in situ from
hafnium tetrachloride and Et3N (entry 12).
T
properties of fluorinated organic compounds has resulted
in their increasingly broad application in medicine, materials
sciences, agrochemicals, and many other areas of research.1 In
order to enable future advances in the discovery and application
of fluorinated materials, practical methods for efficient and
selective fluorination are needed. Within this general
context,1a,2 stereoselective introduction of the trifluoromethyl
and other perfluoroalkyl groups at the α-position of carbonyl
compounds has remained an ongoing challenge, with several
notable developments reported in the past few years. Following
early studies in diastereoselective radical trifluoromethylation of
lithium enolates employing the iodotrifluoromethane−Et3B/O2
system for CF3 radical generation,3 a number of elegant
alternatives based on electrophilic,4 radical,5 or photoredox
organocatalytic strategies6 have been developed.7 These
methods collectively constitute important advances toward
highly selective α-fluoroalkylation of a diverse range of carbonyl
compounds and highlight novel patterns of reactivity. On the
other hand, issues of practicality related to experimental
simplicity, cost of reagents, and energy efficiency (use of
cryogenic conditions or high temperatures) remain persistent,
stimulating continued progress in this area.
Recently, we demonstrated that an experimentally simple,
high-yielding diastereoselective α-trichloromethylation of tita-
nium enolates can be achieved (eq 1).8 The process is based on
a Ru-catalyzed redox formation of the trichloromethyl radical
from BrCCl3 followed by its addition to catalytically generated
titanium enolates derived from chiral N-acyl oxazolidinones.
This type of radical addition may be facilitated by the putative
biradical character of titanium enolates.9 Overall, the process
allows for a direct, one-step chloroalkylation of N-acyl
oxazolidinones, and its utility in the synthesis of natural
products with CCl3-substituted stereogenic centers has been
Received: March 15, 2012
Published: April 9, 2012
© 2012 American Chemical Society
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a
Table 1. Identification of Transition Metal Catalysts Suitable
for Fluoroalkylation of Zirconium and Hafnium Enolates
Table 2. Scope of Perfluoroalkylating Agent
a
b
b
entry
MCl4
ZrCl4
metal catalyst (5−7 mol %) conversion (%) 2 (%)
1
2
3
4
5
6
7
8
9
10
Fe3(CO)12
Co2(CO)8
Ru3(CO)12
FeBr2
17
26
37
31
33
30
46
61
49
87
97
>98
0
0
0
0
f
Cu(OEP)
0
[Rh(cod)Cl]2
0
[(p-cymene)RuCl2]2
[(C6H6)RuCl2]2
22
28
19
59
74
57
IndRu[Ph3P]2Cl•CH2Cl2
Cp*Ru[Ph3P]2Cl
Ru[Ph3P]3Cl2
c
e
g
d
11
e
g
12
HfCl4
Ru[Ph3P]3Cl2
a
Standard conditions: 1 (0.50 mmol), ZrCl4 (1.05 equiv), Et3N (2.0
equiv), n-C4F9I (5.0 equiv), CH2Cl2 (∼0.1 M), mixed and stirred at 45
b
°C for 24 h. Determined by the 500 MHz NMR analysis of the crude
c
a
mixture of products. In addition, 18% of α,β-unsaturated byproduct
Yields of isolated products are reported. The numbers in parentheses
are yields of the corresponding α,β-unsaturated byproduct A, when
observed. Diastereomer ratios were determined by 500 MHz 1H NMR
analysis. 15 mol % of [Ph3P]3RuCl2 were used. brsm = based on
recovered starting material.
d
resulting from HF elimination has also been observed. In addition,
12% of α,β-unsaturated byproduct resulting from HF elimination has
e
f
b
c
also been observed. n-C3F7I (5.0 equiv) was used. OEP =
g
2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphirine. 7 mol % of the
metal catalyst was used.
chemistry can be performed with substrates that have a
stereogenic center at the β-position in the N-acyl substituent
(entries 10, 11). More functionalized heterocyclic substituents
such as benzofurans and benzoxazoles are also compatible with
the reaction conditions (entries 12, 13).
The scope of perfluoroalkylating agent was investigated next
(Table 2).17 No byproduct resulting from α,β-elimination of
hydrogen fluoride was observed in any trifluoromethylation
reactions (entry 1; also see Table 3). We did observe partial
(9−17%) formation of an α,β-unsaturated byproduct (A) with
primary perfluoroalkyl- and perfluorobenzyl-substituted prod-
ucts (entries 2, 3, 5, and 6). As in the trifluoromethylation
reaction, no HF elimination was detected when the 2-
perfluoropropyl group was introduced (entry 4).
A variety of N-acyl oxazolidinones can be successfully
trifluoromethylated using the simple protocol developed in
the course of this investigation (Table 3). We found that
reagents can be mixed all at once in any order at room
temperature with no influence on the isolated yield of the
desired product. Therefore, the reaction setup can be guided
solely by experimental convenience rather than by other factors
intrinsic to the reaction. N-Acyl oxazolidinones obtained from
unfunctionalized alkanoic acids undergo efficient and diaster-
eoselective trifluoromethylations, with yields increasing for β-
branched substrates (entries 1−4). These are clean trans-
formations, where unreacted starting material is the major
byproduct as indicated by yields based on recovered starting
materials (entries 2−4), while auxiliary cleavage (25%) was
observed for the reaction in entry 1. The presence of aryl and
benzyl ethers is well-tolerated (entries 5, 6), as is the presence
of functionalized β-aryl substitution, although the extent of
chiral auxiliary detachment was higher (31−34% for entries 7,
8). Substitution with a phenyl group at the α-position resulted
in a clean reaction (82% yield brsm, entry 9), albeit at a reduced
conversion under the standard conditions (59%). Diastereose-
lective alkylations controlled by the oxazolidinone stereo-
The proposed mechanism of the reaction based on the
related Ru-catalyzed trichloromethylation is depicted in Scheme
1.8a,10 NMR spectroscopic studies of the enolate formation
using N-propionyl oxazolidinone 1, zirconium tetrachloride,
triethylamine, and CDCl3 revealed that a rapid, clean, and
essentially complete enolization producing enolate 4 occurs at
room temperature. We succeeded in obtaining a single-crystal
X-ray structure of a complex between the substrate and ZrCl4
revealing a nearly perfectly planar arrangement of atoms in the
six-membered cyclic chelate 6 which is in all respects similar to
the corresponding titanium complex (not shown). Therefore,
we surmise that the geometric structures of the zirconium (4)
and titanium enolates are similar, and it is the dissimilarities in
their electronic structure that are responsible for differences in
their reactivity in the ruthenium-catalyzed fluoroalkylation
reaction. Once 4 is formed, it undergoes an addition reaction
with the trifluoromethyl radical generated by a redox process
from iodotrifluoromethane and the ruthenium(II) catalyst. The
addition product is probably better represented by resonance
form 5b rather than carbon-centered form 5a, and a potential
biradical character of 4 may facilitate the addition of the CF3
radical. The ruthenium catalyst is recovered by a single electron
transfer from intermediate 5b to Ru(III) species.
Additional insight into the course of the perfluoroalkylation
was acquired from the following experiments. First, when the
catalyst loading in the perfluoropropylation of 1 was increased
from 7 to 30 mol %, the rate of the process was notably
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Table 3. Scope of N-Acyl Oxazolidinones in the
Trifluoromethylation Reaction
Scheme 1. Proposed Mechanism of the Ru-Catalyzed
Trifluoromethylation Reaction
a
Conversion of the reaction products to broadly useful
fluorinated building blocks for organic synthesis is illustrated by
examples in Scheme 2 that include hydrolytic and reductive
Scheme 2. Preparation of Versatile Enantioenriched
Fluorinated Building Blocks by Hydrolytic and Reductive
a
Removal of the Chiral Auxiliary
a
Yields of isolated products are reported. At least two experiments
were carried out to confirm reproducibility. The numbers in
parentheses are yields based on recovered starting material (brsm).
1
Diastereomer ratios were determined by 500 MHz H NMR analysis
a
The chiral auxiliary is recovered in nearly quantitative yield in all
reactions.
of the crude mixture of products.
enhanced. The reaction was complete in 4 rather than 16 h,
showing a substantially reduced level of side reactions and
giving the expected product in 86% isolated yield. Similar, albeit
somewhat lower efficiency was observed when the amount of n-
C3F7I was increased from 5 to 15 equiv. Taken together, these
observations suggest that the generation of the perfluoroalkyl
radical is the rate-limiting step of the process. Second,
monitoring the course of the reaction performed in CD2Cl2
removal of the chiral auxiliary. Trifluoromethyl-substituted
derivative 7 and perfluoropropyl derivative 818 could be readily
hydrolyzed with a LiOH−H2O2 reagent system to the
corresponding carboxylic acids with a high level of retention
of stereochemical integrity. While reductions of these
compounds with sodium borohydride in aqueous THF were
sluggish, removal of the oxazolidinone could be readily
achieved by treatment with lithium aluminum hydride. For
substrate 5, virtually complete preservation of stereochemistry
was observed, while only a minor erosion of stereochemistry
was noted for the perfluoropropyl-substituted substrate.
Notably, these transformations are characterized by very good
yields and nearly quantitative recovery of the chiral auxiliary.
1
by H and 19F NMR spectroscopy revealed that another major
pathway of reactivity for n-C3F7−I is reduction to n-C3F7−H,
which presumably occurs by oxidation of triethylamine. Overall,
these key observations are expected to aid in developing more
efficient perfluoroalkylation processes based on radical
additions to transition metal enolates.
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(5) Examples of asymmetric radical trifluoromethylations: Itoh, Y.;
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In closing, we report an experimentally simple asymmetric
fluoroalkylation reaction of N-acyl oxazolidinones based on the
unique radical reactivity of group IVa metal enolates. For
titanium enolates, the biradical character has been supported by
computational and spectroscopic studies that provide an
intriguing conceptual basis for reaction development. From a
practical perspective, the reaction requires inexpensive reagents,
which can be mixed in any order, and mild heating over the
course of a few hours delivers fluoroalkylation products directly
in good yields and high diastereoselectivities. Ongoing studies
are directed at the development of a more active catalytic
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more detailed picture for the mechanism of the reaction.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, characterization data, copies
of H, 13C, and 19F NMR spectra, and X-ray crystallography
1
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
zakarian@chem.ucsb.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) Fuchikami, T.; Ojima, I. Tetrahedron Lett. 1984, 25, 303−306.
(14) (a) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau,
M. T. J. Am. Chem. Soc. 1990, 112, 8215−8216. (b) Evans, D. A.;
Bilodeau, M. T.; Somers, T. C.; Clardy, J.; Cherry, D.; Kato, Y. J. Org.
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3809−3812.
We are grateful to Dr. Hongjun Zhou (University of California,
Santa Barbara) for continued assistance with NMR spectros-
copy, and Prof. Trevor Hayton (UC Santa Barbara) and
Richard Lewis (UC Santa Barbara) for invaluable assistance
with X-ray crystallography. Financial support was provided by
the National Science Foundation (CHE 0836757), NIGMS
(R01 GM077379), and kind gifts from Amgen and Eli Lilly.
(15) ZrCl4: $0.38/g ($0.09/mmol, Sigma-Aldrich); HfCl4: $1.09/g
($0.35/mmol, Strem).
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