Photoredox catalysis: A mild, operationally simple approach to the synthesis of α-trifluoromethyl carbonyl compounds

Article abstract of DOI:10.1002/anie.201101861

A facile and efficient method for the α-trifluoromethylation of carbonyl compounds and enolsilanes has been accomplished through application of a photoredox catalysis strategy. A one-flask procedure for the direct α-trifluoromethylation and α-perfluoroalk

Full text of DOI:10.1002/anie.201101861

DOI: 10.1002/anie.201101861
Photoredox Catalysis
Photoredox Catalysis: A Mild, Operationally Simple Approach to the
Synthesis of a-Trifluoromethyl Carbonyl Compounds
Phong V. Pham, David A. Nagib, and David W. C. MacMillan*
The unique physical and chemical advantages conferred by
the CÀF bond have led to the broad exploitation of this motif
[
1]
[2]
throughout the pharmaceutical, materials, and agrochem-
[3]
ical sectors. In drug design, for instance, incorporation of
polyfluorinated alkyl groups, such as CF3 moieties, can
profoundly impact the activity, metabolic stability, lipophilic-
[
1,4]
ity, and bioavailability of lead compounds.
Not surpris-
ingly, the development of methods for the production of
carbonyl-based synthons bearing a-CF3 substitution has
emerged as a central objective in the field of chemical
synthesis. Although important recent advances have been
made toward this goal, there are currently few operationally
simple methods for the conversion of enolates (or enolate
equivalents) to a-trifluoromethylated carbonyl motifs. Stan-
dard alkylation methods are generally not productive, due to
the negative polarization of the trifluoromethyl moiety, thus
specially tailored reagents have been developed to furnish an
trifluoromethylation of a range of enolates or enolate
equivalents [Eq. (1)]. In this context, we elected to employ
enolsilanes and silylketene acetals as suitable enolic sub-
strates, given their synthetic accessibility and well-established
[5]
electrophilic CF equivalent. Alternatively, in recent years, a
3
set of radical (Et B/O ) and organometallic (Rh-catalyzed)
3
2
approaches have been pursued to introduce the trifluoro-
[
6,7]
[10]
methyl species through enolate derivatives.
While these
capacity to combine with electrophilic coupling partners.
methods offer significant progress toward solving the “a-CF3
carbonyl problem”, issues of substrate scope, cryogenic
temperatures, and regioselectivity of CF3 incorporation
remain prominent concerns. Herein, we describe a mild,
operationally simple, room temperature method for the a-
trifluoromethylation of enolsilanes, achieved through appli-
cation of our recently described photoredox catalysis strat-
As outlined in Scheme 1, we proposed that photoexcitation of
2
+
[Ru(bpy)3] (1) using a household light bulb, followed by
single-electron reduction of 2 should rapidly generate [Ru-
+
[11]
(bpy) ] (3). As we have previously described, this potent
3
one-electron reductant can readily participate in single-
electron transfer (SET) with CF I to generate the electro-
3
philic trifluoromethyl radical, which we hoped would rapidly
combine with enolsilane 4 to furnish a-silyloxy radical 5. The
oxidation potential of 5 is anticipated to be sufficiently low to
[
8,9]
egy.
Furthermore, a one-pot protocol has been developed
to enable the rapid fluoroalkylation of ketones, esters, and
amides, without the isolation of pre-generated enolsilane
intermediates.
2
+
allow for facile oxidation by *[Ru(bpy) ] (2) (E1/2red = 0.79 V
3
[
12]
vs. SCE in MeCN)
to generate silyloxocarbenium 6, an
Design plan: Recently, our laboratory established a new
activation mode for the direct enantioselective alkylation of
aldehydes. Termed photoredox organocatalysis, this novel
strategy exploits a synergistic relationship between chiral
amine and organometallic photoredox catalysts as a means to
access electrophilic alkyl radicals that rapidly combine with
[
8]
enamines under ambient conditions. We postulated that the
mechanistic logic underlying photoredox catalysis could be
extended to devise a simple yet general approach to the a-
[
*] P. V. Pham, D. A. Nagib, Prof. D. W. C. MacMillan
Merck Center for Catalysis at Princeton University
Washington Road, Princeton NJ 08544-1009 (USA)
Fax : (+1)609-258-5922
E-mail: dmacmill@princeton.edu
Homepage: http://www.princeton.edu/chemistry/macmillan/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101861.
Scheme 1. Proposed mechanism for carbonyl a-trifluoromethylation.
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Communications
unstable species that should rapidly undergo hydrolysis to
yield the desired a-trifluoromethylated carbonyl product.
Table 2: Trifluoromethylation of enolsilanes: ketone scope.
[13]
As shown in Table 1, our initial studies confirmed the
feasibility of the proposed trifluoromethylation when the tert-
butyldimethylsilyl (TBS) substituted enolsilane
7
was
[
a]
Entry
Product
Yield
Table 1: Trifluoromethylation of enolsilanes: initial studies.
[
a]
Entry
SiR3
Variation from
above conditions
Yield
[%]
1
2
3
4
5
6
7
8
TBS
TBS
TBS
TBS
TBS
TBS
none
no light
no photocatalyst
no base
35
0
<1
<1
45
53
84
94
[
b]
+H O
2
[
b]
[c]
[c]
[c]
+H O in THF
2
[
b]
TIPS
TIPS
+H O in THF
2
[
b]
[b,d]
+H O in THF +iPr NEt
2
2
[
[
a] TBS: tert-butyldimethylsilyl; TIPS: triisopropylsilyl. [b] 1.5 equivalents.
c] THF used instead of DMF. [d] Instead of Et N.
3
[
a] Yield of isolated product; SiR =TIPS unless otherwise noted. [b] TES
exposed to CF I, 0.5 mol% [Ru(bpy) Cl ] (1), and a 26 W
household fluorescent lamp in the presence of 1.5 equivalents
3
3
3
2
ether employed. [c] TBS ether employed. [d] 2.2:1 d.r. [e] With NaHCO in
MeCN and TES ether.
3
of Et N in DMF (entry 1, 35% yield). Importantly, no
3
alkylation was observed when either amine base, [Ru-
(
(
bpy) Cl ] catalyst, or light was excluded from this protocol
3 2
entries 2–4). Early investigations further revealed the impor-
maintained in the formation of quaternary carbon centers
(entry 16, 76% yield).
tance of employing a tertiary amine base to serve both as a
sacrificial reductant and to scavenge the deleterious HI
byproduct.
was further enhanced by 1) the use of a more reducing and
more basic amine base, iPr NEt, 2) incorporation of a less
We next sought to examine the applicability of this
trifluoromethylation strategy to other carbonyl classes, spe-
cifically silylketene acetal and N,O-acetal substrates derived
from ester and amide synthons (Table 3). To our initial
surprise, we observed that silylketene acetals of d-valerolac-
[11,14,15]
With this in mind, the reaction efficiency
2
acid-labile silyl group (TIPS) on the enolsilane substrate, and
3
) the addition of water to aid in the capture of the putative
silyl cation intermediate (entries 5–8, 45–94% yield). Indeed,
the observed levels of reaction efficiency using 0.5 mol%
Table 3: Trifluoromethylation of enolsilanes: esters and amides.
[
Ru(bpy) Cl ] (1) with triisopropylsilyl-substituted enolsilane
3 2
7
in the presence of THF-H O and iPr NEt, established these
2 2
conditions as optimal for further exploration.
As revealed in Table 2, a broad range of ketone-derived
enolsilanes that exhibit diverse electronic and steric proper-
ties readily participate in this new photoredox trifluorome-
thylation protocol. Specifically, this fluoroalkylation strategy
is tolerant to enolsilane coupling partners that incorporate
arenes, nitriles, and halogens (entries 1–7, 66–92%), as well as
sulfides, ethers, and carbamates (entries 10–13, 59–73%).
Moreover, sterically demanding substrates (entry 15, ada-
mantyl, 84%), as well as large ring sizes (entry 14, 68%), are
accommodated with minimal impact on yield. Intriguingly, we
observe an important structural bifurcation in that TIPS-
derived enolsilanes of aromatic ketones (entries 1–7, 66–92%
yield) typically achieve higher yields, whereas for aliphatic
ketones, TES-substituted enolsilanes provide generically
higher yields in this trifluoromethylation protocol
[a]
Entry
Product
Yield
[
a] Yield of isolated products. [b] 0.5 mol% 1·H O, Et N, isoamyl alcohol
2 3
(
entries 8–15, 59–84% yield). Interestingly, this trend is also
employed. [c] In MeCN.
6
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Angew. Chem. Int. Ed. 2011, 50, 6119 –6122

tone underwent rapid alkylation in the presence of the 26 W
fluorescent light, without the requirement of the photoredox
catalyst [Ru(bpy) Cl ] (entry 1, 85% yield). In this case we
enolsilanes, silylketene acetals and N,O-acetals derived from
a broad range of ketone, ester, and amide substrates. More-
over, we have devised a one-pot protocol that enables the
rapid and trivial installation of the trifluoromethyl moiety, as
well as other fluoroalkyl groups, directly to a wide array of
carbonyl systems. We expect this novel protocol to be of
broad utility in the synthesis of biologically active organo-
fluorine containing medicinal agents.
3
2
assume that a photon-induced charge-transfer complex
[16]
mechanism is likely operative. Notably, these photoredox
catalyst-free trifluoromethylation conditions can be success-
fully utilized with a range of silylketene acetals and N,O-
acetals, provided monosubstituted enols are employed
(
entries 2 and 4, 76–86% yield). Indeed, the more sterically
demanding disubstituted silylketene acetals were found to be
significantly less activated toward a-trifluoromethylation
using this alternative light-induced charge-transfer mecha-
nism, providing only moderate alkylation yields after
extended reaction times (24 h). Fortunately, high levels of
trifluoromethylation efficiency could be re-established for
these structurally encumbered substrates using our standard
Received: March 16, 2011
Published online: May 23, 2011
Keywords: enolsilanes · photoredox catalysis ·
.
a-perfluoroalkylation · a-trifluoromethylation
[
5
Ru(bpy) Cl ]-catalyzed photoredox conditions (entries 3 and
3 2
, 74–84% yield).
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[
[
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[
a] TBSOTf, iPr EtN used instead of TESCl, LDA.
2
shown, the enolsilane is first formed in situ in the presence of
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amide substrates, delivering the desired products with good
overall efficiency (entries 1–3, 67–78% yield).
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range of a-fluoroalkylations. When subjected to the outlined
procedure, ethyl caprylate underwent perfluoroalkylation (n-
propyl and isopropyl) and difluoroalkylation with excellent
levels of reaction efficiency (entries 4–6, 75–92% yield).
In summary, we have introduced a new photoredox-based
method that allows for facile a-trifluoromethylation of
3
3
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P
MeCN) is much higher than that of enamines (E = 0.36–
p
0.60 V vs. SCE in MeCN). Therefore, the reduction of *[Ru-
2
+
(bpy)3] (E1/2red = 0.79 V vs. SCE in MeCN) is thermodynami-
cally disfavored and no reaction was observed for this system.
[
14a]
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3
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3
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3
4
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[
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catalytic cycle through our proposed reductive quenching
mechanism.
6
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