N-heterocyclic carbene palladium catalyzed regioselective oxidative trifluoroacetoxylation of unactivated methylene sp3 C-H bonds in linear alkyl esters

Article abstract of DOI:10.1021/om200484g

Several N-heterocyclic carbene palladium catalyzed oxidation of nonactivated sp³ C-H bonds in linear primary and secondary trifluoroacetic acid esters have been developed. A high selectivity for the oxidation of the omega-1 carbon atom in trifluoroacetic acid n-propyl to n-octyl esters was realized by an appropriate choice of N-heterocyclic carbene palladium complexes.

Full text of DOI:10.1021/om200484g

NOTE
pubs.acs.org/Organometallics
N-Heterocyclic Carbene Palladium Catalyzed Regioselective Oxidative
Trifluoroacetoxylation of Unactivated Methylene sp3 CÀH Bonds in
Linear Alkyl Esters
Xiu-Feng Hou,*,† Ya-Nong Wang,† and Inigo G€ottker-Schnetmann‡
†Department of Chemistry, Fudan University, Han Dan Road 220, Shanghai 200433, China
‡Department of Chemistry, University of Konstanz, Universit€atstrasse 10, D-78457 Konstanz, Germany
ABSTRACT: Several N-heterocyclic carbene palladium cata-
lyzed oxidation of nonactivated sp3 CÀH bonds in linear
primary and secondary trifluoroacetic acid esters have been
developed. A high selectivity for the oxidation of the omega-1
carbon atom in trifluoroacetic acid n-propyl to n-octyl esters was
realized by an appropriate choice of N-heterocyclic carbene
palladium complexes.
’ INTRODUCTION
The functionalization of unactivated CÀH bonds remains a
significant challenge in organic chemistry, owing to reactivity and
selectivity problems. In principle, complementary selectivities are
accessible by using radical,1 carben(e)oid,2 or nitren(e)oid3 reac-
tivities, which favor the functionalization of tertiary and secondary
carbon atoms, or by using CÀH activation in the coordination
sphere of a transition metal, which on the basis of fundamental
mechanistic studies favors the functionalization of primary
(olefinic) and aromatic carbon atoms.4 While an increasing number
of transition metal catalyzed functionalizations of aromatic sp2
Figure 1. Palladium NHC complexes under investigation.
CÀH bonds provides efficient and more atom economic strategies
in organic syntheses,5 transition metal catalyzed functionalizations
of unactivated sp3 CÀH bonds are much less common, and the
were chosen as precatalysts, which were prepared using slightly
inhibition of the catalytically active site by stronger donors than sp3
CÀH bonds usually poses a serious problem.6À10
modified literature procedures (Figure 1).14 The catalytic system
under investigation consists of palladium NHC complexes AÀF,
trifluoroacetic- acid/-anhydride (TFAH/TFA), and potassium
peroxodisulphate.
In accordance with the aforementioned mechanistic results,
exclusive selectivity for the functionalization of methyl vs methy-
lene carbon atoms in the coordination sphere of transition metals
was experimentally observed in the rhodium/iridium catalyzed
borylation,7 the platinum catalyzed silylation,8 and the iridium
catalyzed dehydrogenation9c of alkane CÀH bonds. The chelate
assisted alkane CÀH functionalizations so far known, i.e., the
palladium catalyzed arylation of alkyl side chains,10 the palladium
catalyzed oxidative acetoxylation of O-methyl oximes,11 or
related electrophilic CÀH functionalizations of α-amino12 or
carboxylic acids13 under platinum catalysis, yield highly selective
(or exclusive) methyl vs methylene functionalized products.
Here, we report the palladium catalyzed oxidative trifluoroace-
toxylation of trifluoroacetic acid esters, which proceed with both
chelate assistance and with so far unprecedented selectivity for
methylene vs methyl functionalization.
Initial experiments were conducted with trifluoroacetic acid
butyl ester (1b) as a substrate in order to ascertain optimal
reaction conditions by varying the catalyst, the reaction tem-
perature, the amount of oxidant, and the reaction time (Table 1).
The yield of the combination of 2b and 3b was consistently
above 90% after 36 h at 80 °C in the presence of 6 equiv of
K2S2O8 and 5 mol % of catalysts AÀE, whereas complex F was
somewhat less active (80%), indicating that the efficiency of
bis(NHC)Pd complexes as catalysts was ascertained.
Figure 2 shows 13C NMR spectra of the neat liquid reaction
mixture (Table 1, entry 4) after 4, 18, and 36 h at 80 °C in the
presence of 6 equiv of K2S2O8 and 5 mol % of catalyst D.
Significantly, independent of the conversion of 1b, 1,4-di(c)butane
(2b) and 1,3-di(trifluoroacetoxy)-butane (3b) in a ca. 1:7.3 ratio
were formed, while no 1,2-di(trifluoroacetoxy)-butane (4b) and
’ RESULTS AND DISCUSSION
High thermal stability and resistance under acidic conditions
Received: June 6, 2011
of palladium N-heterocyclic carbene (NHC) complexes AÀF
Published: October 11, 2011
r
2011 American Chemical Society
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Table 1. Optimization of the Reaction Conditions for Trifluoroacetoxylation of 1-Trifluoroacetoxybutane 1ba
entry
catalyst
1b/K2S2O8 (mol/mol)
temperature (°C)
yield 2b (%) b
yield 3b (%)b
1
A
B
1:6
1:6
1:6
1:6
1:6
1:6
1:1.2
1:3
1:5
1:6
1:6
1:6
1:6
1:6
1:6
1:6
80
80
80
80
80
80
80
80
80
50
60
80
80
70
80
80
13
12
12
11
13
10
7
78
79
2
3
C
78
4
D
80
5
E
78
6
F
70
7
D
42
8
D
9
56
9
D
10
trace
6
71
10
11
12c
13d
14
15
16
D
10
D
33
D
5
38
D
0
0
D
7
42
Pd(OAc)2
trace
trace
trace
trace
a Conditions: 5 mol % catalyst, 1 mmol of 1b in 2 mL TFA/TFAH (6:1, v/v), 36 h. b The yield was determined by gas chromatography (perfluorononane
as internal standard). c 18 h. d 4 h.
1,1-functionalized product were found. In addition, palladium
acetate gave trace products and rapid formation of palladium black.
Therefore, the NHC ligands in AÀF are believed to stabilize the
catalytically active species. Control experiments in the absence of
the catalysts showed trace products, thus pointing to a palladium
catalyzed reaction in presence of complexes AÀF. As complex D
proved to be most active, further studies were conducted in the
presence of D as precatalysts.
(Figure 3). It has to be noted, however, that with increasing
chain lengths of 1, increasing amounts of diastereomeric
mixtures of higher oxidation products are formed and their
conversions decreased.
An instructive formation of trifunctionalized oxidation pro-
ducts avoiding complicated diastereomeric mixtures was accom-
plished by reacting C3- to C7-α,ω-di(trifluoroacetoxy)alkanes
(2aÀd) as substrates. Notably, the main products (GC yields)
are α,β,ω-trifunctionalized products for 2a (23%) or 2b (48%)
and α,γ,ω-trifunctionalized products for 2c (55%) or 2d (76%)
after 50 h, 80 °C, 6 equiv K2S2O8, 5 mol % D. Moreover, 19%
α,α,ω-trifunctionalized products were detected in the reaction
mixture of 2b, and 16% α,β,ω-tri(trifluoroacetoxy)alkane from
2c (Figure 4).
With these optimized complementary reaction condi-
tions in hand, we then explored the trifluoroacetoxylation
of trifluoroacetic acid n-propyl to n-octyl esters (1aÀf). First
of all, methylene functionalization (α, ω-1) products were
formed predominantly in these reactions, which were un-
equivocally identified by the high field methyl doublet
1
(ca. δ 1.7À1.9 ppm) in the H NMR spectra. While 1-(tri-
These data are consistent with a chelate assisted oxidative
alkane trifluoroacetoxylation, which, in contrast to already
known chelate assisted alkane functionalizations catalyzed by
palladium,10,11 exhibits high selectivity for the functionalization
of methylene vs methyl groups. While α,α-functionalization of
1aÀf is not observed because of unfavorable small chelate ring-
sizes, appropriate chelate sizes for the α,ω-functionalization
2b to form α,α,ω-trifunctionalized products are accessible.
The noticeable drop in the conversion of 2a is likely also
due to slower α,β-functionalization and as compared to α,
γ-functionalizations.
fluoroacetoxy)propane (1a) gave higher amounts of the methyl
functionalized (α,ω)-product as compared to 1b, methylene
functionalization still dominates by a 1.6:1 ratio. An even
higher selectivity for the oxidation of methylene vs methyl
carbon atoms was evident when C5- to C8-trifluoroacetic acid
esters 1cÀf were subjected to identical reaction conditions. In
these experiments, no methyl-functionalized (α,ω)-products
could be detected by comparison to gas chromatography
(GC) and NMR analyses of independently prepared samples.
Moreover, a significant discrimination of different methylene
groups was observed, placing the oxidated methylene groups
only in the (α,ω-1)-position for C5-ester 1c and both (α,ω-1)-
position and (α,ω-2)-position for C6- to C8-esters 1dÀf
On the basis of our observation and previous literature,15
a
possible mechanism for this trifluoroacetoxylation reaction is
proposed (Scheme 1). First, ligand-directed CÀH activation
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NOTE
Figure 2. 13C NMR spectra of the reaction mixtures of 1b (Table 1, entry 4) after 4, 18, and 36 h. The signals for CF3COOÀ have been omitted for
clarity.
Figure 4. Trifunctionalized products obtained from α,ω-difunctiona-
lized substrates 2aÀd (the yield was determined by GC and the isolated
yield is shown in parentheses).
Figure 3. Bifunctionalized products obtained from linear (trifluoroacetoxy)-
alkanes 1aÀf(the yield was determined by GC and the isolated yield is shown
in parentheses).
leads to the formation of a five-membered cyclopalladated
intermediate (i), which is then oxidized to generate a Pd(IV)
complex (ii). Subsequent reductive elimination releases the main
product 3b, and the catalyst is regenerated.
Scheme 1. Plausible Mechanism for Trifluoroacetoxylation
of 1-Trifluoroacetoxybutane 1b
In conclusion, the oxidative trifluoroacetoxylation of aliphatic
(trifluoroacetoxy)alkanes was presented. The combination of
chelate assistance and selectivity for methylene groups allows for
a moderate regiodiscrimination of aliphatic methylene groups in
these substrates.
’ TYPICAL PROCEDURE
To a mixture of K2S2O8 (6 mmol, 1.620 g) complex (0.05 mmol) in
2 mL TFA/TFAH (6:1) containing perfluoronane (120 μmol, 59
mg) was added 1 mmol of substrate in a gastight 8 mL screw top vial
under air. The vial was closed, and the reaction mixture was heated
under stirring in an aluminum block for 36 h at 80 °C. After cooling to
room temperature, the vial was carefully opened to release oxygen
overpressure. The solid was then separated by centrifugation, and the
supernatant solution was subjected to NMR (neat reaction solution,
benzene-d6 capillary) and GC (perfluorononane as internal standard)
analyses. Isolated yields were obtained from 20 mmol substrates after
reaction and distillation.
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NOTE
’ AUTHOR INFORMATION
Corresponding Author
*Tel.: +86-21-55664878. Fax: +86-21-65641740. E-mail: xfhou@
fudan.edu.cn.
’ ACKNOWLEDGMENT
Financial support from the National Science Foundation of
China (Grant No. 20871032, 20971026) and Shanghai Leading
Academic Discipline Project, Project Number: B108, is gratefully
acknowledged.
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