Direct Access to β-Fluorinated Aldehydes by Nitrite-Modified Wacker Oxidation

Article abstract of DOI:10.1002/anie.201603424

An aldehyde-selective Wacker-type oxidation of allylic fluorides proceeds with a nitrite catalyst. The method represents a direct route to prepare β-fluorinated aldehydes. Allylic fluorides bearing a variety of functional groups are transformed in high yield and very high regioselectivity. Additionally, the unpurified aldehyde products serve as versatile intermediates, thus enabling access to a diverse array of fluorinated building blocks. Preliminary mechanistic investigations suggest that inductive effects have a strong influence on the rate and regioselectivity of the oxidation.

Full text of DOI:10.1002/anie.201603424

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603424
German Edition: DOI: 10.1002/ange.201603424
Oxidation
Direct Access to b-Fluorinated Aldehydes by Nitrite-Modified Wacker
Oxidation
Crystal K. Chu, Daniel T. Ziegler, Brian Carr, Zachary K. Wickens, and Robert H. Grubbs*
Abstract: An aldehyde-selective Wacker-type oxidation of
allylic fluorides proceeds with a nitrite catalyst. The method
represents a direct route to prepare b-fluorinated aldehydes.
Allylic fluorides bearing a variety of functional groups are
transformed in high yield and very high regioselectivity.
Additionally, the unpurified aldehyde products serve as
versatile intermediates, thus enabling access to a diverse array
of fluorinated building blocks. Preliminary mechanistic inves-
tigations suggest that inductive effects have a strong influence
on the rate and regioselectivity of the oxidation.
T
he demand for organofluorine compounds is rapidly
growing as a result of their prevalence in the pharmaceut-
ical,[1] agrochemical,[2] and materials[3] industries. Because of
a low abundance of fluorinated chemical feedstocks,[4] the
development of efficient routes toward organofluorine build-
ing blocks has been recognized as an important challenge in
the synthetic community.[5] Traditional fluorination protocols
typically employ harsh reagents such as diethylaminosulfur
trifluoride (DAST), thus restricting their tolerance of func-
tional groups. Consequently, careful selection of an appro-
priate fluorinating agent must often be performed on a case-
by-case basis.[6]
Scheme 1. Strategies toward alkylfluorine compounds.
a catalytic approach to directly access b-fluorinated aldehydes
from readily accessible allylic fluorides (Scheme 1B).
The Wacker reaction is a powerful method[12] for the
oxidation of olefins and typically favors Markovnikov selec-
tivity.[13] However, in the presence of proximal functional
groups, regioselectivity of oxidation can be difficult to
rationally predict.[14] In our recent study of a dicationic
palladium-catalyzed Wacker-type oxidation of internal ole-
fins,[15] inductively withdrawing trifluoromethyl groups were
found to substantially enhance selectivity for distal oxida-
tion.[16] In fact, even the oxidation of a terminal olefin, 4,4,4-
trifluoro-1-butene, occurred with modest anti-Markovnikov
selectivity (3:1 aldehyde/ketone). We therefore reasoned that
modified Wacker conditions, combined with the inductive
influence of allylic fluorides, could be employed as a general
strategy for the synthesis of b-fluorinated aldehydes under
mild reaction conditions.
The model allylic fluoride A (Figure 1) was initially
subjected to a range of Wacker-type oxidation conditions
toward optimization of aldehyde selectivity.[17] Traditional
Tsuji–Wacker conditions proved poorly suited for oxidation
of the electron-deficient allylic fluoride, thus resulting in
defluorination and no aldehyde selectivity (Figure 1a). When
subjected to our previously reported dicationic palladium
system, this substrate was oxidized in moderate yield with
preference for the aldehyde (3:1 aldehyde/ketone; Fig-
ure 1b), thus revealing some innate aldehyde selectivity of
the substrate.
Significant progress has been made toward mild, catalytic
alkyl fluorination, with much of this work dedicated to
installing fluorine atoms adjacent to p systems (Sche-
me 1A).[7] a-Fluorination of carbonyl compounds is achieved
efficiently by organocatalysis and transition-metal catalysis.[8]
Allylic fluorides can also be readily prepared by regio- and
enantioselective methods.[7a–d,f,h] For example, iridium-cata-
lyzed allylic substitution[7d,h] and palladium-catalyzed C H
À
fluorination[7f] methods can serve as convenient approaches
to allylic fluorides.
Despite the depth of research dedicated to a-fluorination
of activated p systems, catalytic installation of fluorine b to
functional groups remains a major challenge.[9] One promising
strategy enables the syntheses of b- and g- fluorinated ketones
by catalytic ring opening of strained cyclopropanols and
cyclobutanols, respectively.[10] Alternative methods amenable
to producing b-fluorinated carbonyl compounds have been
reported,[11] but a general solution employing simple starting
materials has yet to be developed. Herein, we report
To emphasize this effect, we next explored nitrite
ligands[18] and exogenous nitrite cocatalysts, utilized by the
group of Feringa and our own group, respectively, for the
catalyst-controlled oxidation of terminal olefins to aldehydes.
When A was subjected to Feringaꢀs conditions, catalyzed by
[PdNO2Cl(MeCN)2],[19] high aldehyde selectivity was
observed (18:1 aldehyde/ketone), albeit in poor yield (Fig-
[*] C. K. Chu, D. T. Ziegler, B. Carr, Z. K. Wickens, Prof. R. H. Grubbs
Division of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, CA 91125 (USA)
E-mail: rhg@caltech.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603424.
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Table 1: Nitrite-modified Wacker oxidations of allylic fluorides: Substrate
scope.
Entry
1
Substrate
Yield [%][a]
82
Selectivity[b]
ꢀ20:1
2
87
ꢀ20:1
3
4
5
94
93
93
ꢀ20:1
ꢀ20:1
ꢀ20:1
6
72
ꢀ20:1
7
8
81[c]
77
ꢀ20:1
ꢀ20:1
Figure 1. Comparison of oxidation conditions with a model substrate.
[a] Selectivity (aldehyde/ketone) determined by 1H NMR analysis.
[b] Oxidation yield (aldehyde + ketone) determined by 1H NMR
analysis versus an internal standard. Only fluorinated products
included (see Table 1 for optimized reaction conditions).
[a] Yield is of the purified product obtained after NaBH4 reduction.
[b] Selectivity (aldehyde/ketone) determined by H NMR analysis of
1
crude reaction mixture prior to reduction. [c] Yield of aldehyde deter-
mined by 1H NMR analysis versus an internal standard. DCM=di-
chloromethane.
ure 1c). Our group recently developed a Wacker system that
employs an exogenous nitrite catalyst in a tBuOH/MeNO2
solvent system, which oxidizes unbiased terminal olefins with
anti-Markovnikov selectivity.[20] This nitrite-cocatalyzed
system oxidized the allylic fluoride A in moderate yield and
high selectivity (26:1 aldehyde/ketone; Figure 1d). Further
optimization, involving exclusion of water from the reaction
system, increased nitromethane concentration, and even
a reduction in catalyst loading, resulted in very high selectivity
for aldehyde formation (36:1 aldehyde/ketone) in high yield
(77%; Figure 1e). Since the use of tBuOH has been
established as a strategy to enhance aldehyde selectivity in
Wacker-type oxidations,[21,22] the importance of the nitrite
catalyst and nitromethane as a cosolvent was assessed.
Elimination of these components from the optimized reaction
conditions led to diminished aldehyde selectivity (8:1 alde-
hyde/ketone) and formation of defluorination products (Fig-
ure 1 f).[23]
With optimized reaction conditions in hand, we next
explored the reaction scope, and found the method to be well
suited for regioselective oxidation of allylic fluorides bearing
a variety of functional groups.[24] Branched allylic fluorides
without added bias were oxidized to the corresponding b-
fluorinated aldehydes in high yield and greater than 20:1
selectivity, with an ester and alkyl chloride being well
tolerated (Table 1, entries 1, 2, 6, and 7). High aldehyde
selectivities were maintained for allylic fluorides bearing an
additional directing group. Olefins with phenyl and benzyl
ethers, benzoate, and phthalimide branches were oxidized to
the corresponding aldehydes with only trace levels of ketone
detected (entries 3, 4, 5, and 8). When comparing previous
nitrite-modified Wacker oxidations of functionalized olefins,
fluoride was shown to be an exceptionally potent directing
group.
Despite the relative instability of b-fluorinated aldehydes,
the high purity of the crude reaction mixture allows direct
transformation into a variety of organofluorine compounds.
Reaction with Oxone furnished the b-fluorinated carboxylic
acid 1 in excellent yield (Scheme 2a). Wittig olefination and
protection of the carbonyl were achieved in synthetically
useful yields in spite of potential base or acid lability of the
fluoride (Scheme 2b,d). The aldehyde was reduced nearly
quantitatively to the g-fluorinated alcohol 3 (Scheme 2c).
Furthermore, nucleophilic addition to aldehydes provides
access to a range of new fluorinated building blocks, as
demonstrated by the addition of allylB(pin) to produce the
homoallylic alcohol 5 (Scheme 2e). Overall, the efficient
preparation of b-fluorinated aldehydes by Wacker-type
oxidation serves as a unique synthetic handle to produce
diverse fluorinated molecules.
To investigate how our method may be used to generate
stereodefined organofluorines, we were interested in the
aldehyde-selective oxidation of enantioenriched allylic fluo-
ride 6 [Eq. (1)].[7h] Under the optimal reaction conditions,
oxidation occurred without erosion of enantiopurity,[25] thus
allowing the isolation of enantioenriched fluorinated product
7 in good yield and enantiomeric excess. This result suggests
that palladium-catalyzed olefin isomerization does not occur
on the time scale of oxidation to the aldehyde product.
2
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Scheme 2. Derivatization of a b-fluorinated aldehyde crude product. All
Figure 2. Influence of fluoride proximity on regioselectivity of oxida-
derivatizations performed using crude Wacker oxidation product.
Yields reported over 2 steps. a) Oxone, DMF. b) MePPh3Br, nBuLi,
THF. c) NaBH4, DCM/EtOH (7:5). d) pTsOH, ethylene glycol, molec-
ular sieves. e) AllylB(pin), DCM. DMF=N,N-dimethylformamide,
THF=tetrahydrofuran, Ts=4-toluenesulfonyl.
tion. [a] Selectivity (aldehyde/total oxidation yield) determined by
1H NMR analysis.
Having demonstrated the synthetic utility of the trans-
formation, we sought to gain insight into the role of the
fluoride in influencing regioselectivity and reactivity. To this
end, a study of the distance-dependence of regioselectivity on
fluoride proximity was conducted. Three alkyl fluoride
isomers were synthesized with systematic variation of the
distance between fluoride and olefin. The oxidations of these
compounds under our standard reaction conditions were then
compared along with that of 1-decene (Figure 2). The high
aldehyde selectivity (96%) in the case of the allylic fluoride
(n = 0) depreciates as n increases. A strong preference for
oxidation to the aldehyde is maintained in the reaction of
a homoallylic fluoride (n = 1), thus suggesting that this
method can provide a convenient route to g-fluorinated
aldehydes. However, aldehyde selectivity diminishes for the
analogue fluorinated in a more distal position (n = 2), and
poor regioselectivity is observed in the oxidation of the
unbiased olefin 1-decene (58%).[26] The gradual loss in
selectivity as fluoride substitution is placed further from the
olefin is consistent with a key inductive effect which enhances
regioselectivity under these nitrite-modified Wacker condi-
tions.
Figure 3. Individual rate and competition experiments performed to
measure relative rates of conversion.
deficient fluorinated olefin reacts at an accelerated rate
relative to the unfunctionalized olefin (Figure 3A). However,
when the two olefins were oxidized in competition in a 1:1
ratio, the non-fluorinated olefin was consumed 2.3 times
faster than the allylic fluoride, potentially because of satu-
ration of the catalyst with the non-fluorinated olefin (Fig-
ure 3B). This inversion of relative reactivity, which results
from a decrease in the rate of conversion of the fluorinated
olefin rather than an increase in the rate of conversion of the
non-fluorinated olefin, suggests that stronger olefin coordi-
nation does not inherently lead to accelerated rate of
oxidation.
The relative rates of conversion of a fluorinated and non-
fluorinated olefin were studied to further elucidate the effect
of fluoride substitution (Figure 3). Individual rate compar-
isons of the two compounds show that the more electron-
In summary, we have developed a practical synthesis of b-
fluorinated aldehydes from readily accessible allylic fluorides.
This method represents a rare example of catalysis to produce
b-fluorinated carbonyl compounds under procedurally simple
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conditions. Direct transformation of crude aldehyde products
demonstrates the versatility of b-fluorinated aldehyde build-
ing blocks. Preliminary mechanistic studies are consistent
with inductive effects having a significant influence on both
the regioselectivity and rate of oxidation and will facilitate
further study of this new catalytic system.
Acknowledgements
We thank Dr. David VanderVelde for NMR assistance and
Dr. Peter Dornan for helpful discussions. We acknowledge
KFUPM and ONR for financial support and the NIH NIGMS
(F32GM116357) for a fellowship to D.Z.
Keywords: aldehydes · fluorine · oxidation · palladium ·
regioselectivity
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1
spectroscopy, a linear allylic alcohol (SN2’) was formed in 28%
yield, confirmed by GC-MS.
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Received: April 7, 2016
Revised: April 26, 2016
Published online: && &&, &&&&
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Communications
Oxidation
C. K. Chu, D. T. Ziegler, B. Carr,
Z. K. Wickens,
R. H. Grubbs*
&&&& — &&&&
Direct Access to b-Fluorinated Aldehydes
by Nitrite-Modified Wacker Oxidation
Out of Wack(er): The aldehyde-selective
Wacker-type oxidation of allylic fluorides
was accomplished using catalytic nitrite,
thus providing a direct route to b-fluori-
nated aldehydes. Allylic fluorides bearing
a variety of functional groups are trans-
formed in high yield and regioselectivity.
Preliminary mechanistic investigations
suggest that inductive effects have
a strong influence on the rate and
regioselectivity of the oxidation.
6
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