Direct catalytic anti-markovnikov addition of carboxylic acids to alkenes

Article abstract of DOI:10.1021/ja4057294

A direct catalytic anti-Markovnikov addition of carboxylic acids to alkenes is reported. The catalyst system is comprised of the Fukuzumi acridinium photooxidant (1) and a substoichiometric quantity of a hydrogen-atom donor. Oxidizable olefins, such as styrenes, trisubstituted aliphatic alkenes, and enamides, can be employed along with a variety of carboxylic acids to afford the anti-Markovnikov addition adducts exclusively. A deuterium-labeling experiment lends insight to the potential mechanism.

Full text of DOI:10.1021/ja4057294

Communication
pubs.acs.org/JACS
Direct Catalytic Anti-Markovnikov Addition of Carboxylic Acids to
Alkenes
Andrew J. Perkowski and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-3290, United States
S
* Supporting Information
albeit in modest yields. Our laboratory has recently disclosed
anti-Markovnikov alkene hydroetherification11 and hydro-
ABSTRACT: A direct catalytic anti-Markovnikov addi-
amination12 reactions catalyzed by 1 and either 2-phenyl-
tion of carboxylic acids to alkenes is reported. The catalyst
system is comprised of the Fukuzumi acridinium photo-
malononitrile (2)13 or thiophenol14 as hydrogen-atom donors.
oxidant (1) and a substoichiometric quantity of a
hydrogen-atom donor. Oxidizable olefins, such as styrenes,
trisubstituted aliphatic alkenes, and enamides, can be
employed along with a variety of carboxylic acids to afford
the anti-Markovnikov addition adducts exclusively. A
deuterium-labeling experiment lends insight to the
potential mechanism.
We sought to take advantage of this generic catalyst platform by
applying it to anti-Markovnikov alkene hydroacetoxylation.
We began our investigation by examining the reaction of
acetic acid with anethole using 1 as the single electron
photooxidant. A number of potential hydrogen-atom donors
were evaluated in the reaction (Table 1, entries 1, 3−6). In
a
Table 1. Optimization Studies
arboxylic esters are among the most important and
C
prevalent functional groups in small organic molecules
and polymers. Classical methods for the introduction of the
ester group rely on the reaction of an alcohol and a carboxylic
acid or activated derivative. Alternatively, photolytic,1 Brønsted
acid,2 Au(I),3 Ag(I),4 Fe(III),5 or Ru(II)6-catalyzed additions of
carboxylic acids to alkene feedstocks provide a direct and
simple route to the regioselective formation of esters with high
Markovnikov selectivity (eq 1). As a compliment to this
reactivity, an anti-Markovnikov-selective variant would offer an
important synthetic tool. Despite the potential utility of such a
transformation, direct methods for anti-Markovnikov hydro-
acetoxylations of olefins by carboxylic acids are rare.7−9 Herein,
we describe an anti-Markovnikov addition of carboxylic acids to
alkenes catalyzed by the Fukuzumi acridinium salt (1)10 and a
hydrogen-atom donor (eq 2).
b
b
entry
1
conditions
conversion
yield
standard
100%
22%
70%
6%
c
2
no H-atom donor
c
3
with 0.25 equiv of 2 instead of PhSO2Na
with 0.25 equiv of 3 instead of PhSO2Na
with 0.25 equiv of 4 instead of PhSO2Na
with 0.25 equiv of 5 instead of PhSO2Na
with 0.25 equiv of 5 instead of PhSO2Na
5 mol % 1
34%
30%
26%
10%
70%
0%
c
4
44%
c
5
c
24%
6
100%
40%
d
7
8
9
100%
100%
100%
100%
70%
64%
58%
54%
10 mol % 1
10
DCE [0.25 M]
11
DCE [0.1 M]
a
b
Containing 5%v/v acetic anhydride. Determined by 1H NMR
c
d
analysis. With 0.25 equiv sodium acetate. Without added base.
general, C−H hydrogen-atom donors 2−5 afforded the desired
hydroacetoxylated adduct with complete anti-Markovnikov
regioselectivity, however in only modest yields with the
remainder of the mass balance attributed to unreacted alkene.
A marked increase in reactivity and yield was obtained when
employing benzenesulfinic acid (5) as a hydrogen-atom donor
In seminal work, Arnold8 and Gassman9 have each reported
single examples of anti-Markovnikov additions of acetic acid to
alkenes employing stoichiometric quantities of single electron
photooxidants. Despite the use of acetic acid as solvent, single
regioisomers of the hydroacetoxylation adducts were obtained,
Received: June 7, 2013
Published: July 1, 2013
© 2013 American Chemical Society
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Communication
a
Chart 1. Scope of the Anti-Markovnikov Addition of Carboxylic Acids to Alkenes
a
b
Isolated yields are averages of two trials. All products observed are single regioisomers unless otherwise noted. Reactions run with 0.25 equiv of
c
NaOAc instead of 2,6-lutidine. 1H NMR yield vs internal standard.
(entry 6), most likely due to the kinetic advantage gained by
the available heteroatom hydrogen bond, given the relative
nucleophilicity of the putative benzylic radical intermediate.15
Given the need for a base to promote the reaction, we were
pleased to see that commercially available sodium benzene
sulfinate was as effective as the combination of benzene sulfinic
acid and sodium acetate. In the absence of hydrogen-atom
donor (entry 2), only trace quantities (6%) of the desired
acetate were obtained. An increase in catalyst loading had a
detrimental effect on the reaction conversion (entries 8−9),
and more concentrated reaction conditions led to an increase in
overall reaction efficiency (entries 10−11).
After determining the optimal reaction conditions, we turned
our attention to the reaction scope (Chart 1). A number of β-
methyl styrenes bearing a variety of substituents were
investigated. Good yields were achieved with both p- and o-
methoxy substitution (71% and 72%, respectively, entries 1 and
2), while slightly diminished yields were observed with the m-
methoxy isomer (50% yield, entry 3). This effect could be due,
in part, to less charge density being located on the alkene
carbon atoms. Good yields were also observed with the less
electron-rich p-methyl-β-methylstyrene (entry 4, 52% yield)
while the even less electron rich β-methylstyrene resulted in
markedly lower yields (entry 5, 29% yield). To our surprise, p-
chloro-β-methylstyrene gave elevated yields relative to β-
methylstyrene. The reaction also tolerated a phthalimide
protected amine and furnished the corresponding ester in
good yield (entry 7, 75% yield).
We next turned to investigate the scope of carboxylic acids
that could be employed in this reaction, using anethole as a
model substrate (entries 8−12). Unfortunately, the standard
conditions outlined above resulted in mixtures of ester products
due to the necessary inclusion of acetic anhydride for efficient
reactivity. The use of other hydrogen-atom donors, such as 9-
cyanofluorene, required prolonged reaction times to reach full
conversion and so was deemed unsuitable. Drawing from our
recently disclosed anti-Markovnikov hydroamination chemistry,
thiophenol was found to be an especially efficient hydrogen-
atom donor for this transformation requiring slightly lower
loadings than sodium benzene sulfinate (20 mol % vs 25 mol %,
respectively) and resulting in high yields of the ester products.
Reaction times generally increased with larger carboxylic acids
and only modest levels of the pivalic acid adduct were obtained
(30% yield, entry 11). Benzoic acid could be effectively
employed, giving the corresponding benzoyl ester in 94%
isolated yield after 30 h (entry 12).
To further probe the effect of alkene structure on the title
transformation, we examined several different classes of alkenes
(entries 13−17). Trisubstituted styrenyl alkenes, such as 1-
phenylcyclohexene, afforded the anticipated anti-Markovnikov
adducts in good yield albeit with poor diastereocontrol (67%
yield; 1.3:1 dr, entry 13). Attempts to increase the
diastereoselectivity by examining additional hydrogen-atom
donors, solvents, and bases were unfortunately fruitless.
Nevertheless, we were pleased to find that trisubstituted
aliphatic alkenes, such as 1-methylcyclopentene and even 2-
methyl-2-butene (entries 14 and 15), were reactive toward the
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esterification reaction with acetic acid, giving the acetate
adducts in respectable levels of chemical efficiency (61% and
74% yields, respectively). This result is further underscored by
the fact that these alkenes have oxidation potentials that are
quite high (≥ +1.4 V vs SCE)16,17 and therefore difficult to
oxidize by most other chemical oxidants.
Lastly, we questioned whether acid-labile alkenes, such as
enamides and enol ethers, could be employed in this protocol.
We were pleasantly surprised to find that CBz-protected
tetrahydropyridines gave the anti-Markovnikov regioisomer
exclusively without perturbing the protecting group (82% yield,
entry 16). Only when we examined the more acid-sensitive
dihydropyran did we first observe the Markovnikov adduct, in a
2:1 ratio with the desired regioisomer (63% yield). This
observation highlights the mildness of the reaction conditions
and indicates that the title reaction is competitive with acid-
promoted acetal formation.
We believe this alludes to the possibility of the hydrogen-atom
transfer step as the rate-limiting process in this mechanism.
Piecing together these details, we propose the following
mechanism (Scheme 1). Oxidation of the alkene by the charge-
transfer excited state of the Fukuzumi catalyst (1*) results in
the formation of the alkene cation radical (6). Addition of the
carboxylate nucleophile to the less substituted position of the
cation radical provides key intermediate 7. For the reactions
using sodium benzenesulfinate, we propose that a rapid acid−
base equilibrium with the excess carboxylic acid generates small
quantities of benzenesulfinic acid (5), the active hydrogen-atom
donor. Based on the results in eq 3, we presume that the
hydrogen-atom transfer step is rate limiting. When d4-acetic
acid is employed, the d1-benzenesulfinic acid results in a
significant kinetic isotope effect that causes buildup of 7 and
side reactions to result that are not observed with protio acetic
acid. The fate of the resultant benzenesulfinyl radical (8) is less
clear, however, based on our prior mechanistic hypothesis, we
believe that this species acts as an oxidant for acridine radical 9,
to regenerate the catalyst (1) and benzenesulfinate. In the
presence of thiophenol, a similar mechanism is presumed
operational.
To lend further insight into the mechanism of the
transformation, we examined the reaction of anethole in the
presence of d4-acetic acid (eq 3). The acetate product was
In summary, we have described a direct organocatalytic
protocol for the anti-Markovnikov addition of carboxylic acids
to alkenes. The use of sodium benzene sulfinate or thiophenol
as the hydrogen-atom donor was necessary for productive
reactivity. Further mechanistic experiments to fully understand
the role of the sulfinate are ongoing.
obtained with 87% deuterium incorporation at the benzylic
position in 38% yield (93% conversion). Since the pKa values
for acetic acid (4.8) and benzene sulfinic acid (2.1) are
relatively close and a 40-fold excess of acetic acid is used
relative to the sodium benzene sulfinate, our working
hypothesis is that small quantities of d1-benzene sulfinic acid
are generated during the course of the reaction, which acts as
the D-atom source. It is also worth noting that the reaction
times were significantly longer than the experiments run with
protio acetic acid (120 vs 24 h) and the yield was far lower due
to the presence of significant quantities of unidentifiable
byproducts (cf. 71% yield with HO2CCH3, Chart 1, entry 1).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
nicewicz@unc.edu
Notes
The authors declare no competing financial interest.
Scheme 1. Proposed Mechanism for the Anti-Markovnikov Alkene Hydroacetoxylation Reaction
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ACKNOWLEDGMENTS
■
The project described was supported by award no. R01
GM098340 from the National Institute of General Medical
Sciences, The University of North Carolina at Chapel Hill, the
Packard Foundation, and an Eli Lilly New Faculty Award.
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