A clean and selective radical homocoupling employing carboxylic acids with titania photoredox catalysis

Article abstract of DOI:10.1021/ol502625w

A titania photoredox catalysis protocol was developed for the homocoupling of C-centered radicals derived from carboxylic acids. Intermolecular reactions were generally efficient and selective, furnishing the desired dimers in good yields under mild neutral conditions. Selective cross-coupling with two acids proved unsuccessful. An intra-molecular adaptation enabled macrocycles to be prepared, albeit in modest yields. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502625w

Letter
pubs.acs.org/OrgLett
A Clean and Selective Radical Homocoupling Employing Carboxylic
Acids with Titania Photoredox Catalysis
David W. Manley and John C. Walton*
University of St. Andrews, EaStCHEM School of Chemistry, St. Andrews, Fife, KY16 9ST, U.K.
S
* Supporting Information
ABSTRACT: A titania photoredox catalysis protocol was
developed for the homocoupling of C-centered radicals
derived from carboxylic acids. Intermolecular reactions were
generally efficient and selective, furnishing the desired dimers
in good yields under mild neutral conditions. Selective cross-
coupling with two acids proved unsuccessful. An intra-
molecular adaptation enabled macrocycles to be prepared,
albeit in modest yields.
omocoupling reactions are a valuable and effective tool
much more effective reagent, and using this, the optimum
Hfor synthetic chemists. Indeed, dimeric moieties are reaction conditions were found to be 8 equiv (with respect to
1) of this material dispersed at 5 mg mL−1 in acetonitrile. Using
these conditions 53% of 2a was isolated following 21 h of
present in a plethora of natural products and pharmaceutical
formulations, underlining the importance of such protocols.1
photolysis. The related benzyloxyacetic acid 1b returned 2b in a
more modest yield of 38% (Table 1; entries 1 and 2).
Irradiation of phenylbutyric acid 1c failed to return any dimer
(entry 3). Surprisingly, photolysis of adamantane-1-carboxylic
acid 1d furnished 1-adamantyl methyl ketone 3 in a yield of
22% as the only product (entry 4). Presumably 3 was formed
by reaction of the adamantyl radicals with the acetonitrile
solvent. Benzyl radicals released from phenylacetic acid 1e
combined cleanly and selectively to furnish bibenzyl 2e in an
excellent yield (entry 5). As might be expected, allyl type
radicals proved unselective, returning several isomers upon
photolysis of β,γ-unsaturated acids 1f and 1g (entries 6 and 7).
Ethynylacetic acid 1h and cyanoacetic acid 1i proved unreactive
in our setup (entries 8 and 9).
From these results it was clear that the process was most
efficient when the acid derived radicals were stabilized by an
adjacent functional group, with benzyl radicals being the most
efficient and selective. Thus, it was decided to examine a range
of acids based on the phenylacetic acid core structure.
Incorporation of substituents on the phenyl ring proved a
success, with dimers bearing both electron-releasing and
-withdrawing groups being formed from the respective
arylacetic acids (Table 2, entries 1 and 2). The extremely
electron-poor perfluorophenylacetic acid 4c was somewhat less
reactive, requiring an extended reaction time of 40 h to return
dimer 5c in a yield of 53% (entry 3). Increasing the size of the
aromatic units with naphthalenylacetic acids 4d and 4e
furnished dimers 5d and 5e accompanied for the first time by
significant quantities of the saturated alkanes (entries 4 and 5).
Transition metal mediated reductive homocouplings have been
highly successful,2 although the majority of these relate to the
tethering of sp2 hybridized carbon centers. Due to their highly
reactive nature, radical dimerizations offer a promising means of
carrying out C(sp3)−C(sp3) assemblies.3 Such reactions
classically employed organohalides in combination with
undesirable reagents such as tin hydride4 or sodium metal.5
The past decade has seen a movement toward greener, more
sustainable synthetic protocols with particular emphasis on
minimizing hazard and environmental impact while maximizing
efficiency.6 We recently developed an effective TiO2-mediated
photoredox protocol for the generation of alkyl radicals from
carboxylic acids under anhydrous, anaerobic conditions.7 CO2
is the only significant byproduct, and the titania can be easily
removed by filtration and subsequently recycled.8 Herein, we
report a fresh use of this approach to afford a range of sp3−sp3
linked homodimers in generally good to excellent yields.
The titania (Degussa’s P25, now supplied by Evonik) was
dispersed in distilled acetonitrile along with the desired
carboxylic acid in an oven-dried Pyrex Schlenk tube. Photolysis
was carried out using two hemispherical face-to-face arrays of
UVA emitting tanning lamps, following purging of the reaction
mixture with argon to exclude oxygen. The titania was removed
by filtration through Celite thus enabling the product(s) to be
easily purified as necessary. The P25 was readily recyclable, but
due to its cheapness, this was seldom implemented.
Optimization of the reaction conditions was undertaken
using phenoxyacetic acid 1a. Overnight irradiation of 1a
furnished the desired 1,2-diphenoxyethane 2a together with
three minor components.9 Using the unaltered P25 resulted in
low overall yields with only modest selectivities being recorded.
P25 doped with a 0.1% (w/w) loading of platinum proved a
Received: September 4, 2014
Published: October 7, 2014
© 2014 American Chemical Society
5394
dx.doi.org/10.1021/ol502625w | Org. Lett. 2014, 16, 5394−5397

Organic Letters
Letter
Table 1. Investigation of Homodimerization Scope
Table 3. Dimerization of α-Substituted Phenylacetic Acids
entry (acid)
Ar
R1
R2
time/h
yield/% (dimer)
1 (6a)
2 (6b)
3 (6c)
4 (6d)
5 (6e)
Ph
Ph
H
H
Ph
H
F
16
40
18
21
20
91 (7a)
ab
,
9-fluorene
7 (7b)
ac
,
Ph
Ph
Ph
−
F
F
90 (7d)
Ph
3 (7e)
a
b
c
NMR yield(s). 9H-Fluorene 8 (83%) also formed. Triphenyl-
methane 9 (50%) and 9-phenyl-9H-fluorene 10 (26%) observed.
transformed to 9 and 10 after encountering the electrons or
holes of the photoexcited titania. Racemic α-fluorophenylacetic
acid 6d was converted to two stereoisomeric dimers 7d in an
excellent combined yield of 90% (entry 4).12 Remarkably,
incorporation of a second fluorine substituent at the same
position in α,α-difluorophenylacetic acid 6e essentially shut
down the reaction. Following overnight irradiation, a mere 3%
of the product dimer 7e was isolated. It is well-known that the
pyramidal character of C-centered radicals increases as more
fluorine substituents are introduced.13 Most probably this alters
the geometry of the acid-derived radical, such that decarbox-
ylation at the TiO2 surface becomes energetically unfavorable.
When alcohol and amine groups were introduced the
chemistry was diverted away from dimerization (Scheme 1).
Racemic mandelic acid 11a was converted to benzaldehyde 12
and benzyl alcohol 13. Probably the α-hydroxybenzyl radical
was reduced by the conduction band of the excited TiO2 to
a
b
22% 1-adamantyl methyl ketone 3 isolated. NMR yield(s).
c
d
Combined yield of three isomeric dimers. Fraction containing five
isomeric dimers isolated.
Table 2. Dimerization of Aryl- and Heteroarylacetic Acids
entry
Ar (acid)
time/h
yield/% (dimer)
1
2
3
4
5
6
7
8
9
4-MeOC6H4 (4a)
4-CF3C6H4 (4b)
C6F5 (4c)
20
19
40
39
52
20
20
22
21
84 (5a)
74 (5b)
53 (5c)
Scheme 1. Reactions of α-Hydroxy- and α-Amino-
Substituted Phenylacetic Acids
ab
,
1-naphth. (4d)
56 (5d)
ac
,
2-naphth. (4e)
56 (5e)
83 (5f)
78 (5g)
2-thiophene (4f)
3-thiophene (4g)
3-benzothiophene (4h)
56 (5h)
3-indole (4i)
−
a
b
c
NMR yield(s). 30% 1-methylnaphthalene also observed. 40% 2-
methylnaphthalene also observed.
Heteroaromatics also proved effective; 2- and 3-thiopheneacetic
acids 4f and 4g furnished the desired dimers in pleasing yields
(entries 6 and 7) while the related benzo[b]thiophen-3-ylacetic
acid 4h reacted more modestly (entry 8). Photolysis of indole-
3-acetic acid 4i returned only unreacted starting material (entry
9).
The influence of additional substituents at the benzylic
position was next examined. Diphenylacetic acid 6a was
converted to tetraphenylethane 7a in a near-quantitative yield
(Table 3, entry 1). In contrast, photolysis of the related 9H-
fluorene-9-carboxylic acid 6b produced the saturated alkane
9H-fluorene 8 as the major product (entry 2). Triphenylacetic
acid 6c gave rise to triphenylmethane 9 and 9-phenyl-9H-
fluorene 10 (entry 3).10 Gomberg’s radical exists in an
equilibrium with the quinoid dimer.11 It is probable that this
dimer was indeed formed during photolysis but that it
converted back to its free radical form which was then
a
NMR yield(s).
5395
dx.doi.org/10.1021/ol502625w | Org. Lett. 2014, 16, 5394−5397

Organic Letters
Letter
form an anion which was then protonated to furnish 13.
Oxidation to a cation and subsequent proton loss accounted for
the formation of 12. Benzilic acid 11b returned benzophenone
14 in a good yield of 67%, presumably formed in a fashion
analogous to 12, accompanied by the homodimer 15 in a
modest yield of 20%. The reaction of α-phenylglycine 16a
probably proceeded in a similar manner. In this instance it
appeared that a condensation then took place between the
products benzaldimine 17a and benzylamine 18a to form the
secondary imine 19a with loss of ammonia. Benzaldehyde 12
was probably also produced by hydrolysis of unreacted 17a
upon exposure to atmospheric moisture. The photolysis of α,α-
diphenylglycine 16b yielded only the secondary ketimine 19b
which was isolated in a pleasing yield of 74%. It is believed that
this was formed in a similar condensation involving
benzophenone imine 17b and benzhydrylamine 18b.
search for new, more efficient macrocyclization methods. Based
on the generally excellent yields and conversions obtained
during the dimerization of arylacetic acids we extended our
study to several intramolecular processes for the purpose of
macrocycle syntheses.
Not surprisingly, in view of the strain involved, Pt−TiO2
photocatalyzed reactions of ortho- and para-phenylenediacetic
acids gave no [2.2]-ortho-cyclophane or [2.2]-para-cyclophane.
Both returned the corresponding bibenzyl derivatives with
evidence for oligomerization being detected by GC-MS.
Three precursor diacids (21, 24, and 27, Scheme 3), each
containing two phenylacetic acid units linked in different ways,
a
Scheme 3. Intramolecular Dimerizations to Cyclophanes
To extend the synthetic utility of this C−C bond forming
process we investigated heterodimerizations between two
different acids. The photocatalyzed reaction of phenylacetic
acid 1e with diphenylacetic acid 6a produced the expected
dimers 2e and 7a together with a minor amount of the cross-
coupled product 20a (Scheme 2). Reactions were carried out
with different proportions of the acids and of TiO2 but always
gave the same three products.
a
Scheme 2. Homocoupling and Cross-coupling
a
b
NMR yields. Head-to-tail trityl dimer not observed.
The persistent radical effect (PRE) leads to selective cross-
coupling between a persistent and a transient radical when both
are formed at equal rates.14 It exploits the reluctance of
persistent radicals to terminate via homodimerization reactions
meaning that they can only be consumed by reaction with a
transient species. Several elegant syntheses have made use of
the PRE in recent years, the majority of these employing
nitroxides.15 We examined the reaction between 1e and
triphenylacetic acid 6c in the hope that selective formation of
the cross-coupled 20b could be achieved. In fact, the
homodimer 2e was formed in excess of 20c (Scheme 2).
Photolyses with various reactant proportions gave similar
results (see Supporting Information for details of this and other
acids). Radical formation in our system arises from interaction
with hole-trap sites on the titania. Therefore, it is probable that
surface effects come into play making it unlikely that the
different acids will react at the same rate, as required for the
PRE. Furthermore, oxidations or reductions of the radicals by
the titania are possible diverting them away from cross-
coupling.
a
b
With Pt-P25, UV in CH3CN for 18−20 h. NMR yield(s).
were prepared by treatment of 4-hydroxyphenylacetate with
K2CO3 in the presence of an appropriate dibromide and
subsequent basic hydrolysis. Photolysis of 21, with its acid units
flexibly linked by a methylene chain, afforded the doubly
reduced, 1,6-bis(p-tolyloxy)hexane 23 as the major product.
Pleasingly, however, the macrocycle 5,12-dioxa-1,4(1,4)-
dibenzenacyclododecaphane 22 was obtained in a modest
yield (13%) via intramolecular dimerization of the intermediate
benzyl type radicals. A rigid, planar, phenyl ring was included in
the linker between the two phenylacetic acid moieties, in the
ortho- and para-xylene based diacids 24 and 27. The objective
was to decrease the rotational freedom of the chain thus
encouraging macrocyclization. Photolysis of the ortho-analogue
24 was more successful with the cyclophane 25 being formed in
23% yield along with 30% of the 1,2-bis((p-tolyloxy)methyl)-
benzene 26. Diacid 27 returned only the dialkane product 28 in
a modest yield of 33% following photolysis. Evidently the two
reaction centers are held too far apart by the rigid p-xylene
linker.
Many drug molecules and total synthesis targets contain
macrocyclic ring systems, the macrolide family of antibiotics
being just one notable example.16 Macrocyclization reactions
are mostly carried out under conditions of extreme dilution in
order to minimize oligomerization and tend to suffer from low
yields.17 This, coupled with the tendency for macrocycle ring
closures to be carried out late in a synthesis, has driven the
A plausible mechanism (Scheme 4) involves photoexcitation
of the TiO2 by ultra-band-gap energy photons leading to the
generation of an electron−hole pair that migrates to surface
5396
dx.doi.org/10.1021/ol502625w | Org. Lett. 2014, 16, 5394−5397

Organic Letters
Letter
63, 1487−1536. Lian, G.; Yu, B. Chem. Biodiversity 2010, 7, 2660−
2691.
Scheme 4. Postulated Mechanism
(2) Venkatraman, S.; Li, C.-J. Org. Lett. 1999, 1, 1133−1135. Lin, G.-
q.; Hong, R. J. Org. Chem. 2001, 66, 2877−2880. Lee, P. H.; Seomoon,
D.; Lee, K. Org. Lett. 2004, 7, 343−345.
(3) Curran, D. P. Synthesis 1988, 1988, 417−439. Jasperse, C. P.;
Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237−1286.
(4) Baguley, P. A.; Walton, J. C. J. Chem. Soc., Perkin Trans. 1 1998,
2073−2082. Studer, A.; Amrein, S. Synthesis 2002, 14, 835−849.
́
(5) Kurti, L.; Czako, B. Strategic Applications of Named Reactions in
̈
Organic Synthesis: Background and Detailed Mechanisms; Elsevier
Academic Press: 2005.
(6) United States Environmental Protection Agrency, Green
Chemistry Page. http://www2.epa.gov/green-chemistry (accessed
Aug 13, 2014).
(7) Manley, D. W.; McBurney, R. T.; Miller, P.; Howe, R. F.;
Rhydderch, S.; Walton, J. C. J. Am. Chem. Soc. 2012, 134, 13580−
13583. Manley, D. W.; McBurney, R. T.; Miller, P.; Walton, J. C.;
Mills, A.; O’Rourke, C. J. Org. Chem. 2014, 79, 1386−1398.
(8) Mills, A.; O’Rourke, C. Catal. Today 2014, 230, 256−264.
(9) Phenoxyacetone, 3-phenoxypropanenitrile, and phenol were also
formed. See Supporting Information for full details.
trapping sites.18 Single electron transfer (SET) to the
carboxylate of an acid at a hole-trap site furnishes a surface
bound carboxylate radical cation. Decarboxylation by β-scission
gives rise to a C-centered radical, in competition with back
electron transfer. EPR studies of similar species have shown
that a significant portion freely tumble in solution without
being bound to the titania surface.7 Termination occurs by
homodimerization of two of these species in solution.
Conversion of these radicals to saturated alkane products is
thought to be the result of reduction/protonation at the TiO2
surface that has some precedent.19 The protons probably
originate from hydroxyls at the titania surface. A simplified
representation of these events is presented in Scheme 4.
In conclusion, we have developed a generally efficient
protocol for the homodimerization of carboxylic acid derived
radicals avoiding the use of harsh conditions and toxic reagents.
This process is most effective with stabilized radicals, especially
those based on the phenylacetic acid core. Efficient cross-
couplings to yield heterodimers could not be achieved by
exploiting a PRE. Macrocyclizations to form cyclophanes were
achieved by photolyses of precursors containing two phenyl-
acetic acid moieties. Yields were modest, but this is a well-
documented feature of macrocyclizations. A straightforward
reaction mechanism has been proposed which is promoted by
TiO2 as a reaction partner and catalyst and that is supported by
previous work in our lab and by literature precedent.
(10) Compound 10 might have formed either by hole-oxidation of
the trityl radical to a cation which then underwent electrophilic
aromatic substitution with a neighbouring phenyl ring or via homolytic
aromatic substitution followed by oxidative rearomatization.
(11) Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry; Oxford
University Press: Oxford, 2012; Vol. 1.
(12) The 1H and 19F NMR spectra revealed that, as expected, the D/L
and meso isomers were present in a 1:1 ratio.
(13) Uneyama, K. Organofluorine Chemistry; Wiley: 2006.
(14) Studer, A. Chem.Eur. J. 2001, 7, 1159−1164. Fischer, H.
Chem. Rev. 2001, 101, 3581−3610.
(15) Studer, A. Chem. Soc. Rev. 2004, 33, 267−273.
(16) Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002, 41,
4632−4653.
(17) Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 2005, 1949−
1964.
(18) Linsebigler, A. L.; Lu, G.; Yates, J. T. Chem. Rev. 1995, 95, 735−
758. Deiana, C.; Fois, E.; Coluccia, S.; Martra, G. J. Phys. Chem. C
2010, 114, 21531−21538. Salazar, C.; Nanny, M. A. J. Catal. 2010,
269, 404−410. Henderson, M. A. Surf. Sci. Rep. 2011, 66, 185−297.
(19) Marinkovic, S.; Hoffmann, N. Chem. Commun. 2001, 1576−
1578. Marinkovic,
3107.
́
S.; Hoffmann, N. Eur. J. Org. Chem. 2004, 3102−
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental procedures and NMR spectra for novel
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jcw@st-and.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the EPSRC for financial support (Grant EP/
I003479/1) and the EPSRC National Mass Spectrometry
Service, Swansea.
REFERENCES
■
(1) Voloshchuk, T.; Farina, N. S.; Wauchope, O. R.; Kiprowska, M.;
Haberfield, P.; Greer, A. J. Nat. Prod. 2004, 67, 1141−1146. Vrettou,
M.; Gray, A. A.; Brewer, A. R. E.; Barrett, A. G. M. Tetrahedron 2007,
5397
dx.doi.org/10.1021/ol502625w | Org. Lett. 2014, 16, 5394−5397