Overturning established chemoselectivities: Selective reduction of arenes over malonates and cyanoacetates by photoactivated organic electron donors

Article abstract of DOI:10.1021/ja4050168

The prevalence of metal-based reducing reagents, including metals, metal complexes, and metal salts, has produced an empirical order of reactivity that governs our approach to chemical synthesis. However, this reactivity may be influenced by stabilization of transition states, intermediates, and products through substrate-metal bonding. This article reports that in the absence of such stabilizing interactions, established chemoselectivities can be overthrown. Thus, photoactivation of the recently developed neutral organic superelectron donor 5 selectively reduces alkyl-substituted benzene rings in the presence of activated esters and nitriles, in direct contrast to metal-based reductions, opening a new perspective on reactivity. The altered outcomes arising from the organic electron donors are attributed to selective interactions between the neutral organic donors and the arene rings of the substrates.

Full text of DOI:10.1021/ja4050168

Communication
pubs.acs.org/JACS
Overturning Established Chemoselectivities: Selective Reduction of
Arenes over Malonates and Cyanoacetates by Photoactivated
Organic Electron Donors
Eswararao Doni, Bhaskar Mondal, Steven O’Sullivan, Tell Tuttle,* and John A. Murphy*
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United
Kingdom
S
* Supporting Information
Scheme 1. Reductions of Esters and Arenes
ABSTRACT: The prevalence of metal-based reducing
reagents, including metals, metal complexes, and metal
salts, has produced an empirical order of reactivity that
governs our approach to chemical synthesis. However, this
reactivity may be influenced by stabilization of transition
states, intermediates, and products through substrate−
metal bonding. This article reports that in the absence of
such stabilizing interactions, established chemoselectivities
can be overthrown. Thus, photoactivation of the recently
developed neutral organic superelectron donor 5 selec-
tively reduces alkyl-substituted benzene rings in the
presence of activated esters and nitriles, in direct contrast
to metal-based reductions, opening a new perspective on
reactivity. The altered outcomes arising from the organic
electron donors are attributed to selective interactions
between the neutral organic donors and the arene rings of
the substrates.
arbonyl groups are key targets for reduction both by
Chydridic reducing agents and by electron transfer.
Reductive electron transfer to esters is seen in classical reactions
such as the Bouveault−Blanc reaction1 or the acyloin reaction2
naphthalene and di-tert-butylbiphenyl) can also be accessed by
(e.g., 1 → 2 in Scheme 1). More recently, the reduction of esters
direct reduction of these arenes with alkali metals.9
by samarium diiodide has been rapidly developed,3 while
These challenging electron transfers all require highly reactive
electrochemical reduction of activated esters has recently been
metal electron donors. Recent papers on the powerful neutral
featured extensively in the literature.4
Arenes are more difficult to reduce than esters, with benzene
rings (in the absence of activating substituents) being among the
most challenging of substrates. The reduction potentials of
organic electron donors 3−5 have shown their ability to perform
reduction reactions that are traditionally the preserve of reactive
metals.10 Reductive cleavage of aryl halides to aryl radicals10a with
3 and to aryl anions10b,c with 4 and 5 and the conversion of alkyl
aliphatic esters are ca. −3.0 V vs SCE,5 while that for benzene is
E0 = −3.42 V vs SHE6 (−3.66 V vs SCE). Hence, reductive
electron transfer to benzene or alkyl-substituted benzenes is
much more difficult than to esters. A clear experimental
demonstration of the relative ease of reduction with Na as the
reducing agent is the conversion of 1 to 2.7 Here selective
reduction of aliphatic esters in the presence of arenes is seen. Not
only are the arene rings within substrate 1 unaltered at the end of
the reaction, but the reaction is even carried out in an arene
solvent, xylene. Reduction of arenes can be achieved via the arene
radical anion under appropriate conditions (e.g., in Birch
reductions8a) using solvated electrons arising either from
dissolution of alkali metals in liquid ammonia or calcium metal
in alkylamine solvents.8b Radical anions of extended arenes (e.g.,
halides to alkyl radicals with 310a represent the first such reactions
to be triggered by neutral organic donors. Subsequently,
reductive cleavage of gem-disulfones, Weinreb amides,10e
arenesulfonamides,10f and acyloin derivatives10i have all been
reported. Most recently, we took advantage of the extensive
chromophores within 3−5 to make them even more powerful
electron donors. Thus, irradiation of the highly conjugated
electron donors 4 and 5 resulted in electron transfer to arenes.
Reduction of cis-1,2-diphenylcyclopropane (6) (Scheme 1)
occurred upon reaction with photoactivated 4 or 5 to afford,
besides the starting cis isomer, both trans-1,2-diphenylcyclopro-
Received: May 24, 2013
Published: July 16, 2013
© 2013 American Chemical Society
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Communication
pane (8) and 1,3-diphenylpropane (9).10k In this case, the
strained cyclopropane performed its celebrated role as a very
rapid and sensitive marker of radical reactivity in the radical anion
7.11
Scheme 3. Reduction of Substrates by Organic Electron
Donor 5
Our aim was now to exploit the strong reducing power of these
photoactivated organic donors in C−C σ-bond cleavages.
Because they are milder reducing reagents than the alkali metals,
they can be expected to react with greater selectivity, but the fact
that no metal ions are involved in the electron transfer might lead
to new types of reactivity. Whereas metal complexes or ions show
preferential coordination to the substrates or products through
lone pairs of electrons on the O atoms of the ester,12 the organic
donor 5 should undergo preferential π complexation to the arene
rings of the substrates, thereby perturbing the energetics of
potential reactions.13 We selected substrates that contain ester
and arene functional groups, which could report on the electron
transfer chemistry carried out by the organic electron donors.
Formation of either an arene radical anion or an ester radical
anion could lead to fragmentation of defined but different C−C σ
bonds to form products whose structures would report what
chemistry had taken place. Dialkyl esters of benzyl malonates
were attractive targets as simple substrates, especially as the
reductive fragmentation of 10a (Scheme 2) by Na metal and by K
Scheme 2. Possibilities for Reduction of Substrates 10
Substrates 19a and 20 afforded the analogous monoesters 24 and
25 in yields of 57% and 59%, respectively, but additionally led to
recovery of the starting compounds (20% and 22%, respectively).
Benzonitrile 21a showed no reaction, and the starting substrate
was recovered (90%) at the end of the reaction. Since the
electron-poor trifluoromethylated arene substrate had under-
gone efficient reaction, this nitrile-bearing substrate 21a was
anomalous. The UV spectrum of the substrate again showed no
overlap with the lamp emission spectrum, so we ascribe the lack
of apparent reactivity to the formation of an arene radical anion
intermediate that is too stable to undergo fragmentation.16 The
mixed substrate 21b also afforded no cleavage, consistent with
reduction of the cyanophenyl ring to its radical anion, which also
refused to fragment. The final substrate from this series, 22,
behaved as substrates 10a, 18a, 19a, and 20, affording monoester
product 26 (64%). To check that the observed reactivity was due
to photoactivation of the donor 5, blank reactions were
performed on substrate 22. These were of two types: (i)
reaction in the absence of donor but with UV irradiation and (ii)
reaction with the donor present but without UV irradiation. In
both cases, no reaction was detected and the starting substrate
was reisolated in excellent yield [see the Supporting Information
(SI)].
metal had already been reported.14 Thus, cleavage of 10a
afforded phenylpropanoate product 13 arising from protonation
of enolate 12 upon workup. In turn, 12 had arisen by electron
transfer to the ester group and fragmentation of the ester ketyl 11
to afford 12 and alkoxyacyl radical 14.
Moving to our study with the organic electron donors, we
selected substrate 10a, and its reduction was performed in the
presence of donor 5 (6 equiv) in N,N-dimethylformamide
(DMF) solvent under UV irradiation at 365 nm (2 × 100 W) for
72 h (Scheme 3). This wavelength is near an absorption
maximum for 5 but is not absorbed by simple arenes like 10a.
The major product was monoester 23a (74%) resulting from
fragmentation of an arene radical anion (see 15 in Scheme 2),15
in contrast to the alkali-metal-induced reactivity. In addition,
starting substrate 10a (19%) was recovered. No product
resulting from C−C bond cleavage within the malonate unit
was detected. A notable point was that no toluene from the likely
intermediate, benzyl radical 16, was observed in this reaction. In
addition, no 1,2-diphenylethane, which might arise via coupling
of two benzyl radicals, was observed. This will be discussed
below, as will the origin of the product 23a from the diester
substrate.
Hence, C−C fragmentation was seen for all substrates except
nitriles 21a and 21b, but it is notable that no product derived
from a fragmenting benzyl group (e.g., toluene) was isolated
from any of the reactions. We recently showed that alkyl radicals
arising from electron transfer reactions of our organic donor 5 are
efficiently trapped by the donor radical cation,10h,n in a likely
example of the persistent radical effect.17 Therefore, the absence
of compounds derived from the benzyl fragment is consistent
To test the generality of this reaction, arenes 18a, 19a, and
20−22 were subjected to the reaction under the same conditions
as used for 10a. Trifluoromethylated substrate 18a showed
complete conversion, affording malonate monoester 24 (73%).
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with malonate anion and benzylic radical as products of the
reaction.
acceptor. To determine the nature of the donor−acceptor
complexes, density functional theory18 was employed to calculate
the electronic structures for donor 5, putative substrates 10b,
18b, and 19b, and the complexes of these substrates with donor
5. All of the structures were optimized with the gradient-
corrected B97-D functional with a long-range dispersion
correction.19 The long-range dispersion correction is particularly
important here for the donor−acceptor π-stacking interactions,
which are the dominant interactions between the donor and
acceptor. All atoms were described with the 6-311++G(d,p) basis
set.20,21 Subsequent single-point energy calculations of the
optimized geometries were performed at the same level of theory
within a polarizable continuum model (CPCM)22 with the
dielectric constant of DMF (ε = 37.219). All of the calculations
were performed using the Gaussian 09 suite of quantum-
chemistry programs.23 The optimized complexes between donor
5 and (i) 10b, (ii) 18b, and (iii) 19b show selective complexation
of the ground-state donor with the arene portion of the substrate,
with complexation energies of −14.2, −20.1, and −22.5 kcal/
mol, respectively; this acts as a platform for localizing the electron
transfer to the arene ring of the acceptor (see the SI).
Returning to laboratory experiments, the mixed-aryl example
29 required only 4 equiv of donor and gave completely selective
cleavage of the trifluoromethylbenzyl group, affording the tert-
butyl-substituted aryl product 37 in 63% yield; this was the
expected fragmentation product, since the LUMO of substrate
29 is located exclusively on the relatively electron-poor
trifluoromethylphenyl ring. Cinnamyl substrate 30 provided a
homologous cleavage reaction to give di-tert-butyl cinnamylmal-
onate (38) in 46% yield together with recovered substrate 30
(42%). Some simpler substrates were also examined. Malonates
31 and 32, which do not contain arene rings, were unreactive.
Substrate 33 was prepared in order to test whether a simple allyl-
substituted substrate could receive an electron from the donor.
However, no fragmentation was detected, and the substrate was
reisolated upon workup (91%). To test whether the electron-
withdrawing ability of a malonate unit was needed, or whether a
group that would provide less stabilization to the anionic product
of a fragmentation would suffice, monoester 34 and sulfone 35
were prepared. However, both of these showed no fragmentation
in the presence of photoactivated donor and led solely to
recovery of the unreacted substrates (92% and 89%,
respectively).
Questions arose about the conversion of one of the ester
groups to the carboxylic acid group seen in the isolated products
23a and 24−26; in particular, we were curious about whether this
arose as a mandatory part of the chemistry that led to the C−C
fragmentation or occurred as a later step. This question was
answered when substrate 10a was subjected to the reaction with
different workup conditions (Scheme 3). In the previous
reactions, workup had been effected by pouring the reaction
mixture into water with subsequent acidification and extraction
into organic solvent (which we call the “basic” workup). When
instead the crude reaction mixture was added directly to dilute
hydrochloric acid with subsequent extraction (called the “acidic”
workup), diester product 23b was isolated (75%). This showed
that the electron transfer chemistry forms the malonate diester in
high yield and that hydrolysis of one of the esters occurs very
rapidly when a “basic” workup is conducted. When di-tert-butyl
malonate derivatives 27−29 were subjected to the reaction
conditions (Scheme 4), diester products were isolated following
fragmentation, even when the basic workup conditions were
used. Substrate 27 afforded product 36 (61%), while substrates
28 and 29 gave 37 (71% and 63%, respectively).
All of these selective debenzylation reactions can arise as a
result of complexation of donor 5 with an arene ring in the
Scheme 4. Reduction of Second-Generation Substrates by
Organic Electron Donor 5
We next sought other cases where the regiochemistry of
known cleavage reactions would be overturned as a result of
perturbations brought about by association of the donor with
arene rings. Kang et al.24 had shown that treatment of
dibenzylcyanoacetate 39 with SmI2 in THF/HMPA leads cleanly
to decyanation product 40 in 87% yield (Scheme 5). In contrast,
upon treatment under our standard conditions followed by an
acidic workup, debenzylation to afford 41 (85%) was exclusively
seen, providing another clear example of perturbation of
reactivity brought about by organic donor 5. Interestingly,
whereas cyanobenzylmalonates did not lead to fragmentations,
cyanoacetate 42 underwent clean decyanobenzylation to afford
41 (75%). In this case, the added stability of the cyanoacetate
leaving group directs the fragmentation. The more complex
substrate 43, on the other hand, underwent competitive loss of
the two benzyl groups in forming 44−46. The isolation of the
dechlorinated product 44 was consistent with our recent studies
on chloroarenes.10k
In summary, while previous reductions of benzyl-substituted
malonate esters and cyanoacetates brought about by metal-based
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Zhou, S.-Z.; Thomson, D. W.; Schoenebeck, F.; Mohan, M.; Park, S. R.;
Tuttle, T.; Berlouis, L. E. A. Angew. Chem., Int. Ed. 2007, 46, 5178.
(c) Murphy, J. A.; Garnier, J.; Park, S. R.; Schoenebeck, F.; Zhou, S.-Z.;
Turner, A. T. Org. Lett. 2008, 10, 1227. (d) Garnier, J.; Murphy, J. A.;
Zhou, S. Z.; Turner, A. T. Synlett 2008, 2127. (e) Cutulic, S. P. Y.;
Murphy, J. A.; Farwaha, H.; Zhou, S. Z.; Chrystal, E. Synlett 2008, 2132.
(f) Murphy, J. A.; Schoenebeck, F.; Zhou, S.-Z.; Uenoyama, Y.; Miclo,
Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368. (g) Murphy, J. A.;
Schoenebeck, F.; Findlay, N. J.; Thomson, D. W.; Zhou, S. Z.; Garnier, J.
J. Am. Chem. Soc. 2009, 131, 6475. (h) Sword, R.; Baldwin, L. A.;
Murphy, J. A. Org. Biomol. Chem. 2011, 9, 3560. (i) Cutulic, S. P. Y.;
Findlay, N. J.; Zhou, S.-Z.; Chrystal, E. J. T.; Murphy, J. A. J. Org. Chem.
2009, 74, 8713. (j) Garnier, J.; Kennedy, A. R.; Berlouis, L. E. A.; Turner,
A. T.; Murphy, J. A. Beilstein J. Org. Chem. 2010, 6, No. 73. (k) Cahard,
E.; Schoenebeck, F.; Garnier, J.; Cutulic, S. P. Y.; Zhou, S.; Murphy, J. A.
Angew. Chem., Int. Ed. 2012, 51, 3673. (l) Jolly, P. I.; Zhou, S.; Thomson,
D. W.; Garnier, J.; Parkinson, J. A.; Tuttle, T.; Murphy, J. A. Chem. Sci.
2012, 3, 1675. (m) Garnier, J.; Thomson, D. W.; Zhou, S.; Jolly, P. I.;
Berlouis, L. E. A.; Murphy, J. A. Beilstein J. Org. Chem. 2012, 8, 994.
(n) Doni, E.; O’Sullivan, S.; Murphy, J. A. Angew. Chem., Int. Ed. 2013,
52, 2239.
(11) (a) Tanko, J. M.; Li, X.; Chahma, M.; Jackson, W. F.; Spencer, J.
N. J. Am. Chem. Soc. 2007, 129, 4181. (b) Newcomb, M.; Toy, P. H. Acc.
Chem. Res. 2000, 33, 449. For other cleavages of ArC−CAr bonds by
reductive electron transfer, see: (c) Maslak, P.; Vallombroso, T. M.;
Chapman, W. H., Jr.; Narvaez, J. N. Angew. Chem., Int. Ed. Engl. 1994, 33,
73. (d) Maslak, P.; Narvaez, J. N.; Vallombroso, T. M., Jr. J. Am. Chem.
Soc. 1995, 117, 12373.
(12) Xu, Q.; Cheng, B.; Ye, X.; Zhai, H. Org. Lett. 2009, 11, 4136.
(13) For a discussion of π-stacking interactions, see: Hunter, C. A.;
Sanders, J. M. K. J. Am. Chem. Soc. 1990, 112, 5525.
Scheme 5. Reduction of Cyanoacetates
reagents lead to loss of an ester or cyano group, photoexcited
organic electron donor 5 promotes benzyl−C bond cleavage.
This results from selective electron transfer to benzenes in the
presence of malonates and cyanoacetates, thereby overturning
established reactivity patterns. These first reductive examples of
this phenomenon raise questions about possible similar
observations more widely across chemistry. Our ongoing
investigations are exploring new possibilities afforded by these
discoveries.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, spectroscopic data, and computational
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(14) Krollpfeiffer, F.; Rosenberg, A. Ber. Dtsch. Chem. Ges. 1936, 69,
465.
(15) Attempted reductions of similar substrates using SmI2 in THF
were recently reported not to produce this cleavage.12
AUTHOR INFORMATION
■
(16) Asensio, X.; Gonzalez-Lafont, A.; Marquet, J.; Lluch, J. M. J. Org.
Chem. 2005, 70, 540.
(17) (a) Fischer, H. Chem. Rev. 2001, 101, 3581. (b) Studer, A. Chem.
Soc. Rev. 2004, 33, 267.
(18) (a) Kohn, W.; Sham, L. J. Phys. Rev. 1965, 140, 1133. (b) Parr, R.
G.; Yang, W. T. Density Functional Theory of Atoms and Molecules;
Oxford University Press: New York, 1989.
(19) S. Grimme, S. J. Comput. Chem. 2006, 27, 1787.
(20) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys.
1980, 72, 650.
Corresponding Author
tell.tuttle@strath.ac.uk, john.murphy@strath.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank ORSAS, EPSRC, and University of Strathclyde for
funding. Mass spectrometry data were acquired at the EPSRC
UK National Mass Spectrometry Facility at Swansea University.
(21) McLean, A. D.; Chandler, G. S. J. Chem. Phys. 1980, 72, 5639.
(22) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999.
(23) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P. ; Dannenberg, J. J.;
REFERENCES
■
(1) (a) Bodnar, B. S.; Vogt, P. F. J. Org. Chem. 2009, 74, 2598.
(b) Bouveault, L.; Blanc, G. C. R. Hebd. Seances Acad. Sci. 1903, 136,
1676.
(2) (a) Finley, K. T. Chem. Rev. 1964, 64, 5733. (b) Ruhlmann, K.
Synthesis 1971, 236.
̈
(3) (a) Sautier, B.; Procter, D. J. Chimia 2012, 66, 399. (b) Parmar, D.;
Price, K.; Spain, M.; Matsubara, H.; Bradley, P. A.; Procter, D. J. J. Am.
Chem. Soc. 2011, 133, 2418. (c) Szostak, M.; Collins, K. D.; Fazakerley,
N. J.; Spain, M.; Procter, D. M. Org. Biomol. Chem. 2012, 10, 5820.
(4) (a) Lam, K.; Marko, I. E. Tetrahedron 2009, 65, 10930. (b) Lam, K.;
Marko, I. E. Org. Lett. 2009, 11, 2752.
(5) (a) Organic Electrochemistry, 3rd ed.; Baizer, M. M., Lund, H., Eds.;
Marcel Dekker: New York, 1991. (b) Portella, C.; Deshayes, H.; Pete, J.
P.; Scholler, D. Tetrahedron 1984, 40, 3635.
(6) Mortensen, J.; Heinze, J. Angew. Chem., Int. Ed. Engl. 1984, 23, 84.
(7) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691.
(8) (a) Birch, A. J. Q. Rev. Chem. Soc. 1950, 4, 69. (b) Benkeser, R. A.;
Belmonte, F. G.; Kang, J. J. Org. Chem. 1983, 48, 2796.
̈
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, revision A.02; Gaussian, Inc.:
Wallingford, CT, 2009.
(24) Kang, H.-Y.; Hong, W. S.; Cho, Y. S.; Koh, H. Y. Tetrahedron Lett.
1995, 36, 7661.
(9) (a) Atherton, N. M.; Weissman, S. I. J. Am. Chem. Soc. 1961, 83,
1330. (b) Carbery, D. R.; Donohoe, T. J. Chem. Commun. 2004, 722.
(10) (a) Murphy, J. A.; Khan, T. A.; Zhou, S.-Z.; Thomson, D. W.;
Mahesh, M. Angew. Chem., Int. Ed. 2005, 44, 1356. (b) Murphy, J. A.;
10937
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