Smooth Photocatalyzed Benzylation of Electrophilic Olefins via Decarboxylation of Arylacetic Acids

Article abstract of DOI:10.1021/acs.joc.6b00984

Arylacetic acids were used as sources of benzyl radicals under tetrabutylammonium decatungstate photocatalyzed conditions for the benzylation of electron-poor olefins. The reaction proceeds smoothly in a mixed aqueous medium (MeCN/H₂O 2/1) in t

Full text of DOI:10.1021/acs.joc.6b00984

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Article
Smooth Photocatalyzed Benzylation of Electrophilic
Olefins via Decarboxylation of Arylacetic Acids
Luca Capaldo, Luca Buzzetti, Daniele Merli, Maurizio Fagnoni, and Davide Ravelli
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00984 • Publication Date (Web): 20 Jun 2016
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Smooth Photocatalyzed Benzylation of Electrophilic
Olefins via Decarboxylation of Arylacetic Acids
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Luca Capaldo, Luca Buzzetti, Daniele Merli, Maurizio Fagnoni, Davide Ravelli*
PhotoGreen Lab, Department of Chemistry, Viale Taramelli 12, 27100 Pavia, Italy
Table of Contents
Abstract: Arylacetic acids were used as source of benzyl radicals under tetrabutylammonium
decatungstate photocatalyzed conditions for the benzylation of electronꢀpoor olefins. The reaction
proceeds smoothly in a mixed aqueous medium (MeCN/H2O 2:1) in the presence of NaHCO3,
NaClO4 and an electron transfer agent (biphenyl). The reaction tolerates a wide variety of functional
groups on the aromatic ring (whether electronꢀdonating or electronꢀwithdrawing), and can be
extended to heteroaromatic analogues. The olefins have the double role of radical trap and electronꢀ
acceptor. The present approach can also be extended to arylpropionic acids (including the
nonsteroidal antiꢀinflammatory drugs ibuprofen and flurbiprofen), as well as mandelic acid
derivatives.
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Introduction
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Carboxylic acids are versatile organic compounds that have stimulated growing attention in recent
years. In particular, they have been adopted in decarboxylative couplings,1 exploiting the role of the
ꢀCOOH group as "traceless activating agent".2 Most of these reactions took place under thermal
conditions with the help of a metal catalyst (often based on silver).3 Decarboxylation is likewise a
smooth route for the generation of radicals. A recent approach involved the photocatalytic
monoelectronic oxidation of carboxylate anions followed by carbon dioxide loss from the thus
formed RCOO• intermediates.4 The photogenerated carbonꢀcentered radicals were then used in
several reactions, as summarized in Scheme 1.
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Scheme 1. Carboxylic Acids as Radical Precursors
O
N R'
.
-
O
O
O
.
H+
N R'
R +
N R'
OH
R
R
O
h
g
.
-
NC
NC
- CO2
NC
CN
CN
- CN-
.
- CO2
R +
h
f
CN
R-COO-
NC
CN
NC
CN
NC
R
EWG
PC*
.
-
PC
a
EWG
b
CO
-
2
COO
R-
R-F
R
N+ Cl
N+
PC = Photocatalyst
F
I
c
NiIILn
e
d
Me
R-R
[H]
Me
R
I
e'
R-H
LnNiIII
Me
R
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A typical case is the conjugate addition onto electronꢀpoor olefins (Scheme 1, path a)2,5 or allyl
sulfones6 forming a new CꢀC bond. Efficient fluorinating agents (e.g. Selectfluor) were likewise
used for CꢀF bond formation (path b).7 In rare instances, the stability of the radical allowed for a
dimerization process (path c),8 whereas the presence of a reducing agent (e.g. a thiol) led to an
overall removal of the carboxylic acid group (path d).9 Dual catalytic processes combining a
photocatalyst (PC) with a metal catalyst (e.g. based on Ni) involved trapping of the photogenerated
radical by the metal complex (path e) and products were then formed from the resulting adduct
(path e').10 A particular case is the photoinduced electron transfer between a carboxylate anion and
an organic compound, such as cyanobenzenes (path f)11,12 or phthalimides (path g)13 causing an
overall functionalization of the latter.
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One of the critical steps of these reactions is the decarboxylation of the RCOO• intermediate, that is
particularly efficient only when the resulting radical (R•) is stabilized. Accordingly, secondary or
tertiary alkyl radicals, along with αꢀamino (from the corresponding aminoacids) or αꢀoxy radicals,
were mainly used in synthetic processes. Benzyl radicals were generated from phenylacetic acids
and used as well, but not in the benzylation of olefins, due to the lack of reactivity of these radicals
towards C=C double bonds. A way to overcome the problem makes use of easily reducible
olefins.14ꢀ16 Scheme 2 shows our proposed plan to benzylate olefins starting from phenylacetic acids
1 (used as the corresponding carboxylate anions 1−). The photocatalytic generation of the benzyl
radical should be followed by regeneration of the photocatalyst via reaction with the olefin (2). In
•
such a way, the high reactivity of the resulting radical anion 2•ꢀ should be sufficient to trap ArCH2 ,
finally leading to the desired compound.
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Scheme 2. Proposed Route for the Benzylation of Electronꢀpoor Olefins
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Apart from photocatalytic applications, the use of arylacetic acids in photochemical processes has
been only sparsely reported.17 Under direct irradiation conditions, the photoelimination of CO2
often took place and triggered the desired process. Early studies demonstrated that the loss of CO2
is pHꢀdependent. In particular, the involvement of radical intermediates was postulated when
phenylacetic acids were irradiated, while the formation of benzyl anions was claimed when
irradiating the corresponding sodium salts.18,19 A recent application deals with materials science and
involved the irradiation of thioxanthone acetic acid ammonium salts that were used as efficient
photobase generators to trigger a polymerization.20 In another instance, the ꢀCOOH moiety was
used as electrofugal group in the route to α,nꢀdidehydrotoluenes (DHTs) starting from isomeric (nꢀ
chlorophenyl)acetic acids.21 Furthermore, the decarboxylation of arylacetic acids is of particular
interest in pharmacokinetic studies, since this process is the main responsible for the in vivo
photodecomposition of several nonsteroidal antiꢀinflammatory drugs (NSAIDs).17
As part of our ongoing interest in photocatalyzed CꢀC bond formation reactions, in this paper we
describe the use of tetrabutylammonium decatungstate (TBADT; (nBu4N)4[W10O32]) as a
convenient, cheap and robust photocatalyst for the benzylation of electronꢀpoor olefins via
decarboxylation of easily available arylacetic acids. In the last years, we found that TBADT is
particularly efficient in hydrogen atom transfer reactions22 and, to a minor extent, as photoredox
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catalyst.14 The excited state of TBADT rapidly decays into a reactive form (a relaxed excited state,
named wO, a virtually unknown species).23 Accordingly, the reduction potential of wO in the
excited state, E(wO/[W10O32]5ꢀ), can only be estimated ranging from + 2.26 to + 2.61 V vs SCE,14,24
thus making feasible the oxidation of carboxylates, whose oxidation potentials E(RꢀCOO•/RꢀCOO−)
fall in the + 1ꢀ1.6 V vs SCE range.7d,25,26
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Results and Discussion
To check the feasibility of the proposed plan reported in Scheme 2, we initially measured by cyclic
voltammetry the oxidation potentials of parent phenylacetic acid 1a and of the carboxylate anions
1aꢀq− (as the tetrabutylammonium salts; Table 1), as well as the reduction potentials of the electronꢀ
poor olefins 2aꢀe (Table 2) employed in this work. In the case of derivatives 1a and 1aꢀq−, typically
irreversible or quasi reversible redox behaviors were observed.27 For this reason, the data reported
in Table 1 refer to E1/2OX (halfꢀwave potential) values of the oxidation process, better appreciated by
plotting the cyclic voltammogram in the semiꢀdifferential mode. In the case of phenylacetic acid 1a
−
in acetonitrile (in the presence of nBu4N+ClO4 0.1 M as the supporting electrolyte), an oxidation
wave was registered at + 2.51 V vs SCE,28 partially superimposed with the anodic oxidation of the
solvent (see Figure S1 in Supporting Information for details). By contrast carboxylate anions 1aꢀq−,
obtained upon addition of a base (1 equiv. of a 1.0 N nBu4N+OH− in MeOH was used), showed
oxidation waves in the + 0.91 (for 1j−) to + 1.39 (for 1i−) V vs SCE range (Table 1; see also Figure
S1).
The electrochemical investigation on electronꢀpoor olefins 2 was performed in acetonitrile (in the
−
presence of nBu4N+ClO4 0.1 M as the supporting electrolyte) and showed a reversible redox
behavior. For this reason, the E1/2RED values could be approximated with the formal redox potentials
(E0'; Table 2), in accordance with a previous work by our group.14 The analysis revealed that the
reduction potentials for 2aꢀe range between ꢀ 1.09 (for 2b)14 and ꢀ 1.65 (for 2e)14 V vs SCE, with
the newly investigated derivative 2c showing a reduction potential at ꢀ 1.20 V vs SCE (Table 2).
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Table 1. Oxidation Potentials of Phenylacetic acid 1a and of Carboxylates (1aꢀq−) Studied in
the Present Work.
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E1/2OX (1•/1–)
[V vs SCE]
E1/2OX (1•/1–)
[V vs SCE]
Arylacetic Acid 1
Arylacetic Acid 1
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+ 2.51a
+ 1.27
+ 1.39
+ 0.91
1i−
1j−
1a
1a−
+ 0.99
+ 1.17
+ 0.97
+ 1.05
1k−
1l−
1b−
1c−
+ 1.07
+ 1.17
+ 1.07
+ 1.11
1m−
1d−
1e−
COO-
1n−
+ 1.11
+ 1.04
1f−
1o−
1p−
1q−
+ 1.25
+ 1.21
+ 1.16
+ 0.97
1g−
1h−
a E1/2OX (1•+/1) [V vs SCE] value has been reported.
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Table 2. Reduction Potentials of the Electronꢀpoor Olefins (2aꢀe) Studied in the Present Work.
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8
E0' (2/2•–)
[V vs SCE]
E0' (2/2•–)
[V vs SCE]
Electronꢀpoor Olefin 2
Electronꢀpoor Olefin 2
9
ꢀ 1.31a
ꢀ 1.09a
ꢀ 1.47a
ꢀ 1.65a
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2a
2d
O
N
Ph
O
2e
2b
ꢀ 1.20
2c
a Data taken from Ref. 14.
Initial experiments were carried out on the reaction between parent phenylacetic acid (1a) and
fumaronitrile (2a) to give benzylsuccinonitrile 3 (Table 3). When an equimolar (0.05 M) solution of
1a and 2a in acetonitrile in the presence of TBADT (4 mol%) was irradiated for 24h (λem centered
at 310 nm), the expected product was not detected by GC analysis (entry 1). When shifting to mixed
aqueous media, however, small amounts of 3 were formed (entries 2, 3). The role of additives was
next evaluated. Comparable results were obtained in the presence of sodium hydrogencarbonate
alone (1 equiv.; entry 4), or when it was coupled with sodium perchlorate (1 equiv.; entry 5), with
the yield never exceeding 20%, despite an almost quantitative consumption of 2a (> 90%). By
contrast, the addition of biphenyl had a tremendous effect and raised the formation of 3 up to 83%
(entries 6, 7). Other experiments (entries 8ꢀ10) demonstrated that the presence of all of the three
additives (NaHCO3, NaClO4 and biphenyl) was mandatory for the success of the reaction and that a
bivalent perchlorate (Mg(ClO4)2) was less beneficial than NaClO4 (entry 11). Interestingly, a good
yield (69% GC yield, entry 12) was likewise observed in the absence of biphenyl when increasing
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the amount of acid (up to 1.5 equiv.). Blank experiments demonstrated the crucial role of both
TBADT and light in the desired process (entries 13, 14).
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Table 3. Optimization of the Reaction Conditions.a
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Entry 1a (equiv.)
Reaction medium
MeCN
Additives
3 Yield (%)b
1
2
3
4
5
1.0
1.0
1.0
1.0
1.0
ꢀ
ꢀ
ꢀ
n.d.
MeCNꢀH2O 5/1
MeCNꢀH2O 2/1
MeCNꢀH2O 2/1
MeCNꢀH2O 2/1
trace
14
NaHCO3 (1.0 equiv.)
17
NaHCO3 (1.0 equiv.)
NaClO4 (1.0 equiv.)
20
6
1.0
MeCNꢀH2O 2/1
NaHCO3 (1.0 equiv.)
NaClO4 (1.0 equiv.)
Biphenyl (0.5 equiv.)
52
7
1.0
MeCNꢀH2O 2/1
NaHCO3 (1.0 equiv.)
NaClO4 (1.0 equiv.)
Biphenyl (1.0 equiv.)
83
8
9
1.0
1.0
MeCNꢀH2O 2/1
MeCNꢀH2O 2/1
NaHCO3 (1.0 equiv.)
Biphenyl (1.0 equiv.)
61
13
NaClO4 (1.0 equiv.)
Biphenyl (1.0 equiv.)
10
11
1.0
1.0
MeCNꢀH2O 2/1
MeCNꢀH2O 2/1
Biphenyl (1.0 equiv.)
23
53
NaHCO3 (1.0 equiv.)
Mg(ClO4)2 (1.0 equiv.)
Biphenyl (1.0 equiv.)
12
1.5
1.0
MeCNꢀH2O 2/1
MeCNꢀH2O 2/1
NaHCO3 (1.5 equiv.)
NaClO4 (1.0 equiv.)
69
8d
13c
NaHCO3 (1.0 equiv.)
NaClO4 (1.0 equiv.)
Biphenyl (1.0 equiv.)
14e
1.0
MeCNꢀH2O 2/1
NaHCO3 (1.0 equiv.)
NaClO4 (1.0 equiv.)
Biphenyl (1.0 equiv.)
n.d.f
a
Reaction conditions: 1a (0.15 mmol), 2a (0.15 mmol), (nBu4N)4[W10O32]
b
(TBADT, 4 mol%) in 3 mL of the chosen reaction medium.
Gas
Chromatography (GC) yields based on the amount of 3 vs an internal
standard, n-octanol; the consumption of 2a was always > 90%, except where
c
d
otherwise noted. No TBADT used. The formation of byꢀproducts has been
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observed by GC analysis. e In the absence of light. f No consumption (< 5%) of the
olefin was observed.
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Table 4. Benzylation of Electronꢀpoor Olefins via Decarboxylation of Arylacetic Acids.a
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R3 R2
TBADT (4 mol%),
h (310 nm), 24h
COOH
R3
R2
EWG
R1
EWG
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13
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+
MeCN/H2O 2:1
NaHCO3 (1 equiv.)
NaClO4 (1 equiv.)
Biphenyl (1 equiv.)
R1
2a-e
R
3-18
R
1a-l
O
CN
CN
CN
CN
N Ph
MeO
3, 80%
4, 72%
5, 81%
O
O
Ph
COOMe
COOMe
N Ph
MeO
MeO
NC
7, 99%
CN
MeO
8, 40%, 61%b (from 2d)
37%c (from 2e)
O
6, 60%
9, 54%
OMe
MeO
CN
CN
CN
CN
CN
Me
F
CN
11, 52%
10, 70%
13, 44%
CN
CN
CN
CN
CN
Ph
Cl
CN
12, 63%, 75%d
14, 56%
CN
CN
CN
Boc
N
H
F3C
CN
15, 44%
17, 71%
16, 79%
CN
CN
CN
CN
O
O
S
18, 52%
a
Reactions carried out on a 0.75 mmol scale (0.05 M); all data are the average of two
experiments. Isolated yields by silica gel chromatography (see Experimental Section). b
c
d
Conditions from Table 1, entry 8. Yield based on 75% consumption of 2e. Reaction
carried out in the absence of biphenyl.
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Having the optimized conditions in hand (entry 7, Table 3), we next evaluated the scope of the
reaction (Table 4), by investigating different combinations of arylacetic acids 1 (see Table 1) and
electronꢀpoor olefins 2 (see Table 2). The reaction of phenylacetic acid 1a with fumaronitrile 2a and
Nꢀphenyl maleimide 2b gave products 3 and 4 in 80% and 72% isolated yield, respectively. The
reaction was next extended to 4ꢀmethoxyphenylacetic acid 1b, that gave products 5ꢀ7 in good to
excellent yields in the reaction with 2a, 2b and benzylidenemalononitrile 2c. By contrast, the
reaction of 1b with dimethyl fumarate 2d gave only a modest yield (40%) of adduct 8, that was
increased (61% yield) when using an excess of 1b (1.5 equiv., biphenyl omitted). When repeating
the synthesis of 8 by using isomeric dimethyl maleate 2e as the radical trap, the process was
sluggish giving the desired product in 37% yield (with only 75% consumption of 2e). The reactions
of 3ꢀmethoxy (1c) and 2ꢀmethoxy (1d) phenylacetic acids likewise gave adducts 9 and 10 in 54 and
70% yield, respectively, in the reaction with 2a. Aliphatic (in 4ꢀmethylphenylacetic acid 1e) or
aromatic (in 4ꢀbiphenylacetic acid 1f) groups in the paraꢀ position were tolerated and the expected
adducts with fumaronitrile were obtained in 52% and 63% yields, respectively (compounds 11, 12).
In the latter case, product 12 was likewise formed in a good yield (75%) in the absence of biphenyl.
Electronꢀwithdrawing substituted 4ꢀchloro (1g), 4ꢀfluoro (1h) and 4ꢀtrifluoromethyl (1i)
phenylacetic acids underwent addition onto fumaronitrile to give compounds 13ꢀ15 in decent yields
(45ꢀ55% range). 4ꢀAminophenylacetic acid was likewise tested, but was not soluble under the
optimized reaction conditions. Protection of the amino group as carbamate in 4ꢀ(tertꢀ
butoxycarbonylamino)phenylacetic acid 1j restored the usual reactivity to give adduct 16 in good
yield (79%) upon reaction with 2a. The reaction could be extended to substrates bearing two
substituents on the aromatic ring, as well as to heteroaryl substituted acetic acids, as demonstrated
by (3,4ꢀmethylenedioxy)phenylacetic acid 1k and 2ꢀthiopheneacetic acid 1l, that reacted with 2a to
give, respectively, compounds 17 and 18.
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Next, we shifted our attention to 2ꢀarylpropionic acids, as reported in Scheme 3a. In particular,
parent 2ꢀphenylpropionic acid 1m gave adduct 19 in 80% yield as a 1:1 diastereomeric mixture.
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Furthermore, since several NSAIDs pertain to this family, we subjected two very wellꢀknown drugs
to our reaction conditions. Indeed, both ibuprofen (1n) and flurbiprofen (1o) gave the expected
adducts 20 and 21 in 57% and 88% isolated yield (as 1:1 diastereomeric mixtures), respectively.
Finally, we tested the effect of oxygenꢀbased substituents in the benzylic position (Scheme 3b).
Thus, when using mandelic acid 1p, benzaldehyde was detected (by GC analysis) as the exclusive
product at the expense of the expected adduct 22. However, when employing αꢀ
methoxyphenylacetic acid 1q, the usual reactivity was restored, allowing to isolate product 23 in
78% yield as a 1:1 diastereomeric mixture in the reaction with 2a.
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Scheme 3. Reactivity of: a) 2ꢀPhenylpropionic Acids and b) Mandelic Acid Derivatives
The present work compares favorably with other decarboxylative photocatalytic strategies
employing arylacetic acids and is complementary to them, since this is one of the rare examples of
electronꢀpoor olefins benzylation.14ꢀ16 The proposed reaction mechanism is gathered in Scheme 4
and is strengthened by the electrochemical investigation reported above. Given the unknown
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reduction potential of wO (up to + 2.61 V vs SCE),14,24 the occurrence of an electron transfer from
1a (E1/2OX (1a•+/1a) = + 2.51 V vs SCE, Table 1) to wO cannot be excluded. The efficiency of this
process, however, is expected to be very low, as also confirmed by the reaction carried out in neat
acetonitrile, where no product 3 has been detected in the reaction with 2a (Table 3, entry 1). By
contrast, when in the anionic form the ꢀCOO− group functions as an electroauxiliary moiety,29 since
it lowers the oxidation potential of the substrate with respect to the corresponding unsubstituted
derivative and also drives the selectivity. Thus, the reaction takes place significantly only on the
carboxylate anions 1− (much better electron donors than the protonated forms 1; see Scheme 4, path
a). It is interesting to note that the reaction medium did not affect the stability of the decatungstate
anion, while this does not tolerate strongly basic conditions.30 Thus, excitation of the [W10O32]4ꢀ
cluster populates the highly oxidizing wO state (see above),14,24 capable to accept an electron from
the carboxylate anion 1− (path b; dashed arrow).
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Scheme 4. Proposed Reaction Mechanism. Selected Redox Potentials (V vs SCE) of the
Species Involved are Reported in Blue Color
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R'
4
5
6
7
Ar
COOH
~+2.5
1
bet
a
b'
- H+
R'
R'
8
.
9
Ar
COO
.
Ar
COO-
.
1-
1
1
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+0.91~+1.39
d
or
BP
+1.95
b
e
CO2
.
wO
+2.26~+2.61
+
BP
c
R'
[W10O32]5-
-0.9~-1.4
.
CH
[W10O32]4-
*
Ar
H2O
hv
.
-
2
g
f
[W10O32]4-
R3
R2
EWG
R1
R'
EWG
R1
Ar
2
R2
R3
-1.09~-1.47
However, this step is not efficient per se, as supported by the low yields observed in entries 2ꢀ5,
Table 3. Two main reasons may explain this behavior. Given that both 1− and wO are negatively
charged, an electrostatic repulsion may hamper path b. Otherwise, a back electron transfer (bet, path
b') may be involved, preventing the otherwise fast decarboxylation (reported to be in the order of
1010 sꢀ1)31 of the thus formed ArCH2ꢀCOO• radical (1•).
The key point to the success of the present reaction is the use of biphenyl (BP).32,33 Thus, BP
(E(BP•+/BP) = + 1.95 V vs SCE)34 can be oxidized (in competition with 1−) to the corresponding
longꢀlived radical cation BP•+ (path c). BP•+ is then capable of oxidizing 1− to 1• (path d), that in
turn loses CO2 to give the corresponding benzyl radical (path e). BP has the role of electron transfer
agent35 and it is able to overcome the electrostatic repulsion between 1− and wO and to separate 1•
from [W10O32]5ꢀ, preventing bet and leading to a productive oxidation of 1− (in turn triggering
decarboxylation). The actual concentration of BP (1 equiv., Table 3) must be high enough to
prevent any competitive (yet, unproductive) direct oxidation of 1−. The presence of NaClO4 is
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likewise important in favoring the electron transfer process.14,36 Another important point is related
to the trapping of ArR'CH•. Benzyl radicals are rather stable species, quite difficult to trap and with
a marked tendency to dimerize.8 As previously demonstrated by our group, this limitation can be
overcome by having recourse to easily reducible olefins (see above).14 Indeed, the olefins have a
role in the regeneration of the photocatalyst (path f) by the concomitant conversion into the
corresponding radical anions (2•ꢀ). The reduction potential of the deactivated photocatalyst has been
estimated to lie in the ꢀ 0.9 to ꢀ 1.4 V vs SCE range. This is due to the possible involvement of the
highly reducing [W10O32]6ꢀ species, in turn obtained via disproportionation of the monoꢀreduced
form [W10O32]5ꢀ.14 As a result, the CꢀC bond forming step occurs via a radicalꢀradical anion
coupling (path g), leading to the desired product upon addition of a proton (from the aqueous
solvent). This behavior has been confirmed in the present system, where the least two reducible
olefins used, viz. isomeric dimethyl fumarate 2d and dimethyl maleate 2e, both gave product 8 in a
modest yield, with an efficiency proportional to their reduction potentials (the more negative the
reduction potential, the worse the efficiency).14 An excess of the acid (1b−), however, ameliorated
the performance of the reaction with 2d (61% yield, even in the absence of biphenyl), highlighting
that the limitations related to path b (see above) can be overcome by increasing the absolute
concentration of the electron donor.
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As for the employed acids, despite their oxidation potentials span over a quite large range (ca. 0.5
V, from + 0.91 for 1j− to + 1.39 for 1i− V vs SCE; Table 1), the reaction proceeds satisfactorily,
demonstrating the potential of TBADT as photoredox catalyst. The presence of a biphenyl moiety
in compound 1f allowed the reaction to proceed even in the absence of the electron transfer agent.
Another interesting case is the selective activation of the ꢀCOOH group in (3,4ꢀ
methylenedioxy)phenylacetic acid 1k, despite the presence of the two methylene hydrogen atoms,
likewise prone to be activated under TBADT photocatalyzed conditions.30 Phenylpropionic acids
behave quite similarly to the corresponding C2ꢀhomologues despite the stability imparted by the
methyl group to the resulting benzyl radical. Different is the case of mandelic acid derivatives,
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where the presence of the benzylic ꢀOH group in 1p completely diverted the reactivity, leading to a
formal decarboxylation/oxidation rather than the desired CꢀC bond formation, as previously
observed.9b,37 However, when using substrate 1q bearing a αꢀmethoxy substituent, the usual
reactivity was restored.
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Conclusions
The present work demonstrates that CꢀC bond forming reactions starting from arylacetic acids and
easily reducible olefins are feasible. The success of the protocol is based on the use of TBADT as
photoredox catalyst and the ꢀCOOH moiety in the role of electroauxiliary group. The reaction
requires a fine tuning of the conditions and a mixed aqueous solvent is mandatory to solubilize all
the compounds present in solution. Interestingly, biphenyl, acting as an electron transfer agent, has
a fundamental role in improving the performance of the reaction. Further work is currently ongoing
in our lab to extend the present methodology to other classes of carboxylic acids.
EXPERIMENTAL SECTION
General
Compounds 1 and 2 were commercially available and used as received, except for 4ꢀ(tertꢀ
butoxycarbonylamino)phenylacetic acid (1j)38 and benzylidenemalononitrile (2c)39 that were
synthesized according to published procedures. The photocatalyst TBADT has been prepared
according to a published procedure.40 Acetonitrile and water (HPLC purity grade) used as solvents
were commercially available and used as received. NMR spectra were recorded on a 300 MHz
spectrometer; the attributions were made on the basis of H and 13C NMR, as well as DEPT
1
experiments, and chemical shifts reported in ppm downfield from TMS. Reactions were monitored
by gas chromatographic (GC) analyses (HPꢀ5 capillary column) using nꢀoctanol as an internal
standard.
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The electrochemical measurements were carried out by a computerꢀcontrolled electrochemical
analyzer. Electrochemical measurements (cyclic voltammetry) were performed in a threeꢀelectrode
cell (volume 10 mL; acetonitrile as solvent, nBu4N+ClO4 0.1 M as the supporting electrolyte, 2 mM
ꢀ
9
concentration of the tested compound)26 at glassy carbon (diameter: 3 mm) as the working
electrode, Pt wire as the auxiliary electrode, and Ag/AgCl (3 M NaCl) as the reference electrode.
Scan speed was 100 mV·sꢀ1. The potential ranges investigated for oxidations were: 0/+3.0 V and
0/+2.0 V vs Ag/AgCl (3 M NaCl) for 1a and 1aꢀq–, respectively. By contrast, for reduction
processes the 0/ꢀ2.0V vs Ag/AgCl (3 M NaCl) range has been explored. The potentials measured
were then referred to SCE by applying the equation:
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E (vs SCE) = E (vs Ag/AgCl; 3 M NaCl) ꢀ 35 mV
General Procedure for the TBADTꢀphotocatalyzed Decarboxylative Benzylation of Electronꢀ
poor Olefins. An acetonitrile/water 2:1 solution (15 mL) of the acid 1 (0.75 mmol, 0.05 M, 1
equiv.) and the olefin 2 (1 equiv.), in the presence of TBADT (2×10ꢀ3 M, 4 mol%), NaHCO3 (1
equiv.), NaClO4 (1 equiv.) and biphenyl (1 equiv.), was poured in a quartz tube and purged for 3
minutes with nitrogen, septum capped and irradiated for 24h in a multiꢀlamp apparatus fitted with
10×15W phosphorꢀcoated lamps (emission centered at 310 nm). The solvent was removed under
reduced pressure from the photolyzed solution and the product isolated by purification of the
residue by column chromatography (hexane/ethyl acetate as eluants).
2ꢀBenzylsuccinonitrile (3). Colorless oil (102 mg, 80% yield). Purification: silica gel
chromatography (hexane/ethyl acetate 8:2). Spectroscopic data of 3 were in accordance with the
literature.41 Anal. Calcd. for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C: 77.7; H 5.8; N, 16.2.
3ꢀBenzylꢀ1ꢀphenylpyrrolidineꢀ2,5ꢀdione (4). White solid (143 mg, 72% yield). Purification: silica
gel chromatography (hexane/ethyl acetate 8:2). M.p. 123ꢀ125 °C (Lit.14 128ꢀ130 °C). Spectroscopic
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data of 4 were in accordance with the literature.14 Anal. Calcd. for C17H15NO2: C, 76.96; H, 5.70; N,
4
5
6
5.28. Found: C, 76.8; H, 5.9; N, 5.2.
7
8
9
2ꢀ(4ꢀMethoxybenzyl)succinonitrile (5). Colorless oil (122 mg; 81% yield). Purification: silica gel
chromatography (hexane/ethyl acetate 8:2). Spectroscopic data of 5 were in accordance with the
literature.14 Anal. Calcd. for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 72.0; H, 6.2; N,
13.9.
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3ꢀ(4ꢀMethoxybenzyl)ꢀ1ꢀphenylpyrrolidineꢀ2,5ꢀdione (6). Offꢀwhite solid (133 mg, 60% yield).
1
Purification: silica gel chromatography (hexane/ethyl acetate 8:2). M.p. 128ꢀ130 °C. H NMR
(CDCl3, 300 MHz) δ 7.49ꢀ7.35 (m, 3H), 7.19ꢀ7.12 (m, 4H), 6.86 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H)
13
3.33ꢀ3.24 (m, 1H), 3.19ꢀ3.03 (m, 2H), 2.88 (dd, J = 18, 9 Hz, 1H), 2.64 (dd, J = 18, 5 Hz, 1H). C
NMR (CDCl3, 75 MHz) δ 178.5, 175.5, 159.0, 132.0, 130.4, 129.3, 128.8, 128.7, 126.6, 114.4,
55.4, 41.6, 35.8, 33.4. Anal. Calcd. for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.2; H,
5.9; N, 4.6.
2ꢀ(2ꢀ(4ꢀMethoxyphenyl)ꢀ1ꢀphenylethyl)malononitrile (7). Colorless oil (205 mg; 99% yield).
1
Purification: silica gel chromatography (hexane/ethyl acetate 8:2). H NMR (CDCl3, 300 MHz) δ
7.48ꢀ7.33 (m, 5H), 7.09 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 3.86 (d, J = 5.1 Hz, 1H), 3.79
(s, 3H), 3.44ꢀ3.38 (m, 1H), 3.21 (d, J = 8 Hz, 2H). 13C NMR (CDCl3, 75 MHz) δ 159.1, 136.6,
130.1, 129.3, 129.2, 128.6, 128.2, 114.7, 112.3, 111.6, 55.4, 48.7, 37.8, 28.5. Anal. Calcd. for
C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.2; H, 5.9; N, 10.0.
Dimethyl 2ꢀ(4ꢀmethoxybenzyl)succinate (8). Colorless oil (80 mg; 40% yield). Purification: silica
gel chromatography (hexane/ethyl acetate 8:2). Spectroscopic data of 8 were in accordance with the
literature.41 Anal. Calcd. for C14H18O5: C, 63.15; H, 6.81. Found: C, 63.2; H, 6.7.
2ꢀ(3ꢀMethoxybenzyl)succinonitrile (9). Colorless oil (81 mg; 54% yield). Purification: silica gel
chromatography (hexane/ethyl acetate 8:2). Spectroscopic data of 9 were in accordance with the
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literature.14 Anal. Calcd. for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.8; H, 6.1; N,
13.9.
6
7
8
2ꢀ(2ꢀMethoxybenzyl)succinonitrile (10). Colorless oil (105 mg; 70% yield). Purification: silica gel
9
1
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chromatography (hexane/ethyl acetate 8:2). H NMR (CDCl3, 300 MHz) δ 7.31 (td, J = 8, 2 Hz,
1H), 7.21 (dd, J = 7, 1 Hz, 1H), 6.95 (td, J = 7, 1 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.85 (s, 3H),
3.41ꢀ3.23 (m, 1H), 3.16ꢀ3.00 (m, 2H), 2.71ꢀ2.54 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ 157.4,
131.3, 129.6, 123.1, 121.0, 119.1, 115.9, 110.7, 55.4, 32.9, 28.3, 20.4. Anal. Calcd. for C12H12N2O:
C, 71.98; H, 6.04; N, 13.99. Found: C, 71.9; H, 6.2; N, 13.8.
2ꢀ(4ꢀMethylbenzyl)succinonitrile (11). Colorless oil (72 mg; 52% yield). Purification: silica gel
chromatography (hexane/ethyl acetate 9:1). Spectroscopic data of 11 were in accordance with the
literature.42 Anal. Calcd. for C12H12N2: C, 78.23; H, 6.57; N, 15.21. Found: C, 78.2; H, 6.7; N, 15.1.
2ꢀ([1,1'ꢀBiphenyl]ꢀ4ꢀylmethyl)succinonitrile (12). White solid (116 mg, 63% yield). Purification:
1
silica gel chromatography (hexane/ethyl acetate 8:2). M.p.: 117ꢀ119 °C. H NMR (CDCl3, 300
MHz) δ 7.62ꢀ7.57 (m, 4H), 7.48ꢀ7.43 (m, 2H), 7.40ꢀ7.33 (m, 3H), 3.26ꢀ3.08 (m, 3H), 2.70 (d, J = 6
Hz, 2H). 13C NMR (CDCl3, 75 MHz) δ 141.3, 140.4, 133.4, 129.7, 129.0, 128.1, 127.8, 127.2,
118.6, 115.6, 36.8, 30.2, 20.3. Anal. Calcd. for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C,
82.8; H, 5.9; N, 11.3.
2ꢀ(4ꢀChlorobenzyl)succinonitrile (13). White solid (68 mg, 44% yield). Purification: silica gel
chromatography (hexane/ethyl acetate 8:2). M.p.: 79ꢀ82 °C (Lit.43 80ꢀ82 °C). The spectroscopic
data of 13 were in accordance with the literature.14 Anal. Calcd. for C11H9ClN2: C, 64.56; H, 4.43;
N, 13.69. Found: C, 64.4; H, 4.5; N, 13.6.
2ꢀ(4ꢀFluorobenzyl)succinonitrile (14). Colorless oil, that solidified upon standing (79 mg, 56%
yield). Purification: silica gel chromatography (hexane/ethyl acetate 8:2). M.p.: 82ꢀ85 °C (Lit.43 84ꢀ
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86 °C). Spectroscopic data of 14 were in accordance with the literature.43 Anal. Calcd. for
4
5
6
C11H9FN2: C, 70.20; H, 4.82; N, 14.88. Found: C, 70.1; H, 4.9; N, 14.8.
7
8
9
2ꢀ(4ꢀ(Trifluoromethyl)benzyl)succinonitrile (15). Colorless oil (79 mg, 44% yield). Purification:
silica gel chromatography (hexane/ethyl acetate 8:2). 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.1
Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 3.28ꢀ3.08 (m, 3H), 2.70 (d, J = 5.9 Hz, 2H). 13C NMR (75 MHz,
CDCl3) δ 138.6 (s), 130.5 (q, J = 33 Hz), 129.7 (s), 126.2 (q, J = 4 Hz), 123.7 (q, J = 272 Hz), 118.5
(s), 115.5 (s), 36.8 (s), 30.0 (s), 20.4 (s). Anal. Calcd. for C12H9F3N2: C, 60.51; H, 3.81; N, 11.76.
Found: C, 60.4; H, 3.9; N, 11.8.
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tertꢀButyl (4ꢀ(2,3ꢀdicyanopropyl)phenyl)carbamate (16). White solid (169 mg, 79% yield).
Purification: silica gel chromatography (hexane/ethyl acetate 8:2). M.p.: 146ꢀ148 °C. 1H NMR (300
MHz, CDCl3) δ 7.38 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 6.49 (s, 1H), 3.24ꢀ2.88 (m, 3H),
2.63 (d, J = 5.9 Hz, 2H), 1.52 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 152.8, 138.5, 129.9, 128.8,
119.2, 119.1, 118.6, 115.6, 36.5, 30.3, 28.5, 20.1. Anal. Calcd. for C16H19N3O2: C, 67.35; H, 6.71;
N, 14.73. Found: C, 67.2; H, 6.9; N, 14.6.
2ꢀ(1,3ꢀBenzodioxolꢀ5ꢀylmethyl)succinonitrile (17). Colorless oil (114 mg; 71% yield). Purification:
silica gel chromatography (hexane/ethyl acetate 8:2). 1H NMR (CDCl3, 300 MHz) δ 6.79 (d, J = 8.0
Hz, 1H), 6.76ꢀ6.69 (m, 2H), 5.97 (s, 2H), 3.18ꢀ2.91 (m, 3H), 2.65 (d, J = 6.3 Hz, 2H). 13C NMR
(CDCl3, 75 MHz) δ 148.3, 147.6, 128.0, 122.6, 118.7, 115.7, 109.3, 108.9, 101.4, 36.8, 30.3, 20.1.
Anal. Calcd. for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.2; H, 4.9; N, 13.0.
2ꢀ(Thiophenꢀ2ꢀylmethyl)succinonitrile (18). Slightly yellow oil (69 mg; 52% yield). Purification:
silica gel chromatography (hexane/ethyl acetate 8:2). 1H NMR (CDCl3, 300 MHz) δ 7.29 (dd, J = 5,
2 Hz, 1H), 7.12ꢀ6.97 (m, 2H), 3.43ꢀ3.13 (m, 3H), 2.75ꢀ2.67 (m, 2H). 13C NMR (CDCl3, 75 MHz) δ
135.9, 127.8, 127.6, 125.9, 118.4, 115.5, 31.3, 30.4, 20.0. Anal. Calcd. for C9H8N2S: C, 61.34; H,
4.58; N, 15.90. Found: C, 61.4; H, 4.7; N, 15.8.
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2ꢀ(1ꢀPhenylethyl)succinonitrile (19). Colorless oil (111 mg; 80% yield; 1:1 mixture of
diastereoisomers). Purification: silica gel chromatography (hexane/ethyl acetate 9:1). Spectroscopic
data of 19 were in accordance with the literature.14 Anal. Calcd. for C12H12N2: C, 78.23; H, 6.57; N,
15.21. Found: C, 78.1; H, 6.6; N, 15.2
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2ꢀ(1ꢀ(4ꢀIsobutylphenyl)ethyl)succinonitrile (20). Colorless oil (103 mg; 57% yield; 1:1 mixture of
diastereoisomers). Purification: silica gel chromatography (hexane/ethyl acetate 9:1). 1H NMR (300
MHz, CDCl3) δ 7.28ꢀ7.12 (m, 8H), 3.22ꢀ2.95 (m, 4H), 2.65ꢀ2.37 (m, 8H), 1.93ꢀ1.82 (m, 2H), 1.57
(d, J = 7 Hz, 3H), 1.56 (d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 6H), 0.92 (d, J = 7 Hz, 6H). 13C NMR
(75 MHz, CDCl3) δ 142.1, 142.0, 137.5, 136.0, 130.2, 129.9, 127.6, 126.8, 118.5, 117.9, 116.0,
115.7, 45.1, 45.1, 41.1, 39.7, 36.1, 35.8, 30.3, 22.5, 22.5, 20.1, 19.7, 19.5, 19.2. Anal. Calcd. for
C16H20N2: C, 79.96; H, 8.39; N, 11.66. Found: C, 79.9; H, 8.5; N, 11.5.
2ꢀ(1ꢀ(2ꢀFluoroꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀyl)ethyl)succinonitrile (21). White thick paste (184 mg; 88%
yield; 1:1 mixture of diastereoisomers). Purification: silica gel chromatography (hexane/ethyl
1
acetate 8:2). H NMR (300 MHz, CDCl3) δ 7.56ꢀ6.99 (m, 16H), 3.35ꢀ3.10 (m, 2H), 3.09ꢀ2.92 (m,
2H), 2.73ꢀ2.63 (m, 2H), 2.55ꢀ2.44 (m, 2H), 1.59 (d, J = 7 Hz, 3H), 1.58 (d, J = 7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 159.9 (d, J = 248 Hz), 159.8 (d, J = 248 Hz), 141.4 (d, J = 7 Hz), 140.0 (d, J =
7 Hz), 135.1 (d, J = 8 Hz), 135.1 (d, J = 8 Hz), 131.9 (d, J = 4 Hz), 131.6 (d, J = 4 Hz), 129.3 (d, J
= 14 Hz), 129.2 (d, J = 14 Hz), 129.1, 129.0, 128.7, 128.7, 128.6, 128.2, 128.1, 127.5, 124.0 (d, J =
3 Hz), 123.3 (d, J = 3 Hz), 118.0, 117.6, 115.7, 115.6 (d, J = 23 Hz), 115.4, 114.8 (d, J = 23 Hz),
40.8, 39.7, 35.9, 35.6, 20.2, 19.6, 19.3. Anal. Calcd. for C18H15FN2: C, 77.68; H, 5.43; N, 10.07.
Found: C, 77.6; H, 5.5; N, 10.0.
2ꢀ(Methoxy(phenyl)methyl)succinonitrile (23). Colorless oil (117 mg; 78% yield; 1:1 mixture of
diastereoisomers). Purification: silica gel chromatography (hexane/ethyl acetate 8:2). 1H NMR (300
MHz, CDCl3) δ 7.53ꢀ7.34 (m, 10H), 4.49ꢀ4.43 (m, 2H), 3.35 (s, 3H), 3.31 (s, 3H), 3.26ꢀ3.11 (m,
2H), 2.97ꢀ2.60 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 135.8, 135.8, 129.7, 129.6, 129.2, 129.2,
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127.1, 126.9, 117.0, 116.9, 115.9, 115.8, 81.0, 80.8, 57.5, 57.4, 36.7, 36.3, 18.4, 17.8. Anal. Calcd.
for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.8; H, 6.1; N, 13.9.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website. Copies of
1H NMR and 13C NMR of all compounds; details on the electrochemical investigation and on the
optimization of reaction conditions (PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: davide.ravelli@unipv.it
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
D.R. thanks MIUR for financial support (SIR Project "Organic Synthesis via Visible Light
Photocatalytic Hydrogen Transfer"; Code: RBSI145Y9R). Thanks are due to Mr. Marco Catalano
(University of Pavia) for preliminary experiments and fruitful discussions.
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