Protodecarboxylation of benzoic acids under radical conditions

Article abstract of DOI:10.1039/c2cc33306f

A new approach to protodecarboxylation is described that enhances the substrate scope for benzoic acids. The reaction uses oxidative radical conditions to decarboxylate a variety of acids in acetonitrile.

Full text of DOI:10.1039/c2cc33306f

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COMMUNICATION
Protodecarboxylation of benzoic acids under radical conditionsw
Sangwon Seo,a John B. Taylorb and Michael F. Greaney*a
Received 8th May 2012, Accepted 29th May 2012
DOI: 10.1039/c2cc33306f
A new approach to protodecarboxylation is described that
enhances the substrate scope for benzoic acids. The reaction
uses oxidative radical conditions to decarboxylate a variety of
acids in acetonitrile.
conversions to acetophenone. Raising the catalyst loading was
counterproductive (entry 3), but raising the amount of K2S2O8
was beneficial (entry 4). The reaction was effective for a variety
of silver salts, with acetate, sulfate, carbonate, oxide and
trifluoroacetate all being good (entries 1, 5, 6, 7 and 11). Silver
halides, triflate and nitrate were poor (entries 8, 9, 10 and 12).
Finally, we could reduce the reaction time to 1 h using
microwave heating with little loss in yield (entry 13).
The decarboxylation of benzoic acids using transition metal
catalysis has received considerable attention in recent years.1
Decarboxylative metallation is at the heart of numerous C–C,
C–X and C–H bond formations, all of which capitalise on the
versatility of carboxylic acids as readily available starting
materials. This latter transformation, protodecarboxylation,
is important in syntheses that use a carboxylate to direct
aromatic functionalisation,2 but do not require the acid group
in the final molecule.3 Moreover, the loss of CO2 is often the
key step in any decarboxylative coupling, and studying this
step in protodecarboxylation has been a productive avenue for
catalyst design and refinement.4–6
To investigate the scope of the reaction we examined a
variety of functionalised carboxylic acids (Table 2), and were
pleased to observe effective protodecarboxylation for a wide
substrate range. meta-Substituted benzoic acids were equally
effective as the para-substituted isomers, with good to excellent
yields being obtained for ketones, esters, nitro, trifluoromethyl,
fluoro and bromo substituents (2a–2g) in the m and p-positions.
The reactions were generally clean when monitored by LC–MS,
with unreacted starting material being the only other identifiable
component. p-Iodobenzoic acid (1l) was an exception, under-
going decomposition in the reaction and affording a rather low
conversion to iodobenzene.10 We were pleased to see that benzoic
Pioneering work from the groups of Goossen and Larrosa
established Ag-catalysed protodecarboxylation at 120 1C as
the current state of the art, having good substrate scope for
heteroaromatic acids, but requiring an ortho substituent for
benzoic acids.4 This requirement of an ortho-substituent,
frequently a heteroatom, for benzoic acid protodecarboxyla-
tion is a significant restriction.7 Our interest in decarboxylative
chemistry8 prompted us to address this issue, as we have
recently developed an intramolecular decarboxylative C–H
arylation that proceeds under oxidative radical conditions
(K2S2O8/Ag(I)).9 The reaction conditions we developed
enabled decarboxylation of substrates that were resistant to
conventional Pd/Cu or Ag co-catalysis. We were thus interested
in applying this radical approach to protodecarboxylation with
the aim of expanding the scope beyond ortho-substituted
benzoic acids.
Table 1 Optimisation dataa
Catalyst
Entry loading (mol %)
Ag(I)
catalyst
K2S2O8
(equiv.)
T/
1C
Yield 2ab
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
20
20
40
20
10
10
10
20
20
20
20
20
20
20
AgOAc
AgOAc
AgOAc
AgOAc
Ag2SO4
Ag2CO3
Ag2O
AgF
Ag(OTf)
AgI
3
3
3
5
5
5
5
5
5
5
5
5
5
5
100
120
100
100
100
100
100
100
100
100
100
100
130
100
71
69
45
84
81
67
68
32
We selected the para-substituted 4-acetylbenzoic acid (1a) as
a starting point and screened conditions using the combination
of Ag(I) salts and K2S2O8 in acetonitrile (Table 1). We were
pleased to find that the reaction was productive using AgOAc
(20 mol%) with excess K2S2O8 at 100 1C, providing good
o10
o10
75
Ag(TFA)
AgNO3
AgOAc
AgOAc
40
77
a School of Chemistry, University of Manchester, Oxford Rd,
Manchester M13 9PL, UK.
E-mail: michael.greaney@manchester.ac.uk
b Syngenta, Jealott’s Hill International Research Centre, Bracknell,
RG42 6EY, UK
w Electronic supplementary information (ESI) available: Data for new
compounds and experimental procedures. See DOI: 10.1039/
c2cc33306f
78d
a
Conditions: 1a (0.3 mmol), indicated amount of Ag(I) catalyst and
b
K2S2O8, MeCN (3.0 mL), 24 h. Yield determined by 1H NMR
c
analysis using nitromethane as an internal standard. Microwave
d
heating for 1 h. Isolated yield.
c
8270 Chem. Commun., 2012, 48, 8270–8272
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Table 2 Substrate scopea
Table 2 (continued )
Entry
Acid
Product
Yieldb (%)
Entry
Acid
Product
Yieldb (%)
18
2m
45d
58
1
2a
63
19
2
3
4
75
82
81
a
Reaction conditions: Benzoic acid 1 (0.3 mmol), AgOAc (0.06 mmol)
b
and K2S2O8 (1.5 mmol) in MeCN (3.0 mL) at 100 1C for 24 h. Isolated
yields. 40 mol% AgOAc (0.12 mmol) was used. Yield determined by
1H NMR analysis using nitromethane as an internal standard.
c
d
2c
acid itself, 1i, underwent protodecarboxylation to benzene
indicating that electron-withdrawing groups per se are not a
requirement for the reaction. The parent acid has been conspicuous
by its absence as a substrate in TM-catalysed decarboxylative
transformations. The ortho-nitro compound 1n, a classic
decarboxylation substrate, was likewise effectively transformed
into nitrobenzene 2d. m,p-Disubstituted benzoic acids were also
good substrates for the reaction (1o–1q).
5
6
7
8
9
54c
61c
68d
64d
57d
2d
Electron rich benzoic acids, by contrast, were less effective
substrates for protodecarboxylation. p-Methoxybenzoic acid
1r afforded only a low yield of anisole (34%, entry 17), with
the deconjugated m-methoxybenzoic acid 1s being slightly
better, producing anisole in 45% yield. The deactivating effect
of simple p-donors on loss of CO2 from ArCO2is known, with
p-MeOC6H4CO2 undergoing decarboxylation six times slower
than the parent benzoyloxy radical in CCl4.11 This deactivation
could be partially ameliorated with electron withdrawing groups,
with substrate 1t (entry 20) undergoing protodecarboxylation
to 2n in 58% yield.
2f
10
11
12
67d
40d
52d
The mechanism of oxidative decarboxylation with K2S2O8
and Ag(I) has been investigated by Koichi in seminal work on
the alkanoic acid series.12 Ag(I) is oxidised to Ag(II) in situ
which oxidises the carboxylate in turn to the radical 4. Loss of
CO2 would then afford the aryl radical 5. Applications to aroic
acids are rare,9 with the loss of CO2 from 4 being slower than
the alkyl case and requiring higher reaction temperatures.11,13
For the reaction at hand, however, we can effectively trap 5
through H-atom transfer from acetonitrile (Scheme 1).14
In conclusion, we have developed an oxidative radical
process for the protodecarboxylation of benzoic acids. The
reaction uses a cheap inorganic oxidant and catalytic amounts
of silver under simple reaction conditions. The substrate scope
is substantially expanded from existing methods for benzoic
13
14
2d
84
43
15
74d
16
17
75d
34d
Scheme 1 Proposed mechanism for protodecarboxylation.
Chem. Commun., 2012, 48, 8270–8272 8271
c
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acid decarboxylation, and applications of this chemistry are
underway in our group.
Pd-catalysis: J. S. Dickstein, C. A. Mulrooney, E. M. O’Brien,
B. J. Morgan and M. Kozlowski, Org. Lett., 2007, 9, 2441.
6 For protodecarboxylations using strong acid or stoichiometric metals,
see: (a) R. W. Hay and M. J. Taylor, Chem. Commun., 1966, 525;
(b) T. Cohen and R. A. Schambach, J. Am. Chem. Soc., 1970, 92, 3189;
(c) A. Cairncross, J. R. Roland, R. M. Henderson and W. A. Sheppard,
J. Am. Chem. Soc., 1970, 92, 3187; (d) J. Chodowska-Palicka and M.
Nilsson, Acta Chem. Scand., 1970, 24, 3353; (e) J. Chodowska-Palicka
and M. Nilsson, Acta Chem. Scand., 1971, 25, 3451; (f) T. Cohen, R. W.
Berninger and J. T. Wood, J. Org. Chem., 1978, 43, 837; (g) S. O. C.
Mundle and R. Kluger, J. Am. Chem. Soc., 2009, 131, 11674.
7 For a study on the activating role of ortho-substituents in proto-
decarboxylation, see: L. Xue, W. Su and Z. Lin, Dalton Trans.,
2011, 40, 11926.
8 (a) F. Zhang and M. F. Greaney, Org. Lett., 2010, 12, 4745; (b) F.
Zhang and M. F. Greaney, Angew. Chem., Int. Ed., 2010, 49, 2768.
9 S. Seo, M. Slater and M. F. Greaney, Org. Lett., 2012, 14, 2650.
10 Aryl iodides are known to undergo deiodination with peroxydi-
sulfate. See: J. F. Bunnett and C. C. Wamser, J. Am. Chem. Soc.,
1967, 89, 6712.
We thank Syngenta, the University of Manchester and the
EPSRC for funding (Leadership fellowship to M. F. G.).
Notes and references
1 Reviews: (a) W. I. Dzik, P. P. Lange and L. J. Goossen, Chem. Sci.,
2012, DOI: 10.1039/C2SC20312J, Advance article published 3 May
2012; (b) J. Cornella and I. Larrosa, Synthesis, 2012, 44, 1670;
(c) N. Rodriguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40, 5030.
2 (a) O. Daugulis, H.-Q. Do and D. Shabashov, Acc. Chem. Res.,
2009, 42, 1074; (b) X. Chen, K. M. Engle, D.-H. Wang and
J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094.
3 (a) J. Cornella, M. Righi and I. Larrosa, Angew. Chem., Int. Ed.,
2011, 50, 9429; (b) E. M. O’Brien, B. J. Morgan and
M. C. Kozlowski, Angew. Chem., Int. Ed., 2008, 47, 6877.
4 Ag catalysis: (a) L. J. Goossen, C. Linder, N. Rodriguez, P. P. Lange
and A. Fromm, Chem. Commun., 2009, 7173; (b) J. Cornella,
C. Sanchez, D. Banawa and I. Larrosa, Chem. Commun., 2009, 7176;
(c) P. Lu, C. Sanchez, J. Cornella and I. Larrosa, Org. Lett., 2009,
11, 5710; (d) L. J. Goossen, N. Rodriguez, C. Linder, P. P. Lange and
A. Fromm, ChemCatChem, 2010, 2, 430.
11 J. Chateauneuf, J. Lusztyk and K. U. Ingold, J. Am. Chem. Soc.,
1988, 110, 2886.
12 J. M. Anderson and J. K. Kochi, J. Am. Chem. Soc., 1970, 92, 1651.
13 (a) D. H. R. Barton, B. Lacher and S. Z. Zard, Tetrahedron, 1987,
43, 4321; (b) M. P. Bertrand, H. Oumar-Mahamat and J. M.
Surzur, Tetrahedron Lett., 1985, 26, 1209.
5 For Cu-catalysis at elevated temperatures, see: (a) L. J. Goossen,
F. Manjolinho, A. B. Khan and N. Rodriguez, J. Org. Chem.,
2009, 74, 2620; (b) L. J. Goossen, W. R. Thiel, N. Rodriguez,
C. Linder and B. Melzer, Adv. Synth. Catal., 2007, 349, 2246;
14 Conducting the reaction of 1a in d3-MeCN gave a ca. 40% yield of
the deuterated product d-2a.
c
8272 Chem. Commun., 2012, 48, 8270–8272
This journal is The Royal Society of Chemistry 2012