Metal-free synthesis of aryl esters from carboxylic acids and diaryliodonium salts

Article abstract of DOI:10.1021/ol2012082

An efficient arylation of carboxylic acids with diaryliodonium salts has been developed, giving aryl esters in high yields within short reaction times for both aromatic and aliphatic substrates. The transition-metal-free conditions are compatible with a range of functional groups, and good chemoselectivity is observed with unsymmetric diaryliodonium salts. Furthermore, steric hindrance in the ortho positions is well tolerated both in the carboxylic acid and in the diaryliodonium salt, yielding aryl esters that cannot be obtained via other esterification protocols.

Full text of DOI:10.1021/ol2012082

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3462–3465
Metal-Free Synthesis of Aryl Esters from
Carboxylic Acids and Diaryliodonium Salts
Tue B. Petersen, Rehan Khan, and Berit Olofsson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
berit@organ.su.se
Received May 6, 2011
ABSTRACT
An efficient arylation of carboxylic acids with diaryliodonium salts has been developed, giving aryl esters in high yields within short reaction times
for both aromatic and aliphatic substrates. The transition-metal-free conditions are compatible with a range of functional groups, and good
chemoselectivity is observed with unsymmetric diaryliodonium salts. Furthermore, steric hindrance in the ortho positions is well tolerated both in
the carboxylic acid and in the diaryliodonium salt, yielding aryl esters that cannot be obtained via other esterification protocols.
Aryl esters are prevalent subunits in pharmaceuticals,
agrochemicals, and polymers, as well as in naturally
occurring compounds and building blocks for organic
Scheme 1. Synthesis of Aryl Esters from Carboxylic Acids
synthesis. Despite the plethora of synthetic methods avail-
able toward this compound class, sterically congested aryl
esters remain difficult to obtain.1
Efficient esterification of carboxylic acids with phenols
requires activation of the substrate(s) and removal of 1
equiv of water.2 Both of these issues can be addressed
utilizing acid halides or anhydrides, but such reagents limit
the functional group tolerance and usually require separate
preparation (Scheme 1, path a).3 Modern coupling reagents
can generate the activated intermediate in situ, but stoichio-
metric amounts of multiple reagents are typically needed.4
Transition-metal-catalyzed alternatives include the
copper-mediated ChanꢀLam reaction5 (Scheme 1, path
(1) (a) Otera, J. Chem. Rev. 1993, 93, 1449–1470. (b) Otera, J.;
Nishikido, J. Esterification, 2nd ed.; Wiley-VCH: Weinheim, 2009. (c)
Vorbr€uggen, H. Synlett 2008, 1603–1617.
(2) (a) Aelony, D. J. Am. Oil Chem. Soc. 1955, 32, 170–172. (b)
b) or Pd-catalyzed coupling of aryl halides and phenols
under carbonylative conditions.6 Synthesis of aryl es-
ters via CꢀH activation of arenes often requires internal
aryl acetates.7 Metal-catalyzed oxidative arylation of
Offenhauer, R. D. J. Chem. Educ. 1964, 41, 39. (c) Ishihara, K.; Ohara,
S.; Yamamoto, H. Science 2000, 290, 1140–1142. (d) Ishihara, K.
Tetrahedron 2009, 65, 1085–1109.
(3) (a) Parish, R. C.; Stock, L. M. Tetrahedron Lett. 1964, 1285–1288.
directing groups and has focused on formation of
(b) Kim, S.; Lee, W. J.; Lee, J. I. Bull. Korean Chem. Soc. 1984, 5, 187–
190. (c) Hosseini Sarvari, M.; Sharghi, H. Tetrahedron 2005, 61, 10903–
10907. (d) Chakraborti, A. K.; Shivani J. Org. Chem. 2006, 71, 5785–
5788.
(4) (a) Neises, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17,
522–524. Mitsunobu reactions:(c) Fitzjarrald, V. P.; Pongdee, R.
Tetrahedron Lett. 2007, 48, 3553–3557. (d) Iranpoor, N.; Firouzabadi,
H.; Khalili, D.; Motevalli, S. J. Org. Chem. 2008, 73, 4882–4887.
(5) (a) Zhang, L.; Zhang, G.; Zhang, M.; Cheng, J. J. Org. Chem.
2010, 75, 7472–7474. (b) Luo, F.; Pan, C.; Qian, P.; Cheng, J. Synthesis
2010, 2005–2010. (c) Kim, S.; Lee, J. I. J. Org. Chem. 1984, 49, 1712–
1716. (d) For a Cu-catalyzed coupling of an aryl halide with a carboxylic
acid, see: Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.;
Young, L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379–9382.
r
10.1021/ol2012082
Published on Web 05/26/2011
2011 American Chemical Society

aldehydes has been established almost exclusively for
aromatic aldehydes.8
In the course of our continued investigation of the
synthesis12aꢀd and applications16 of diaryliodonium salts,
we have examined the arylation of carboxylic acids. Here-
in, we present our preliminary results on this reaction,
which proved to be tolerant of steric hindrance as well as a
range of functionalities.
The early reports on this transformation utilized excess
sodium benzoate and diaryliodonium halides or hydrogen
sulfates in refluxing protic solvents.10 These conditions are
potentially problematic for a number of functional groups,
e.g., enolizable carbonyls. We sought to develop a general
synthesis of aryl esters using aprotic solvents and diarylio-
donium triflates or tetrafluoroborates, as these conditions
allowed for lower reaction temperatures in the efficient
arylation of phenoxides.16b
Metal-free oxidative esterifications can be performed
with hypervalent iodine reagents.9 The reaction of diary-
liodonium salts with sodium carboxylates was briefly
reported in the 1950s,10 and one diaryliodonium salt has
also been utilized as benzyne precursor in the synthesis of
phenyl esters.11
The preparation of diaryliodonium salts has recently
been facilitated by the development of efficient one-pot
routes to these hypervalent iodine compounds.12 They
can be utilized as electrophilic arylating agents both
in metal-catalyzed13,14 and metal-free13,15 protocols
and can often replace organometallic reagents with less
benign profiles.
The conditions were optimized using benzoic acid (1a)
and diphenyliodonium triflate (2a) asmodel substrates. An
initial screening of solvents with several bases revealed that
the conversion to phenyl benzoate (3a) was much higher
in toluene than in THF, acetonitrile, or DMF. Further
studies were thus carried out in toluene, and the results are
summarized in Table 1.
(6) (a) Satoh, T.; Ikeda, M.; Miura, M.; Nomura, M. J. Mol. Catal.
A: Chem. 1996, 111, 25–31. (b) Watson, D. A.; Fan, X.; Buchwald, S. L.
J. Org. Chem. 2008, 73, 7096–7101. (c) Wu, X.-F.; Neumann, H.; Beller,
M. ChemCatChem 2010, 2, 509–513. (d) For a coupling with diarylio-
donium salts, see: Kang, S.-K.; Yamaguchi, T.; Ho, P.-S.; Kim, W.-Y.;
Ryu, H.-C. J. Chem. Soc., Perkin Trans. 1 1998, 841–842.
(7) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–
1169. For selected examples with hypervalent iodine, see:(b) Kalyani,
D.; Sanford, M. S. Org. Lett. 2005, 7, 4149–4152. (c) Gou, F.-R.; Wang,
X.-C.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org. Lett. 2009,
11, 5726–5729. (d) Chernyak, N.; Dudnik, A. S.; Huang, C.; Gevorgyan,
V. J. Am. Chem. Soc. 2010, 132, 8270–8272.
Table 1. Optimization of the Model Reactiona
(8) (a) Qin, C.; Wu, H.; Chen, J.; Liu, M.; Cheng, J.; Su, W.; Ding, J.
Org. Lett. 2008, 10, 1537–1540. (b) Rosa, J. N.; Reddy, R. S.; Candeias,
N. R.; Cal, P. M. S. D.; Gois, P. M. P. Org. Lett. 2010, 12, 2686–2689.
(9) (a) For a review, see: Merritt, E. A.; Olofsson, B. Synthesis 2011,
517–538. For catalytic systems (no aryl esters), see: (b) Ochiai, M.;
Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem.
Soc. 2005, 127, 12244–12245. (c) Dohi, T.; Maruyama, A.; Yoshimura,
M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem. Int. Ed. 2005, 44,
6193–6196. (d) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K. Angew.
Chem. Int. Ed. 2011, 50, 5331ꢀ5334.
entry
base
equiv of base tempb (°C) time (h) yieldc (%)
(10) (a) Beringer, F. M.; Brierley, A.; Drexler, M.; Gindler, E. M.;
Lumpkin, C. C. J. Am. Chem. Soc. 1953, 75, 2708–2712 (arylation of
sodium benzoate, 5 equiv, with three different salts in 40ꢀ85% yield). (b)
Nesmeyanov, A. N.; Makarova, L. G.; Tolstaya, T. P. Tetrahedron 1957,
1, 145–157 (no details given). (c) Fuson, R. C.; Albright, R. L. J. Am.
Chem. Soc. 1959, 81, 487–490 (Cu-catalyzed synthesis of 2-acetoxy-20-
iodobiphenyl).
1
2
NaOH
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.55
1.1
1.1
0.55
0.55
130
130
130
130
130
130
130
130
130
130
100
70
1
1
<5
<5
78
79
85
89
95
87
92
95
83
<5
93
63
NaO-t-Bu
NaO-t-Bu
KOH
3
16
1
4
5
K3PO4
1
(11) (a) Xue, J.; Huang, X. Synth. Commun. 2007, 37, 2179–2185. For
the use of other aryne precursors in esterification, see: (b) Liu, Z.;
Larock, R. C. Org. Lett. 2004, 6, 99–102. (c) Liu, Z.; Larock, R. C.
J. Org. Chem. 2006, 71, 3198–3209.
(12) (a) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007,
349, 2610–2618. (b) Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem.
2008, 73, 4602–4607. (c) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett 2008,
592–596. (d) Merritt, E. A.; Malmgren, J.; Klinke, F. J.; Olofsson, B.
Synlett 2009, 2277–2280. (e) Hossain, M. D.; Ikegami, Y.; Kitamura, T.
J. Org. Chem. 2006, 71, 9903–9905. (f) Hossain, M. D.; Kitamura, T.
Bull. Chem. Soc. Jpn. 2007, 80, 2213–2219.
6
K2CO3
2
7
KOt-Bu
KOt-Bu
Cs2CO3
Cs2CO3
KOt-Bu
KOt-Bu
Cs2CO3
Cs2CO3
1
8d
9
1
0.5
10
11
12
13
14
1
4
16
2
100
70
16
(13) For a review, see: Merritt, E. A.; Olofsson, B. Angew. Chem. Int.
Ed. 2009, 48, 9052–9070.
a Base and benzoic acid (1.1 equiv) were mixed in toluene (3 mL) at rt
before addition of 2a (0.50 mmol) and heating to the tabulated tem-
perature. b Oil bath temperature. c Isolated yield. d Toluene not dried.
(14) (a) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.;
Gaunt, M. J. Angew. Chem. Int. Ed. 2011, 50, 458–462. (b) Duong, H. A.;
Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J. Angew. Chem.
Int. Ed. 2011, 50, 463–466. (c) Wagner, A. M.; Sanford, M. S. Org. Lett.
2011, 13, 288–291. (d) Allen, A. E.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2011, 133, 4260–4263. (e) Xiao, B.; Fu, Y.; Xu, J.;
Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468–469.
(15) (a) Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi,
T. J. Am. Chem. Soc. 2009, 131, 1668–1669. (b) Dohi, T.; Ito, M.;
Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Angew. Chem. Int.
Ed. 2010, 49, 3334–3337. (c) Morimoto, K.; Yamaoka, N.; Ogawa, C.;
Nakae, T.; Fujioka, H.; Dohi, T.; Kita, Y. Org. Lett. 2010, 12, 3804–
3807. (d) Ackermann, L.; Dell’Acqua, M.; Fenner, S.; Vicente, R.;
Sandmann, R. Org. Lett. 2011, 13, 2358–2360.
The rate of the reaction shows strong dependence on
the cation of the base: sodium bases effected almost no con-
version to 3a in 1 h at reflux (entries 1 and 2), while potassium
and cesium bases resulted in good yields (entries 4ꢀ9).
Cesium carbonate proved most efficient, as 0.55 equiv of
this diprotic base was sufficient to obtain 3a in high yield
(entry 10), but the price difference between Cs2CO3
and KOt-Bu does not justify the use of this base in general.
The reaction was slow or absent at lower temperatures,
(16) (a) Norrby, P.-O.; Petersen, T. B.; Bielawski, M.; Olofsson, B.
Chem.;Eur. J. 2010, 16, 8251–8254. (b) Jalalian, N.; Ishikawa, E. E.;
Silva, L. F.; Olofsson, B. Org. Lett. 2011, 13, 1552–1555.
Org. Lett., Vol. 13, No. 13, 2011
3463

although cesium carbonate enabled significant conversion
also at 70 °C (entries 11ꢀ14).
Table 3. Phenylation of Carboxylic Acidsa
With the optimized conditions in hand, the influence of
different diaryliodonium anions was investigated. As ex-
pected, tetrafluoroborate 2b works just as efficiently as
triflate 2a (Table 2, entries 1 and 2). Tosylate 2c also
furnished 3a in high yield (entry 3), whereas bromide 2d
gave poor results (entry 4).
The modest yield obtained with 2d appears not to be
caused by radical side reactions, as addition of the radical
trap 1,1-diphenylethene had no effect (entry 5). The low
yield can instead be explained by the moderate solubility of
2d and the formation of bromobenzene from intramole-
cular coupling with the bromide anion, as previously
reported.17
Table 2. Influence of the Diphenyliodonium Aniona
entry
salt 2
X
yieldb (%)
1
2
2a
2b
2c
2d
2d
2d
OTf
BF4
OTs
Br
95
97
90
19
19
21
3
4
5c
6d
Br
Br
a KOt-Bu (1.1 equiv) and benzoic acid (1.1 equiv) were mixed in toluene
(3 mL) at rt before addition of 2 (0.50 mmol) and heating to reflux.
b Isolated yields. c With 1,1-diphenylethene (1.0 equiv). d In DMF.
a See Table 2 for conditions. b Isolated yields. c No etherification
products detected.
Information).12 Aryl groups with substituents ranging
from electron-donating to electron-withdrawing could be
transferred efficiently, as demonstrated with the sym-
metric salts 2e and 2f (Table 4, entries 1 and 2). The
unsymmetric salt 2g selectively transferred the nitro-
substituted aryl moiety to the carboxylate, delivering
product 3k (entry 3).
Steric bulk in the ortho positions was very well tolerated,
as demonstrated by arylations with salts 2h and 2i to yield
highly congested products, including the novel esters
3mꢀp (entries 4ꢀ8). Excellent chemoselectivity was ob-
served with the unsymmetric salt 2i, which transferred the
tri(isopropyl)phenyl group (TRIP) in high yield (entries
5ꢀ8). Thus, unsymmetric diaryliodonium salts can be used
with advantage when the symmetric reagent is expensive or
cumbersome to prepare.
The reaction scope was initially explored by pheny-
lating carboxylic acids 1 with diphenyliodonium tri-
flate (2a) and tetrafluoroborate (2b) (Table 3). As
expected, the nucleophilicity of the carboxylic acid
influenced the outcome of the reaction, and 2,4-di-
methoxybenzoate was phenylated in better yield than
4-nitrobenzoate (entries 1 and 2). On the other hand,
steric bulk of the carboxylic acid does not affect the
reaction greatly and even highly hindered ester 3f was
formed in 90% yield (entries 3ꢀ5).
In contrast to classical esterification protocols, the
presence of a primary alcohol moiety did not hamper
the ester formation, and hydroxy ester 3g was obtained
as the only product (entry 6). N-Boc-phenylglycine
could also be arylated to give amino acid derivative
3h (entry 7).18
Further exploration of the reaction scope involved ar-
ylation with substituted diaryliodonium salts, which are
easily available via one-pot reactions (see the Supporting
(19) Oh, C. H.; Kim, J. S.; Jung, H. H. J. Org. Chem. 1999, 64, 1338–
1340.
(20) This so called ortho-effect varies with the nucleophile and is
sometimes overriden by electronic properties, so that aryl groups with
electron-donating ortho-substituents are not transferred; see refs 17 and
19 and: Ochiai, M.; Kitagawa, Y.; Takayama, N.; Takaoka, Y.; Shiro,
M. J. Am. Chem. Soc. 1999, 121, 9233–9234.
(17) Carroll, M. A.; Wood, R. A. Tetrahedron2007, 63, 11349–11354.
(18) Racemic N-Boc-phenylglycine was used. Arylation of enantio-
merically enriched carboxylic acids will be investigated for the full paper.
3464
Org. Lett., Vol. 13, No. 13, 2011

are transferred more readily than electron-rich aryl groups
(entry 3)19 and that ortho-substituted aryl groups are
transferred preferentially over aryl groups lacking such
substituents (entries 5ꢀ8).20
Table 4. Arylation of Carboxylic Acidsa
Interestingly, the opposite chemoselectivity trends are
observed with diaryliodonium salts used in the presence of
a transition-metal catalyst. Then the more electron-rich, or
least bulky, aryl group is generally transferred and the
TRIP group is often used as a dummy ligand to increase
the selectivity toward transfer of the other group.13,14
Finally, the carboxylic acid scope was further investi-
gated, and aliphatic substrates were arylated without
problems (entries 2, 7, and 8; see also Table 3, entry 6).
Furthermore, a ketosubstituent posednoproblem, as ester
3o was obtained in high yield without formation of detect-
able amounts of byproducts via base-catalyzed condensa-
tion reactions (entry 7).
For reasons of atom economy, it should be stressed that
the equivalent of iodoarene formed in the reaction can be
isolated and utilized to regenerate the diaryliodonium salt,
as demonstrated by the isolation of 1-bromo-4-iodoben-
zene in entry 2.
In conclusion, a fast synthesis of aryl esters directly from
carboxylic acids and diaryliodonium salts has been devel-
oped. Good toexcellent yields are obtained without the use
of metal catalysts, halogenated solvents or excess reagents.
Aryl esters can be synthesized in the presence of primary
alcohols, N-Boc substituents and ketones, and both aro-
matic and aliphatic substrates are tolerated. The scope
includes synthesisof remarkably hindered esters, which are
impossible to obtain via direct esterification.
With the recent advances in efficient diaryliodonium salt
synthesis, these reagents are now readily available. Con-
tinued investigations on the arylation of heteroatoms with
diaryliodonium salts are underway, and the results will be
reported in due course.
Acknowledgment. This work was financially supported
by the Carl Trygger Foundation, the Swedish Research
Council, Bergvalls’Foundation, and the HigherEducation
Commission of Pakistan.
a See Table 2 for conditions. b Isolated yield. c 1-Bromo-4-iodoben-
zene isolated in 92% yield. d No 3i detected. e No phenyl ester detected.
f 3% 3e isolated as byproduct.
Supporting Information Available. Synthesis of diary-
liodonium salts 2, experimental procedures, analytical
1
The observed chemoselectivity trends with diaryliodo-
nium salts 2g and 2i follow previously reported selectivities
for metal-free reactions, i.e., that electron-poor aryl groups
data, and H and 13C NMR spectra of products 3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
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