Carboxylation and esterification of functionalized arylcopper reagents

Article abstract of DOI:10.1021/jo047731s

Functionalized arylcopper reagents have been produced in good yields at 25 °C from activated copper and the corresponding functionalized aryl iodides without the need of traditional organolithium or Grignard precursors. These organocopper compounds will undergo carboxylation with CO₂ to form the corresponding copper benzoates. In turn, these salts can be acidified to produce the functionalized aryl acids or treated with appropriate alkyl halides in the presence of a dipolar aprotic solvent to generate the corresponding aryl esters. This methodology permits the formation of functionalized organic acids and esters that could not be generated by the carboxylation of organomagnesium compounds.

Full text of DOI:10.1021/jo047731s

Carboxylation and Esterification of Functionalized Arylcopper
Reagents§
Greg W. Ebert,* Wayne L. Juda, Robert H. Kosakowski, Bing Ma, Liming Dong,
Keith E. Cummings, Mwita V. B. Phelps, Adel E. Mostafa, and Jianyuan Luo
Department of Chemistry, State University of New York College at Buffalo, 1300 Elmwood Avenue,
Buffalo, New York 14222
ebertgw@bscmail.buffalostate.edu
Received December 29, 2004
Functionalized arylcopper reagents have been produced in good yields at 25 °C from activated copper
and the corresponding functionalized aryl iodides without the need of traditional organolithium or
Grignard precursors. These organocopper compounds will undergo carboxylation with CO2 to form
the corresponding copper benzoates. In turn, these salts can be acidified to produce the functionalized
aryl acids or treated with appropriate alkyl halides in the presence of a dipolar aprotic solvent to
generate the corresponding aryl esters. This methodology permits the formation of functionalized
organic acids and esters that could not be generated by the carboxylation of organomagnesium
compounds.
Introduction
useful” to “extremely attractive” as illustrated:
The importance of functionalized benzoic acid and ester
derivatives in the realm of organic chemistry cannot be
overemphasized. From natural products to pharmaceu-
ticals and from protective coatings to synthetic fibers,
these compounds play a major role.1
CO2
0
G-ArI Cu 8G-ArCu
8G-ArCOOCu RX8G-ArCOOR
(1)
where G ) ester, ketone, nitrile, halogen, etc. It would
permit the formation of a variety of functionalized benzoic
acids and derivatives, some of which would be very
difficult to synthesize by other methods. This approach
would compliment many of the other existing methods
for producing aryl acids and derivatives and in many
cases would have definite advantages in terms of the
scope and the conditions of reaction.
While several methods exist for carboxylating organic
compounds, many of the approaches are of limited scope
and applicability. Organocadmium,3 zinc,3 and alumi-
num4 compounds are resistant to carboxylation unless
the reactions are run at elevated temperatures and
pressures. The Kolbe-Schmitt synthesis5 and the Henkel
reaction6 both require high temperature and pressure.
The oxidation of arenes also requires harsh conditions
employing strong oxidants such as KMnO4 or K2Cr2O7
The carboxylation of arylcopper reagents is a useful
approach to the synthesis of aryl acids and derivatives.
The position of the entering carboxyl group during
carbonation is unambiguous, the reaction conditions are
quite mild, yields are usually excellent with few side
reactions, and the resulting copper carboxylates can be
subsequently converted into esters and other acid deriva-
tives within the same reaction vessel.2 If, however, the
arylcopper reagents were produced by the active copper
approach, a wide variety of functionality could be incor-
porated into the arylcopper reagents, which would not
be possible if traditional lithium and Grignard precursors
were employed. The ability to carboxylate and subse-
quently esterify functionalized arylcopper reagents would
raise the status of this carbonation reaction from “merely
§ Dedicated to Professor Reuben D. Rieke in honor of his academic
retirement and for his career in pioneering work on the activation of
metals for organic synthesis.
(3) (a) Terent’ev, A. P. J. Gen. Chem. USSR 1947, 17, 2075. (b) The
Chemistry of Carboxylic Acids and Esters; Patai, S., Ed.; Interscience-
Publishers: New York, 1969; p 144.
(4) Ziegler, K. Organometallic Chemistry; Zeiss, H., Ed.; American
Chemical Society Monograph No. 147, Reinhold Publishing Corpora-
tion: New York, 1960; p 197.
(5) Kolbe, H. Ann. Chem. 1860, 113, 125.
(6) Raecke, B. Angew. Chem. 1958, 70, 1.
(1) The Chemistry of Carboxylic Acids and Esters; Patai, S., Ed.;
Interscience-Publishers: New York, 1969.
(2) (a) Capella, L.; Deg’Innocenti, A.; Reginato, G.; Ricci, A.; Taddei,
M. J. Org. Chem. 1989, 54, 1473. (b) Lewin, A. H.; Goldberg, N. L.
Tetrahedron Lett. 1972, 491. (c) Cohen, T.; Lewin, A. H. J. Am. Chem.
Soc. 1966, 88, 4521.
10.1021/jo047731s CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/26/2005
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J. Org. Chem. 2005, 70, 4314-4317

Functionalized Arylcopper Reagents
at elevated temperatures.7 In contrast, the carboxylation
of arylcuprates takes place at room temperature and
1 atm.
ing copper is sufficiently reactive to allow direct oxidative
addition to alkyl and aryl halides:
Li+ nap- + CuI‚PR3 f Cu0 + nap + PR3 + LiI (2)
Several workers have developed reactions of transition-
metal carbonyl catalysts capable of producing acids and
esters from suitable feedstocks. The Na2Fe(CO)4 system
was studied by Cooke and Collman,8 NaCo(CO)4 by Heck
et al.,9 and Ni(CO)4 by Tsutsumi and co-workers10 to
name a few. In most cases aliphatic acids and esters could
be produced in high yields, but vinyl and aryl systems
were unreactive.8,9 The nickel catalyst is capable of
producing aryl acids but suffers from the drawback of
the acute toxicity of Ni(CO)4.10 By comparison, arylcopper
compounds readily undergo carboxylation with CO2 and
the toxicity of copper salts is much less than that of nickel
compounds.
Aryllithium and Grignard reagents tend to react with
their carbonated analogues to produce side products
consisting of ketones and tertiary alcohols unless a large
excess of CO2 is employed and care is taken.11 In addition,
the high reactivity of these organometallics severely
limits the functionality that can be incorporated into
these reagents. It is for this reason that arylcopper
compounds produced from these traditional precursors
offer little advantage over the lithium and Grignard
compounds themselves. However, the synthesis of aryl-
copper reagents via the active copper approach does not
suffer from these constraints and such reagents can
tolerate a wide variety of functionality.
2Cu0 + RX f CuR + CuX
(3)
In more recent work, Rieke and co-workers have
studied the reduction of other copper salts to produce an
activated copper. These include the reduction of lithium
2-thienylcyanocuprate,17 the 2 equiv reduction of Cu(I)
complexes to form copper anion complexes,18 and the low-
temperature reduction of CuCN‚2LiBr.19 Each of these
methods will produce an activated form of copper,
although the degree of reactivity and general synthetic
utility for each of these approaches varies considerably.
In our own laboratory we have focused on developing
functionalized organocopper compounds by the use of
active copper produced from the reduction of CuI‚PR3 and
have most recently completed a study on the formation
and reaction of (haloaryl)copper nucleophiles produced
from haloiodobenzenes and active copper.20 In the work
presented here we study the carboxylation and subse-
quent esterification of functionalized arylcopper com-
pounds and examine the advantages such a scheme
offers.
Results and Discussion
The carboxylation of functionalized arylcopper com-
pounds is accomplished in moderate to good yields as
illustrated in Table 1. The reaction conditions are mild
and a wide variety of functionality can be tolerated in
the arylcopper reagent without adverse effects. When
direct comparisons are made, the product yields for the
various isomeric benzenes follow the general order ortho
> para > meta. This is expected on the basis of the well-
known “ortho effect” that has been noted for both the
formation and reactions of arylcopper compounds.21 The
reason for the low yield conversion of 4-cupriobenzo-
phenone to the corresponding acid is not readily appar-
ent, and efforts to increase this yield are ongoing.
Active Copper. Rieke12 and Ebert13 have developed
a highly active copper, which allows the direct formation
of a wide variety of organocopper reagents from the
respective organic halides without utilizing traditional
organolithium or Grignard precursors.14-16 This activated
copper is formed by reducing under argon an ethereal
solution of CuI‚PR3 with an ethereal solution of pre-
formed lithium naphthalenide or biphenylide. The result-
(7) Hudlicky, T. Oxidations in Organic Chemistry; American Chemi-
cal Society: Washington, DC, 1990; pp 105-109.
(8) (a) Cooke, M. P. J. Am. Chem. Soc. 1970, 92, 6080. (b) Collman,
J. P. Acc. Chem. Res. 1975, 8, 342.
A wide variety of alkyl halides can be used to esterify
cuprio 2-fluorobenzoate in moderate to good yields as
shown in Table 2. The precise mechanism for this
reaction has not yet been determined and may vary
depending upon the alkyl halide.2b,c,22-23 Although a
(9) Organic Synthesis Via Metal Carbonyls; Wender, I., Pino, P.,
Eds.; Wiley: New York, 1968; Vol. 1, pp 373-404.
(10) Myeong, S. K.; Sawa, Y.; Ryang, M.; Tsutsumi, S. Bull. Chem.
Soc. Jpn. 1965, 38, 330.
(11) (a) Schlosser, M. Angew. Chem., Int. Ed. Engl. 1964, 3, 362.
(b) Gilman, H.; Morton, J. W., Jr. Org. React. 1954, 8, 258. (c) Kharasch,
M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic Substances;
Prentice-Hall: New York, 1954; p 5.
(12) (a) Ebert, G. W.; Rieke, R. D. J. Org. Chem. 1984, 49, 5280.
(b) Ebert, G. W.; Rieke, R. D. J. Org. Chem. 1988, 53, 4482. (c) Rieke,
R. D.; Wehmeyer, R. M.; Wu, T.-C.; Ebert, G. W. Tetrahedron 1989,
45, 443.
(17) (a) Klein, W. R.; Rieke, R. D. Synth. Commun. 1992, 22, 2635.
(b) Rieke, R. D.; Klein, W. R.; Wu, Tse-Chong J. Org. Chem. 1993, 58,
2492.
(18) Stack, D. E.; Klein, W. R.; Rieke, R. D. Tetrahedron Lett. 1993,
34, 3063.
(13) (a) Ginah, F. O.; Donovan, T. A., Jr.; Suchan, S. D.; Pfennig,
D. R.; Ebert, G. W. J. Org. Chem. 1990, 55, 584. (b) Ebert, G. W.; Klein,
W. R. J. Org. Chem. 1991, 56, 4744. (c) Ebert, G. W.; Cheasty, J. W.;
Tehrani, S. S.; Aouad, E. Organometallics 1992, 11, 1560.
(14) (a) Massey, A. G.; Humpheries, R. E. Aldrichimica Acta 1989,
22(2), 31. (b) Heaney, H. Chem. Rev. 1962, 62, 81. (c) Sell, M. S.;
Hanson, M. V.; Rieke, R. D. Synth. Commun. 1994, 24, 2379.
(15) For reviews on the direct syntheses of organometallic com-
pounds, see the following papers and the references therein: (a) Rieke,
R. D. Science 1989, 246, 1260. (b) Davis, S. C.; Klabunde, K. J. Chem.
Rev. 1982, 82, 153.
(16) Knochel and co-workers have developed functionalized copper-
zinc reagents by treatment of functionalized organozinc compounds
with CuCN. This methodology also avoids highly reactive lithium and
Grignard precursors. For leading references, see: (a) Chen, H. G.; Gage,
J. L.; Barrett, S. D.; Knochel, P. Tetrahedron Lett. 1990, 31, 1829.
(b) Majid, T. N.; Knochel, P. Tetrahedron Lett. 1990, 31, 4413.
(c) Retherford, C.; Knochel, P. Tetrahedron Lett. 1992, 32, 441.
(19) (a) Stack, D. E.; Dawson, B. T.; Rieke, R. D. J. Am. Chem. Soc.
1991, 113, 4672. (b) Stack, D. E.; Dawson, B. T.; Rieke, R. D. J. Am.
Chem. Soc. 1992, 114, 5110.
(20) (a) Ebert, G. W.; Pfennig, D. R.; Suchan, S. D.; Donovan, T. A.,
Jr. Tetrahedron Lett. 1993, 34, 2279. (b) Ebert, G. W.; Pfennig, D. R.;
Suchan, S. D.; Donovan, T. A., Jr.; Aouad, E.; Tehrani, S. S.;
Gunnersen, J. N.; Dong, L. J. Org. Chem. 1995, 60, 2361.
(c) Haloarylcopper Reagents Undergo Coupling at Room Temperature.
In Chem. Eng. News 1995, 73, 3 (37), 45. This review was based upon
the talk entitled “Direct Formation of Halophenylcopper Reagents Via
Haloiodobenzenes and Zerovalent Copper”, Ebert, G. W.; Pfennig, D.
R.; Suchan, S. D.; Donovan, T. A., Jr.; Aouad, E.; Tehrani, S. S.;
Gunnersen, J. N.; Dong, L. Presented at the 210th National Meeting
of the American Chemical Society, Chicago, IL, August 1995; abstract
ORGN 5.
(21) Forest, J. J. Chem. Soc. 1960, 592.
(22) Pfeffer, P. E.; Silbert, L. S. J. Org. Chem. 1976, 41, 1373.
J. Org. Chem, Vol. 70, No. 11, 2005 4315

Ebert et al.
TABLE 2. Esterification of Copper o-Fluorobenzoate
TABLE 1. Carboxylation of Functionalized Arylcopper
Compounds
a Quantitative results were obtained by GC analyses. The first
value represents the yield based upon the amount of organocopper
(2a) present just prior to the addition of CO2. The second value
(in parentheses) represents the overall yield from starting material
(1a).
TABLE 3. Methyl Esterification of Functionalized
Copper Benzoates
a The first value represents the yield based upon the amount
of organocopper (2) present just prior to the addition of CO2. The
second value (in parentheses) represents the overall yield from
starting material (1).
simple SN2 mechanism can explain many of the reactions,
it obviously cannot account for the production of the tert-
butyl ester. It is thought that the formation of sterically
hindered esters proceeds through a radical mechanism.2b,c
The overall three-step synthetic process, consisting of
the oxidative addition of activated copper to the func-
tionalized aryl iodide followed by carboxylation and
subsequent esterification, can be accomplished in moder-
ate yields as illustrated in Table 3. This demonstrates
the viability and utility of the process. The ease by which
this one-pot procedure can be applied opens the door to
a new synthesis of a variety of compounds. Some of these
compounds have important applications such as methyl
2,4-difluorobenzoate (2p), which is an intermediate in the
syntheses of novel antifungal derivatives.24
a Quantitative results were obtained by GC analyses. The first
value represents the yield based upon the amount of organocopper
(2) present just prior to the addition of CO2. The second value (in
parentheses) represents the overall yield from starting material
(1).
Preliminary Studies of Ester Synthesis Utilizing
Alkyl Chloroformates. An alternative pathway to the
reported ester synthesis would be the reaction of func-
tionalized organocopper reagents with organo chloro-
formates. We have begun preliminary work to explore
the feasibility of this approach by examining the reactions
of 2-fluorophenylcopper and 2-chlorophenylcopper with
methyl-, ethyl-, and isopropyl chloroformate. Ethyl 2-flu-
orobenzoate (6b) was produced in 54% yield, and iso-
propyl 2-fluorobenzoate (6e) in 10% yield. All other
reactions produced yields below 10%. These reactions are
still under active investigation.
(23) (a) Klump, G. W.; Bos, H.; Schakel, M.; Schmitz, R. F.; Vrielink,
J. J. Tetrahedron Lett. 1975, 3429. (b) Cohen, T.; Wood, J.; Dietz, A.
G. Jr. Tetrahedron Lett. 1974, 3555.
(24) Dickinson, R. P.; Bell, A. S.; Hitchcock, C. A.; Narayanaswami,
S.; Ray, S. J.; Richardson, K.; Troke, P. F. Bioorg. Med. Chem. Lett.
1996, 6, 2031.
4316 J. Org. Chem., Vol. 70, No. 11, 2005

Functionalized Arylcopper Reagents
into the solution neat. Liquid starting materials were then
injected neat, or solid starting materials were dissolved in THF
(5 mL) and then injected via syringe. The solution was stirred
for 30 min, after which an aliquot (0.5 mL) of the solution was
removed, quenched with a few drops of 0.1 M HCl, and and
analyzed by gas chromatography using the internal standard
method to obtain the yield of organocopper intermediate
(2a-p). Carbon dioxide (gas cylinder) was then bubbled
through the reaction mixture for 30 min, after which the
solution was allowed to stir for 24 h under an atmosphere of
CO2. At this point the functionalized copper benzoate (3) was
either esterified or converted to the acid and isolated. The
functionalized aryl acid was isolated by acidifying the contents
of the reaction flask with 1 M HCl followed by filtration to
remove the insoluble salts. The solution was extracted with
ethyl ether (3 × 10 mL), and the aqueous layer discarded. In
turn, the ether solution was extracted with saturated NaHCO3
(3 × 10 mL). The aqueous solution was acidified with 1 M HCl
and extracted with ether (3 × 10 mL). The ether solution was
then dried over MgSO4, after which the ether was removed
by rotary evaporation to reveal the functionalized aryl acid.
Quantitation was based upon the isolated yield. The acids were
characterized by comparing their spectral and physical proper-
ties to those of authentic commercial samples or to data
reported in the literature. Purity was established by melting
point and also by HPLC. All acids synthesized in this work
have been previously reported, and most are commercially
available.
Synthesis of Functionalized Aryl Esters (6, 7). To the
reaction flask containing the previously formed functionalized
copper benzoate (3) is added 15 mL of a dipolar aprotic solvent
(DMF or DMSO) followed by an excess (15 mmol, 3 equiv, neat)
of the desired alkyl halide (5). The reaction is heated to reflux
(typically 70 °C for THF solutions and 85 °C for DME
solutions) for 5 h to produce the ester. To isolate the ester,
the contents of the reaction flask (typically 45 mL) were poured
into HCl (0.1 M, 50 mL). Ethyl ether was added (25 mL), and
the layers were separated. The organic layer was washed twice
with saturated NaHCO3 (25 mL) and once with water and
dried over MgSO4. The ester was isolated by flash chroma-
tography after separating the more volatile compounds by
rotary evaporation. The esters were characterized by their
spectral and physical properties. The majority of the esters
synthesized in this work have been previously reported, and
most are commercially available. For newly reported com-
pounds, NMR, IR, LRMS, and physical properties have been
provided as Supporting Information. Quantitation and the
purity of the esters were determined by gas chromatography
using the internal standard method. Authentic samples of the
esters were used to establish response factors.
Conclusions
A useful and practical method for producing function-
alized aryl acids and esters from the corresponding aryl
iodides has been developed. The reaction conditions are
gentle, yields are moderate to good, and the position of
the entering carboxyl group is unambiguous. This ap-
proach compliments existing methods for producing aryl
acids and esters and, in many cases, offers definite
advantages in terms of the scope of application and
conditions of reaction.
Experimental Section
Starting Materials. All starting materials were com-
mercially purchased as reagent grade or better and used as
received unless otherwise stated below.
4-Iodobenzophenone (1n)13b,25 and Methyl 2-Iodo-
benzoate (1i).13c,26 Both of these compounds were previously
synthesized in bulk in our laboratory by published procedures.
1
The purity of the compounds was established by H NMR.
Methyl 3-Iodobenzoate (1j). This compound was synthe-
sized27 by heating 3-iodobenzoic acid in an excess of methanol
containing a catalytic amount of H2SO4 to produce a solid
(4.40 g, 16.8 mmol, 80% yield). The literature IR data28 and
13C NMR data29 matched that of the sample. Purity was
established by 13C NMR.
Methyl 4-Iodobenzoate (1k). This compound was synthe-
sized in a manner analogous to that for 1j beginning with
4-iodobenzoic acid to produce a solid (4.51 g, 17.2 mmol, 82%
yield). The literature mp,30 IR data,31 and H NMR data31 all
1
matched that of the sample. Purity was established by
1H NMR.
Formation of Activated Copper. All reactions were
carried out in 50-mL two-neck round-bottomed flasks equipped
with a reflux condenser and rubber septum and containing a
small Teflon-clad stirring bar. The condenser was connected
to an argon/vacuum manifold via a tubing connector. The oven-
dried glassware was placed in a glovebox and charged with Li
(0.076 g, 11 mmol, 1 equiv, small chips from lithium rod,
Aldrich) and either naphthalene or biphenyl (12 mmol, 1.1
equiv) and then attached to the argon/vacuum manifold.
Freshly distilled THF or DME (15-25 mL) was syringed into
the flask, and stirring commenced. When the reduction was
complete (2-3 h, no chips of Li remaining) a mixture of CuI‚
32
P(Et)3 (3.09 g, 10 mmol, 0.91 equiv) in THF or DME (5-
10 mL) was injected into the lithium naphthalenide or bi-
phenylide solution. After 5 min the formation of the brownish
red suspension of activated copper was complete.
Synthesis of Functionalized Aryl Acids (4a-p). The
functionalized aryl iodide or bromide starting material
(1a-p) was added (5 mmol, 0.5 equiv) to the activated copper
solution along with an internal standard (typically decane,
0.40 mL, 2.05 mmol). First, the internal standard was injected
Acknowledgment. We gratefully acknowledge par-
tial support of this work by the donors of the Petroleum
Research Fund, administered by the American Chemi-
cal Society. Acknowledgment is also made to the Re-
search Foundation of SUNY for partial support of this
work through the Incentive Grant Program adminis-
tered by the Office of Sponsored Programs at the State
University College at Buffalo.
(25) McCarty, F. J.; Tilford, C. H.; Van Campen, M. G., Jr. J. Am.
Chem. Soc. 1957, 79, 472.
(26) Brown, H. C.; Okamoto, Y.; Ham, G. J. Am. Chem. Soc. 1957,
79, 1906.
(27) Vogel, A. I.; Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.;
Tatchell, A. K. Vogel’s Textbook of Practical Organic Chemistry, 5th
ed.; Longman Scientific & Technical and John Wiley & Sons: New
York, 1989; p 1077.
(28) SDBSWeb: http://www.aist.go.jp/RIODB/SDBS/(Nov. 18, 2003).
(29) Sadtler Standard Carbon-13 NMR Spectra; Sadtler Research
Laboratores: Philadelphia, PA.
Supporting Information Available: Spectroscopic and
physical data used to characterize previously reported com-
pounds are referenced. For newly reported compounds, NMR,
IR, LRMS, and physical data have been provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(30) Branch G. E. K.; Nixon, A. C. J. Am. Chem. Soc. 1936, 58, 2499.
(31) Jalil, A. A.; Kurono, N.; Tokuda, M. Tetrahedron 2002, 58, 7477.
(32) Kauffman, G. B.; Teter, L. A. Inorg. Synth. 1963, 7, 9.
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