Key words
carboxylation - carbon dioxide - C1 source - dry ice - arylcarboxylic acids
Carboxylic acid functional groups play a major role in chemistry as biologically relevant
substituents, medicinally relevant pharmacophores, or synthetically relevant handles
that can be used to deliver more complex moieties.[1]
[2]
[3] Whereas the synthesis of carboxylic acids has been well studied, the impetus provided
by green chemistry has driven a demand for new methods that use renewable chemical
feedstocks.[4] To meet this demand, carbon dioxide (CO2) has been widely employed as a cheap, renewable, and atom-economical C1 building
block.[5]
[6]
[7] The use of solid CO2 in the synthesis of carboxylic acids from aryl lithiates or Grignard reagents has
been known for some time.[8]
[9] Green chemistry examples have also been reported in which catalytic methods are
used to deliver the desired carboxylic acids through the use of CO2 gas. Recently, Zhang and co-workers reported a visible-light-mediated carboxylation
of aryl halides with gaseous CO2.[10] Interestingly, this method employed a phosphine ligand whose twofold role involved
first impeding the formation of the undesired protodehalogentated product through
use of a basic moiety and secondly encouraging emulsion formation in the biphasic
mixture of water and toluene. This surfactant-promoted emulsion technique exploits
the high availability of CO2 present in solution to deliver the desired carboxylic acids in good yields. Alternative
methods have reported the use of ultrahigh pressures and temperatures as forcing conditions
in carboxylation reactions.[11] We recently reported a convenient synthetic route to deliver xanthylium and acridinium
photocatalysts, in which ortho-lithiated biaryl ethers were condensed onto methyl benzoate derivatives in high yield.[12] While the scope of this reaction proved to be robust, its scalability was limited
by difficulties in obtaining the benzoic acid starting materials. Notably, lithium–halogen
exchange conditions of the corresponding aryl bromide followed by subsequent addition
of gaseous CO2 at ambient pressures gave 4-fluoro-2,6-dimethylbenzoic acid (1; see Scheme [1] below) in only a modest 17% yield.
These syntheses entail many of the drawbacks associated with the use of CO2 as a reagent, chiefly that of delivering readily available dry CO2 in solution. This task is often cumbersome, requiring the gas to be passed through
a drying agent such as calcium sulfate, molecular sieves, or neat sulfuric acid, thereby
greatly limiting the practicality of the method.[12]
[13] Furthermore, the solubility of CO2 varies greatly in organic solvents, leading to solvent–reaction incompatibilities.[14,15] To address these shortcomings, we envisioned the deployment of dry ice, milled in
a pestle and mortar, as a desirable CO2 source that has a markedly enhanced surface area and, in turn, delivers a greatly
increased availability of CO2 in solution. The solid CO2 provides a marked practical improvement upon CO2 gas in terms of both its ease of use and in permitting larger scale reactions.
To deliver acid 1 in a more synthetically useful yield than the 17% yield previously reported, we sought
to develop reaction conditions that implement principles discussed in the literature,
and that also overcome the undesired introduction of water through condensation on
milled dry ice, a common problem associated with its use. These goals were accomplished
by washing the milled dry ice with THF under nitrogen.[16] With milled dry ice as the CO2 source, the use of THF as a solvent instead of diethyl ether gave the desired acid
1 in an improved 43% yield. Decreasing the temperature of the lithium–halogen exchange
from 0 to –78 °C compounded this improvement, resulting in a yield of 96% (Scheme
[1a]). This significant increase in yield is probably due to suppression of the decomposition
of the aryl–lithium intermediate, which occurs at higher temperatures.[17] Fortunately, the low reagent loading and the high efficiency of the reaction permitted
the delivery of the desired product after a simple acid–base workup, circumventing
the need for column chromatography or solvent recrystallization. This practicality
was supportive of a multigram-scale reaction (3.04 g from 14.8 mmol of the starting
aryl bromide), permitting the delivery of 1 in a consistent 96% yield.
Scheme 1 Substrate scope. Yields reported as the average isolated yield of two separate trials
run on 1.0 mmol scale. a Highest yield reported in the literature through aryllithium or arylmagnesium addition
to gaseous CO2 at atmospheric pressure.[12]
,
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
b
n-BuLi (2.1 equiv). c LiTMP (1.0 equiv). d After the standard reaction conditions were employed, K2CO3 (1.5 equiv), MeI (1.2 equiv), and DMF were added to the reaction flask.
With these improved reaction conditions in hand, we applied our method to a range
of other substrates. The general reaction procedure gave 2,6-dimethylbenzoic acid
(2) in a comparable 93% yield. 2,6-Diisopropylbenzoic acid (4), with bulkier isopropyl substituents at the two ortho-positions, was also obtained in good yield (71%). Changing the electronics of the
para-substituent had little impact on reaction yield: fluoro (8, 73%), trifluoromethyl (9, 71%), methoxy (10, 65%), and trifluoromethoxy (11, 69%) substituents were all well tolerated. Notably, these reaction conditions are
chemoselective, delivering the desired carboxylic acid 16 in 80% yield in the presence of two chloro substituents.
We then sought to elaborate this method to the lithiation of aryl moieties through
proton removal instead of lithium–halogen exchange (Scheme [1b]). Notably, removal of an aryl proton was achieved in the presence of a bromo substituent
through the use of LiTMP instead of n-BuLi, delivering the bromobenzoic acid (17) in a good 81% yield. Moreover, lithiation and subsequent carboxylation of 1-benzothiophene
to give 18 proceeded almost quantitatively (99% yield).
We also sought to elaborate our carboxylation method to install additional substrate
functionality in one-pot fashion via the carboxylate intermediate. After formation
of 2,6-dimethylbenzoic acid (2) under the reaction conditions previously described, 1.2 equivalents of iodomethane
were added to the reaction mixture in an attempt to deliver the corresponding methyl
ester 19. However, after 24 hours, none of the desired product was obtained. A subsequent
acidic quench, workup, and trituration, delivered acid 2 in a slightly reduced yield (80%). Simple subsequent addition of DMF, potassium carbonate,
and methyl iodide to the general reaction conditions then gave the desired methyl
ester 19 in a decent 43% yield. Again, the corresponding methyl 2,6-dimethylbenzoate (20) was delivered in a comparable yield (44%). The apparent decrease in yield relative
to the two-step method reported in the literature is probably a result of the strong
coordination of the lithium ion to the carboxylate intermediate. Consequently, a stepwise
synthetic route to these products is probably more desirable.[12]
In summary, the direct carboxylation of aryl bromides by using milled dry ice as a
C1 source is demonstrated. The use of milled dry ice produced a significant increase
in yields compared with methods previously reported in the literature that employ
gaseous CO2. Aryl and hetaryl substrates with ether, halogen, nitrile, or alcohol functional
groups underwent conversions in yields of 57–99%. The reaction provides rapid access
to carboxylic acid derivatives with a low reagent loading and permits the production
of these synthetically useful products without the need for column chromatography
or solvent recrystallization. The reactive carboxylate intermediates were also elaborated
to provide ester functionalities in a one-pot synthesis.
