Milled Dry Ice as a C1 Source for the Carboxylation of Aryl Halides

Article abstract of DOI:10.1055/a-1384-0159

The use of carbon dioxide as a C1 chemical feedstock remains an active field of research. Here we showcase the use of milled dry ice as a method to promote the availability of CO ₂in a reaction solution, permitting practical synthesis of arylcarboxylic acids. Notably, the use of milled dry ice produces marked increases in yields relative to those obtained with gaseous CO ₂, as previously reported in the literature.

Full text of DOI:10.1055/a-1384-0159

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 814–816
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C. J. O’Brien, D. A. Nicewicz
Letter
Synlett
Milled Dry Ice as a C1 Source for the Carboxylation of Aryl Halides
Connor J. O’Brien
Previous work, addition into gaseous CO2
17% yield
David A. Nicewicz*
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3-1
1
9
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-9
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Me
Me
O
Li
O
C
O
OH
Me
Department of Chemistry, The University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599-3290, USA
nicewicz@unc.edu
F
Me
F
This work, addition into milled dry ice
96% yield
• Readily available C1 source
• 20 examples, up to 99% yield
• No column chromatography
• Multigram-scale reactions
DeMaevpaiaidClrotnAmri.rceNenswipcteioocwnfzd@iCcihunzengmcA.eiusdtturhyo,rThe University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA
Received: 18.12.2020
Accepted after revision: 04.02.2021
Published online: 04.02.2021
temperatures as forcing conditions in carboxylation reac-
tions.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 lim-
ited by difficulties in obtaining the benzoic acid starting
materials. Notably, lithium–halogen exchange conditions of
the corresponding aryl bromide followed by subsequent ad-
dition of gaseous CO2 at ambient pressures gave 4-fluoro-
2,6-dimethylbenzoic acid (1; see Scheme 1 below) in only a
modest 17% yield.
DOI: 10.1055/a-1384-0159; Art ID: st-2020-r0633-l
Abstract The use of carbon dioxide as a C1 chemical feedstock re-
mains an active field of research. Here we showcase the use of milled
dry ice as a method to promote the availability of CO2 in a reaction solu-
tion, permitting practical synthesis of arylcarboxylic acids. Notably, the
use of milled dry ice produces marked increases in yields relative to
those obtained with gaseous CO2, as previously reported in the litera-
ture.
Key words carboxylation, carbon dioxide, C1 source, dry ice, arylcar-
boxylic acids
These syntheses entail many of the drawbacks associat-
ed with the use of CO2 as a reagent, chiefly that of delivering
readily available dry CO2 in solution. This task is often cum-
bersome, requiring the gas to be passed through a drying
agent such as calcium sulfate, molecular sieves, or neat sul-
furic acid, thereby greatly limiting the practicality of the
method.12,13 Furthermore, the solubility of CO2 varies great-
ly in organic solvents, leading to solvent–reaction incom-
patibilities.14,15 To address these shortcomings, we envi-
sioned the deployment of dry ice, milled in a pestle and
mortar, as a desirable CO2 source that has a markedly en-
hanced surface area and, in turn, delivers a greatly in-
creased availability of CO2 in solution. The solid CO2 pro-
vides 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 devel-
op reaction conditions that implement principles discussed
in the literature, and that also overcome the undesired in-
troduction 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 de-
sired acid 1 in an improved 43% yield. Decreasing the tem-
perature of the lithium–halogen exchange from 0 to –78 °C
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.1–3
Whereas the synthesis of carboxylic acids has been well
studied, the impetus provided by green chemistry has driv-
en 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.5–7 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 meth-
ods 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 phos-
phine 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 ex-
ploits the high availability of CO2 present in solution to de-
liver the desired carboxylic acids in good yields. Alternative
methods have reported the use of ultrahigh pressures and
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 814–816
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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C. J. O’Brien, D. A. Nicewicz
Letter
Synlett
a) carboxylation using milled dry ice
O
Br
1.1 equiv. n-BuLi
THF, –78 °C, then milled dry ice
R
OH
R
O
C O
F
iPr
OH
CO2H
Me
Me
F
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
F
Me
Me
iPr
CN
3
6
1
2
4
5
7
73% yield
57% yield
96% yield
93% yield
(54% lit. yield)a
CO2H
71% yield
(72% lit. yield)a
CO2H
82% yield
(45% lit. yield)a
70% yieldb
(17% lit. yield)a
CO2H
CO2H
CO2H
CO2H
MeO
CO2H
N
Me
F3C
F3CO
F
MeO
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9
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73% yield
69% yield
80% yield
69% yield
71% yield
(43% lit. yield)a
65% yield
(70% lit. yield)a
62% yield
(30% lit. yield)a
b) carboxylation via aryl deprotonation
c) one-pot ester formation
F3C
CO2H
Cl
CO2H
CF3
Me
Me
S
CO2H
CO2H
CO2Me
CO2Me
CF3
Cl
F3C
Br
F
Me
Me
20
44% yieldd
15
90% yield
16
80% yield
17
18
19
43% yieldd
81% yieldc
99% yield
(82% lit. yield)a
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.12,18–25 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.
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–lithi-
um 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 prod-
uct after a simple acid–base workup, circumventing the
need for column chromatography or solvent recrystalliza-
tion. This practicality was supportive of a multigram-scale
reaction (3.04 g from 14.8 mmol of the starting aryl bro-
mide), permitting the delivery of 1 in a consistent 96% yield.
With these improved reaction conditions in hand, we
applied our method to a range of other substrates. The gen-
eral 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-posi-
tions, was also obtained in good yield (71%). Changing the
electronics of the para-substituent had little impact on re-
action yield: fluoro (8, 73%), trifluoromethyl (9, 71%), me-
thoxy (10, 65%), and trifluoromethoxy (11, 69%) substitu-
ents were all well tolerated. Notably, these reaction condi-
tions are chemoselective, delivering the desired carboxylic
acid 16 in 80% yield in the presence of two chloro substitu-
ents.
livering the bromobenzoic acid (17) in a good 81% yield.
Moreover, lithiation and subsequent carboxylation of 1-
benzothiophene to give 18 proceeded almost quantita-
tively (99% yield).
We also sought to elaborate our carboxylation method
to install additional substrate functionality in one-pot fash-
ion 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 gener-
al 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 carbox-
ylate 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 sub-
strates with ether, halogen, nitrile, or alcohol functional
We then sought to elaborate this method to the lithia-
tion 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, de-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 814–816

816
C. J. O’Brien, D. A. Nicewicz
Letter
Synlett
groups underwent conversions in yields of 57–99%. The re-
action 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.
flame-dried 100 mL round-bottomed flask and then diluted
with anhyd THF (20 mL). The solution was cooled to –78 °C and
a 1.6 M solution of n-BuLi (1.055 g, 1.1 equiv, 16.47 mmol) in
hexanes (10.29 mL) was added dropwise. The resulting solution
was then stirred at –78 °C for 1 h.
Separately, under a constant stream of N2, anhyd THF (~50 mL)
was added to a flame-dried, 250 mL Erlenmeyer flask and
cooled to –78 °C. Freshly milled dry ice (~75 g) was slowly added
to the flask from a powder funnel. The flask was vigorously
swirled, ensuring that the milled dry ice remained completely
submerged in the solvent. The resulting slurry was filtered by
vacuum filtration under a constant stream of N2. After complete
removal of the solvent, the resulting milled dry ice was quickly
transferred to the original round-bottomed reaction flask by
using a powder funnel (see the Supporting Information for
additional details).
Funding Information
National Institute of General Medical Sciences (R35 GM136330)Natio
n
alInsitute
o
f
G
eneral
M
edical
S
ciences(R
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5
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0)
Supporting Information
The resulting reaction mixture was removed from the cooling
bath and stirred at r.t. until complete sublimation of the dry ice
was observed. (Safety Note: Sublimation of dry ice produces a
large amount of gas. To prevent a dangerous buildup of pres-
sure, the reaction flask was left open to the atmosphere after
dry ice addition.) The solution was then concentrated in vacuo,
and the residue was dissolved in H2O (25 mL) and CH2Cl2 (25
mL). The resulting bilayer mixture was transferred to a separa-
tory funnel, and the organic layer was removed. The aqueous
layer was washed with CH2Cl2 (3 × 25 mL) and acidified to pH 2–
3 with 1 M aq HCl. The resulting aqueous solution was then
extracted with CH2Cl2 (4 × 25 mL), and the organic layers were
collected, dried (MgSO4), filtered, and concentrated in vacuo to
give a white solid; yield: 2.409 g (14.32 mmol, 95.68%, n = 4). 1H
NMR (400 MHz, CDCl3):  = 6.81 (d, J = 9.3 Hz, 2 H), 2.47 (s, 6 H).
The spectral data agreed with those previously reported.
(17) Wu, J.; Yang, X.; He, Z.; Mao, X.; Hatton, T. A.; Jamison, T. F.
Angew. Chem. Int. Ed. 2014, 53, 8416.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1384-0159.
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References and Notes
(1) Ruzi, R.; Liu, K.; Zhu, C.; Xie, J. Nat. Commun. 2020, 11, 3312.
(2) Lassalas, P.; Gay, B.; Lasfargeas, C.; James, M. J.; Tran, V.;
Vijayendran, K. G.; Brunden, K. R.; Kozlowski, M. C.; Thomas, C.
J.; Smith, A. B. III.; Huryn, D. M.; Ballatore, C. J. Med. Chem. 2016,
59, 3183.
(3) Ballatore, C.; Huryn, D. M.; Smith, A. B. III. ChemMedChem 2013,
8, 385.
(4) Sheldon, R. A. Green Chem. 2014, 16, 950.
(5) Vechorkin, O.; Hirt, N.; Hu, X. Org. Lett. 2010, 12, 3567.
(6) Fujihara, T.; Tsuji, Y. Front. Chem. 2019, 7, 430.
(7) Liu, Q.; Wu, L.; Jackstell, R.; Beller, M. Nat. Commun. 2015, 6,
5933.
(8) Gilman, H.; Beel, J. A. J. Am. Chem. Soc. 1949, 71, 2328.
(9) Hussey, A. S. J. Am. Chem. Soc. 1951, 73, 1364.
(10) Zhang, Z.; Roisnel, T.; Dixneuf, P. H.; Soulé, J. F. Angew. Chem. Int.
Ed. 2019, 58, 14110.
(11) Luo, J.; Larrosa, I. ChemSusChem 2017, 10, 3317.
(12) White, A. R.; Wang, L.; Nicewicz, D. A. Synlett 2019, 30, 827.
(13) Wiberg, E.; Holleman, A. F.; Wiberg, N. Inorganic Chemistry;
Academic Press 2001.
(14) Miller, M. B.; Chen, D.-L.; Luebke, D. R.; Johnson, J. K.; Enick, R.
M. J. Chem. Eng. Data 2011, 56, 1565.
(18) Shiina, I.; Miyao, R. Heterocycles 2008, 76, 1313.
(19) Zhang, Q.; Zhang, F. M.; Zhang, C. S.; Liu, S. Z.; Tian, J. M.; Wang,
S. H.; Zhang, X. M.; Tu, Y. Q. Nat. Commun. 2019, 10, 2507.
(20) Paridala, K.; Lu, S.-M.; Wang, M.-M.; Li, C. Chem. Commun. 2018,
54, 11574.
(21) Schlosser, M.; Cottet, F.; Heiss, C.; Lefebvre, O.; Marull, M.;
Masson, E.; Scopelliti, R. Eur. J. Org. Chem. 2006, 729.
(22) Correa, A.; Martín, R. J. Am. Chem. Soc. 2009, 131, 15974.
(23) Screttas, C. G.; Steele, B. R. J. Org. Chem. 1989, 54, 1013.
(24) Nagaraj, H. K. M.; Bandodkar, B. S.; Ravilla, L.; Yellapu, S.;
Rudresha, A. S.; Singh, J. K. ; G, V. WO 2016027285, 2016.
(25) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1 DOI:
10.1002/0471264180.or026.01.
(15) Kunerth, W. Phys. Rev. 1922, 19, 512.
(16) 4-Fluoro-2,6-dimethylbenzoic Acid (1); Typical Procedure
Under a positive pressure of N2, 2-bromo-5-fluoro-1,3-dimeth-
ylbenzene (3.040 g, 1.0 equiv, 14.97 mmol) was added to a
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 814–816