Light-Driven Carboxylation of o-Alkylphenyl Ketones with CO2

Article abstract of DOI:10.1021/jacs.5b10032

o-Alkylphenyl ketones undergo a C-C bond forming carboxylation reaction with CO₂ simply upon irradiation with UV light or even solar light. The reaction presents a clean process exploiting light energy as the driving force for carboxylation of organic molecules with CO₂.

Full text of DOI:10.1021/jacs.5b10032

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Communication
Light-Driven Carboxylation of o-Alkylphenyl Ketones with CO2
Yusuke Masuda, Naoki Ishida, and Masahiro Murakami
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10032 • Publication Date (Web): 26 Oct 2015
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Light-Driven Carboxylation of o-Alkylphenyl Ketones with CO2
Yusuke Masuda, Naoki Ishida, and Masahiro Murakami*
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Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
Supporting Information Placeholder
(DMA) was also effective for the production of 2a, less
ABSTRACT: o-Alkylphenyl ketones undergo a C–C
polar solvents like benzene and acetonitrile failed to af-
ford 2a, and produced benzocyclobutenol 3 instead.10
bond forming carboxylation reaction with CO2 simply
upon irradiation with UV light or even solar light. The
reaction presents a clean process exploiting light energy
as the driving force for carboxylation of organic mole-
cules with CO2.
UV light
(365 nm)
O
O
CO2
(1 atm)
+
(1)
Ph
H
Ph
DMSO
rt, 2 h
CO2H
1a
2a 89%
OH
Ph
C–C bond forming carboxylation reactions of organic
molecules with carbon dioxide (CO2) have gained con-
siderable attention in organic synthesis.1 Most of con-
ventional methods including Grignard reactions and
transition metal catalysis use stoichiometric amounts of
reducing agents or bases.2-4 The major driving force of
these carboxylation reactions derives from the chemical
3
Shown in Scheme 1 is a probable mechanistic scenario
for the photochemical carboxylation reaction of 1a.
Firstly, 1a absorbs a photon to produce the excited state.
The oxygen of the excited carbonyl group abstracts a
hydrogen of the ortho methyl group to furnish a 1,4-
biradical species A, which possesses a phenylene linker
inbetween. Such a biradical species spontaneously gen-
erates the o-quinodimethane B. Whereas the (Z)-isomer
rapidly undergoes 1,5-hydrogen shift to revert to the
starting ketone 1a, the (E)-isomer possesses a lifetime
long enough to react with CO2. The 1,3-diene moiety of
(E)-B undergoes a [4+2] cycloaddition reaction with the
reagents.
Alternatively, electro-5 or photo6-assisted
reductive carboxylation reactions have been devised.
Electron donors like triethylamine were used as the sac-
rificial reducing agents in most cases. Herein, we report
a unique and clean carboxylation reaction which uses no
sacrificial reagent but light energy as the driving force;
simply upon UV irradiation of a DMSO solution of o-
alkylphenyl ketones, CO2 is efficiently incorporated to
produce o-acylphenylacetic acids.
Photoirradiation of o-alkylphenyl ketones induces an
endergonic isomerization to highly energetic o-
quinodimethanes through the Norrish Type II photoreac-
tion (referred to as “photoenolization”).7 The resulting
o-quinodimethanes are highly reactive 1,3-dienes which
facilely participate in a [4+2] cycloaddition reaction
with various dienophiles like acrylates and aldehydes.8
We questioned whether the o-quinodimethanes might
react with CO2. Such a photoreaction-based process
would present a clean carboxylation reaction driven by
light.9 With this idea in mind, a reaction of o-
methylbenzophenone (1a) with CO2 was examined using
an LED lamp (365 nm) as the light source under various
reaction conditions. We discovered that the carboxyla-
tion reaction was effected by a remarkably simple opera-
tion. When a DMSO solution of 1a (0.04 M) was irradi-
ated under an atmospheric pressure of CO2, carboxylic
acid 2a was cleanly produced (eq 1). Simple acid-base
extraction of the reaction mixture afforded 2a in a pure
form in 89% yield. Whereas N,N-dimethylacetamide
Scheme 1. Proposed Mechanism
Ph
OH
CH2
*
O
O
hν
Ph
H
Ph
H
A
1a
1a*
OH
Ph
O
HO Ph
O
CO2
Ph
CO2H
O
(E)-B
Ph
OH
2a
C
O
1,5-H
shift
Ph
H
(Z)-B
1a
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C–O double bond of CO2 to afford the six-membered
cycloadduct C. Finally, a ring opening reaction gives
the carboxylic acid 2a.
reagents. Light energy gained in the photoenolization
step serves as the driving force for the whole process.
1
2
3
4
5
6
7
8
(a)
‡
OH
Ph
It is possible to generate the assumed o-
quinodimethane intermediate (E)-B from benzocyclobu-
tenol 3 by a thermal torquoselective11 ring-opening reac-
tion with outward rotation of the hydroxy group.12 We
thus examined a thermal reaction of 3 with CO2 in the
absence of light to gain a mechanistic insight (Scheme
2). When a DMSO solution of 3 was simply heated at
110 °C under an atmospheric pressure of CO2, the car-
boxylated product 2a was produced in 17% yield togeth-
er with the ring-opening product 1a (50%). This result
indicates that o-quinodimethane (E)-B thermally reacts
with CO2. Although the simple yield of trapping of (E)-
B with CO2 is low, the isomerization of 1a back to (E)-B
repeats under photoirradiation conditions until 1a is ful-
ly carboxylated.
O
C
O
OH
Ph
HO Ph
O
+
CO2
+17.1 (+6.9)
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(E)-B
O
C
−11.7 (−24.5)
(b)
OH
Ph
+
CO2
O
(E)-B
R
Scheme 2. A thermal reaction of 3 with CO2
+38.2 (+38.0)
CO2H
O
2a
OH
Ph
OH
Ph
Ph
H
+
CO2
CO2
(1 atm)
+
+17.3 (+6.6)
DMSO
1a
110 °C, 18 h
3
(E)-B
O
O
Figure 1. (a) Energy diagram of [4+2] cycloaddition be-
tween (E)-B and CO2. (b) Energy diagram of 1a, (E)-B and
2a. These structures are optimized with the B3LYP-D/6-
311+G(d,p) level of theory using polarizable continuum
model (PCM, solvent = DMSO). The numbers are Gibbs’
energy (kcal/mol, at 298 K, 1 atm) and the numbers in pa-
rentheses are enthalpies (kcal/mol).
+
Ph
Ph
H
CO2H
1a 50%
2a 17%
A wide variety of dienophiles including aldehydes and
ketones undergo a [4+2] cycloaddition reaction with 1,3-
dienes.13 To the best of our knowledge, however, a [4+2]
cycloaddition reaction in which CO2 acts as the dieno-
phile is unprecedented in literature14 probably due to the
much lower reactivity of CO2. Therefore, we next inves-
tigated the energetics of the cycloaddition step using
DFT calculations15 to assess the validity of the proposed
[4+2] cycloaddition pathway (Figure 1a). The six-
membered transition state could be located with the rea-
sonable activation energy (ΔG‡ = +17.1, ΔH‡ = +6.9
kcal/mol) and the transition state connected to the cy-
cloadduct C at the local minimum, which was thermo-
dynamically more stable than the o-quinodimethane (E)-
B and CO2 (ΔG = -11.7, ΔH = -24.5 kcal/mol). These
results demonstrate the thermal [4+2] cycloaddition re-
action of o-quinodimethane (E)-B with CO2 is energeti-
cally feasible.
Various o-alkylphenyl ketones 1 underwent the car-
boxylation reaction with an atmospheric pressure of CO2
at room temperature (Table 1).16 Alkyl o-tolyl ketones
1b and 1c (R1 = alkyl) afforded the carboxylic acid 2b
and 2c in good yields. Functional groups like chloro,
fluoro, hydroxyl and acetal groups were tolerated on the
aromatic ring (2f-i). Bis(o-tolyl) ketone (1j) underwent
monocarboxylation selectively (2j). In case of substrate
1k having a methyl group at the benzylic position, a
ring-closing reaction forming the corresponding benzo-
cyclobutenol competed with the [4+2] cycloaddition
with CO2, lowering the yield of the carboxylated product
2k (33%). Nonetheless, addition of KOH (10 mol %)
promoted the reversion of the benzocyclobutenol to the
starting ketone,17 improving the yield of the carboxylat-
ed product 2k to 71% (entry 10). Sterically more con-
gested ketones like 2-isopropylphenyl ketone and 2,4,6-
trimethylphenyl ketone failed to give the carboxylated
products. The 2,5-dimethylphenyl ketone 1l underwent
site-selective carboxylation at the 2-position (ortho to
the carbonyl group) (2l). The methoxy-substituted ke-
tone 1m and the trifluoromethyl-substituted ketone 1n
also afforded the carboxylated products, although a
longer reaction time (4 h) was required for 1n.
The whole process from 1a to 2a is a formal insertion
reaction of CO2 into the benzylic C–H bond. It should
be noted that DFT calculations suggest the insertion pro-
cess is energetically uphill (ΔG = +17.3, ΔH = +6.6
kcal/mol, Figure 1b). Nevertheless, intervention of the
considerably endergonic photoisomerization of 1a to
(E)-B (ΔG = +38.2, ΔH = +38.0 kcal/mol) energetically
allows the incorporation of CO2 without any additional
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a
Table 1. Photocarboxylation of 1 with CO2
1
2
3
4
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O
O
UV light (365 nm)
CO2
(1 atm)
+
R1
R1
R2
R2
DMSO, rt, 2 h
H
CO2H
1
2
7
8
9
O
O
O
O
O
Ph
Me
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CO2H
CO2H
t-Bu
OMe
Cl
2b 63%
2c 87%
CO2H
CO2H
CO2H
2f 61%c
2d 84%
2e 69%
O
O
O
O
Me
O
Ph
CO2H
F
OH
CHO
CO2H
CO2H
2h 63%d
CO2H
2i 91%e
CO2H
Me
2k 71%f
2g 88%
2j 95%
O
O
O
Me
Ph
CO2H
Ph
CO2H
Ph
CO2H
MeO
F3C
2l 83%
2m 65%
2n 83%g
a Reaction conditions: 1 (0.20 mmol), CO2 (1 atm), DMSO (5 mL), UV light (365 nm, LED
lamp), rt, 2 h. b Isolated yield. c 1 mL DMSO was used. d 10 mL DMSO was used. e Acetal 1i
was used as the substrate. The crude reaction mixture was treated with an aqueous H2SO4 solution
(2M) at rt for 1.5 h. f KOH (10 mol %) was added and the reaction was conducted for 5 h. g Reac-
tion time = 4 h.
O
O
H
O
1i
Solar light also effected the present carboxylation re-
action (eq 2). A DMSO solution (5 mL) of ketone 1a
(0.20 mmol) was placed in an ordinary Pyrex® Erlen-
meyer flask (100 mL) filled with CO2 (1 atm). The flask
was then put on a rooftop on a sunny day to be irradiated
with solar light. After 7 h (total amount of solar radia-
tion was 4.2 kWh/m2), acid-base extraction of the reac-
tion mixture was conducted to isolate analytically pure
carboxylic acid 2a in 72% yield.
aqueous HCl solution (2N) in-
duced condensation to furnish 2,3-benzodiazepine 4 in
72% yield.
Scheme 3. Synthesis of 2,3-benzodiazepine 4
UV light
(365 nm)
O
O
CO2
(1 atm)
+
Ph
H
Ph
DMSO
rt, 2 h
CO2H
1a
2a
O
O
solar light
CO2
(1 atm)
Ph
+
(2)
Ph
H
Ph
1) H2NNH2•H2O
100 °C, 16 h
DMSO
N
CO2H
ambient temp
7 h
NH
1a
2) 2N HCl aq
rt, 2 h
2a 72%
O
The present carboxylation reaction provides a simple
and straightforward access from readily available mate-
rials (o-alkylphenyl ketones, CO2, and hydrazine) to 2,3-
benzodiazepines, which constitute a versatile pharmaco-
phore of various biologically active compounds includ-
ing Tofisopam and Girisopam.18 Initially, carboxylation
of 1a was conducted under the standard reaction condi-
tions, and then hydrazine was added to the reaction mix-
ture directly (Scheme 3). Subsequent treatment with an
4 72%
(one-pot)
In conclusion, o-alkylphenyl ketones undergo a C–C
bond forming carboxylation reaction with CO2 by ex-
ploiting UV light or even solar light as the driving force.
The reaction presents an interesting example of usage of
light energy for carboxylation of organic molecules with
CO2.
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powicz, T. G.; Schmitz, M.; Krystof, M.; Klankermayer, J.;
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AUTHOR INFORMATION
Corresponding Author
murakami@sbchem.kyoto-u.ac.jp
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported in part by Grants-in-Aid for Sci-
entific Research (S) (15H05756) from MEXT, the ACT-C
Program of the JST, and Yazaki Memorial Foundation for
Science and Technology. Y.M. acknowledged JSPS fellow-
ship for young scientists.
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Graphical Abstract
1
2
3
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UV light
or
Solar light
O
O
R1
H
R1
CO2
(1 atm)
+
CO2H
No base
R2
R2
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