Synthesis of symmetric anhydrides using visible light-mediated photoredox catalysis

Article abstract of DOI:10.1039/c2ob25463h

A new approach to anhydride formation is reported via activation of C-O bonds by the Vilsmeier-Haack reagent formed by Ru(bpy)₃Cl₂ and CBr₄ in DMF. Various aryl and alkyl carboxylic acids are converted to the corresponding anhydrides in excellent yields.

Full text of DOI:10.1039/c2ob25463h

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COMMUNICATION
Synthesis of symmetric anhydrides using visible light-mediated photoredox
catalysis†‡
Marlena D. Konieczynska, Chunhui Dai and Corey R. J. Stephenson*
Received 2nd March 2012, Accepted 12th April 2012
DOI: 10.1039/c2ob25463h
We began our study by subjecting para-methoxybenzoic acid,
CBr4 and 2,6-lutidine in DMF to visible light irradiation (blue
LEDs, λmax = 435 nm) in the presence of Ru(bpy)3Cl2 (1.0 mol
%) at 25 °C for 12 h, which led to the formation of the corre-
sponding anhydride in 85% isolated yield (Table 1, entry 1).
Increasing the temperature to 35 °C furnished the product in a
slightly decreased yield (entry 2). In both cases, we observed a
significant decomposition of the anhydride to the starting acid
upon purification on silica gel. Therefore, we reasoned that low-
ering the amount of CBr4 from 2.0 equiv to 1.0 equiv and per-
forming an alkaline aqueous work-up would allow for the
isolation of analytically pure product without the need for
further purification. Indeed, this new protocol led to the for-
mation of the anhydride in 90% yield (entry 3). Additional
control experiments were performed in the absence of the cata-
lyst and careful exclusion of light, in which no reaction was
observed, supporting the necessity of the photoredox catalyst
and a light source (entries 4 and 5). Excluding the oxidative
quencher (CBr4) gave no desired product (entry 6). Furthermore,
the reaction was run in the absence of a base, providing a
mixture of product and starting material in a 3 : 1 ratio (entry 7).
A new approach to anhydride formation is reported via acti-
vation of C–O bonds by the Vilsmeier–Haack reagent
formed by Ru(bpy)3Cl2 and CBr4 in DMF. Various aryl and
alkyl carboxylic acids are converted to the corresponding
anhydrides in excellent yields.
The development of methods for the preparation of anhydrides
remains a significant goal since these structural motifs serve as
precursors for amides and esters,1 and have applications in
peptide synthesis.2 Various strategies for the synthesis of car-
boxylic anhydrides have been reported. The majority of methods
currently available utilize carboxylic acids with dehydrative
coupling agents, including phosgene,3 thionyl and sulfonyl
chlorides,4,5 phosphoranes,6 isocyanates,7 pyridazin-3(2H)-
ones,8 1,3,5-triazines,9 and carbodiimides.10 Other approaches
have centered around reactions of carboxylate salts with strong
acylating agents such as acid chlorides or acid anhydrides,11 or
more recently, polymer-supported cobalt phosphine complexes.12
Due to anhydride instability, finding a mild and practical method
is crucial. Based on our recent study into visible light-mediated
halogenation of alcohols to the corresponding bromides and
iodides, we sought to expand this methodology to the use of the
in situ formed Vilsmeier–Haack reagent13 for the synthesis of
anhydrides. Herein we report a conversion of carboxylic acids
into symmetrical anhydrides via visible light photoredox
catalysis.14
Table 1 Optimization of reaction parametersa
Previously, we have shown that the catalytic generation of a
Vilsmeier–Haack reagent can be accomplished under mild con-
2+
ditions via the oxidative quenching15 of *Ru(bpy)3 by poly-
halomethanes CBr4 (Ered = −0.30 V vs. standard calomel
electrode [SCE])16 or CHI3 (Ered = −0.49 V vs. SCE)16 in DMF.
The Vilsmeier–Haack reagent activates the alcohol and allows
for nucleophilic substitution by the halide. Hence, we anticipated
that this protocol could be applied to the activation of carboxylic
acid C–O bonds for nucleophilic addition reactions to form
anhydrides.
Oxidative quencher
(equiv)
Entry Catalyst
Base
Yield (%)
1b
2b,e
3
Ru(bpy)3Cl2 CBr4 (2.0)
Ru(bpy)3Cl2 CBr4 (2.0)
Ru(bpy)3Cl2 CBr4 (1.0)
CBr4 (2.0)
Ru(bpy)3Cl2 CBr4 (1.0)
Ru(bpy)3Cl2 None
2,6-lutidine 85
2,6-lutidine 79
2,6-lutidine 90
2,6-lutidine NR
2,6-lutidine NR
2,6-lutidine NR
4
None
5d
6c
7c
Ru(bpy)3Cl2 CBr4 (1.0)
None
77
a All reactions were performed on a 0.5 mmol scale and were degassed
(freeze-pump-thaw). Yields (%) were obtained after aqueous work-up
unless otherwise noted. b Isolated yield (%) after purification by
chromatography on SiO2. c Conversion (%) determined by crude 1H
NMR. d Experiment was conducted in absence of light. e Experiment
was run at 35 °C.
Department of Chemistry, Boston University, 590 Commonwealth
Avenue, Boston, Massachusetts 02215, USA. E-mail: crjsteph@bu.edu
†Electronic supplementary information (ESI) available: Details and
characterization data for all new compounds. See DOI: 10.1039/
c2ob25463h
‡This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4509–4511 | 4509

Table 2 Substrate scope
Entry
1
Product
Yield (%)
99
Entry
2
Product
Yield (%)
98
3
5
7
97
99
91
4
6
8
95
96
90
9
92
61
10
12
90
99
11
13
15
98
14
16
97
<5%
<5%
Reactions were performed on a 0.5 mmol scale and were degassed (freeze-pump-thaw). Yields (%) were obtained after aqueous work-up.
In this case, lower conversion could be the result of an acid-
mediated decomposition of the anhydride.
With the optimized reaction conditions in hand, a series of
electronically diverse carboxylic acids were evaluated (Table 2).
Aryl carboxylic acids bearing electron-rich substituents were
readily accommodated and provided the corresponding anhy-
drides in greater than 90% yield (entries 2–9). The use of elec-
tron-withdrawing ortho-chlorobenzoic acid (entry 11) gave rise
to the desired product in lower yield, presumably due to the
decreased nucleophilicity of the acid or instability of the product.
trans-Cinnamic acid provided the anhydride in excellent yield
Fig. 1 Proposed mechanism.
(entry 10). Phthalic acid was also a viable substrate in this reac-
tion, furnishing the intramolecular cyclization product in 99%
yield (entry 12). Aliphatic carboxylic acids were also subjected
to the reaction conditions and afforded the corresponding pro-
ducts in outstanding yields (entries 13 and 14). However, when
α-amino acids or aryl carboxylic acids bearing strongly electron-
withdrawing groups were utilized, less than 5% of the anhy-
drides were obtained (entries 15 and 16).
As proposed for the conversion of alcohols to halides, a
mechanistic hypothesis for the anhydride formation involves
trapping of the electron-deficient ·CBr3 by DMF to form the
Vilsmeier–Haack reagent A. Subsequently, an attack by the car-
boxylic acid to furnish the iminium intermediate B, followed by
displacement by another carboxylic acid to provide the anhy-
dride and liberate DMF (Fig. 1).
To demonstrate the efficiency of the anhydride protocol on a
preparative scale, the reaction of 4-tert-butylbenzoic acid (2.5 g)
was performed with a lower catalyst loading (0.2 mol%). Grati-
fyingly, no significant loss of efficacy was observed and the
desired anhydride was obtained in 85% yield after work-up
(Fig. 2A). Additionally, when the reaction of 4-tert-butylbenzoic
acid was conducted in a flow reactor, the reaction time was sig-
nificantly shortened, providing the anhydride in 97% yield
(Fig. 2B).
4510 | Org. Biomol. Chem., 2012, 10, 4509–4511
This journal is © The Royal Society of Chemistry 2012

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In summary, we have demonstrated the application of visible
light-mediated photoredox catalysis for the synthesis of sym-
metric anhydrides. This method is highlighted by the use of mild
reaction conditions and isolation of analytically pure products
after simple aqueous work-up. Furthermore, the efficacy of the
protocol is exemplified by performing scale-up and flow reac-
tions, in which high yields of the anhydrides were obtained. The
exploration of different nucleophiles, other than the carboxylates,
to give access to a wider range of products is currently
underway.
Financial support for this research from the NSF
(CHE-1056568), the Alfred P. Sloan Foundation, Amgen, Boeh-
ringer Ingelheim, and Boston University is gratefully acknowl-
edged. C.D. thanks AstraZeneca for a graduate fellowship. NMR
(CHE-0619339) and MS (CHE-0443618) facilities at BU are
supported by the NSF.
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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4509–4511 | 4511