On the role of CO2 in NHC-catalyzed oxidation of aldehydes

Article abstract of DOI:10.1021/ol2006538

Chemical equations presented. NHC-catalyzed oxidations using carbon dioxide as the stoichiometric oxidant have been carefully investigated. These studies support a secondary role of CO₂ in suppressing side reactions and exogenous oxygen as the actual oxidant.

Full text of DOI:10.1021/ol2006538

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2422–2425
On the Role of CO2 in NHC-Catalyzed
Oxidation of Aldehydes
Pei-Chen Chiang and Jeffrey W. Bode*
Department of Chemistry, University of Pennsylvania, Pennsylvania 19104,
United States, and Laboratorium fu€r Organische Chemie, ETHÀZu€rich,
Zu€rich 8093, Switzerland
bode@org.chem.ethz.ch
Received March 11, 2011
ABSTRACT
NHC-catalyzed oxidations using carbon dioxide as the stoichiometric oxidant have been carefully investigated. These studies support a
secondary role of CO2 in suppressing side reactions and exogenous oxygen as the actual oxidant.
Recent communications reported the intriguing oxida-
tion of aldehydes using N-heterocyclic carbenes as cata-
lysts and carbon dioxide as the stoichiometric oxidant
(eq 1).1 These reports postulated that CO2 is reduced to
CO under catalytic conditions, a process that would be an
attractive approach to CO2 fixation provided that an in-
expensive aldehyde reaction partner could be identified. At
least two different mechanisms have been proposed, one
involving addition of the catalyst to the aldehyde to form
the nucleophilic Breslow intermediate2 and one which pro-
posed direct activation of CO2 by the NHC. Similar
reports of NHC-mediated reduction of CO2 with silanes
have also generated considerable interest.3
CO2.4 One postulated mechanism involved oxygen atom
transfer from CO2 to the aldehyde, a process that is coun-
terintuitive and thermodynamically questionable.5 Given
our interest in the chemistry of NHC catalysis and the
current importance of new catalytic methods for CO2
fixation,3,6 we have investigated these reactions further.
Through these extensive studies, we conclude that the
actual oxidant in these reactions is exogenous oxygen.7,8
Our studiesbegan witha careful investigation ofthe CO2
fixation reaction with the goal of using labeled CO2 as a
mechistic probe. Despite dozens of attempts, we were
unable to reproduce the reported yields and observations
of either Zhang (Table 1, entries 1À3) on the oxidation of
freshly purified cinnamaldehyetocinnamic acid or Nairon
(5) Jiang, Z.; Xiao, T.; Kuznetsov, V. L.; Edwards, P. P. Philos.
Trans. R. Soc. London, Ser. A 2010, 368, 3343–3364.
(6) (a) Kayaki, Y.; Yamamoto, M.; Ikariya, T. Angew. Chem., Int.
Ed. 2009, 48, 4194–4197. (b) Mak, X. Y.; Ciccolini, R. P.; Robinson,
J. M.; Tester, J. W.; Danheiser, R. L. J. Org. Chem. 2009, 74, 9381–9387.
(c) Zhou, H.; Zhang, W.-Z.; Liu, C.-H.; Qu, J.-P.; Lu, X.-B. J. Org.
Chem. 2008, 73, 8039–8044. (d) Tommasi, I.; Sorrentino, F. Tetrahedron
Lett. 2009, 50, 104–107.
We were particularly intrigued with these findings as they
were contrary to the usual chemistry of NHC-catalyzed
reactions of R-ketoacids, which generate aldehydes and
(7) Lin, L.; Li, Y.; Du, W.; Deng, W.-P. Tetrahedron Lett. 2010, 51,
3571–3574.
(8) Yoshida, M.; Katagiri, Y.; Zhu, W.-B.; Shishido, K. Org. Biomol.
Chem. 2009, 7, 4062–4066.
(1) (a) Gu, L.; Zhang, Y. J. Am. Chem. Soc. 2010, 132, 914–915.
(b) Nair, V.; Varghese, V.; Paul, R. R.; Jose, A.; Sinu, C. R.; Menon,
R. S. Org. Lett. 2010, 12, 2653–2655.
(2) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
(3) (a) Riduan, S. N.; Zhang, Y.; Ying, J. Y. Angew. Chem., Int. Ed.
2009, 48, 3322–3325. (b) Huang, F.; Lu, G.; Zhao, L.; Li, H.; Wang,
Z.-X. J. Am. Chem. Soc. 2010, 132, 12388–12396.
(4) For a recent mechanistic study, see: Gonzalez-James, O. M.;
Singleton, D. A. J. Am. Chem. Soc. 2010, 132, 6896–6897.
(9) Cinnamaldehyde was purified by vacuum distillation prior to use.
Solvents were obtained from a solvent drying system.
(10) Zhang reports that commerical aldehydes were used without
prior purification. Under these conditions, we have observed
slightly greater amounts of oxidized products under all conditions
tested.
r
10.1021/ol2006538
Published on Web 04/12/2011
2011 American Chemical Society

Table 1. Oxidation of Cinnamaldehyde with NHCs
a
a
entry
conditions
CO2
N2
aira
1
2
dry, K2CO3 (2 equiv), DMSO
dry, K2CO3 (2 equiv), DMF
dry, t-BuOK ((2 equiv), DMF
dry, DBU (20 mol %), THFb
as shown in reaction scheme
0.1 M/3 days
8%
4%
3%
À
À
4%
8%
3
45%
20%
23%
27%
40%
1%
À
4
10%
14%
17%
14%
2%
11%e
5%
13%
57%
64%
32%
0%
À
5
6
7
0.5 M/3 days
8
without NHC precatalyst
triazolium cat. 4c (5 mol %)
thiazolium cat. 5d (5 mol %)
dry, MeOH (2 equiv)
9
15%f
2%
10
11
12
13
2%
64%
À
À
À
Figure 1. 1H NMR comparison in different atmospheres.
trans-azobenzene (1.0 equiv)
MeOH (2 equiv), azobenzene
21%
0%g
52%
0%h
À
a See Supporting Information for detailed conditions. Conversion to
cinnamic acid 2 was calculated from 1H NMR of crude mixtures.
b Purged with a slow stream of gas for 30 min. Hydrocinnamic acid
was the major product regardless of reaction atmopsheres. c 1,4-Di-
methyl-4H-1,2,4-triazol-1-ium iodide (4, CAS No. 120317-69-3) was
hydrocinnamic acid via the known internal redox reaction
(entry 9).13 The increased formation of hydrocinnamic
acid under CO2 is likely due to the formation of carbonic
acid that serves as the proton source for β-protonation.
Thiamine, a thiazolium salt, did not give significant
amounts of any product (entry 10). Control experiments
and careful analysis of the reaction mixtures and products
excluded a Cannizzarro-type reaction14 as the origin of the
cinnamic acid.
The use of air as an oxidant in NHC-catalyzed oxida-
tions of electron-deficient aldehydes to acids and esters has
been previously reported by Yoshida using a slightly
different imidazolium catalyst.8 Their mechanistic propo-
sal invokes the formation of an acyl azolium, which under-
goes esterification or hydrolysis. This mechanism is con-
sistent with numerous reports of NHC-catalyzed oxidative
esterification of aldehydes with oxidants including azo-
benzene,15 diphenoquinone,16 and MnO2.17 To test if our
observations followed this proposal, we conducted the
reactionunder air in the presenceof MeOH; tooursurprise
only the acid, rather than the expected ester, was detected
(entry 11). In contrast, the use of trans-azobenzene as the
oxidant afforded cinnamic acid in the presence of water
(entry 12) and methyl cinnamate in the presence of MeOH
used. d Thiamine HCl (5, CAS No. 67-03-8) and 3 equiv of K2CO3 were
3
employed. e 84% yield of hydrocinnamic acid. f 30% yield of hydro-
cinnamic acid. g 4% yield of methyl cinnamate. h 44% yield of methyl
cinnamate.
the oxidation of either cinnamaldehyde or para-fluoro-
benzaldehyde (entry 4 and Supporting Information).9,10
After extensive optimization, we found that reproducible
formation of cinnamic acid could be achieved under
slightly modified Zhang conditions: with 5 mol % IMesCl
(3) and 2 equiv of K2CO3 in DMF (entries 5À8). Rigor-
ously dried reaction conditions gave lower yields or irre-
producible production of cinnamic acid, which was over-
come by the addition of a small amount of water (1
equiv).8,11 To be consistent with Zhang’s experiments, we
also attempted the reactions for 3 days, which gave slightly
higher conversions under all conditions (entry 6). Higher
concentration did not provide improved results due to
competing dimerization and other side reactions (entry 7).
A more extensive list of reaction conditions attempted can
be found in the Supporting Information. Unpurified
NMR spectra from the reaction mixtures under various
atmospheres show clean formation of the acid under air,
trace conversion under CO2, and the formation of bypro-
ducts under N2 or vacuum.12
(13) (a) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873–3876.
(b) Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021–6024.
(c) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 9518–9519.
(14) (a) Cannizzaro, S. Liebigs Ann. Chem. 1853, 88, 129–130.
(b) Sreenivasulu, M.; Kumar, K. A.; Reddy, K. S.; Kumar, K. S.;
Kumar, P. R.; Chandrasekhar, K. B.; Pal, M. Tetrahedron Lett. 2011,
52, 727–732.
(15) (a) Inoue, H.; Higashiura, K. J. Chem. Soc., Chem. Commun.
1980, 549–550. (b) Noonan, C.; Baragwanath, L.; Connon, S. J. Tetra-
hedron Lett. 2008, 49, 4003–4006. (c) Rose, C. A.; Zeitler, K. Org. Lett.
2010, 12, 4552–4555.
(16) (a) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Angew.
Chem., Int. Ed. 2008, 47, 8727–8730. (b) De Sarkar, S.; Grimme, S.;
Studer, A. J. Am. Chem. Soc. 2010, 132, 1190–1191.
(17) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Tetra-
hedron 2009, 65, 3102–3109.
Our studies confirmed that IMesCl (3) was essential for
formation of the carboxylic acid product; only trace
amounts of cinnamic acid were observed in its absence
(entry 8). Triazolium precatalysts favored the formation of
(11) (a) Lim, M.; Yoon, C. M.; An, G.; Rhee, H. Tetrahedron Lett.
2007, 48, 3835–3839. (b) An, G.; Ahn, H.; De Castro, K. A.; Rhee, H.
Synthesis 2010, 477–485.
(12) Atmosphere exchange for the reactions shown in Figure 1 was
performed by freezeÀpumpÀthaw, and reactions were conducted in a
sealed tube.
Org. Lett., Vol. 13, No. 9, 2011
2423

(entry 13). These observations indicate that under these
conditions the oxidation occurs by addition of the NHCÀ
aldehyde complex to molecular oxygen rather than oxida-
tion of the Breslow intermediate to the acyl azolium.18
The only experimental observation of both Zhang and
Nair that is not consistent with exogenous air acting as the
oxidant is their detection of CO at the completion of the
reaction. According to the experimental procedures, this
was achieved by injecting the residual gas in the ballon of
CO2 into a solution of PdCl2 in acidic water. After 2 h of
stirring, the formation of Pd black was taken as an indica-
tion that CO was present in the reaction atmosphere. The
long reaction times needed for formation of Pd black
suggested to us that factors other than CO may be respon-
sible for its formation.19
especially γ-lactone products23 that could be the origin of
the messy reaction mixtures observed when conducted
under a N2 atmosphere. To test this hypothesis, we exam-
ined the effect of CO2 on a different NHC-catalyzed
reaction, the formation of cyclopentenes from the same
substrate (cinnamaldehyde, 1) and chalcone (8) in the
presence of either imidazolium or triazolium precatalysts
(Table 2).24 These experiments revealed a pronounced rate
deceleration in the presence of CO2, diminishing product
formation but without causing the formation of side
products. This effect was also observed on the oxidation
of cinnamaldehyde using azobenzene under CO2 (Table 1,
entry 12).
We have previously found that cinnamaldehydes are
particularly prone toair oxidation in the presence of NHC-
catalysts.13a The reports of CO2 catalyzed oxidation of
aldehydes also examined other substrates, which we suspected
were also oxidized by air rather than with CO2. To confirm
this, we briefly explored the application of the open-air
oxidation conditions to other substrate classes (Scheme 1).
Table 2. CO2 Effect in NHC-Catalyzed Annulation
Scheme 1. Substrate Scope of Aerobic Oxidation of Aldehydesa
yield of
entry
conditions
cyclopentene
1
2
3
4
CO2, IMesCl
N2, IMesCl
CO2, RMesCl
N2, RMesCl
8%
59%
36%
62%
Although all of these results strongly suggested that CO2
was not playing a direct rolein the reaction, we consistently
noted that reactions performed under a CO2 atmosphere
were cleaner, albeit with lower conversion, than those
conducted under N2 or in completely degassed solvents.
We postulated that CO2 played a role in reducing the
formation of side products, possibly by attenuating the
activity of the N-heterocyclic carbenes.20 This could deter,
for example, the formation of benzoin,21 Stetter,22 or
a All of the reactions were carried out in 0.5 mmol scale; isolated yields
of pure products after acidÀbase extraction. b 10 mol % IMesCl
was used.
In general, we observed results similar to the reported
CO2 conditions: cinnamaldehyde gave a quantitative yield
ofthe corresponding acid, and reasonableisolatedyieldsof
carboxylic acids were obtained from simple aromatic alde-
hydes. Aliphatic and sterically hindered aldehydes gave
lower conversions. These observations are consistent with
a number of reports of NHC-catalyzed oxidations of alde-
hydes with air or added stoichiometric oxidants.7,8,15À17
In light of these investigations, we conclude that the
apparent NHC-catalyzed oxidation of aldehydes with CO2
actually involves exogenous O2 as the stoichiometric oxi-
dant. The observed effect of CO2 lies in a reduction of the
side products formed by aldehyde dimerization or oligo-
merization under the reaction conditions.
(18) After the submission of this manuscript, two publications on
NHC-catalyzed oxidations of aldehydes with air have appeared. These
reports confirm that oxidation occurs by direct addition of an
NHCÀaldehyde complex to molecular oxygen: (a) Maji, B.; Vedachalan,
S.; Ge, X.; Cai, S. Liu, X.-W. J. Org. Chem. 2011, 76, DOI: 10.1021/
jo200275c. (b) Park, J. H.; Bhilare, S. V.; Youn, S. W. Org. Lett. 2011,
13, DOI: 10.1021/ol200481u.
(19) In our experience, this is a good test if Pd black forms within
minutes but is less reliable with prolonged reaction times, particularly if
metal needles or syringes are used in the reaction setup.
(20) (a) Kuhn, N.; Al-Sheikh, A. Coord. Chem. Rev. 2005, 249, 829–
857. (b) Duong, H. A.; Tekavec, T. N.; Arif, A. M.; Louie, J. Chem.
Commun. 2004, 112–113. (c) Van Ausdall, B. R.; Glass, J. L.; Wiggins,
K. M.; Aarif, A. M.; Louie, J. J. Org. Chem. 2009, 74, 7935–7942.
(21) Miyashita, A.; Suzuki, Y.; Okumura, Y.; Iwamoto, K.-i.;
Higashino, T. Chem. Pharm. Bull. 1998, 46, 6–11.
(22) Matsumoto, Y.; Tomioka, K. Tetrahedron Lett. 2006, 47, 5843–
5846.
(23) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370–14371. (b) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed.
2004, 43, 6205–6208.
(24) (a) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem.
Soc. 2007, 129, 3520–3521. (b) Nair, V.; Vellalath, S.; Poonoth, M.;
Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736–8737.
2424
Org. Lett., Vol. 13, No. 9, 2011

Acknowledgment. This work was supported by NIH
€
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
R01-079339 and ETH-Zurich. P.-C.C. is grateful to
the government of Taiwan for a predoctoral fellow-
ship.
Org. Lett., Vol. 13, No. 9, 2011
2425