NHC-iron-catalyzed aerobic oxidative aromatic esterification of aldehydes using boronic acids

Article abstract of DOI:10.1021/ol100302e

(Figure presented) NHC-iron complexes prepared in situ very efficiently afforded benzoates via the aerobic oxidative aromatic esterification of aldehydes with boronic acids. This method uses equimolar amounts of both the aldehyde and the boronic acid allo

Full text of DOI:10.1021/ol100302e

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2686-2689
NHC-Iron-Catalyzed Aerobic Oxidative
Aromatic Esterification of Aldehydes
using Boronic Acids
Joa˜o N. Rosa, R. Sudarshan Reddy, Nuno R. Candeias, Pedro M. S. D. Cal, and
Pedro M. P. Gois*
iMed.UL, Faculdade de Farma´cia da UniVersidade de Lisboa, AV. Prof. Gama Pinto,
1649-003 Lisboa, Portugal
pedrogois@ff.ul.pt
Received February 4, 2010
ABSTRACT
NHC-iron complexes prepared in situ very efficiently afforded benzoates via the aerobic oxidative aromatic esterification of aldehydes with
boronic acids. This method uses equimolar amounts of both the aldehyde and the boronic acid allowing the preparation of benzoates in yields
up to 97%.
N-Heterocyclic carbenes (NHCs), which are neutral, two-
electron donor (σ-donating) species with reduced π-back-
bonding tendency, are very useful ligands for homogeneous
catalysis mediated by transition metals such as palladium,
rhodium, platinum, or ruthenium.1 Despite the immense
utility of these catalytic systems, precious metals are quite
expensive and often very toxic, which constitutes a serious
drawback, namely in the context of large-scale production.
Therefore, the discovery of old and new reactions catalyzed
by cheap and nontoxic metals such as iron has become a
major goal for organic chemistry.2
the years, NHCs have been generally overlooked as ligands
for catalysis based on iron complexes.1a This reality is
changing, and among the recent reports on this topic,3 the
highly successful cross-coupling reaction of Grignard re-
agents with aryl and heteroaryl halides to give unsymmetrical
biaryls catalyzed by iron fluorides, and a saturated NHC
ligand (SIPr) disclosed by Nakamura et al. has brought NHCs
ligands into the limelight of iron catalysis.4
In line with our interest in this family of ligands,5 we
initiated a program in order to evaluate NHC-Fe systems
Ligands play a pivotal role in the modulation of the metal
center reactivity. This is particularly true for iron as it
displays different oxidation states and is amenable to ligation
with nitrogen-, oxygen-, or phosphine-based ligands.2 Over
(3) (a) Scepaniak, J. J.; Youg, J. A.; Bontchev, R. P.; Smith, J. M. Angew.
Chem., Int. Ed. 2009, 48, 1364. (b) Liu, B.; Xia, Q.; Chen, W. Angew.
Chem., Int. Ed. 2009, 48, 5513. (c) Danopoulos, A. A.; Wright, J. A.;
Motherwell, W. B. Chem. Commun. 2005, 784. (d) Louie, J.; Grubbs, R. H.
Chem. Commun. 2000, 1479. (e) McGuinness, D. S.; Gibson, V. C.; Steed,
J. W. Organometallics 2004, 23, 6288. (f) Hatakeyama, T.; Nakamura, M.
J. Am. Chem. Soc. 2007, 129, 9844. (g) Plietker, B.; Dieskau, A.; Mo¨ws,
K.; Jatsch, A. Angew. Chem., Int. Ed. 2008, 47, 198.
(1) (a) Gonza´lez, S. D.; Marion, N.; Nolan, S. P. Chem. ReV. 2009, 109,
3612. (b) Hahn, F. E. Angew. Chem., Int. Ed. 2006, 45, 1348. (c) Herrmann,
W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (d) N-Heterocyclic Carbenes
in Transition Metal Catalysis. In Topics in Organometallic Chemistry;
Glorius, F., Ed.; Springer: Berlin, Heidelberg, 2007; Vol. 21. (e) N-
Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-VCH:
Weinheim, 2006. (f) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem. 2008,
47, 3317.
(4) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J. Am.
Chem. Soc. 2009, 131, 11949.
(5) (a) Gois, P. M. P.; Trindade, A. F.; Veiros, L. F.; Andre, V.; Duarte,
M. T.; Afonso, C. A. M.; Caddick, S.; Cloke, F. G. N. Angew. Chem., Int.
Ed. 2007, 46, 5750. (b) Trindade, A. F.; Gois, P. M. P.; Veiros, L. F.;
Andre, V.; Duarte, M. T.; Afonso, C. A. M.; Caddick, S.; Cloke, F. G. N.
J. Org. Chem. 2008, 73, 1076. (c) Esposito, O.; Gois, P. M. P.; Lewis,
A. K.; de, K.; Caddick, S.; Cloke, F. G. N.; Hitchcock, P. B. Organometallics
2008, 27, 6411. (d) Gomes, L. F. R.; Trindade, A. F.; Candeias, N. R.;
Gois, P. M. P.; Afonso, C. A. M. Tetrahedron Lett. 2008, 49, 7372.
(2) (a) Bolm, C.; Legros, J.; Paih, J. L.; Zani, L. Chem. ReV. 2004, 114,
6217. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2009, 48, 1364. (c) Czaplik,
W. M.; Mayer, M.; Cvengrsˇ, J.; von Wangelin, A. J. ChemSusChem 2009,
2, 396.
10.1021/ol100302e  2010 American Chemical Society
Published on Web 05/21/2010

iron could be a more successful catalyst than palladium for
this important transformation as iron is known for its rich
redox chemistry.11
Scheme 1. Ligand Evaluation Using FeCl3 as the Iron Source
We initiated our study reacting benzaldehyde with phe-
nylboronic acid in the presence of NHC precursor 4 and
FeCl3 in dioxane at 90 °C and under a N2 atmosphere. Very
disappointingly, we only detected the formation of ester 3
in traces amounts. Screening different ligands, the yield of
3 was improved to 15% when using imidazolium 5. Bulkier
NHCs generated from 7-9 afforded no product (Scheme 1).
Table 1. Iron Source Evaluation Using NHC Precursor 5
as catalysts for the direct oxidative aromatic esterification
of aldehydes.
entry
ligand
iron source
FeCl3
FeCl3·6H2O
FeCl2·4H2O
Fe(OTf)2
Fe(NO3)3·9H2O
TPPFeCl
Fe(acac)2
Fe(OTf)2
No iron
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
yielda (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
41
39
62
95
The ester functionality is present ubiquitously in the
structure of important natural and synthetic molecules and
for this reason constitutes an important synthetic target. The
existent strategies to prepare carboxylic esters under mild
conditions usually involve the activation of the carboxylic
acid as an acyl halide, anhydride, or activated ester followed
by nucleophilic substitution. The direct oxidative esterifica-
tion of aldehydes remains as an attractive possibility to
readily access esters.6 Recently, Darcel et al. reported the
one-pot oxidative esterification of aldehydes using
Fe(ClO4)3·xH2O and H2O2 in the presence of different
alcohols.7 Less attention though has been paid to the
synthesis of aryl benzoate derivatives despite their importance
as building blocks of numerous active compounds and as
cross coupling partners.8 Usually, these compounds are
prepared via esterification or transesterification reactions
which normally involve strong acidic or basic conditions
limiting the reaction scope.9 The Baeyer-Villiger oxidation
reaction is another classical method to prepare benzoate deri-
vatives though low regioselectivities are obtained when asym-
metric benzophenoes derivatives are used.10 Fully aware of these
limitations Wu, Cheng et al. reported the NHC-palladium-
catalyzed aromatic esterification of aldehydes with boronic
acids in toluene at 120 °C under air.8 Despite the vast
potential of this reaction, only modest yields were obtained,
typically between 5 and 68%. Therefore, we envisioned that
22
no product
no product
no product
no product
80
no ligand
9
5
5
5
5
5
10b
11c
12d
13e
48
76
CuSO4·5H2O
no product
a Isolated yield after preparative thin-layer chromatography (hexanes/
AcOEt). Reaction conditions: benzaldehyde (0.247 mmol), phenylboronic
acid (0.247 mmol), iron (20.0 mol %), 5 (20.0 mol %), KOtBu (0.247 mmol),
dioxane 1.5 mL, 90 °C for 24 h. b The same reaction conditions as in
footnote a with the following exception: 80 °C for 24 h. c The same reaction
conditions as in footnote a with the following exception: iron (10.0 mol
%) and 5 (10.0 mol %). d The same reaction conditions as in footnote a
with the following exception: iron (15.0 mol %) and 5 (15.0 mol %). e The
same reaction conditions as in footnote a with the following exception:
CuSO4·5H2O (20.0 mol %).
Having identified the most efficient ligand, we performed
exactly the same reaction under air. The presence of air was
crucial for this reaction as the yield was improved up to 41%
(Table 1, entry 1). Performing the reaction using Schlenk
line techniques, no product was obtained. Therefore, the
screening of different iron sources was carried out in the
presence of air (Table 1, entries 2-7). Very gratifyingly,
Fe(OTf)2 afforded the desired ester in 95% isolated yield
using equimolar amounts of benzaldehyde and phenylboronic
acid. The importance of both the ligand and the iron source
was undoubtedly demonstrated as without one of them the
(6) Kovi, K. E.; Wolf, C. Chem.sEur. J. 2008, 14, 6302.
(7) Wu, X.-F.; Darcel, C. Eur. J. Org. Chem. 2009, 1144.
(8) Qin, C.; Wu, H.; Chen, J.; Liu, M.; Cheng, J.; Su, W.; Ding, J. Org.
Lett. 2008, 10, 1537.
(9) (a) Sarvari, M. H.; Sharghi, H. Tetrahedron 2005, 61, 10903. (b)
Tamaddon, F.; Amrollahi, M. A.; Sharafat, L. Tetrahedron Lett. 2005, 46,
7841. (c) Shah, S. T. A.; Khan, K. M.; Hussain, H.; Anwar, M. U.; Fecker,
M.; Voelter, W. Tetrahedron 2005, 61, 6652. (d) Oohashi, Y.; Fukumoto,
K.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2005, 78, 1508.
(10) (a) Olah, G. A.; Wang, Q.; Trivedi, N. J.; Prakash, G. K. S. Synthesis
1991, 739. (b) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.
Chem. Lett. 2004, 33, 248. (c) Kotsuki, H.; Arimura, K.; Araki, T.;
Shinohara, T. Synlett 1999, 462. (d) Toda, F.; Yagi, M.; Kiyoshige, K.
J.Chem. Soc., Chem. Commun. 1988, 958.
(11) Selected examples: (a) Li, Y. Z.; Li, B.-J.; Lu, X.-Y.; Lin, S.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2009, 48, 3817. (b) Li, Z.; Yu, R.; Li, H.
Angew. Chem., Int. Ed. 2008, 47, 7497. (c) Shi, F.; Tse, M. K.; Li, Z.;
Beller, M. Chem.sEur. J. 2008, 14, 8793. (d) Nakanishi, M.; Bolm, C.
AdV. Synth. Catal. 2007, 349, 861. (e) Meyer, N. J.; Lough, A. J.; Morris,
R. H. Chem.sEur. J. 2009, 15, 5605.
Org. Lett., Vol. 12, No. 12, 2010
2687

reaction simply fails (Table 1, entries 8 and 9). Decreasing
the temperature and the quantity of iron was also detrimental
for the yield (Table 1, entries 10-12). Finally, no product
was formed when a copper source instead of iron was used
(Table 1, entry 13).
Table 2. Methodology Scope Using the Optimized Conditions
With the optimum reaction conditions at hand, the protocol
was extended to different aldehydes. As shown in Table 2,
the aerobic oxidative aromatic esterification of benzaldehyde
proceeded in good to excellent yieds using boronic acids
regardeless of their electonic nature (Table 2, entries 1-5).
The reaction was also quite tolerant concerning the electronic
nature of the aldehyde aryl substituents. For instance,
4-cyanobenzaldehyde and 4-fluorobenzaldehyde afforded the
ester in 75% and 80% yield, respectively (Table 2, entries
12 and 13), and aldehydes bearing electron-donating sub-
stituents such as piperonal or 4-methoxybenzaldehyde were
readily converted in the esters in yields up to 80% (Table 2,
entries 14 and 15). Conversely, ortho substitution in the
boronic acid resulted in a poor yield of ester 25 (Table 2,
Entry 16). Finally, cyclohexanecarboxaldehyde was also
converted into the corresponding phenyl ester, proving that
this protocol is not exclusive for aromatic aldehydes (Table
2, entry 17).
Recently, Li et al. reported the 1,2-addition of boronic
acids to electron-deficient aryl aldehydes in the presence of
FeCl3 and a phosphine ligand.12 This clearly shows that the
NHC ligand plays a crucial role in the aerobic oxidative
aromatic esterification of aldehydes.13 As shown in Table
1, entry 9, when NHC was used without an iron source no
ester was formed. Apart from the aldehyde, which was
isolated in 53% yield, and benzoic acid, no other products
were isolated from the reaction mixture. This result indicates
that the NHC is most probably involved in the in situ
generation of a catalytic active NHC-iron complex.
In order to probe the reaction mechanism, we performed
the reaction between benzaldehyde and phenylboronic acid
in the presence of H218O. The existence of water in the media
was quite detrimental for the reaction yield as the ester 3
was obtained in only 10% yield. The ESI-MS and MS2
spectrum of the ester 3 revealed the incorporation of 18O
(2:1) in the [Ph-Cd18O]+ fragment. This incorporation
probably results from the in situ isotopic labeling of the
aldehyde with H218O prior to the reaction and indicates that
the carbonyl functionality is the same in the aldehyde and
ester. This result suggests that the sequence of events is not
the oxidation of the aldehyde to the carboxylic acid followed
by a cross coupling with the boronic acid. This was further
demonstrated by the unsuccessful attempt of reacting benzoic
acid with phenylboronic acid (Scheme 2). Furthermore, when
the alcohol 28 was submitted to our catalytic system it
afforded a rather complex mixture in which no ester was
identified; indeed, the major product formed was the ketone
a Isolated yield after preparative thin-layer chromatography (hexanes/
AcOEt). Reaction conditions: aldehyde (0.247 mmol), boronic acid (0.247
mmol), Fe(OTf)2 (20.0 mol %), 5 (20.0 mol %), KOtBu (0.247 mmol),
dioxane 1.5 mL, 90 °C for 24 h. b Reaction time ) 6 h. c The reaction was
performed on a 1 mmol scale maintaining the standard reaction conditions.
d 1.2 equiv of boronic acid was used.
(12) Zou, T.; Pi, S.-S.; Li, J. H. Org. Lett. 2009, 11, 453.
(13) Selected examples: (a) Yu, H.; Fu, Y.; Guo, Q.; Lin, Z. Organo-
metallics 2009, 28, 4443. (b) Popp, B. V.; Wendlandt, J. E.; Landis, C. R.;
Stahl, S. S. Angew. Chem. 2007, 46, 601. (c) Gligorich, K. M.; Sigman,
M. S. Chem. Commun. 2009, 3854. (d) Sigman, M. S.; Jensen, D. R. Acc.
Chem. Res. 2006, 39, 221. (e) Urkan, K. B.; Sigman, M. S. Angew. Chem.,
Int. Ed. 2009, 48, 3146.
2688
Org. Lett., Vol. 12, No. 12, 2010

29 in 21% yield (Scheme 2). This clearly highlighted the
fact that the ester formation does not occur via the 1,2-
addition of boronic acids to aldehydes.
strated by the fact that no reaction took place in the absence
of boronic acid and a less reactive ester, formed with
phenylboronic acid, afforded the amide 30 in only 43%.
Scheme 2
.
Attempts To Prepare Aryl Benzoate from Benzoic
Acid and Aromatic Secondary Alcohols
Scheme 3. One-Pot Synthesis of Amides
In summary, we have developed an efficient methodology
to prepare benzoates and amides via the aerobic oxidative
aromatic esterification of aldehydes catalyzed by NHC-Fe
using boronic acids. This method uses equimolar amounts
of both the aldehyde and the boronic acids affording the
desired benzoates in yields up to 97%. The relatively mild
conditions, the use of air as the oxidant, and the possibility
of using aldehydes with multiple electronic profiles including
the alkylic ones constitutes a considerable improvement over
the existing methods.
Finally, in our standard reaction conditions (without
aldehyde) we did not observe a clear conversion of boronic
acid into phenol, though when we performed the reaction
between phenol and benzaldehyde under the optimized
reaction conditions, the ester 3 was obtained in 88%
suggesting that phenol may indeed be an intermediate of this
transformation. On the basis of the aforementioned, a
plausible mechanism for the benzoate esters formation may
involve the in situ generation of phenol species from the
boronic acid followed by the oxidative esterification of the
aldehyde.
Once the synthesis of this family of compounds was
established, we considered that the aryl benzoate could also
be used as a scaffold to prepare other molecules via
displacement of the phenol moiety. Therefore we attempted
the one-pot synthesis of amides directly from the aldehyde.
By simply adding an amine to the reaction mixture we were
able to convert the aldehyde into amides 30 and 31 (Scheme
3). This transformation proceeds via the ester formation
followed by the reaction with the amine. This was demon-
Acknowledgment. The Fundac¸a˜o para a Cieˆncia e Tec-
nologia and FEDER (PTDC/QUI-QUI/099389/2008; SFRH/
BPD/46589/2008;/48219/2008;/65455/2009;REDE/1518/REM/
2005) are thanked for the financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL100302E
Org. Lett., Vol. 12, No. 12, 2010
2689