Aerobic oxidation of NHC-catalysed aldehyde esterifications with alcohols: Benzoin, not the Breslow intermediate, undergoes oxidation

Article abstract of DOI:10.1039/c3cc42597e

Benzoin (and neither the Breslow intermediate nor the NHC-aldehyde tetrahedral adduct) has been unambiguously identified as the oxidised species in aerobic NHC-catalysed aldehyde esterifications.

Full text of DOI:10.1039/c3cc42597e

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Aerobic oxidation of NHC-catalysed aldehyde
esterifications with alcohols: benzoin, not the Breslow
Cite this: DOI: 10.1039/c3cc42597e
intermediate, undergoes oxidation†
Eoghan G. Delany,a Claire-Louise Fagan,a Sivaji Gundala,a Kirsten Zeitler*b and
Stephen J. Connon*a
Received 9th April 2013,
Accepted 3rd June 2013
DOI: 10.1039/c3cc42597e
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Benzoin (and neither the Breslow intermediate nor the NHC–aldehyde
tetrahedral adduct) has been unambiguously identified as the oxidised
species in aerobic NHC-catalysed aldehyde esterifications.
In the previous communication,1 the first examples of broad scope,
efficient, N-heterocyclic carbene (NHC)-catalysed aerobic oxidative
methyl esterifications of aromatic aldehydes in the absence of alkylating
agents, solid stoichiometric oxidants or co-oxidation catalysts were
reported. Previously these reactions (when O2/air had been used as
the oxidant) had been postulated to proceed either through the
oxidation of the Breslow intermediate or its immediate precursor. We
wished to ascertain the nature of the oxidised intermediates that were
involved in these aerobic oxidative esterifications, and began by
examining the scope of the process with respect to the alcohol
component. If the reaction proceeds through a highly electrophilic acyl
triazolium 14 (Fig. 1), one would not expect to observe significant
differences between esterifications using different alcohols (Scheme 1).
Experiments were carried out using two sets of conditions
(Scheme 1): a 1 : 1 THF–alcohol solvent mixture (condition set A) and
use of 3.0 equivalents of alcohol in THF solvent (condition set B). We
commenced our study with a series of alcohols which form esters 3
(amenable to different deprotection methodologies). Both benzylic
and allylic alcohols were suitable substrates; providing the corres-
ponding products 4 and 5 in good (condition set B) to excellent yields
Scheme 1 Reaction scope: alcohol component. Yield determined by 1H NMR
spectroscopy using styrene (114 mL, 1 mmol, 1 equiv.) as an internal standard; yield
of isolated product given in parentheses. Transformation to 7, 8 and 9 performed at rt.
(condition set A) yields. The formation of the trichloroethanol-derived
6 proceeded in ca. 60% yield irrespective of the conditions employed.
Interestingly, the synthesis of the corresponding trifluoro-analogue 7
was limited by the volatility of the alcohol, and could only be formed
under condition set B. Similar difficulties were encountered with the
more hindered hexafluoroisopropanol – resulting in the formation of
8 in low yield. The more hindered and less acidic isopropanol proved
resistant to esterification: ester 9 could not be generated.
(1)
Using precatalyst 2 and DBU, 1 could also be cleanly oxidised to the
acid 10 in THF/H2O (10 : 1 v/v) in excellent isolated yield (eqn (1)).
Recently disclosed examples of imidazolium ion derived carbene-
mediated aerobic oxidations of aromatic aldehydes to carboxylic acids
in the presence of water2 either require significantly elevated tem-
peratures (60 1C) and reaction times >36 h (ref. 2a) or are only
efficacious with highly activated aldehyde substrates (e.g. formation of
10 with o10% yield).2b
Fig. 1 Current prevalent mechanistic rationales proposed in literature.
a Centre for Synthesis and Chemical Biology, Trinity Biomedical Sciences Institute,
School of Chemistry, The University of Dublin, Trinity College, Dublin 2, Ireland.
E-mail: connons@tcd.ie; Fax: +353 16712826
b
¨
¨
Institut fur Organische Chemie, Universitat Leipzig, D-04103 Leipzig, Germany.
E-mail: kzeitler@uni-leipzig.de; Fax: +49-341-97-36599
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for all new compounds. See DOI: 10.1039/c3cc42597e
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With the breadth of the reaction scope and the intriguing
dependency on steric effects established, we attempted to
divine some information regarding the reaction mechanism.
The results of our studies (outlined in Scheme 1) are not readily
reconciled with either ‘oxidative’ or ‘oxygenative’ mechanisms (Fig. 1).3
For instance, the ‘oxygenative’ esterification reaction requires alkyl
transfer from an electrophile (such as an alkyl halide). The ‘oxidative’
esterification mechanism is also unsatisfactory here, as the sensitivity of
the process described in this work to the steric bulk of both the
nucleophilic and electrophilic reaction components is not consistent
with that we observed in a previous study involving the use of
azobenzene as a stoichiometric reactant4 (e.g. in esterifications involving
azobenzene as an oxidant, o-tolualdehyde and isopropanol served as
excellent coupling partners, while in the current study both are poor
substrates). This strongly indicates that our aerobic oxidative esterifica-
tions outlined above do not proceed via acyl azolium ion intermediates.
Since the esterifications do not proceed in the absence of O2, we
were forced to consider alternative species which are oxidised in
these reactions. The most likely candidate appeared to be benzoin
(16) – the slow, base-catalysed aerobic oxidation of which to benzil
(17) by O2 is known.5 While we never isolated/observed 17 in any of
the reactions outlined above, it is a highly electrophilic species:
therefore its rapid destruction in the presence of the relatively
unhindered carbene derived from 2 and methanol would not be
implausible. In addition, while the sensitivity of the esterifications to
steric factors did not match that of known processes involving acyl
azolium ions, it was consistent with the influence of steric bulk on
the benzoin condensation,6 which encouraged us to further inves-
tigate in the direction of this hypothesis.
Scheme 3 The anaerobic conversion of benzil to methyl benzoate.
Under these conditions we observed rapid conversion of 17 to
methyl benzoate (19), 16 and aldehyde 1 at ambient temperature
(Scheme 3).9,10 Similarly, the carbene-catalysed reaction of 16 with an
equivalent amount of 17 in the absence of both air and MeOH generated
the hydroacylation product 18 as the major constituent of the crude
reaction mixture (Scheme 4), indicating that benzoin may also be able
to play the role of the nucleophilic alcohol in these reactions.11
The hydroacylation product 18 is conspicuously absent in the
1H NMR spectra of reactions involving methanol or other smaller
alcohols. Therefore we next assessed the stability of 18 under
anerobic reaction conditions; whereupon smooth acyl transfer to
afford methyl benzoate (19) in excellent yield was observed (eqn (2)).
(2)
Finally, to gain some insight regarding the origins of the influence of
the alcohol structure on reaction efficiency, benzil (17) was reacted
in the presence of the NHC under anaerobic conditions in a
competition experiment using alcohol and water solvent mixtures
(yielding either an ester or acid resp., Scheme 5).12 We expected
products derived from nucleophilic attack of the less hindered water
molecule to dominate over the ester analogues stemming from the
more hindered alcohols. Surprisingly, the 1 : 1-solvent mixture of
methanol and water generated the methyl ester 19 as the major
We began by subjecting benzaldehyde (1) to the esterification
conditions in the absence of methanol.7 To our delight, we observed
the formation of both 16 and 17 after just 5 min reaction time
(Scheme 2). After 20 min, both these species have been replaced by a
hydroacylation product 18 (in good yield) and the acid 10 (presum-
ably formed due to the presence of adventitious water).
Chan and Scheidt8 have previously reported the formation of 18 in
the NHC-mediated reaction between 1 and 17. They rationalised this in
terms of a hydride transfer process between the carbene–aldehyde
adduct and 17, which generates an acyl azolium ion and benzoin
(Scheme 2, inset). To the best of our knowledge the reaction outlined in
Scheme 2 is the first example of the efficient NHC-mediated formation
of a hydroacylation product from an aldehyde alone in the presence of
air. Next, we attempted to establish if 17 is a catalytically relevant
intermediate in the presence of alcohol. Accordingly, benzil was
exposed to methanol and the carbene under an argon atmosphere.
Scheme 4 The NHC-mediated reaction of benzil with benzoin in the absence of O2.
Scheme 2 The observation of benzil in the absence of methanol.
Scheme 5 Competition between alcohols and water.
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The formation of benzoin (16) from benzil (17) in the absence of O2
(but presence of CH3OH) also requires explanation: we would suggest
that – by analogy with a recent proposal10 in a distinct but related
transformation – attack by the enaminol 23 on diketone 17 would yield
27 (isolated by Massi et al.10). In the presence of excess base and
methanol, the cleavage of 27 to yield ester 19 and 16 via hemiacetal 28
is conceivable. This model was supported by the inefficiency of the
corresponding amidation chemistry (Scheme 6) involving pyrrolidine –
a more nucleophilic but less acidic reagent than MeOH.
We suggest that this may be related to the attack of the more
hindered amine on the very bulky ketone 25. This reaction
would also be hampered by considerably less efficient general
base catalysis of the attack on the ketone involving the con-
siderably less acidic amine.
In summary these reactions have been shown to be mechan-
istically distinct from other either NHC-catalysed ‘oxidative’ or
‘oxygenative’ esterifications in that the species which reacts with
oxygen in the air is not the Breslow intermediate, but the aryloin
(or more accurately, its enolate). In aqueous solvent benzoic acid
(10) is accessible from aldehyde 1 in excellent yield. Investigations
to further develop the scope and utility of these reactions are
underway. Financial support from the IRCSET, Science Founda-
tion Ireland and the DFG is gratefully acknowledged.
Fig. 2 Mechanistic rationale: all highlighted compounds have been either
isolated and/or detected in situ.
product (Scheme 5A; only low levels of acid 10 and aldehyde 1). The
use of ethanol as a co-solvent also diverted the process towards the
generation of ester 20 (Scheme 5B), however, acid formation was
more favourable here (together with of small amounts of aldehyde 1
and benzoin 16). In aqueous isopropanol conversion is incomplete.
No esterification occurs: oxidation to 10 and reversion to aldehyde 1
are the major fates of 17 (Scheme 5C). It appears that the factors
which govern selectivity in these processes are not simply related to
either acidity or steric bulk, but a confluence of factors: a weak
correlation between acidity and propensity for ester formation was
found, while the outcome of the experiment involving isopropanol is
difficult to rationalise based on its pKa alone.13
Overall, a mechanistic rationale consistent with the data outlined
above is shown in Fig. 2. The carbene 22 reacts with 1 to form the
enaminol 23, which, on addition to another molecule of 1 results in the
rapid formation of 16 (also see Scheme 2), which is oxidised by air in
the presence of base to benzil (17).14 Since our results are not consistent
with acyl azolium ion formation, we would propose that the electro-
philic diketone 17 is attacked by NHC 22 to give the tetrahedral
intermediate 25, which is converted to 26 (presumably via intra-
molecular general base catalysis – also see Scheme 2). The hemiacetal
26 (ref. 15) can then collapse to reform the enaminol 23 and methyl
benzoate 19. The formation of the hindered hemiacetal 26 would be
likely to depend on both the steric bulk and the pKa of the alcohol. In
the absence of added alcohol, it is possible that a similar process occurs
involving 16 as the nucleophile, which affords the hydroacylation
product 18. In the presence of MeOH 18 is converted to 16 via 24
(also see eqn (2)).16
Notes and references
1 E. G. Delany, C.-L. Fagan, S. Gundala, A. Mari, T. Broja, K. Zeitler
and S. J. Connon, DOI: 10.1039/c3cc42596g.
2 (a) W. Yang, G.-Z. Gou, Y. Wang and W.-F. Fu, RSC Adv., 2013,
3, 6334; (b) M. Yoshida, Y. Katagiri, W.-B. Zhu and K. Shishido, Org.
Biomol. Chem., 2009, 7, 4062.
3 C. E. I. Knappke, A. Imami and A. J. von Wangelin, ChemCatChem,
2012, 4, 937.
4 C. Noonan, L. Baragwanath and S. J. Connon, Tetrahedron Lett.,
2008, 49, 4003.
5 (a) J. L. Ihrig and R. G. Caldwell, J. Am. Chem. Soc., 1956, 78, 2097;
(b) T. C. Bruice and J. P. Taulane, J. Am. Chem. Soc., 1976, 98, 7769.
6 (a) L. Baragwanath, C. A. Rose, K. Zeitler and S. J. Connon, J. Org.
Chem., 2009, 74, 9214; (b) S. E. O’Toole and S. J. Connon, Org.
Biomol. Chem., 2009, 7, 3584; (c) S. E. O’Toole, C. A. Rose,
S. Gundala, K. Zeitler and S. J. Connon, J. Org. Chem., 2011,
76, 347; (d) C. A. Rose, S. Gundala, S. J. Connon and K. Zeitler,
Synthesis, 2011, 190; (e) C. A. Rose, S. Gundala, C.-L. Fagan,
J. F. Franz, S. J. Connon and K. Zeitler, Chem. Sci., 2012, 3, 735.
7 Quoted yields within the figures are determined by 1H NMR spectro-
scopy with an internal standard. See the ESI† for details.
8 A. Chan and K. A. Scheidt, J. Am. Chem. Soc., 2006, 128, 4558.
9 This process features a comparison of reactions of different mole-
cularity; therefore (to avoid confusion), we have quote the yields as
mmol of product.
10 It is noteworthy that Massi et al. have recently observed the benzoyla-
tion of PEG400 on treatment of benzil with a thiazolium ion-derived
NHC, see: O. Bortolini, G. Fantin, M. Fogagnolo, P. P. Giovannini,
V. Venturi, S. Pacifico and A. Massi, Tetrahedron, 2011, 67, 8110.
11 It must be acknowledged that reversion of 16 to 1, followed by a
hydroacylation reaction as proposed by Scheidt (see Scheme 2)
cannot be ruled out at this juncture.
12 For use of an unsymmetrical benzil, see the ESI†.
13 It is noteworthy that in mixtures with MeCN, MeOH has been found
to be more nucleophilic than EtOH: (a) S. Minegishi, S. Kobayashi
and H. Mayr, J. Am. Chem. Soc., 2004, 126, 5174; (b) T. B. Phan and
H. Mayr, Can. J. Chem., 2005, 83, 1554.
14 In a control experiment under standard aerobic conditions in the
absence of 2, 16 (1.0 mmol) was converted to 17 (0.19 mmol) after
just one 1 h reaction time.
15 We note that a similar intermediate has been suggested (in a different
process) by Massi et al., see ref. 10.
16 This process occurs in both the presence and absence of 2.
Scheme 6 The NHC-mediated oxidative amidation of 1.
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