Selenide ions as catalysts for homo- and crossed-Tishchenko reactions of expanded scope

Article abstract of DOI:10.1021/ol203439g

Selenide ions have been shown to catalyze the Tishchenko reaction for the first time. These catalysts are superior to previously reported thiolate analogues and promote the disproportionation of aldehydes with increased reaction rates and broader scope at lower catalyst loadings and temperatures. Significantly improved catalyst performance was also observed in the aryl selenide mediated crossed intermolecular Tishchenko reaction.

Full text of DOI:10.1021/ol203439g

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1074–1077
Selenide Ions as Catalysts for Homo- and
Crossed-Tishchenko Reactions of
Expanded Scope
Simon P. Curran and Stephen J. Connon*
School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity Biomedical
Sciences Institute, University of Dublin, Trinity College, Dublin 2, Ireland
connons@tcd.ie
Received December 23, 2011
ABSTRACT
Selenide ions have been shown to catalyze the Tishchenko reaction for the first time. These catalysts are superior to previously reported thiolate
analogues and promote the disproportionation of aldehydes with increased reaction rates and broader scope at lower catalyst loadings and
temperatures. Significantly improved catalyst performance was also observed in the aryl selenide mediated crossed intermolecular Tishchenko
reaction.
The Tishchenko reaction (in its simplest form) involves
the disproportionation of two aldehyde molecules to
generate a single coupled ester product.1 Several promo-
ters have been developed for this metal-ion-catalyzed2À6
Cannizarro-type7 process. However, it has been regarded
more as a mechanistic curiosity than as a powerful synthetic
tool by contemporary chemists, despite over a century of
research, largely due to a narrow substrate scope, which
until recently8 was limited (in an intermolecular context) to
the homocoupling of aldehydes, in often variable yields.9
Inspired by the mode of action of the glycolytic enzyme
glyceraldehyde-3-phosphate dehydrogenase, involving hy-
dride transfer from a hemithioacetal-based intermediate
(A, Scheme 1),10 we recently developed the first thiolate-
catalyzed Tishchenko processes (A, Scheme 1).11,12 The
smooth conversion of benzaldehyde (1) to the corresponding
(1) (a) Claisen, L. Ber. Dtsch. Chem. Ges. 1887, 20, 646. (b)
Tischtschenko, W. J. Russ. Phys. Chem. 1906, 38, 355. (c) Tischtschenko, W.
Chem. Zentralbl. 1906, 771, 1309.
(2) Boric acid: Stapp, P. R. J. Org. Chem. 1973, 38, 1433.
(3) Aluminium alkoxides: (a) Child, W. C.; Adkins, H. J. Am. Chem.
Soc. 1925, 47, 798. (b) Villani, F. J.; Nord, F. J. Am. Chem. Soc. 1947, 69,
2605. (c) Lin, L.; Day, A. R. J. Am. Chem. Soc. 1952, 74, 5133. (d)
Saegusa, T.; Ueshima, T. J. Org. Chem. 1968, 33, 3310. (e) Ooi, T.;
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(4) Transition-metal-based catalysts (selected examples): (a) Yamashita,
M.; Watanabe, Y.; Mitsudo, T.; Takegami, Y. Bull. Chem. Soc. Jpn. 1976,49,
3597. (b) Ito, T.; Horino, H.; Koshiro, Y.; Yamamoto, A. Bull. Chem. Soc.
Jpn. 1982, 55, 504. (c) Bergens, S. H.; Fairlie, D. P.; Bosnich, B. Organo-
metallics 1990, 9, 566. (d) Morita, K.; Nishiyama, Y.; Ishii, Y. Organo-
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Chem 1993, 7, 357. (f) Barrio, P.; Esteruelas, M. A.; Onate, E. Organo-
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K.; Katoh, T. Synlett 2005, 1450. (h) Ogoshi, S.; Hoshimoto, Y.; Ohashi, M.
Chem. Commun. 2010, 46, 3354.
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R.; Abaee, M. S. Org. Lett. 2007, 9, 2791. (b) Waddell, D. C.; Mack, J.
Green Chem. 2009, 11, 79. (c) Werner, T; Koch, J. Eur. J. Org. Chem.
2010, 6904.
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A. G. M.; Hill, M. S.; Procopiou, P. A. Org. Lett. 2007, 9, 331. (b) Day,
B. M.; Mansfield, N. E.; Coles, M. P.; Hitchcock, P. B. Chem. Commun.
2011, 47, 4995.
(7) Cannizzaro, S. Justus Liebigs. Ann. 1853, 88, 129.
(8) Very recently the first examples of the selective intermolecular
cross-coupling of aliphatic with aromatic aldehydes has been reported:
Ogoshi, S.; Hoshimoto, Y.; Ohashi, M. J. Am. Chem. Soc. 2011, 133,
4668.
(9) Recent reviews: (a) Seki, T.; Nakajo, T.; Onaka, M. Chem. Lett.
€
€
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Freeman: New York, 2002; p 433. (b) Soukri, A.; Mougin, A.; Corbier, C.;
Wonacott, A.; Branlant, C.; Branlant, G. Biochemistry 1989, 28, 2856.
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r
10.1021/ol203439g
Published on Web 02/03/2012
2012 American Chemical Society

benzoate ester 2 upon exposure to an in situ formed
simple bromomagnesium thiolate derived from 4-
tert-butylbenzylmercaptan (3) was possible in excellent
yield. The proposed mechanism (B, Scheme 1) involves
initial attack of the thiolate on the aldehyde to furnish
4, which then transfers a hydride to another molecule of
1 to form both the alkoxide 5 and thioester 6, which
then couple to give 2 and the regenerated catalyst,
which re-enters the cycle. Somewhat suprisingly, it is
the acyl transfer (and not the hydride transfer) process
which is rate-determining.11
Table 1. Homo-Tishchenko Reaction of Aldehydes at 25 °C
Scheme 1. Thiolate-Catalyzed Tishchenko Reactions: Condi-
tions and Mechanistic Rationale
The process is of relatively broad scope and provided
consistently high yields of homodimers from a range of
substituted benzaldehydes for the first time. A key
strength of the methodology is the control achievable
through the modification of the thiol component,
which is present in two key reaction steps: the addition
of the thiolate to the aldehyde to form 4, and the acyl
transfer process (as the leaving group associated with
thioester 6). This allowed the development of the first
crossed intermolecular Tishchenko reactions between
aldehydes and (trifluoromethyl)ketones catalyzed by
less nucleophilic substituted aryl thiolates. We later
found that the use of microwave irradiation allowed a
significant reduction in the reaction time,12 with little
impact on either scope or efficacy.
a Isolated yield. b Determined by 1H NMR spectroscopy using an
internal standard.
Nonetheless, significant scope for improvement re-
mained. In particular, it was desirable to remove the
requirement for reflux temperatures, relatively high cata-
lyst loadings, and extended reaction times up to 96 h. The
extension of the substrate scope to include aldehydes that
incorporated metal-chelating functionality and an increase
in the efficiency of reactions involving aliphatic aldehydes
would also be important, if the process was to be consid-
ered of general utility.
enough to generate the reductant (i.e., 4) efficiently, while
also serving as a powerful leaving group in the subsequent
acyl transfer process, we postulated that the corresponding
alkyl selenide anions might serve as superior catalyst
systems. Examples of selenium-based catalysts are rare,13
and to the best of our knowledge, only one report has
emerged involving the use of a nucleophilic (in situ
generated) selenide ion as a catalyst (to promote the
formation of alkenes from 1,2-dimesylalkanes) in the
literature.14
Since the key to efficient promotion of this reaction
appeared to be the use of a catalyst which was nucleophilic
Our preliminary investigations were hampered by the
difficulty in generating the requisite magnesium sele-
nide counterpart of the previously used thiolates con-
veniently in the absence of other metal ions, oxygen
(which leads to rapid oxidation of the alkylselenide to
(11) Cronin, L.; Manoni, F.; O’Connor, C. J.; Connon, S. J. Angew.
Chem., Int. Ed. 2010, 49, 3045.
(12) O’Connor, C. J.; Manoni, F.; Curran, S. P.; Connon, S. J. New J.
Chem. 2011, 35, 551.
Org. Lett., Vol. 14, No. 4, 2012
1075

Table 2. Crossed Intermolecular Tishchenko Reaction
Scheme 2. Crossed-Tishchenko Reactions: Catalyst Screening
the diselenide), and moisture (resulting in competitive
acyl selenide hydrolysis). After considerable experi-
mentation, it was found that the addition of com-
mercially available dibutyl magnesium to dibenzyl dis-
elenide in THF at room temperature led to rapid
formation of the desired alkyl selenide in solution. We
then evaluated this reagent as a catalyst in the homo-
Tishchenko reaction of aldehydes (Table 1).
We were delighted to find that the benzyl selenide
anion, at only 2.5 mol % loading, was capable of
promoting the dimerization of benzaldehyde in essen-
tially quantitative isolated yield at 25 °C (entry 1). We
found that the use of molecular sieves led to improved
catalytic efficacy, most likely due to the suppression of
deleterious acyl seleonate hydrolysis by adventitious
water. The isolation of the butylbenzyl selenide 7 from
the reaction mixture and the superiority of a catalyst
derived from a 1:2 (as opposed to a 1:1) mole ratio of
alkyl magnesium to diselenide strongly indicated that
the catalytically active species was the selenide 8.
Electron-deficient, -neutral, and -rich aldehydes could
be converted to the esters 9, 10, 11 (a product of
potential interest as a polymer synthesis substrate),
and 12 respectively (entries 2À5) in excellent yield at
low loadings relative to those required in the analogous
thiolate-catalyzed reactions.
A problem traditionally associated with Tishchenko
chemistry is the transformation of substrates bearing
(13) Electrophilic or radical selenium-based catalysts: (a) ten
Brink, G.-J.; Vis, J.-M.; Arends, I. W. C. E.; Sheldon, R. A. J. Org.
Chem. 2001, 66, 2429. (b) Wojtowicz, H.; Brzaszcz, M.; Kloc, K.;
Mzochowski, J. Tetrahedron 2001, 57, 9743. (c) Crich, D.; Sannigrahi,
M. Tetrahedron 2002, 58, 3319. (d) Miyake, Y.; Nishibayashi, Y.;
Uemura, S. Bull. Chem. Soc. Jpn. 2002, 75, 2233. (e) Crich, D.;
Rumthao, S. Tetrahedron 2004, 60, 1513. (f) Ichikawa, H.; Usami,
Y.; Arimoto, M. Tetrahedron Lett. 2005, 46, 8665. (g) Crich, D.; Patel,
~
M. Org. Lett. 2005, 7, 3625. (h) Lenardao, E. J.; Mendes, S. R.;
a Isolated yield. b Determined by 1H NMR spectroscopy using an
internal standard.
Ferreira, P. C.; Perin, G.; Silveira, C. C.; Jacob, R. G. Tetrahedron
Lett. 2006, 47, 7439. (i) Browne, D. M.; Niyomura, O.; Wirth, T. Org.
Lett. 2007, 9, 3169. (j) Clive, D. L. J.; Pham, M. P.; Subedi, R. J. Am.
Chem. Soc. 2007, 129, 2713. (k) Browne, D. M.; Niyomura, O.; Wirth,
T. Phosphorus, Sulfur, and Silicon 2008, 183, 1026. (l) Lenardao, E. J.;
Feijo, J. O.; Thurow, S.; Perin, G.; Jacob, R. G.; Silveira, C. C.; Jacob,
R. G. Tetrahedron Lett. 2009, 50, 5215. (m) Shahzad, S. A.; Venin, C.;
Wirth, T. Eur. J. Org. Chem. 2010, 3465. (o) Singh, F. V.; Wirth, T.
Org. Lett. 2011, 13, 6504.
(14) Crich, D.; Neelamkavil, S.; Sartillo-Piscil, F. Org. Lett. 2000, 2,
4029.
metal-chelating functionality.2À6,11 This has led to alde-
hydes possessing heterocyclic substituents residing largely
outside the orbit of the methodology. Here, the conversion
of pyridine-3-carbaldehyde and thiophene-2-carbaldehyde
to 13 and 14 respectively occurs in excellent yield at 5 mol %
~
ꢀ
1076
Org. Lett., Vol. 14, No. 4, 2012

catalyst loading (entries 6À7). 2-Furfural was a more
recalcitrant substrate, yet 15 could be prepared from this
aldehyde in good yield (entry 8).
Another obstacle which the previous thiolate-based
catalysts found difficult to negotiate was the disproportio-
nation of the aliphatic aldehyde 16, due to competing aldol
pathways at high temperature. Gratifyingly, in the pre-
sence of catalyst 8, ester 16 was isolated in near-quantitative
yield (entry 9).
it was found that both unsubstituted, activated, and
deactivated R,R,R-trifluoromethylacetophenones were
compatible with the methodology, furnishing the coupled
products 18 and 21À23 in excellent yields (entries 1À4).
By keeping the ketone substrate constant and vary-
ing the aldehyde component, it was demonstrated that
electron-neutral, -rich, and (strongly) -withdrawing substitu-
ents on the aromatic ring were also well tolerated by the
catalyst (i.e., 24À28, entries 5À9). Previously challenging
heterocyclic aldehydes incorporating chelating functional-
ity (even the particularly recalcitrant 2-furfural) proved
amenable to coupling, allowing the synthesis of 29À31 in
good to excellent yields for the first time (entries 10À12).17
Finally, the activity of this catalyst system allowed the
coupling of a heterocyclic aldehyde with either a substi-
tuted trifluoroacetophenone (entry 10) or a heterocyclic
analogue (entry 11) to generate ester products (32 and 33)
also outside the scope of the previous literature benchmark
methodology.
In summary, the exchange of selenide ions for thiolates as
catalysts in the Tishchenko reaction leads to faster rates at
lower catalyst loadings and reaction temperatures. A sig-
nificant expansion of reaction scope is also possible; high
yields of products derived from the disproportionation of a
hitherto problematic hindered aliphatic aldehyde and het-
erocyclic substrates, previously capable of disrupting the
catalytic cycle by metal chelation, can now be subjected to
efficient homo- and crossed Tishchenko chemistry. A simple
dibenzyldiselenide-derived catalyst can be utilized in the
homo-Tishchenko reaction, while the crossed intermolecu-
lar variant involving activated ketones requires an arylsele-
nide catalyst that is better able to accelerate the slow acyl-
transfer step.
With a convenient methodology of improved activity
and scope in hand, we next investigated its use in inter-
molecular crossed-Tishchenko chemistry using trifluoro-
methylketone electrophiles. This process was previously
developed using thiolate catalysts, and it was found that
the use of a catalyst which (when acylated) conferred high
electrophilicity on the thioester was the key to securing
high catalytic activity. This arises due to the poor nucleo-
philicity of the relatively hindered and less basic magne-
sium alkoxide 17a, formed after the hydride transfer step,
which retards an already inherently sluggish acyl transfer
process.
Accordingly, we attempted the 1:1 coupling of benzal-
dehyde (1) with R,R,R-trifluoromethylacetophenone (17)
in the presence of dibutylmagnesium and dibenzyldisele-
nide, diphenyldiselenide (19), or its m-CF3 substituted
analogue 20 at 25 °C (Scheme 2). As expected, the simple
alkyl selenide 8 (i.e., derived from dibenzyldiselenide) was
not efficacious in this more challenging reaction. The
corresponding aryl selenide ions prepared from 19 and
20 proved superior, with the m-CF3 substituted catalyst
capable of synthetically useful activity. We would propose
that this is mainly due to the formation of the highly
electrophilic acylating agent 20a.
We were now in a position to evaluate the scope of the
intermolecular15 crossed-Tishchenko process (Table 2).16
Here the superiority of the selenide-based system is perhaps
most readily apparent. Beginning by using benzaldehyde as
the aldehyde component and varying the ketone substrate,
Studies to further explore the potential of alkyl/aryl
selenides as nucleophilic catalysts are underway.
Acknowledgment. This material was based on work
funded by The European Research Council.
(15) For related intramolecular Tishchenko and Tishchenko-like
processes, see: (a) Lu, L.; Chang, H.-Y.; Fang, J.-M. J. Org. Chem.
1999, 64, 84. (b) Hsu, J. L.; Fang, J. M. J. Org. Chem. 2001, 66, 8573. (c)
Shen, Z.; Khan, H. A.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2916.
(d) Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131,
15608. (e) Omura, S.; Fukuyama, T.; Murakami, Y.; Okamoto, H.; Ryu, I.
Chem. Commun. 2009, 6741.
Supporting Information Available. General experimen-
tal procedures, catalyst synthesis, 1H and 13C NMR
spectra, characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) We use the term ‘crossed’ in a Tishchenko reaction context. This
does not refer to Tishchenko variants such as the Tishchenko-aldol (see
ref 16a) or TishchenkoÀMichael (for an example see ref 16b) reactions:
(a) Mlynarski, J. Eur. J. Org. Chem. 2006, 4779. (b) Michrowska, A.;
List, B. Nat. Chem. 2009, 1, 225.
(17) Aliphatic aldehydes are currently incompatible with this
crossed-Tishchenko methodology.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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