Microwave-assisted efficient thiolate-catalysed homo- and crossed intermolecular Tishchenko reactions

Article abstract of DOI:10.1039/c0nj00790k

Recently, the first efficient intermolecular crossed Tishchenko reactions were reported. The utility of these processes is curtailed by long reaction times of up to 4 days (at reflux). Herein we report that these reactions are highly susceptible to acceleration by microwave irradiation-allowing fast, efficient, high-yielding coupling to proceed in 10-180 min.

Full text of DOI:10.1039/c0nj00790k

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LETTER
Microwave-assisted efficient thiolate-catalysed homo- and crossed
intermolecular Tishchenko reactionsw
Cornelius J. O’ Connor, Francesco Manoni, Simon P. Curran and
Stephen J. Connon*
Received (in Gainesville, FL, USA) 12th October 2010, Accepted 13th January 2011
DOI: 10.1039/c0nj00790k
Recently, the first efficient intermolecular crossed Tishchenko
reactions were reported. The utility of these processes is
curtailed by long reaction times of up to 4 days (at reflux).
Herein we report that these reactions are highly susceptible to
acceleration by microwave irradiation—allowing fast, efficient,
high-yielding coupling to proceed in 10–180 min.
The Tishchenko reaction1,2 is a hydride-transfer mediated
process related to (but potentially more synthetically useful
than) the Cannizzaro reaction,3 where two aldehyde molecules
can undergo disproportionation, with subsequent coupling to
form a single ester product. This intriguing aldehyde-to-ester
transformation reaction has been known for over a century,
yet few practical applications of the process have been developed
Fig. 1 The thiolate catalysed homo-Tishchenko reaction.
and it is little-used as a synthetic strategy by contemporary
chemists.4
There are several limitations which have curtailed the utility
as intermediates (Fig. 1) and a slow acyl-transfer step was
and applicability of the reaction: several metal-based catalytic
obtainable by 1H NMR spectroscopy. This mechanistic
systems for promoting the reaction have been devised,5–10
information subsequently guided the development of thiol
however the reaction is of poor substrate scope: only ‘dimer-
precatalysts tailored to promote the first selective inter-
isation’ of aldehydes was possible, yields of homo-Tishchenko
molecular16 crossed-Tishchenko reactions between aldehydes
esters using substituted benzaldehyde substrates are often
and activated ketones.
variable and until recently the coupling of aldehydes to
The major drawback associated with this protocol was the
ketones (in an intermolecular context) was unknown.4
reaction rate—the reaction must be held at reflux temperature
Recently—inspired by the mode of action of the glycolytic
for prolonged times: up to 4 days for cases involving recalcitrant
enzyme glyceraldehyde-3-phosphate dehydrogenase11–13—we
substrates. Cognisant of the impact long reaction times
developed the first thiol(ate) catalysed Tishchenko reactions.14
will have on the widespread applicability and utility of the
The catalysts required are simple, inexpensive thiols, used in
reaction, we embarked on a programme aimed at increasing
the presence of a Grignard reagent base.15 Homo-Tishchenko
the reaction rate without resorting to the use of impractical
reactions involving either benzaldehyde or (significantly) sub-
catalyst loadings.
stituted analogues proceeded in good–excellent yields with
The reaction is most efficient in ethereal solvents (THF
5–20 mol% catalyst loading (Fig. 1).
was identified as the optimal medium studied in our initial
Perhaps more significantly, considerable direct evidence
investigations);17 thus we attempted to carry out the process in
supporting the proposed reaction mechanism involving 2–4
higher boiling ethers such as 2-methyltetrahydrofuran and
1,4-dioxane (at reflux), without observing any rate acceleration.
It was next decided to investigate the effect of microwave
Centre for Synthesis and Chemical Biology, School of Chemistry,
University of Dublin, Trinity College, Dublin 2, Ireland.
E-mail: connons@tcd.ie; Fax: +353 16712826
w Electronic supplementary information (ESI) available: General
experimental procedures, 1H and 13C NMR spectra for all crossed
products, characterisation data for all new products. See DOI:
10.1039/c0nj00790k
radiation on the process. The results of our preliminary
experiments involving the microwave-aided homo-Tishchenko
reaction are outlined in Table 1.
We were very pleased to observe significant rate accelerations
on irradiating to a maximum reaction temperature of 110 1C
c
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New J. Chem., 2011, 35, 551–553 551

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Table 1 Microwave-assisted homo-Tishchenko reactions
Table
reactions
2
Microwave-assisted intermolecular crossed-Tishchenko
Entry
1
Product
Time/h
3
Yielda (%)
82
Entry Catalyst Loading/mol% Conc./M Time/min Yielda (%)
1
2
3
4
5
6
8
9
10
8
8
8
8
8
8
8
10
10
10
10
10
10
10
5
0.68
0.68
0.68
1.0
1.2
1.2
1.8
1.8
1.8
2.0
10
10
10
10
10
30
10
30
10
30
70
64
28
85
83
82
85
92 (90)
85
91
2
3
81
7
8b
9
3
4
5
3
3
3
81
5
5
10
a
Determined by 1H NMR spectroscopy using (E)-stilbene as an
b
internal standard. Isolated yield in parenthesis.
63
under conditions otherwise identical to those used in the
original study.14,18 Under these conditions 4-tert-butylbenzyl-
mercaptan (8—at 10 mol% levels) could promote the formation
of benzyl ester 7 from benzaldehyde (6) in good yield in only
10 minutes (entry 1). As expected, catalysts 9 and 10, which
previously proved useful in the catalysis of crossed Tishchenko
reactions, were less effective here (entries 2–3).19
51b
6
7
8
9
3
3
2
3
68
0
We next set about optimising the conditions associated with
the microwave-mediated process. Increasing the reaction
concentration (a desirable modification in its own right)
resulted in a marked improvement in product yields: a
concentration of 1.0–1.2 molar allowed the formation of 7 in
yields >80% (entries 4–6), while using 1.8–2.0 M reaction
concentrations makes the isolation of 7 in >90% yield
possible after 30 minutes reaction time with a reduced catalyst
loading of 5 mol% (entries 7–10). It is noteworthy that a
minimum of 10 mol% catalyst loading was required to achieve
a product yield of >90% in the corresponding thermal
process reported previously.14 Attempted reactions at
concentrations higher than 2.0 M led to poor solubility and
inconsistent results.
73
83
Attention now turned to the more challenging crossed-
Tishchenko process (Table 2). In these reactions, acyl-transfer
between the thioester intermediate and the ketone-derived
alkoxide (after hydride transfer) is rate-determining; therefore
use of the substituted thiophenol catalyst 10 (which results in a
more electrophilic thioester intermediate which undergoes
more rapid acyl-transfer) is required. Treatment of a 1 : 1
mixture of benzaldehyde and 2,2,2-trifluoromethylacetophenone
in THF under microwave irradiation in the presence of 10
(20 mol%) resulted in the formation of the coupled product 11
in high yield (entry 1) after only 3 hours. The reaction
proceeded chemoselectively—1H NMR spectroscopic analysis
did not detect any homo-Tishchenko product (i.e. 7) in the
crude reaction mixture.
10
11
3
76
3
3
56c
12
34c,d
Isolated yields. Determined by 1H NMR spectroscopy using
a
b
c
(E)-stilbene as an internal standard. Using 2.0 equiv. of the ketone.
d
Isolated as a 4 : 1 mixture of diastereomers.
c
552 New J. Chem., 2011, 35, 551–553
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Benzaldehyde could also be reacted with halo-substituted
activated ketones to furnish 12–14 without difficulty
(entries 2–4). The (relatively) deactivated 2-thiophenyl
substituted ketone proved a more challenging substrate which
afforded ester 15 in 51% yield (entry 5). Substituted benzalde-
hydes also participate in the process—use of 2-naphthaldehyde
gave 16 in good yield (entry 6), however the highly hindered
mesitaldehyde appears to be beyond the orbit of this methodology
and failed to produce 17 under these conditions (entry 7).
Smooth coupling was observed in cases involving halobenzal-
dehydes and trifluoromethylketones within 3 hours reaction
time (18–20, entries 8–10).
5 For the use of aluminium alkoxides see: (a) W. C. Child and
H. Adkins, J. Am. Chem. Soc., 1925, 47, 798; (b) F. J. Villani and
F. Nord, J. Am. Chem. Soc., 1947, 69, 2605; (c) L. Lin and
A. R. Day, J. Am. Chem. Soc., 1952, 74, 5133; (d) T. Saegusa
and T. Ueshima, J. Org. Chem., 1968, 33, 3310; (e) T. Ooi,
T. Miura, K. Takaya and K. Maruoka, Tetrahedron Lett.,
1999, 40, 7695; (f) T. Ooi, K. Ohmatsu, K. Sasaki, T. Miura and
K. Maruoka, Tetrahedron Lett., 2003, 44, 3191; (g) Y.
Hon, C. Chang and Y. Wong, Tetrahedron Lett., 2004, 45,
3313.
6 For the use of boric acid see: P. R. Stapp, J. Org. Chem., 1973, 38,
1433.
7 For selected examples using transition-metal catalysts see:
(a) T. Ito, H. Horino, Y. Koshiro and A. Yamamoto, Bull. Chem.
Soc. Jpn., 1982, 55, 504; (b) K. Morita, Y. Nishiyama and Y. Ishii,
Organometallics, 1993, 12, 3748; (c) M. Yamashita, Y. Watanabe,
T. Mitsudo and Y. Takegami, Bull. Chem. Soc. Jpn., 1976, 49,
3597; (d) M. Yamashita and T. Ohishi, Appl. Organomet. Chem.,
1993, 7, 357; (e) P. Barrio, M. A. Esteruelas and E. Onate,
Organometallics, 2004, 23, 1340; (f) S. H. Bergens, D. P. Fairlie
and B. Bosnich, Organometallics, 1990, 9, 566; (g) T. Suzuki,
T. Yamada, T. Matsuo, K. Watanabe and T. Katoh, Synlett,
2005, 1450.
8 For the use of Group I metal salts: (a) M. M. Mojtahedi,
E. Akbarzadeh, R. Sharifi and M. S. Abaee, Org. Lett., 2007, 9,
2791; (b) D. C. Waddell and J. Mack, Green Chem., 2009, 11, 79.
9 For the use of lanthanide/actinide metal complexes see:
(a) S.-Y. Onozawa, T. Sakakura, N. Tanaka and M. Shino,
Tetrahedron, 1996, 52, 4291; (b) H. Berberich and P. W. Roesky,
Of particular interest is the coupling of an aliphatic
aldehyde (entry 11) with trifluoromethylacetophenone. This
reaction is complicated by competing deleterious thiolate-
catalysed aldol pathways, however in the presence of a modest
excess of the ketone (entry 11), a substantial yield of the
coupled product 21 could be isolated. The use of the more
enolisable 2-phenylpropanal led to the formation of 22 with
reduced product yield as a mixture of diastereomers (entry 12).
To the best of our knowledge these represent the first example
of such a coupling between these substrate classes.
To summarise, the synthetic utility of the recently developed
thiolate-catalysed Tishchenko reaction was potentially limited
by poor catalyst turnover frequency, which led to a requirement
for long reaction times. As part of a programme aimed at
circumventing this problem it was found that the corresponding
microwave assisted reactions proceeded with significant rate
acceleration—the prototype disproportionation of benzaldehyde
proceeded with over 90% yield in 30 min in the presence of
half the catalyst loading required to achieve a similar product
yield in 48 h using the previously reported thermal procedure.
The more challenging crossed-Tishchenko process was also
found to be susceptible to the influence of microwave irradiation.
Product yields were marginally lower than those possible using
the thermal process; however good–excellent yields of crossed-
products were obtainable in 3 h or less across a range of
substrates. The microwave-assisted protocol was also utilised
to demonstrate the first examples of the intermolecular
Tishchenko coupling of aliphatic aldehydes and an activated
ketone.
Angew. Chem., Int. Ed., 1998, 37, 1569; (c) M. R. Burgstein,
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H. Berberichand and P. W. Roesky, Chem.–Eur. J., 2001, 7,
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10 For the use of an active calcium complex see: M. R. Crimmin,
A. G. M. Barrett, M. S. Hill and P. A. Procopiou, Org. Lett., 2007,
9, 331.
11 J. M. Berg, J. L. Tymoczko and L. Stryer, Biochemistry, Freeman,
New York, 5th edn, 2002.
12 A. Soukri, A. Mougin, C. Corbier, A. Wonacott, C. Branlant and
G. Branlant, Biochemistry, 1989, 28, 2586.
13 K. D’Ambrosio, A. Pailot, F. Talfournier, C. Didierjean,
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2006, 45, 2978.
14 L. Cronin, F. Manoni, C. J. O’Connor and S. J. Connon, Angew.
Chem., Int. Ed., 2010, 49, 3045.
15 The use of thiolates as catalysts is a little-explored domain. For
representative examples of thiolate catalysis of Michael addition
reactions see: (a) J.-K. Erguden and H. W. Moore, Org. Lett.,
1999, 1, 375; (b) C. E. Aroyan and S. J. Miller, J. Am. Chem. Soc.,
2007, 129, 256.
16 For the synthesis of 6-membered lactones via the intramolecular
Samarium iodide-mediated Tishchenko coupling of an aldehyde
and a ketone see: (a) J.-L. Hsu and J.-M. Fang, J. Org. Chem.,
2001, 66, 8573; (b) L. Lu, H.-Y. Chang and J.-M. Fang, J. Org.
Chem., 1999, 64, 84.
17 The reaction does not proceed with appreciable efficiency in
alternative solvents such as CH2Cl2, MeCN, PhMe or EtOAc.
18 Given its superior microwave radiation conducting properties
(relative to THF) we also investigated the use of 1,4-dioxane in
microwave-irradiated reactions, without any observable
improvement.
Studies to further improve the scope and utility of these
microwave assisted Tishchenko processes are underway in our
laboratories.
This material is based upon works supported by the Science
Foundation Ireland and the European Research Council.
Notes and references
1 (a) W. Tischtschenko, J. Russ. Phys. Chem., 1906, 38, 355;
(b) W. Tischtschenko, Chem. Zentralbl., 1906, 771, 1309.
2 L. Claisen, Ber. Dtsch. Chem. Ges., 1887, 20, 646.
3 S. Cannizzaro, Justus Liebigs Ann. Chem., 1853, 88, 129.
4 For recent reviews see: (a) T. Seki, T. Nakajo and M. Onaka,
19 We would suggest that this is because in the case of the
homo-Tishchenko reaction (unlike in the crossed variant) that
acyl-transfer is not rate-determining. Therefore the use of a
catalyst such as 10 (designed to make the thioester electrophile as
reactive as possible at the expense of thiolate nucleophilicity) is not
advantageous.
Chem. Lett., 2006, 35, 824; (b) O. P. Tormakangas and A. M. P.
¨
Koskinen, Recent Res. Dev. Org. Chem., 2001, 5, 225.
¨
c
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New J. Chem., 2011, 35, 551–553 553