9696
J. Am. Chem. Soc. 2001, 123, 9696-9697
the reaction conditions or interfere with the thiazolium catalyst.
Arylsulfonylamides are stable, readily accessible substrates which
can undergo elimination of sulfinic acid to an acylimine under
very mild conditions. We envisioned that by employing a
tosylamide in a reaction with an aldehyde and a thiazolium salt
with a base such as triethylamine, we might be able to effect
such a process. We were pleased to find that exposing tosylamide
1 to a mixture of 4-pyridine-carboxaldehyde, a commercially
available thiazolium salt 2 and triethylamine provided the desired
amido ketone 3 (eq 3).
Synthesis of r-Amido Ketones via Organic Catalysis:
Thiazolium-Catalyzed Cross-Coupling of Aldehydes
with Acylimines
Jerry A. Murry,* Doug E. Frantz,* Arash Soheili,
Richard Tillyer, Edward J. J. Grabowski, and Paul J. Reider1
Process Research Department
Merck Research Laboratories, Merck and Co. Inc.
P.O. Box 2000, Rahway, New Jersey 07065
ReceiVed July 11, 2001
Table 1. Effects of Solvent and Base on Thiazolium-Catalyzed
Addition of Aldehydes to Acylimines
R-Amido ketones are an important class of biologically relevant
molecules.2 Efforts to prepare diverse arrays of these compounds
as enzyme inhibitors are current and extensive. In addition, these
substrates represent a subclass of building blocks that may be
used to make stereochemically complex targets as well as valuable
heterocycles.3 We have been interested in designing nonmetal,
organo-catalytic processes toward biologically interesting mol-
ecules.4 In this communication, we disclose a general, practical
method for the synthesis of R-ketoamides which utilizes a
thiazolium salt to catalyze a cross-coupling reaction of various
aldehydes with acylimines.
The use of thiazolium-catalyzed processes to prepare com-
pounds which are the result of an acyl-anion addition reaction
have shown general utility in synthetic organic chemistry. The
benzoin condensation5 (eq 1) and the Stetter reaction6 (eq 2, Y
) CH) represent two of the most powerful examples of these
types of transformations.
entry
solvent
base
equiv
time
24 h
24 h
10 h
4 h
30 min
30 min
24 h
yield 3 (%)
1
2
3
4
5
6
7
THF
Toulene
DMF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
TEA
TEA
TEA
TEA
TEA
TEA
K2CO3
5
5
5
5
5
2
5
66
34
48
66
98
94
75
An initial survey of solvents demonstrated that CH2Cl2 is the
solvent of choice (Table 1).8 Furthermore, we found that triethyl-
amine is the optimum base, and we typically employ an excess
(5-15 equiv) to ensure complete consumption of the reactants.
However, it is possible to use as little as 2 equiv of TEA and
achieve complete conversion and good yield (entry 6). Other
amine bases such as DBU, tetramethyl guanidine, and DABCO
provided little or none of the desired product. However, hetero-
geneous bases such as potassium carbonate can be utilized, albeit
in lower yields (entry 7).
In subsequent investigations, we discovered that the reaction
demonstrates wide scope with respect to the aldehyde (eq 4, Table
2). Electron-deficient aldehydes perform much better than their
electron-rich counterparts; 3-methoxybenzaldehyde required longer
reaction times and higher catalyst loadings relative to the parent
compound (entry 11, Table 2). Aliphatic aldehydes (entries 15-
16) were also shown to provide the corresponding ketoamides in
good yield. We were surprised to find that R,â-unsaturated
aldehydes were viable substrates (entry 17) and did not undergo
1,4-addition as has been shown for the Stetter process.6
To expand this catalytic methodology toward the synthesis of
amido ketones, we envisioned trapping the intermediate thiazo-
lium-stabilized acyl anion with an acylimine (eq 2, Y ) NH).7
There are several potential problems with successfully executing
this approach. Most importantly, the acylimine has to be suf-
ficiently reactive to compete with another molecule of aldehyde
(benzoin condensation), yet stable enough not to decompose under
(1) We dedicate this paper to Professor David A. Evans on the occasion
of his 60th birthday.
The reaction is very tolerant to the amide portion of the
tosylamide (entries 1-8), and common amine-protecting groups
such as BOC (R2 ) OtBu) and CBZ (R2) OBn) could be
(2) (a) Lee, A.; Huang, L.; Ellman, J. J. Am. Chem. Soc. 1999, 121, 9907-
9914. (b) Rano, T. A.; Timkey, T.; Peterson, E. P.; Rotonda, J.; Nicholson,
D. W.; Becker, J. W.; Chapman, K. T.; Thornberry, N. A. Chem. Biol. 1997,
4, 149-155. (c) Marquis, R. W.; Ru. Y.; Yamashita, D. S.; Oh, H. J.; Yen,
J.; Thompson, S. K.; Carr, T. J.; Levy, M. A.; Tomaszek, T. A.; Ijames, C.
F.; Smith, W. W.; Zhao, B.; Janson, C. A.; Abdel-Meguid, S.; D’Alessio, K.
J.; McQueeney, M. S.; Veber, D. F. Bioorg. Med Chem 1999, 7, 581-588.
(3) Gupta, R. R.; Kumar, M.; Gupta, V. Five-membered Heterocycles. In
Heterocyclic Chemistry; Springer: Berlin, 1998; Chapter 2.
(6) (a) Stetter, H.; Kuhlman, H. Chem. Ber. 1976, 2890-2896. (b) Stetter,
H.; Kuhlman, H. Synthesis. 1975, 379-380. (c) Stetter, H. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 639-712. (d) Harrington, P. E.; Tius, M. A. Org.
Lett. 1999, 1, 649-651. (e) Hempenius, M. A.; Langeveld-Voss, B. M. W.;
van Haare, J. A. E. H.; Janssen, R. A. J.; Sheiko, S. S.; Spatz, J. P.; Moller,
M.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 2798-2804. (f) Woo, P. W.
K.; Hartman, J.; Huang, Y.; Nanninga, T.; Bauman, K.; Butler, D. E.; Rubin,
J. R.; Lee, H. T.; Huang, C. C. J. Labelled Compd. Radiopharm. 1999, 42,
121-127.
(7) (a) Kinoshita, H.; Hayashi, Y.; Murata, Y.; Inomata, K. Chem. Lett.
1993, 1437. (b) Castells, J.; Lopez-Calahora, F.; Bassedas, M.; Urios, P.
Synthesis 1988, 314. (c) Katritzky, A. R.; Cheng, D.; Musgrave, R. P.
Heterocycles 1996, 42, 1, 273.
(4) Recent advances from other laboratories include the use of secondary
amines to catalyze Friedel-Crafts, Diels-Alder, 1,3 dipolar cycloaddition
and Michael reactions: (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2001, 123, 4370-4371. (b) Ahrendt, K. A.; Borths, C. J.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2000, 122, 4243-4244. (c) Jen, W. S.; Wiener,
J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874-9875.
(5) (a) Hassner, A.; Rai, K. M. L. Comp. Org. Syn. 1991, 1, 541-577. (b)
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726. (c) Breslow, R.;
Schmuck, C. Tetrahedron Lett. 1996, 37, 8241-8242. (d) Chen, Y. T.; Barletta,
G. L.; Haghjoo, K.; Cheng, J. T.; Jordan, F. J. Org. Chem. 1994, 59, 7714-
7722. (e) White, M. J.; Leeper, F. J. J. Org Chem. 2001, 66, 5124-5131.
(8) It should be noted that in entries 1-4, the remainder of the material
was starting aldehyde and tosylamide and not decomposition. No further
attempt was made to optimize these reactions.
10.1021/ja0165943 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001