N-alkyl-N-phenacylamides in solution.8 Miller et al. have
provided the only exemplification of this solid-phase linker
strategy by the preparation of a small range of N-benzylpip-
erazine amides.9
(<5%). Lowering the temperature to ambient reduced the
efficiency considerably, suggesting that the milder cleavage
conditions reported by Miller et al. for unconstrained tertiary
amines are not general.9 It was also observed that the
methoxy substitution present in 2 resulted in cleavage
efficiency comparable to that of 1, in contrast with the studies
of Coskun and Tirli.8 This suggests that a single alkoxy
substitution (i.e., resin 3) is necessary and sufficient to
activate the nitrogen-benzyl carbon bond scission by acid
chloride. The simple monoalkoxybenzyl system 3 was the
preferred linker for the subsequent library synthesis.
This Letter describes the preparation of an array of N-alkyl-
N-(â-keto)amides (Scheme 1). The strategy is effcient as it
introduces functional diversity in three out of the four
synthetic steps, including the cleavage reaction. Since only
the correctly assembled tertiary amines should quaternize and
cleave, pure product would be expected. Prior assembly of
the tertiary amines on resin by reductive amination and
N-alkylation of the resultant secondary amines permits
independent variation of each substituent of the tertiary amide
core. Excess acid chloride from the cleavage step could be
removed using a scavenger resin.10 Cyclization of the cleaved
ketoamides with ammonia to the corresponding 1,2,4,5-
tetrasubstituted imidazoles allows the option of a second,
distinct compound library from the synthetic sequence.
To study the linker chemistry, two tertiary amines, 1 and
2, were first synthesized in solution following a literature
procedure11 and loaded onto Merrifield resin (Aldrich, 1.05
mmol/g) by alkylation to give resins 3 and 4 (Scheme 2).
The reaction sequence for N-alkyl-N-(â-keto)amides syn-
thesis is shown in Scheme 3. 4-Hydroxybenzaldehyde was
immobilized on chloromethylpolystyrene resin (Polymer Lab,
3.75 mmol/g) by alkylation using sodium hydride. The
alkylation was monitored by FTIR spectroscopic analysis of
the intensity of the aryl aldehyde peak at 1695 cm-1 relative
to a polystyrene backbone peak at 1600 cm-1. An “average”
set of reagents considered to have moderate electronic and
steric properties were chosen for optimization of all subse-
quent reactions to test the generality of the chemistry. The
reagents selected were n-butylamine, 4-chlorophenacyl bro-
mide, and benzoyl chloride. Selection of 4-chlorophenacyl
bromide also facilitated quantitation of yields by chlorine
elemental analysis of the N-alkylated product. Resin 5 was
treated with 5 equiv of n-butylamine in THF/TMOF and the
imine reduced using LiBH4. The reaction was monitored by
gel phase FTIR spectroscopy which detected the disappear-
ance of the aldehyde band at 1695 cm-1 and the appearance
of the imine band at 1645 cm-1, followed by the loss of the
latter band; gel phase 13C NMR spectra of 5 and 6a clearly
resolved all the substrate signals. The loading was determined
to be 2.30 mmol/g by N-analysis (94% yield from Merrifield
resin). The resin-bound secondary amine 6a was alkylated
using 2 equiv of 4-chlorophenacyl bromide in the presence
of 1.9 equiv of diisopropylamine at 45 °C for 16 h to generate
â-keto amine 7a on resin. Overalkylation of the tertiary
amine occurred when excess bromoketone was used. Owing
to its apparent instability, the resin-bound keto-amine 7a
was promptly subjected to cleavage by acylation.
Scheme 2. Studies on Linker Chemistry
Both resins were treated with 5 equiv of acetyl chloride at
50 °C for 5 h to generate the desired tertiary amide in each
case in 80% crude yield with 95% purity by HPLC UV
analysis. Cleavage efficiency was comparable in anhydrous
THF, DMF, DCE, or TMOF, and the use of additives such
as potassium carbonate,12 potassium iodide,8 and lithium
chloride13 showed only marginal improvement in yield
To explore the acylation-cleavage step the reaction
between resin-bound tertiary amine 7a and benzoyl chloride
was studied. This reaction proved to be sensitive to both
solvent and the added base. Treatment of 7a with 5 equiv of
benzoyl chloride in DCM, THF, or DCE resulted in a low
yield of the corresponding tertiary amide 8q (typically 23%)
and detectable formation of side products that included
N-butylbenzoylamide, presumably formed by benzoylation
and cleavage of the unreacted secondary amine. No side
products were detected in the more basic solvent DMF.
Inclusion of triethylamine base further improved the cleavage
reaction, increasing the yield dramatically from 23% to 67%.
However the product contained detectable contaminants
including N,N-dimethylbenzoylamide,14 plus 10-15% yield
of the overbenzoylated tertiary amide N-(n-butyl)-N-(4-
(4) A review on combinatorial chemistry: Jung, G.; Fruchtel, J. S. Angew.
Chem., Int. Ed. Engl. 1996, 35, 17-42.
(5) Another example of tertiary amide synthesis on solid phase: Barn,
D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron Lett. 1996, 37, 3213-6.
(6) A review on linkers for solid-phase organic synthesis: James, I. W.
Tetrahedron 1999, 55, 4855-946.
(7) Cooley, J. H.; Evain, E. J. Synthesis 1989, 1-7.
(8) Coskun, N.; Tirli, F. Synth. Commun. 1997, 27, 1-9.
(9) Miller, M. W.; Vice, S. F.; McCombie, S. W. Tetrahedron Lett. 1998,
39, 3429-32.
(10) A review on solid supported reagents for purification: Booth, R.
J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18-26.
(11) Venkov, A. P.; Vodenicharov, D. M. Synthesis 1990, 253-255.
(12) Shults, E. E.; Mukhametyanova, T. S.; Spirikhin, L. V.; Sultanova,
V. S.; Tolstikov, G. A. Zh. Org. Khim. 1993, 29, 1149-62.
(13) King, J. A.; Bryant, G. L. J. Org. Chem. 1992, 57, 5136-9.
(14) Presumably a result of benzoylation of N,N-dimethylamine from
traces of dimethylamine due to DMF degradation.
324
Org. Lett., Vol. 2, No. 3, 2000
Lee, H. Boon
