Solid-supported cyclohexane-1,3-dione (CHD): A "capture and release" reagent for the synthesis of amides and novel scavenger resin

Article abstract of DOI:10.1021/ol027503p

A three-step synthesis of cyclohexane-1,3-dione (CHD) resin 6 on polystyrene resin is described. Resin 6 was used to prepare an amide library of high purity by microwave-assisted serial "capture and release" and can be recycled for this purpose. High-loading CHD resin 10 was also shown to scavenge allyl cations in solution.

Full text of DOI:10.1021/ol027503p

ORGANIC
LETTERS
2003
Vol. 5, No. 6
849-852
Solid-Supported Cyclohexane-1,3-dione
(CHD): A “Capture and Release”
Reagent for the Synthesis of Amides
and Novel Scavenger Resin
Cara E. Humphrey,† Morag A. M. Easson,‡ Jason P. Tierney,‡,§ and
,†
Nicholas J. Turner*
Department of Chemistry, UniVersity of Edinburgh, Kings Buildings,
West Mains Road, Edinburgh, EH9 3JJ, UK, and Organon Laboratories, Ltd.,
Newhouse, Lanarkshire, ML1 5SH, UK
n.j.turner@ed.ac.uk
Received December 19, 2002
ABSTRACT
A three-step synthesis of cyclohexane-1,3-dione (CHD) resin 6 on polystyrene resin is described. Resin 6 was used to prepare an amide library
of high purity by microwave-assisted serial “capture and release” and can be recycled for this purpose. High-loading CHD resin 10 was also
shown to scavenge allyl cations in solution.
Polymer-supported reagents and scavenger resins1 have been
widely used to aid the production of a large number of target
libraries by combinatorial chemistry.2 This technique affords
ease of purification and isolation of compounds and is widely
applicable to the pharmaceutical industry in order to meet
the high demand for novel compounds as drug candidates.
During the past five years, many new resins have become
available, including those able to scavenge amines, acid
chlorides, alcohols, and aldehydes.
in the palladium-catalyzed deprotection of allyl carbamates
and carbonates.5
We envisaged that polymer-supported dimedone would be
useful as a scavenger resin for a wide variety of function-
alities, including cations, nucleophiles and electrophiles.
Previous examples of solid-supported dimedone analogues
include the work of Bycroft6 based on a Dde protecting group
with dimedone linked to the solid support via the C2 ring
position. We envisaged attaching dimedone to the solid phase
via the gem-dimethyl C5 position, therefore leaving the 1,3-
diketone moiety free.
(1) Review: Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor,
S. J. J. Chem. Soc., Perkin Trans. 1 2000, 23, 3815-4195.
(2) Bunin, B. A. The Combinatorial Index; Academic Press: New York,
1998.
Dimedone 1 is well-known to be able to react with amines3
and aldehydes4 in solution as well as scavenge allyl cations
(3) Halpern, B.; James, L. B. Aust. J. Chem. 1964, 17, 1282-1287.
(4) Horning, E. C.; Horning M. G. J. Org. Chem. 1946, 11, 95-99.
(5) (a) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. Engl. 1984, 23,
436-437. (b) Review: Guibe, F. Tetrahedron 1998, 54, 2967-3042.
(6) Nash, I. A.; Bycroft, B. W.; Chan, W. C. Tetrahedron Lett. 1996,
37, 2625-2628.
† University of Edinburgh.
‡ Organon Laboratories, Ltd.
§ Current address: High-Throughput Chemistry, GlaxoSmithKline Re-
search and Development, Ltd., New Frontiers Science Park, Harlow, Essex,
CM19 5AW, UK.
10.1021/ol027503p CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003

Herein we report the synthesis of the novel functionalized
resin 6 from cheap and readily available starting materials
and demonstrate its utility as a multifunctional solid-phase
reagent.
The synthesis of cyclohexan-1,3-dione (CHD) resin 6 via
bis-enol ether 4 is shown in Scheme 1. 1-Ethyl-3,5-
examples of the use of polymer-supported reagents in
conjunction with microwave heating.11 Complete hydrolysis
of 3-methoxy cyclohexen-1-one resin 5 was achieved by
microwave heating of a 1:1:1 TFA/H2O/THF suspension at
110 °C, 50 W for 10 min in a microwave synthesizer (CEM
Explorer), followed by washing with butylamine to give
CHD 6. Higher TFA concentrations resulted in acidic
cleavage of the linker, whereas direct hydrolysis of bis-enol
ether resin 4 resulted in incomplete hydrolysis. Resins 4-6
were fully characterized by FT-IR and MAS-probe 1H
NMR.12,13
Scheme 1a
Parallel robotic screening of a range of potential reactive
functional groups (e.g., aldehydes, amines, acid chlorides,
hydrazines) indicated that CHD resin 6 reacted with benzoyl
chloride to give enol ester 7a (Scheme 2).14 The addition of
acetic acid was essential for preventing base-catalyzed
migration of the acyl group from OfC.
Scheme 2a
a Reagents and conditions: (a) DIC, 1:1 DCM/DMF, 2.5 h, rt,
double coupling;7 (b) 90:5:5 TFA/H2O/DMF, rt, 2.5 h; (c) 1:1:1
n
TFA/H2O/DMF, ω, 50 W, 110 °C, 10 min; (d) BuNH2 wash.
dimethoxy-cyclohexa-2,5-dienecarboxylic acid 3 was pre-
pared by the Birch reduction and alkylation of 3,5-
dimethoxybenzoic acid8 and coupled directly to resin 2 (N-
methylaminomethyl polystyrene resin 2 is commercially
available but can be prepared by the reductive amination of
formylpolystyrene9) using DIC in 1:1 DCM/DMF to give
resin bound bis-enol ether 4.
a Reagents and conditions: (a) PhCOCl, MeCO2H, DCM, rt,
overnight; (b) PhCH2NH2, MeOH, rt, overnight.
Attempts to convert bis-enol ether 4 to CHD 6 using a
variety of acidic conditions proved to be unsuccessful,
resulting in incomplete hydrolysis and the formation of resin-
bound 3-methoxy cyclohexen-1-one 5. We postulate that the
methoxy cyclohexenone intermediate acts as a thermo-
dynamic sink for this reaction, thus preventing complete enol
ether hydrolysis. The corresponding solution-phase reaction
proceeds to the diketone in less than 1 h. This demonstrates
how the kinetics of solid-phase reactions can differ markedly
from those in solution.
Enol ester 7a was reacted with benzylamine in methanol
at room-temperature overnight to yield benzamide 8a in high
purity (95% by LC-MS), thus demonstrating the use of CHD
resin as a capture and release reagent for the synthesis of
amides.
“Resin capture-release” methodology15 can be used to aid
impurity removal and facilitate product purification. Func-
tionalized polymers developed for the synthesis of amides
include polymer-supported dimethylamino pyridine (PS-
The kinetics of solid-phase reactions are often very slow
and reactions can be accelerated by microwave-assisted
heating.10 However, there are relatively few literature
(11) Review: Kappe, C. O. Am. Lab. 2001, 33, 13-19. (a) Westman, J.
Org. Lett. 2001, 3, 23, 3745-3747. (b) Desai, B.; Danks, T. N. Tetrahedron
Lett. 2001, 42, 5963-5965. (c) Ley, S. V.; Leach, A. G.; Storer, R. I. J.
Chem. Soc, Perkin Trans. 1 2001, 358-361. (d) O¨ hberg, L.; Westman, J.
Synlett 2001, 12, 1893-1896. (e) Brain, C. T.; Brunton, S. A. Synlett 2001,
3, 382-384.
(7) Reactions were performed more than once to ensure maximum
loading.
(8) (a) Birch, A. J.; Slobbe, J. Aust. J. Chem. 1977, 30, 1045-1049. (b)
Liepa, A. J.; Wilkie, J. S.; Winzenberg, K. N. Aust. J. Chem. 1989, 42,
1217-1225.
(12) De Miguel, Y. R., Shearer, A. S. Biotech. Bioeng. 2000, 71, 119-
129.
(13) Shapiro, M.; Gounarides, J. S. Biotech. Bioeng. 2000, 71, 130-
148.
(9) Fivush, A. M.; Wilson, T. M. Tetrahedron Lett. 1997, 38, 7151-
7154.
(14) For solution-phase analogues: (a) Lakhvich, F. A.; Petrusevich, I.
I.; Sergeeva, A. N. Russ. J. Org. Chem. 1995, 31, 1473-1479. (b) Akhrem,
A. A.; Lakhvich, F. A.; Budai, S. I.; Khlebnicova, T. S.; Petrusevich, I. I.
Synthesis 1978, 12, 925-927.
(15) Review: Kischning, A.; Monenschein, H.; Wittenberg, R. Chem.
Eur. J. 2000, 6, 4445-4450.
(10) Reviews: (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A.
R. J. Comb. Chem. 2002, 4, 95-105. (b) Lidstrom, P.; Westman, J.;
Anthony, L. Comb. Chem. High Throughput Screening 2002, 5, 441-458.
(c) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225-9283.
850
Org. Lett., Vol. 5, No. 6, 2003

Table 1. Capture and Release of Amides
a Yields by weight. b Purity by LC-MS at 220 nm. c Resin recycling.
DMAP),16 1-hydroxy-benzotriazole (PS-HOBT),17 and tet-
rafluorophenol (PS-TFP).18
reaction, residual enol ester was observed on the resin unless
excess amine was present. Excess amine was scavenged from
the reaction mixture using Dowex-50WX sulfonic acid resin.
Higher release levels were observed when the resin mixture
was subjected to continuous microwave irradiation while
being continuously cooled, compared to runs without cool-
ing.19
CHD resin 6 was used to prepare a library of amides20
shown in Table 1 in varying purity and yields. Aromatic enol
esters generally gave higher yields and purities of their
corresponding amides than aliphatic enol esters. Aniline gave
lower yields overall, presumably due to reduced amine
nucleophilicity. Upon second use of CHD resin 6, amide 8a
was obtained in 63% yield (by weight) and 100% purity (by
LCMS at 220 nm), thus demonstrating the ability to recycle
CHD resin 6 (Table 1, entry 1).
To gain further insight into the kinetics of microwave-
assisted synthesis of amides using CHD resin 6, we decided
to monitor the reaction using FT-IR. Comparing carbonyl
and carbon-carbon double-bond peak intensities in FT-IR
allowed the level of acylation to be determined. High levels
of acylation were achieved using microwave-assisted heating
compared to lower acylation levels at room temperature
(Figure 1). To ensure maximum acylation, CHD resin 6 was
subjected to a double-microwave acylation twice for 10
minutes. The loading with respect to capture and release was
deemed to be 0.2 mmol/g by elemental analysis.
The release of amide into solution was also accelerated
by microwave heating. In similar kinetic studies of the release
(16) Rodriguez, J.; Martin-Villamil, R.; Ramos, S. New J. Chem. 1998,
865-868.
(17) Pop, I. E.; De´prez, B. P.; Tartar, A. L. J. Org. Chem. 1997, 62,
2594-2603.
(18) Salvino, J. M.; Kumar, N. V.; Orton, E.; Airey, J.; Kiesow, T.;
Crawford, K.; Mathew, R.; Krolikowski, P.; Drew, M.; Enger, D.;
Krolikowski, D.; Herpin, T.; Gardyan, M.; McGeehan, G.; Labaudiniere,
R. J. Comb. Chem. 2000, 2, 691-697.
(19) CEM Discover microwave allows continuous cooling of samples,
thus enabling higher levels of irradiation over the time-course of the reaction.
The temperature of the reaction mixture was monitored using a temperature
and pressure probe inserted through the seal of the reaction tube.
(20) Synthesis of resin bound enol-carbonates was achieved, but release
of carbamates occurred in poor yield and purity.
Org. Lett., Vol. 5, No. 6, 2003
851

Scheme 3a
a Reagents and conditions: (a) 3, DIC, 1:1 DCM/DMF, 2.5 h,
rt, double coupling; (b) 90:5:5 TFA/H2O/DMF, rt, 2.5 h; (c) 10,
Pd(PPh3)4, THF, rt, overnight (87%).
Figure 1. (a) Plot of peak intensity against time for the conversion
6 f 7a. (b) FT-IR spectrum showing relative CdO and CdC
intensities.
In summary, we have shown that CHD resin 6 can be used
as a capture and release reagent for the synthesis of amides
and to scavenge allyl cations in the deprotection of O-alloc
carbonates. We are currently investigating further applica-
tions of CHD resin 6 as a linker for the solid-phase synthesis
of peptides.
By attachment of carboxylic acid 3 to commercially
available trisamine resin21 9, high-loading CHD resin 10 was
prepared using the same procedure as before (Scheme 3).22
The loading of resin 10 was determined by elemental analysis
to be 2.78 mmol/g. The scavenging ability of CHD resin 10
was demonstrated in the palladium-catalyzed O-alloc depro-
tection of alloc benzyl alcohol 11 (Scheme 3). Insufficient
scavenging was observed with lower-loading resin 6. Evi-
dence for C-allylation of the resin was given by the presence
Acknowledgment. This investigation was generously
supported by funds provided by Organon Laboratories, Ltd.,
and the Engineering and Physical Sciences Research Council
(EPSRC No. 00316713). The authors thank CEM for
provision of a Discover microwave synthesizer, Dr. Ian
Sadler for his NMR assistance, and Dr. Dan Fletcher at
Organon Laboratories for MAS-probe analysis of resins.
1
of C-allyl signals at 5.1 and 5.6 ppm in the MAS-probe H
NMR. Benzyl alcohol 12 was obtained in 87% yield with
minimal formation of allyl benzyl ether byproduct, thus
eliminating the need for column chromatography.
Supporting Information Available: Detailed experi-
mental procedures and characterization of resins 2 and
4-7(a-e). This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882-
4886.
(22) Dentritic linker of resin 10 was unstable to microwave irradiation
and thus was not hydrolyzed to completion. The resin was used as a mixture
of methoxy cyclohexenone and CHD functionalities.
OL027503P
852
Org. Lett., Vol. 5, No. 6, 2003