Synthetic applications of azolium ylides to a traceless solid-phase synthesis of 2-substituted azoles.

Article abstract of DOI:10.1021/ol0266727

A new approach for the preparation of 2-substituted azole libraries using a polystyrene-carbamyl chloride resin in a traceless fashion is described. Azole substrates II are assembled in a one-pot condensation reaction of azoles and aldehydes with a resin-

Full text of DOI:10.1021/ol0266727

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4017-4020
Synthetic Applications of Azolium Ylides
to a Traceless Solid-Phase Synthesis of
2-Substituted Azoles
Yijun Deng and Dennis J. Hlasta*
Drug DiscoVery, Johnson & Johnson Pharmaceutical Research & DeVelopment,
Welsh and McKean Roads, Spring House, PennsylVania 19477-0776
dhlasta@prdus.jnj.com
Received August 5, 2002
ABSTRACT
A new approach for the preparation of 2-substituted azole libraries using a polystyrene-carbamyl chloride resin in a traceless fashion is
described. Azole substrates II are assembled in a one-pot condensation reaction of azoles and aldehydes with a resin-bound carbamyl chloride.
Treatment of the azolyl-carbamate II with boron trifluoride etherate under thermal or microwave-assisted solvolysis conditions afforded
2-substituted azoles.
New methods for the solid-phase synthesis of organic
molecules are needed in drug discovery to permit the
continued expansion of compound collections with large
numbers of druglike molecules.1 The use of traceless solid-
phase methods is a particularly effective strategy in library
syntheses, because undesirable functional groups are not
needed to link the substrates onto the resin support.2 Azole
derivatives are important components in many biologically
active molecules.3 Libraries of azole derivatives bearing a
wide diversity of substitution patterns should then be a rich
source of lead compounds when assayed in high-throughput
screens against biological drug targets. We recently reported
our results in developing a new method using imidazolium
ylides/carbenes4 in the preparation of 2-substituted azoles
through a one-pot three-component reaction.5 The simplicity
and efficiency of this reaction is ideally suited for application
to the traceless solid-phase synthesis of azole libraries. In
two reaction steps, azoles are formed with three centers of
diversity that are arrayed in a compact fashion around a
single carbon atom.
Imidazoles are known to acylate at the 2-position, and the
reaction of an imidazole with a benzoyl chloride is reported
to initially form an imidazolium ylide as an intermediate.
The ylide is proposed to react in a bimolecular fashion with
a second benzoyl chloride to form a 2-benzoylimidazole on
workup.6 If a resin-bound acid chloride were substituted in
this reaction, we expected that the intermediate ylide I would
form; however, acylation should not occur at the 2-position,
(1) Balkenhol, F.; von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-2337. Watson, C. Angew.
Chem., Int. Ed. 1999, 38, 1903-1908. Ellman, J. A.; Gallop, A. Curr. Opin.
Chem. Biol. 1998, 2, 317-319. Schreiber, S. L. Bioorg. Med. Chem. 1998,
6, 1127-1152.
(2) Wilson, L. J.; Klopfenstein, S. R.; Li, M. Tetrhedron Lett. 1999, 40,
3999-4002. van Maarseveen, J. H. Comb. Chem. High Throughput
Screening 1998, 1, 185-214. Reitz, A. B. Curr. Opin. Drug Discuss. DeV.
1999, 2, 358-364. Paio, A.; Zaramella, A.; Feritto, R.; Conti, N.; Marchioro,
C.; Seneci, P. J. Comb. Chem. 1999, 1, 317-325.
(3) Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry; Katritz-
ky, A. R., Ress, C. W., Scrivn, E. F. V., Eds; Pergamon Press: Oxford,
1996; Vol. 3, pp 77-220.
(4) A recent report describes the use of similar N-carbamyl-imidazolium
carbenes/ylides as ligands for Pd(II) catalysts in the Sonogashira reaction.
Batey, R. A.; Shen M.; Lough A. J. Org. Lett. 2002, 4, 1411-1414.
(5) Hlasta, D. J. Org. Lett. 2001, 3, 157-159. Deng, Y.; Hlasta, D. J.
Tetrahedron Lett. 2002, 43, 189-192.
10.1021/ol0266727 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/23/2002

since a second acid chloride on the resin surface would not
be close enough to the reactive center (Scheme 1). Analogous
consistent with the 2-acylation of the resin-bound ylide being
the major pathway, unexpectedly following the same pathway
as reported for the solution-phase reaction.6 Our attempts to
improve the overall yields by varying the reaction concentra-
tion and equivalents of reagents and using resin with lower
loading were not successful.
Scheme 1. Solid-Phase Synthesis of 2-Substituted Azoles
Scheme 2. Polystyrene-Carbamyl Chloride in the Synthesis of
2-Substituted Imidazoles
We turned next to a carbamyl chloride, which should limit
the cross-reaction as a result of the lower chemical reactivity
of a carbamyl chloride compared to that of an acid chloride.
Resin-bound carbamyl chloride was prepared by the treat-
ment of N-methylaminomethyl polystyrene with phosgene
or triphosgene in toluene.10 The resulting resin-bound car-
bamyl chloride 1 is quite stable, unlike polystyrene carbonyl
chloride, which is hygroscopic and water-sensitive. The dried
carbamyl chloride resin 1 could be stored for more than 1
month in a drybox and still give good results. The one-pot
reaction of the resin-bound carbamyl chloride 1 with ben-
zaldehyde and 1-benzylimidazole in the presence of N,N-
diisopropylethylamine or triethylamine yielded the resin-
bound 2-substituted imidazole 2 in 70% yield.11 Cleavage
of the imidazole off resin with aqueous trifluoroacetic acid
in tetrahydropyran at 60 °C for 16 h gave material that was
95% pure by LC/MS and after flash chromatography gave a
70% isolated yield of (1-benzyl-1H-imidazol-2-yl)phenyl-
methanol (3) (Scheme 2).
to our solution-phase method5 the ylide would not be acylated
but would be able to condense with an aldehyde that is
present in the reaction media. After an intramolecular acyl
transfer, the resin-bound 2-substituted imidazole II would
be formed. Therefore in this key step the 2-substituted azoles
II are assembled by the reaction of a resin-bound carbonyl
chloride with an azole and an aldehyde (Scheme 1).
Solvolysis of the resin-bound azole II results in cleavage of
the azole off resin, presumably in the form of a carbonium
ion, which is then trapped with a nucleophile. This two-step
sequence would readily afford a library of 2-substituted
azoles (III) with three centers of diversity.
This traceless solid-phase method was brought into
practice. Initially, we chose polystyrene-carbonyl chloride
as the resin-bound acid chloride.7 In a one-pot reaction
polystyrene-carbonyl chloride was generated in situ by
treatment of carboxypolystyrene with a coupling reagent,
2-chloro-1,3-dimethylimidazolinium chloride, and N,N-di-
isopropylethylamine (DIEA).8 After 4 h at room temperature,
an excess of 1-benzylimidazole and benzaldehyde was added,
and the resin-bound 2-substituted imidazole II was obtained.9
The reaction of the resin-bound imidazole II with aqueous
trifluoroacetic acid in tetrahydropyran at 60 °C for 16 h gave
(1-benzyl-1H-imidazol-2-yl)phenylmethanol in 15-25% over-
all yields from the starting carboxypolystyrene resin. We
found that more than 60% of the azole species that was
loaded onto the resin was not cleaved off even under forcing
conditions (based on elemental analysis). This result is
(9) General Procedure. To carboxypolystyrene resin (1 g, 1.10 mmol/
g, from Novabiochem) in dichloroethane (20 mL) was added 2-chloro-1,3-
dimethylimidazolinium chloride (3 equiv) and N,N-diisopropylethylamine
(6 equiv). The resulting mixture was shaken at room temperature for 4 h,
followed by addition of 1-benzylimidazole (3 equiv) and benzaldehyde (5
equiv) and shaken for another 24 h at room temperature. The solvent was
drained, and the resin was washed three times with dichloromethane and
dried under vacuum.
(10) Wang, G. T.; Chen, Y.; Wang, S.; Sciotti, R.; Sowin, T. Tetrahedron
Lett. 1997, 38, 1895-1898. General procedure for preparing carbamyl
chloride resin 1: N-methylaminomethyl polystyrene (1 g, 1.38 mmol/g, from
Novabiochem) was swelled in dichloromethane (20 mL) for 30 min at room
temperature. To the resin suspension was added N,N-diisopropylethylamine
(2.4 mL, 13.8 mmol), followed by portionwise addition of phosgene (10
equiv, 20% solution in toluene) or triphosgene (1.25 g, 4.2 mmol) under
nitrogen at 0 °C. After the addition of phosgene was completed, the ice
bath was removed, and the resulting mixture was shaken for 3 h at room
temperature. The resin was washed with dry toluene and dichloromethane
and dried under vacuum at 50 °C overnight. The dried carbamyl chloride
resin was then stored in a sealed drybox for future use.
(6) Regel, E.; Buchel, K. H. Liebig Ann. Chem. 1977, 145-158; 159-
168.
(7) Fyles, T. M.; Leznoff, C. C.; Weatherston, J. Can. J. Chem. 1978,
56, 1031-1041.
(8) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984-6988.
4018
Org. Lett., Vol. 4, No. 23, 2002

Previously we described solvolysis chemistry that was
useful in the transformation of carbamates into various
functionalized azole derivatives.5 Following these conditions
in cleavage reactions with the resin-bound imidazole 2
generally gave good results; however, little or no desired
products were isolated in reactions with high pKa amines.
We found that amines with pKa > 8.5, such as piperidine
(pKa 11.1), 1-methyl piperazine (pKa 9.7), and primary
amines, did not give good yields when using TFA as the
only catalyst. To solve this problem we have further
examined the solution-phase reaction to determine the best
and most general reaction conditions to use in the resin
cleavage reactions.
Microwave-assisted technology has been applied to various
reactions as a practical method to reduce the reaction time,
often by orders of magnitude.14 Recently, microwave was
used to accelerate automated library generation15 and solid-
phase reactions.16 Using the same equivalents of reagents as
in the thermal reaction (method B), the reactions on
microwave irradiation to 120 °C internal temperature for 5
min gave similar isolated yields of products (Table 1, method
C). These microwave-assisted reaction conditions also sig-
nificantly reduced the reaction time for the solid-phase
cleavage reactions. In Figure 1 are shown our results for the
Table 1. Comparison of Thermal versus Microwave-Assisted
Solvolysis of Carbamate
methoda
entry
nucleophile
piperidine
1-methylpiperazine
morpholine
imidazole
pKa
A (%)
B (%)
C (%)
1
2
3
4
5
11.1
9.7
8.5
7.1
4.7
traceb
traceb
50
55
85c
85
80
82
78
86
87
85
82
80
86
aniline
a Isolated yield. Method A: nucleophile (5 equiv), TFA (3 equiv), reflux
in THF for 24 h. Method B: nucleophile (5 equiv), TFA (4.5 equiv),
BF3Et2O (1.5 equiv), reflux in THF for 1 h. Method C: nucleophile (5
equiv), TFA (4.5 equiv), BF3Et2O (1.5 equiv), microwave in THP for 5
min at 120 °C in a Personal Chemistry, SmithSynthesizer. bDetected by
LC/MS. c Reaction was refluxed for only 4 h.
Figure 1. Comparison of HPLC purity of products from the
nucleophilic cleavage of resin 2 by method B and method C. Results
for method B are shown in gray bars, and results for method C are
shown in black bars. Method B: nucleophile (5.0 equiv), TFA (4.5
equiv), BF3Et2O (1.5 equiv), THP, 60 °C for overnight. Method
C: nucleophile (5.0 equiv), TFA (4.5 equiv), BF3Et2O (1.5 equiv),
microwave in THP for 10 min at 120 °C in a Personal Chemistry,
SmithSynthesizer.
Under our previously described solvolysis conditions
(Table 1, method A) moderate to good yields of 2-substituted
imidazoles were obtained with amines of pKa ) 8.5.
Increasing the equivalents of TFA to equal piperidine or even
to excess gave only a trace of the cleavage product. Lewis
acids are known to mediate the solvolysis reactions of
propargylic esters.12 We examined the use of Lewis acids
as an additive and found that addition of boron trifluoride
etherate to the reaction media (method B) significantly
improved the yield of the solvolysis reactions.13 The desired
products were obtained in good isolated yields, although
refluxing reaction conditions were needed.
cleavage reactions of resin 2 comparing the thermal reaction
(method B) with the microwave-assisted reaction (method
C). The purity as measured by LC/MS of the crude products
was consistently improved under microwave-assisted reaction
conditions compared to that of the thermal reaction. The
isolated yields were similar for both methods and were in
the range of 50-70%.17 The reaction on solid phase required
extended reaction times at elevated temperatures to obtain
good yields, whereas the microwave-assisted reactions were
complete in 10 min. Parallel synthesis using the microwave-
(11) General procedure for preparing resin-bound 2-substituted imidazoles
2: To a suspension of the carbamyl chloride resin (1.0 g) in dichloromethane
(20 mL), was added 1-benzylimidazole (300 mg, 3.6 mmol), benzaldehyde
(650 mg, 6.4 mmol) and N,N-diisopropylethylamine (1.3 mL, 7.2 mmol),
and then agitated for 24 h at room temperature. The resin was washed with
dichloromethane (3x) and then MeOH (2x), and dried under vacuum. The
loading was 0.9 mmol/g (70% overall from N-methylaminomethyl poly-
styrene) determined by elemental analysis for nitrogen content.
(12) Bartels, A.; Mahrwald, R.; Quint, S. Tetrahedron Lett. 1999, 40,
5989-5990. Mahrwald, R.; Quint, S. Tetrahedron 2000, 56, 7463-7468.
(13) Lewis acids, including ZnCl2, ZnBr2, ScOTf3, TiCl4, Ti(O-i-Pr)4,
SnCl2, SnCl4, TMSOTf, and BF3Et2O were examined. The effect of the
various Lewis acids and equivalents of reagents on the solvolysis conversion
rate was monitored by LC/MS. BF3Et2O (1.5 equiv) gave the best results.
(14) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge,
L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279-282. Caddick, S. Tetra-
hedron 1995, 51, 10403-10432.
(15) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624-630.
Coleman, C. M.; MacElroy, J. M. D.; Gallagher, J. F.; O’Shea, D. F. J.
Comb. Chem. 2002, 4, 87-93.
(16) Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6(30), 314-320.
Wilson, S. R.; Reinhard, K. High-Throughput Synth. 2001, 55-64.
(17) The yield is based on the loading of 2 (70% determined by elemental
analysis).
Org. Lett., Vol. 4, No. 23, 2002
4019

for the formation of the resin-bound 2-substituted azoles,11
and the thermal cleavage conditions (method B) resulted in
the preparation of 34 of 36 of the desired compounds. After
a solid-supported liquid-liquid extraction (SLE)18 of the
crude products, we found that 80% of the prepared com-
pounds were g80% pure by LC/MS determination.
Scheme 3. Solid-Phase Synthesis of a 3 × 4 × 3
2-Substituted Azole Library
In conclusion, we have developed a traceless solid-phase
method for the preparation of 2-substituted azole libraries.
In one step, using a resin-bound carbamyl chloride, the azoles
and aldehydes are loaded onto the solid phase to form resin-
bound 2-substituted azoles. In a second step, reaction with
nucleophiles under acid catalysis results in the formation of
2-substituted azoles. Our improved solvolysis conditions
significantly broadened the range of nucleophiles that can
be used in this chemistry. Therefore, in two reaction steps,
azoles are formed with three centers of diversity that are
arrayed in a compact fashion around a single carbon atom.
Acknowledgment. We thank the Johnson & Johnson
Corporate Office of Science and Technology for postdoctoral
fellowship funding for Y.D. through the Excellence in
Science Award Program, and we thank Drs. Steven Coats,
Kevin Pan, and Jung Lee for their helpful discussions on
solid-phase methodology.
Supporting Information Available: General experimen-
tal details, isolated yields, and the characterization data of
products showed in Figure 1 by H NMR, 13C NMR and
MS. LC/MS results for the azole library in Scheme 3. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
assisted reactions is limited to moderate-sized libraries, since
sequential reactions are the most efficient with the current
reactor systems.
We demonstrated the utility of this new traceless solid-
phase reaction in the preparation of a 3 × 4 × 3 2-substituted
azole library using the Bohdan Miniblock system (Scheme
3). We followed the reactions conditions described earlier
OL0266727
(18) Breitenbucher, J. G.; Arienti, K. L.; McClure, K. J. J. Comb. Chem.
2001, 3, 528-533.
4020
Org. Lett., Vol. 4, No. 23, 2002