p synthesis of benzoxazoles andm carboxylic acids

yl R. Sauer and Stevan W. Djuric

hemistry Technologies, Global Pharmaceutical Research and

rk Road, Abbott Park, IL 60064-6113, United States

5 M

cienly. Tzimi

quently, a critical part of the lead molecular skeleton hasbeen studied and shown to be crucial for a particular

library whilst still maintaining critical pharmacophores,hence diering from the traditional focused libraryapproach.

1,2,4-oxadiazoles 1 and 1,3,4-oxadiazoles 2. Notably,both methods start from easily accessible carboxylic

matrix of distinct monomer units (Fig. 1). In this letter,

* Corresponding author. Tel.: +1 847 935 3058; fax: +1 847 9355212; e-mail: wang.ying@abbott.com

R OHN N

O

N

NR'R

RR'

R''(H)

R= Aryl, Alkyl24

Figure 1. Syntheses of diverse structural motifs from carboxylic acidwith PS-PPh3/CCl3CN.

Tetrahedron Letters 47 (2006) 48234826Over the past decade, focused libraries have been suc-cessfully utilized throughout the lead optimization pro-cess in order to incorporate modications to targetedregions of the lead molecular skeleton, which in turn,helps to establish initial SAR studies and determinefuture optimization strategies. Frequently, analogs bear-ing this common molecular skeleton dier only by dis-crete and dierent substituents. It is in this contextthen, that in order to increase the chance of nding anoptimal drug candidate, our goal has been to maximizethe structural complexity and skeletal diversity of a

we report the further extension of our strategy to synthe-size benzoxazoles 3 and benzimidazoles 4, both of which

O

N

NO

N

OR

O

NH

R'

R'R RR'

1 3biological activity, while other parts of the molecularskeleton need chemical modications so as to achievethe desired properties of a development candidate. Suchprocesses include ne tuning the activity through SARstudies and improving the selectivity and pharmaco-kinetics of the lead compound.

acids as the common precursor and utilize the same re-agent combination PS-PPh3/CCl3CN

4 under microwaveheating conditions. The key advantage of this approachis that from a common carboxylic acid scaold, by sim-ply using common reagents and a common operation,distinct structures can be easily accessed by utilizing aA simple and ecient one stebenzimidazoles fro

Ying Wang,* Kathy Sarris, Dar

High-Throughput Organic Synthesis Group, Medicinal C

Development, Abbott Laboratories, 100 Abbott Pa

Received 20 April 2006; revised

AbstractBenzoxazoles or benzimidazoles can be rapidly and ephenols or 1,2-phenylenediamines in one simple step, respectivemicrowave heating delivered a variety of benzoxazoles and ben 2006 Elsevier Ltd. All rights reserved.

Lead optimization is one of the most critical phaseswithin the drug discovery paradigm. Lead compoundsmust display favorable properties for further develop-ment, including desirable chemical features that canfacilitate medicinal chemistry optimization eorts.1 Fre-0040-4039/$ - see front matter 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.tetlet.2006.05.052ay 2006; accepted 9 May 2006

tly synthesized from a variety of carboxylic acids with 2-amino-he use of commercially available PS-PPh3 resin combined withdazoles in high yields and purities.

To this end, we have been actively involved in the prep-aration of diverse biologically relevant heterocyclesfrom precursors containing common chemical function-alities. In recent letters, we have reported general andecient reaction protocols for the preparation of

2 3

are important structural motifs in drug discovery pro-grams, from carboxylic acids (Fig. 1).5

Common synthetic routes to benzoxazoles and benzim-idazoles have typically involved coupling of carboxylicacids or their derivatives with 2-aminophenols or 1,2-phenylenediamines in the presence of strong acids athigh temperatures.6 As mentioned previously, we haveshown that the reagent combination of PS-PPh3 andCCl3CN is particularly eective in enabling the transfor-mation of carboxylic acids into their corresponding1,2,4-oxadiazole and 1,3,4-oxadiazole derivatives in afacile manner. We were delighted to nd that the samereagent combination also worked equally well for theexpeditious generation of benzoxazoles and benzimidaz-oles from carboxylic acids.

Benzoic acid 5 and 2-aminophenol 6 were chosen for themodel study. When the reaction was carried out inCH2Cl2 or CH3CN at room temperature for an ex-

fact that the reaction was very easy to workup by simpleltration of the resin and evaporation of the solvents. Inmany cases, simple ash chromatography aorded thedesired benzoxazole in high purity.7

Naturally, having now developed a general and ecientprotocol for benzoxazole synthesis starting from 2-aminophenol and carboxylic acid, we wondered if sub-stitution of the 2-aminophenol scaold with 2-aminothio-phenol and 1,2-phenylenediamines, would allow access

Table 2. Synthesis of benzoxazoles from carboxylic acids and 1,2-aminophenol with PS-PPh3/CCl3CN

R1

O

OH+ R2

OH

NH2

2 equiv. CCl3CN3 equiv. PS-PPh3

CH3CN, MW150 C, 15 mins O

NR1R2(1 equiv.)

Entry Product Yielda (%)

1O

N97

2O

N93

3

O

NNO2

79

4O

N 85

5O

NCl94

6 O

N

O

O 83

7N

O89

8O

N77

9O

N85

10O

NCl93

4824 Y. Wang et al. / Tetrahedron Letters 47 (2006) 48234826tended 20 h period, only the acylation product 7 was ob-served by LC/MS analysis along with other unidentiedpeaks. At higher temperature (75 C) in CH3CN, wewere able to obtain the desired product although thereaction was not clean as observed from crude LC/MSanalysis. Optimal result was obtained when the reactionmixture was heated in the microwave at 150 C for15 min in acetonitrile. Inferior results were obtainedwhen either the reaction temperature was lowered to140 C or the reaction time was cut to 10 min. With1.5 equiv of CCl3CN, both the acylated product 7 andthe cyclized product 8 were observed by LC/MS analysisof the crude mixture. Exploitation of microwave tech-nology allowed us to quickly identify the optimized reac-tion conditions within a short time frame (Table 1).

With this protocol at hand, we quickly found that thisone step procedure worked well for a variety of alkyland aryl carboxylic acids as well as a diverse selectionof 2-aminophenols (Table 2). Of particular note is the

Table 1. Optimization of reaction conditions for the synthesis ofrepresentative benzoxazole 8

NH2

OH

+

O

OH

NO

5

6

HNO

OH

7 8

3 equiv. PS-PPh3

2 equiv. CCl3CN

Entry Reaction condition 7 (%)a 8 (%)a

1 CH2Cl2, rt, >20 h 90 c

2 CH3CN, rt, >20 h 55 c

3 CH3CN, 75 C, >14 h 15 804 MW, CH3CN, 140 C, 15 min b 705 MW, CH3CN, 150 C, 10 min b 806 MW, CH3CN, 150 C, 15 min b 97

aConversion based on crude LC/MS analysis.b The % conversion was not determined.c Trace amount of 8 was observed.11O

N

N

S94

12O

NCN 86

13O

N80

14N

N 91

O

a Isolated yield after purication.

to the corresponding benzthiazole and benzimidazolederivatives. In practice, with 2-aminothiophenol underthe same reaction conditions, the desired benzthiazolewas obtained along with several side products as shownfrom the crude LC/MS analysis and the isolated yieldwas low. No further attempts were made to optimize

benzimidazoles starting from carboxylic acids. The gen-erality of these reactions, as demonstrated in Tables 2

our case a carboxylic acid, using a combination of thesame reagents and a common operation, multiple het-

Table 3. Synthesis of benzoxazoles from carboxylic acids and 1,2-phenylenediamine with PS-PPh3/CCl3CN

R1

O

OH+

2 equiv. CCl3CN3 equiv. PS-PPh3

CH3CN, MW150 C, 15 mins

(1 equiv.)R2NH2

NHR3(H)

N

NR1

R3(H)

R2

Entry Product Yielda (%)

1NH

N79

2NH

NCl

Cl76

3NH

N94

4NH

N87

5NH

N89

6 NH

N85

7N

N

93

8NH

NO

O 80

9NH

N90

10NH

NCl

Cl90

11NH

N83

12NH

N89

HN

Y. Wang et al. / Tetrahedron Le13N

N 80

14 N

HN

69a Isolated yields after purication.erocyclic scaolds with distinct structure complexityand diversity can be easily accessed. We believe that thisapproach combines the advantages of both focusedlibrary synthesis and diversity-oriented synthesis. Becauseof the generality of the reaction protocols that we havebeen developed, thorough SAR studies are possiblewithin the structure skeletons that are constructed.More importantly, diverse structure skeletons can alsobe obtained within one library to greatly facilitate eithera hit to lead or the lead optimization process.

Supplementary data

Supplementary data associated with this article can befound, in the online version, at doi:10.1016/j.tetlet.2006.05.052.

References and notes

1. For some reviews, see: (a) Bleicher, K. H.; Bohm, H.;Muller, K.; Alanine, A. Nature Rev. 2003, 2, 369378; (b)Hann, M. M.; Leach, A. R.; Harper, G. J. Chem. Inf.Comput. Sci. 2001, 41, 856864; (c) Oprea, T. I.; Davis, A.M.; Teague, S. J.; Leeson, P. D. J. Chem. Inf. Comput. Sci.2001, 41, 13081315.

2. Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W. Org.Lett. 2005, 7, 925928.

3. Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett.2006, 47, 105108.

4. For the use of CCl3CN/PS-PPh3 in acylation, see: (a) Jang,D. O.; Park, D. J.; Kim, J. Tetrahedron Lett. 1999, 43,53235326; (b) Buchstaller, H.; Ebert, H. M.; Anlauf, U.Synth. Commun. 2001, 31, 10011005.

5. For some examples, see: (a) Griengl, A. H.; Petsch, M.;Schoo, P. N.; Weber, H. Tetrahedron: Asymmetry 1996, 7,and 3, is important for library analog production as di-verse substituent patterns are often used with one set ofreaction conditions in a single library. More impor-tantly, the methods we have developed t into our over-all strategy where starting from a common precursor, inthe protocol with this reagent system and attentionwas focused on the benzimidazoles. Gratifyingly, with1,2-phenylenediamines, again under the same reactionconditions, benzimidazoles were obtained with highyields and purities. As with the benzoxazoles, this proto-col worked for a variety of carboxylic acids and 1,2-phenylenediamines to aord the corresponding benz-imidazole in good yields in a single step (Table 3).7 Sig-nicantly, fair to good yields of the correspondingbenzimidazoles were also obtained with electron de-cient 4,5-dichlorobenzene-1,2-diamine (Table 3, entries2 and 10), which is generally a recalcitrant substratefor acylation paradigms.

In summary, we have developed an ecient and generalreaction protocol for the synthesis of benzoxazoles and

tters 47 (2006) 48234826 4825473490; (b) Clemens, J. J.; Davis, M. D.; Lynch, K. R.;Macdonold, T. L. Bioorg. Med. Chem. Lett. 2004, 14, 4903

4906; (c) Philips, G. B.; Wei, G. Tetrahedron Lett. 1996, 37,48874890, and reference therein; (d) Beebe, X.; Wodka,D.; Sowin, T. J. J. Comb. Chem. 2001, 3, 360366.

6. For some recent examples using other methods, see: (a)Yun, Y. K.; Porco, J. A., Jr.; Labadie, J. Synlett 2002, 5,739742; (b) Kawashita, Y.; Nakamichi, N.; Kawabata, H.;Hayashi, M. Org. Lett. 2003, 5, 37133715; (c) Evindar, G.;Batey, R. A. Org. Lett. 2003, 5, 133136; (d) Evindar, G.;Batey, R. A. J. Org. Chem. 2006, 71, 18021808; (e) Heuser,S.; Keenana, M.; Weichert, A. G. Tetrahedron Lett. 2005,46, 90019004; (f) Lin, S.; Isome, Y.; Stewart, E.; Jiu, J.;Yohannes, D.; Yu, L. Tetrahedron Lett. 2006, 47, 28832886; (g) Boyd, G. V. In Science of Synthesis; Neier, R.,Ed.; Georg Thieme: New York, 2002; pp 481492; (h)Grimmett, M. R. In Science of Synthesis; Neier, R., Ed.;

Georg thieme Verlag: New York, 2002; pp 529612; (i)Preston, P. N. Chem. Rev. 1974, 74, 279314.

7. General procedure: A Smith process vial (0.52 mL) wascharged with a stir bar. To the vessel were added 0.2 mmolof the carboxylic acid and 0.2 mmol of the 2-aminophenolor 1,2-phenylenediamine in 1.5 mL dry CH3CN. 0.6 mmolPS-PPh3 (3 mmol/g) was added to the reaction mixturefollowed by 0.4 mmol CCl3CN. The reaction vessel wassealed and heated in microwave to 150 C for 15 min. Aftercooling, the reaction vessel was uncapped and the resin wasltered and washed by additional CH3CN and MeOH. Thedesired benzoxazole or benzimidazole was isolated by ashchromatography. All products thus obtained were greaterthan 98% pure as determined by LC/MS and 1H NMRanalysis.

4826 Y. Wang et al. / Tetrahedron Letters 47 (2006) 48234826

A simple and efficient one step synthesis of benzoxazoles and benzimidazoles from carboxylic acidsSupplementary dataReferences and notes