Fluorinated Heterocycles - American Chemical Society

Chapter 15

Trifluoromethoxy Containing Azoles and Azines: Synthesis and Biological Activity 1,

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Mykhaylo V. Vovk *, Oleksandr M. Pinchuk , Volodymyr A. Sukach , Andrij O. Tolmachov , and Andrei A. Gakh

Downloaded by NANYANG TECH UNIV LIB on November 2, 2014 | http://pubs.acs.org Publication Date: January 1, 2009 | doi: 10.1021/bk-2009-1003.ch015

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Institute of Organic Chemistry, National Academy of Science of Ukraine, Murmans'ka 5, 02094 K y i v , Ukraine National Taras Shevchenko University, Volodymyrs'ka 62, 01033 Kyiv, Ukraine O a k Ridge National Laboratory, P.O. Box 2008, Oak Ridge, T N 37831-6242 * C o r r e s p o n d i n g author: [email protected] 2

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The synthesis and biological properties of trifluoromethoxy-containing azoles and azines are discussed and analyzed systematically in this review. Recent literature reports including results from the authors' research are covered.

Introduction Fluorine-containing functional groups are widely used as unique tools for fine-tuning the biological activity of organic compounds. Due to its unique properties fluorine is frequently introduced as a substituent in biologically active compounds. Fluorine-containing compounds have a wide spectrum of activities and are extensively used as insecticides, fungicides, and herbicides in agrochemical applications, and have broad applications in medicine for example as anti-cancer agents, corticoids, neuroleptics or cardiovascular agents. The presence of fluorine-containing functional groups often leads to higher lipophilicity and increased metabolic stability of biologically active compounds. Trifluoromethyl containing compounds are currently being used as synthetic reagents (7), biologically active compounds and advanced materials (2-5). O f © 2009 American Chemical Society

In Fluorinated Heterocycles; Gakh, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

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special interest are the heterocyclic compounds bearing trifluoromethoxy group, some of which showed remarkable biological activity and have been applied as pro-insecticides (Indoxacarb) (6), acaricide (Flufenerim) (7), plant growth regulator (Fluprimidol) (8) and neurologic agents (Riluzole) (9), These practical applications clearly indicate that trifluoromethoxy derivatives of azines and azoles are prospective biologically active compounds and drug candidates. This review summarizes for the first time the scattered literature data on synthesis and biological activities of trifluoromethoxy derivatives of five and six membered nitrogen containing heterocycles.

Synthesis The chemistry of trifluoromethoxy containing compounds was initiated in 1957 by the pioneering research of Prof. L . Yagupolskii who synthesized 4trifluoromethoxyaniline (10) from the corresponding amide through the Hoffman reaction. The same compound was resynthesized by Prof. W. Shepard in 1964 by reduction of 4-trifluoromethoxynitrobenzene (//). In 1963, the Prof. L. Yagupolskii team developed a synthesis of 2-amino-6trifluoromethoxybenzthiazole (Riluzole) (12) from 4-trifluoromethoxyaniline. Riluzole is a neuroprotective agent used to slow the progress of amyotrophic lateral sclerosis (ALS). The beneficial properties of this drug stimulated further investigation in the area and attracted considerable research attention to heterocyclic compounds containing trifluoromethoxy and trifluoromethoxy phenyl groups. Over the last five years over 60 articles have been published dealing with the search for biologically active hetorocyclic compounds that contain the trifluoromethoxy group. A retrosynthetic approach applied to the development of synthetic strategies for preparation of heterocyclic compounds containing the trifluoromethoxy group identifies four starting materials. These consist of two nucleophilic compounds, including 4-trifluoromethoxyaniline (13) (1) and 4-trifluoromethoxyphenyl-hydrazine (14) (2) and two electrophilic reagents - 4trifluoromethoxyphenyl-isothiocyanate (15) (3) and 4-trifluoromethoxyphenylisocyanate (4) (16). Despite the fact that these compounds are commercially available their methods of synthesis were not optimized and required the use of toxic intermediates. Therefore the elaboration of convenient and safe synthetic methods constituted an important synthetic challenge. Our group has synthesized aniline 1 through the reduction of the corresponding nitrobenzene with tin(II) chloride. Amine 1 was used for the synthesis of hydrazine 2 in high yield. We have also developed a facile method for synthesizing 4-trifluoromethoxyphenylisothiocyanate 3 which does not require the use of thiophosgene (Scheme 1) (17),



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Pyrroles The generation of diverse libraries of nitrogen-containing heterocyclic structures bearing trifluoromethoxy groups represents an important contribution to the drug discovery process. We have developed a facile method for the synthesis of previously unknown trifluoromethoxy-containing pyrroles that can be used for the synthesis of large combinatorial libraries. Condensation of trifluoromethoxyaniline 1 with diketone 5 followed by functionalization at the 3position of pyrrole 6 with chloroacetonitrile resulted in compound 7 which was hydrolized to give active chloroketone 8. The Hantsch reaction of compound 8 with thioureas and thioamides led to the library of comopounds 9 containing pharmacophore thiazole structural unit (Scheme 2) (17). It was established that chloroacetylpyrrole 8 is an effective alkylating agent for nitrogen-, sulfur- and oxygen-containing compounds. Experimental conditions were optimized for N-alkylation of imidazole, thiazole, and triazole, for S-alkylation of thiadiazole, oxadiazole, and tetrazole derivatives, and for Oalkylation of izoxazole carboxylic acids and pyridylacetic acids to afford new pyrrole compounds 10-12 in good preparative yields (Scheme 3) (17).

Indoles The classical Fisher method was used for the synthesis of 5trifluoromethoxy indoles 13-15, functionalized with carboxylic (18), carboxymethyl (19) and benzyl groups (20) (Scheme 4). 5-Trifluoromethoxyindole 16 bearing a pendant amide substituent at the 3position was obtained through a polymer supported synthetic procedure shown in Scheme 5 (21). These compounds were investigated as NKj antagonists. As part of a program to develop potassium channel activators, Buterea and coworkers prepared the trifluoromethoxy derivative 19 of 5,10-dihydroindenof 1,2-b]indole-1 -carboxylic acid by condensation of hydrazine 2 with indone carboxylic acid 17 followed by the microwave-faci 1 itated Fisher cyclization of hydrazone 18 (Scheme 6) (22). The reaction of hydrazone 20 with anthranilic acid lead to quinazolino-βcarbolin-5-one 21 - a potential antipoliferative agent (Scheme 7) (23). 2-Methyl-6-trifluoromethoxyindole (23) was used as a starting material for the synthesis of metabolically robust N-benzyl-indols with either a 3-benzoyI or 3-benzisoxazoyl moiety that function as selective peroxisome proliferatoractivated receptor gamma (PPARy) modulators (24). Compound 23 was prepared by treatment of 3-trifluoromethoxyaniline with /-butyl hypochlorite, thiomethyl acetone and triethylamine followed by reduction of 3thiomethylindole 22 by Raney N i in ethanol (Scheme 8).



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MeO



313



Scheme 4

2

13(R=H,X=C00H) 14 (R=H, X = C H C O O H )



315

3



316

-s:

CO


In Fluorinated Heterocycles; Gakh, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009. Scheme 7


318 The Fisher reaction of 2 with cyclic ketones 24 gave trifluoromethoxy indoles 25 in 80% yield. The structural diversity of compounds 25 makes them useful for systematic of structure-activity relationships (Scheme 9) (17).

Azoles There are only a few examples of F CO-containing pyrazoles described in the literature. 1 -(4-Trifluoromethoxy)-phenyl pyrazoles (25,26) functionalized at position 5 were obtained through the condensation of diketoethers 26 with 4trifluoromethoxyphenylhydrazine hydrochloride 2. The intermediate esters of pyrazole-3-carbonic acids 27 were transformed into acid 28, alcohol 29, bromide 30 and ether 31 (25) (Scheme 10). The reaction of compound 2 with beta-dicarbonyl compound 32 and ester 33 resulted in the benzodipyrazole (27) 34 and pyrazolo[3,4-d]pyridine (28) 35, respectively representing a new class of potent CDK2 inhibitors (Scheme 11). Trifluoromethoxy benzimidazole 37 containing a chloromethyi group in the 2position was synthesized through acid catalized condensation of 4trifluoromethoxyortho-phenylene diamine 36 with chloroacetic acid (29). Compound 37 was used as an efficient alkylating agent for the preparation of pharmacologically active derivatives of pyperazine (Scheme 12). It has been shown that the presence of the trifluoromethoxy group in diamine 36 influences the formation of the imidazole ring. For example, 2methylbenzimidazole 38 can be obtained only through the condensation with acetic anhydride. On the other hand the condensation with hydroxyacetic and propionic acids was shown to be the optimal method for the synthesis of 2-hydroxymethyland 2-ethylbenzimidazoles 39, respectively, whereas 2-aryl- and 2-heteroaryl benzimidazoles 40 can be synthesized via the reaction with the corresponding aldehydes in the presence of nitrobenzene as an oxidizer (Scheme 13) (17). Some trifluoromethoxy derivatives of thiazole and benzthiazole showed remarkable biological activity. The syntheses of 2-amino-5-trifluoromethoxy benzthiazole (12) 41 (Riluzole (9)), and thiazolo-5-carboxylic acid 42 (fungicide Thifluzamide), are shown in Scheme 14 (30). It is known that 2-thiohydantoins are starting materials for the synthesis of many therapeutic substances, fungicides and herbicides. The S-alkylated hydantoins exhibit activity against herpes simplex virus (31) (HSV) and human immunodeficiency virus (32) (HIV). In an attempt to modify biological activity of 2-thiohydantoins the trifluoromethoxy derivative 43 was prepared through the reaction of methyl ester of N-ethylglycine with isothiocyanate 3 (Scheme 15) (33). A facile method for the synthesis of thiohydantoins 44 containing the F C O group is presented in Scheme 16. Further modification of compounds 44 with pharmacophore heteroarylaldehydes afforded 4-ylidene substituted thiohydantoins 45. Alkylation of these compounds provides an easy access to various derivatives 46 (Scheme 16) (17).


3

3



319

eu

ω

Τ

Χ a

II cC

CD

II

a



320



321



322



3

F C(X

"NH,

.NH?

2

F

3

C

0

F3CO

Scheme 13

P h N 0 , 0°C, 0.5h

A r C H O , 20°C, 0.5h

100°C, 6h

RCOOH

130°C, 7h

2

(MeCO) 0

40

39

Ν H

N

Ν Η

Ν

Me

y—Alk

38 (44%)

Ν y~ Ν Η


[I

Ν

Ο

V _

R=Ph (78%),

2

(69%)

(40%),

A I k = H O C H (73%), Et (78%)


324

3



325



3

+

RS

/>—Ν

Ο

MeOOC

46 (89-92%)

F CO^\

NCS

^

^

2

20°C,5h

2

3

DMF, K C 0 ,

RHal

80°C,15h

3

Et N, AcOEt

Scheme 16

* HC1

Het

NH c o

Ν

Ο

45 (79-83%)

/>-N

Ο

HetCHO

44 (84%)

\\ //

120°C,5h

F CO—(\ 3

'

CH3C00H

F


Fluorinated Heterocycles - American Chemical Society

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