Fluorinated Heterocycles - American Chemical Society

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Chapter 4

Efficient One-Pot Synthesis of Novel Fluorinated Heterocycles Using Trimethylsilyl Trifluoromethanesulfonate as a Metal-Free Homogeneous Lewis Acid Catalyst G . K. S u r y a P r a k a s h , C h i r a d e e p P a n j a , C l e m e n t D o , Inessa B y c h i n s k a y a , H a b i b a V a g h o o , T h o m a s M a t h e w , a n d George A. Olah Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089

Metal free homogeneous catalysis is highly significant and advantageous in the design of various therapeutic drugs in the pharmaceutical industry. The presence of organofluorine substituents in drug molecules can highly affect their physicochemical and pharmacokinetic properties. This chapter describes the one-pot synthesis of biologically active fluorinated heterocycles such as benzimidazolines, benzothiazolines, benzoxazolines, dihydrobenzoxazinones, 1,2,3,4tetrahydroquinazolines, 4H-3,1-benzoxazines and 3,1-benzoxathiin-4-ones using trimethylsilyl trifluoromethyl-sulfonate as a metal free catalyst.

© 2009 American Chemical Society

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

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Introduction Heterocyclic compounds such as benzimidazolines, benzothiazolines, benzoxazolines, dihydrobenzoxazinones, 1,2,3,4-tetrahydroquinazolines, 4 H 3,1-benzoxazines and 3,1 -benzoxathiin-4-ones are important classes of compounds. Benzimidazolines, often referred to as organic hydrides, can act as good reducing agents and good hydrogen storage materials in many organic reactions [1]. Benzothiazolines and benzoxazolines are used as plant growth régulants, herbicides, anticonvulsants, in photochromic dyes and for the treatment of A D D (Attention Deficiency Disorder) [2]. Dihydrobenzoxazinones are used in analgesics and also as useful building blocks for drugs and pharmaceuticals, which possess antiviral, antifungal, antibacterial and antiparasitic properties [3]. 1,2,3,4-Tetrahydroquinazolines, 4H-3,1 benzoxazines and 3,1 -benzoxathiin-4-ones also show similar biological activities [4]. In addition, 4H-3,1 -benzoxazines are used in lithium ion batteries [5], as anti-knock agent for gasoline [6], and as stabilizers, especially for jet fuels and turbine fuels [7]. Fluorinated heterocycles are becoming increasingly important in the pharmaceutical industry and development of new reaction methodologies for their convenient and efficient synthesis has attracted the efforts of a large number of synthetic chemists in recent years. It is well known that the presence of fluorine can result in substantial functional changes in the biological as well as physicochemical properties of organic compounds [8]. Incorporation of fluorine into drug molecules can highly affect their physicochemical properties, such as bond strength, lipophilicity, bioavailability, conformation, electrostatic potential, dipole moment, pK etc; pharmacokinetic properties, such as tissue distribution, rate of metabolism; and pharmacological consequences, such as pharmacodynamics and toxicology. Considering the increasing importance of fluorinated heterocycles and knowing the effect of fluorine substitution, we became interested in synthesizing the fluorinated analogs of the abovementioned classes of compounds. Recently [9], we have shown that gallium triflate in dichloromethane is the best catalyst-solvent combination for the effective condensation-cyclization reaction of fluorinated ketones with ortho-anilim derivatives for the synthesis of fluorinated heterocycles such as fluorinated benzimidazolines 7a, benzothiazolines 7b, benzoxazolines 7c, and dihydrobenzoxazinones 8. However, cognizant of the fact that metal-free organocatalysis [10] has drawn considerable attention of chemists in recent times and metal-free homogeneous catalysis is highly significant and advantageous for designing suitable drugs completely devoid of any metal content, we realized it would be very useful to perform similar reactions using metal-free Lewis acid catalysts. a



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Since the late 1970s, trimethylsilyl trifluoromethanesulfonate (TMSOTf) is known to be an efficient silylating agent as well as a strong Lewis acid [11]. In the late 1980s our group has successfully carried out the reductive coupling of ketones, to produce the corresponding symmetrical ethers using T M S O T f as the catalyst [12]. In the last decade, varieties of organic transformations, including Friedel-Crafts reactions, Diels-Alder reactions, C - 0 couplings, epimerizations etc. have been carried out successfully using T M S O T f as a homogeneous Lewis acid catalyst [13,14]. Recently, we have accomplished the direct three component Strecker reaction of aldehydes, ketones and fluorinated ketones using T M S O T f as the catalyst [15]. Considering all these facts, we envisioned T M S O T f as a good metal-free, homogeneous Lewis acid catalyst for the condensation-cyclization reaction of various afunctional arenes with aldehydes and ketones. Also, in our previous studies we have shown that the synthesis of four different kinds of fluorinated heterocycles from aniline derivatives can be carried out using gallium triflate as the catalyst. In our current studies, we succeeded in expanding our methodology to other possible 1,2-disubstituted benzene derivatives such as thiosalicylic acid, anthranilic acidamides, ohydroxybenzyl amine, etc., showing the versatility of this condensationcyclization methodology. Hence we could easily prepare 3,l-benzoxathiin-4ones 12 and similar derivatives under relatively mild conditions. Herein, we report in detail the results of our studies for the efficient synthesis of many previously unknown fluorinated heterocycles using catalytic amounts of trimethylsilyl triflate as the Lewis acid catalyst.

Synthesis of Fluorinated Benzimidazolines, Thiazolines, Oxazolines and Oxazinones Benzimidazolines 3 are generally synthesized from the reaction of 1,2phenylenediamines 1 and benzaldehyde (Scheme 1) [16]. However, when ketones ( R R = alkyl, phenyl) were used under similar conditions, 1,5 benzodiazepine derivatives 4 were formed as the major products (Scheme 1) [17]. This reaction proceeds through the diimine intermediate 10a (Scheme 3), which then undergoes an internal Michael type addition reaction to give rise to the corresponding 1,5-benzodiazepine derivatives 4 (Scheme 1). Reports on the direct synthesis of fluorinated benzimidazolines are very rare [18]. To our best knowledge, an easy and convenient method was not available until we recently communicated our preliminary results on condensationcyclization [9]. Funabiki et al. [19] have prepared fluorinated benzimidazolines from fluorinated alkynyl carboxylic acids 5 (Scheme 2). Synthesis of more diverse and functionalized starting materials for this reaction is tedious. Since the reaction conditions and chemical yields are not very impressive in all cases, b

2



Scheme /. Reactions of benzaldehyde and ketones with 1,2-phenylenediamines

finding a convenient and efficient method feasible under ambient conditions has been an important goal. We explored the synthesis of fluorinated benzimidazolines directly from fluorinated ketones and diamines using gallium triflate as the Lewis acid catalyst (Scheme 3). In our previous communication [9] we have discussed the results of our studies. We found that Ga(OTf) is a very unique and highly efficient catalyst for this transformation under mild conditions. High efficiency and greater versatility of this reaction, including high selectivity and purity of the products, reveal the significance of using Ga(OTf)3 as a highly suitable catalyst for these reactions. It is clear from our earlier results that the number of fluorine atoms present in the fluorinated ketone has a significant governing effect on the path of the reaction. This is because the electrophilicity at the carbon center of the monoimine intermediate 9 depends strongly on the number of fluorine atoms attached to the α-carbon. An increase in the number of fluorine atoms significantly increases the electrophilicity at the carbon center of the monoimine intermediate. Because of this the non-bonding electron pair on the nitrogen atom of the second amino group rapidly attacks the highly electrophilic carbon center of the internal fluorinated imine. This is followed by a 1,3-proton transfer, which leads to the formation of the corresponding 5-membered ring (Scheme 3). On the other hand, when the number of fluorine atoms in the ketone drops to one or zero, the electrophilicity at the carbon center of the monoimine 9a is not sufficient to facilitate internal attack by the electron pair on the nitrogen atom of the second amino group. Thus, the second amine moiety reacts faster with another molecule of ketone to form the diimine intermediate 10a, which undergoes further rearrangement to give rise to the corresponding 7-membered ring (Scheme 3). 3


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

5

2

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Scheme 2. Synthesis of fluorinated benzimidazolines from fluorinated alkynyl car boxy lie acids and vicinal-diamines

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X=NH,S,0 Rf = C H F , C H F C F C F C F

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Fluorinated Heterocycles - American Chemical Society

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