Copper-Catalyzed Trifluoromethylation of Alkenes : Synthesis of Trifluoromethylated Benzoxazines

Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal By-pass Road, Bhauri, Bhopal, Madhya Pradesh, India, Pin: 462 066 E-mail: sangitkumar@iiserb.ac.in Page Table of

Benzoxazines, N,O-containing six membered heterocycles, are present in many drug molecules and herbicides and are also widely used as building blocks for bioactive molecules.They show interesting biological and pharmaceutical properties such as progesterone receptor (PR) modulation, and antianxiety, anti-HIV, agonist, and antagonist activities (Fig. 1). 1,2ncorporation of the CF 3 group in the organic molecule enhances several biological properties such as solubility, lipophilicity, metabolic stability, binding selectivity etc. 3 As a result, several trifluoromethylated heterocycles such as efavirenz and celecoxib were used as potential drugs for the treatment of HIV infection, arthritis, and spondylitis. 4][7][8][9][10][11][12] However, the synthesis of CF 3 -containing heterocycles through intramolecular cyclization has been less explored.In 2013, Buchwald et al. reported copper-catalyzed intramolecular oxytrifluoromethylation of unactivated alkenes using Togni's reagent for the synthesis of trifluoromethylated lactones. 6Subsequently, intramolecular aminotrifluoromethylation 7 and carbotrifluoromethylation 8 of simple alkenes have been successfully established.The Fu group had developed transition metal-free synthesis of trifluoromethylated oxazolines exploiting CF 3 SO 2 Na as a CF 3 source. 9onstruction of the benzoxazine ring has been achieved by the intramolecular cyclization of alkenes using electrophiles such as Br + , I + , and KSCN and K 2 S 2 O 8 combination. 13,14enzoxazines comprising the CF 3 group has remained an unexplored area.Recently, Xiao et al. has demonstrated photocatalytic oxytrifluoromethylation of N-allylamides for the synthesis of trifluoromethylated benzoxazines using the expensive Ru(bpy) 3 (PF 6 ) 2 catalyst and a base by a radical pathway.15d Copper-catalyzed trifluoromethylation of terminal alkenes through allylic C-H bond activation has been accomplished by Fu and Liu et al. exploiting the copper catalyst, Umemoto's reagent, and the 2,4,6-trimethyl pyridine reaction system (Scheme 1, eqn (1)).10a In view of the recent advances in Cu-catalyzed functionalization of alkenes, 16,17 we envisioned, trifluoromethylation of the terminal alkene followed by intramolecular addition of oxygen for the synthesis of trifluoromethylated benzoxazines keeping the allylic C-H bond intact (eqn (2)).Herein, we present a simple base and ligand-free Cucatalyzed synthesis of trifluoromethylated benzoxazine heterocycles from N-(2-( prop-1-en-2yl)benzamide substrates 1 using Umemoto's reagent 2 (Scheme 1, eqn (2)).Synthesized trifluoromethylated benzoxazines were also selectively converted into trifluoromethylated allylic and (E)-vinylic benzamides.
We initially examined the reaction of N-(2-( prop-1-en-2-yl)benzamide 1a with CuI (20 mol%) and various trifluoromethylating reagents in DCE (Table 1, entries 1-4).TMSCF 3 was observed to be sluggish and the formation of the desired product was not realized.Togni's reagent gave a mixture of the desired trifluoromethylated product 3a in low yield (30%) along with 45% allylic trifluoromethylated product 4a (entry 1, Table 1).Shreeve's reagent, a triflate analogue of 2 provided 37% yield of 3a.The use of Umemoto's reagent 2, led to further increase in the yield by 15% of the desired product 3a.The presence of copper is crucial for trifluoromethylation as the reaction failed to provide even traces of 3a in the absence of copper (entry 5, Table 1).Although, various Cu sources (Table 1, entries 6-9, 14), ligands, and bases were screened (see ESI, Table S1, pp.S5-S6 † for detailed optimization study), CuI alone was observed to be effective.The change in solvent from DCE to DMF, DMAc, NMP, and DMSO (Table 1, entries 10-13) led to further improvement in the yield and the best yield (68%) was obtained in DMSO (entry 13, Table 1).
Next, the substrate scope of trifluoromethylation of the alkenes using 20 mol% of CuI at 80 °C in DMSO was studied.The substitution in the amide ring of 1a was explored (Scheme 2).Alkenes with electron donating substituents such as CH 3 , OCH 3 , and t Bu at the para-position of the benzamide ring, gave trifluoromethylated benzoxazines 3b-3d in moderate yields (50-59%) whereas the electron withdrawing groups such as NO 2 , F, Cl, and Br favoured the trifluoromethylation which indeed led to good yields (74-92%) of 3e-3h.
Structures of CF 3 -benzoxazines 3f and 3z are also established by the single crystal structure study (Fig. 2, for 3z and crystallographic details, please see the ESI, pp.S202-S232 †).meta-Methoxy substituted benzoxazine 3i was obtained in moderate yield (46%) whereas Cl and NO 2 substituted benzoxazines 3j and 3k were obtained in 67 and 91% yields, respectively.The reaction of the meta-di-OCH 3 -subtituted substrate was observed to be sluggish and only trace amounts of the respective trifluoromethylated benzoxazine 3l were isolated.On the other hand, meta-di-chloro-substituted benzoxazine 3m was obtained in 74% yield.a All reactions were carried out using 0.2 mmol of 1a, 0.35 mmol of 2 in 1 mL solvent at 80 °C in a Schlenk tube under nitrogen and the progress of the reaction was monitored by TLC up to 35 h.b Percentage yield was determined by 19 F-NMR using fluorobenzene as an internal standard.c Yield of 4a.ND = not detected, CuTc = thiophene-2-carbonyloxylate copper(I).
Scheme 2 Synthesis of CF 3 -benzoxazines: scope with respect to amide and aniline rings.
Similarly, the substrate with ortho-chloro substitution in the amide ring, gave the desired trifluoromethylated benzoxazine 3n in good yield (71%). ortho-Methyl and trifluoromethyl substituted substrates failed to yield trifluoromethylated benzoxazines 3o and 3p and recovered quantitatively and this could be due to the steric effect of CH 3 and CF 3 which may prevent the coordination of the -CONHPh group with CuCF 3 (vide infra).
On the other hand, bromo-substitution in the aniline ring para to NH has a negative effect on the trifluoromethylation reaction as only trace amounts of 3q were obtained.The substrate with a chloro substituent in the aniline ring, para to the alkene, underwent trifluoromethylation smoothly and yielded chloro benzoxazines 3r in 72% yield.
Next, the substrates with various N-aromatics such as naphthyl heteroaromatics; thiophenyl, furanyl, and pyridinyl were subjected to trifluoromethylation reaction.Indeed, the reaction also showed compatibility with naphthyl and heteroaryl containing substrates and respective trifluoromethyl benzoxazines 3s-3v were obtained in 49-72% yields.
Substrates not only with various aryl benzamides but also with alkyl amides such as methyl and tert-butyl substituents were tolerated and yielded trifluormethylated benzoxazines 3w and 3x in 73 and 74% yields, respectively.
After studying various N-aryl, alkyl and benzamide substrates, C-2 substituted alkenes were explored in the coppercatalyzed C-CF 3 and C-O bond formation reaction (Scheme 3).Alkenes with H and Ph substituents at the C-2 position provided excellent yields (90 and 94%) of trifluoromethylated benzoxazines 3y and 3z.C-2 substituted methyl, ethyl, and isopropyl benzoxazines (3a, vide supra), 3aa, and 3bb were obtained in 68, 74, and 35% yields, respectively.In the case of 3bb, formation of trifluoromethylated, the uncyclized product 4bb in 45% yield was also observed.
Next, the synthetic utility of trifluoromethylated benzoxazines was explored (Scheme 4).An addition of KO t Bu to benzoxazines 3a, 3e, and 3k provided trifluoromethylated allylic benzamides 4a, 5a, and 5b, respectively.Interestingly, treatment of 3a and 3y with CH 3 Li provided trifluoromethylated (E)-vinyl benzamides 5c and 5d, respectively.The structure of 5d is also established by the X-ray single crystal study (Fig. 2).It seems that KO t Bu removes the less hindered methyl proton whereas CH 3 Li prefers abstraction of the highly acidic proton adjacent to the CF 3 group.
In the mechanistic consideration, copper(I) can form the Cu(III)CF 3 intermediate by the reaction of Umemoto's reagent 2 (Scheme 5).10a The formation of the Cu(I)CF 3 intermediate is also possible by the disproportionation of Cu(I) into Cu(II) and Cu(0) followed by the reaction of Cu(0) with Umemoto's reagent ( please see the ESI, pp.S8-S13 † for details).12e,18 Nevertheless, both Cu(I)CF 3 and Cu(III)CF 3 could act as a trifluoromethylating reagent.12e Ligand exchange with the alkenamide substrate would lead to the substrate-copper intermediate I. 19 Intramolecular coordination of an alkene followed by the formation of the Heck-type four-membered ring would generate the transition state II.This could allow the formation of the C-CF 3 bond leading to III, subsequent reductive elimination may give benzoxazine, by concomitant release of the catalyst.It seems unlikely that the reaction proceeds via a radical pathway because the reaction mixture failed to give any signal in the EPR spectrum.The non-reactive nature of ortho-methyl and trifluoromethyl substituted substrates (vide supra, 3o and 3p) and formation of the trifluoromethylated allylic product 4bb could be rationalized based on the proposed intermediates I-III.It seems that allylic trifluoromethylation of the alkene through the allylic C-H bond activation process 10a also occurred along with the formation of new C-CF 3 and C-O bonds.This may be due to the steric effect of the iso-propyl substituent, therefore, giving a mixture of the C-CF 3 and C-O bond forming product 3bb and the trifluoromethylated allylic product 4bb.
In conclusion, we have developed a simple, ligand and base free copper catalyzed method for the construction of trifluoromethylated benzoxazines by using Umemoto's reagent.As the reaction involves mild conditions, trifluoromethylated benzoxazines with functionalities such as nitro and bromo could be constructed which are useful for the later stage modifications.The synthetic utility of trifluoromethylation reaction has also been demonstrated by converting CF 3 -containing benzoxazines into allylic and (E) vinylic benzamides.The stereoselective synthesis utilizing a chiral ligand and copper catalytic system as well as the biological study of trifluoromethylated benzoxazines are under investigation in our laboratory.
S.K. thanks DRDO, New Delhi and IISER, Bhopal for generous funding.S.J., S.K. and A.V. acknowledge IISER, Bhopal and UGC, New Delhi, respectively, for the fellowship.S.K. also thanks Ch.Durga Prasad for proofreading the manuscript.

Table 1
Optimization of the reaction conditions a