Copper-Catalyzed, Directing Group-Assisted Fluorination of Arene and Heteroarene C-H Bonds

Abstract

We have developed a method for direct, copper-catalyzed, auxiliary-assisted fluorination of β-sp² C-H bonds of benzoic acid derivatives and γ-sp² C-H bonds of α,α-disubstituted benzylamine derivatives. The reaction employs CuI catalyst, AgF fluoride source, and DMF, pyridine, or DMPU solvent at moderately elevated temperatures. Selective mono- or difluorination can be achieved by simply changing reaction conditions. The method shows excellent functional group tolerance and provides a straightforward way for the preparation of ortho-fluorinated benzoic acids.

Fluoroaromatic compounds possess inertness, high chemical, thermal, and metabolic stability, as well as unique electronic properties. They are widely used as pharmaceuticals, agrochemicals, and imaging materials.¹ Classical methods for synthesis of fluoroaromatics such as Balz-Schiemann reaction employ prefunctionalized starting materials and typically require harsh reaction conditions thus limiting the scope of transformations.^2,3 More recently, aryl-fluorine bonds have been created by using transition-metal catalysis. Specifically, Buchwald has shown that aryl triflates can be converted to aryl fluorides under palladium catalysis.⁴ Ritter has developed methods for stannane, boronic acid, and phenol conversion to fluoroaromatics.⁵ Hartwig has shown that aryl iodides can be converted to aryl fluorides by a combination of stoichiometric copper(I) complex and AgF.⁶ Aryl stannanes and aryl borates have been converted to aryl fluorides by employing Cu(I) in combination with electrophilic fluoride source.⁷ Many of these processes have been developed based on mechanistic studies.⁸ However, these methods require use of prefunctionalized starting materials. Non-directed fluorination of sp³ C-H bonds by radical methods has also been investigated.⁹ Only a few groups have reported directed catalytic sp² C-H bond fluorination. In a pioneering work, Sanford has shown that pyridine directing group can be employed for a palladium-catalyzed arene fluorination by electrophilic fluorine sources. Mechanistic studies support involvement of high-valent palladium complexes in these reactions.¹⁰ Yu has demonstrated palladium-catalyzed benzylamine triflamide and benzoic acid perfluoroaniline amide ortho-fluorination by N-fluoropyridine derivatives.¹¹ A recent paper by Sanford has shown that Pd(OAc)₂/AgF/PhI(OPiv)₂ system¹² can be employed for 8-methylquinoline benzylic C-H bond fluorination.¹³ A general method for directed arene C-H bond fluorination by employing a first-row transition metal catalyst has not yet been reported.¹⁵ We disclose here a method for aminoquinoline and picolinamide-directed benzoic acid and benzylamine derivative ortho-fluorination under copper catalysis.

In 2005, we introduced 8-aminoquinoline and picolinic acid auxiliaries for palladium-catalyzed sp² and sp³ C-H bond arylation.^14a Recently copper-catalyzed sulfenylation and amination of C-H bonds in 8-aminoquinoline benzamides and benzylamine picolinamides was demonstrated.^14b,c We hypothesized that 8-aminoquinoline and picolinic acid auxiliaries would promote copper-catalyzed ortho-fluorination of sp² C-H bonds based on the following considerations: (1) copper-catalyzed aryl halide fluorination has been reported in a macrocyclic polyamine system,^16a (2) copper-promoted C-H activation has been reported in the same system,^16b and (3) it appears that both macrocyclic amine and 8-aminoquinoline benzamide ligands stabilize high-valent copper intermediates.

The reaction of 8-aminoquinoline p-trifluoromethyl-benzamide was investigated with respect to copper catalyst, fluorine source, oxidant, and solvent (Table 1). Best results for monofluorination were obtained by employing CuI catalyst, NMO oxidant, and DMF solvent. Use of PhI(OPiv)₂ oxidant resulted in lower yields (entry 2). Dimethyl sulfoxide solvent is inferior to DMF due to starting material decomposition (entry 1 vs. 4). Reaction can be run in pyridine (entry 7) which slows decomposition of starting material, albeit at the expense of reaction rate. Selective difluorination can be achieved by employing higher loading of CuI (entries 9–11). Longer reaction times require the use of pyridine additive (2 equiv) to prevent decomposition of amide substrate (entry 11).

Table 1.

Optimization of Reaction Conditions^a

Entry	Catalyst (mol %)	T, °C	1, %	2, %	3, %
1b	Cu(OAc)2 (25%)	100	4	17	5
2e,f	Cu(OAc)2 (25%)	100	<2	13	4
3	Cu(OAc)2 (25%)	100	20	42	8
4	CuI (25%)	100	11	54	6
5	CuI (25%)	80	20	60	5
6	CuI (15%)	80	18	70	3
7d	CuI (15%)	80	4	79	7
8d,e	CuI (15%)	80	16	80	3
9f	CuI (20%)	80	<2	17	38
10d,e	CuI (20%)	80	10	52	33
11f,g	CuI (20%)	80	<2	5	78

^aAmide 0.25 mmol, AgF 3 equiv, NMO 4 equiv, DMF 1 mL. Yields were determined by GC analysis.

^bDMSO solvent.

^cPhI(OPiv)₂ oxidant instead of NMO.

^dAgF 4 equiv, NMO 5 equiv.

^ePyridine solvent.

^fAgF 6 equiv, 8 equiv NMO, 1.5 h.

^gPyridine additive 2 equiv.

Reaction scope with respect to monofluorination of 8-aminoquinoline benzamides is presented in Table 2. Both electron-rich (entries 2 and 6) as well as electron-poor (entries 1, 3–5, 7, 8) benzamides are reactive. Heterocyclic carboxamides containing indole (entry 9) and pyridine (entry 10) moieties are fluorinated in good yields. The reaction is functional group tolerant, with carboxylate (entry 3), nitrile (entry 4), and nitro groups (entry 7) compatible with the fluorination conditions. For strongly electron-deficient substrates such as 4-nitrobezoyl and pyridyl derivatives (entries 7 and 10) reaction has to be run in pyridine solvent to prevent decomposition of product. However, somewhat longer reaction times are required if pyridine solvent is employed.

Table 2.

Monofluorination of Carboxylic Acid Derivatives^a

entry	Ar	product	yield, %
1	4-CF3C6H4		71
2	4-MeC6H4		75
3	4-MeO2CC6H4		56
4	4-NCC6H4		62 60b
5	2-CF3C6H4		80
6	2-MeC6H4		63
7c	4-NO2C6H4		60
8	3-CF3C6H4		71
9	3-(N-Me-indolyl)		54
10c	4-Pyridyl		62

^aAmide 0.25 mmol, DMF 1 mL. Yields are isolated yields. Please see Supporting information for details.

^bReaction scale: 5 mmol.

^cPyridine solvent.

Optimization results in Table 1 show that by increasing CuI and AgF loading and reaction time, clean difluorination can be obtained. Longer reaction times require the use of pyridine to prevent decomposition of aminoquinoline amides. Difluorination examples are presented in Table 3. Similar to monofluorination, electron-rich (entries 4, 5, 7), electron-poor (entries 1–3, 6) and heterocyclic (entry 8) amides can be efficiently difluorinated in good yields. Interestingly, difluorination of m-substituted amides is possible (entries 4, 7). This contrasts with palladium-catalyzed C-H bond functionalization where substitution at more hindered positions is typically not observed,¹⁷ and is consistent with results obtained in copper-promoted sulfenylation of sp² C-H bonds where functionalization of hindered positions is possible.^14b

Table 3.

Difluorination of Carboxylic Acid Derivatives^a

entry	Ar	product	yield, %
1	4-CF3C6H4		67
2	4-MeO2CC6H4		62
3	NCC6H4		70
4	2-Naphthyl		70
5	4-MeOC6H4		75
6	4-FC6H4		61
7	3-MeC6H4		77
8b	4-Pyridyl		61

^aAmide 0.25 mmol, DMF 1 mL. Yields are isolated yields. Please see Supporting information for details.

^bPyridine solvent.

Fluorination of benzylamine derivatives is also possible by employing a picolinamide directing group (Scheme 1). However, the reactions are substantially less efficient, requiring 50 mol% CuI catalyst, higher temperature, and DMPU solvent. Additionally, reasonable conversions could be obtained only with α,α-disubstituted benzylamines. This behavior is consistent with copper-catalyzed amination and sulfenylation of C-H bonds.^14b,c

Scheme 1.

Fluorination of Picolinamides

Auxiliary can be cleaved by base hydrolysis. Thus, heating amide 6 with NaOH in ethanol for 24 h afforded high yield of trifluorobenzoic acid (Scheme 2).

Scheme 2.

Auxiliary Cleavage

While speculations about the reaction mechanism are premature at this point, Ribas has shown that copper-catalyzed nucleophilic aryl fluorination and aryl halide exchange is possible in a highly geometrically constrained system.^16a The reactions proceed via Cu(III) intermediates, thus showing that C-F reductive elimination from Cu(III) is possible under very mild conditions.^7b Given that aminoquinoline amides stabilize high oxidation states in transition metals,^14d it is likely that copper-catalyzed aminoquinoline amide fluorination also proceeds via Cu(III) intermediates.

In conclusion, we have developed a method for direct, copper-catalyzed, auxiliary-assisted fluorination of β-sp² C-H bonds of benzoic acid derivatives and γ-sp² C-H bonds of benzylamine derivatives. The reaction employs catalytic CuI, AgF as nucleophilic fluoride source, and DMF, pyridine, or DMPU solvent at moderately elevated temperatures. The method allows for selective mono- or difluorination of benzamide substrates. The reaction shows excellent functional group tolerance and provides a straightforward way for the preparation of ortho-fluorinated benzoic acids. Future directions of the work involve mechanistic studies of the transformation and attempts to isolate reaction intermediates.