Aldrichimica Acta Vol. 45, No. 3 - Sigma-Aldrich

76
Transition-Metal-Mediated Fluorination, Difluoromethylation, and Trifluoromethylation
Zhuang Jin, Gerald B. Hammond,* and Bo Xu*
R
1,10-phenanthroline (1 equiv)
KF, DMF, air, 100 o Me3SiCF3 (5 equiv)
CuI (1 equiv)
(a)
75
C
R CF3
76, 47–91%
(Ref. 69)
R = alkyl, Ph, aryl, heteroaryl
R B(OH)2
Ag2CO3 (1.0 equiv)
KF, K3PO4, DMF, 45 o Me3SiCF3 (5 equiv)
(CuOTf)2 C6H6 (0.6 equiv)
1,10-phenanthroline (1.2 equiv)
(b)
20
C
R CF3 66, 68–90%
(d)
R = alkenyl, aryl, heteroaryl
Me3SiCF3 (2 equiv)
Cu(OAc)2 (1 equiv)
(c) R B(OH)2
20
1,10-phenanthroline (1.1 equiv)
CsF, O2 (1 atm), 4 Å MS
DCE or i-PrCN, rt
R CF3
66, 34–68%
(e)
R = aryl, heteroaryl
R
20
O
Ar B
O
78
B(OH)2
Me
Me
Me
Me
Ar = aryl, heteroaryl
S8, Me3SiCF3
CuSCN (10 mol %)
1,10-phenanthroline (20 mol %)
Ag 2CO 3, K 3PO 4, 4 Å MS
DMF, rt, 24 h
K[(OMe)3BCF3] (4, 2 equiv)
O2 (1 atm), Cu(OAc)2 (1 equiv)
DMSO, 60 o C, 16 h
77, 58–91%
R = H, Ph, PhO, BnO, t-Bu, Br, (MeO)3, H2C=CH, MeO2C, CN,
MeSO2, PhC(O), H2NC(O); ArB(OH)2 (Ar = 1-Np, 6-MeO-2-Np)
Ar CF3
66, 36–99%
(Ref. 72a)
(Ref. 73)
SCF3 (Ref. 74)
(Ref. 75)
Scheme 15. Oxidative Trifluoromethylation of Terminal Alkynes and Aryl-
and Alkenylboronic Acids.
(a)
R3 (c)
Ar
N N
O
Me3SiCF3 (4 equiv)
Cu(OAc)2 (40 mol %)
1,10-phenanthroline (40 mol %)
t-BuONa (1.1 equiv)
NaOAc (3 equiv), air, DCE
4 Å MS, sealed tube, 80 o C, 6 h
R
N N
Ar O
43–91%
CF3
Ar = Ph, 1-Np, 4-XC6H4 (X = Me, t-Bu, MeO, CF3, NO2, Cl, MeO2C)
Y
Me3SiCF3 (4 equiv)
Cu(OAc)2 (40 mol %)
1,10-phenanthroline (40 mol %)
(b)
N t-BuONa (1.1 equiv)
NaOAc (3 equiv)
t-BuOOt-Bu (3 equiv), N2, DCE
4 Å MS, sealed tube, 80 o R
C, 6 h
R
Y = O, S, NMe, N(CH2)2CH=CH2; R = H, Me, Ph, Cl, Br
R 1
N
R 2
Me3SiCF3 (3 equiv)
Cu(OH)2 (10 mol %)
1,10-phenanthroline (10 mol %)
KF (3 equiv)
Ag2CO3 (2 equiv), N2, DCE
sealed tube, 80 oC, 12 h
R 1 = Me, i-Pr, Cy, c-Pent; R 2 = Me, Et, Bn, Ph; R 3 = H, Cl, Br, MeO2C
R 3
Y
CF3
N
32–88%
R 1
N
R2 CF3
64–89%
Scheme 16. Copper-Catalyzed, Direct, C–H Oxidative Trifluoromethylation of
Heteroarenes Employing Me 3SiCF 3 and Oxidizing Reagents. (Ref. 77)
Gooßen and co-workers reported that arylboronic acid pinacol
esters can be converted into the corresponding benzotrifluorides
with an easy-to-use, one-component trifluoromethylating reagent,
potassium (trifluoromethyl)trimethoxyborate (4), mediated by copper
acetate under an oxygen atmosphere (Scheme 15, Part (e)). 75 Qi, Shen,
and Lu reported a Cu-mediated ligandless aerobic fluoroalkylation
of arylboronic acids using an R fI–Cu combination. 76 Although no
examples of trifluoromethylation were provided, this method can, at
least in theory, be used for trifluoromethylation when ICF 3 is employed.
A copper–catalyzed, direct C–H oxidative trifluoromethylation
of heteroarenes has been achieved using Me 3SiCF 3 and a variety of
oxidants such as air or t-BuOOt-Bu (Scheme 16). 77 1,3,4-Oxadiazoles,
1,3-azoles, and indoles were trifluoromethylated in yields ranging from
moderate to excellent, and the reaction was compatible with a variety
of substituents and functional groups.
The copper-catalyzed oxidative trifluoromethylation approach can
also use suitable electrophilic trifluoromethylation reagents. Sodeoka
and co-workers have developed a copper-catalyzed C2-selective
trifluoromethylation of indoles using 5b. 78 Substituted indoles were
trifluoromethylated by 5b in the presence of copper catalyst to give
low-to-excellent yields of C2-trifluoromethylated indoles (Scheme 17,
Part (a)). Indoles having electron-withdrawing groups, such as an ester
or ketone at R 1 or R 2 , resulted in low product yields using this protocol.
The proposed reaction mechanism assumes that the copper catalyst
increases the electrophilicity of the hypervalent iodine reagent.
Xiao and co-workers have reported a copper(0)-mediated, ligand-free
trifluoromethylation of arylboronic acids using 6b to give moderate-tosatisfactory
yields of products (Scheme 17, Part (b)). 79 This methodology
tolerates a variety of substituents and functional groups including halo,
aldehydo, and cyano. The authors proposed that the reaction might
involve a Cu(II) or Cu(III) oxidative pathway. On the other hand, Lei
Liu’s group discovered that copper(I) triflate (20 mol %), supported by
2 equiv of 2,4,6-trimethylpyridine, catalyzed the trifluoromethylation of
aryl-, heteroaryl-, and vinylboronic acids with 6a at room temperature. 80
Independently, Tianfei Liu and Qilong Shen reported the copper-catalyzed
trifluoromethylation of a broad range of aryl- and alkenylboronic acids
with Togni’s reagent (5a), to give trifluoromethylated systems in goodto-excellent
yields (Scheme 17, Part (c)). 81
Sodeoka and co-workers reported the trifluoromethylation of
allylsilanes through the use of CuI and 5b under mild conditions.
The reaction of allylsilanes unsubstituted at the 2 position furnished
vinylsilanes, while C2-substituted allylsilanes afforded desilylated
products (Scheme 17, Part (d)). 82 Hu’s group reported that CuF 2•2 H 2O
catalyzed the reaction between electrophilic fluoroalkylating agents
such as 5b and α,β-unsaturated carboxylic acids by activating both
reactants, affording di- and trifluoromethylalkenes in high yields and
excellent E/Z selectivity (Scheme 17, Part (e)). 83
Furthermore, Shen and collaborators reported a sequential
iridium-catalyzed C–H activation borylation and copper-catalyzed
trifluoromethylation of arenes. 84 The reaction is conducted under mild
reaction conditions and tolerates a variety of functional groups. The
advantage of this tandem procedure was further demonstrated by the
late-stage trifluoromethylation of a number of biologically active
molecules.
3.1.3. Other Copper-Mediated Trifluoromethylations
The copper-catalyzed trifluoromethylation of unactivated terminal
alkenes with 5b was reported by Parsons and Buchwald to afford linear
allylic trifluoromethylated products in good yields and with high E/Z
selectivity (Scheme 18, Part (a)). 85 This mild trifluoromethylation