Page 5 of 7
Journal of the American Chemical Society
motes Cross-Coupling of Difluoroalkyl Bromides by Iron Catalysis.
Angew. Chem. Int. Ed. 2018, 57, 6921-6925.
7) For examples of radical-based approaches, see: (a) Zhou, Q.;
Applications. J. Chem. Soc., Chem. Commun. 1989, 1138-1139. (b)
1
2
3
4
5
6
7
8
9
Yamauchi, Y.; Fukuhara, T.; Hara, S.; Senboku, H. Electrochemical
(
Carboxylation of α,α-Difluorotoluene Derivatives and Its Application
to the Synthesis of α-Fluorinated Nonsteroidal Anti-Inflammatory
Drugs. Synlett 2008, 3, 438-442. (c) Clavel, P.; Léger-Lambert, M-P.;
Biran, C.; Serein-Spirau, F.; Bordeau, M.; Roques, N.; Marzouk, H.
Selective Electrosynthesis of (Trimethylsilyldifluoro)methylbenzene,
Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran,
P. S. Direct Synthesis of Fluorinated Heteroarylether Bioisosteres.
Angew. Chem. Int. Ed. 2013, 52, 3949-3952. (b) Douglas, J. J.; Al-
bright, H.; Sevrin, M. J.; Cole, K. P.; Stephenson, C. R. J. A Visible‐
Light‐Mediated Radical Smiles Rearrangement and its Application to
the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist.
Angew. Chem. Int. Ed. 2015, 54, 14898-14902. (c) Sumino, S.; Uno,
M.; Fukuyama, T.; Ryu, I.; Matsuura, M.; Yamamoto, A.; Kishikawa,
Y. Photoredox-Catalyzed Hydrodifluoroalkylation of Alkenes Using
Difluorohaloalkyl Compounds and a Hantzsch Ester. J. Org. Chem.
2017, 82, 5469-5474. (d) Yang, B.; Xu, X.-H.; Qing, F.-L. Synthesis of
Difluoroalkylated Arenes by Hydroaryldifluoromethylation of Alkenes
with α,α-Difluoroarylacetic Acids under Photoredox Catalysis. Org.
Lett. 2016, 18, 5956-5959. (e) Jung, J.; Kim, E.; You, Y.; Cho, E. J.
Visible Light‐Induced Aromatic Difluoroalkylation. Adv. Synth. Catal.
–
a PhCF Precursor; Conditions for a Molar Scale Preparation without
2
HMPA. Synthesis 1999, 5, 829-834. (d) Clavel, P.; Lessene, G.; Biran,
C.; Bordeau, M.; Roques, N.; Trévin, S.; de Montauzon, D. Selective
electrochemical synthesis and reactivity of functional benzylic fluoros-
ilylsynthons. J. Fluorine Chem. 2001, 107, 301-310. (e) Utsumi, S.;
Katagiri, T.; Uneyama, K. Cu-deposits on Mg metal surfaces promote
electron transfer reactions. Tetrahedron 2012, 68, 1085-1091.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
14) (a) Chen, K.; Berg, N.; Gschwind, R.; König, B. Selective Sin-
3
gle C(sp )–F Bond Cleavage in Trifluoromethylarenes: Merging Visi-
ble-Light Catalysis with Lewis Acid Activation. J. Am. Chem. Soc.
2
017, 139, 18444-18447. (b) Wang, H.; Jui, N. T. Catalytic Defluoro-
2
014, 356, 2741-2748. (f) Lemos, A.; Lemaire, C.; Luxen, A. Progress
alkylation of Trifluoromethylaromatics with Unactivated Alkenes. J.
Am. Chem. Soc. 2018, 140, 163-166. (c) During the review of this
manuscript, Jui reported an impressive expansion of the method de-
scribed in 14b, see: Vogt, D. B.; Seath, C. P.; Wang, H.; Jui, N. T.
Selective C–F Functionalization of Unactivated Trifluoro-
methylarenes. J. Am. Chem. Soc. 2019, 141, 13203-13211.
in Difluoroalkylation of Organic Substrates by Visible Light Photore-
dox Catalysis. Adv. Synth. Catal. 2019, 361, 1500-1537.
(8) For routes from difluoromethylarenes, see: (a) Geri, J. B.;
Wade Wolfe, M. M.; Szymczak, N. K. The Difluoromethyl Group as a
Masked Nucleophile: A Lewis Acid/Base Approach. J. Am. Chem. Soc.
2
018, 140, 9404-9408. (b) Haas, A.; Spitzer, M.; Lieb, M. Syntheses
(
15) For related photochemical promoted reactions involving tri-
of new aromatic compounds with fluorinated side chains and their
chemical reactivity. Chem. Ber. 1988, 121, 1329-1340.
fluoromethylarenes, see: (a) Mattay, J.; Runsink, J.; Rumbach, T.; Ly,
C.; Gersdorf, J. Selectivity and Charge Transfer in Photoreactions of
α,α,α-Trifluorotoluene with Olefins. J. Am. Chem. Soc. 1985, 107,
2557-2558. (b) Kako, M.; Morita, T.; Torihara, T.; Nakadaira, Y.
(9) (a) Jaroschik, F. Picking One out of Three: Selective Single
C−F Activation in Trifluoromethyl Groups. Chem. Eur. J. 2018, 24,
1
4572-14582. (b) Hamel, J.-D.; Paquin, J.-F. Activation of C–F bonds
α to C–C multiple bonds. Chem. Commun. 2018, 54, 10224-10239.
10) For discussion and values of C–F bond strengths, see: (a)
Photoinduced Novel Silylation of CF
Disilane and Trisilane. J. Chem. Soc., Chem. Commun. 1993, 678-680.
c) Nakadaira, Y.; Kawasaki, M.; Zhou, D.-Y.; Kako, M. Photochemi-
cal Reactions of CF -Substituted Benzenes with Tetraalkylated Group
4 Organometals. Main Group Met. Chem. 1994, 17, 553-557. (d)
3
-substituted Benzenes with
(
(
Luo, Y. R., Comprehensive Handbook of Chemical Bond Energies,
CRC Press, Boca Raton, FL, 2007. (b) O’Hagan, D. Understanding
organofluorine chemistry. An introduction to the C–F bond. Chem.
Soc. Rev. 2008, 37, 308-319. (c) Wiberg, K. B.; Rablen, P. R. Origin of
the stability of carbon tetrafluoride: negative hyperconjugation reex-
amined. J. Am. Chem. Soc. 1993, 115, 614-625.
3
1
Gilbert, A.; Krestonosich, S.; Westover, D. L. Photochemical Reac-
tions of Substituted Benzenes with Aliphatic Amines. J. Chem. Soc.,
Perk. Trans. 1, 1981, 295-302.
(
16) Yoshida, S.; Shimomori, K.; Kim, Y.; Hosoya, T. Single C−F
(
11) For examples and reviews of the functionalization of multiple
Bond Cleavage of Trifluoromethylarenes with an ortho‐Silyl Group.
Angew. Chem. Int. Ed. 2016, 55, 10406-10409.
C–F bonds in trifluoromethylarenes, see: (a) Saito, K.; Umi, T.;
Yamada, T.; Suga, T.; Akiyama, T. Niobium(V)-catalyzed defluorina-
tive triallylation of α,α,α-trifluorotoluene derivatives by triple C–F
bond activation. Org. Biomol. Chem. 2017, 15, 1767-1770. (b) Scott,
V. J.; Çelenligil-Çetin, R.; Ozerov, O. V. Room-Temperature Catalyt-
(
17) (a) Luo, C.; Bandar, J. S. Superbase-Catalyzed anti-
Markovnikov Alcohol Addition Reactions to Aryl Alkenes. J. Am.
Chem. Soc. 2018, 140, 3547-3550. (b) Puleo, T. R.; Strong, A. J.;
Bandar, J. S. Catalytic α-Selective Deuteration of Styrene Derivatives.
J. Am. Chem. Soc. 2019, 141, 1467-1472.
3
ic Hydrodefluorination of C(sp )−F Bonds. J. Am. Chem. Soc. 2005,
1
27, 2852-2853. (c) Gu, W.; Haneline, M. R.; Douvris, C.; Ozerov, O.
(
18) (a) Schwesinger, R.; Schlemper, H. Peralkylated Polyamino-
3
V. Carbon−Carbon Coupling of C(sp )−F Bonds Using Alumenium
Catalysis. J. Am. Chem. Soc. 2009, 131, 11203-11212. (d) Henne, A.
L.; Newman, M. S. The Action of Aluminum Chloride on Fluorinated
Compounds. J. Am. Chem. Soc. 1938, 60, 1697-1698. (e) Zhu, J.;
Pérez, M.; Caputo, C. B.; Stephan, D. W. Use of Trifluoromethyl
Groups for Catalytic Benzylation and Alkylation with Subsequent
Hydrodefluorination. Angew. Chem. Int. Ed. 2016, 55, 1417-1421. (f)
Stahl, T.; Klare, H. F. T.; Oestreich, M. Main-Group Lewis Acids for
C–F Bond Activation. ACS Catal. 2013, 3, 1578-1587. (g) Shen, Q.;
Huang, Y.-G.; Liu, C.; Xiao, J.-C.; Chen, Q.-Y.; Guo, Y. Review of
recent advances in C–F bond activation of aliphatic fluorides. J. Fluo-
rine Chem. 2015, 179, 14-22.
phosphazenes—Extremely Strong, Neutral Nitrogen Bases. Angew.
Chem. Int. Ed. 1987, 26, 1167-1169. (b) Streitwieser, A., Jr.; Mares, F.
Acidity of hydrocarbons. XXIX. Kinetic acidities of benzal fluoride
and 9-fluorofluorene. A pyramidal benzyl anion. J. Am. Chem. Soc.
1968, 90, 2444-2445. (c) Wang, L.; Wei, J.; Wu, R.; Cheng, G.; Li, X.;
Hu, J.; Hu, Y.; Sheng, R. The stability and reactivity of tri-, di-, and
monofluoromethyl/methoxy/methylthio groups on arenes under
acidic and basic conditions. Org. Chem. Front. 2017, 4, 214-223.
(
19) (a) Suzawa, K.; Ueno, M.; Wheatley, A. E. H.; Kondo, Y.
Phosphazene base-promoted functionalization of aryltrimethylsilanes.
Chem. Commun. 2006, 4850-4852. (b) Kondoh, A.; Koda, K.; Terada,
M. Organocatalytic Nucleophilic Substitution Reaction of gem-
Difluoroalkenes with Ketene Silyl Acetals. Org. Lett. 2019, 21, 2277-
(
12) For the monoselective reduction of trifluoromethylarenes,
see: (a) Dang, H.; Whittaker, A. M.; Lalic, G. Catalytic activation of a
single C–F bond in trifluoromethyl arenes. Chem. Sci. 2016, 7, 505-
509. (b) Munoz, S. B.; Ni, C.; Zhang, Z.; Wang, F.; Shao, N.;
Mathew, T.; Olah, G. A.; Prakash, G. K. S. Selective Late‐Stage Hy-
drodefluorination of Trifluoromethylarenes: A Facile Access to
Difluoromethylarenes. Eur. J. Org. Chem. 2017, 2322-2326.
2
280. (c) Ueno, M.; Hori, C.; Suzawa, K.; Ebisawa, M.; Kondo, Y.
Catalytic Activation of Silylated Nucleophiles Using tBu-P4 as a Base.
Eur. J. Org. Chem. 2005, 1965-1968.
(20) For reviews of Lewis base chemistry and allylsilane activation,
see: (a) Denmark, S. E.; Beutner, G. L. Lewis Base Catalysis in Organ-
ic Synthesis. Angew. Chem. Int. Ed. 2008, 47, 1560-1638. (b)
Chabaud, L.; James, P.; Landais, Y. Allylsilanes in Organic Synthesis –
Recent Developments. Eur. J. Org. Chem. 2004, 3173-3199. (c) Chuit,
(
13) For examples of electrochemical and related processes, see:
a) Saboureau, C.; Troupel, M.; Sibille, S.; Périchon, J. Electroreduc-
tive Coupling of Trifluoromethylarenes with Electrophiles: Synthetic
(
ACS Paragon Plus Environment