Journal of the American Chemical Society
Page 12 of 14
(5) For a review on applications of Minisci chemistry in medicinal
by Palla, see reference 12b. Very low yields of selective C3
chemistry see: (a) Duncton, M. A. J. MedChemComm 2011, 2, 1135-
1161. Intramolecular examples of homolytic aromatic substitutions on
heterocycles are more commonly used in synthesis, see for example:
(b) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36, 1803-
1822; (c) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Org. Biomol.
Chem. 2003, 1, 4047-4057.
(6) (a) Ji, Y.; Brückl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.;
Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 14411-14415; (b) Fujiwara, Y.; Dixon, J. A.; Rodriguez,
R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.;
Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494-1497; (c) Fujiwara,
Y.; Dixon, J. A.; O'Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez,
R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.; Ishihara, Y.;
Baran, P. S. Nature 2012, 492, 95-99; (d) Zhou, Q.; Ruffoni, A.;
Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. An-
gew. Chem., Int. Ed. 2013, 52, 3949-3952; (e) O’Hara, F.; Baxter, R.
D.; O’Brien, A. G.; Collins, M. R.; Dixon, J. A.; Fujiwara, Y.; Ishi-
hara, Y.; Baran, P. S. Nat. Protoc. 2013, 8, 1042-1047.
(7) The zinc sulfinate reagents used in this report, and other related
alkylsulfinate salts, are commercially available from Aldrich, with the
following catalog numbers: TFMS (trifluoromethylation reagent)
771406; DFMS (difluoromethylation reagent) 767840; IPS
(isopropylation reagent) L511161.
(8) For a comprehensive review of the Minisci reaction, which is
the most widely studied system, see: Punta, C.; Minisci, F. Trends
Heterocycl. Chem. 2008, 13, 1-68.
substitution were reported for the reaction of 4-cyanoquinoline with
dioxanyl and α-amidoalkyl radicals generated from solvent. This was
attributed to the CN group activating homolytic substitution more
than the nuclear nitrogen.
(16) For an example of radical methylation of 3-picoline showing a
strong preference for C2 substitution, see: Abramovitch, R. A.; Ke-
naschuk, K. Can. J. Chem. 1967, 45, 509-513.
(17) For an example of substituent effects in the Minisci alkylation
of unsymmetrical 3,6-disubstituted pyridines, see: Cowden, C. J. Org.
Lett. 2003, 5, 4497-4499. The regioselectivity was attributed to a
preference for reaction ortho to the more electronegative substitutent.
(18) Studies into the regioselectivity of radical substitution of
arenes has also shown substituent effects, see: Shelton, J. R.; Uzel-
meier, C. W. J. Am. Chem. Soc. 1966, 88, 5222-5228.
(19) The previous reports describing the production of C3 products
involve altering the means of radical generation to in situ hydrogen
abstraction from a vast excess of solvent. Alkylsulfinate salts may be
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
used to append
a variety of alkyl and fluoroalkyl groups to
heterocycles, including several which would not be plausible to
generate from solvent excess, such as the pharmaceutically valuable
CF3 and CF2H groups.
(20) All the reactions appeared to become acidic during the reac-
tion, and addition of base (calcium carbonate) hindered reaction pro-
gress. Nevertheless, addition of stoichiometric quantities of strong
acid had a significant effect on rate and regioselectivity.
(21) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-
195.
(22) Sterics will also play a role in determining the observed C3:C2
ratio, but this appears to be a relatively minor affect.
(23) (a) Viehe, H. G.; Janousek, Z.; Merényi, R.; Stella, L. Acc.
Chem. Res. 1985, 18, 148-154; (b) Viehe, H. G.; Merényi, R.; Stella,
L.; Janousek, Z. Angew. Chem. Int. Ed. Engl. 1979, 18, 917-932; (c)
we thank a referee for this suggestion.
(9) Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
Res. 2012, 45, 826-839.
(10) For an example of use of an acid additive to induce a regio-
chemical preference in Gomberg-Bachmann phenylation of pyridine,
and calculations that showed that this selectivity correlated with the
localization energy, see: (a) Lynch, B. M.; Chang, H. S. Tetrahedron
Lett. 1964, 5, 2965-2968; (b) Dou, H. J. M.; Lynch, B. M. Tetrahe-
dron Lett. 1965, 6, 897-901; (c) Brown, R. D. J. Chem. Soc. 1956,
272-275.
(11) For a study on the solvent effect in the α to γ regioselectivity
of substitution of protonated pyridines for a variety of radicals, see:
Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle, M.;
Giordano, C. J. Org. Chem. 1987, 52, 730-736.
(24) De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.;
Geerlings, P.; De Proft, F. Org. Lett. 2007, 9, 2721-2724.
(25) Minisci, F. In NATO Advanced Research Workshop on
Substituent Effects in Radical Chemistry; Viehe, H. G., Janousek, Z.,
Merényi, R., Eds.; D. Reidel Publishing Company: Louvain-la-Neuve,
Belgium, 1986; Vol. 189, p 391-434.
(12) The more pronounced solvent effect observed for more nucle-
ophilic radicals was attributed to the enhanced contribution from polar
forms of the intermediate radical adduct, see: (a) Minisci, F.; Ber-
nardi, R.; Bertini, F.; Galli, R.; Perchinummo, M. Tetrahedron 1971,
27, 3575-3579; (b) Palla, G. Tetrahedron 1981, 37, 2917-2919.
(13) For a study of the substituent effect on the rate of C2 exclusive
substitution of C4-substituted pyridines, see: (a) Minisci, F.;
Mondelli, R.; Gardini, G. P.; Porta, O. Tetrahedron 1972, 28, 2403-
2413. The rate of C2 substitution of C4-substituted pyridines closely
followed the electron density, with the exception of the OMe and Cl
substrates. This was attributed to the “enhanced electron-releasing
effects” associated with the C4 substituent lone pair interacting with
the pyridine nitrogen, see: (b) Belli, M. L.; Illuminati, G.; Marino, G.
Tetrahedron 1963, 19, 345-355.
(14) For a study of substituent effect on the rate of radical phenyla-
tion of C4 substituted pyridines, see: (a) Minisci, F.; Vismara, E.;
Fontana, F.; Morini, G.; Serravalle, M.; Giordano, C. J. Org. Chem.
1986, 51, 4411-4416. The rate at C3 was generally higher than that at
C2 under neutral conditions, but when protonated, the rate at C2 far
exceeded that at C3. See also a similar result showing that the in-
crease in reactivity of pyridine on protonation is due to enhanced rate
at the C2 and C4 positions, while the rate at C3 shows little change:
(b) Bonnier, J.-M.; Court, J. Compt. Rend. 1967, 265, C, 133-136.
(15) For an observation of an apparent ortho-para directing effect
in the cyclohexylation or dioxanylation of acetyl, ester or cyano sub-
stituted pyridines under neutral conditions, which was attributed to a
preference for reactivity at positions where the unpaired electron can
be delocalized into the substituent for additional stability, see: (a)
Tiecco, M. In NATO Advanced Research Workshop on Substituent
Effects in Radical Chemistry; Viehe, H. G., Janousek, Z., Merényi, R.,
Eds.; D. Reidel Publishing Company: Louvain-la-Neuve, Belgium,
1986; Vol. 189, p 435-442; (b) Chianelli, D.; Testaferri, L.; Tiecco,
M.; Tingoli, M. Tetrahedron 1982, 38, 657-663. For a related result
(26) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett.
1991, 32, 7525-7528.
(27) It is important to note that the δ+ sites identified in this manner
indicate only that the position may be capable of reacting with a nu-
cleophilic radical, not that it must do so. Furthermore, the magnitude
of the δ+ charge on a position does not generally relate to relative
reactivity in any straightforward manner. Simple calculations of
Hückel charges failed to adequately predict regioselectivity, as did
examination of the proton and carbon NMR spectra of substrates.
Although more sophisticated calulations may be able to better model
the reaction, our aim was to provide a method of predicting
regioselectivity and reaction outcome in a quick and simple manner.
(28) (a) Fleming, I. Frontier Orbitals and Organic Chemical
Reactions, 1st ed, Wiley: London, 1976, p. 192-193; (b) Fleming, I.
Molecular Orbitals and Organic Chemical Reactions: Reference
Edition, 1st ed, Wiley: London, 2010, p. 284-285; (c) The ionization
potential of trifluoromethyl radical is reported as 9.05 eV in Asher, R.
L.; Ruscic, B. J. Chem. Phys. 1997, 106, 210-221, corresponding to a
SOMO energy of -9.05 eV. The SOMO energy of a secondary alkyl
radical (s-Bu) is given as -7.4 eV in (a).
(29) Chmurzyński, L. J. Heterocycl. Chem. 2000, 37, 71-74.
(30) Minisci, F.; Vismara, E.; Morini, G.; Fontana, F.; Levi, S.;
Serravalle, M.; Giordano, C. J. Org. Chem. 1986, 51, 476-479.
(31) Litwinienko, G.; Beckwith, A. L. J.; Ingold, K. U. Chem. Soc.
Rev. 2011, 40, 2157-2163.
(32) De Vleeschouwer, F.; Geerlings, P.; Proft, F. Theor. Chem.
Acc. 2012, 131, 1-13.
(33) This does not address the overwhelming preference for
production of 2,5-dialkylated products in DMSO, or the similar
pattern observed under non-protonative conditions by Tiecco and
Testaferri.
12
ACS Paragon Plus Environment