Metal-free fluorination of C(sp3)-H bonds using a catalytic N-oxyl radical

Article abstract of DOI:10.1021/ol4006757

A direct conversion of C(sp³)-H bonds to C(sp³)-F bonds has been developed. In this process, a catalytic N-oxyl radical generated from N,N-dihydroxypyromellitimide abstracts hydrogen from the C(sp ³)-H bond and Selectfluor acts to trap the resulting carbon radical to form the C(sp³)-F bond. This simple metal-free protocol enables the chemoselective introduction of a fluorine atom into various aromatic and aliphatic compounds and serves as a powerful tool for the efficient synthesis of fluorinated molecules.

Full text of DOI:10.1021/ol4006757

ORGANIC
LETTERS
Metal-Free Fluorination of C(sp3)ÀH
XXXX
Vol. XX, No. XX
000–000
Bonds Using a Catalytic N‑Oxyl Radical
Yuuki Amaoka, Masanori Nagatomo, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
inoue@mol.f.u-tokyo.ac.jp
Received March 13, 2013
ABSTRACT
A direct conversion of C(sp3)ÀH bonds to C(sp3)ÀF bonds has been developed. In this process, a catalytic N-oxyl radical generated from N,N-
dihydroxypyromellitimide abstracts hydrogen from the C(sp3)ÀH bond and Selectfluor acts to trap the resulting carbon radical to form the
C(sp3)ÀF bond. This simple metal-free protocol enables the chemoselective introduction of a fluorine atom into various aromatic and aliphatic
compounds and serves as a powerful tool for the efficient synthesis of fluorinated molecules.
Organofluorine compounds are widely used in many
different applications, ranging from pharmaceuticals and
agrochemicals to advanced materials and polymers.1,2
Thirty to forty percent of agrochemicals and twenty percent
of pharmaceuticals currently on the market contain at least
one fluorine atom (e.g., CETP inhibitor3 and fluticasone
propionate4 in Figure 1). It has been recognized that
fluorine substitution can confer useful molecular proper-
ties, such as enhanced stability and hydrophobicity.5 In
addition, fluorine substitution of an sp3-rich carboskeleton
can modify the overall molecular shape by changing the
conformational preference through dipoleÀdipole inter-
actions or hyperconjugation.6
The one-step fluorination of CÀH bonds at the sp3-
carbon centers dramatically simplifies the synthetic routes
to such characteristic fluorinated carboskeletons in com-
parison to conventional methodologies.7,8 However, only
a limited number of direct fluorination methods have been
developed, and those involving catalysis are especially
(7) For recent reviews on synthesis of fluorinated compounds, see: (a)
Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214. (b) Kirk,
K. L. Org. Process Res. Dev. 2008, 12, 305. (c) Ma, J.-A.; Cahard, D.
Chem. Rev. 2008, 108, PR1. (d) Furuya, T.; Klein, J. E. M. N.; Ritter, T.
Synthesis 2010, 1804. (e) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv.
Synth. Catal. 2010, 352, 2708. (f) Landelle, G.; Bergeron, M.; Turcotte-
Savard, M.-O.; Paquin, J.-F. Chem. Soc. Rev. 2011, 40, 2867.
(8) For recent reviews on CÀH transformations, see: (a) Handbook
of CÀH Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005;
Vols. 1 and 2. (b) Handbook of Reagents for Organic Synthesis: Reagents
for Direct Functionalization of CÀH Bonds; Paquette, L. A., Fuchs, P. L.,
Eds.; Wiley: Chichester, 2007. (c) Special issue on “CÀH Functionalizations
in Organic Synthesis: Chem. Soc. Rev. 2011, 40 (4). (d) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960.
(9) For representative examples of catalytic C(sp3)ÀH fluorination,
see: (a) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 7134. (b) McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S.
Org. Lett. 2012, 14, 4094. (c) Bloom, S.; Pitts, C. R.; Miller, D. C.;
Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. Angew. Chem., Int.
Ed. 2012, 51, 10580. (d) Liu, W.; Huang, X.; Cheng, M.-J.; Nielsen, R. J.;
Goddard, W. A., III; Groves, J. T. Science 2012, 337, 1322. (e) Bloom, S.;
Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.; Lectka, T. Org.
Lett. 2013, 15, 1722. For a recent account, see: (f) Sibi, M. P.; Landais, Y.
Angew. Chem., Int. Ed. 2013, 52, 3570.
(1) (a) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (b) Hagmann,
W. K. J. Med. Chem. 2008, 51, 4359. (c) Jeschke, P. Pest Manag. Sci.
2010, 66, 10. (d) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.;
Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496.
(2) Thayer, A. M. Chem. Eng. News 2006, 84 (23), 15.
€
€
(3) Paulsen, H.; Antons, S.; Brandes, A.; Logers, M.; Muller, S. N.;
Naab, P.; Schmeck, C.; Schneider, S.; Stoltefuß, J. Angew. Chem., Int,
Ed. 1999, 38, 3373.
(4) Phillipps, G. H.; Bailey, E. J.; Bain, B. M.; Borella, R. A.;
Buckton, J. B.; Clark, J. C.; Doherty, A. E.; English, A. F.; Fazakerley,
H.; Laing, S. B.; Lane-Allman, E.; Robinson, J. D.; Sandford, P. E.;
Sharratt, P. J.; Steeples, I. P.; Stonehouse, R. D.; Williamson, C. J. Med.
Chem. 1994, 37, 3717.
(10) F2-induced direct fluorination of C(sp3)ÀH bonds: (a) Rozen, S.
Acc. Chem. Res. 1988, 21, 307. (b) Chambers, R. D.; Kenwright, A. M.;
Parsons, M.; Sandford, G.; Moilliet, J. S. J. Chem. Soc., Perkin Trans. 1
2002, 2190. (c) Sandford, G. J. Fluorine Chem. 2007, 128, 90.
€
(5) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b)
O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (c) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(6) Hunter, L. Beilstein J. Org. Chem. 2010, DOI: 10.3762/bjoc.6.38.
r
10.1021/ol4006757
XXXX American Chemical Society

rare.9,10 Recently, Lectka’s group described C(sp3)ÀH
fluorination employing a combination of Selectfluor, a
copper(I) bisimine complex, an anionic phase-transfer
catalyst and N-hydroxyphthalimide (NHPI).9c Herein,
we report metal-free direct C(sp3)ÀH fluorination using
a catalytic system consisting of N,N-dihydroxypyromelli-
timide (NDHPI)11 and Selectfluor12 (Scheme 1). The pre-
sent transformation is applicable to benzylic or aliphatic
C(sp3)ÀH bonds of 1 and generates the corresponding
monofluorinated derivatives 2 under mild conditions in a
highly chemoselective fashion.
Table 1. Screening of Reaction Conditions for the Direct
Fluorination of Benzylic C(sp3)ÀH Bondsa
yieldb (%)
entry
catalyst
F-source
2a
3a
1a (recovery)
1
NHPI
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor PF6
Selectfluor II
Accufluor
NFSI
21
10
72c
42
0
0
0
73
90
2
NHNPI
NDHPI
NDHPI
3
0
21
13
4d
5
21
0
100
16
6
NDHPI
NDHPI
NDHPI
NDHPI
NDHPI
55
51
17
0
15
13
25
0
7
21
8
39
9
88
10
NFPY
0
0
98
a Conditions: aromatic compound 1a, catalyst (2.5 mol %), F-source
(2 equiv), MeCN (0.1 M), at 50 °C for 5 h under an Ar atmosphere.
b Yield was determined by NMR analysis of the crude mixture. c Isolated
yield. d The reaction time was 8 h.
Figure 1. Biologically active compounds incorporating C(sp3)ÀF
bonds.
Scheme 1. C(sp3)ÀH Fluorination Using
N,N-Dihydroxypyromellitimide (NDHPI) and Selectfluor
fluorination (Table 1).14 Treatment of 1a with 2.5 mol %
of NHPI and 2 equiv of Selectfluor at 50 °C for 5 h in
MeCN15 chemoselectively provided the desired benzyl-
fluoride 2a in low yield along with a significant quantity
of unreacted 1a (entry 1). As shown in entries 2 and 3, we
subsequently applied two NHPI analogues16 in an attempt
to enhance the catalytic activity. Although the use of
N-hydroxy-4-nitrophthalimide (NHNPI) decreased the yield
of 2a (entry 2), N,N-dihydroxypyromellitimide (NDHPI),17
which has an additional imide-N-hydroxy group, was
found to significantly increase the yield (entry 3). A longer
reaction time (entry 4) resulted in lower yield of 2a and the
formation of acetamide 3a through nucleophilic attack by
MeCN,13a suggesting the activated nature of the resulting
benzylic C(sp3)ÀF bond. The lack of any products in the
Previously, we developed methodologies for the high-
yield transformations of benzylic C(sp3)ÀH bonds to
C(sp3)ÀO and C(sp3)ÀN bonds, using NHPI as the pre-
cursor of the hydrogen-abstracting N-oxyl radical.13 In the
present study, the benzylic compound 1a and a number of
NHPI derivatives were employed in combination with
various fluorinating reagents to realize the C(sp3)ÀH
(11) For reviews on NHPI-catalyzed reactions, see: (a) Ishii, Y.;
Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343, 393. (b)
Recupero, F.; Punta, C. Chem. Rev. 2007, 107, 3800. (c) Coseri, S.
Catal. Rev. 2009, 51, 218.
ꢀ
(12) For reviews on Selectfluor, see: (a) Nyffeler, P. T.; Duron, S. G.;
Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed.
2005, 44, 192. (b) Stavber, S. Molecules 2011, 16, 6432.
(13) (a) Kamijo, S.; Amaoka, Y.; Inoue, M. Tetrahedron Lett. 2011,
52, 4654. (b) Amaoka, Y.; Kamijo, S.; Hoshikawa, T.; Inoue, M. J. Org.
Chem. 2012, 77, 9959.
(15) The choice of MeCN as a solvent was critical to obtain 2a. No
reaction occurred in any other solvent.
(16) Sun, Y.; Zhang, W.; Hu, X.; Li, H. J. Phys. Chem. B 2010, 114,
4862.
(17) Shibamoto, A.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002,
43, 8859.
(14) Fluorination of carbon radicals has been demonstrated; see: (a)
Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C. T.; Okbinoglu, T.;
Kennepohl, P.; Paquin, J.-F.; Sammis, G. M. J. Am. Chem. Soc. 2012,
134, 4026. (b) Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012,
134, 10401. (c) Barker, T. J.; Boger, D. L. J. Am. Chem. Soc. 2012, 134,
13588.
B
Org. Lett., Vol. XX, No. XX, XXXX

absence of NDHPI confirmed its importance as the
N-oxyl radical precursor (entry 5).18,19 Three structural
variants of Selectfluor20 (entries 6À8) were shown to be
less effective fluorinating reagents than Selectfluor itself,
while the application of N-fluorobenzenesulfonimide (NFSI,
entry 9) and N-fluoropyridinium triflate (NFPY, entry 10)
did not give any fluorinated products. The results in
entries 6À10 clarified the superiority of Selectfluor for
metal-free C(sp3)ÀH fluorination.21
Table 2. Direct C(sp3)ÀH Fluorination of Aromatic
Compounds Having a Functional Group on the Side Chaina
substrate 1
To examine the functional group compatibility, various
benzene derivatives having different functionalities on
their side chains were submitted to the optimized condi-
tions determined previously (Table 2). The reactions of
benzoates 1aÀc all took place, producing benzylfluorides
2aÀc (entries 1À3). The lower yield of 2c (55%, entry 3) in
comparison to those of 2a (72%, entry 2) and 2b (72%,
entry 1) reflects the general preference of electrophilic
N-oxyl radical for electron-rich CÀH bonds.13,22 Specifi-
cally, the lower reactivity of 1c results from the electron-
deficient nature of the benzylic CÀH bond, due to the
shorter tether length between the benzyl methylene and the
electron-withdrawing benzoyloxy group.
As long as alcohol and amine functionalities on the
substrate were properly protected, our reagent system
allowed formation of the expected benzylfluorides in high
yields. Namely, methanesulfonyl (Ms) ester 2d (entry 4)
and phthaloyl (Phth) imide 2e (entry 5) were obtained in
good yields. In addition, the reaction occurred without
affecting electrophilic methyl ester (1f, entry 6) and cyanide
(1g, entry 7) moieties to provide 2f and 2g, respectively.
Importantly, the CÀH fluorination proceeded even in the
presence of a free carboxyl group (1h, entry 8) and a free
tertiary hydroxyl group (1i, entry 9), resulting in formation
of 2h and 2i, respectively. Despite the radical mechanism
of the reaction (vide infra), the C(sp3)ÀBr bond of 1j
remained intact, and 2j was isolated in good yield (entry 10).
The subsequent synthesis of a wide variety of benzyl
fluorides 2kÀu from the corresponding aromatic com-
pounds 1kÀu demonstrated the versatility of the pre-
sent methodology (Scheme 2). Electron-rich phenol (2k)
and aniline derivatives (2l) could be synthesized using
reduced reaction times, whereas longer time spans were
necessary when the reaction involved substrates with
entry
R1
n
time (h)
product 2
yield (%)
1
2
OBz
3 (1b)
2 (1a)
1 (1c)
2 (1d)
2 (1e)
2 (1f)
2 (1g)
2 (1h)
1 (1i)
2 (1j)
5
5
7
6
5
6
5
5
3
6
2b
2a
2c
2d
2e
2f
72
72
55
70
74
70
64
51
72
51
OBz
3
OBz
4
OMs
5
NPhth
CO2Me
CN
6
7
2g
2h
2i
8
CO2H
C(Me)2OH
Br
9
10
2j
a Conditions: aromatic compound 1, NDHPI (2.5 mol %), Select-
fluor (2 equiv), MeCN (0.1 M), at 50 °C for the indicated time under an
Ar atmosphere.
electron-withdrawing methoxycarbonyl (2m) and acetyl
(2n) functionalities. No significant differences in reactivity
were observed between p-benzoyloxy-substituted 1k,
meta-substituted 1o, and ortho-substituted 1p when gen-
erating 2k, 2o, and 2p. The tertiary CÀH bonds of 1q and
1r were also fluorinated to introduce the tetrasubstituted
carbon centers of 2q and 2r, respectively. The reaction of
1,3-diphenylpropane 1s gave the monofluorinated com-
pound 2s as the major product. Moreover, the CÀH
fluorinations of homophenylalanine derivative 1t and
ibuprofen derivative 1u exhibited high chemoselectivity
for the benzylic positions despite their structural complex-
ity, delivering monofluorides 2t and 2u, respectively.
Finally, this synthetic protocol was successfully applied
to the direct fluorination of the CÀH bonds of alkanes
(1vÀz), which are known to be less reactive than benzylic
CÀH bonds (Scheme 2). The secondary aliphatic CÀH
bonds of cyclododecane 1v underwent the functionaliza-
tion, providing the expectedmonofluoride2v. The reaction
of adamantane derivatives 1wÀy proceeded chemoselec-
tively at the tertiary CÀH bonds, in the presence of several
secondary CÀH bonds, togive the corresponding fluorides
2wÀy as the sole products. Furthermore, the fluorination
of 2-oxaadamantan-1-ol 1z proceeded chemoselectively at
the nonoxygen substituted position to provide 2z.
(18) While compound 2a was recovered in 90% yield upon submis-
sion of 2a to the reaction conditions of entry 3, treatment of HBF4
(1 equiv) in MeCN efficiently converted 2a into 3a in 87% yield. These
separate experimentssuggested that the C(sp3)ÀF bond was activatedby
HBF4 that was generated during the course of the reaction.
(19) Addition of stoichiometric 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) completely inhibited the formation of 2a, whereas addition of
catalytic TEMPO (0.1 equiv) partially suppressed the formation of 2a
(25% yield). These results indicate continuous generation of N-oxyl
radical from NDHPI. Therefore, not only B but also Selectfluor would
participate in oxidation of NDHPI (see Scheme 3).
(20) Banks, R. E.; Besheesh, M. K.; Mohialdin-Khaffaf, S. N.;
Sharif, I. J. Chem. Soc., Perkin Trans. 1 1996, 2069.
(21) High electrophilicity of Selectfluor appears to be important for
generation of N-oxyl radical. Gilicinski, A. G.; Pez, G. P.; Syvret, R. G.;
Lal, G. S. J. Fluorine Chem. 1992, 59, 157.
A proposed reaction mechanism for the NDHPI/Select-
fluor-promoted fluorination of C(sp3)ÀH bonds is pre-
sented in Scheme 3. In the first step, NDHPI is oxidized by
Selectfluor in situ to generate the electrophilic N-oxyl
radical, which is the key reactive species.11,13 Then, che-
moselective abstraction from the electron-rich C(sp3)-H
bond takes place to form carbon radical A and NDHPI.
The subsequent trapping of the carbon radical A by
Selectfluor in turn provides the corresponding fluoride 2
(22) (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (b)
Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. Tetrahedron
2009, 65, 3042. (c) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed.
2011, 50, 3362. (d) White, M. C. Science 2012, 335, 807.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Direct C(sp3)ÀH Fluorination of Various Substratesa
Scheme 3. Proposed Mechanism for Transformation of
C(sp3)ÀH Bonds to C(sp3)ÀF Bonds
by hydrogen abstraction at the electron-rich position,
and the carbon radical is intermolecularly trapped by
Selectfluor, resulting in installation of a fluorine atom.
The most important features of this synthetic procedure
are: (1) predictable chemoselectivity toward the benzylic
C(sp3)ÀH bonds of aromatic compounds and the tertiary
C(sp3)ÀH bonds of aliphatic compounds and (2) high
compatibility with various functionalities, including benzoyl-
and methanesulfonyl-protected alcohols and phthaloyl-
protected amines, as well as carboxylic acids, tertiary
alcohols, cyanides, and bromides. As the result of these
advantages, the present one-step methodology should
serve as a unique tool for the efficient synthesis of various
fluorinated compounds with pharmaceutical and agro-
chemical applications.
a Conditions: starting material 1, NDHPI (2.5 mol %), Selectfluor
(2 equiv), MeCN (0.1 M), at 50 °C for the indicated time under an Ar
atmosphere.
Acknowledgment. This research was financially sup-
ported by the Funding Program for Next Generation
World-Leading Researchers (JSPS) to M.I. A fellowship
from JSPS to Y.A. is gratefully acknowledged.
and the amino radical cation B. When B abstracts a
hydrogen from NDHPI, it regenerates the N-oxyl radical
species and forms protonated amine C, thus closing the
catalytic cycle.
In conclusion, this paper describes the metal-free fluo-
rination of C(sp3)ÀH bonds under mild conditions, em-
ploying a simple reagent system composed of NDHPI
and Selectfluor. This radical-based reaction is initiated
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for relevant
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX