The direct C-H difluoromethylation of heteroarenes based on the photolysis of hypervalent iodine(III) reagents that contain difluoroacetoxy ligands

Article abstract of DOI:10.1021/acs.orglett.7b02416

In this letter, an efficient method for the photolytic generation of difluoromethyl radicals from [bis(difluoroacetoxy)iodo]benzene reagents is described. The present approach enables the introduction of difluoromethyl groups into various heteroarenes und

Full text of DOI:10.1021/acs.orglett.7b02416

Letter
pubs.acs.org/OrgLett
The Direct C−H Difluoromethylation of Heteroarenes Based on the
Photolysis of Hypervalent Iodine(III) Reagents That Contain
Difluoroacetoxy Ligands
Ryu Sakamoto, Hirotaka Kashiwagi, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: In this letter, an efficient method for the photolytic generation of
difluoromethyl radicals from [bis(difluoroacetoxy)iodo]benzene reagents is described.
The present approach enables the introduction of difluoromethyl groups into various
heteroarenes under mild conditions in the absence of any additional reagents or catalysts.
suffer from functional (in)compatibility and the need for
he preparation of organofluorine compounds is an area of
Tconsiderable importance in pharmaceutical, agrochemical, expensive and/or toxic fluorinating agents. In recent years, the
development of radical-based difluoromethylation methods has
been the subject of intensive research. In 2013, Baran and co-
workers reported zinc bis(difluoromethanesulfinate) as a useful
difluoromethylating agent that generates a difluoromethyl
radical in the presence of the oxidant tert-butyl hydroperoxide
(TBHP).8 Sodium difluoromethanesulfinate may also act as a
source for a difluoromethyl radical.9 Alternatively, photoredox
radical difluoromethylations have recently been realized by
using difluoromethanesulfonyl chloride,10 difluoromethyl-
phosphonium salts,11 and difluoromethylsulfone12 or -sulfox-
imine13 as difluoromethyl radical sources. The synthetic utility
of these methods still remains counterbalanced by the
difficulties associated with the handling of some of the
expensive and/or gaseous starting materials required to prepare
these agents, as well as the necessity for high temperatures,
additional oxidants, and/or transition-metal catalysts for the
generation of the difluoromethyl radicals. Therefore, alternative
strategies that generate mild, efficient, and cost-effective
difluoromethyl radicals should be highly desirable.
and materials science, as the introduction of fluoro substituents
into organic molecules has a profoundly positive impact on
their physical properties, including metabolic stability,
solubility, and lipophilicity.1−3 Among various fluoroalkyl
groups, the difluoromethyl group has attracted particular
attention in medicinal chemistry, due to the fact that the
CF2H moiety is isosteric and isopolar to the hydroxyl and thiol
groups and may also act as a lipophilic hydrogen donor.4 Thus,
considerable research efforts have been devoted to the efficient
introduction of difluoromethyl groups into organic compounds.
However, compared to the well-established trifluoromethyla-
tions,5 methods for the corresponding difluoromethylations
remain scarce and challenging.6
Classically, difluoromethylated compounds are prepared by
the deoxyfluorination of aldehydes with SF4 or dialkylamino-
sulfur trifluorides such as N,N-dimethylaminosulfur trifluoride
(DAST) or bis(2-methoxyethyl)aminosulfur trifluoride
(Deoxo-Fluor) (Figure 1).7 These methods, however, often
Difluoroacetic acid is an inexpensive and commercially
available reagent that is easy handled, and we envisioned that
this acid could be used as a source of difluoromethyl
substituents. However, to the best of our knowledge,
difluoromethylations using the acid as a difluoromethyl radical
source remain elusive. The generation of alkyl radicals from the
corresponding carboxylic acids via decarboxylation generally
requires strong oxidants, transition-metal catalysts, and/or high
temperatures.14 Therefore, we were interested in using
hypervalent iodine(III) reagents with carboxylic acid ligands,
as these are highly susceptible to photodecomposition upon
exposure to weak UV or visible light to furnish carboxyl radicals
that generate the corresponding alkyl radicals upon decarbox-
Figure 1. Commonly used difluoromethylating agents and strategies to
generate difluoromethyl radicals.
Received: August 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02416
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Letter
ylation.15 Herein, we report the photolytically induced direct
C−H difluoromethylation of heteroarenes using hypervalent
iodine(III) reagents (1) that contain difluoroacetoxy ligands.
The easily prepared iodine(III) reagents 1 smoothly generate
difluoromethyl radicals upon irradiation with visible light (λ =
400 nm) in the absence of any additional reagents or catalysts
(Scheme 1).
substituents (1b and 1c) reduced the reaction time (14 h). A
screening of solvents revealed that the use of deuterated
chloroform (CDCl3) slightly improved the product yield (entry
7).16 On the other hand, the reaction in chloroform decreased
the yield of 2a, due to the formation of a large amount of
unknown byproducts, which might be derived from the
abstraction of hydrogen atoms from chloroform (entry 8).17
Finally, increasing concentration afforded the best product yield
for 2a (entry 9).
Scheme 1. Generation of Difluoromethyl Radicals by
Photolysis of 1
With the optimized conditions in hand, we subsequently
investigated the generality of this reaction (Scheme 2). The
Scheme 2. Substrate Scope for the Photolytic
a b
,
Difluoromethylation Using 1
To test its utility as a difluoromethyl radical source, 1 was
subjected to photolysis conditions in the presence of caffeine as
a model substrate (Table 1). When the reaction was conducted
Table 1. Optimization of the Reaction Conditions for the
Transformation of Caffeine into Difluoromethylated
a
Caffeine (2a)
b
entry
1
I(III)
solvent
2a yield (%)
1a
1a
1b
1c
1d
1e
1b
1b
1b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CDCl3
CHCl3
CDCl3
37
34
53
43
41
49
54
22
56
c
2
d
3
d
4
5
6
d
7
d
8
de
,
9
a
Unless otherwise specified, reactions were conducted in the specified
solvent (0.2 M) in the presence of caffeine (0.2 mmol) and 1 (0.4
a
b
Unless otherwise specified, reactions were conducted in CDCl3 (0.4
M) in the presence of heterocycle (0.2 mmol) and 1b (2a−d) or 1c
(2e−n) (0.4 mmol) under irradiation with visible light (λ = 400 nm).
mmol) under irradiation with visible light (λ = 400 nm). The yield
1
was determined by H NMR spectroscopy using 1,1,2,2-tetrachloro-
c
ethane as an internal standard. The reaction was conducted under
b
c
d
e
Isolated yield. NMR yield.
irradiation with UV light (λ = 365 nm). t = 14 h. c = 0.4 M.
introduction of difluoromethyl groups on pentoxifylline
afforded 2b in 47% yield. The reactions involving uracile
derivatives proceeded well, and the corresponding difluorome-
thylated uraciles (2c and 2d) were obtained in moderate yield.
In the case of pyridines, 1c furnished better results than 1b, and
the difluoromethyl groups were introduced mainly at the 2-
position of the pyridines (2e−h).18 In the case of 2e and 2g,
only small amounts of bis-difluoromethylated products were
obtained. The reactions with pyrimidines, pyridazine, pyrazine,
triazine, and pyrazole also afforded the corresponding products
(2i−n) in moderate to good yields.
with [bis(difluoroacetoxy)iodo]benzene (1a) under exposure
to visible light (λ = 400 nm), difluoromethylated caffeine 2a
was obtained in 37% yield (entry 1), while an almost equimolar
amount of caffeine (37%) remained unchanged. Changing the
wavelength from 400 to 365 nm afforded similar results (entry
2). Subsequently, we tested substituted iodine(III) reagents
(1b−e), which afforded the products in slightly improved yields
(entries 3−6). While the electronic nature of the substituents
had virtually no effect on the product yields (entries 3 and 4 vs
entries 5 and 6), the presence of electron-donating tert-butyl
The utility of the present approach was further demonstrated
by the introduction of other fluoroalkyl groups into caffeine
(Scheme 3).19 The reaction of caffeine with iodine(III) reagent
B
DOI: 10.1021/acs.orglett.7b02416
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ascertained by radical trapping experiments. When a reaction
mixture containing caffeine and 1a was irradiated with visible
light (λ = 400 nm) in the presence of the radical scavenger
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), the formation
of the difluoromethyl adduct 6 was observed (Scheme 5c).20
On the basis of these results, we tentatively concluded that the
present reaction should proceed by a radical mechanism that
involves the generation of difluoromethyl radicals induced by
the photodecomposition of iodine(III) reagent 1 (Figure 2).
Scheme 3. Scope with Respect to the Carboxylic Acid
Ligands in the Fluoroalkylation Reagents, Using Caffeine as
a Model Substrate
3a, which contains chlorodifluoroacetoxy groups, afforded 4a in
60% yield. The use of iodine(III) reagents 3b and 3c
successfully transferred the corresponding difluoroalkyl sub-
stituents onto caffeine, affording 4b and 4c in acceptable yields.
Unfortunately, the introduction of a trifluoromethyl group
using 3d was relatively inefficient, and trifluoromethylated
caffeine 4d was obtained in only 20% yield.
The reaction of caffeine with the in situ generated iodine(III)
agent 1c also proceeded well and furnished 2a in moderate
yield (Scheme 4). It should be noted that generation of
Figure 2. Plauisible reaction mechanism.
Scheme 4. Difluoromethylation of Caffeine by in Situ
Generated 1c
First, the photolysis of hypervalent iodine(III) reagents 1 would
generate a carboxyl radical 7 and an iodanyl radical 8. Then, the
decarboxylation of 7 would afford a difluoromethyl radical,
while iodanyl radical 8 would degrade to provide 7 and
iodoarene. The difluoromethyl radical subsequently would react
with heteroarenes to generate a radical intermediate 9. The
oxidation of 9 by 1 or iodanyl radical 8 would give a
carbocation intermediate 10. Finally, the deprotonation of 10
would furnish a desired product.
In summary, we have developed a method for the
photolytically induced direct C−H difluoromethylation of
heteroarenes using hypervalent iodine(III) reagents that
contain difluoroacetoxy ligands. The iodine(III) reagents used
in this study can be easily prepared from convenient starting
materials and are easy to handle. Further applications of the
photoreaction presented herein are currently under inves-
tigation in our laboratory.
methylated caffeine 5, which would be potentially formed by
the reaction of caffeine with a methyl radical derived from
acetoxy radicals, was not observed.
Finally, we conducted several control experiments (Scheme
5). When the difluoromethylation of caffeine with 1a was
conducted in the dark, the formation of 2a was not observed
(Scheme 5a). A similar reaction under an atmosphere of oxygen
significantly reduced the product yield of 2a (Scheme 5b).
Moreover, the generation of difluoromethyl radicals was
ASSOCIATED CONTENT
Scheme 5. Control Experiments
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02416.
Experimental procedures and characterization data for all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: maruoka@kuchem.kyoto-u.ac.jp.
ORCID
Keiji Maruoka: 0000-0002-0044-6411
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.7b02416
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Letter
(13) Arai, Y.; Tomita, R.; Ando, G.; Koike, T.; Akita, M. Chem. - Eur.
J. 2016, 22, 1262.
(14) Duncton, M. A. MedChemComm 2011, 2, 1135.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research from the MEXT (Japan).
(15) (a) Minisci, F.; Vismara, E.; Fontana, F.; Barbosa, M. C. N.
Tetrahedron Lett. 1989, 30, 4569. (b) Togo, H.; Aoki, M.; Yokoyama,
M. Tetrahedron Lett. 1991, 32, 6559. (c) Togo, H.; Aoki, M.;
Yokoyama, M. Chem. Lett. 1992, 21, 2169. (d) Togo, H.; Aoki, M.;
Kuramochi, T.; Yokoyama, M. J. J. Chem. Soc., Perkin Trans. 1 1993,
2417. (e) Togo, H.; Aoki, M.; Yokoyama, M. Tetrahedron 1993, 49,
8241. (f) Togo, H.; Muraki, T.; Yokoyama, M. Synthesis 1995, 1995,
155. (g) Togo, H.; Taguchi, R.; Yamaguchi, K.; Yokoyama, M. J. Chem.
Soc., Perkin Trans. 1 1995, 2135.
(16) The use of other solvents, such as CCl4, DMF, DMSO, or
CH3CN, was much less effective than CDCl3; the yields of 2a were
10% (CCl4), 8% (DMF), 11% (DMSO), and trace (CH3CN),
respectively.
REFERENCES
■
(1) (a) Hiyama, T. Organofluorine Compounds: Chemistry and
Applications; Springer: New York, 2000. (b) Kirsch, P. Modern
Fluoroorganic Chemistry: Synthesis Reactivity, Applications; Wiley-VCH:
Weinheim, 2004. (c) Ojima, I., Ed. Fluorine in Medicinal Chemistry and
Chemical Biology; Wiley-Blackwell: Chichester, 2009.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (b) Hagmann, W. K. J. Med. Chem. 2008, 51,
4359. (c) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529. (d) Cametti,
M.; Crousse, B.; Metrangolo, P.; Milani, R.; Resnati, G. Chem. Soc. Rev.
2012, 41, 31. (e) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo,
́
́
̃
(17) (a) Clive, D. L. J.; Cantin, M.; Khodabocus, A.; Kong, X.; Tao,
Y. Tetrahedron 1993, 49, 7917. (b) Chatalova-Sazepin, C.; Binayeva,
M.; Epifanov, M.; Zhang, W.; Foth, P.; Amador, C.; Jagdeo, M.;
Boswell, B. R.; Sammis, G. M. Org. Lett. 2016, 18, 4570.
C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432.
(3) (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470.
(b) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48, 2929.
(c) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013,
52, 8214. (d) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765.
(e) Pan, X.; Xia, H.; Wu, J. Org. Chem. Front. 2016, 3, 1163.
(4) (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111,
4475. (b) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950. (c) Barata-
1
(18) The regioisomeric ratios of products were determined by H
NMR spectroscopy.
(19) (a) Gu, J.-W.; Zhang, X. Org. Lett. 2015, 17, 5384. (b) Wan, W.;
Ma, G.; Li, J.; Chen, Y.; Hu, Q.; Li, M.; Jiang, H.; Deng, H.; Hao, J.
Chem. Commun. 2016, 52, 1598. (c) Wan, W.; Li, J.; Ma, G.; Chen, Y.;
Jiang, H.; Deng, H.; Hao, J. Org. Biomol. Chem. 2017, 15, 5308. See
also refs 9b, 10e, and 12a.
Vallejo, S.; Lantano, B.; Postigo, A. Chem. - Eur. J. 2014, 20, 16806.
̃
(d) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115, 650.
̈
(20) For details, see Supporting Information.
(5) (a) Blackburn, G. M.; England, D. A.; Kolkmann, F. J. J. Chem.
Soc., Chem. Commun. 1981, 930. (b) Blackburn, G. M.; Kent, D. E.;
Kolkmann, F. J. J. Chem. Soc., Perkin Trans. 1 1984, 1119.
(c) Motherwell, W. B.; Tozer, M. J.; Ross, B. C. J. Chem. Soc.,
Chem. Commun. 1989, 1437. (d) Erickson, J. A.; McLoughlin, J. I. J.
Org. Chem. 1995, 60, 1626.
(6) (a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
(b) Ni, C.; Hu, J. Synthesis 2014, 46, 842. (c) Shen, X.; Hu, J. Eur. J.
Org. Chem. 2014, 2014, 4437. (d) Chen, B.; Vicic, D. Top. Organomet.
Chem. 2014, 52, 113. (e) Xu, P.; Guo, S.; Wang, L.; Tang, P. Synlett
2014, 26, 36. (f) Lu, Y.; Liu, C.; Chen, Q.-Y. Curr. Org. Chem. 2015,
19, 1638. (g) Belhomme, M.-C.; Besset, T.; Poisson, T.; Pannecoucke,
X. Chem. - Eur. J. 2015, 21, 12836.
(7) (a) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis
1973, 1973, 787. (b) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(c) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. J.
Org. Chem. 1999, 64, 7048.
(8) (a) 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. (b) 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.
(c) Liu, J.; Zhuang, S.; Gui, Q.; Chen, X.; Yang, Z.; Tan, Z. Eur. J. Org.
Chem. 2014, 2014, 3196.
(9) (a) Li, Z.; Cui, Z.; Liu, Z.-Q. Org. Lett. 2013, 15, 406. (b) He, Z.;
Tan, P.; Ni, C.; Hu, J. Org. Lett. 2015, 17, 1838. (c) Ma, J.-J.; Liu, Q.-
R.; Lu, G.-P.; Yi, W.-B. J. Fluorine Chem. 2017, 193, 113.
(10) (a) Tang, X.-J.; Thomoson, C. S.; Dolbier, W. R., Jr. Org. Lett.
2014, 16, 4594. (b) Tang, X.-J.; Dolbier, W. R., Jr. Angew. Chem., Int.
Ed. 2015, 54, 4246. (c) Tang, X.-J.; Zhang, Z.; Dolbier, W. R., Jr.
Chem. - Eur. J. 2015, 21, 18961. (d) Zhang, Z.; Tang, X.; Thomoson,
C. S.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 3528. (e) Zhang, Z.; Tang,
X.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 4401. (f) Zhang, Z.; Tang,
X.-J.; Dolbier, W. R., Jr. Org. Lett. 2016, 18, 1048.
(11) (a) Lin, Q.-Y.; Ran, Y.; Xu, X.-H.; Qing, F.-L. Org. Lett. 2016,
18, 2419. (b) Lin, Q.-Y.; Xu, X.-H.; Zhang, K.; Qing, F.-L. Angew.
Chem., Int. Ed. 2016, 55, 1479. (c) Ran, Y.; Lin, Q.-Y.; Xu, X.-H.; Qing,
F.-L. J. Org. Chem. 2016, 81, 7001.
(12) (a) Rong, J.; Deng, L.; Tan, P.; Ni, C.; Gu, Y.; Hu, J. Angew.
Chem., Int. Ed. 2016, 55, 2743. (b) Fu, W.; Han, X.; Zhu, M.; Xu, C.;
Wang, Z.; Ji, B.; Hao, X.-Q.; Song, M.-P. Chem. Commun. 2016, 52,
13413.
D
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