Photoredox-Catalyzed Tandem Insertion/Cyclization Reactions of Difluoromethyl and 1,1-Difluoroalkyl Radicals with Biphenyl Isocyanides

Article abstract of DOI:10.1021/acs.orglett.5b02061

Using visible-light photoredox conditions, difluoromethylation and 1,1-difluoroalkylation of biphenyl isocyanides have allowed the synthesis of a series of 6-(difluoromethyl)- and 6-(1,1-difluoroalkyl)phenanthridines via tandem addition/cyclization/oxidation processes. The reactions are carried out in wet dioxane at room temperature using fac-Ir(ppy)₃ as catalyst to form a large variety of substituted phenanthridine products in good to excellent yield.

Full text of DOI:10.1021/acs.orglett.5b02061

Letter
pubs.acs.org/OrgLett
Photoredox-Catalyzed Tandem Insertion/Cyclization Reactions of
Difluoromethyl and 1,1-Difluoroalkyl Radicals with Biphenyl
Isocyanides
Zuxiao Zhang, Xiaojun Tang, and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States
S
* Supporting Information
ABSTRACT: Using visible-light photoredox conditions, difluor-
omethylation and 1,1-difluoroalkylation of biphenyl isocyanides
have allowed the synthesis of a series of 6-(difluoromethyl)- and
6-(1,1-difluoroalkyl)phenanthridines via tandem addition/cycliza-
tion/oxidation processes. The reactions are carried out in wet
dioxane at room temperature using fac-Ir(ppy)3 as catalyst to
form a large variety of substituted phenanthridine products in
good to excellent yield.
The phenanthridine core occurs widely in natural products
he introduction of fluorine-containing alkyl groups into
Tmolecules has attracted researchers’ interest for several and biological molecules.10 One effective method for preparing
phenanthridines bearing substituents at the 6-position has
involved reactions of various radicals, including trifluoromethyl,
with 2-isocyano-1,1′-biphenyl.11,12 With respect to the
difluoromethyl group, thus far, only Yu’s group has reported
a method for difluoromethylation of isocyanides, in his case
using a stepwise strategy involving initial reaction with the
carboethoxydifluoromethyl radical (Scheme 1 (a)).13 The direct
difluoromethylation of isocyanides is still unreported.
decades because of the beneficial properties that their presence
can bestow, including enhanced reactivity, lipophilicity, and
bioactivity.1 A host of elegant approaches have been developed
to introduce fluoro substitutents and fluorinated alkyl groups;
in particular, the trifluoromethyl group, into diverse skeletons.2
However, methodologies to introduce CF2H have been
considerably less studied.3,4 Traditional methods for the
synthesis of difluoroalkylated molecules generally involved the
use of expensive and highly reactive reagents such as SF4,
(diethylamino)sulfur trifluoride (DAST), and other related
reagents to carry out deoxyfluorination of aldehydes and
ketones.5 In addition to the many undesirable aspects of these
methodologies, they also generally suffer from poor functional
group tolerance. Therefore, the development of new methods
for introduction of CF2H and other gem-difluoroalkyl groups
into organic compounds remains a challenging and worthwhile
endeavor.
Scheme 1. Preparation of 6-(Difluoromethyl)phenanthridine
Recently, there has been much excellent work in the area of
direct introduction of the difluoromethyl group into aromatic
and heteroaromatic compounds mainly via radical processes or
cross-coupling reactions.6−8 For instance, in 2012, Baran’s
group developed a new reagent Zn(SO2CF2H)2 which under
oxidative conditions generates the difluoromethyl radical that
will allow difluoromethylation of heterocycles.6 In the same
year, Hartwig and Prakash independently reported copper-
mediated difluoromethylation of aryl iodides using
(trimethylsilyl)difluoromethane (TMSCF2H) and tributyl-
(difluoromethyl)stannane (n-Bu3SnCF2H), respectively, as
their sources of difluoromethyl.7 Shen and his co-workernd
co-workers realized difluoromethylation of aryl iodides and
bromides using TMSCF2H with copper and silver as
cocatalyst.8 The Goossen group also reported Sandmeyer
difluoromethylation of aryl diazonium salts.9
In recent work, our group has demonstrated that, under
photoredox catalysis, CF2HSO2Cl can be a very good
difluoromethyl radical precursor, with the generated radical
showing good reactivity toward both electron-rich and electron-
poor double bonds.14 We envisioned that a similarly generated
CF2H radical would react with 2-isocyano-1,1′-biphenyl (1a),
with the intermediate radical then cyclizing with subsequent
oxidation and deprotonation to form 6-(difluoromethyl)-
phenanthridine (Scheme 1 (b)).
Received: July 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To test our hypothesis, 1a was used as substrate under the
photoredox conditions that we had used previously to generate
the difluoromethyl radical, using fac-Ir(ppy)3 as catalyst with 1
mol % loading. Considering their previously determined
significance, several bases were examined (Table 1). Unfortu-
Scheme 2. Substrates Scope of Difluoromethylation of
Isocyanides
a
a,b
Table 1. Screening Conditions
entry
catalyst
solvent
base
yield (%)
1
2
3
4
5
6
7
8
9
10
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Na2CO3
K2HPO4
Ag2CO3
K2CO3
trace
trace
ND
ND
ND
ND
ND
ND
ND
ND
54
K3PO4
KOAc
NaOAc
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
Na2CO3
Na2CO3
DMAc
NMP
c
11
dioxane
dioxane
dioxane
dioxane
dioxane
c
12
[Ir{df(CF3)ppy}2(dtbpy)]PF6
[Ir(dtbpy) (ppy)2]PF6
Ir(ppy)3
63
c
13
c
56
14
84
15
Ir(ppy)3
20
a
Reactions were run with 0.1 mmol of 1a, 0.2 mmol of HCF2SO2Cl,
0.2 mmol of base, and 0.001 mmol of catalyst in 1 mL of solvent under
b
a
visible light. All yields were based on 1a using fluorobenzene as
Reactions were run with 0.2 mmol of 1a, 0.4 mmol of HCF2SO2Cl,
c
internal standard. 4−6 mg of water as additive
0.4 mmol of base, and 0.002 mmol of catalyst in 2 mL of dioxane with
b
c
8 mg water under visible light. Isolated yield. Regioselectivity (2.6:1)
d
Yields were determined by 19F NMR using fluorobenzene as internal
nately, only trace amounts of product were detected when
using Na2CO3 and K2HPO4 (entries 1 and 2), and looking at a
few other bases did not improve the situation, with 1a largely
remaining unreacted (entries 3−7). Solvent dependence was
then examined. Using K2HPO4 as base, highly polar solvents
were found to be ineffective (entries 8−10), but combining
dioxane with a small amount of water led to 54% of the desired
product (entry 11). Other Ir photoredox catalysts gave similar
results (entry 12 and 13). However, changing the base to
Na2CO3 led to an increase in yield to 84%, which was
considered to be satisfactory (entry 14). It should be
mentioned that only 20% of product was obtained in the
absence of water (entry 15). The exact effect of water is still
unclear, but it is probable that water promotes the solubility of
the base in dioxane.
standard.
Scheme 3. Substrate Scope of Other gem-Difluoroalkylations
of Isocyanides
To study the scope of the reaction, various biarylisonitriles
were tested (Scheme 2). A variety of substituents, both electron
rich and electron poor, on the isonitrile arene moiety, including
methyl (1b), carbomethoxy (1g), methoxy (1e, 1f), fluoro
(1d), and CF3 (1c), produced the corresponding products in
good to excellent yields. Substitution on the other phenyl ring
indicated that the reaction did not tolerate electron-poor
substituents on this ring, with compounds 2n and 2o being
formed in poor yield. Otherwise, it appears that this reaction is
quite versatile with respect to substitution and multisubstitution
of the two phenyl rings.
a
Reactions were run with 0.1 mmol of 1a, 0.13 mmol of PhCF2Br, 0.2
mmol of base, and 0.002 mmol of catalyst in 1 mL of solvent under
visible light. Isolated yield.
b
To further explore the application of the tandem reaction,
RCF2X was employed under the optimized conditions (Scheme
3). Since the PhCF2Br is liquid and easier to prepare than the
respective sulfonyl chloride, it was used as the precursor of the
PhCF2 radical instead of the sulfonyl chloride. Using a higher
B
DOI: 10.1021/acs.orglett.5b02061
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chemistry; Wiley-VCH: Weinheim, 2004. (e) Ojima, I. Fluorine in
Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Chi-
chester, 2009. (f) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Fischer, H.;
temperature and 2% loading of catalyst, very good yields were
able to be obtained for a variety of substrates.
Additionally, CH3CF2SO2Cl proved effective as a source of
1,1-difluoroethyl radical for addition to the isocyanides, leading
to formation of the corresponding phenanthridine products (4)
in good yield.
Kansy, M.; Zimmerli, D.; Carreira, E. M.; Muller, K. J. Fluorine Chem.
̈
2013, 152, 119. (g) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del
́
́
̃
Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.
Chem. Rev. 2014, 114, 2432.
A photoredox catalytic cycle was proposed as the mechanism
of these reactions, based on precendent (Scheme 4). First, the
(2) (a) Wen, L.; Shen, Q.; Lu, L. Org. Lett. 2010, 12, 4655. (b) Liu,
C.; So, L.; Lo, J. C. Y.; Chan, M. C. W.; Kaneyoshi, H.; Makio, H.
Organometallics 2012, 31, 5274. (c) Rudnitskaya, A.; Huynh, K.;
Torok, B.; Stieglitz, K. J. Med. Chem. 2009, 52, 878. (d) Watson, W. J.
̈
̈
Scheme 4. Proposed Mechanism
Org. Process Res. Dev. 2006, 10, 1314. (e) O’Hagan, D. J. Org. Chem.
2012, 77, 3689. (f) Torok, M.; Abid, M.; Mhadgut, S. C.; Torok, B.
̈
̈
̈
̈
Biochemistry 2006, 45, 5377. (g) Amii, H.; Kageyama, K.; Kishikawa,
Y.; Hosokawa, T.; Morioka, R.; Katagiri, T.; Uneyama, K. Organo-
metallics 2012, 31, 1281. (h) Jin, G.; Zhang, X.; Cao, S. Org. Lett. 2013,
15, 3114. (i) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. J. Med. Chem.
2014, 57, 2832.
(3) For recent reviews, see: (a) Liang, T.; Neumann, C. N.; Ritter, T.
Angew. Chem., Int. Ed. 2013, 52, 8214. (b) Hu, J.; Zhang, W.; Wang, F.
Chem. Commun. 2009, 7465. (c) Mace,
Chem. 2012, 2012, 2479.
́
Y.; Magnier, E. Eur. J. Org.
(4) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626.
(5) (a) Wang, J.; Stolowich, N. J.; Scott, A. I. Tetrahedron Lett. 1995,
36, 2389. (b) Turkman, N.; An, L.; Pomerantz, M. Org. Lett. 2010, 12,
4428. (c) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (d) Blackburn,
G. M.; England, D. A.; Kolkmann, F. J. Chem. Soc., Chem. Commun.
1981, 930. (e) Horne, D. B.; Bartberger, M. D.; Kaller, M. R.;
Monenschein, H.; Zhong, W.; Hitchcock, S. A. Tetrahedron Lett. 2009,
50, 5452. (f) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(6) 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.
(7) (a) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(b) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood,
K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, 12090.
(8) Gu, Y.; Leng, X.-B.; Shen, Q. Nat. Commun. 2014, 5, 5405.
(9) Matheis, C.; Jouvin, K.; Goossen, L. Org. Lett. 2014, 16, 5984.
(10) (a) Suffness, M.; Cordell, G. A. The Alkaloids; Academic Press:
New York, 1985; Vol. 25, p 178. (b) Nakanishi, T.; Suzuki, M. J. J. Nat.
Prod. 1998, 61, 1263. (c) Nakanishi, T.; Suzuki, M.; Saimoto, A.;
Kabasawa, T. J. J. Nat. Prod. 1999, 62, 864. (d) Nakanishi, T.; Suzuki,
M. Org. Lett. 1999, 1, 985. (e) Nakanishi, T.; Masuda, A.; Suwa, M.;
Akiyama, Y.; Hoshino-Abe, N.; Suzuki, M. Bioorg. Med. Chem. Lett.
2000, 10, 2321.
excited Ir catalyst reduces the sulfonyl chloride to form the
difluoromethyl radical, which then adds to the isonitrile to
generate the imidoyl radical A, which cyclizes on the arene to
give cyclohexadienyl radical B. Then B is oxidized by the high-
valent catalyst to form cationic intermediate C with
regeneration of catalyst. Finally, intermediate C is depronated
to form the product.
In conclusion, the first example of difluoromethyl and 1,1-
difluoroalkyl radical isonitrile insertion reactions which afford
phenanthridine derivatives under mild conditions is reported.
The difluoromethyl radical as well as α,α-difluorobenzyl or 1,1,-
difluoroethyl radicals exhibited excellent reactivity with
isonitriles. The respective sulfonyl chlorides were excellent
precursors for the difluoromethyl and 1,1-difluoroethyl radicals,
whereas (bromodifluoromethyl)benzene proved effective as the
precursor for the α,α-difluorobenzyl radical.
ASSOCIATED CONTENT
* Supporting Information
■
S
(11) For recent reviews, see: (a) Zhang, B.; Studer, A. Chem. Soc. Rev.
2015, 44, 3505. (b) Encyclopedia of Radicals in Chemistry, Biology, and
Materials; Studer, A., Ed.; Wiley: Chichester, 2012. (c) Ryu, I.; Sonoda,
N.; Curran, D. P. Chem. Rev. 1996, 96, 177. (d) Curran, D. P.; Liu, H.
J. Am. Chem. Soc. 1991, 113, 2127.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02061.
Experimental procedures, characterization data, and
NMR spectra of new compounds (PDF)
(12) For recent CF3 radical reactions with isonitriles, see: (a) Zhang,
B.; Mu ck-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A. Angew. Chem.,
̈
Int. Ed. 2013, 52, 10792. (b) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L.
Org. Lett. 2013, 15, 4846. (c) Cheng, Y.; Jiang, H.; Zhang, Y.; Yu, S.
Org. Lett. 2013, 15, 5520. (d) Zhang, B.; Studer, A. Org. Lett. 2014, 16,
1216. (e) Cheng, Y.; Yuan, X.; Jiang, H.; Wang, R.; Ma, J.; Zhang, Y.;
Yu, S. Adv. Synth. Catal. 2014, 356, 2859. (f) Zhang, B.; Studer, A. Org.
Lett. 2014, 16, 3990. (g) Wang, R.; Jiang, H.; Cheng, Y.; Kadi, A. A.;
Fun, H.-K.; Zhang, Y.; Yu, S. Synthesis 2014, 46, 2711.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wrd@chem.ufl.edu.
Notes
The authors declare no competing financial interest.
(13) Sun, X.; Yu, S. Org. Lett. 2014, 16, 2938.
ACKNOWLEDGMENTS
Support of this research in part by Syngenta Crop Protection is
acknowledged with thanks.
(14) (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.
■
REFERENCES
■
(1) Recent reviews: (a) Muller, K.; Faeh, C.; Diederich, F. Science
2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) O’Hagan, D.
Chem. Soc. Rev. 2008, 37, 308. (d) Krisch, P. Modern Fluoroorganic
C
DOI: 10.1021/acs.orglett.5b02061
Org. Lett. XXXX, XXX, XXX−XXX