PhI(OAc)2-mediated synthesis of 6-(trifluoromethyl) phenanthridines by oxidative cyclization of 2-isocyanobiphenyls with CF 3SiMe3 under metal-free conditions

Article abstract of DOI:10.1021/ol4022589

A mild and efficient method for the synthesis of 6-(trifluoromethyl) phenanthridines through oxidative cyclization of 2-isocyanobiphenyls with CF₃SiMe₃ under metal-free conditions was developed. The reaction allows the direct formation of C-CF₃ bonds and rapid access to phenanthridine ring systems in one catalytic cycle.

Full text of DOI:10.1021/ol4022589

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
PhI(OAc)2‑Mediated Synthesis of
6‑(Trifluoromethyl)phenanthridines
by Oxidative Cyclization of
2‑Isocyanobiphenyls with CF3SiMe3
under Metal-Free Conditions
Qile Wang, Xichang Dong, Tiebo Xiao, and Lei Zhou*
School of Chemistry and Chemical Engineering, Sun Yat-Sen University,
135 Xingang West Road, Guangzhou 510275, China
zhoul39@mail.sysu.edu.cn
Received August 8, 2013
ABSTRACT
A mild and efficient method for the synthesis of 6-(trifluoromethyl)phenanthridines through oxidative cyclization of 2-isocyanobiphenyls with
CF3SiMe3 under metal-free conditions was developed. The reaction allows the direct formation of CꢀCF3 bonds and rapid access to
phenanthridine ring systems in one catalytic cycle.
Phenanthridines are common structural units present in
a wide variety of naturally occurring alkaloids1 and exhibit
interesting biological activities and potential pharmaceu-
tical applications.2 Substituted phenanthridines are also
widely used in material science due to their significant
optoelectronic properties.3 For these reasons, diverse meth-
ods have been reported for their synthesis in the last decades.4
Meanwhile, the development of new methodologies for
preparing trifluoromethylated heterocyclic compounds
has become a subject of great interest in organic synthesis,
because the CF3 group can often influence chemical and
metabolic stability, lipophilicity, and binding selectivity.5
Although the synthesis of phenanthridines has been largely
described in the literature, methods leading to the trifluor-
omethylated substrates are still limited.6 Only recently, Wu
et al. reported a Rh-catalyzed [2 þ 2þ2] cycloaddition for
(1) (a) Suffness, M.; Cordell, G. A. The Alkaloids; Academic: New
York, 1985; Vol. 25, pp 178ꢀ189. (b) Nakanishi, T.; Suzuki, M. J. Nat.
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Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2005, 13, 6782. (d)
Bernardo, P. H.; Wan, K. F.; Sivaraman, T.; Xu, J.; Moore, F. K.; Hung,
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P.; Charnay, Y.; Rault, S.; Cailly, T.; Fabis, F. J. Med. Chem. 2012, 55,
9693.
(4) For recent examples, see: (a) Read, M. L.; Gundersen, L.-L.
J. Org. Chem. 2013, 78, 1311. (b) Wu, Y.; Wong, S. M.; Mao, F.; Chan,
T. L.; Kwong, F. Y. Org. Lett. 2012, 14, 5306. (c) Intrieri, D.; Mariani,
M.; Caselli, A.; Ragaini, F.; Gallo, E. Chem.;Eur. J. 2012, 18, 10487.
(d) McBurney, R. T.; Slawin, A. M. Z.; Smart, L. A.; Yu, Y.; Walton,
J. C. Chem. Commun. 2011, 47, 7974. (e) Peng, J.; Chen, T.; Chen, C.; Li,
B. J. Org. Chem. 2011, 76, 9507. (f) Linsenmeier, A. M.; Williams, C. M.;
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Brase, S. J. Org. Chem. 2011, 76, 9127. (g) Zhou, Y.; Dong, J.; Zhang, F.;
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Gong, Y. J. Org. Chem. 2011, 76, 588. (h) Buden, M. E.; Dorn, V. B.;
Gamba, M.; Pierini, A. B.; Rossi, R. A. J. Org. Chem. 2010, 75, 2206. (h)
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Ca, N. D.; Motti, E.; Mega, A.; Catellani, M. Adv. Synth. Catal. 2010,
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Fensterbank, L.; Lacote, E.; Malacria, M. Org. Lett. 2010, 12, 5692.
(5) (a) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima,
I., Ed.; Wiley: Chichester, 2009. (b) Purser, S.; Moore, P. R.; Swallow, S.;
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Bondarev, S. L.; Knyukshto, V. N.; Tikhomirov, S. A.; Pyrko, A. N. Opt.
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r
10.1021/ol4022589
XXXX American Chemical Society

the construction of fluorine-containing phenanthridines.6a
Zhang and co-workers developed a method for 6-trifluor-
omethyl phenanthridine via a palladium-catalyzed tandem
Suzuki/CꢀH arylation reaction of N-aryltrifluoroacetimi-
doyl chlorides with arylboronic acids.6b However, the above-
reported strategies remain associated with certain disadvan-
tages such as harsh reaction conditions, use of transition-
metal catalysts and difficult to obtain trifluoromethylated
building blocks.
Undoubtedly, the ideal and promising route for the
preparation of trifluoromethylated organic compounds is
the direct generation of CꢀCF3 bonds.7 In the past decade,
transition-metal catalyzed or -mediated cross-poupling
reactions are widely applied for the formation of these
bonds.8 Another frequently used strategy is the utilization
of high reactivity of CF3 radical.9,10 For example, Baran et al.
reported direct CꢀH trifluoromethylation of nitrogen-
containing heterocyclic compounds with the combination
t
of NaSO2CF3 and BuOOH.10c Shibata and co-workers
developed a method for the oxidative trifluoromethylation
of unsymmetrical biaryls.10a Unfortunately, these radical
transformations always result in the trifluoromethylated
products withpoor regioselectivity, which make them have
little application in the trifluoromethylation of polycyclic
aromatic compounds. Thus, a more practical method for
the synthesis of trifluoromethylated phenanthridines with
high regioselectivity must be devised.
Recently, an elegant Mn(III)-mediated annulation of
2-isocyanobiphenyls with boronic acid under heating con-
ditions was developed by Chatani et al.11 In this reaction,
an isocyano group was used as the radical acceptor, which
followed by a radical cyclization to give phenanthridines.
Inspired by these results, we envisioned bringing together
the advantages of both strategies by combining 2-isocya-
nobiphenyls with CF3 radicals (scheme 1). Herein, we
report a PhI(OAc)2-mediated synthesis of 6-trifluoro-
methyl phenanthridines by oxidative cyclization of 2-iso-
cyanobiphenyls with CF3SiMe3 at room temperature
under metal-free conditions. This transformation allows
the direct formation of CꢀCF3 bonds and phenanthridine
ring systems in one reaction.
(6) (a) Li, Y.; Zhu, J.; Zhang, L.; Wu, Y.; Gong, Y. Chem.;Eur. J.
2013, 19, 8294. (b) Wang, W.-Y.; Feng, X.; Hu, B.-L.; Deng, C.-L.;
Zhang, X.-G. J. Org. Chem. 2013, 78, 6025.
(7) For reviews, see: (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
2011, 473, 470. (b) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475. (c) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int.
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Ed. 2012, 51, 5048. (d) Mace, Y.; Magnier, E. Eur. J. Org. Chem. 2012,
2479. (e) Wu, X.-F.; Neumann, H.; Beller, M. Chem.;Asian J. 2012, 7,
1744.
(8) For selected recent examples, see: (a) Cho, E. J.; Senecal, T. D.;
Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328,
1679. (b) Chu, L. L.; Qing, F. L. Org. Lett. 2010, 12, 5060. (c) Wang, X.;
Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem.
Soc. 2011, 133, 16410. (d) Zhang, C. P.; Wang, Z. L.; Chen, Q. Y.;
Zhang, C. T.; Gu, C. Y.; Xiao, J. C. Angew. Chem., Int. Ed. 2011, 50,
1896. (e) Chu, L. L.; Qing, F. L. J. Am. Chem. Soc. 2010, 132, 7262. (f)
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2011, 50, 3793. (g) Knauber, T.; Arikan, F.;
Scheme 1. PhI(OAc)2-Mediated Oxidative Cyclization of
2-Isocyanobiphenyls with CF3SiMe3
€
Roschenthaler, G. V.; Goossen, L. J. Chem.;Eur. J. 2011, 17, 2689.
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(h) Tomashenko, O. A.; Escudero-Adan, E. C.; Belmonte, M. M.;
Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655. (i) Liu, T. F.;
Shen, Q. L. Org. Lett. 2011, 13, 2342. (j) Litvinas, N. D.; Fier, P. S.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 536. (k) Xu, J.; Luo,
D. F.; Xiao, B.; Liu, Z. J.; Gong, T. J.; Fu, Y.; Liu, L. Chem. Commun.
2011, 47, 4300. (l) Zhang, C. P.; Cai, J.; Zhou, C. B.; Wang, X. P.; Zheng,
X.; Gu, Y. C.; Xiao, J. C. Chem. Commun. 2011, 47, 9516. (m) Khan,
B. A.; Buba, A. E.; Goossen, L. J. Chem.;Eur. J. 2012, 18, 1577. (n)
Initially, the reaction was carried out by using 2-isocya-
nobiphenyl 1a and CF3SiMe3 (4 equiv) in NMP (0.4 mL)
with PhI(OAc)2 (2.1 equiv) as the oxidant at room
temperature.12 Gratifyingly, the desired phenanthridine
2a was obtained as the major product in 43% yield as
determined by 1H NMR spectroscopy (Table 1, entry 1). It
was observed that the use of inorganic bases such as
K2CO3, Cs2CO3, and NaOAc promoted the reactions,
and NaOAc gave the best result (Table 1, entries 2ꢀ4).
ꢀ
Novak, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem., Int. Ed.
2012, 51, 7767. (o) Ye, Y. D.; Sanford, M. S. J. Am. Chem. Soc. 2012,
134, 9034. (p) Jiang, X. L.; Chu, L. L.; Qing, F. L. J. Org. Chem. 2012, 77,
1251. (q) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem.
2011, 76, 1174. (r) Xu, J.; Xiao, B.; Xie, C. Q.; Luo, D. F.; Liu, L.; Fu, Y.
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Angew. Chem., Int. Ed. 2012, 51, 12551. (s) Novak, P.; Lishchynskyi, A.;
Grushin, V. V. J. Am. Chem. Soc. 2012, 134, 16167. (t) Wang, X.; Xu, Y.;
Mo, F.; Ji, G.; Qiu, D.; Feng, J.; Ye, Y.; Zhang, S.; Zhang, Y.; Wang, J.
J. Am. Chem. Soc. 2013, 135, 10330. (u) Ilchenko, N. O.; Janson, P. G.;
Szabo, K. J. Chem. Commun. 2013, 49, 6614. (v) Seo, S.; Taylor, J. B.;
Greaney, M. F. Chem. Commun. 2013, 49, 6385. (w) Wang, X.; Ye, Y.; Ji,
G.; Xu, Y.; Zhang, S.; Feng, J.; Zhang, Y.; Wang, J. Org. Lett. 2013, 15,
3730. (x) Dai, J.-J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu, X.;
Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436.
(9) For reviews, see: (a) Ma, J. A.; Cahard, D. Chem. Rev. 2008, 108,
PR1. (b) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950. (c) Ye, Y.;
Sanford, M. S. Synlett 2012, 23, 2005. (d) Liu, H.; Gu, Z.; Jiang, X. Adv.
Synth. Catal. 2013, 355, 617.
t‑
H2O2 and BuOOH (TBHP) were also attempted as the
oxidants, but only a trace of the desired product was
detected (Table 1, entries 5 and 6). Among various solvents
examined, DMF provided a slightly lower yield (Table 1,
entry 7). Other solvents such as MeCN, 1,4-dioxane, THF,
toluene, and EtOH were all less efficient compared with
NMP (Table 1, entries 8ꢀ12). These results indicated poorly
nucleophilic polar solvents are crucial for this transforma-
tion. Notably, the reaction could also proceed smoothly in
(10) For examples of arene/heteroarene trifluoromethylation with
CF3 , see: (a) Yang, Y.-D.; Iwamoto, K.; Tokunaga, E.; Shibata, N.
•
€
Chem. Commun. 2013, 49, 5510. (b) Hafner, A.; Brase, S. Angew. Chem.,
Int. Ed. 2012, 51, 3713. (c) Ji, Y.; Brueckl, 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. (d) Nagib, D. A.; MacMillan, D. W. C.
Nature 2011, 480, 224. (e) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett.
2011, 13, 5464. (f) Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.;
Uraguchi, D.; Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131,
98. (g) Kamigata, N.; Ohtsuka, T.; Fukushima, T.; Yoshida, M.;
Shimizu, T. J. Chem. Soc., Perkin Trans. 1 1994, 1339. (h) Langlois,
B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991, 32, 7525.
(11) Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem.,
Int. Ed. 2012, 51, 11363.
(12) The concentration of CF3SiMe3 is highly important in this
reaction. The yield of 2a decreased sharply when 2 mL of NMP was
used as the solvent under the standard reaction conditions.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditionsa
Table 2. Reaction of TMSCF3 with Various Isocyanidesa
entry
base
oxidant
solvent
NMP
yieldb (%)
1
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
H2O2
43
2
K2CO3
Cs2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NMP
74
3
NMP
60
4
NMP
85
5
NMP
trace
trace
81
6
TBHP
NMP
7
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2/BQ
PhI(OAc)2/BQ
PhI(OAc)2/BQ
DMF
8
MeCN
1,4-dioxane
THF
29%
17%
NDc
ND
ND
63
9
10
11
12
13d
14e
15f
16g
toluene
EtOH
NMP
NMP
NMP
91
26
NMP
9
a Reaction conditions if not otherwise noted: 1a (0.2 mmol),
TMSCF3 (4 equiv), oxidant (2.1 equiv), base (2.1 equiv) in 0.4 mL of
solvent for 4 h under N2. b Yields determined by 1H NMR analysis using
CH2Br2 as internal standard. c ND: not detected. d The reaction was
carried out in the open air. e 0.2 equiv of BQ was added. f 2 equiv of
TMSCF3 was used. g 1 equiv of TMSCF3 was used.
the open air conditions, albeit affording the product with
slightly diminished yield (Table 1, entry 13). It is reported
that catalytic amount of benzoquinone (BQ) could improve
the reaction efficiency,13 wewerepleasedtofindthattheyield
of the desired product could be increased to 91% with the
addition of 0.2 equiv of BQ (Table 1, entry 14). However, the
role of BQ in the reaction is not clear at this stage. Finally,
the amount of TMSCF3 was optimized (Table 1, entries 15
and 16). Unfortunately, we found the yield of 2a decreased
sharply when a lower amount of TMSCF3 was used.
With the optimized reaction conditions in hand, the
present oxidative cyclization method was applied to a
series of 2-isocyanobiaryl compounds, which can be read-
ily prepared from corresponding anilines. As shown in
Table 2, the isocyanides bearing either electron-rich or
electron-deficient substituents on 40-position of the aro-
matic ring all underwent the reactions smoothly to afford
the corresponding 6-(trifluoromethyl)phenanthridines 2bꢀg
in good yields. A wide range of functional groups, such as
phenyl (2d), chloro (2e), and ester (2g), were tolerated under
the present oxidative conditions. The reaction also worked
well when only one ortho hydrogen atom was available in the
biaryl isocyanides, albeit giving the products in moderate
yields (2h and 2i). When two nonequivalent ortho hydrogen
atoms were available, this reaction suffered from poor
regioselectivity, and two isomers 2j and 2j0 were isolated in
yields of 42% and 35%, respectively. In addition, we found
a Reaction conditions: isocyanides 1 (0.2 mmol), TMSCF3 (4 equiv),
PhI(OAc)2 (2.1 equiv), NaOAc (2.1 equiv) and BQ (0.2 equiv) in 0.4 mL of
NMP for 4 h under N2.b Isolated yield. c The reaction was carried out at 0 °C.
that 2-(2-thienyl)phenyl isocyanide (1k) was also a suitable
substrate in this annulation reaction to generate a thieno-
[3,2-c]quinoline system (2k). Subsequently, we studied the
effect of the substituents on the aromatic ring attached to
isocyanide and were pleased to find that the oxidative
cyclization of CF3SiMe3 with isocyanides 1lꢀo afforded
the corresponding 6-(trifluoromethyl)phenanthridines 2lꢀo
in moderate to goods yields, respectively. The sensitive
(14) See the Supporting Information for evidence for the in situ
formation of intermediate A.
(15) For use of an isocyano group as the acceptor of a CF3 radical,
see: (a) Tsuchii, K.; Imura, M.; Kamada, N.; Hirao, T.; Ogawa, A.
J. Org. Chem. 2004, 69, 6658. (b) Tordeux, M.; Wakselman, C. Tetra-
hedron 1981, 37, 315.
(13) Wu, X.; Chu, L.; Qing, F.-L. Tetrahedron Lett. 2013, 54, 249.
Org. Lett., Vol. XX, No. XX, XXXX
C

was almost shut down, while the TEMPOꢀCF3 adduct was
formed in 60% yield as estimated by 19F NMR analysis
(Scheme 2). This result indicates that the CF3 radical may be
involved in the transformation.
Scheme 2. Experiment for Mechanistic Study
Onthe basisof thisresult, a plausiblereaction pathway is
proposed in Scheme 3. Initially, PIDA reacts with CF3SiMe3
to give intermediate A upon release of TMSOAc.14 The
following homolysis generates the hypervalent iodine(III)-
centered radical B and CF3 radical.10a Intermolecular addi-
tion of CF3 radical to isocyanide 1,15 followed by intra-
molecular aromatic substitution of the resulting imidoyl
radical C, generated the intermediate D. Subsequently, D is
oxidized to cyclohexadienyl cation E through a single elec-
tron transfer (SET) by the intermediate B.16 Finally, depro-
tonation of E by the acetate anion leads to the desired
6-(trifluoromethyl)phenanthridines 2.
Scheme 3. Mechanistic Rationale
In conclusion, we have developed a mild and efficient
method for the synthesis of 6-(trifluoromethyl)phenanthridines
through oxidative cyclization of 2-isocyanobiphenyls with
CF3SiMe3 under metal-free conditions. The reaction al-
lows the direct formation of CꢀCF3 bonds and rapid
access to phenanthridine ring systems in one catalytic
cycle. Diversified phenanthridines bearing a CF3 group
at the C6 position were obtained in good yields with high
regioselectivity at ambient temperature. Further investiga-
tions on the substrate scope and related cascade radical
processes are currently underway in our laboratory.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 21202207 and J1103305),
the Research Fund for Guangzhou Peal River New Star of
Science and Technology (Grant No. 2013J2200017), and the
Beijing National Laboratory of Molecular Sciences
(BNLMS) for financial support.
chlorine in isocyanides 1o was also compatible with the
reaction conditions, providing potential possibility for
further functionalization.
To gain insight into the reaction mechanism, we inves-
tigated the reaction in the presence of 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO), which is known as an effective
radical scavenger. When 2.5 equiv of TEMPO was added
in the reaction of 1a under identical conditions, the reaction
Supporting Information Available. Procedures for synthe-
sis and characterization of products (1H and 13C NMR
data). This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) Huang, J.; He, Y.; Wang, Y.; Zhu, Q. Chem.;Eur. J. 2012, 18,
13964.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX