Synthesis of 6-Trifluoromethylphenanthridines through Radical Trifluoromethylation of Isocyanides with Sodium Triflinate under Visible Light

Article abstract of DOI:10.1002/ejoc.201701487

Trifluoromethylation enabled by photochemistry enriched the toolbox of synthetic chemists, to allow the simple and efficient installation of CF₃ groups in organic molecules. Herein, we report a cascade addition/annulation reaction of 2-isocyanobiphenyls towards the synthesis of 6-trifluoromethylphenanthridines. It is proposed that this reaction is triggered by the CF₃ radical generated from photoexcited 2,3-butanedione (diacetyl) and sodium triflinate. In contrast to classical aromatic trifluoromethylations, this work does not require any additives and features formation of a C–CF₃ bond with concomitant construction of an aromatic scaffold.

Full text of DOI:10.1002/ejoc.201701487

A Journal of
Accepted Article
Title: Synthesis of 6-trifluoromethylphenanthridines via radical
trifluoromethylation of isocyanides with sodium triflinate under
visible light
Authors: Jianbin Li, Clarice Caiuby, Márcio W. Paixão, and Chao-Jun
Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701487
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701487
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10.1002/ejoc.201701487
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 6-trifluoromethylphenanthridines via radical
trifluoromethylation of isocyanides with sodium triflinate under
visible light
Jianbin Li,[a],[c] Clarice A. D. Caiuby,[a],[b],[c] Márcio W. Paixão*[b] and Chao-Jun Li*[a]
Abstract: Trifluoromethylation enabled by photochemistry enriched the toolbox of synthetic chemists, allowing the simple and efficient
installation of CF3 group in organic molecules. Herein, we report a cascade addition/annulation reaction of 2-isocyanobiphenyls towards
synthesizing 6-trifluoromethylphenanthridines. This reaction was proposed to be triggered by the CF3 radical generated from
photoexcited 2,3-butanedione (diacetyl) and sodium triflinate. In contrast to classical aromatic trifluoromethylations, this work does not
require any additives and features a C-CF3 bond formation with the concomitant construction of an aromatic scaffold.
Introduction
The installation of CF3 moiety in organic molecules – the
so called trifluoromethylation - has attracted the interest of
the synthetic community over the past decades.[1] Upon
introducing the CF3 group, the altered chemical and physical
properties could lead to biological and pharmacological
benefits include greater lipophilicity, enhanced metabolic
stability and bioavailability.[1c, 2] Intensive research over the
years featured diverse synthetically appealing C-CF3 bond
formation strategies. Among them, transition-metal catalyzed
or mediated cross coupling reactions showed successful
achievements.[3] Recently, radical trifluoromethylation
induced by light emerged as a unique and robust method to
shuttle CF3 radical toward unsaturated bonds.[4] Typically,
Scheme 1. (a) Biologically active phenanthridines. (b) Selected work on
trifluoromethylation of biarylisocyanides enabled by different CF3
radical sources.
the combination of visible light photochemistry and
trifluoromethylating reagents, i.e. Togni’s reagents,[5]
Umemoto’s reagents,[6] CF3SO2X (X = Cl[7] or Na[8],
Langlois’s reagent), CF3X (X = I[9] or TMS[10], Ruppert-
Prakash reagent) and others displayed particular
advantages, offering a mild route to construct C-CF3 bond.[11]
Arylisocyanides are of synthetically versatile heterocyclic
scaffolds and well established as a radical acceptor in
tandem reactions.[12] Radical-triggered addition and
sequential annulation of readily prepared biarylisocyanides
enabled rapid construction of the phenanthridine frameworks,
which represented one of the most ubiquitous structures in
natural products and biological compounds.[13] Well-known
members comprised ethidium (a common DNA stain),[14]
trisphaeridine (DNA intercalator)[15] and fagaronine (protein
kinase C and DNA topoisomerase 1 inhibitor).[13a]
On the other hand, a myriad of radical precursors generated
by boronic acid,[16] halides,[17] aldehydes,[18] peroxides,[19]
amides,[20] ethers,[21] alkanes,[22] hydrazines[23] and others
were proven effective in tailoring the phenanthridine
scaffolds. In 2013, Studer and co-workers have disclosed a
pioneering work by the application of Bu4NI as an initiator for
the synthesis of 6-trifluoromethylphenanthridines. In this
approach, Togni’s reagent was used as CF3 radical
precursor.[24] Later, the same group unveiled another
methodology based on Ni-catalyzed or thermally promoted
homolysis of CF3I.[25] Meanwhile, Zhou and co-workers
reported an important work on oxidative cyclization of 2-
isocyanobiphenyls mediated by PhI(OAc)2 with TMSCF3 as
CF3 radical source and benzoquinone as additive.[26] Shortly
thereafter, several effective strategies were also
developed.[27] Notably, photoredox chemistry, which has
witnessed its renaissance in organic synthesis, offered
routes to access CF3 radical via single-electron transfer (SET)
process in a controlled manner. Transforming CF3SO2Cl to
CF3 radical via UV-promoted homolysis, Zhang’s group
reported a photocatalyst-free tandem addition/cyclization
reaction of 2-isocyanobiphenyls initiated by CF3 radical
generation.[27c] Almost concurrently, Hu and co-worker
displayed an elegant and innovative example to afford CF3
[a]
[b]
Department
of
Chemistry,
McGill
University
801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
E-mail: cj.li@mcgill.ca
Homepage: http://www.cjlimcgill.ca/prof-chao-jun-li/
Center of Excellence for Research in Sustainable Chemistry
(CERSusChem), Department of Chemistry, Federal University of
São Carlos UFSCar, Rodovia Washington Luís, km 235 - SP-310 -
São Carlos - São Paulo - Brazil -13565-905.
E-mail: mwpaixao@ufscar.br
[c]
These two authors contributed equally.
radical
species
from
Supporting information for this article is given via a link at the end.
of the document.
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10.1002/ejoc.201701487
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimization of reaction conditions
Entry
Variation from ‘optimal conditions’
EtOAc/diacetyl (9:1, 0.10 M)
THF/diacetyl (8:2, 0.10 M)
Yielda
13
1
2
72
3
iPrOH/diacetyl (8:2, 0.10 M)
EtOAc/diacetyl (8:2, 0.20 M)
4.0 equiv NaSO2CF3
83
4
26
Scheme 2. (a) Working hypothesis inspired by prior art. (b) Visible-light-
mediated radical trifluoromethylation of biarylisocyanides to synthesize
6-trifluorophenanthridines.
5
63
6
UV (254 nm), EtOAc/diacetyl (8:2, 0.10 M)
UV (254 nm), acetone (0.10 M)
blue LED (455 nm)
72
7
71
8
70
fluorinated sulfones by polypyridyl metal complexes-based
visible light photoredox catalysis.[27e] Subsequent radical
addition and intramolecular homolytic aromatic substitution
(HAS) proceeded smoothly under mild conditions.
Despite the enormous success accomplished above,
producing CF3 radical generally necessitated elevated
temperature, environmentally unfriendly additives, precious
transition metal/ligands or special equipment (quartz tubes
for UV radiation). Recently, our group described a simple and
9
50
℃, in the dark
NR
91
10
6 hrs instead of 12 hrs
aDetermined through 1H NMR analysis by using 1,3,5-
trimethoxybenzene as internal standard; NR = no reaction.
8). Light was found essential in this reaction as substrates
remained intact under thermal conditions (entry 9). GC-MS
monitoring indicated that the reaction was completed after 6-
hour CFL irradiation (entry 10).
With the optimized conditions in hand, we prepared
various biarylisocyanides 2a-2o from commercially available
and cheap 2-bromoanilines and examined the generality of
this methodology. Initially, the tolerance of different
functionalities installed at the para-position on biphenyl core
was examined. Electronic bias was not observed in this
transformation, since both substrates with electron-
withdrawing and electron-donating functional groups were
proven effective, resulting in moderate to good yields. Chloro
clean trifluoromethylation method on arenes via
a
photoinduced radical process by employing diacetyl as
photosensitizer, which showcased diradical properties under
visible light.[8a] This prompted us to envision our contribution
to aforementioned isocyanide chemistry. Herein, we wish to
report
isocyanobiphenyls
a
radical trifluoromethylation reaction of 2-
towards synthesizing the 6-
trifluoromethylphenanthridines by using the visible-light-
excited diacetyl and sodium triflinate.
(
3b), fluoro (3c) and methoxy (3j) groups were well tolerated
Results and Discussion
despite phenyl (3d) and methoxycarbonyl (3i) led to slight
decrease of on-target reactivity. Gratifyingly, potentially
sensitive acetyl (3h) and cyano (3k) remained intact during
the reaction, furnishing 82% and 56% of the desired products,
respectively. Difunctionalized biarylisocyanides underwent the
To test the feasibility of our hypothesis, we began our
investigation by choosing 2-isocyano-1,1’-biphenyl (2a) as
our model substrates. To our delight, when our model
substrate was subject to EtOAc/diacetyl (9:1, 0.1 M) mixed
solvent, the reaction proceeded in accordance to our
expectation and resulted in 13% desired product after 12-
hour compact-fluorescence-light (CFL) lumination at room
temperature (Table 1, entry 1). Strikingly, slight increase of
the ratio of photosensitizer productively led to quantitative
product formation, marking the optimal conditions. The
reaction
smoothly
and
6,7,9-
tri(trifluoromethyl)phenanthridine (3l) was obtained in 54%
yield. Substituents at meta- and ortho-positions were also
compatible with our protocol. As expected, the method
suffered from regiocontrol with 2f, giving two isomers (3f and
3f’) in similar quantity. Presumably due to only one ortho
hydrogen being available, the reaction incurred significant
i
reaction in THF and PrOH also proceeded well albeit in
yield drop with 3g
.
Besides, substrates bearing
inferior yields (entries 2-3). Concentrating the reaction
mixture dramatically curtailed the product formation (entry 4).
Doubling the dosage of NaSO2CF3 exhibited deleterious
effect as product yield dropped to 63% (entry 5). UV radiation
was beneficial to this transformation since both diacetyl and
acetone displayed similarly high reactivity (entries 6 and 7).
Reaction efficiency decreased to some extent if blue LED
(centered at 455 nm) was employed, which was explained by
the broad absorption range of diacetyl in visible region (entry
functionalities on the aromatic rings of the isocyano group
were also investigated. Nitro group (3m), known to be
vulnerable toward photochemical conditions, worked well in
this chemistry albeit with a lower yield. Multiple fluorine atoms
present did not affect the efficacy, successfully affording a
semi-perfluorophenanthridine building block (3n). Notably,
the reaction was still high-yielding in the case of 6-
(trifluoromethyl)benzo[c][1,8]naphthyridine
(
3o),
which
incorporated a heteroatom in the biaryl framework.
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10.1002/ejoc.201701487
European Journal of Organic Chemistry
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Scheme 3. Substrate scope. All reactions were performed on 0.10
mmol scale in 1.0 mL of EtOAc/diacetyl (8:2) mixed solvent at r.t.
under argon atmosphere irradiated by CFL (2*40 W) for 12 hrs and all
yields reported are referred to isolated ones and in parentheses
Scheme 4. (a) Radical trapping experiments by different types of
radical scavengers. (b) Proposed mechanism.
To confirm the radical nature of this tandem
addition/annulation reaction, several control experiments
were performed (Scheme 4a). It was found that the reaction
was almost quenched in the presence of different types of
radical scavengers. Among them, (3,3,3-trifluoropropane-
1,1-diyl)dibenzene was formed in the case of 1,1-
diphenylethylene, indicating the involvement of CF3 radical.
Additionally, photophysical properties of this reaction were
explored in order to gain more mechanistic insight (see
electronic supplementary information for details). UV-Vis
spectrometry revealed that both diacetyl and 2a showed
absorption in the visible region; however, considering the
stoichiometry, the excessive diacetyl was probably the major
active photosensitizer. Furthermore, the Stern-Volmer
relationship demonstrated the excited state-quencher
interaction between the diacetyl and NaSO2CF3.
that the re-aromatization of
feasible.[24]
B to give the final product 3a is
Conclusions
In summary, we have developed a simple and efficient route
to synthesize the 6-trifluoromethylphenanthridines via a
radical-triggered pathway involving the CF3 radical generated
from visible-light-excited diacetyl and NaSO2CF3. 2-
arylisocynides bearing a broad range of functionalities were
viable for this transformation at room temperature, which did
not involve transition metal catalyst and additional additives.
Based on the mechanistic study above and previous
literature,[24-27]
a
plausible mechanism was proposed
(Scheme 4b). Upon visible light excitation, the carbonyl
group of diacetyl was promoted from ground state to (n, *)
Experimental Section
π
General Procedure: To a reaction tube (5.0 mL) equipped with a Teflon-
coated magnetic stirring bar was added the isocyanide (0.10 mmol, 1.0
equiv), sodium triflinate (0.20 mmol, 2.0 equiv), diacetyl (0.20 mL) and
EtOAc (0.80 mL). The resulting mixture was evacuated by three freeze-
pump-thaw cycles and back-filled with ultra-purified argon (>99.999%).
The reaction was stirred at room temperature under photo irradiation by
using Compact Fluorescent Lamp (2*40W) until the starting material was
completely consumed as monitored by TLC. The reaction mixture was then
diluted with EtOAc, filtered through a pad of silica gel and the organic
excited state, which exhibited as a diradical species.
Reductive quenching of the excited diacetyl by NaSO2CF3
will generate the CF3 radical with concomitant release of one
equivalent of SO2. Subsequently, terminal carbon in 2a was
attacked by the CF3 radical, which induced an intramolecular
HAS process to afford intermediate
B with cyclohexadienyl
radical moiety. DFT calculation by Studer has shown
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10.1002/ejoc.201701487
European Journal of Organic Chemistry
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solvent was evaporated. The desired product was isolated by flash column
chromatography on silica gel.
CDCl3) δ 8.63 – 8.60 (m, 1H), 8.49 (s, 1H), 8.31 – 8.27 (m, 2H), 7.84 –
7.76 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 2.69 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 146.4 (q, J = 32.9 Hz), 142.1, 142.0, 134.2, 131.1, 129.9, 129.2,
128.9, 125.8 (q, J = 3.3 Hz), 125.0, 122.1, 122.0 (d, J = 277.1 Hz), 122.1,
119.9, 22.4. 19F NMR (377 MHz, CDCl3) δ -63.52 (s, 3F). M.P.: 85.0 – 86.0
ºC. HRMS: calculated for C15H11F3N (M+H)+ 262.0838; found 262.0849.
6-(Trifluoromethyl)phenanthridine (3a): According to the general
procedure, the 2-isocyano-1,1'-biphenyl (2a) (18 mg, 0.1 mmol) afforded
3a (83%, 20.5 mg) as a light solid. 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J
= 8.4 Hz, 1H), 8.61 (dd, J = 7.1, 2.4 Hz, 1H), 8.41 – 8.36 (m, 1H), 8.31 –
8.28 (m, 1H), 7.95 – 7.90 (m, 1H), 7.84 – 7.75 (m, 3H). 13C NMR (125 MHz,
CDCl3) δ 146.5 (q, J = 32.9 Hz), 141.8, 134.0, 131.4, 131.2, 129.4, 129.2,
128.1, 126.0 (q, J = 3.3 Hz), 125.1, 122.6, 122.1, 122.0 (q, J = 277.1
Hz),121.8. 19F NMR (471 MHz, CDCl3) δ -63.45 (s, 3F). M.P.: 74.1-75.1
ºC. HRMS: calculated for C14H8F3NNa (M+Na)+ 270.0507; found 270.0501.
7-Methyl-6-(trifluoromethyl)phenanthridine (3f’): According to the
general procedure, the 2-isociano-3'-metil-1,1'-bifenil (2f) (19.3 mg, 0.1
mmol) afforded 3f’ (41%, 10.75 mg) as a colorless liquid. 1H NMR (400
MHz, CDCl3) δ 8.69 – 8.60 (m, 2H), 8.30 – 8.24 (m, 1H), 7.85 – 7.76 (m,
3H), 7.65 (d, J = 7.2 Hz, 1H), 2.96 (d, J = 2.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 145.1 (q, J = 35.3 Hz), 140.7, 136.0, 135.6, 132.7, 130.7, 130.6,
129.2, 129.1, 125.4, 122.4, 122.3, 122.1 (q, J = 275.9 Hz), 120.8, 23.5 (q,
J = 8.8 Hz). 19F NMR (377 MHz, CDCl3) δ -59.80 (s, 3F). HRMS:
calculated for C15H11F3N (M+H)+ 262.0838; found 262.0839.
8-Chloro-6-(trifluoromethyl)phenanthridine (3b): According to the
general procedure, the 4'-chloro-2-isocyano-1,1'-biphenyl (2b) (21.3 mg,
0.1 mmol) afforded 3b (86%, 24.2 mg) as a light solid. 1H NMR (500 MHz,
CDCl3) δ 8.63 (d, J = 8.9 Hz, 1H), 8.58 – 8.53 (m, 1H), 8.35 (dd, J = 3.7,
1.8 Hz, 1H), 8.32 – 8.28 (m, 1H), 7.88 (dd, J = 8.9, 2.1 Hz, 1H), 7.85 – 7.81
(m, 2H). 13C NMR (125 MHz, CDCl3) δ 145.4 (q, J = 33.4 Hz), 141.7, 134.3,
132.3, 132.1, 131.3, 129.7 (d, J = 1.1 Hz), 125.2 (q, J = 3.5 Hz), 124.9,
124.5, 124.2, 122.5, 121.9, 121.6 (q, J = 277.0 Hz). 19F NMR (471 MHz,
CDCl3) δ -63.62 (s, 3F). M.P.: 122.1-122.3 ºC. HRMS: calculated for
C14H8ClF3N (M+H)+ 282.0292; found 282.0291.
10-Methyl-6-(trifluoromethyl)phenanthridine (3g): According to the
general procedure, the 2-isocyano-2'-methyl-1,1'-biphenyl (2g) (19.3 mg,
0.1 mmol) afforded 3g (42%, 11.0 mg) as a light solid. 1H NMR (500 MHz,
CDCl3) δ 8.67 – 8.59 (m, 1H), 8.51 (s, 1H), 8.35 – 8.25 (m, 2H), 7.81 (m,
2H), 7.62 (d, J = 8.5 Hz, 1H), 2.70 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
146.5 (q, J = 30.24 Hz), 142.1, 142.0, 134.2, 131.1, 129.9, 129.2, 128.9,
125.8 (q, J = 3.3 Hz), 125.0, 122.1, 122.1, 121.5 (q, J = 277.2 Hz), 119.9,
22.4. 19F NMR (471 MHz, CDCl3) δ -62.99 (s, 3F). M.P.: 122.1 – 122.3 ºC.
HRMS: calculated 262.0838 for C15H11NF3 (M+H)+ ; found 262.0839.
8-Fluoro-6-(trifluoromethyl)phenanthridine (3c): According to the
general procedure, the 4'-fluoro-2-isocyano-1,1'-biphenyl (2c) (17.7 mg,
0.1 mmol) afforded 3c (72%, 17.1 mg) as a light solid. 1H NMR (500 MHz,
CDCl3) δ 8.74 (dd, J = 9.2, 5.3 Hz, 1H), 8.61 – 8.56 (m, 1H), 8.34 – 8.29
(m, 1H), 8.06 – 8.01 (m, 1H), 7.86 – 7.81 (m, 2H), 7.71 (ddd, J = 9.2, 7.9,
2.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 161.5 (q, J = 250.1 Hz), 145.6,
141.5, 131.3, 130.7, 129.7, 129.3, δ 125.2 (d, J = 8.7 Hz), 124.8, 122.9 (d,
J = 8.7 Hz), 121.9, 121.7 (q, J = 276.9 Hz) 120.9 (d, J = 24.0 Hz), 110.8
(dq, J = 23.2 Hz, 3.5 Hz). 19F NMR (471 MHz, CDCl3) δ -63.03 (s, 3F), -
109.91 a -109.96 (m, 1F). M.P.: 91.3 - 93.8 ºC. HRMS: calculated for
C14H8F4N (M+H)+ 266.0587; found 266.0585.
1-(6-(Trifluoromethyl)phenanthridin-8-yl)ethan-1-one (3h): According
to the general procedure, the 1-(2'-isocyano-[1,1'-biphenyl]-4-yl)ethan-1-
one (2h) (22.1 mg, 0.1 mmol) afforded 3h (82%, 23.7 mg) as a light solid.
1H NMR (500 MHz, CDCl3) δ 8.11 – 8.09 (m, 1H), 7.66 – 7.63 (m, 2H),
7.56 – 7.50 (m, 2H), 7.48 – 7.43 (m, 2H), 2.69 (s, 3H). 13C NMR (125 MHz,
Acetone-d6) δ 196.1, 146.3 (q, J = 32.6 Hz), 142.3, 136.6, 136.4, 130.9,
130.7, 130.3, 130.1, 125.7 (q, J = 3.3 Hz), 124.5, 124.1 (q, J = 276.2
Hz),123.8, 123.4, 120.9, 26.0. 19F NMR (471 MHz, Acetone-d6) δ -63.82
(s, 3F). M.P.: 116.3-119.0 ºC. HRMS: calculated for C16H11F3NO (M+H)+
290.0787; found 290.0785.
8-Phenyl-6-(trifluoromethyl)phenanthridine (3d): According to the
general procedure, the 2-isocyano-1,1':4',1''-terphenyl (2d) (25.5 mg, 0.1
mmol) afforded 3d (58%, 18.8 mg) as a light solid. 1H NMR (500 MHz,
CDCl3) δ 8.75 (d, J = 8.7 Hz, 1H), 8.62 (dd, J = 6.0, 3.4 Hz, 1H), 8.56 (s,
1H), 8.31 (dd, J = 6.0, 3.3 Hz, 1H), 8.16 (dd, J = 8.6, 1.5 Hz, 1H), 7.84 –
7.78 (m, 2H), 7.75 (d, J = 7.4 Hz, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.46 (t, J =
7.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 146.6 (q, J = 33.0 Hz), 141.7,
141.0, 139.8, 133.0, 131.2, 130.8, 129.4, 129.3, 129.2, 128.3, 127.5,
125.0, 123.8 (q, J = 3.3 Hz), 123.2, 122.2, 122.1, 122.0 (q, J = 277.1 Hz).
19F NMR (471 MHz, CDCl3) δ -63.33 (s, 3F). M.P.: 138.5 - 139.5 ºC.
HRMS: calculated for C20H13F3N (M+H)+ 324.0995; found 324.0990.
Methyl
6-(trifluoromethyl)phenanthridine-8-carboxylate
(3i):
According to the general procedure, the methyl 2'-isocyano-[1,1'-biphenyl]-
4-carboxylate (2i) (23.7 mg, 0.1 mmol) afforded 3i (60%, 18.3 mg) as a
light solid. 1H NMR (500 MHz, CDCl3) δ 9.12 – 9.07 (m, 1H), 8.78 (d, J =
8.7 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.55 (dd, J = 8.7, 1.6 Hz, 1H), 8.34
(dd, J = 8.0, 1.2 Hz, 1H), 7.93 – 7.84 (m, 2H), 4.07 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 166.0, 147.0 (q, J = 35.3 Hz), 142.5, 136.8, 131.3, 131.2,
130.5, 129.7,128.1 (q, J = 3.5 Hz)., 124.5, 123.0, 122.7, 121.6 (q, J = 275.5
Hz), 121.3, 52.7. 19F NMR (471 MHz, CDCl3) δ -63.21 (s, 3F). M.P.: 161.6
- 162.7 ºC. HRMS: calculated for C16H10F3NO2Na (M+Na)+ 328.0556;
found 328.0565.
8-Methyl-6-(trifluoromethyl)phenanthridine (3e): According to the
general procedure, the 2-isocyano-4'-methyl-1,1'-biphenyl (2e) (19.3 mg,
0.1 mmol) afforded 3e (80%, 20.9 mg) as a light solid. 1H NMR (500 MHz,
CDCl3) δ 8.64 – 8.53 (m, 1H), 8.33 – 8.24 (m, 1H), 8.16 (s, 1H), 7.82 –
7.77 (m, 1H), 7.77 – 7.74 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 146.2 (q,
J = 32.8 Hz), 141.4, 138.2, 133.2, 131.9, 131.1, 129.1, 128.9, δ 125.2 (q,
8-Methoxy-6-(trifluoromethyl)phenanthridine (3j): According to the
general procedure, the 2-isocyano-4'-methoxy-1,1'-biphenyl (2j) (21.0 mg,
0.1 mmol) afforded 3j (86%, 23.8 mg) as a light solid. 1H NMR (500 MHz,
CDCl3) δ 8.61 (d, J = 9.1 Hz, 1H), 8.53 (dd, J = 6.1, 3.5 Hz, 1H), 8.29 –
8.26 (m, 1H), 7.80 – 7.74 (m, 2H), 7.70 (s, 1H), 7.56 (dd, J = 9.1, 2.5 Hz,
1H). 13C NMR (125 MHz, Acetone-d6) δ 159.4, 144.9 (q, J = 32.6 Hz),
140.9, 130.7, 129.7, 128.6, 128.4, 125.3, 124.9, 122.9, 122.4, δ 122.2 (q,
J = 276.2 Hz), 122.2, 105.3 (q, J = 3.5 Hz), 55.2. 19F NMR (471 MHz,
Acetone-d6) δ -64.76 (s, 3F). M.P.: 97.0-101.0 ºC. HRMS: calculated for
C15H11F3NO (M+H)+ 278.0787; found 278.0785.
J = 3.2 Hz), 125.2, 122.4, 122.0 (q, J = 277.2 Hz),122.0, 121.9, 21.9. 19
F
NMR (471 MHz, CDCl3) δ -64.76 (s, 3F). M.P.: 122.1 - 122.3 ºC. HRMS:
calculated for C15H11F3N (M+H)+ 262.0838; found 262.0836.
9-Methyl-6-(trifluoromethyl)phenanthridine (3f): According to the
general procedure, the 2-isociano-3'-metil-1,1'-bifenil (2f) (19.3 mg, 0.1
mmol) afforded 3f (31%, 8.13 mg) as a light solid. 1H NMR (400 MHz,
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6-(Trifluoromethyl)phenanthridine-8-carbonitrile (3k): According to the
general procedure, the 2'-isocyano-[1,1'-biphenyl]-4-carbonitrile (2k) (20.5
mg, 0.1 mmol) afforded 3k (80%, 21.8 mg) as a light solid. H NMR (400
MHz, CDCl3) δ 8.81 (d, J = 8.7 Hz, 1H), 8.71 (s, 1H), 8.63 (d, J = 7.8 Hz,
1H), 8.35 (d, J = 7.9 Hz, 1H), 8.11 (dd, J = 8.7, 1.5 Hz, 1H), 7.98 – 7.87
(m, 2H). 13C NMR (125 MHz, CDCl3) δ 145.7 (q, J = 33.8 Hz), 142.6, 136.3,
132.5, 131.5, 131.3 – 131.1 (m), 130.2, 123.6 (d, J = 277.1 Hz), 124.0,
123.8, 122.6, 121.1, 120.3, 118.0, 111.9. 19F NMR (377 MHz, CDCl3) δ -
63.24 (s, 3F). M.P.: 177.3 - 179.9 ºC. HRMS: calculated for C15H8F3N2
(M+H)+ 273.0634; found 273.0633.
CNPq (INCT-Catalysis) and FAPESP (14/50249-8 and 15/17141-
1). M. W. Paixão and C. A. D. Caiuby acknowledge GSK, as well,
for the financial support. CJL thanks Canada Research Chair,
NSERC, CFI, and FQRNT for support of this research.
1
Keywords: Trifluoromethylation • Phenanthridines • Isocyanides
• Sodium triflinate • Visible light
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mg, 0.1 mmol) afforded 3l (52%, 20.0 mg) as a light solid. H NMR (400
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276.7 Hz), 118.0. 19F NMR (377 MHz, CDCl3) δ -55.15 (q), -61.86 (q), -
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Acknowledgements
C. A. D. Caiuby acknowledges CNPq for the graduate fellowship.
M. W. Paixão gratefully acknowledges financial support from
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FULL PAPER
Key Topic*
Trifluoromethylation • Phenanthridines
Jianbin Li, Clarice A. D. Caiuby, Márcio
W. Paixão* and Chao-Jun Li*
Page No. – Page No.
Synthesis
trifluoromethylphenanthridines
radical trifluoromethylation
isocyanides with sodium triflinate
under visible light
of
6-
via
of
A simple method to rapidly construct the 6-trifluoromethylphenathridine scaffolds was
developed by employing diacetyl as a visible light sensitizer. In the absence of
transition metals and additives, this CF3 radical-triggered cyclization reaction
proceeded smoothly and tolerated a broad scope of functionalities.
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