Synthesis of polyfluoroalkyl aza-polycyclic aromatic hydrocarbons enabled by addition of perfluoroalkyl radicals onto vinyl azides

Article abstract of DOI:10.1021/ol501997n

Radical perfluoroalkylation of α-(biaryl-2-yl)vinyl azides is capable of supplying polyfluoroalkyl aza-polycyclic aromatic hydrocarbons (aza-PAHs). Commercially available Me₃SiR_f (R_f = CF ₃, C₂F₅

Full text of DOI:10.1021/ol501997n

Letter
pubs.acs.org/OrgLett
Synthesis of Polyfluoroalkyl Aza-Polycyclic Aromatic Hydrocarbons
Enabled by Addition of Perfluoroalkyl Radicals onto Vinyl Azides
Yi-Feng Wang, Geoffroy Herve Lonca, Maïwenn Le Runigo, and Shunsuke Chiba*
́
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: Radical perfluoroalkylation of α-(biaryl-2-yl)vinyl azides
is capable of supplying polyfluoroalkyl aza-polycyclic aromatic
hydrocarbons (aza-PAHs). Commercially available Me3SiRf (Rf =
CF3, C2F5, and C3F7) are employed as the sources of perfluoroalkyl
radicals upon oxidation with PhI(OAc)2. The addition of perfluoroalkyl
radicals to biarylvinyl azides generates the corresponding iminyl
radicals, which subsequently cyclize with the intramolecular arene
moiety, furnishing aza-PAH skeletons having polyfluoroalkyl (RfCH2)
function.
he incorporation of perfluoroalkyl groups (Rf) onto
Scheme 1. Synthesis of Polyfluoroalkyl Phenanthridine
T
organic molecules is capable of altering their chemical,
Derivatives
physical, and biological properties1 which leads to broad
applications of fluorine-containing molecules in the fields of
medicinal chemistry and material sciences. In this context, a
variety of perfluoroalkylation reactions have been developed to
prepare diverse fluorine-containing molecules.2 Especially, the
synthesis of azaheterocycles having a per- or polyfluoroalkyl
group at a specific position has drawn considerable attention,3
owing to the potent and broad applications of azaheterocycles
in various fields.4
Phenanthridine derivatives have shown a broad spectrum of
biological activity5 and optoelectronic properties.6 Installation
of the polyfluoroalkyl function might render these compounds
more valuable in the subject of drug discovery and material-
based applications. However, a few methods have been
exploited to date for the construction of phenanthridines and
their derivatives with installation of the polyfluoroalkyl group.7,8
Very recently, Studer,7a Zhou,7b and Yu7c,d have independently
developed synthetic methods of 6-perfluoroalkyl phenanthri-
dines through radical or ionic perfluoroalkylation of biaryl
isonitriles (Scheme 1a). We describe herein a new protocol to
access phenanthridines and their derivatives (aza-polycyclic
aromatic hydrocarbons: aza-PAHs) having trifluoroethyl or other
perfluoroalkylmethylene moieties,9 which is enabled by
oxidative radical perfluoroalkylation of readily accessible α-
(biaryl-2-yl)vinyl azides (Scheme 1b). Readily available and
handled perfluoroalkyltrimethylsilanes (Me3SiRf) could be
utilized as the sources of perfluoroalkyl radicals under
PhI(OAc)2-mediated oxidative reaction conditions.10
the CF3 radical generated from Me3SiCF3 upon oxidation with
PhI(OAc)2 adds to the CC bond of vinyl azides to form α-
CF3 iminyl radicals that readily dimerize to afford α-CF3 azines.
On this basis, we envisioned that the putative iminyl radicals
could be trapped with an intramolecular aryl function installed
at the ortho-position of α-arylvinyl azides such as 1a, enabling
C−N bond forming cyclization to construct trifluoroethyl
phenanthridines such as 2a (Scheme 2b).
A brief outline for the preparation of α-(biaryl-2-yl)vinyl
azides 1 is shown in Scheme 3. The biaryl structure was
constructed by the Pd-catalyzed Suzuki−Miyaura coupling of
arylboronic acids and ortho-bromoaryl aldehydes, which was
followed by the Wittig olefination. The vinyl azide function was
then readily installed by following the modified Hassner
Vinyl azides have been utilized as a versatile synthon for the
synthesis of various nitrogen-containing molecules.11 By taking
advantage of vinyl azides as a potential radical acceptor,12 we
have recently disclosed an oxidative radical trifluoromethylation
reaction of vinyl azides that led to the formation of α-
trifluoromethyl (CF3) azines (Scheme 2a).13 In this process,
Received: July 9, 2014
Published: July 28, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Scheme 2. Trifluoromethylation of Vinyl Azides for the
Table 1. Optimization of the Reaction Conditions
Formation of Azines and Phenanthridines
F−
source
additive
[equiv]
b
entry solvent
conditions
2a [%]
c
1
2
3
4
5
MeCN
MeCN
MeCN
MeCN
DMF
CsF
KF
KF
KF
KF
−
−
0 °C, 1 h
0 °C, 2 h
0 °C, 2 h
0 °C−rt, 21 h
0 °C, 5 min
60
50
d
BQ (0.2)
BQ (2.0)
BQ (0.2)
91 (86)
e
f
0
69
a
Unless otherwise noted, the reactions were carried out on the scale of
0.3−0.5 mmol of vinyl azide 1a with 5 equiv of Me3SiCF3 under a
b
nitrogen atmosphere. 1H NMR yields using 1,1,2,2-tetrachloroethane
c
as an internal standard. 6-Methylphenanthridine (3) was formed in
d
e
6% yield. Isolated yield of 2a. The reaction was conducted in the
f
absence of PhI(OAc)2. 1a was recovered in 95% yield. BQ =
benzoquinone.
Scheme 3. Preparation of α-(Biaryl-2-yl)vinyl Azides 1
Scheme 4. Perfluoroalkylation of Vinyl Azide 1a
optimized reaction conditions (Scheme 4), leading to the
corresponding 6-polyfluoroalkylphenanthridines 4 and 5,
respectively, in good yields, while the use of Me3SiCHF2 did
not result in the desired phenanthridine construction at all.
The generality of this transformation was next explored using
a variety of biarylvinyl azides 1 for the synthesis of
trifluoroethyl-substituted phenanthridines and other aza-poly-
cyclic aromatic hydrocarbons (aza-PAHs)18,19 (Scheme 5).
Biarylvinyl azides bearing electron-donating and -withdrawing
functional groups could be converted to the corresponding
phenanthridines in good yields (for 2b−2i). In order to test the
regioselectivity of the C−N bond forming cyclization step, a
couple of substrates possessing a meta-substituted benzene ring
were subjected to the present reaction conditions (for 2j−2l).
In all cases, the cyclization occurred preferentially at the
sterically more hindered position (marked in purple) with an
acceptable level of regioselectivity. The reaction of 2-(1-
azidovinyl)-1-phenylnaphthalene (1m) provided trifluoroethyl
tetracyclic benzo[k]phenanthridine 2m in 67% yield. For the
reaction of vinyl azide 1n having a 2-naphthyl moiety, the C−N
bond formation occurred exclusively at the α-carbon (marked
in purple), enabling selective synthesis of trifluoroethyl aza-
chrysene (benzo[c]phenanthridine) 2n. This interesting
regioselectivity in the cyclization onto the 2-naphthyl moiety
was capable of constructing pentanuclear aza-PAHs, dibenzo-
[c,k]phenanthridine 2o and dibenzo[c,d]phenanthridine 2p,
from the corresponding vinyl azides. The tetra- and
pentanuclear aza-PAHs 2m−2p exhibited quite good solubility
in commonly used organic solvents such as ethyl acetate, THF,
chloroform, and toluene, thereby demonstrating the unique
method14 via addition of IN3 followed by elimination of HI
with t-BuOK (method A) or via a sequence of dibromonation,
diazidation, and elimination of HN3 with DBU (method B)
(see the Supporting Information for more details).
To test this hypothesis as shown in Scheme 2b, we examined
the reaction of α-(biaryl-2-yl)vinyl azide 1a with Me3SiCF3.15
The reaction of 1a with Me3SiCF3 (5 equiv) in the presence of
PhI(OAc)2 (2.0 equiv) and CsF (1.5 equiv) in CH3CN
proceeded as expected at 0 °C to afford 6-trifluoroethyl-
phenanthridine 2a in 60% yield, along with formation of 6-
methylphenanthridine (3) as a side product in 6% yield (Table
1, entry 1).16 It is noted that the corresponding azine derived
from dimerization of the putative iminyl radical intermediate
was not observed at all. In order to improve the reaction
efficiency for the synthesis of phenanthridine 2a, optimization
of the reaction conditions was then undertaken (see the
Supporting Information for mode details). Use of KF instead of
CsF under otherwise identical reaction conditions also provided
phenanthridine 2a, while the yield was moderate (entry 2).
Interestingly, the addition of benzoquinone (BQ, 0.2 equiv)
dramatically enhanced the reaction17 to give 2a in 86% yield
with perfect inhibition of formation of 3 (entry 3). No reaction
with 95% recovery of vinyl azide 1a was observed only with 2
equiv of BQ in the absence of PhI(OAc)2 (entry 4). Switching
the solvent to DMF could accelerate the reaction, but the yield
of 2a was only 69% (entry 5).
It is worthy to note that the reactions of vinyl azide 1a with
Me3SiC2F5 and Me3SiC3F7 proceedeed well under the
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Letter
anticipate that the present method might be readily adopted to
supply various aza-PAHs for potential use in medicinal and
material-based applications.
Scheme 5. Substrates Scope on Synthesis of Triflluoroethyl
Aza-PAHs 2
a
,b
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: shunsuke@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from Nanyang
Technological University and Singapore Ministry of Education.
Y.-F.W. is thankful for a Lee Kuan Yew postdoctoral fellowship
(the LKY PDF). G.H.L. and M.L.R. are grateful for the financial
support from Ecole Polytechnique and University of Stras-
broug, respectively.
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