6-perfluoroalkylated phenanthridines via radical perfluoroalkylation of isonitriles

Article abstract of DOI:10.1021/ol5018195

A simple and efficient approach to 6-perfluoroalkylated phenanthridines starting with readily prepared isonitriles and commercially available cheap perfluoroalkyl iodides as perfluoroalkyl radical precursors is described. Various 6-perfluoroalkylated phenanthridines are obtained in moderate to excellent yields. The sequence comprises a perfluoroalkylation with concomitant arene formation.

Full text of DOI:10.1021/ol5018195

Letter
pubs.acs.org/OrgLett
6‑Perfluoroalkylated Phenanthridines via Radical Perfluoroalkylation
of Isonitriles
Bo Zhang and Armido Studer*
Institute of Organic Chemistry, Westfalische Wilhems-University, Corrensstraße 40, 48149 Munster, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A simple and efficient approach to 6-perfluoroalkylated phenanthridines starting with readily prepared isonitriles
and commercially available cheap perfluoroalkyl iodides as perfluoroalkyl radical precursors is described. Various 6-
perfluoroalkylated phenanthridines are obtained in moderate to excellent yields. The sequence comprises a perfluoroalkylation
with concomitant arene formation.
Scheme 1. Strategies for Preparation of 6-Fluoroalkylated
Phenanthridines via Isonitrile Insertion Reactions
he introduction of fluorine-containing functional groups
Tinto organic molecules enhances their solubility, bioavail-
ability, and metabolic stability.1 Therefore, development of
novel synthetic methods for the construction of C−Rf bonds is
important.2 Among fluorine-containing functional groups, the
trifluoromethyl and perfluoroalkyl substituents are highly
important structural units, which can be found in many
compounds used in medicinal chemistry, agrochemistry, and
also in materials science.3 Over the past decades, significant
progress has been made on aromatic trifluoromethylation.2,4 In
contrast, aromatic perfluoroalkylation has been less intensively
investigated.5 Hence, the development of novel and efficient
methods for perfluoroalkylation of aromatic compounds is
highly desirable, but challenging.
The structural entity of the phenanthridines can be found in
various bioactive natural alkaloids and in medicinally relevant
compounds,6 which show diverse biological activities such as
antibacterial, antitumoral, cytotoxic, and antileukemic.7 There-
fore, it is important to develop novel methods for their
preparation. Recently, the radical isonitrile insertion reaction
has emerged as a powerful strategy for the construction of the
phenanthridine scaffold.8,9 Using this approach, a series of 6-
substituted phenanthridines were readily prepared by radical
addition to 2-isocyanobiphenyls with subsequent homolytic
aromatic substitution (HAS). Due to potential applications of
6-fluoroalkylated phenanthridines in medicinal chemistry, we9b
and Zhou9d independently reported the preparation of 6-
trifluoromethylated phenanthridines via radical trifluoromethy-
lation of 2-isocyanobiphenyls (Scheme 1, a and b). Moreover,
Yu reported the preparation of the same compound class via a
nonradical pathway (Scheme 1, c).10 However, all of these
methods are mostly restricted to the preparation of
trifluoromethylated phenanthridines, and it is difficult to
construct 6-perfluoroalkylated phenanthridines, since perfluor-
oalkyl analogues of the applied trifluoromethylation reagents
(Togni’s reagent, Umemoto’s reagent, or Ruppert−Prakash
reagent) are expensive and/or not commercially available.
Therefore, we decided to develop a simple, efficient, and
general method for the construction of 6-perfluoroalkylated
phenanthridines using readily available perfluoroalkyl sources.
Perfluoroalkyl iodides are commercially available and cheap
reagents, which have been utilized as perfluoroalkyl radical
sources.2g However, in the reported radical aromatic perfluor-
oalkylation, the generation of perfluoroalkyl radicals from these
iodides usually requires harsh reaction conditions or precious
iridium and ruthenium photocatalysts.5,11 More recently, Hu
Received: June 24, 2014
Published: July 23, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol5018195 | Org. Lett. 2014, 16, 3990−3993

Organic Letters
Letter
and co-workers have reported iron-catalyzed 1,2-addition of
perfluoroalkyl iodides to alkynes and alkenes using perfluor-
oalkyl iodides as perfluoroalkyl radical sources.12 Since
perfluoroalkylated iodides are rather strong single electron
transfer oxidants, we envisioned that the 6-perfluoroalkylated
phenanthridines might be readily constructed via radical
perfluoroalkylation of isonitriles by the base-promoted
homolytic aromatic substitution using simple and cheap
perfluoroalkyl iodides as reagents and metal salts as radical
chain initiators.13 Herein, we disclose a simple and efficient
method for the construction of 6-perfluoroalkylated phenan-
thridines using readily available 2-isocyanobiphenyls and
perfluoroalkyl iodides as perfluoroalkyl radical sources (Scheme
1, d).
We initiated our studies by investigating radical perfluor-
oalkylation of readily prepared isonitrile 1a with a 3-fold excess
of perfluorobutyl iodide 2a in the presence of FeBr2 (5 mol %)
as initiator and Cs2CO3 (1.5 equiv) as base in 1,4-dioxane at
100 °C in a sealed tube for 20 h. Pleasingly, the targeted
product 3aa was obtained in 70% yield (Table 1, entry 1).
but as initiators. Moreover, as a typical signature for a base-
promoted homolytic aromatic substitution, we found that this
radical cascade also occurred well with Cs2CO3 as the base in
the absence of any metal salt initiator (Table 1, entry 9). Other
bases such as Na2CO3 and K2CO3 provided only traces of 3aa
(Table 1, entries 10 and 11). Yield decreased by using 1.0 and
0.5 equiv of Cs2CO3, respectively (Table 1, entries 12 and 13).
In addition, decreasing the amount of perfluorobutyl iodide 2a
also led to lower yields (Table 1, entries 14 and 15), and
reaction did not proceed in the absence of Cs2CO3 (Table 1,
entries 16 and 17). These results clearly imply that Cs2CO3 as a
base is essential for this transformation.
With optimized reaction conditions in hand, the scope and
limitations of this process were investigated. We first explored
the scope with respect to the 2-isocyanobiphenyl component
using NiCl2 as the initiator (Scheme 2). Arylisonitriles bearing
a,b
Scheme 2. Scope of Arylisonitriles
a,b
Table 1. Optimization of Reaction Conditions
c
entry
initiator
base
yield (%)
1
FeBr2
FeCl2
FeI2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
none
70
65
62
68
36
2
3
4
Fe(acac)2
Fe(OAc)2
NiCl2
CoCl2
CuI
5
d
e
6
73 (70 )
7
65
64
8
f
9
none
none
72 (68 )
10
11
trace
trace
39
none
g
12
none
h
13
none
32
i
14
none
48
j
15
none
43
a
All reactions were carried out with 1 (0.2 mmol), 2a (0.6 mmol),
16
17
NiCl2
none
trace
trace
NiCl2 (0.01 mmol), and Cs2CO3 (0.3 mmol) in 1,4-dioxane (1 mL) at
none
b
100 °C under Ar for 20 h. Isolated yields. Yields given in parentheses
are those obtained for the reactions conducted without added NiCl2
initiator.
a
All reactions were carried out with 1a (0.2 mmol), 2a (0.6 mmol),
catalyst (0.01 mmol), and base (0.3 mmol) in 1,4-dioxane (1 mL) at
100 °C under Ar for 20 h. The reaction was conducted in a sealed
tube. Isolated yields. NiCl2 (99.99%) from Aldrich was used. NiCl2
b
c
d
e
f
(98%) from Alfa was used. Cs2CO3 (99.995%) from Aldrich was used.
g
h
i
electron-donating substituents at the para-position of the arene
ring that does not carry the isonitrile functionality provided the
products 3ba (4-Me), 3ca (4-t-Bu), and 3da (4-MeO) in good
yields (74−80%). Isonitriles bearing electron-withdrawing
substituents such as Cl, F, and COMe underwent the radical
cascade smoothly to provide the corresponding phenanthri-
dines in moderate yields (3ea: 54%, 3fa: 43%, 3ha: 43%). A
slightly lower but still good yield was obtained for an ortho-
substituted system, probably for steric reason (see 3ja: 50%).
Arylisonitriles bearing electron-donating or electron-withdraw-
ing substituents at the arene moiety containing the isonitrile
functionality were successfully converted to the corresponding
phenanthridines 3ja−3ma (40−80%).
Using 1.0 equiv of Cs2CO3. Using 0.5 equiv of Cs2CO3. Using 2.0
j
equiv of 2a. Using 1.5 equiv of 2a.
Reaction at higher or lower temperature did not provide a
better result (see Supporting Information). Subsequently, a
series of other metal salts as initiators was investigated,
revealing that NiCl2 is best suited to run this reaction to afford
3aa in 73% yield (Table 1, entry 6). Other metal salts such as
FeX2 salts (X = Cl, I, acac, and OAc), CoCl2, and CuI, resulted
in lower yields (36−68% yield; Table 1, entries 2−5, 7, 8). The
fact that various transition metal salts promote the cascade
reaction shows that the metal salts do likely not act as catalysts
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Organic Letters
Letter
All experiments were then repeated by using the metal-free
protocol (see yields in parentheses). In most cases, compared
to NiCl2-initiated reactions, slightly lower yields were obtained.
Along with higher yields, we observed that addition of NiCl2 (5
mol %) generally provided a cleaner reaction. However, for
arylisonitriles 1j and 1l leading to 3ja and 3la yields improved
in the absence of Ni-salt.
On the basis of this experiment and previous reports,9b,12 we
propose the following mechanism (Scheme 4). For the Ni-free
Scheme 4. Proposed Reaction Mechanism
We next investigated the scope of the cascade with respect to
the perfluoroalkyl reagent (Scheme 3). To this end, various
a,b c
,
Scheme 3. Scope of Fluoroalkyl Reagents
protocol, perfluoroalkyl radicals are likely generated from
perfluoroalkyl iodides thermally upon C−I homolysis. We do
currently not think that traces of transition metals derived from
the base initiate the reaction, since an experiment conducted
with Cs2CO3 of very high purity (99.995%) provided a similar
result (see Table 1, entry 9). Moreover, we also discard CsI,
which might be formed from the starting iodide and the
Cs2CO3, as an initiator since reaction with CsI and Na2CO3 as
a base provided only traces of the product. The special role of
Cs2CO3 on the initiation is not understood.12 In the presence
of NiCl2, the Ni-salt somehow accelerates generation of the
perfluoroalkyl radical from the corresponding iodide. Notable,
similar results were obtained by using different sources of NiCl2
(see Table 1), and NiCl2 in combination with Na2CO3 afforded
only traces of the targeted product, again highlighting the
special role of the Cs2CO3 base for these reactions. Addition of
the perfluoroalkyl radical to the isonitrile functionality in 1
provides the imidoyl radical A, which undergoes cyclization to
generate cyclohexadienyl radical B. We assume that B, due to
the very high acidity of the α-proton,9b gets deprotonated by
Cs2CO3 to give radical anion C, which then further reacts with
perfluoroalkyl iodides in a single electron transfer process to
product 3 and the perfluoroalkyl radical, thereby sustaining the
radical chain reaction.13,14
In summary, we have demonstrated a simple and efficient
approach for the construction of 6-perfluoroalkylated phenan-
thridines starting with readily prepared 2-isocyanobiphenyls
and the commercially available and cheap perfluoroalkyl iodides
as precursors of the perfluoroalkyl radicals. Various 6-
perfluoroalkylated phenanthridines were prepared in moderate
to excellent yield. Furthermore, 6-trifluoromethylated phenan-
thridine was also prepared using this novel method. The
reaction shows good functional group tolerance, and
importantly, this transformation occurs without precious
metal photocatalysts. These issues make this protocol very
practical for the synthesis of 6-perfluoroalkylated phenanthri-
dines.
a
All reactions were carried out with 1 (0.2 mmol), 2a (0.6 mmol),
NiCl2 (0.01 mmol), and Cs2CO3 (0.3 mmol) in 1,4-dioxane (1 mL) at
100 °C under Ar for 20 h. Isolated yields. The reactions in the
parentheses were conducted without NiCl2. The reaction was
conducted in a standard Schlenk tube. The reaction was conducted
in a sealed tube.
b
c
d
perfluoroalkyl iodides were surveyed. We found that along with
C4F9I other commercially available perfluoroalkyl iodides such
as C3F7I, C6F13I, C8F17I, C10F21I, and C12F25I reacted well, and
the corresponding products 3cc−3ag were obtained in
moderate to good yields (40−68%). In addition, we
successfully ran a reaction using CF3I as CF3 radical precursor
for the preparation of 6-trifluoromethyl phenanthridine and
obtained the product 3ab in 60% isolated yield (Scheme 3).
To address the regioselectivity of this reaction, meta-
substituted arylisonitrile 1n was prepared and successfully
converted to the corresponding product 3nd in moderate yield
with complete regiocontrol. Cyclization preferably occurred at
the position distal to the meta substituent (Scheme 3). Also for
the series depicted in Scheme 3, reactions were repeated by
using the metal-free initiation protocol (see yields in
parentheses). In most cases similar or slightly lower yields as
compared to the Ni-salt-initiated cascades were obtained.
To support the radical nature of the cascade, reaction of 1a
with 2b in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) as a radical scavenger was tested under the standard
reaction conditions. Formation of 3ab was completely
suppressed and the TEMPO−CF3 adduct was identified by
19F NMR spectroscopy.
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Organic Letters
Letter
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Pharm. Bull. 2010, 58, 1047. (e) Li, K.; Frankowski, K. J.; Frick, D. N.
J. Med. Chem. 2012, 55, 3319.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(8) (a) Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863.
(b) Curran, D. P.; Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. Engl.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: studer@uni-muenster.de.
Notes
The authors declare no competing financial interest.
(9) For selected examples, see: (a) Tobisu, M.; Koh, K.; Furukawa,
T.; Chatani, N. Angew. Chem., Int. Ed. 2012, 51, 11363. (b) Zhang, B.;
ACKNOWLEDGMENTS
We thank the Deutsche Forschungs-gemeinschaft (DFG) for
supporting our work.
Muck-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int. Ed.
̈
■
2013, 52, 10792. (c) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.;
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Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846. (e) Leifert,
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