6-phosphorylated phenanthridines from 2-isocyanobiphenyls via radical C-P and C-C bond formation

Article abstract of DOI:10.1021/ol403256e

A C-P bond and a C-C bond are formed in the synthesis of 6-phosphorylated phenanthridines starting with readily prepared 2-isocyanobiphenyls and commercially available P-radical precursors. The radical cascade reaction comprises addition of an oxidatively generated P-centered radical to the isonitrile functionality and subsequent homolytic aromatic substitution. Various 6-phosphorylated phenanthridines are formed in moderate to excellent yield. In contrast to the currently intensively investigated direct arene phosphorylation, the arene core is constructed with concomitant phosphorylation using this approach.

Full text of DOI:10.1021/ol403256e

Letter
pubs.acs.org/OrgLett
6‑Phosphorylated Phenanthridines from 2‑Isocyanobiphenyls via
Radical C−P and C−C Bond Formation
Bo Zhang, Constantin Gabriel Daniliuc, and Armido Studer*
Institute of Organic Chemistry, Westfalische Wilhems-University, Corrensstraße 40, 48149 Munster, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A C−P bond and a C−C bond are formed in the
synthesis of 6-phosphorylated phenanthridines starting with
readily prepared 2-isocyanobiphenyls and commercially available
P-radical precursors. The radical cascade reaction comprises
addition of an oxidatively generated P-centered radical to the
isonitrile functionality and subsequent homolytic aromatic
substitution. Various 6-phosphorylated phenanthridines are
formed in moderate to excellent yield. In contrast to the currently
intensively investigated direct arene phosphorylation, the arene
core is constructed with concomitant phosphorylation using this approach.
romatic organophosphorus compounds belong to a highly
important class of compounds which have attracted
Scheme 1. Arene Phosphorylation and Formation of P-
Substituted Phenanthridines
A
considerable attention because of their wide application in
organic synthesis,1 medicinal chemistry,2 and materials science.3
Recent studies have revealed that many heterocycles containing
P-substituents show excellent bioactivity.4 In light of the
importance of this compound class, there is continuing interest
in the development of synthetic methods for C−P bond
construction.5 Traditional methods for C−P bond formation
rely on the reaction of organometallic reagents with an
electrophilic P-reagent such as Ph2P(O)Cl (Scheme 1, a).
Since the pioneering work of Hirao and co-workers in 1981,6
a transition-metal-catalyzed coupling reaction of aryl halides,7
triflates,8 tosylates,9 diazonium salts,10 and boronic acids11 with
H-phosphonates has become a practical and valuable method
for C(sp2)−P bond formation (Scheme 1, b). In recent years,
transition-metal-catalyzed12 and radical13 arene CH phosphor-
ylation, which provide a direct and atom economic approach to
P-substituted arenes, have been studied intensively (Scheme 1,
c). Although various methods for C(sp2)−P bond formation
have been established, the development of alternative and
complementary methods for C(sp2)−P bond construction is
still highly desirable due to the importance of P-substituted
arenes in various fields as mentioned above.
Recently, aryl isonitriles have gained renewed attention as
radical acceptors in cascade reactions for the construction of
heteroarenes.14 Along these lines, we have disclosed that 2-
isocyanobiphenyls can be used as highly efficient CF3 radical
acceptors for preparation of 6-trifluoromethylated phenanthri-
dines.15a Moreover, 6-aroylated phenanthridines are readily
prepared by reaction of acyl radicals with biarylisonitriles.15c
Encouraged by these results, we decided to test whether
biarylisonitriles can be used as P-radical acceptors in cascade
reactions.
isonitriles (Scheme 1, d). The significance of the herein
presented chemistry is 3-fold: (1) Although arylisonitriles are
well established C-radical acceptors in cascade reactions,14 to
our knowledge they have not been used as P-radical acceptors
to date. (2) In contrast to the currently intensively studied
arene phosphorylation, where C−P bond formation generally
occurs at an intact arene ring, the presented chemistry
comprises a phosphorylation with concomitant arene formation
Herein, we disclose the first results on the preparation of 6-P-
substituted phenanthridines by radical phosphorylation of
Received: November 11, 2013
Published: December 9, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
and regiochemistry problems which may be observed in direct
arene CH phosphorylation are not occurring using our
approach. (3) In contrast to the reported methods, which
proceed through single C−P bond-forming transformations,
our process comprises a C−P bond along with a C−C bond
formation.
It has been reported that P-centered radicals can be
generated from P−H derivatives with Mn(OAc)3 as oxi-
dant.16,13c Based on these precedences, we initiated our studies
by investigating radical phosphorylation of readily prepared
isonitrile 1a with diphenylphosphine oxide 2a in the presence
of Mn(OAc)3·2H2O as oxidant in AcOH at 100 °C for 4 h.
Pleasingly, the targeted product 3aa was obtained in 37% yield
(Table 1, entry 1). The structure of 3aa was unambiguously
azobisisobutyronitrile (AIBN) as initiator and oxidant (1.5
equiv), phenanthridine 3aa was not formed. We identified the
phenanthridine derived from addition of the 2-cyanopropyl
radical as the major product (entry 9).14c
Various solvents were surveyed next, revealing that DMF is
best suited to run this reaction to provide 3aa in 91% yield
(Table 1, entries 2−4). The yield was decreased by using 1.5
equiv of 2a (Table 1, entry 5) and decreasing the amount of
AgOAc led to an even worse result (Table 1, entry 6).
With optimized conditions in hand, the scope and limitations
of the synthesis of 6-phosphorylated phenanthridines were
investigated (Figure 2). Variation of the arene that does not
Table 1. Radical Phosphorylation of Isonitrile 1a under
a
Various Conditions
b
entry
oxidant (equiv)
solvent
yield (%)
1
2
3
4
Mn(OAc)3·2H2O (3)
AgOAc (3)
AcOH
AcOH
CH3CN
DMF
37
79
77
91
78
30
22
12
AgOAc (3)
AgOAc (3)
c
5
AgOAc (3)
DMF
6
7
8
9
AgOAc (2)
DMF
AgNO3 (0.2) + K2S2O8 (3)
Bu4NI (0.2) + TBHP (3)
AIBN (1.5)
DMF
CH3CN
DMF
a
All reactions were carried with 1a (0.2 mmol), 2a (0.4 mmol), and
b
oxidant in solvent (1 mL) at 100 °C under Ar for 4 h. Isolated yields.
c
Using 1.5 equiv of 2a.
confirmed by X-ray analysis (Figure 1). Motivated by this
result, we further optimized the radical cascade reaction by
varying the oxidant and solvent.
Figure 2. Various 6-phosphorylated phenanthridines prepared ((a)
regioisomer ratio = 7:1).
Figure 1. X-ray structure of 3aa (thermals ellipsoids are shown with
30% probability).
We found that yield was improved by using AgOAc17 as an
oxidant (Table 1, entry 2). Other oxidants which should allow
for generation of P-radicals from the corresponding P−H
compounds such AgNO3/K2S2O813b and Bu4NI/TBHP18 were
also investigated, but the reaction did not work well under
these conditions (Table 1, entries 7 and 8). With α,α′-
carry the isonitrile functionality was studied first (see 3ba−ha).
We found that the reactions with substrates bearing electron-
withdrawing and also electron-donating substituents at the para
position proceeded well, and the corresponding products 3ba−
ha were isolated in moderate to good yields (45−80%, Figure
2). Slightly lower but still good yields were obtained for the
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Organic Letters
Letter
ortho-substituted systems, probably for steric reasons (3ja and
3ka, Figure 2). A heteroarene such as pyridine was also
tolerated in the biaryl moiety and product 3la was isolated in
54% yield.
development of the presented method and its application
toward the synthesis of bioactive compounds.
ASSOCIATED CONTENT
* Supporting Information
■
To investigate the regioselectivity of this cascade reaction,
meta-substituted arylisonitriles 1m−o were prepared and
successfully converted to the corresponding products 3ma−
oa in moderate to good yields. Whereas 3ma was formed with
good regioselectivity (7:1, selectivity was readily determined by
31P NMR spectroscopy), products 3na and 3oa were obtained
with complete regiocontrol. Cyclization preferably occurred at
the position distal to the meta substituent (in Figure 2 only the
major isomer is shown for 3ma). Arylisonitriles bearing
substituents at the arene moiety containing the isonitrile
functionality also underwent smooth addition/cyclization to
form the corresponding products in moderate to good yields
(3qa and 3ra, Figure 2). Finally, we showed that ethyl
phenylphosphinate (2b) is also a suitable P-radical precursor
for this transformation and phenanthridine 3ab was isolated in
85% yield (Figure 2).
S
Experimental details and characterization data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: studer@uni-muenster.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Deutsche Forschungs-gemeinschaft (DFG) for
support of our work.
■
A plausible reaction mechanism is depicted in Scheme 2. It is
known that P-centered radicals can be generated from
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