6-Aroylated phenanthridines via base promoted homolytic aromatic substitution (BHAS)

Article abstract of DOI:10.1021/ol403147v

Readily accessible 2-isocyanobiphenyls react with aromatic aldehydes via base promoted homolytic aromatic substitution (BHAS) to give 6-aroylated phenanthridines. Reactions occur via addition of acyl radicals to the isonitrile functionality and subsequent intramolecular BHAS of the intermediate imidoyl radicals. Initiation of the radical chain reaction is best achieved with small amounts of FeCl₃ (0.4 mol %), and the commercially available and cheap tBuOOH is used as the oxidant.

Full text of DOI:10.1021/ol403147v

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
6‑Aroylated Phenanthridines via
Base Promoted Homolytic Aromatic
Substitution (BHAS)
Dirk Leifert, Constantin Gabriel Daniliuc, and Armido Studer*
€
Fachbereich Chemie, Organisch-Chemisches Institut, Westfalische
Wilhelms-Universitat, Corrensstrasse 40, 48149 Munster, Germany
€
€
studer@uni-muenster.de
Received November 1, 2013
ABSTRACT
Readily accessible 2-isocyanobiphenyls react with aromatic aldehydes via base promoted homolytic aromatic substitution (BHAS) to give
6-aroylated phenanthridines. Reactions occur via addition of acyl radicals to the isonitrile functionality and subsequent intramolecular BHAS of
the intermediate imidoyl radicals. Initiation of the radical chain reaction is best achieved with small amounts of FeCl3 (0.4 mol %), and the
commercially available and cheap tBuOOH is used as the oxidant.
Phenanthridines are biologically important compounds
that occur in nature and are successfully used as drugs or
drug candidatesinmedicinalchemistry. Theseheterocycles
show antibacterial, antitumoral, cytotoxic, and antileu-
kemic activity,1 and therefore the development of novel
methods for their preparation is important. Along with the
traditional methods, phenanthridines have recently been
successfully prepared by radical chemistry using cascades
involving C-radical addition to 2-isocyanobiphenyls with
subsequent homolytic aromatic substitution:2,3 Tobisu
and Chatani showed that aryl radicals derived from
aryl boronic acids under oxidative conditions react with
2-isocyanobiphenyls to give the corresponding 6-arylated
phenanthridines (Scheme 1, a).2a,4 We2b and Zhou2c in-
dependently published work on the radical trifluoromethyl-
ation of biarylisonitriles for the preparation of 6-trifluoro-
methylated phenanthridines (Scheme 2, b). Guided by
recent studies on base promoted homolytic aromatic sub-
stitution (BHAS) using aromatic aldehydes as C-radical
(4) For an early example of the synthesis of 6-phenyl-phenanthridine
via phenyl radical addition to 2-isocyanobiphenyl, see ref 3c.
(5) (a) Wertz, S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928–931.
See also: (b) Denney, D. B.; Klemchuk, P. P. J. Am. Chem. Soc. 1958, 80,
3289–3290. (c) Shi, Z.; Glorius, F. Chem. Sci. 2013, 4, 829–833. (d) Rao,
H.; Ma, X.; Liu, Q.; Li, Z.; Cao, S.; Li, C.-J. Adv. Synth. Catal. 2013, 355,
2191–2196.
(1) (a) Simeon, S.; Rios, J. L.; Villar, A. Pharmazie 1989, 44, 593–597.
(b) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 223–232. (c)
Abdel-Halim, O. B.;Morikawa, T.;Ando, S.;Matsuda,H.;Yoshikawa, M.
J. Nat. Prod. 2004, 67, 1119–1124. (d) Sripada, L.; Teske, J. A.; Deiters, A.
Org. Biomol. Chem. 2008, 6, 263–265.
(2) Recent examples: (a) Tobisu, M.; Koh, K.; Furukawa, T.;
Chatani, N. Angew. Chem., Int. Ed. 2012, 51, 11363–11366. (b) Zhang,
B.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A. Angew. Chem., Int.
(6) Review on acyl radical chemistry: (a) Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991–2069. Selected
examples of chemistry involving acyl radical addition to arenes: (b)
€
ꢀ
Ed. 2013, 52, 10792–10795. (c) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L.
Org. Lett. 2013, 15, 4846–4849.
Miranda, L. D.; Cruz-Almanza, R.; Pavon, M.; Alva, E.; Muchowski,
J. M. Tetrahedron Lett. 1999, 40, 7153–7157. (c) Motherwell, W. B.;
Vazquez Tetrahedron Lett. 2000, 41, 9667–9671. (d) Allin, S. M.; Barton,
ꢀ
(3) Early examples of radical chemistry with isonitriles: (a) Curran,
D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863–5864. (b) Curran, D. P.;
Ko, S.-B.; Josien, H. Angew. Chem., Int. Ed. 1996, 34, 2683–2684. (c)
Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, T. Tetra-
hedron 1995, 51, 9045–9062. (d) Janza, B.; Studer, A. Org. Lett. 2006, 8,
1875–1878. Reviews: (e) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev.
1996, 96, 177–194. (f) Spagnolo, D.; Nanni, D. In Encyclopedia of
Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer,
A., Eds.; John Wiley & Sons: Chichester, 2012; Vol. 2, pp 1019ꢀ1057.
W. R. S.; Bowman, W. R.; McInally, T. Tetrahedron Lett. 2001, 42,
7887–7890. (e) Matcha, K.; Antonchick, A. P. Angew. Chem., Int. Ed.
2013, 52, 2082–2086. (f) Liu, T.; Yang, H.; Jiang, Y.; Fu, H. Adv. Synth.
Catal. 2013, 355, 1169–1176. (g) Intermolecular acyl radical additions to
heteroarenes, reviews: Minisci, F. Synthesis 1973, 1–24. Minisci, F. Top.
Curr. Chem. 1976, 62, 1–48.
(7) Concept BHAS: Studer, A.; Curran, D. P. Angew. Chem., Int. Ed.
2011, 50, 5018–5022.
r
10.1021/ol403147v
XXXX American Chemical Society

precursors,5ꢀ7 we decided to investigate the modular
synthesis of 6-aroylated phenanthridines by BHAS
(Scheme 2, c). Since the biphenyl core in the starting
2-isocyanobiphenyls is readily constructed via cross-
coupling chemistry, our method allows for preparation
of the targeted 6-aroylated phenanthridines in a modular
approach, which renders the method highly valuable for
library synthesis.
diminishing the yield to a large extent (entry 20). However,
further lowering of the aldehyde amount to 1.5 and 1.2 equiv
led to a significant reduction of the yield (entries 21, 22).
Therefore, 2 equiv were regarded as optimal with respect to
aldehyde economy and yield. The yield sharply dropped if
reaction was conducted at 60 °C (entry 23).
Table 1. Reaction Optimization Using 1a as a Substrate
Scheme 1. 6-Substituted Phenanthridines via C-Radical
Addition to 2-Isocyanobiphenyls
PhCHO
(equiv)
tBuOOH
initiator
(mol %)
yielda
(%)
entry
(equiv)
1
4.0
4.0
3.0
2.0
1.2
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
2.0
1.2
1.5
2.0
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1.7
1.1
2.2
2.2
2.2
2.2
FeCp2 (1.0)
FeCp2 (1.0)
FeCp2 (1.0)
FeCp2 (1.0)
FeCp2 (1.0)
FeCp2 (1.0)
CuOAc (1.0)
Bu4NI (1.0)
Bu4NBr (1.0)
CuBr (1.0)
CuI (1.0)
65b
71
68
68
7
2
3
4
5
6
9c
7
5
8
60
4
9
The reaction was optimized using biarylisonitrile 1a in
combination with benzaldehyde as a C-radical precursor
andtBuOOH asthe oxidantusingvarious radicalinitiators
under different conditions to provide phenanthridine 2a
(Table 1). The initial reaction was conducted in benzene
using a 4-fold excess of benzaldehyde and 2.2 equiv of
tBuOOH in the presence of FeCp2 as the initiator (1 mol %)
at 90 °C (sealed tube) for 24 h. Pleasingly, 2a was formed in
65% yield (entry 1). Since benzene is known to act as a
radical acceptor we switched to MeCN as a solvent at 90 °C,
and the yield was further improved to 71% (entry 2).
Slightly lower yields were achieved upon lowering the
amount of benzaldehyde to 3 and 2 equiv, respectively
(68%, entries 3 and 4). However, the yield dramatically
dropped to 7% if only 1.2 equiv of PhCHO were used under
otherwise identical conditions (entry 5). Reaction did not
work well in the presence of AcOH (entry 6). CuOAc, CuBr,
and CuCl2 were not efficient initiators for this radical
cascade reaction (entries 7, 10, and 12), but CuI afforded a
good yield (57%, entry 11). Likely, it is the iodide anion in
CuI rather than the Cu-metal which is the initiator. Indeed,
the nontransition metal based initiator Bu4NI, which has
recently been successfully used in radical chemistry,8 af-
forded a good result (entry 8), but Bu4NBr turned out to be
an inefficient initiator (entry 9). The yield slightly improved
to 76% by replacing FeCp2 with FeCl3 (entry 13). With
the optimal initiator in hand we also varied the amount
of initiator and found 0.4 mol % to be the ideal loading
(entries 14ꢀ17). Lowering the concentration of the oxidant
led to slightly lower yields (entries 18 and 19). Importantly,
the amount of aldehyde could be lowered to 2 equiv without
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5
57
6
CuCl2 (1.0)
FeCl3 (1.0)
FeCl3 (0.1)
FeCl3 (0.4)
FeCl3 (2.0)
FeCl3 (4.0)
FeCl3 (0.4)
FeCl3 (0.4)
FeCl3 (0.4)
FeCl3 (0.4)
FeCl3 (0.4)
FeCl3 (0.4)
76
33
78
76
67
75
61
74
56
62
21d
a Determined by 1H NMR using an internal standard. b Reaction
conducted in benzene. c Addition of AcOH (1 equiv). d At 60 °C.
With optimized conditions in hand (Table 1, entry 20)
we next studied the scope and limitations of the phenan-
thridine synthesis by first varying the aldehyde component
in the reaction with isonitrile 1a (Scheme 2). Ortho-, meta-,
and para-tolylaldehyde provided the corresponding
products 2bꢀd in 50ꢀ64% isolated yield, and as expected
a similar yield was also obtained for the reaction with
para-tert-butylbenzaldehyde (2e, 65%). Electronic effects
in the aldehyde component turned out to be weak since
similar yields were obtained with benzaldehyde derivatives
bearing electron-donating and -accepting substituents at
the para position (see 2fꢀj). A slightly lower yield was
noted in the reaction of 1a with β-naphthaldehyde (see 2k).
We continued the studies by varying the 2-isocyanobiphenyl
component which is readily prepared by using literature
protocols (see Supporting Information). Reactions were
(8) Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 45, 979–999.
B
Org. Lett., Vol. XX, No. XX, XXXX

high selectivity: phenanthridine 2r was formed in 72%
yield containing traces of its regioisomer (analytically pure
2r was isolated after crystallization).9 As expected, the
meta-methyl derivative provided the targeted products 2s
and 2s0 with moderate regioselectivity. The structure of the
major isomer 2s0 was unambiguously confirmed by X-ray
analysis (Figure 1). The arene ring in the biphenyl bearing
the isocyano substituent can be further substituted as
shown by the successful transformation of the meta fluoro
derivative to 2t (64%).
Scheme 2. Variation of the Aldehyde Component
Scheme 3. Variation of the Isonitrile Component
Figure 1. X-ray structure of phenanthridine 2s0.
Finally, we also tested whether aliphatic aldehydes work
as substrates and reacted pentanal under the optimized
conditionswithisonitrile 1a(Scheme 4). Phenanthridine 2u
was isolated in 39% yield.10
Scheme 4. Reaction with Pentanal
In Scheme 5 the suggested mechanism for the phenan-
thridine synthesis is presented. Initiation likely occurs by
reducing tBuOOH with FeX2 to give the tert-butoxyl
radical along with an Fe(III) complex.11 The tert-butoxyl
radical then abstracts the H-atom from the aldehyde to
studied with benzaldehyde as a second component under the
above-described optimized conditions (Scheme 3).
2-Isocyanobiphenyl and the its para-methyl derivative
provided the same isolated yield (2l,m: 64%). The ortho-
methylbiphenylisonitrile afforded a slightly lower yield
(2n, 49%). Interestingly, we found 8% of the demethylated
phenanthridine 2l as an inseparable side product resulting
from a radical ipso attack with subsequent methyl radical
fragmentation in this transformation. Electronic effects
exerted by a para substituent at the arene of the biphenyl
moiety lacking the isonitrile functionality are weak, and
similar yields were achieved with halo and methoxy sub-
stituted 2-isocyanobiphenyl derivatives (see 2oꢀq). We
also investigated the regioselectivity of the BHAS process
and found that the naphthyl derivative cyclized with very
(9) Due to signal overlap it was not possible to unambiguously
determine the regioisomer ratio. The major isomer was assigned based
in literature precedence; see ref 2a.
(10) 6-Butylphenanthridine derived from decarbonylation of the
intermediate pentoyl radical was not observed. However, if 1a was
reacted with cyclohexanecarbaldehyde, the targeted 6-acylated product
was observed along with the decarbonylated 6-cyclohexylphenanthridine
(ratio 43:57, 44% combined yield).
(11) The FeCl3 salt is first reduced by tBuOOH to FeCl2 via ligand
exchange to form FeCl2OOtBu followed by FeꢀO homolysis to give
FeCl2 and the tert-butyl hydroperoxyl radical which can also initiate a
chain by aldehyde H-abstraction. See: Liu, W.; Li, Y.; Liu, K.; Li, Z.
J. Am. Chem. Soc. 2011, 133, 10756–10759 and references cited therein.
Org. Lett., Vol. XX, No. XX, XXXX
C

Biaryl radical anion D reduces tBuOOH by SET to
eventually provide phenanthridine 2 and the chain propa-
gating tert-butoxyl radical along with the basic hydroxide
anion. We believe that the radical anion D and the
cyclohexadienyl radical C can reduce the Fe(III) complex
generated in the initiation step thereby regenerating the
active Fe(II)-initiator.12
Scheme 5. Suggested Mechanism
In conclusion, we disclosed a novel method for the
synthesis of 6-aroylated phenanthridines starting with
readily prepared 2-isocyanobiphenyls and commercially
available aromatic aldehydes. The phenanthridine core,
which can be found in many natural products and in drugs
or drug candidates, is constructed during the radical
cascade process. Reactionswhichcomprisetwo CꢀC bond
forming steps occur via acyl radical addition to the iso-
nitrile functionality of the 2-isocyanobiphenyls and sub-
sequent base promoted homolytic aromatic substitution of
the intermediately generated imidoyl radical. The aroyl
substituent is introduced into the phenanthridine core with
complete regioselectivity at the 6-position. As oxidant for
this cross dehydrogenative coupling reaction, cheap and
commercially available tBuOOH was used. The radical
chains are long because only a small amount of initiator is
necessary to run these cascades. As the initiator, commer-
cially available and cheap FeCl3 can be used. Due to the
modularity of the presented synthesis, the method should
be useful for preparation of phenanthridine libraries.
give acyl radical A which attacks the isonitrile functionality
in substrate 1 to give the imidoyl radical B. This radical
then cyclizes to the arene to generate the cyclohexadienyl
radical C. Radical C can be deprotonated with the basic
hydroxide anion to give biaryl radical anion D.
We have previously calculated that similar cyclohexa-
dienyl radicals show surprisingly high acidity.2b Moreover,
the reaction did not work well in the presence of acetic acid
(see Table 1, entry 6) indicating the importance of the
hydroxide anion in this chain reaction. Therefore, we
currently disfavor the alternative mechanism where the
cyclohexadienyl radical C gets oxidized by tBuOOH.
Acknowledgment. This work was supported by the
program “Sustainable Chemical Synthesis (SusChemSys)”
which is cofinanced by the European Regional Develop-
ment Fund (ERDF) and the state of North Rhine-
Westphalia, Germany, under the Operational Program
“Regional Competitiveness and Employment” 2007ꢀ2013.
Supporting Information Available. Experimental de-
tails and characterization data for the products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) These processes can only be side reactions since only a very small
amount of initiator is necessary to run these cascades.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX