Phenanthridine synthesis through iron-catalyzed intramolecular N-arylation of O-Acetyl oxime

Article abstract of DOI:10.1021/ol4020392

O-Acetyl oximes derived from 2′-arylacetophenones undergo N-O bond cleavage/intramolecular N-arylation in the presence of a catalytic amount of iron(III) acetylacetonate in acetic acid. In combination with the conventional cross-coupling or directed C-H arylation, the reaction offers a convenient route to substituted phenanthridines.

Full text of DOI:10.1021/ol4020392

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Phenanthridine Synthesis through
Iron-Catalyzed Intramolecular N‑Arylation
of O‑Acetyl Oxime
Indubhusan Deb and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
nyoshikai@ntu.edu.sg
Received July 19, 2013
ABSTRACT
O-Acetyl oximes derived from 20-arylacetophenones undergo NꢀO bond cleavage/intramolecular N-arylation in the presence of a catalytic amount
of iron(III) acetylacetonate in acetic acid. In combination with the conventional cross-coupling or directed CꢀH arylation, the reaction offers a
convenient route to substituted phenanthridines.
Phenanthridine is an important fused heteroaromatic
skeleton that occurs frequently in natural products, phar-
maceutical drugs, and other functional molecules.1 For
example, nitidine and fagaronine belong to a class of
phenanthridine alkaloids, which display activity against
leukemia.1a Consequently, methods for efficient and selec-
tive synthesis of phenanthridine derivatives could serve as
important tools in medicinal chemistry and material
science.2 Among many possible approaches to the phenan-
thridine skeleton, those involving closure of the central
ring through intramolecular CꢀC or CꢀN bond forma-
tion of an ortho-functionalized biaryl precursor are parti-
cularly attractive in light of the ready accessibility of the
starting material by cross-coupling reactions. In this con-
text, the classical PictetꢀHubert phenanthridine synthesis
from ortho-acetaminobiphenyl derivatives remains an at-
tractive option, while the reaction typically requires harsh
conditions (Scheme 1a).3 Recent studies of the groups of
Tobisu/Chatani and Chiba led to milder and modular
routes to phenanthridines. The former group developed
manganese-mediatedoxidative cyclization ofortho-isocya-
nobiphenyls with organoboronic acids (Scheme 1b),4 while
the latter group devised a one-pot two-step protocol
involving Grignard addition to ortho-cyanobiphenyls fol-
lowed by copper-catalyzed CꢀN bond formation under
aerobic conditions (Scheme 1c).5
Besides the above-mentioned approaches, intramolecu-
lar CꢀN cyclization of oxime derivatives of biaryl alde-
hydes/ketones represents an attractive approach to phen-
anthridines (Scheme 1d), particularly considering the
improved accessibility to the starting materials owing to
the recent progress in direct arylation of aryl ketones
and imines.6 Indeed, the feasibility of such cyclization re-
actions has been demonstrated by the groups of Rodrıguez
and Walton under photochemical conditions, which
(4) Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem.,
Int. Ed. 2012, 51, 11363.
(5) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2010, 12, 3682.
(6) (a) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783.
(b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc.
2005, 127, 5936. (c) Ackermann, L. Org. Lett. 2005, 7, 3123. (d)
Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Angew.
Chem., Int. Ed. 2009, 48, 2925. (e) Kim, M.; Kwak, J.; Chang, S. Angew.
Chem., Int. Ed. 2009, 48, 8935. (f) Tredwell, M. J.; Gulias, M.; Bremeyer,
N. G.; Johansson, C. C. C.; Collins, B. S. L.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2011, 50, 1076. (g) Gao, K.; Lee, P. S.; Long, C.; Yoshikai, N.
Org. Lett. 2012, 14, 4234.
(1) (a) Cushman, M.; Mohan, P.; Smith, E. C. R. J. Med. Chem. 1984,
27, 544. (b) Fang, S. D.; Wang, L. K.; Hecht, S. M. J. Org. Chem. 1993,
58, 5025. (c) Lynch, M. A.; Duval, O.; Sukhanova, A.; Devy, J.;
MacKay, S. P.; Waigh, R. D.; Nabiev, I. Bioorg. Med. Chem. Lett.
2001, 11, 2643. (d) Stevens, N.; O’Connor, N.; Vishwasrao, H.; Samaroo,
D.; Kandel, E. R.; Akins, D. L.; Drain, C. M.; Turro, N. J. J. Am. Chem.
Soc. 2008, 130, 7182.
(2) Keller, P. A. In Science of Synthesis, Vol. 15; St. Black, D. C., Ed.;
Thieme: Stuttgart, 2004; p 1065.
(3) Xi, J.; Dong, Q.-L.; Liu, G.-S.; Wang, S.; Chen, L.; Yao, Z.-J.
(7) (a) Alonso, R.; Campos, P. J.; Garcia, B.; Rodriguez, M. A. Org.
Lett. 2006, 8, 3521. (b) Alonso, R.; Caballero, A.; Campos, P. J.;
Rodriguez, M. A. Tetrahedron 2010, 66, 8828.
Synlett 2010, 1674 and references cited therein.
r
10.1021/ol4020392
XXXX American Chemical Society

presumably involve iminyl radicals as reactive species.7ꢀ10
However, these photochemical reactions required high
dilution or the use of a stoichiometric photosensitizer.
We report here that the same CꢀN cyclization reaction
can be achieved starting from O-acetyloximes under simple
conditions using an iron(III) salt as a catalyst. The reaction
appears mechanistically distinct from the photochemical
reaction, likely proceeding through a nonradical pathway.
acetylacetonate, a simple iron salt that appears redox-
insensitive under the present conditions, promoted the
reaction cleanly to afford 2a in 96% yield (entry 4). The
same level of the reaction efficiency was achieved either by
reducing the loading of Fe(acac)3 to 10 mol % or by
lowering the temperature to 60 °C (entries 5 and 6). The
reaction at 60 °C became sluggish with a lower catalyst
loading of 10or 5 mol % (entries 7 and 8). While FeCl3 also
promoted the reaction albeit in modest yield (entry 9),
acetylacetonate salts of the neighboring metal elements,
that is, Mn(acac)3, Co(acac)3, and Ni(acac)2, were not
effective at all (entries 10ꢀ12). The reaction became very
sluggish in solvents other than AcOH (entries 13ꢀ15).
While the screening study was performed using a pure
E-isomer of oxime 1a, a mixture of E- and Z-isomers
(ca. 4:1) could also be used without problem, affording
2a in 90% yield. Note that free oxime of 20-phenylaceto-
phenone did not participate in the cyclization reaction.
Scheme 1. Approaches to Phenanthridines from
ortho-Functionalized Biaryls
Table 1. Screening of Reaction Conditionsa
temp
yield
(%)b
entry
MLn (mol %)
solvent
(°C)
1c
2
CuI (20)
DMSO
DMSO
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
DMSO
dioxane
toluene
80
80
80
80
80
60
60
60
60
60
60
60
60
60
60
40
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Fe(acac)3 (20)
Fe(acac)3 (10)
Fe(acac)3 (20)
Fe(acac)3 (10)
Fe(acac)3 (5)
FeCl3 (20)
55
70
96 (93)c
90
92
51
8
3
4
5
6
7
We came across the present cyclization reaction while
studying pyridine synthesis through copper-catalyzed
oxime NꢀO cleavage that we reported recently.11 Thus,
the reaction of O-acetyl oxime of 20-phenylacetophenone
(1a) in the presence of CuI (20 mol %) in DMSO at 80 °C
resulted in the formation of phenanthridine 2a in 40%
yield (Table 1, entry 1). The yield of 2a was improved by
using Cu(OAc)2 instead of CuI (entry 2), and further by
changing the solvent to AcOH (entry 3).
8
9
48
0d
0d
0d
5
10
11
12
13
14
15
Mn(acac)3 (20)
Co(acac)3 (20)
Ni(acac)2 (20)
Fe(acac)3 (20)
Fe(acac)3 (20)
Fe(acac)3 (20)
5
8
a The reaction was performed on a 0.2 mmol scale in 1.2 mL of the
solvent. b Determined by 1H NMR using 1,1,2,2-tetrachloroethane
as an internal standard. c Isolated yield is shown in the parentheses.
d Determined by GC.
While we initially thought that the ability of Cu(I) to
reduce the oxime NꢀO bond was crucial for the cyclization
reaction,9b it turned out not to be true. Thus, iron(III)
With the optimized catalytic system in hand, we ex-
plored the scope of the present cyclization reaction
(Scheme 2). First, CꢀN cyclization of oxime derivatives
of various 20-arylacetophenones was examined. The reac-
tion tolerated chloro, fluoro, trifluoromethyl, cyano, and
methyl substituents on the para position of the aryl group,
affording the phenanthridines 2bꢀ2f in moderate to
good yields. Blockage of one of the ortho positions was
tolerable, as demonstrated by the formation of 1-fluoro-
phenanthridine 2g and benzo[a]phenanthridine 2h in
(8) (a) Portela-Cubillo, F.; Scanlan, E. M.; Scott, J. S.; Walton, J. C.
Chem. Commun. 2008, 4189. (b) Portela-Cubillo, F.; Lymer, J.; Scanlan,
E. M.; Scott, J. S.; Walton, J. C. Tetrahedron 2008, 64, 11908. (c)
McBurney, R. T.; Slawin, A. M. Z.; Smart, L. A.; Yu, Y. P.; Walton,
J. C. Chem. Commun. 2011, 47, 7974.
(9) For reviews on reactions involving iminyl radicals, see: (a) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) Narasaka, K.;
Kitamura, M. Eur. J. Org. Chem. 2005, 4505. (c) Kitamura, M.;
Narasaka, K. Bull. Chem. Soc. Jpn. 2008, 81, 539. (d) Zard, S. Z. Chem.
Soc. Rev. 2008, 37, 1603. (e) Chiba, S. Synlett 2012, 23, 21.
(10) Microwave-assisted, thermal cyclization was also reported: Portela-
Cubillo, F.; Scott, J. S.; Walton, J. C. J. Org. Chem. 2009, 74, 4934.
(11) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756.
B
Org. Lett., Vol. XX, No. XX, XXXX

moderate yields. Interestingly, no regioselectivity was ob-
served for cyclization reactions of substrates bearing m-tolyl
and m-methoxyphenyl groups (see products 2i/2i0 and 2j/2j0).
The reaction tolerated variation of the aromatic ring
of the acetophenone moiety (see products 2k and 2l),
and oximes derived from 20-phenylpropiophenone and
20-phenylbenzophenone (see products 2m and 2n). On
the other hand, oxime derived from 20-phenylbenzalde-
hyde failed to undergo the desired CꢀN cyclization but
produced 2-cyanobiphenyl through elimination of acetic
acid. Note again that the stereochemistry of the oxime
CdN bond did not have a significant influence on the
reactivity. For example, the products 2m and 2n were
obtained in good yields from 1:1 mixtures of E- and
Z-isomers of the respective oximes.
Scheme 3
Scheme 2. Cyclization of Various Biaryl Oximesa
Scheme 4. Proposed Reaction Mechanism
(Scheme 3a). This observation is in sharp contrast to the
reaction of similar substrates under photochemical condi-
tions, which afforded the desired phenanthridine deriva-
tives without problem.7,8 In another experiment, we noted
that the addition of TEMPO (1 equiv) did not interfere
with the cyclization of 1a to 2a (Scheme 3b). Finally,
comparison of individual reactions of the parent substrate
1a and its pentadeuterated analogue 1a-d5 showed that
initial conversion of 1a-d5 takes place much more slug-
gishlythanthatof 1a, curiously withaninduction periodof
ca. 20min (Scheme 3c). While the presenceofthe induction
a Unless otherwise noted, the reaction was performed on a 0.2 mmol
scale in 1.2 mL of AcOH. Yields refer to isolated yields.
During the exploration of the substrate scope, we found
that oximes bearing p- and o-methoxyphenyl groups, upon
exposure to the catalytic conditions, immediately decom-
posed to give black, tarry materials of unknown identity
Org. Lett., Vol. XX, No. XX, XXXX
C

period makes it difficult to derive a quantitative kinetic
isotope effect, these observations strongly suggest that the
CꢀH bond cleavage is involved in the rate-determining
step of the reaction.
In summary, we have developed a convenient iron(III)-
catalyzed protocol for the cyclization of 2-biarylketone
O-acetyl oximes to phenanthridine derivatives. The reac-
tion likely proceeds through a nonradical mechanism
with activation of the acetoxy leaving group by the iron
catalyst. Further studies on the development of new
transition-metal-catalyzed condensation methods for carbo-
and heterocycles are ongoing.11,12
On the basis of the above observations, we consider that
the present reaction is mechanistically distinct from the
photochemical cyclization and does not involve formation
of an iminyl radical. We speculate that the reaction pro-
ceeds through a FriedelꢀCrafts type mechanism with
Lewis acid activation of the acetoxy group (Scheme 4a).
Alternatively, it is possible to draw a mechanism involving
6π-electrocyclization and subsequent elimination of acetic
acid (Scheme 4b). At this moment, we prefer the Friedelꢀ
Crafts type pathway, because such a mechanism involving
electrophilic attack on the aromatic ring appears to better
account for the failure of the reaction of the substrate
bearing p-methoxyphenyl group (Scheme 4c).
Acknowledgment. This work was supported by the Na-
tional Research Foundation Singapore (NRF-RF2009-05
toN.Y.)andNanyangTechnologicalUniversity. Wethank
Boon-Hong Tan (Nanyang Technological University) for
technical assistance.
Supporting Information Available. Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134,
9098. (b) Hajra, A.; Wei, Y.; Yoshikai, N. Org. Lett. 2012, 14, 5488. (c)
Yamakawa, T.; Yoshikai, N. Org. Lett. 2013, 15, 196.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX