Palladium-catalyzed annulation of benzynes with N-substituted-N-(2- halophenyl)formamides: Synthesis of phenanthridinones

Article abstract of DOI:10.1039/c4ob00997e

A novel and efficient procedure for the synthesis of N-substituted phenanthridinones via palladium-catalyzed annulation of benzynes with N-substituted-N-(2-halophenyl)formamides has been developed. This methodology constructs two new C-C bonds via an arylation/annulation process, and provides the desired products in good yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00997e

Organic &
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Palladium-catalyzed annulation of benzynes with
N-substituted-N-(2-halophenyl)formamides:
synthesis of phenanthridinones†
Cite this: Org. Biomol. Chem., 2014,
12, 5351
Received 14th May 2014,
Accepted 3rd June 2014
Yuan Yang,a Hui Huang,a Lijun Wua and Yun liang*a,b
DOI: 10.1039/c4ob00997e
www.rsc.org/obc
A novel and efficient procedure for the synthesis of N-substituted
phenanthridinones via palladium-catalyzed annulation of
benzynes with N-substituted-N-(2-halophenyl)formamides has
been developed. This methodology constructs two new C–C
bonds via an arylation/annulation process, and provides the
desired products in good yields.
Phenanthridinones are one of the important classes of hetero-
cycles in a myriad of bioactive natural products and pharma-
ceutical molecules.1 As a result, considerable efforts were
directed toward the development of efficient methods for their
synthesis.3–9 Among them, the palladium-based method-
ologies2 have been used as an important synthetic tool for the
synthesis of phenanthridinones because of their functional
group tolerance, stereo- and regioselectivity and significant
yields under mild reaction conditions. Recently, most of these
approaches have focused on: (1) palladium-catalyzed intra-
molecular C–C bond formation through annulation of N-(2-
haloaryl)benzamides or C–H bond functionalization of N-aryl-
benzamides;7 (2) palladium-catalyzed intramolecular C–N
bond formation of biarylcarboxyamides;8 (3) palladium-
catalyzed intermolecular C–C and C–N bond formation
through sequential aryl–aryl and N-aryl coupling;9 (4) palla-
dium-catalyzed C(sp2)–H aminocarbonylation of o-arylani-
lines.10 However, the approach of palladium-catalyzed double
C–C bond formation to synthesize phenanthridinones has never
been reported. To enrich synthetic methods of phenanthridi-
nones, we envisioned that phenanthridinones could be prepared
by simultaneously constructing two C–C bonds (Scheme 1).
Arynes have been attracting considerable attention since
2-(trimethylsilyl)aryl triflates, aryne precursors, were first
Scheme 1 Methods for the synthesis of phenanthridinones.
reported by Kobayashi.11,12 The carboannulations of arynes
have become an important methodology for constructing a
variety of carbocycles and heterocycles.12a Especially, palla-
dium-catalyzed annulations of arynes displayed particular
efficiency for the construction of these cycles.13,14 We were
also interested in this synthetic strategy, and have successfully
synthesized 6H-benzo[c]chromenes,14a 1H-inden-1-ones,14b
and phenanthrenes14c through formation of multiple C–C
bonds. In the persistent research, we found that benzynes and
N-substituted-N-(2-halophenyl)formamide undergo a cascade
aNational & Local Joint Engineering Laboratory for New Petro-chemical Materials
and Fine Utilization of Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of Education, Hunan Normal
University, Changsha, Hunan 410081, China. E-mail: yliang@hunnu.edu.cn;
Fax: +86(0731)88872533
bBeijing National Laboratory for Molecular Sciences, Beijing, 100871, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00997e
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Table 1 Optimization of reaction conditionsa
Table 2 Palladium-catalyzed annulation of N-substituted-N-(2-halo-
phenyl)formamides (1) with o-silyl phenyltriflate (2a)a,b
Yield of
Entry
Catalyst
Ligand
Solvent
3ab (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
—
PPh3
Xantphos
P(cy)3
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN–toluene (1 : 1)
MeCN
93
45
46
85
64
64
47
42
29
48
0
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
dppp
10
11
12c
P(o-tol)3
P(o-tol)3
P(o-tol)3
Toluene
MeCN–toluene (1 : 1)
88
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), [Pd] catalyst
(5 mol%), ligand (10 mol%), solvent (2 mL), 110 °C, under a N2
atmosphere for 18 h. b Isolated yields. c 80 °C.
process to afford phenanthridinones. To the best of our knowl-
edge, this is the first example of synthesis of phenanthridi-
nones from benzynes and aryl halides by sequential double
C–C bond formation.
Initially, the reaction of N-benzyl-N-(2-iodophenyl)form-
amide 1a with 2-(trimethylsilyl)phenyl triflate 2a, a benzyne
precursor, was chosen as a model reaction to optimize the
reaction conditions (Table 1). Our investigation started with an
attempted annulation of the substrate 1a with 2a in 2 mL of
1 : 1 MeCN–toluene at 110 °C in the presence of Pd(OAc)2 and
P(o-tolyl)3 (entry 1). To our delight, the desired product 3a
could be isolated in 93% yield. This result encouraged us to
develop an efficient method for the synthesis of phenanthridi-
none. A variety of palladium catalysts, such as Pd(OAc)2, PdCl2,
Pd(PPh3)4, and Pd2dba3, were investigated (entries 2–4), and
the results demonstrated that Pd(OAc)2 as a catalyst displayed
the highest efficiency in this reaction. In order to check the
a Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), Pd(OAc)2 (5 mol
%), P(o-tol)3 (10 mol%), CsF (0.9 mmol), MeCN–toluene (1 : 1, 2 mL),
110 °C, under a N2 atmosphere. b Isolated yields. c N-Benzyl-N-(2-
iodophenyl)formamide was replaced by N-benzyl-N-(2-bromophenyl)-
formamide.
effects of ligands, no ligand and a series of ligands, including conditions, and the results are summarized in Table 2. Various
P(o-tolyl), PPh3, Xantphos, PCy3 and dppp, were examined phenanthridinones (Type I–V) were obtained in good to perfect
(entries 5–9). The ligand of P(o-tolyl)3 achieved the best result. yields. For Type I (R1 = benzyl), the phenyl ring could be sub-
Then, the effects of the solvent were also screened (entries 10 stituted with either an electron-donating group such as methyl
and 11). No desired product 3a was observed when using (1b) or electron-withdrawing groups such as COOMe and NO2
toluene as the medium, and only 48% yield of 3a was obtained (1c and 1d). N-(2-Iodophenyl)-N-(4-methylbenzyl)formamide
when using MeCN as the medium. Finally, the reaction temp- and N-(2-iodophenyl)-N-(4-nitrobenzyl)formamide, for ex-
erature was evaluated (entry 12), and the reaction was less ample, were treated with 2-(trimethylsilyl)phenyl triflate 2a,
effective at 80 °C. Therefore, the optimized reaction conditions furnishing the corresponding products 3b and 3d in 88% and
were as follows: 1a (0.3 mmol), 2a (0.36 mmol), Pd(OAc)2 85% yield respectively. Furthermore, 5-(naphthalen-2-ylmethyl)-
(5 mol%), P(o-tolyl)3 (10 mol%), CsF (0.9 mmol), in MeCN– phenanthridin-6(5H)-one was obtained in 89% yield. For Type
toluene (1 : 1, 2 mL) at 110 °C.
II (R1 = alkyl), similarly, N-alkyl phenanthridinones 3f–3h
With the optimal reaction conditions in hand, various N-(2- could be obtained in good to high isolated yields. However,
iodophenyl)formamides were employed to react with 2-(tri- for Type III, the yields of the corresponding products 3i
methylsilyl)phenyl triflate 2a under the standard reaction and 3j from N-aryl-N-(2-iodophenyl)formamide were decreased.
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For instance, 5-phenylphenanthridin-6(5H)-one 3i was only
obtained in 60% yield. Subsequently, we also examined a
series of substituted N-benzyl-N-(2-iodophenyl)formamides
(Type IV). Substituted N-benzyl-N-(2-iodophenyl)formamide
with either electron-withdrawing groups such as fluoro, chloro,
cyano, and trifluoromethyl groups (3k–3n and 3p) or an elec-
tron-donating group such as the methyl group (3o) on the
benzene rings were all well-tolerated under the reaction con-
ditions and proceeded with almost equal efficiency. These
results indicated that the electronic effect on the benzene ring
did not play a significant role in regulating the reaction, and
revealed the inherent high reactivity of N-benzyl-N-(substi-
tuted-2-iodophenyl)formamides. Finally, we investigated the reac-
tivity of N-benzyl-N-(2-bromophenyl)formamide, affording the
corresponding product 3a in 88% yield (Type V). Compared
with N-benzyl-N-(2-iodophenyl)formamide, the yield of 3a was
decreased slightly. The possible reason was that the reactivity
of oxidative addition of Pd(0)Ln with the C–Br bond was lower
than that with the C–I bond.
Table 3 Palladium-catalyzed annulation of N-benzyl-N-(2-iodophenyl)-
formamide (1a) with the o-silyl aryltriflates (2)a
Entry
1
Substrate 2
Product 3b (%)
2
To expand the scope of this methodology, a set of sub-
stituted o-silyl aryltriflates 2b–2e reacted with N-benzyl-N-(2-
iodophenyl)formamide 1a, CsF, Pd(OAc)2 and P(o-tolyl)3 was
examined (Table 3). The o-silyl aryltriflates 2b and 2c, bearing
alkyl groups on the aryl moiety, afforded the target products
in 83% and 91% yields. However, the reaction of o-silyl aryl-
triflates 2d and 2e bearing two fluoro groups or a chloro group
with N-benzyl-N-(2-iodophenyl)formamide 1a was conducted in
24% and 32% yields. Among these substituted o-silyl aryltriflates,
substrates 2c and 2d provided two regioisomers, respectively, in
a 1.1 : 1 ratio and a 1.6 : 1 ratio. The lack of regioselectivity of the
reaction is consistent with insertion of unsymmetrical benzyne
into a palladium–carbon bond. These results clearly support that
the reaction takes place through a benzyne mechanism.
3
4
On the basis of the present results and the reported
mechanism,13–15 a possible mechanism is proposed as out-
lined in Scheme 2. First, oxidative addition of Pd(0)Ln with
N-substituted-N-(2-iodophenyl)formamide 1 affords intermediate
A. Insertion of a benzyne into intermediate A forms intermedi-
ate B. Subsequently, the phenanthridinone synthesis proceeds
from intermediate B through either of possible pathways: one
pathway involves addition of intermediate B itself to the carbo-
nyl group16 and a following β-hydride elimination to give the
desired product 3 (path a), and the other pathway is oxidative
addition of intermediate B to the aldehyde C–H bond,17
leading to intermediate C; subsequently, sequential reductive
elimination of intermediate C provides the desired product
and regenerates the Pd(0) catalyst (path b).
a Reaction conditions: 1a (0.3 mmol), 2 (0.36 mmol), Pd(OAc)2 (5 mol
%), P(o-tol)3 (10 mol%), CsF (0.9 mmol), MeCN–toluene (1 : 1, 2 mL),
110 °C, 18 h, under a N2 atmosphere. b Isolated yields.
In summary, we have developed a high-efficiency method
for the synthesis of N-substituted phenanthridinones by palla-
dium-catalyzed annulation of benzynes with N-substituted-N-
(2-halophenyl)formamide. In the reaction, double C–C bonds
are formed via an arylation/annulation process, and the corres-
ponding products are obtained in good yields. In addition, the
reaction has been proved to be tolerant of a wide variety of
functional groups. Work to probe the detailed mechanism and
apply the reaction in organic synthesis is currently ongoing.
Scheme 2 Possible mechanism for the reaction.
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Acknowledgements
We thank the Natural Science Foundation of China
(21072054), Ministry of Education of China (20094306120003,
213027A), Hunan Provincial Natural Science Foundation of
China (12JJ2009), Scientific Research Fund of Hunan Provin-
cial Education Department (12A095), and Aid Program for
Science and Technology Innovative Research Team in Higher
Educational Institutions of Hunan Province for financial
support, and Y. Yang also acknowledges the Postgraduate
Innovation Program of Hunan Province (CX2013B232).
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