Synthesis of phenanthridinones from N-methoxybenzamides and arenes by multiple palladium-catalyzed C-H activation steps at room temperature

Article abstract of DOI:10.1002/anie.201104311

Many steps make light work: Substituted phenanthridinones can be obtained with high regioselectivity and in very good yields by palladium-catalyzed cyclization reactions of N-methoxybenzamides with arenes (see scheme). The reaction proceeds through multiple oxidative C-H activation and C-C/C-N formation steps in one pot at room temperature, and thus provides a simple method for generating bioactive phenanthridinones. Copyright

Full text of DOI:10.1002/anie.201104311

Communications
DOI: 10.1002/anie.201104311
À
C H Activation
Synthesis of Phenanthridinones from N-Methoxybenzamides and
À
Arenes by Multiple Palladium-Catalyzed C H Activation Steps at
Room Temperature**
Jaganathan Karthikeyan and Chien-Hong Cheng*
The phenanthridinone unit is often found in alkaloids, many
of which have shown various biological activities.[1] Despite
the existence of several methods for the synthesis of
phenanthridinone derivatives,[2,14] versatile and flexible meth-
odologies to construct phenanthridinones are still desirable.
thridinone from N-methoxybenzamides with aryl iodides
using a palladium catalyst and metal oxidant at elevated
temperatures (Scheme 1).[10] To the best of our knowledge,
À
multiple C H activation reactions of N-methoxybenzamides
À
Transition-metal-catalyzed oxidative C H coupling of
two different arenes has emerged as a powerful method for
À
the construction of C C bonds and functionalized biaryl
linkages in organic synthesis.[3,4] Despite the increasing
attention given to this area, most of these reactions still
require a high temperature, powerful oxidants, and/or long
reaction times, all of which significantly limit the scope and
functional-group tolerance of these reactions. Thus, it is highly
desirable to develop a milder, more efficient, environmentally
benign, and atom-economical method for metal-catalyzed
À
C H functionalization reactions. Recently, palladium-cata-
lyzed directing-group-assisted ortho functionalization of aro-
À
matic C H bonds has been explored by coupling with simple
arenes.[4e–l] Various substrates, such as pyridines,[4e–f] pyridine-
N-oxide,[4g] anilides,[4h–i] amides,[4j] imines,[4k] and o-phenyl-
carbamates,[4l] have been employed for the palladium-cata-
lyzed arylation with simple arenes. We have also investigated
the synthesis of fluorenones from aldoxime ethers and arenes
Scheme 1. Synthesis of phenanthridinone derivatives.
with simple arenes at ambient temperatures have not been
reported to date. However, recent efforts have shown that
À
by multiple palladium-catalyzed C H functionalization reac-
tions.[5] Apart from the above-mentioned functional groups,
only a few examples are known to have CONHOMe as a
palladium complexes can catalyze the C H functionalization
À
at room temperature.[11]
2
3
À
À
À
directing group for the activation of C(sp ) H and C(sp ) H
Our continuing efforts in metal-catalyzed C H activation
bonds.[6–10] In 2008, Yu and co-workers first reported the use
and cyclization reactions[12] prompted us to explore the
reaction of N-methoxybenzamides with arenes. Herein, we
report a palladium-catalyzed highly regioselective dehydro-
genative cyclization of N-methoxybenzamides with arenes to
give biologically active phenanthridinone derivatives through
of CONHOMe as a directing group for the palladium-
3
À
catalyzed functionalization of a C(sp ) H bond with aryl and
alkyl boronic acids.[7] Subsequently, the same research group
developed a palladium-catalyzed synthesis of biologically
À
À
À
À
active lactam derivatives by intramolecular oxidative C H
multiple oxidative C H activation and C C/C N formation
steps in one pot under mild conditions.
À
activation and C N formation using benzhydroxamic acids as
substrates.[8] In 2010, Wang and Yuan reported a palladium-
catalyzed alkoxylation of N-methoxybenzamides.[9] Very
recently, Wang et al. demonstrated the synthesis of phenan-
Treatment of N-methoxybenzamide 1a with toluene 2a in
the presence of Pd(OAc)2 (10 mol%) and K2S2O8 (2.0 equiv)
in TFA (20 equiv) at 258C for 16 h gave phenanthridinone 3a
in 92% yield (Table 1, entry 1). It is important to note that the
reaction is highly regioselective with respect to 1a and 2a; we
did not observe any regioisomer of 3a. The transformation
[*] J. Karthikeyan, Prof. Dr. C.-H. Cheng
Department of Chemistry
À
À
appears to include three C H and N H activation steps, and
National Tsing Hua University
Hsinchu 30013 (Taiwan)
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/%7Echcheng
À
À
C C/C N formation steps. The identity of product 3a was
confirmed by H/13C NMR spectroscopy and mass spectro-
1
metry. Among the various oxidants examined, K2S2O8 was
most effective, and its use resulted in the formation of 3a in
92% yield. Other oxidants, such as meta-chloroperoxybenzoic
acid (mCPBA), oxone, and Na2S2O8, were also active but led
to 3a in only 42%, 52%, and 78% yield, respectively.
[**] We thank the National Science Council of the Republic of China
(NSC 98-2119-M-007-002-MY3) for support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104311.
9880
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Angew. Chem. Int. Ed. 2011, 50, 9880 –9883

Table 1: Results of the catalytic reaction of N-methoxybenzamides with simple arenes.(a)
Entry
1
2
Product 3
Yield
[%][b]
Entry
11
1
2
Product 3
Yield
[%][b]
1
2
3
4
5
6
7
8
1a 2a
1b 2a
1c 2a
1d 2a
1e 2a
1 f 2a
1g 2a
1h 2a
3a 92
1k 2a
1l 2a
1m 2a
1n 2a
1o 2a
1p 2b
1a 2b
1a 2c
3k 70
3b 90
3c 86
3d 80
3e 84
3 f 81
3g 78
3h 86
12
3l 90
3m 85
3n 89
3o 64
3p 71
3q 90
3r 86
13
14
15
16
17
18
9
1i 2a
3i 74
19
20
1a 2d
3s 65
10
1j 2a
3j 89
1a 2e
3t 83
[a] Unless stated otherwise, all reactions were carried out using an N-methoxybenzamide 1 (0.70 mmol) and an arene 2 (17.5 mmol) in the presence of
Pd(OAc)2 (10.0 mol%) and K2S2O8 (1.40 mmol) in TFA (140 mmol) at 258C for 16 h. [b] Yield of isolated product. TFA=trifluoroacetic acid.
Replacement of the oxidant with silver or copper salts did not
lead to product 3a. The choice of palladium catalysts was also
crucial for this reaction. Use of Pd(OAc)2 provided the
highest yield for the catalytic reaction. Use of other palladium
catalysts, such as Pd(acac)2 (acac = acetylacetonate) and
Pd(TFA)2, was also effective and afforded 3a in 58% and
64% yield, respectively. The presence of an acid is important
to the catalytic reaction. Among the acids tested, TFA was
most effective; toluene-p-sulfonic acid (PTSA, 2 equiv)
afforded product 3a in 47% yield. The other acids surveyed,
including CH3COOH, DMSO, and pivalic acid, were totally
ineffective. The amount of TFA is also crucial for the yield of
the product; the use of more or less than 20 equivalents of
TFA led to a lower yield of 3a. Control experiments showed
that the reaction did not proceed in the absence of either
palladium or TFA. The reaction proceeded at elevated
temperatures, but the yield of 3a decreased because of the
decomposition of the starting material. For example, the yield
of 3a was only 79% when the reaction was carried out at
1108C.
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Communications
With the optimized reaction conditions established (see
Table 1, footnote), we examined the reaction of various
substituted N-methoxybenzamides (1b–o) with toluene (2a).
Gratifyingly, excellent yields and high regioselectivities were
generally observed for most of these substrates (Table 1).
Thus, 4-methyl-, 3-methyl-, 2-methyl-, 3,4-dimethyl-, and
4-methoxy-N-methoxybenzamides (1b–f) afforded products
3b–3 f in excellent yields (Table 1, entries 2-6). The incorpo-
ration of the sterically demanding 4-tert-butyl substituent in
1g did not affect the reaction with 2a to a great extend, and
product 3g was afforded in 78% yield (Table 1, entry 7). In a
similar manner, 4-bromo-, 3-bromo-, 4-chloro-, 2-chloro-, and
4-fluoro-N-methoxybenzamides (1h–1l) also underwent the
reaction smoothly to give products 3h–3l in 86%, 74%, 89%,
70%, and 90% yield, respectively (Table 1, entries 8–12).
Comparison of these results indicates that the product yield is
slightly affected by the position of the substituent in 1. As
shown in Table 1, entries 2–4 and 10–11, the yield for the
methyl- or chloro-substituted substrate 1 follows the order:
para > meta > ortho. The observed trend may be rationalized
on the basis of the steric effect of the substituent. For meta-
Scheme 2. Proposed mechanism for the catalytic reaction of
N-methoxybenzamide (1a) with toluene (2a).
species. Michael and co-workers also suggested that the para-
selective arylation proceeds via a PdIV species.[13d–e] The initial
step involves the coordination of 1a to a PdII species, and is
À
substituted substrates 1, there are two possible C H activa-
À
tion sites C2 and C6, but the activation occurs only at C6. The
followed by an ortho C H activation to form a five-
À
C H activation at C2 is less likely because the steric repulsion
membered palladacycle 4, and the release of protons. The
oxidation of 4 by persulfate gives PdIV species 5, which is
arylated by substrate 2a to afford intermediate 6. Reductive
elimination leads to ortho-arylated product 7 and a PdII
between the meta-substituent and the palladium center is
stronger, if the activation process takes place at C2 (Table 1,
entries 3, 5, 9, and 15).
À
Finally, the present catalytic reaction is compatible with a
wide scope of functional groups. Compounds 1 with either
electron-withdrawing substituents, such as 4-F, 4-CF3,
4-CO2Me, and 3-NO2 groups (Table 1, entries 12, 13, 14, and
15), or electron-donating groups, such as 4-methyl, 3,4-
dimethyl, 4-methoxy, and 3,4-methylenedioxy groups
(Table 1, entries 2, 5, 6, and 16) react smoothly with arenes
to give the expected products 3.
To further explore the scope of the reaction, various
arenes 2b–e were employed to react with 1a under the
optimized conditions. Treatment of 1a with benzene 2b
afforded phenanthridinone 3q in 90% yield (Table 1,
entry 17). The reaction of electron-rich anisole (2c) with 1a
was highly regioselective and gave product 3r in 86% yield
(Table 1, entry 18). The reaction of 1a with o-xylene (2e;
Table 1, entry 20) also gave only one regioisomeric product
(3t) in 83% yield. It is noteworthy that chlorobenzene 2d also
reacted with 1a to afford the cyclization product 3s in
moderate yield (Table 1, entry 19). Thus, the present method
provides an efficient way to a fast assembly of phenanthri-
dinones with diverse substituents.
species. Subsequent deprotonation of the N H group in 7
and coordination of the nitrogen atom to a PdII species forms
À
intermediate 8. Further C H activation gives the seven-
membered palladacycle 9. Reductive elimination of 9 affords
3a and a Pd0 species, which is oxidized by K2S2O8 to
regenerate the active PdII species for the next catalytic cycle.
To support the intermediacy of 7, we prepared 7a and
examined its reactivity under various conditions. First, 7a was
treated with Pd(OAc)2 (10 mol%) and K2S2O8 (1 equiv) in
TFA (20.0 equiv) at 258C for 3 h, and cyclization product 3q
was obtained in 96% yield [Eq. (1)]. When the same reaction
was carried out in the absence of K2S2O8, 3q was obtained in
8% yield. These observations suggest that Pd(OAc)2 and TFA
can convert 7a into final product 3q. The observations also
indicate that K2S2O8 acts as an oxidant to transform Pd0 to
PdII.
On the basis of known metal-catalyzed directing-group-
À
assisted C H activation reactions, a plausible mechanism for
the reaction of 1a with 2a to give 3a is proposed in Scheme 2.
The arylation of N-methoxybenzamides most likely proceeds
through a pathway similar to the para-selective arylation of
amides with simple arenes,[4j] a reaction in which a persulfate
salt is used as the oxidant and which proceeds through a PdII/IV
pathway. Similarly, the acetoxylation of oximes[13a] and
anilides,[13b] the alkoxylation of N-methoxybenzamides,[9]
and the dimerization of 2-phenylpyridines[13c] in the presence
of persulfate salt was proposed to also proceed via PdII/IV
The present methodology appears to be very useful for the
synthesis of natural products that contain the phenanthridi-
none core. For example, crinasiadine (9a, Scheme 3) can be
very conveniently synthesized by reaction of N-methoxy-
benzamide 1p. Reaction of 1p with benzene under the
standard catalytic conditions gave 3p in 71% yield. Photolysis
of 3p in methanol afforded crinasiadine in 90% yield.[14] This
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Angew. Chem. Int. Ed. 2011, 50, 9880 –9883

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Scheme 3. Synthesis of crinasiadine (9a) from 3p.
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In conclusion, we have successfully demonstrated the
palladium-catalyzed synthesis of phenanthridinone deriva-
tives from N-methoxybenzamides and arenes through multi-
À
À
À
ple oxidative C H activation and C C/C N formation steps
in one pot at room temperature. This method allows the rapid
generation of phenanthridinone derivatives with diverse
substituents (demonstrated with the synthesis of natural
product crinasiadine) that are of importance in biochemistry
and medicinal chemistry.
[5] V. S. Thirunavukkarasu, C.-H. Cheng, unpublished results.
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Experimental Section
General procedure for the palladium-catalyzed synthesis of phenan-
thridinones.
A
sealed tube (20 mL) containing Pd(OAc)2
(0.070 mmol, 10.0 mol%), N-methoxybenzamide (0.70 mmol), and
K2S2O8 (1.40 mmol) was evacuated and purged three times with
nitrogen gas. Toluene (17.5 mmol, 1.95 mL) and TFA (14.0 mmol,
1.1 mL) were added to the mixture by syringe. The reaction mixture
was stirred at 258C for 16 h, then diluted with dichloromethane and
stirred in air for 10 min. The mixture was filtered through Celite and
silica gel pads and washed with dichloromethane. The filtrate was
concentrated and the residue was purified by column chromatogra-
phy on silica gel with hexane/ethyl acetate as eluent to afford the
desired product 3a (154 mg) in 92% yield.
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Received: June 22, 2011
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Published online: September 2, 2011
Keywords: cyclization · homogeneous catalysis ·
.
N-methoxybenzamides · palladium · phenanthridinones
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Angew. Chem. Int. Ed. 2011, 50, 9880 –9883
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