Palladium-catalyzed cyclization of benzamides with arynes: Application to the synthesis of phenaglydon and N-methylcrinasiadine

Article abstract of DOI:10.1039/c4cc05252h

N-Methyl or methoxy benzamides reacted with benzynes in the presence of Pd(OAc)₂, organic acid and K₂S₂O₈ in CH₃CN yielding tricyclic phenanthridinone derivatives in good yields. This journal is

Full text of DOI:10.1039/c4cc05252h

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Palladium-catalyzed cyclization of benzamides
with arynes: application to the synthesis of
phenaglydon and N-methylcrinasiadine†
Cite this: Chem. Commun., 2014,
50, 12116
Received 8th July 2014,
Accepted 18th August 2014
Sandeep Pimparkar and Masilamani Jeganmohan*
DOI: 10.1039/c4cc05252h
www.rsc.org/chemcomm
N-Methyl or methoxy benzamides reacted with benzynes in the
Transition metal-catalyzed cyclization of heteroatom substi-
presence of Pd(OAc)2, organic acid and K2S2O8 in CH3CN yielding tuted aromatics with carbon–carbon p-components via chelation-
tricyclic phenanthridinone derivatives in good yields.
assisted C–H bond activation is a practical method to synthesize
heterocyclic molecules in one pot.7 By using nitrogen containing
Phenanthridinones are the key core units found in various chelating groups such as amide, oxime and imine substituted
natural products and biologically active molecules.1 These aromatics or alkenes, various nitrogen-containing mono- and
molecules are used as potential PARP-1 inhibitors in anticancer bicyclic heterocycles are prepared through the consecutive C–C
drugs as well as neurotrophin activity enhancers for the treat- and C–N bond formation.7 In the cyclization reaction, alkynes,
ment of nerve diseases.2 Traditionally, phenanthridinones are alkenes and allenes are extensively used as carbon–carbon
synthesized by cyclization of nitrocarbonyl-biphenyls, Beckmann/ p-components (eqn (1)). However, benzyne as a p-component
Schmidt rearrangement of fluorenones and photoinduced has not been well explored in the literature. In fact, there are
rearrangement of 2-halobenzamides.3 However, in these reactions, several challenges to utilize benzyne as a p-component in the
the preparation of key starting materials needs more steps and the reaction due to its high reactivity. It is very important to note
overall yields observed are lower. Subsequently, phenanthridinones that in the cyclization of substituted aromatics with benzynes,
are prepared by a palladium-catalyzed homo coupling of ortho-halo a tricyclic ring system can be constructed in one pot.
benzamides and coupling of aromatic halides with ortho-halo
We focused on utilization of a highly reactive benzyne as a
benzamides.4 Very recently, Larock’s group reported the synthesis p-component in the cyclization reaction. Initially, we tried the
of phenanthridinones via a palladium-catalyzed cyclization of cyclization of N-methoxy 4-methoxy benzamide (1a) with o-(tri-
ortho-halo N-substituted benzamides with benzynes (eqn (1)).5 methylsilyl)aryl triflate (2a) in the presence of [{RuCl2(p-cymene)}2],
But a preactivated carbon–halogen partner on the aromatic AgSbF6 and Cu(OAc)2 in CH3CN at 100 1C for 12 h (Table 1, entry 1).
moiety is required for the reaction. Apart from these reactions, CsF in CH3CN was used to generate benzyne from benzyne
phenanthridinones are prepared by a metal-catalyzed ortho arylation precursor 2a.8 In the reaction, only N-arylated benzamide 3a was
of benzamides with iodobenzenes or aromatic boronic acids or observed in 30% yield and the expected cyclization product 4a
electron-rich aromatics followed by intramolecular C–N bond was not observed. Next, the cyclization reaction of 1a with 2a was
formation.6
examined in the presence of Pd(OAc)2 (5 mol%) and acetic acid or
CF3COOH (10.0 equiv.) in CH3CN (entries 2 and 3). In the reaction,
no N-arylation product 3a or cyclization product 4a was observed. It
seems AcOH or CF3COOH might quench the CsF base. Then, acetic
acid was replaced by the sterically hindered pivalic acid (entry 4).
Interestingly, in the reaction, the expected cyclization product 4a
was observed in 35% yield and competitive product 3a was also
observed in 10% yield. To avoid product 3a, the reaction was tested
with a catalytic amount of 1-adamantanecarboxylic acid (Adm-1-
COOH) (30 mol%) (entry 5). Surprisingly, in the reaction, product 4a
was observed in 45% yield and no N-arylated product 3a was
observed. To increase the yield of product 4a, the reaction was
examined with oxidants (1.0 equiv.) (entries 6–11). Interestingly,
using K2S2O8, product 4a was observed in 74% GC yield and 66%
(1)
Department of Chemistry, Indian Institute of Science Education and Research,
Pune 411021, India. E-mail: mjeganmohan@iiserpune.ac.in
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data. CCDC 1012984. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4cc05252h
12116 | Chem. Commun., 2014, 50, 12116--12119
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Cyclization of benzamide 1a with benzyne precursor 2aa
which the ortho C–H bond activation takes place selectively at a
sterically less hindered side. Whereas, benzamide 1g provided
mixtures of regioselective cyclization products 4g and 4g0 in 60%
combined yield in a 1.5 : 1 ratio. Furthermore, the cyclization
reaction was tested with 4-bromo and 4-chloro benzamides 1h
and 1i. However, only N-arylated benzamides 3h and 3i were
observed in 47% and 51% yields, respectively, and the expected
cyclization products 4 were not observed. Similarly, 4-trifluoro-
methyl, 4-cyano and 4-nitrobenzamides were also not favorable
for the reaction. These results clearly reveal that electron-
donating substituents on the aromatic moiety of benzamides
favor the ortho C–H bond activation–cyclization reaction. But,
halogen and electron deficient aromatic benzamides favor only
competitive nucleophilic addition of the free N–H moiety of
benzamide with benzyne. Surprisingly, the palladacycle of
4-chloro benzamide 5a reacted with benzyne precursor 2a,
yielding cyclization product 4h in 45% yield. This result clearly
says that the ortho C–H bond activation process is very slow
in the electron deficient benzamides, and the competitive
nucleophilic addition is very fast. Although, at present, the
catalytic reaction was compatible with only electron-rich
benzamides, it has been shown that a highly reactive benzyne
can be used as a p-component for the cyclization reaction.
The cyclization reaction was also examined with benzyne
precursors 2b–e (Scheme 2). Treatment of benzamide 1a with
benzyne precursors 2b and 2c gave phenanthridinones 4i and 4j
in 61% and 55% yields, respectively. Interestingly, synthetically
Entry
Catalyst/additive
Oxidant
3a/4a yieldb (%)
c
1
2
[RuCl2(p-cymene)]2/AgSbF6
Pd(OAc)2/AcOH
Cu(OAc)2
—
30/0
—
3
4
5
6
7
8
9
10
11
Pd(OAc)2/TFA
—
—
—
Ag2O
Ag2CO3
AgOAc
K2S2O8
PhI(OAc)2
(NH4)2S2O8
—
Pd(OAc)2/pivalic acid
Pd(OAc)2/Adm-1-COOHd
Pd(OAc)2/Adm-1-COOHd
Pd(OAc)2/Adm-1-COOHd
Pd(OAc)2/Adm-1-COOHd
Pd(OAc)2/Adm-1-COOHd
Pd(OAc)2/Adm-1-COOHd
Pd(OAc)2/Adm-1-COOHd
10/35
0/45
0/33
0/27
0/45
0/74
—
—
a
Reactions conditions: 1a with 2a (1.5 equiv.) in the presence of cat
(5.0 mol%), additive (10.0 equiv.) and oxidant (2.0 equiv.) in CH3CN at
b
c
d
100 1C for 12 h. GC yield. AgSbF6 (20 mol%) was used. Adm-1-COOH
(30 mol%) was used.
isolated yield (entry 9). Remaining oxidants were partially effective or
totally ineffective, yielding 4a in 0–45% yields (entries 6–11).
The scope of the catalytic reaction was tested with substi-
tuted N-methoxy benzamides 1b–i (Scheme 1). 2-Methoxy (1b),
4-methyl (1c) and N-methoxy benzamides (1d) underwent cycli-
zation with 2a, yielding phenanthridinones 4b–d in 55%, 62%
and 61% yields, respectively. Next, the cyclization reaction was
tested with unsymmetrical benzamides. N-Methoxy 3,4-dimethoxy
benzamide (1e) and meta methoxy benzamide 1f afforded phenan-
thridinones 4e and 4f in 61% and 58% yields, respectively, in
Scheme 2 Scope of the benzyne precursors 2b–e.
Scheme 1 Scope of the N-methoxy benzamides 1.
Scheme 3 Scope of the N-methyl benzamides 6a–d.
Chem. Commun., 2014, 50, 12116--12119 | 12117
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
useful benzyne precursors 2d and 2e reacted with 1e, giving
products 4k and 4l in 70% and 63% yields, respectively.
The catalytic reaction was further tested with other N-methyl
benzamides (Scheme 3). N-Methyl benzamide (6a) underwent
cyclization with 2a, providing N-methyl phenanthridinone 7a in
49% yield, in which ortho C–H bond activation takes place
selectively at the sterically less hindered side. Further, N-methyl
4-methoxy benzamide (6b) and N-methyl benzamide (6c) reacted
with 2a or 2c affording cyclization products 7b–d in 45%, 43% and
38% yields, respectively. Treatment of N-methyl benzamide 6d
with 1a gave natural product N-methylcrinasiadine9b (7e) in 30%
yield and other regioisomer 7e0 in 25% yield. It is important to
point out that natural product N-methylcrinasiadine (7e) shows
several biological activities.1
Scheme 5 Mechanistic investigation.
N–H arylation of benzamide with benzyne providing compound 3
followed by intramolecular dehydrogenative aryl–aryl coupling are
also possible.7 To support the proposed mechanism in Scheme 4,
the following reactions were done (Scheme 5). ortho-Arylated
benzamide 12 was prepared separately and treated with Pd(OAc)2,
CsF and K2S2O8 in CH3CN at 100 1C for 12 h. In the reaction, no
cyclization product 4a was observed. Subsequently, N-arylated
benzamide 3a was treated with Pd(OAc)2 and K2S2O8 under similar
reaction conditions. However, no cyclization product 4a was
observed. Further, a five-membered palladacycle intermediate 5b
was prepared separately and treated with benzyne precursor 2a in
the presence of CsF in CH3CN at 100 1C for 12 h. As expected, the
cyclization product 4f was observed in 75% yield. These results
clearly revealed that the present reaction proceeds via a coordina-
tive insertion pathway. To support the hypothesis that benzyne is
involved in the cyclization reaction, the reaction of benzamide 1e
with unsymmetrical benzyne precursor 2g was performed. In the
reaction, a mixture of regioisomeric compounds 4n and 4n0 was
observed in 53% combined yield in a 2 : 1 ratio. The lack of
regioselectivity of the reaction is consistent with insertion of
unsymmetrical benzyne into a Pd–carbon bond in intermediate 5.
In conclusion, we have demonstrated a palladium-catalyzed
oxidative cyclization of N-substituted benzamides with benzynes
providing phenanthridinones with diverse substituents.
(2)
Later, OMe groups on the cyclic amides of 4c and 4d were
cleaved into the natural product phenaglydon9a,b 8a in 69%
yield and 6(5H)-phenanthridinone 8b in 67% yield under the
photochemical irradiation conditions7a,b (eqn (2)). Later, com-
pound 8b underwent nitration at the C-5 position of phenan-
thridinone in the presence of HNO3/H2SO4, providing 5-nitro
phenanthridinone 9 in 75% yield. It is important to note that
compound 9 is a key precursor for the preparation of anti-
cancer drug PJ34.9c
A possible reaction mechanism is proposed in Scheme 4 to
account for the present cyclization reaction. Coordination of
the amide nitrogen of benzamide 1 to the palladium species
followed by ortho-metalation provides a five-membered pallada-
cycle intermediate 5. Coordinative insertion of benzyne 10 into
intermediate 5 yields a seven-membered palladacycle intermediate
11. Subsequent C–N bond formation and reductive elimination
afford product 4 and regenerate the active palladium species in the
presence of RCOOH and K2S2O8.
We thank the DST (SR/S1/OC-26/2011), India for the support
of this research. S. P. thanks the BRNS for a fellowship.
Apart from the above proposed mechanism, other possible
pathways such as ortho-arylation of benzamide with benzyne yield-
ing product 12 followed by intramolecular C–N bond formation or
Notes and references
1 (a) F. Aprile-Garcia, M. Antunica-Noguerol, M. L. Budzinski, A. C. Liberman
and E. Arzt, Endocr. Connect., 2014, 3, 1; (b) S. E. Nasrabady,
A. Kuzhandaivel, M. Mladinic and A. Nistri, Cell. Mol. Neurobiol.,
2011, 31, 503; (c) Z. Jin, Nat. Prod. Rep., 2009, 26, 363; (d) J. P. Michael,
Nat. Prod. Rep., 1995, 12, 465.
2 (a) T. Harayama, H. Akamatsu, K. Okamura, T. Miyagoe, T. Akiyama,
H. Abe and Y. Takeuchi, J. Chem. Soc., Perkin Trans. 1, 2001, 523;
(b) T. Harayama, Y. Akiyama, K. Nakano, H. Shibaike, A. Akamatsu,
H. Hori, H. Abe and Y. Takeuchi, Synthesis, 2002, 237; (c) V. Holl,
D. Coelho, D. Weltin, P. Dufour and P. Bischoff, Anticancer Res., 2000,
20, 3233; (d) S. Patil, S. Kamath, T. Sanchez, N. Neamati,
R. F. Schinazi and J. K. Buolamwini, Bioorg. Med. Chem., 2007,
15, 1212.
3 (a) A. K. Mohanakrishnan and P. C. Srinivasan, J. Org. Chem., 1995,
60, 1939; (b) R. Kleppinger, C. P. Lillya and C. Yang, J. Am. Chem. Soc.,
1997, 119, 4097; (c) M. G. Banwell, D. W. Lupton, X. Ma, J. Renner and
M. O. Sydnes, Org. Lett., 2004, 6, 2741; (d) R. Kleppinger, C. P. Lillya
and C. Yang, J. Am. Chem. Soc., 1997, 119, 4097; (e) L. M. N. Meseroll,
J. R. McKee and M. Zanger, Synth. Commun., 2011, 41, 2557;
Scheme 4 Proposed mechanism.
12118 | Chem. Commun., 2014, 50, 12116--12119
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
( f ) A. Padwa, M. Dimitroff, A. G. Waterson and T. Wu, J. Org. Chem.,
1998, 63, 3986; (g) H. Suzuki, T. Enya and Y. Hisamatsu, Synthesis,
1997, 1273.
C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879;
( f ) L. Ackermann, Acc. Chem. Res., 2014, 47, 281; (g) T. W. Lyons
and M. S. Sanford, Chem. Rev., 2010, 110, 1147.
4 (a) T. Furuta, Y. Kitamura, A. Hashimoto, S. Fujii, K. Tanaka and 7 (a) T.-T. Yuan, D.-D. Li and G.-W. Wang, Angew. Chem., Int. Ed., 2011,
T. Kan, Org. Lett., 2007, 9, 183; (b) P. H. Bernardo, W. Fitriyanto and
C. L. L. Chai, Synlett, 2007, 1935; (c) R. Ferraccioli, D. Carenzi,
O. Rombola and M. Catellani, Org. Lett., 2004, 6, 4759;
(d) V. Rajeshkumar, T.-H. Lee and S.-C. Chuang, Org. Lett., 2013,
15, 1468.
5 C. Lu, A. V. Dubrovskiy and R. C. Larock, J. Org. Chem., 2012, 77, 8648,
references therein.
50, 1380; (b) J. Karthikeyan and C.-H. Cheng, Angew. Chem., Int. Ed.,
2011, 50, 9880; (c) J. Karthikeyan, R. Haridhadharan and C.-H. Cheng,
Angew. Chem., Int. Ed., 2012, 51, 12343; (d) N. Senthilkumar,
K. Parthasarathy, G. Parthasarathy and C.-H. Cheng, Chem. – Asian
J., 2013, 8, 2175; (e) C. S. Yeung, X. Zhao, N. Borduas and V. M. Dong,
Chem. Sci., 2010, 1, 331.
8 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211.
6 (a) P. Thansandote and M. Lautens, Chem. – Eur. J., 2009, 15, 5874; 9 (a) G. Wurz, O. Hofer and H. Greger, Nat. Prod. Lett., 1993, 3, 177;
(b) T. Satoh and M. Miura, Chem. – Eur. J., 2010, 16, 11212; (c) G. Song,
F. Wang and X. Li, Chem. Soc. Rev., 2012, 41, 3651; (d) H. Wang and
F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 7318; (e) P. B. Arokiam,
(b) R. Suau, A. I. Gomez and R. Rico, Phytochemistry, 1990, 29, 1710;
(c) Z. Tu, W. Chu, J. Zhang, C. S. Dence, M. J. Wench and R. H. Mach,
Nucl. Med. Biol., 2005, 32, 437.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 12116--12119 | 12119