Palladium-catalyzed oxidative insertion of carbon monoxide to N -sulfonyl-2-aminobiaryls through C-H bond activation: Access to bioactive phenanthridinone derivatives in one pot

Article abstract of DOI:10.1021/ol4001922

Palladium-catalyzed oxidative carbonylation of N-sulfonyl-2-aminobiaryls through C-H bond activation and C-C, C-N bond formation under TFA-free and milder conditions has been developed. The reaction tolerates a variety of substrates and provides biologically important phenanthridinone derivatives in yields up to 94%.

Full text of DOI:10.1021/ol4001922

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Oxidative
Insertion of Carbon Monoxide to
N‑Sulfonyl-2-aminobiaryls through CꢀH
Bond Activation: Access to Bioactive
Phenanthridinone Derivatives in One Pot
Venkatachalam Rajeshkumar,† Tai-Hua Lee,† and Shih-Ching Chuang*
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010,
Taiwan, R.O.C.
jscchuang@faculty.nctu.edu.tw
Received January 22, 2013
ABSTRACT
Palladium-catalyzed oxidative carbonylation of N-sulfonyl-2-aminobiaryls through CꢀH bond activation and CꢀC, CꢀN bond formation under
TFA-free and milder conditions has been developed. The reaction tolerates a variety of substrates and provides biologically important
phenanthridinone derivatives in yields up to 94%.
The structural moiety of phenanthridinones is widely
occurring in a variety of natural products and biologically
active drug intermediates (Figure 1).1 Since the molecular
skeleton has biological importance, such as antitumor
activity, antiviral activity, and cytotoxicity, the development
of a more straightforward synthetic method has been an
attractive topic of research.2 The transition-metal-catalyzed
CꢀH bond activation strategy has grown as an efficient
method for constructing CꢀC, CꢀN, CꢀO bonds and
has been extensively used to synthesize various natural
products and bioactive molecules.3 Independent re-
ports by Cheng and Wang’s research groups have re-
cently displayed the Pd- and Rh-catalyzed synthesis of
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† These authors contributed equally.
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r
10.1021/ol4001922
XXXX American Chemical Society

phenanthridinones from N-methoxy benzamides with
aryl iodides or arylboronic acids via dual CꢀH bond
activations (Scheme 1).4
Scheme 1. Approaches for Synthesis of Phenanthridinones
through CꢀH Bond Activation
Figure 1. Naturally occurring phenanthridone-based natural
products.
aminobiaryls with [60]fullerene through Pd(II)-catalyzed
CꢀH bond activation that afforded [60]fulleroisoquino-
linones and [60]fulleroazepines, respectively.9 There are a
number of strategies through which phenanthridines10
and carbazoles11 have been synthesized from 2-amino-
biaryl systems; however, insertion of CO for making
phenanthridinones has yet to be explored further. We
anticipated that if the C60 in our previous work9c were
replaced with CO, we would access exclusively bioactive
phenanthridinone derivatives (Scheme 1). Owing to the
synthetic values of the phenanthridinone structure and
our continuing interests in the Pd-catalyzed CꢀH activa-
tion reactions, herein we report the oxidative insertion of
carbon monoxide withN-sulfonyl-2-aminobiaryls through
CꢀH bond activation under trifluoroacetic acid (TFA)-
free and milder conditions (Scheme 1).
In this context, transition-metal-catalyzed carbonyla-
tion of organic compounds has turned into one of the
most important approaches in CꢀC, CꢀN bond-forming
processes.5 In this regard, Yu et al.6 have demonstrated
the ortho carbonylation of anilides and carboxylic acids
through Pd(II)-catalyzed CꢀH bond activation under a
CO atmosphere. A recent report by Chatani, Rovis, Booker-
Milburn and co-workers revealed the synthesis of phthal-
imides7 through oxidative carbonylation of benzamides via
Pd-, Ru-, and Rh-mediated CꢀH bond activation, re-
spectively. Similarly, Pd-catalyzed oxidative dual CꢀH
functionalization/carbonylation of diaryl ethers for the
synthesis of xanthones was achieved by Lei.8 We recently
reported the annulation of benzamides and N-sulfonyl-2-
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2012, 354, 2473–2483.
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Table 1. Optimization of Reaction Conditionsa
oxidants
(equiv)
solvent
(mL)
temp (°C), yield of yield of
time (h) 2a (%)b 3 (%)b
entry
1
2
3
4
5
6
7
8
9
CH3COOAg (2) DMSO (4)
CH3COOAg (2) THF (4)
100, 4 h 36 (57)
70, 4 h 45 (85)
28
trace
ꢀ
CH3COOAg (2) CH3CN (4) 80, 24 h 40 (89)
CH3COOAg (3) CH3CN (4) 80, 24 h 79 (98)
CH3COOAg (4) CH3CN (4) 80, 24 h 90 (98)
CH3COOAg (5) CH3CN (4) 80, 24 h 94 (100)
ꢀ
ꢀ
ꢀ
Cu(OAc)2 (2)
Ag2O (2)
BQ (2)
CH3CN (4) 80, 20 h 44 (66)
CH3CN (4) 80, 20 h 46 (64)
ꢀ
ꢀ
CH3CN (4) 80, 20 h
0
ꢀ
10 KHSO5 (2)
11 K2S2O8 (2)
12 CH3COOAg (2) Bu-CN (4) 110, 24 h
13c CH3COOAg (5) CH3CN (4) 80, 24 h 81 (99)
14d CH3COOAg (2) CH3CN (4) 80, 24 h 18 (89)
CH3CN (4) 80, 20 h 35 (66)
25
17
49
ꢀ
CH3CN (4) 80, 20 h
0
0
ꢀ
(11) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 14560–14561. (b) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115–1118. (c) Jordan-Hore, J. A.;
Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 16184–16186. (d) Cho, S. H.; Yoon, J.; Chang, S. J. Am.
Chem. Soc. 2011, 133, 5996–6005. (e) Youn, S. W.; Bihn, J. H.; Kim, B. S.
Org. Lett. 2011, 13, 3738–3741.
a All the reactions were performed with 1a (50 mg, 0.154 mmol),
10 mol % of Pd(OAc)2 (3.47 mg, 0.015 mmol) under CO balloon. b Yields
were measured by 1H NMR spectroscopy, using mesitylene as an internal
standard. Values in parentheses are based on converted 1a. c 15 mol % of
Pd(OAc)2 was employed. d PdCl2(PPh3)2 was used as a catalyst.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Palladium-Catalyzed Synthesis of Phenanthridinone Derivativesa
a All reactions were carried out with substrate 1 (50.0 mg), Pd(OAc)2 (10 mol %), and CH3COOAg (5 equiv) in 4 mL of anhydrous CH3CN at 80 °C
for 24 h under CO balloon. b Isolated yields. Values in parentheses are based on converted 1.
We initiated our studies to understand the nature of the
present carbonylation reaction by performing a series of
optimization reactions using N-tosyl-2-aminobiphenyl
(1a) as a model substrate, and the results are summarized
Org. Lett., Vol. XX, No. XX, XXXX
C

in Table 1. We used the tosyl group in this study because it
can direct the palladium center to activate the ortho CꢀH
bond of the other aryl ring with ease for later deprotection
as compared to N-alkyl groups,11c and it may provide the
opportunity for further elaboration via ortho CꢀH activa-
tion on the other aryl ring through sulfonyl group modi-
fication.12 At first, we performed the reaction of 1a with CO
in the presence of 10 mol % Pd(OAc)2 and 2 equiv of
CH3COOAg in DMSO at 100 °C for 4 h. Surprisingly, we
found the formation of desired product 2a in 36% yield
together with 28% of N-tosyl carbazole 3 as byproducts
(Table 1, entry 1). We then tested various reaction conditions
so that the formation of 3 is lessened in the reaction through
direct amination. When we switched the solvent to THF, we
isolated the compound 2a in 45% yield with trace amounts
of 3 (entry 2). The use of anhydrous CH3CN extensively
reduced the byproduct formation and produced the desired
product 2a in 40% yield (entry 3). After controlling the
formation of 3 in the reaction, we proceeded next to screen
conditions to increase the reaction yield. We concluded
through our observations that the choice of solvents and
amounts of oxidizing agent are important for the present
carbonylation reaction. When the use of CH3COOAg was
increased from 2 to 3 equiv, the desired product 2a was
isolated in good yield (79%, entry 4). Then, we performed the
reaction with a higher amount of silver acetate such as 4 and
5 equiv; the product 2a was isolated in excellent yields, 90 and
94%, respectively (entries 5 and 6). Other metal oxidizing
agents, such as Cu(OAc)2 or Ag2O, were not effective for this
carbonylation reaction (entries 7 and 8). No reaction oc-
curred when the reaction was performed with benzoquinone
as oxidants (entry 9). Product 2a and 3 were formed in 35 and
25% yields, respectively, when the reaction was tested with
KHSO5 (entry 10), while the reaction with K2S2O8 was
totally ineffective (entry 11). When solvent CH3CN was
replaced with butyronitrile, the reaction selectivity was also
changed; we observed the formation of 3 exclusively in 49%
yield (entry 12). Further, increasing catalytic amounts of
Pd(OAc)2 was not useful for increasing reaction yields
(entry 13). Another palladium source, PdCl2(PPh3)2, was
rather less effective for this transformation (entry 14).
electron-donating methyl group on aryl rings reacted smoothly
to deliver corresponding phenanthridinones 2cꢀi in good to
excellent yields, 71ꢀ94% (entries 3ꢀ9). We isolated phe-
nanthridinone derivatives 2jꢀl in 94, 86, 91% yields, respec-
tively, in very high regioselectivity from 1jꢀl under our
optimal reaction conditions (entries 10ꢀ12). Further, sub-
strates 1mꢀp equipped with strong electron-withdrawing
groups, such as chloro, fluoro, and trifluoromethoxy, af-
forded the desired products 2mꢀp in good to excellent yield,
89, 86, 88, and 93%, respectively (entries 13ꢀ16). Highly
electron-rich substrates such as 1qꢀr gave the correspond-
ing carbonylated products 2qꢀrin good yields, 81 and 82%,
respectively, and in excellent yields based on converted
starting materials (entries 17 and 18). Further, the present
carbonylation reaction is applicable to a heteroaromatic
system, such as substrate 1s with a 2-thienyl moiety, which
produced 2s in 86% yield (entry 19).13 In a similar way, the
polyaromatic substrates 1tꢀx gave the corresponding pro-
ducts 2tꢀx in moderate to excellent yields (entries 20ꢀ24).
Further, we achieved the detosylation14 of 2c, 2o, and 2q
using TBAF that produced 2c0, 2o0, and crinasiadine 2q0 in
97, 77, and 82% yields, respectively. Thus, the present
oxidative carbonylation reaction provides an efficient way
to access bioactive phenanthridinone derivatives under
milder reaction conditions with a wide range of substrates.
The rational reaction pathway for the present carbonylation
is proposed on the basis of our experimental results and
known metal-mediated CꢀH bond activation reactions.15
In conclusion, we have established an efficient Pd-
catalyzed oxidative carbonylation of N-sulfonyl-2-amino-
biaryls via one NꢀH and CꢀH bond cleavage and one new
CꢀC and CꢀN bond formation under TFA-free and
milder conditions with a tolerence for a large number of
substrates in excellent yields. The present carbonylation
reaction brings into existence a straightforward way to
access phenanthridinone derivatives which are a structural
moiety existing widely in amaryllidaceae alkaloids, various
natural products, and bioactive molecules.
Acknowledgment. We thank the National Science Coun-
cil and NCTU for financial support of this research and
Dr. V. Rajeshkumar thanks NSC for a postdoctoral fellowship.
We also thank Mr. P.-Y. Tseng for checking heterocyclic
examples and Prof. C.-S. Lee for providing CO gas.
After obtaining the optimal reaction conditions, we next
proceeded to examine the substrate scope of the present
carbonylation reaction, and the results are summarized in
Table 2. Under standard reaction conditions, substrates
1aꢀb having no substitutions underwent carbonylation
smoothly to give phenanthridinone derivatives 2aꢀb in
good yields, 94 and 84%, respectively (Table 2, entries
1ꢀ2). It was found that the substrates, 1cꢀi, bearing an
Supporting Information Available. Detailed experimen-
tal procedures and spectral characterization of all new
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
(12) Urones, B.;Arrayas, R. G.;Carretero, J. C. Org. Lett. 201310.1021/
ol400206k.
(15) See the Supporting Information for the proposed reaction
mechanism (Scheme S1). During the preparation of this manuscript,
the Pd(MeCN)2Cl2 catalyzed carbonylation of unprotected o-arylani-
lines was reported. Reaction conditions: o-Arylanilines (0.2 mmol),
Pd(MeCN)2Cl2 (5 mol %), Cu(TFA)2 (1.0 equiv), TFA (1.0 equiv),
CO balloon (1 atm), dioxane (1.0 mL), 110 °C, 7ꢀ65 h. Liang, D.; Hu,
Z.; Peng, J.; Huang, J.; Zhu, Q. Chem. Commun. 2013, 49, 173–175.
(13) The present standard condition is not applicable to the heterocyclic
examples with the pyridyl moiety such as 4-methyl-N-(2-(pyridin-2-yl)-
phenyl)-, 4-methyl-N-(2-(pyridin-3-yl)phenyl)-, 4-methyl-N-(2-(pyridin-4-
yl)phenyl)benzenesulfonamides. No corresponding CO insertion products
were observed, likely due to their electron-defficient and unreactive nature.
(14) (a) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2012,
ꢀ
14, 2304–2307. (b) Peron, F.; Fossey, C.; Cailly, T.; Fabis, F. Org. Lett.
2012, 14, 1827–1829. (c) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T.
J. Org. Chem. 2010, 75, 3900–3903.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX