Synthesis of phenanthridinones from N-methoxybenzamides and aryltriethoxysilanes through RhIII-catalyzed C-H and N-H bond activation

Article abstract of DOI:10.1002/asia.201300356

An efficient method for the one-pot synthesis of substituted phenanthridinone derivatives from N-methoxybenzamides and aryltriethoxysilanes through rhodium-catalyzed dual C-H bond activation and annulation reactions is described. A double-cycle mechanism is proposed to account for this catalytic reaction. In addition, isotope-labeling studies were performed to understand the intimate mechanism of the reaction. Keeping active: The rhodium-catalyzed C-H bond activation and annulation reactions of N-methoxybenzamides with aryltriethoxysilanes to give substituted phenanthridinone derivatives in good-to-excellent yields is described. Copyright

Full text of DOI:10.1002/asia.201300356

FULL PAPER
FULL PAPER
À
C H Activation
Natarajan Senthilkumar,
Kanniyappan Parthasarathy,
Parthasarathy Gandeepan,
Chien-Hong Cheng*
&&&& — &&&&
Keeping active: The rhodium-catalyzed
C H bond activation and annulation
reactions of N-methoxybenzamides
with aryltriethoxysilanes to give substi-
tuted phenanthridinone derivatives in
good-to-excellent yields is described.
Synthesis of Phenanthridinones from
N-Methoxybenzamides and Aryltrie-
thoxysilanes through RhIII-Catalyzed
À
À
À
C H and N H Bond Activation
1
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Chien-Hong Cheng et al.
DOI: 10.1002/asia.201300356
Synthesis of Phenanthridinones from N-Methoxybenzamides and
III
À
À
Aryltriethoxysilanes through Rh -Catalyzed C H and N H Bond
Activation
Natarajan Senthilkumar, Kanniyappan Parthasarathy, Parthasarathy Gandeepan, and
Chien-Hong Cheng*[a]
Abstract: An efficient method for the one-pot synthesis of substituted phenanthri-
dinone derivatives from N-methoxybenzamides and aryltriethoxysilanes through
À
Keywords: annulation · C H acti-
À
rhodium-catalyzed dual C H bond activation and annulation reactions is de-
vation
·
phenanthridinones
·
scribed. A double-cycle mechanism is proposed to account for this catalytic reac-
tion. In addition, isotope-labeling studies were performed to understand the inti-
mate mechanism of the reaction.
rhodium · synthetic methods
Introduction
Several decades ago, this kind of benzannulation reaction
towards the synthesis of phenanthrene from naphthylcar-
bene was reported by Dçtz and co-workers.[10] The same
group also reported the synthesis of a chromium-coordinat-
ed tetracyclic benzannulated product from a dibenzocyclo-
heptenylidene complex.[11] Nakata and co-workers reported
the total synthesis of kendomycin by using a Dçtz intramo-
lecular benzannulation reaction.[12]
À
In recent years, catalytic C H bond activation by transition-
metal complexes has become a powerful and attractive tool
in organic synthesis.[1] In the C H functionalization process,
À
suitable heteroatoms in the substrates are commonly utilized
À
to direct a metal complex towards a specific proximal C H
bond. Although many Pd-[2] and RhI-catalyzed transmetala-
tion reactions[1a,3] that use arylsilanes as reagents have been
reported, RhIII-catalyzed transmetalation reactions of arylsi-
loxanes have rarely been explored.[4] The Hiyama coupling
reaction of organosilanes with various aryl halides is well-
known.[5] Recently, Shi and co-workers reported the direct
oxidative arylation of substituted 2-phenyl pyridine by aryl-
À
Recently, a large number of rhodium-catalyzed C H
bond activation reactions that involve a benzannulation step
have been developed, owing to their high catalytic activities,
low catalyst loadings, and high regioselectivities.[13] In view
of the advantage of using rhodium complexes as catalysts,
we have examined and demonstrated the catalytic activity of
À
silanes, which proceeded through a rhodium-catalyzed C C
rhodiumACTHNGUTERNN(UG III) complexes for the oxidative coupling and an-
bond cleavage.[4a] Miura and co-workers reported nickel-cat-
nulation of N-methoxybenzamides with arylboronic acids to
give phenanthridinone derivatives.[14] To date, there are no
reports on the use of aryltrialkoxysilanes for the coupling
À
alyzed C H arylation and alkenylation reactions of hetero-
arenes with organosilicon reagents.[6] Arylsiloxanes are of
particular interest because of their low toxicity and safe han-
dling compared with other types of reagents.[7]
and annulation reaction with N-methoxybenzamides
III
À
through Rh -catalyzed C H activation and annulation reac-
À
Wang et al. reported the synthesis of phenanthridinones
by using N-methoxybenzamides with aryl iodides through
Pd-catalyzed dual C H activation reactions. We have also
developed a method for the synthesis of phenanthridinones
tions. Our continuing interest in metal-catalyzed C H acti-
vation[15] prompted us to explore the reaction of N-methoxy-
benzamides with aryltrialkoxysilanes. Herein, we report an
effective method for the formation of phenanthridinone de-
rivatives from N-methoxybenzamides and aryltrialkoxysi-
lanes by using [(RhCp*Cl2)2] as the catalyst precursor
[Eq. (1)].
[8]
À
from N-methoxybenzamides and arenes through multiple
[9]
À
Pd-catalyzed C H activation steps at room temperature.
[a] Dr. N. Senthilkumar, Dr. K. Parthasarathy, Dr. P. Gandeepan,
Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University
Hsinchu, 30013 (Taiwan)
Fax : (+886)3572-4698
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300356.
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Chien-Hong Cheng et al.
Results and Discussion
obtain product 3aa by using polar solvents, various nonpolar
solvents were employed. Among the solvents that we exam-
ined, DCE gave the highest yield of the phenanthridinone
product (3aa) in 87% yield, as determined by integration of
the NMR spectrum, or the isolated product in 82% yield
(Table 1, entry 5). Other solvents, such as 1,2-dichloroben-
zene (DCB), 1,4-dioxane, and toluene, were also effective,
thus giving compound 3aa in 20–55% yield (Table 1, en-
tries 6–8), whereas THF failed to give compound 3aa
(Table 1, entry 9). The choice of fluoride source was also
vital to the catalytic reaction. Of the fluoride sources that
were tested, the best result was obtained with AgF, which
afforded compound 3aa in 82% yield (Table 1, entry 5).
Other salts, like KF, CsF, and Bu4NF, were less effective,
thus giving compound 3aa in low yields (Table 1, entries 10–
12). In the absence of a copper salt, compound 3aa was ob-
tained in 42% yield (Table 1, entry 13). Next, the reaction
was tested with 4.5 equivalents of the oxidant, instead of
4 equivalents. When the reaction was performed in the pres-
ence of 4.5 equivalents of AgF, compound 3aa was formed
in 91% yield (Table 1, entry 14). When 2 equivalents of AgF
First, we chose N-methoxybenzamide (1a) and phenyltrie-
thoxysilane (2a) as the substrates for the catalytic reaction.
After testing a wide range of catalytic reactions conditions,
we found that the treatment of compound 1a (0.050 g,
0.33 mmol) with phenyltriethoxysilane (2a, 0.159 g,
0.66 mmol) in the presence of [(RhCp*Cl2)2] (0.0041 g,
2.0 mmol%), AgF (0.085 g, 0.66 mmol), and CuACTHUNRGTNEUNG(OAc)2
(0.120 g, 0.66 mmol) in 1,2-dichloroethane (DCE, 2 mL) at
608C for 3 h gave phenanthridinone 3aa in 82% yield. The
1
structure of compound 3aa was confirmed by its H NMR,
13C NMR, and mass spectra.
À
This rhodium-catalyzed C H activation reaction appeared
to greatly depend on the solvent, fluoride salt, and reaction
temperature. First, we chose AgF/CuACTHNUTRGENUG(N OAc)2 as oxidants,
based on literature reports, and tried to find a suitable sol-
vent and reaction temperature. At high temperatures
(1308C and 1008C), all of the solvents listed in Table 1 gave
only trace amounts or no product formation. Next, we low-
ered the reaction temperature and tested the reaction with
various solvents. At 608C, polar solvents, such as tert-amyl
alcohol and EtOH, gave trace amounts of the product
(Table 1, entries 1 and 2), but DMF and MeCN were com-
pletely inactive (Table 1, entries 3 and 4). Having failed to
and 2.5 equivalents of CuACHTNUTRGENNG(U OAc)2 were used, the yield of
compound 3aa decreased slightly to 86% (Table 1,
entry 15). When 1.0 equivalent of AgF and 3.5 equivalents
of CuACTHNUTRGNE(UNG OAc)2 were employed, the yield of compound 3aa
dramatically decreased (Table 1, entry 16). Longer reaction
times (8 h and 12 h) did not have any effect on the yield of
compound 3aa. Without a Rh catalyst, the reaction failed to
give compound 3aa (Table 1, entry 17). When Ag2O was
used instead of AgF, no expected product was observed
either (Table 1, entry 18).
Table 1. Optimization studies for the RhIII-catalyzed synthesis of phenan-
thridinones from compounds 1a and 2a.[a]
Under similar reaction conditions, various substituted N-
methoxybenzamides (1b–1n) were reacted with compound
2a to give their corresponding phenanthridinone derivatives
(3, Table 2). Thus, 4-methylbenzamide (1b) afforded com-
pound 3ba in 87% yield. This catalytic reaction is nicely tol-
erant of halo substituents on the aromatic ring of the N-me-
thoxybenzamides. As a result, 4-bromo-, 4-chloro-, and 4-
fluoro-N-methoxybenzamides (1c–1e) afforded their corre-
sponding phenanthridinones (3ca, 3da, and 3ea) in 84, 80,
and 79% yield, respectively. This catalytic reaction also
worked well with benzamides that contained electron-with-
drawing CF3 and NO2 groups (1 f and 1g), thus giving phe-
nanthridinones 3 fa and 3ga in 75 and 78% yield, respec-
tively. However, 4-cyano- and heteroaryl amides, such as
benzofuran-2-amide and benzothiophene-2-amide, failed to
give their corresponding phenanthridinones. The reaction of
4-phenyl-N-methoxybenzamide 1h with compound 2a pro-
vided phenanthridinone 3ha in 81% yield. In all of these re-
actions, biphenyl was formed as a side product.
Entry
Fluoride salt
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
KF
t-amylOH
EtOH
DMF
CH3CN
DCE
<10
<10
0
0
87 (82)
55
20
40
0
<10
20
15
DCB
toluene
1,4-dioxane
THF
9
10
11
12
13
14
15
16
17
18
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CsF
Bu4NF
AgF
AgF
AgF
AgF
AgF
–
42[c]
91[d]
86[e]
57[f]
0[g]
DCE
0[h]
[a] Unless otherwise noted, all of the reactions were performed by using
N-methoxybenzamide (1a, 0.050 g, 0.33 mmol), arylsilane 2a (0.159 g,
0.66 mmol), [(RhCp*Cl2)2] (4.1 mg, 0.0066 mmol), AgF (0.085 g,
To understand the regioselectivity of meta-substituted N-
methoxybenzamides in this catalytic reaction, we employed
3-methyl-, 3-bromo-, 3,4-dimethyl-, 3-nitro-, and 3,4-(meth-
ylenedioxy)-N-methoxybenzamides ACTHNUTRGNE(NUG 1i–1m) as the sub-
strates. For compounds 1i–1l, their reactions with com-
0.66 mmol), and Cu
608C for 3 h. [b] Yields were determined by integration of the 1H NMR
spectra. [c] AgF (0.66 mmol, 2.0 equiv) in the absence of Cu(OAc)2.
[d] AgF (4.5 equiv) in the absence of Cu(OAc)2. [e] AgF (2 equiv) and
Cu(OAc)2 (2.5 equiv). [f] AgF (1 equiv) and Cu(OAc)2 (3.5 equiv).
ACHTUNGTRENNUNG(OAc)2 (0.120 g, 0.66 mmol) in solvent (2 mL) at
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
pound 2a proceeded in a regioselective manner, in which
G
ACHTUNGTRENNUNG
À
[g] Without a Rh catalyst. [h] Ag2O was used instead of AgF.
C H bond activation occurred at the less-hindered C6 posi-
3
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Chien-Hong Cheng et al.
Table 2. Rhodium-catalyzed annulation of N-methoxybenzamides with
arylsilanes.[a]
Table 2. (Continued)
Entry
1
2
Product 3
Yield [%][b]
10
1j
2a
3ja
3ka
3la
77
11
12
1k
1l
2a
2a
84
70
Entry
1
1
2
Product 3
Yield [%][b]
13
1m
2a
3ma
74
1a
2a
3aa
3ba
3ca
3da
82
14
15
1n
1a
2a
2b
3na
3ab
80
80
2
3
4
1b
1c
1d
2a
2a
2a
87
84
80
16
17
1a
1a
2c
3ac
3ad
85
79
2d
5
6
1e
1 f
2a
2a
3ea
3 fa
79
75
18
19
20
1a
1a
1a
2e
2 f
2g
3ae
3af
3ag
80
75
87
7
8
9
1g
1h
1i
2a
2a
2a
3ga
3ha
3ia
78
81
80
21
1b
2e
3be
73
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Chien-Hong Cheng et al.
ed N-methoxybenzamide derivatives 1b, 1c, and 1j with
substituted phenyltriethoxysilanes 2b and 2e also proceeded
well. The expected reaction products (3be, 3cb, 3ce, and
3je) were obtained in 73–83% yield.
Table 2. (Continued)
Entry
1
2
Product 3
Yield [%][b]
À
Based on the chemistry of known rhodium-catalyzed C H
activation reactions, a possible mechanism that can account
for this catalytic reaction is proposed in Scheme 1. The cata-
22
1c
2b
3cb
3ce
83
23
1c
3e
79
24
25
1j
3e
2a
3je
81
69
1o
3oa
[a] Unless otherwise noted, all of the reactions were performed by using
substituted N-methoxybenzamide (0.33 mmol), arylsilane
(0.66 mmol), [(RhCp*Cl2)2] (4.1 mg, 0.0066 mmol), AgF (0.085 g,
0.66 mmol), and Cu(OAc)2 (0.120 g, 0.66 mmol) in DCE (2 mL) for 3 h.
1
2
Scheme 1. Proposed mechanism for the formation of phenanthridinones.
ACHTUNGTRENNUNG
[b] Yield of isolated product.
lytic cycle is likely initiated by the removal of a chloride
group from [(RhCp*Cl2)2] by a Ag+ ion, followed by the de-
protonated coordination of an amide nitrogen atom to the
tion to give products 3ia–la in 70–84% yield. However, in
the case of compound 1m, contrary to the above observa-
tions, the activation occurred at the sterically hindered C2
position, instead of the less-hindered C6 position, to give
compound 3ma in 74% yield.[15f,16] In all of these cases, the
other possible regioisomers were not observed. ortho-
Chloro-substituted amide 1n also reacted effectively with
compound 2a to give its corresponding phenanthridinone
(3na) in 80% yield.
Having achieved the synthesis of phenanthridinones with
various N-methoxybenzamide derivatives, we turned to the
reaction of various aryltriethoxysilanes with compound 1a.
Thus, 4-methyl-, 4-methoxy-, and 4-fluorophenyltriethoxysi-
lanes (2b–2d) with compound 1a gave phenanthridinone
derivatives 3ab, 3ac, and 3ad in 85, 79, and 71% yield, re-
spectively. To understand the regioselectivity of this reac-
tion, 3-substituted phenyltriethoxysilanes were employed as
the substrates in reactions with compound 1a. Thus, 3-
methyl- and 3-methoxyphenyltriethoxysilanes (2e and 2 f)
provided compounds 3ae and 3af in 80 and 75% yield, re-
spectively. No other regioisomeric products were detected in
these reactions. However, in the case of 2-substituted silox-
anes, such as 2-methyl- and 2-methoxyphenyltriethoxysi-
lanes, the reactions failed to give their corresponding phe-
nanthridinone derivatives. Then, we tested the reaction of
compound 1a with 3,4-(methylenedioxy)phenyltriethoxysi-
À
rhodium species and subsequent ortho-C H activation to
form a five-membered rhodacycle (4). Then, this intermedi-
ate undergoes a transmetalation reaction with a pentavalent
silicate, which is generated in situ from the reaction of phe-
nyltriethoxysilane (2a) with fluoride, to give a phenyl(benza-
mide)RhIII species (5). Subsequent reductive elimination af-
fords arylated N-methoxybenzamide (6) and a RhI species,
which is oxidized into RhIII by Ag+ ions or Cu
ACTHNGUTERN(UNG OAc)2. De-
À
protonation of the amide N H group of compound 6, fol-
lowed by coordination to the RhIII center, gives intermediate
À
7. Further C H activation at the ortho-carbon atom of the
phenyl ring affords a seven-membered rhodacycle (8). Sub-
sequent reductive elimination of compound 8[18] gives the
final product (3aa) and a RhI species, which is then convert-
ed into a RhIII species by CuII or Ag+ for the next catalytic
cycle.
To support the intermediacy of compound 6, we prepared
it independently by using a literature procedure.[8,9] The
treatment of compound 6 under standard catalytic reaction
conditions afforded compound 3aa in 92% yield [Eq. (2)].
Notably, during the course of the catalytic reaction of com-
pound 1a with compound 2a to give compound 3aa, we
could only observe the two substrates (1a and 2a) and the
final product (3aa), that is, we were unable to isolate or ob-
serve compound 6 (Scheme 1), thus suggesting that the fur-
ther reaction of intermediate 6 to give the final product
(3aa) is fast compared with the reaction between the two
substrates (1a and 2a).
À
lane. This reaction gave compound 3ag, in which the C N
bond was formed at the less-hindered C6 position. Interest-
À
ingly, this result is contrary to the C H activation of 3,4-
(methylenedioxy)-N-methoxybenzamide (1m), which oc-
curred at the C2 position. Finally, the reactions of substitut-
5
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Chien-Hong Cheng et al.
To further understand the intimate mechanism of this cat-
alytic reaction, we measured the inter- and intramolecular
kinetic isotope effects (KIEs) in the catalytic reaction of
compound 1a with compound 2a. An intermolecular KIE of
kH/kD =2.33 was observed for the competition reaction be-
tween compound 1a and deuterium-labeled [D5]-1a with
compound 2a [Eq. (3)]. On the other hand, an intramolecu-
lar competition experiment between [D1]-1a and compound
2a gave a KIE of kH/kD =4.88 [Eq. (4)]. The difference be-
tween these intermolecular and intramolecular KIE values
indicates that the pre-binding of substrate 1a (likely through
[4+2] cycloaddition of N-methoxybenzamide with an aryl
iodide, arene, or arylboronic acid, catalyzed by palladium
and rhodium complexes, are known. In addition, examples
of [3+2] cycloaddition reactions of benzaldehyde oxime
ether with an aryl iodide or an arylboronic acid, catalyzed
by palladium complexes, have been reported.[15b,c,19] In all of
these examples, the aryl group acts as an aryne equivalent
by the removal of a proton on the ortho-carbon atom, pre-
À
sumably through C H activation of the aryl group.
the amide nitrogen atom) to the rhodiumACTHNUTRGNE(NUG III) center takes
À
place prior to an irreversible C H cleavage to form inter-
mediate 4. The substrate-binding step would not show selec-
tivity for compound 1a or [D5]-1a. However, the subsequent
À
Conclusions
We have successfully developed a new method for the syn-
thesis of substituted phenanthridinone derivatives in
a highly regioselective manner from N-methoxybenzamides
C H bond-cleavage step would give different rates. In gen-
eral, a smaller KIE for the intermolecular competition reac-
tion than the intramolecular competition reaction would be
observed. The large primary KIE value (4.88) suggests that
À
and aryltrialkoxysilanes through rhodium-catalyzed C H
bond activation and annulation reactions. The aryl group of
the aryltrialkoxysilane acts like a benzyne equivalent by un-
dergoing cyclization with N-methoxybenzamide to give the
expected phenanthridinone product. Further application of
this method in natural-product synthesis and investigation of
the detailed reaction mechanism are underway.
À
cleavage of the C H bond would be the product-determin-
ing step and a primary KIE was observed.[17] We also per-
formed an intermolecular competition reaction between
phenyltriethoxysilanes [D5]-2a and 2a with compound 1a to
give products [D4]-3aa or 3aa [Eq. (5)]. We expect that
there is no kinetic isotope effect for the ortho-phenylation
of compound 1a by compounds [D5]-2a and 2a to give inter-
À
mediate 6 (Scheme 1), but the subsequent ortho-C H bond
Experimental Section
cleavage of the phenyl ring should show an isotope effect.
The measured KIE value is kH/kD =1.94, in agreement with
the fact that the binding of the phenyl ring of compound 6
to the rhodium center, which would not show selectivity for
General Information
All of the reactions were performed under a nitrogen atmosphere on
a dual-manifold Schlenk line, unless otherwise noted, in oven-dried glass-
ware. All solvents were dried according to known methods and distilled
prior to use.[20] All of the siloxanes were prepared from their correspond-
ing aryl bromides according to a literature procedure.[21] 1H NMR spectra
were recorded at 400 MHz; 13C NMR spectra were recorded at 100 MHz.
Chemical shifts were calibrated to tetramethylsilane as an external stan-
dard.
À
À
À
a C H or C D bond, presumably occurs before the C H
bond is cleaved.
Interestingly, in this catalytic reaction, the aryl group in
silane 2 acts like an aryne, by undergoing a [4+2] cyclization
reaction with N-methoxybenzamide. Similar examples of the
General Procedure for the Synthesis of
Phenanthridinones
A
sealed tube that contained
[(RhCp*Cl2)2] (2.0 mol%), AgF
(0.66 mmol), Cu(OAc)2 (0.66 mmol),
AHCTUNGTRENNUNG
and amide 1 (0.33 mmol) was evacuat-
ed and purged with nitrogen gas three
times. Then, DCE (2.0 mL) and silox-
ane 2 (0.66 mmol) were sequentially
added to the system by syringe under
a nitrogen atmosphere and the reac-
tion mixture was stirred at 608C for
3 h. When the reaction was complete, the mixture was cooled and diluted
with EtOAc (10 mL). The mixture was filtered through a pad of Celite
and the Celite was washed with EtOAc (30 mL) and MeOH (20 mL).
The combined filtrate was concentrated in vacuo and the residue was pu-
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Chien-Hong Cheng et al.
rified by column chromatography on silica gel (EtOAc/n-hexane, 1:10) to
9-Bromo-5-methoxy-2-methylphenanthridin-6(5H)-one (3ce)
afford the desired product (3).
Brown solid; m.p. 194–1968C; 1H NMR (400 MHz, CD2Cl2): d=8.38–
8.36 (m, 2H), 7.94 (s, 1H), 7.66 (dd, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz,
1H), 7.41–7.39 (m, 1H), 4.09 (s, 3H), 2.47 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=156.9, 141.5, 136.2, 134.7, 130.8, 130.3, 128.0,
124.7, 124.6, 124.5, 123.2, 114.9, 112.8, 62.7, 21.9 ppm; IR (neat) n˜ =1669,
1599, 1475 cmÀ1; HRMS (FAB+): m/z calcd for C15H12BrNO2: 317.0051;
found: 317.0045.
7-Chloro-5-methoxyphenanthridin-6(5H)-one (3na)
White solid; m.p. 150–1528C; 1H NMR (400 MHz, CDCl3): d=8.54–8.53
(m, 1H), 8.27 (dd, J=8.4 Hz, 3.4 Hz, 2H), 7.79–7.75 (m, 1H), 7.68–7.65
(m, 1H), 7.61–7.55 (m, 1H), 7.36–7.32 (m, 1H), 4.13 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=157.3, 135.8, 133.0, 132.6, 130.0, 128.5,
128.3, 128.1, 126.4, 123.2, 121.9, 118.6, 112.6, 62.7 ppm; IR (neat): n˜ =
1662, 1606, 1438, 1324 cmÀ1; HRMS (FAB+): m/z calcd for C14H10ClNO2:
259.0400; found: 259.0402.
8-Bromo-5-methoxy-3-methylphenanthridin-6ACHTNUTRGNE(NUG 5H)-one (3je)
White solid; m.p. 202–2048C; 1H NMR (400 MHz, CD2Cl2): d=8.65 (sd,
J=2.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.82 (dd, J=
9.0 Hz, 2.2 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.41–7.38 (m, 1H), 4.09 (s,
3H), 2.47 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=155.9, 135.5,
133.6, 133.1, 131.7, 131.4, 131.1, 127.8, 123.7, 123.2, 122.0, 117.7, 112.7,
62.7, 21.1 ppm; IR (neat) n˜ =1669, 1599, 1478 cmÀ1; HRMS (FAB+): m/z
calcd for C15H12BrNO2: 317.0051; found: 317.0054.
3,5-Dimethoxyphenanthridin-6(5H)-one (3ac)
White solid; m.p. 127–1298C; 1H NMR (400 MHz, CDCl3): d=8.54 (d,
J=7.6 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.77–7.72 (m, 1H), 7.70 (st, J=
1.8 Hz, 1H), 7.60–7.56 (m, 2H), 7.23–7.14 (m, 1H), 4.11 (s, 3H),
3.92 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=156.7, 155.8, 145.4,
132.6, 132.4, 130.1, 128.4, 126.7, 121.9, 119.6, 117.1, 114.0, 107.0, 62.6,
55.8 ppm; IR (neat) n˜ =1645, 1519, 1437 cmÀ1; HRMS (FAB+): m/z calcd
for C15H13NO3: 255.0895; found: 255.0895.
Intermolecular Kinetic Isotope Effect [Eq. (3)]
A
sealed tube that contained [(RhCp*Cl2)2] (2.0 mol%), AgF
3-Fluoro-5-methoxyphenanthridin-6(5H)-one (3ad)
(0.66 mmol), Cu(OAc)2 (0.66 mmol), and mixture of amides 1a
A
a
White solid; m.p. 182–1848C; 1H NMR (400 MHz, CDCl3): d=8.56–8.52
(m, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.86–7.83 (m, 1H), 7.66–7.57 (m, 2H),
7.35–7.24 (m, 2H), 4.11 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
(0.165 mmol) and [D5]-1a (0.165 mmol) was evacuated and purged with
nitrogen gas three times. Then, DCE (2.0 mL) and phenyltriethoxysilane
(2a, 0.66 mmol) were sequentially added to the system by syringe under
a nitrogen atmosphere and the reaction mixture was stirred at 608C for
45 min. Then, the mixture was cooled and diluted with EtOAc (10 mL).
The mixture was filtered through a pad of Celite and the Celite was
washed with EtOAc (30 mL) and MeOH (20 mL). The combined filtrate
was concentrated in vacuo and the residue was purified by column chro-
matography on silica gel (EtOAc/n-hexane, 1:10) to afford the desired
products (3aa and [D5]-3aa) in a combined 31% yield. 1H NMR analysis
of the mixture gave kH/kD =2.33.
165.6 (d, J
(d, J(C,F)=9.8 Hz), 130.7, 123.4, 123.3, 122.8, 117.7 (d, J
116.3 (d, J(C,F)=23.5 Hz), 112.7, 107.9 (d, J(C,F)=23.5 Hz), 62.7 ppm;
IR (neat) n˜ =2071, 1635, 1310 cmÀ1 HRMS (FAB+): m/z calcd for
C14H10FNO2: 243.0696; found: 243.0691.
ACHTUNGTRENNUNG(C,F)=251.5 Hz), 156.6, 136.2, 135.5 (d, JACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
;
5-Methoxy-4-methylphenanthridin-6(5H)-one (3ae)
White solid; m.p. 189–1918C; 1H NMR (400 MHz, CDCl3): d=8.52 (d,
J=8.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.76–
7.72 (m, 1H), 7.57–7.53 (m, 1H), 7.47 (s, 1H), 7.16–7.14 (m, 1H), 4.13 (s,
3H), 2.52 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=157.4, 140.6,
135.8, 133.1, 132.5, 128.5, 127.6, 124.4, 123.1, 121.7, 116.2, 112.7, 62.7,
21.9 ppm; IR (neat) n˜ =2952, 1670, 1492 cmÀ1; HRMS (FAB+): m/z calcd
for C15H13NO2: 239.0946; found: 239.0945.
Intramolecular Kinetic Isotope Effect [Eq. (4)]
A
sealed tube that contained [(RhCp*Cl2)2] (0.0066 mmol), AgF
(0.44 mmol), Cu(OAc)2 (0.44 mmol), and amide [D1]-1a (0.33 mmol) was
AHCTUNGTRENNUNG
evacuated and purged with nitrogen gas three times. Then, DCE
(2.0 mL) and phenyltriethoxysilane (2a, 0.66 mmol) were sequentially
added to the system by syringe under a nitrogen atmosphere and the re-
action mixture was stirred at 608C for 45 min. Then, the mixture was
cooled and diluted with EtOAc (10 mL). The mixture was filtered
through a pad of Celite and the Celite was washed with EtOAc (30 mL)
and MeOH (20 mL). The combined filtrate was concentrated in vacuo
and the residue was purified by column chromatography on silica gel
(EtOAc/n-hexane, 1:10) to afford the desired products (3aa and [D1]-
6-Methoxy-[1,3]dioxoloACHTUNGTRENNUNG[4,5-b]phenanthridin-5(6H)-one (3ag)
White solid; m.p. 203–2058C; 1H NMR (400 MHz, CDCl3): d=8.49–8.47
(m, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.72–7.68 (m, 1H), 7.58 (s, 1H), 7.52–
7.48 (m, 1H), 7.14 (s, 1H), 6.06 (s, 2H), 4.09 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=157.1, 150.0, 144.6, 133.0, 132.5, 132.1, 128.5,
127.0, 125.2, 121.4, 112.3, 101.9, 93.9, 62.6 ppm; IR (neat) n˜ =2340, 1657,
1614 cmÀ1; HRMS (FAB+): m/z calcd for C15H11NO4: 269.0688; found:
269.0685.
1
3aa) in a combined 33% yield. H NMR analysis of the mixture gave kH/
kD =4.88.
Intermolecular Kinetic Isotopic Effect [Eq. (5)]
5-Methoxy-2,9-dimethylphenanthridin-6(5H)-one (3be)
White solid; m.p. 150–1528C; 1H NMR (400 MHz, CDCl3): d=8.40 (d,
J=8.0 Hz, 1H), 8.01 (s, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.36 (t, J=7.5 Hz,
2H), 4.09 (s, 3H), 2.53 (s, 3H), 2.47 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=157.1, 143.0, 133.8, 132.8, 132.5, 130.8, 129.3, 128.4, 124.1,
123.2, 121.9, 118.4, 112.5, 62.6, 22.1, 21.1 ppm; IR (neat) n˜ =2935, 1666,
1620 cmÀ1; HRMS (FAB+): m/z calcd for C16H15NO2: 253.1103; found:
253.1101.
A
sealed tube that contained [(RhCp*Cl2)2] (0.0066 mmol), AgF
(0.66 mmol), Cu(OAc)2 (0.66 mmol), and N-methoxybenzamide (1a,
AHCTUNGTRENNUNG
0.33 mmol) was evacuated and purged with nitrogen gas three times.
Then, DCE (2.0 mL) and mixture of phenyltriethoxysilane (2a,
0.33 mmol) and [D5]-2a (0.33 mmol) were sequentially added to the
system by syringe under a nitrogen atmosphere and the reaction mixture
was stirred at 608C for 45 min. Then, the mixture was cooled and diluted
with EtOAc (10 mL). The mixture was filtered through a pad of Celite
and the Celite was washed with EtOAc (30 mL) and MeOH (20 mL).
The combined filtrate was concentrated in vacuo and the residue was pu-
rified by column chromatography on silica gel (EtOAc/n-hexane, 1:10) to
afford the desired products (3aa and [D1]-3aa) in a combined 37% yield.
1H NMR analysis of the mixture gave kH/kD =1.94.
9-Bromo-5-methoxy-3-methylphenanthridin-6(5H)-one (3cb)
Brown solid; m.p. 210–2128C; 1H NMR (400 MHz, CD2Cl2): d=8.36 (d,
J=8.8 Hz, 1H), 8.33 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.64 (t, J=8.4 Hz,
1H), 7.45 (s, 1H), 7.15 (t, J=8.0 Hz, 1H), 4.11 (s, 3H), 2.51 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=156.9, 141.5, 136.2, 134.7, 130.8, 130.3,
128.0, 124.7, 124.6, 124.5, 123.2, 114.9, 112.8, 62.7, 21.9 ppm; IR (neat)
n˜ =1670, 1599, 1475 cmÀ1; HRMS (FAB+): m/z calcd for C15H12BrNO2:
317.0051; found: 317.0050.
Cyclization of ortho-Arylated N-Methoxybenzamides [Eq. (2)]
A
sealed tube that contained [(RhCp*Cl2)2] (0.0044 mmol), AgF
(0.44 mmol), Cu(OAc)2 (0.44 mmol), and N-methoxy-[1,1’-biphenyl]-2-
AHCTUNGTRENNUNG
carboxamide (6, 0.22 mmol) was evacuated and purged with nitrogen gas
7
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Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

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Chien-Hong Cheng et al.
three times. Then, DCE (2.0 mL) was added to the system by syringe
under a nitrogen atmosphere and the reaction mixture was stirred at
608C for 2 h. Then, the mixture was cooled and diluted with EtOAc
(10 mL). The mixture was filtered through a pad of Celite and the Celite
was washed with EtOAc (30 mL) and MeOH (20 mL). The combined fil-
trate was concentrated in vacuo and the residue was purified by column
chromatography on silica gel (EtOAc/n-hexane, 1:10) to afford the de-
sired product (3aa) in 92% yield.
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Received: April 25, 2013
Published online: && &&, 0000
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Chem. Asian J. 2013, 00, 0 – 0
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ÝÝ These are not the final page numbers!