Biaryl coupling reactions of 3-methoxy-n-(2-iodophenyl)-N-methylbenzamide and 3-methoxycarbonyl-N-(2-iodophenyl)-N-methylbenzamide using palladium reagent

Article abstract of DOI:10.3987/COM-06-S(W)10

We examined palladium-assisted biaryl coupling reactions of 3-methoxy and 3-methoxycarbonyl benzanilides, and propose an aspect of the mechanism involved in forming a biaryl bond using Pd reagent.

Full text of DOI:10.3987/COM-06-S(W)10

HETEROCYCLES, Vol. 70, 2006
549
HETEROCYCLES, Vol. 70, 2006, pp. 549 - 555. © The Japan Institute of Heterocyclic Chemistry
Received, 26th June, 2006, Accepted, 11th September, 2006, Published online, 12th September, 2006. COM-06-S(W)10
BIARYL
COUPLING
REACTIONS
OF
3-METHOXY-N-(2-IODOPHENYL)-N-METHYLBENZAMIDE AND 3-
METHOXYCARBONYL-N-(2-IODOPHENYL)-N-METHYLBENZAMIDE
USING PALLADIUM REAGENT
Hiromi Nishioka, * Chie Nagura, Hitoshi Abe, Yasuo Takeuchi, and Takashi
†
Harayama*,
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1,
Okayama 700-8530, Japan
e-mail:koi@pharm.okayama-u.ac.jp
Abstract – We examined palladium-assisted biaryl coupling reactions of
3-methoxy and 3-methoxycarbonyl benzanilides, and propose an aspect of the
mechanism involved in forming a biaryl bond using Pd reagent.
Palladium-assisted biaryl coupling reactions have been used to synthesize many polycyclic aromatic
compounds.1 Recently, we reported that an intramolecular biaryl coupling reaction of
2-halo-N-arylbenzamides using palladium reagents was a convenient, versatile method for synthesizing
condensed aromatic lactams, some of which can be transformed into polycyclic aromatic alkaloids.2
Moreover, we successfully synthesized benzonaphthazepine, a new skeletal compound, and
pyrrolophenanthridine (Amaryllidaceae) alkaloids, utilizing a Pd-assisted biaryl coupling reaction with
regioselective C–H activation via the intramolecular coordination of an amine to Pd.3 Subsequently, we
applied the biaryl coupling reaction using Pd to the synthesis of quinazoline alkaloids4 and
graphislactones.5
Buchwald et al. recently proposed three possible mechanisms for the formation of oxindole from
α-chloroacetanilide via Pd-catalyzed C–H functionalization: electrophilic substitution, carbopalladation
(Heck-type reaction), and C–H activation.6 Considering Buchwald et al.’s proposal, the three reaction
mechanisms for the formation of the biaryl bond using Pd, as shown in Chart 1, would be possible.7
To determine some of the mechanistic aspects of the Pd-mediated biaryl coupling reaction, we examined
cyclization reactions of 3-methoxy-N-(2-iodophenyl)-N-methylbenzamide (1a), which possesses an
This paper is dedicated to Professor Steven M. Weinreb on the occasion of his 65th birthday.

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HETEROCYCLES, Vol. 70, 2006
electron-donating group on the benzoyl part, and 3-methoxycarboyl-N-(2-iodophenyl)-N-
methylbenzamide (1b), which possesses an electron-withdrawing group on the benzoyl part, under
several reaction conditions using 0.1 eq of Pd(OAc)2, 0.2 eq of PPh3, and 2 eq of K2CO3 in DMF. The
starting materials (1) for the coupling reaction were prepared from the appropriate benzoic acids and
2-iodoanilines. Successive treatment of 3-methoxybenzoic acid with oxalyl chloride and 2-iodoaniline
produced the amide (4), which was methylated with methyl iodide to afford 1a. The amidation of
3-methoxycarbonylbenzoic acid with 2-iodo-N-methylaniline8 gave 1b.
-HX
H
+
reductive
elimination
Pd
L
Pd
L
X-
electrophilic
substitution
L
L
route 1
route 2
-HPdX
H
Pd
X
L
L
carbopalladation
(Heck type)
PdX
L
L
reductive
elimination
route 3
C-H
activation
(!-bond metathesis)
-HX
Pd
Pd
L
L
L : phosphorous ligand
Pd : Pd(II)
H
L
L
X
R
PdX
R
or
N
N
Me
Me
O
XPd
O
(A)
Chart 1
The results of coupling reactions at several reaction temperatures are summarized in Table 1 and show
that the reaction time of 1a and 1b until the completion of coupling reaction is not influenced by the
electronic character of the substituents, whereas the substituent effect on the regioselectivity in biaryl
coupling reaction is observed. Since, in the classical aromatic electrophilic substitution mechanism (route
1), electron donating groups should increase the rate of reaction, this result indicates that the biaryl
coupling reaction using Pd reagent would not proceed via the classical aromatic electrophilic substitution
process such as route 1, although reports related with electrophilic substitution mechanism have been
presented.1f, 9, 10

HETEROCYCLES, Vol. 70, 2006
551
R
I
N
N
N
Me
O
R
Me
R
Me
O
O
3
2
1
a : R =OMe
b : R =COOMe
Table 1. Results of coupling reaction of benzanilides (1) to phenanthridones (2 and 3 )a)
ratiob)
2 : 3
substance
time (h)
yield
temp. (˚C)
reflux
100
50
reflux
100
50
0.15
0.25
5.5
0.15
0.5
93
92
92
78
qunat
quant
1.0 : 1
0.81 : 1
0.67 : 1
0.3 : 1
0.16 : 1
0.10 : 1
1a
1b
5.0
a) All reactions were carried out in DMF using 0.1 eq of Pd(OAc)2, 0.2 eq.
of PPh3, and 2 eq of K2CO3 unde argon atmosphere.
b) Determined by HPLC and NMR analysis.
The Heck-type reaction process should usually proceed via cis addition and syn-β-elimination.
Therefore, since route 2 would be less likely,7a an alternative mechanism involving anti-elimination
or isomerization and syn-elimination was proposed.11 In our case, when the biaryl coupling reaction
proceeds via the Heck-type process, such as route 2, we postulated that the para-product (3) would
always be the major product because of the steric repulsion in the intermediate group (A), regardless of
the character of the substituent group. However, we found that the substituent can affect the ratio of the
product of the biaryl coupling reaction,12 and therefore postulated that route 2 is a less plausible
mechanism for the Pd-mediated arylation of aromatics. We thus propose that formation of the biaryl bond
proceeds via a C–H activation process (route 3).
Detailed investigations of the substituent effect on the regioselectivity of Pd-mediated biaryl coupling are
now in progress, although we have reported a tentative mechanism for the reaction.12
EXPERIMENTAL
Melting points were measured on a micro-melting point hot-stage apparatus (Yanagimoto) and are
uncorrected. IR spectra were recorded on a JASCO FT/IR 350 spectrophotometer and 1H-NMR spectra in
deuteriochloroform on Varian Mercury 300 or VXR-500 spectrometers. NMR spectral data are reported
in parts per million downfield from tetramethylsilane as the internal standard (δ 0.0), and the coupling
constants are given in Hertz. MS spectra were obtained on a VG-70SE. Analytical HPLC was performed

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HETEROCYCLES, Vol. 70, 2006
with a Shimadzu SPD-6A on a silica gel column (Chemcosorb 5Si-U). Column chromatography was
carried out on a Merck silica gel (230–400 mesh). All the extracts were washed with brine, dried over
anhydrous MgSO4, and filtered; the filtrate was concentrated to dryness under reduced pressure.
Pd(OAc)2 was treated with boiling benzene, and the mixture was filtered while hot. The hot filtrate was
then concentrated to dryness to give purified Pd(OAc)2.
N-(2-Iodophenyl)-3-methoxybenzamide (4)
A few drops of dry DMF and oxalyl chloride (0.60 mL, 6.57 mmol) were added to a solution of
3-methoxybenzoic acid (500 mg, 3.29 mmol) in dry CH2Cl2 (25 mL) and the mixture was stirred for 3 h
under ice cooling. Then, the reaction mixture was concentrated to dryness under reduced pressure. A
solution of 2-iodoaniline (720 mg, 3.29 mmol) in dry CH2Cl2 (15 mL) and dry NEt3 (0.55 g, 3.94 mmol)
was added to this residue and the whole was stirred for 3 h at rt. The reaction mixture was concentrated to
dryness, diluted with CHCl3, and then washed with 10% HCl, aqueous 5% NaOH solution, and brine. The
residue in CHCl3 was subjected to column chromatography on silica gel. Elution with hexane:AcOEt
(4:1) gave 4 (836 mg, 72%) as colorless needles (from Et2O), mp 94–95.5˚C. IR (KBr) cm-1: 3270, 1650,
1
1520. H-NMR (500 MHz) δ : 3.89 (3H, s), 6.89 (1H, dd, J=8.0, 1.5 Hz), 7.12 (1H, ddd, J=8.0, 2.0, 1.0
Hz), 7.41 (1H, ddd, J=8.0, 8.0, 1.5 Hz), 7.43 (1H, dd, J=8.0, 8.0 Hz), 8.29 (1H, br s), 8.45 (1H, dd, J=8.0,
1.5 Hz). Anal. Calcd for C14H12NO2I : C, 47.61; H, 3.43; N, 3.97. Found : C, 47.62; H, 3.35; N, 3.84.
N-(2-Iodophenyl)-3-methoxy-N-methylbenzamide (1a)
Methyl iodide (0.84 mL, 12.75 mmol) was added to a suspension of 4 (3. 0g, 8.49 mmol) and NaH (60%,
1.02 g, 25.47 mmol) in dry DMF (90 mL). After stirring for 15 min at rt, the excess NaH was
decomposed with ice water, and extracted with AcOEt. The organic layer was washed with brine. The
residue in AcOEt was subjected to column chromatography on a silica gel. Elution with hexane:AcOEt
(1:1) gave 1a (2.78 g, 89%) as colorless prisms (from Et2O), mp 105–106˚C. IR (KBr) cm-1: 1635.
1H-NMR (500 MHz) δ : 3.38 (3H, s), 3.67 (3H, s), 6.77 (1H, dd, J=7.8, 2.0 Hz), 6.89-6.95 (3H, m),
7.04-7.08 (2H, m), 7.21 (1H, dd, J=7.0, 7.0 Hz), 7.82 (1H, br d, J=7.8 Hz). Anal. Calcd for C15H14NO2I :
C, 49.07; H, 3.84; N, 3.82. Found : C, 49.21; H, 4.01; N, 3.66.
3-Carbomethoxy-N-(2-iodophenyl)-N-methylbenzamide (Methyl 3-[N-(2-Iodophenyl)-
N-methylcarbamoyl]benzoate) (1b)
A mixture of 3-methoxycarbonylbenzoic acid (4.00 g, 22.0 mmol) in a few drops of dry DMF and thionyl
chloride (2.40 mL, 33.0 mmol) was first refluxed for 15 min and then concentrated to dryness under
reduced pressure. A solution of 2-iodo-N-methylaniline12 (5.10 g, 22.0 mmol) in dry CH2Cl2 (26 mL) and
dry NEt3 (3.70 mL, 26.4 mmol) was added to this residue and the whole was stirred for 1 h at rt. The
reaction mixture was concentrated to dryness and diluted with AcOEt, and then washed with 10% HCl
and brine. The residue in CHCl3 was subjected to column chromatography on silica gel. The elution with

HETEROCYCLES, Vol. 70, 2006
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hexane:AcOEt (2:1) gave 1b (7.39 g, 85%) as colorless needles (from hexane-AcOEt), mp 85–87˚C. IR
1
(KBr) cm-1: 1720, 1645. H-NMR (500 MHz) δ : 3.39 (3H, s), 3.86 (3H, s), 6.90 (1H, br t, J=7.5 Hz),
7.14 (1H, br d, J=7.5 Hz), 7.22-7.26 (2H, m), 7.56 (1H, br d, J=7.5 Hz), 7.78 (1H, br d, J=7.5 Hz),
7.90(1H, br d, J=7.5 Hz), 8.07 (1H, br s). Anal. Calcd for C16H14NO5I : C, 48.63; H, 3.57; N, 3.54.
Found : C, 48.86; H, 3.66; N, 3.34.
General Procedure for the Coupling Reaction of Phenylbenzamides (1)
Phenylbenzamide (1) (0.2 mmol) was reacted with Pd(OAc)2 (4.5 mg, 20 mol%), triphenylphosphine
(10.5 mg, 40 mol%), and K2CO3 (55.3 mg, 400 mol%) in dry DMF (2 mL) at the temperatures and for the
times indicated in Table 1. Then, the reaction mixture was diluted with AcOEt, and the precipitates were
removed by filtration. The filtrate was washed with brine.
Biaryl Coupling Reaction of 3-Methoxy-N-(2-iodophenyl)-N-methylbenzamide (1a)
The residue was dissolved in CHCl3 and was subjected to column chromatography on silica gel. Elution
with hexane:isopropyl ether (2:1) gave 5-methyl-10-methoxyphenanthridin-6(5H)-one (2a) and
successive elution with the same solvent gave 5-methyl-8-methoxyphenanthridin-6(5H)-one (3a)
5-Methyl-10-methoxyphenanthridin-6(5H)-one (2a) : colorless prisms (from Et2O), mp 167.5-168.5˚C.
IR (KBr) cm-1: 1730. 1H-NMR (500 MHz, CDCl3) δ: 3.83 (3H, s), 4.09 (3H, s), 7.30 (2H, m), 7.31 (1H,
dd, J=8.5, 1.0 Hz), 7.54 (1H, ddd, J=8.5, 7.3, 1.0 Hz), 7.54 (1H, dd, J=7.5, 7.3 Hz), 8.28 (1H, dd, J=7.5,
1.0 Hz), 9.30 (1H, dd, J=8.5, 1.0 Hz). Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N,5.85. Found: C,
75.30; H, 5.82; N, 5.81.
5-Methyl-10-methoxyphenanthridin-6(5H)-one (3a) : colorless needles (from hexane), mp 133-135˚C.
(lit.13 134-135.5˚C )
Biaryl Coupling Reaction of Methyl 3-[N-(2-Iodophenyl)-N-methylcarbamoyl]benzoate (1b)
The residue was dissolved in CHCl3 and subjected to column chromatography on silica gel. Elution with
CHCl3:acetone (30:1) gave a mixture of coupling products, which was separated by preparative thin layer
chromatography using CHCl3. The upper zone gave 10-methoxycarbonyl-5-methylphenanthridin-6(5H)-
one (2b) and the lower zone gave 8-methoxycarbonyl-5-methylphenanthridin-6(5H)-one (3b).
10-Methoxycarbonyl-5-methylphenanthridin-6(5H)-one (2b) : colorless needles (from AcOEt), mp
1
154-155˚C. IR (KBr) cm-1: 1720, 1650. H-NMR (300 MHz, CDCl3) δ: 3.81 (3H, s), 3.96 (3H, s), 7.24
(1H, ddd, J=7.8, 7.2, 1.2 Hz), 7.44 (1H, dd, J=8.4, 1.2 Hz), 7.56 (1H, ddd, J=8.4, 7.2, 1.5 Hz), 7.61 (1H,
dd, J=7.5, 7.5 Hz), 7.79 (1H, dd, J=7.5, 1.2 Hz), 7.88 (1H, dd, J=7.5, 1.2 Hz), 8.68 (1H, dd, J=7.8, 1.5
Hz). High resolution MS (FAB) m/z : Calcd for C16H14NO3 [M+1]+: 268.0974. Found: 268.0999.
8-Methoxycarbonyl-5-methylphenanthridin-6(5H)-one (3b) : colorless needles (from CHCl3-hexane),
1
mp 211-213˚C. IR (KBr) cm-1: 1720, 1650. H-NMR (300 MHz, CDCl3) δ: 3.84 (3H, s), 4.00 (3H, s),
7.36 (1H, ddd, J=7.2, 6.9, 1.5 Hz), 7.45 (1H, dd, J=8.7, 0.9 Hz), 7.62 (1H, ddd, J=7.2, 6.9, 1.5 Hz),

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8.30-8.35 (2H, m), 8.39 (1H, dd, J=8.7, 1.8 Hz), 9.21 (1H, dd, J=1.8, 0.9 Hz).. Anal. Calcd for
C16H13NO3: C, 71.90; H, 4.90; N,5.24. Found: C, 71.72; H, 4.96; N, 5.37.
ACKNOWLEDGEMENTS
The authors thank the SC-NMR Laboratory of Okayama University for performing the NMR
experiments.
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†
Present address : Faculty of Pharmaceutical Sciences at Kagawa campus, Tokushima Bunri
University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
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