Concise synthesis of tetrahydrophenanthridone by palladium reagent

Article abstract of DOI:10.3987/COM-02-S51

Heck reaction of N-(2-halophenyl)-N-methyl-1-cyclohexene-1carboxamide (1) and 2-bromo-N-methyl-N-phenyl-1-cyclohexene-1-carboxamide (4) using a palladium reagent under several reaction conditions was examined. Reaction of 4 using Pd(OAc)₂, DPPP, and Bu₃P afforded tetrahydrophenanthridone (5) in excellent yield.

Full text of DOI:10.3987/COM-02-S51

HETEROCYCLES, Vol. 59, No. 2, 2003, pp. 541 - 546, Received, 5th August, 2002
CONCISE SYNTHESIS OF TETRAHYDROPHENANTHRIDONE
BY PALLADIUM REAGENT†
Takashi Harayama,* Hiroko Toko, Hiromi Nishioka, Hitoshi Abe, and Yasuo
Takeuchi
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1,
Okayama 700-8530, Japan
E-mail: harayama@pharm.okayama-u.ac.jp
Abstract---Heck reaction of N-(2-halophenyl)-N-methyl-1-cyclohexene-1-
carboxamide (1) and 2-bromo-N-methyl-N-phenyl-1-cyclohexene-1-carboxamide
(4) using a palladium reagent under several reaction conditions was examined.
Reaction of 4 using Pd(OAc)2, DPPP, and Bu3P afforded tetrahydrophenanthridone
(5) in excellent yield.
Palladium-assisted arylation of alkenes, such as the Heck, Suzuki-Miyaura, and Stille reactions, is a
powerful method for the preparation of functionalized aromatics.1 Recently, we reported that the aryl-aryl
coupling reactions using palladium reagents including a novel palladium reagent prepared from Pd(OAc)2,
DPPP (1,3-bis(diphenylphosphino)propane), and Bu3P were very versatile for the synthesis of
heteroaromatic compounds.2, 3 In order to examine an application of the reaction conditions to arylation of
alkenes, we designed the synthesis of 7,8,9,10-tetrahydrophenanthridone (A), because functionalized
phenanthridones (A, R1 = OMe) were versatile starting materials for the synthetic studies on dynemicin A.4
Two routes (Routes A and B) could be accessible for the preparation of compound A. (Scheme 1) However,
Overman et al. have revealed that Heck reaction of compound B (R=Me, X=Br or I) with a catalytic amount
of Pd(OAc)2, PPh3, and NEt3 in acetonitrile produced not phenanthridone (A) but 3-spiro-2-oxoindoles.5
Thus, we planned to apply other reaction conditions, including our novel method,3a and an arylation reaction
of compound C using Pd reagents. Here we describe the results of these reactions.
Application of our reaction conditions3 to B afforded spiro compounds, as shown in Table 1, similar to
Overman’s results. However, interestingly, alkene isomerization occurred to a smaller extent. (see runs 3
and 7) Subsequently, Route B was investigated and the results are summarized in Table 2, indicating that a
novel palladium reagent3a prepared from Pd(OAc)2, DPPP, and Bu3P was very effective for Heck reaction of
compound C, which was prepared from bromo acid and aniline via N-methylation in 49% total yield.
Synthetic studies on tetrahydrophenanthridone possessing a variety of substituents are currently under way.
† Dedicated to Professor Yuichi Kanaoka for the celebration of his 75th birthday.

R1
N
OH O OH
H
X
Route B
Pd
Route A
Pd
X
MeO
O
N
N
NH O OH
R
R
HOOC
R
O
O
O
A
Me
B
C
Scheme 1
dynemicin A
Table 1. Results of cyclization reactions of N-(2-halogenophenyl)-N-methyl-1-
cyclohexene-1-carboxamides (1) to 3-spiro-2-oxoindoles (2 and 3).
Pd(OAc)2
X
phosphine
+
N
a)
N
N
Ag2CO3
in DMF
Me
Me
Me
O
O
O
2
3
1a : X=Br
1b : X=I
c)
ratio
2 : 3
yield (%)
b)
Pd(OAc)2
(eq.)
temp. time
run substrate
phosphine (P/Pd)
(2+3)
1
1
2
3
4
5
6
7
1a
1a
1a
1a
1b
1b
1b
reflux 10 h
reflux 8 h
reflux 10 min
100˚C 1 h
reflux 6 h
reflux 20 min
reflux 20 min
43
93
92
86
90
97
98
41
2
-
-
9
-
91: 9
73:27
93: 7
32:68
84:16
74:26
89:11
PPh3 (2)
P(2-tol)3 (2)
0.2
0.2
1.0
0.1
0.2
0.2
0.2
n-Bu3P (1), DPPP (1)
d)
e)
-
PPh3 (2)
P(2-tol)3 (2)
n-Bu3P (1), DPPP (1)
-
a) 2 eq. of Ag2CO3 was added unless otherwise noted. b) Molar ratio between phosphine and Pd.
c) Determined by HPLC analysis. d) 5.5 eq. of AcOK was added as base. e) 2 eq. of n-Bu4NCl was
added as additive.
Table 2. Results of cyclization reactions of 2-bromo-N-phenyl-1-cyclohexene-1-
carboxamides (4) to 7,8,9,10-tetrahydrophenanthridones (5).a)
Br
N
N
Me
Me
O
O
4
5
d)
b)
c)
yield (%)
Pd(OAc)2
(eq.)
base
time
h
2.5 h
10 min
run
phosphine (P/Pd)
5
4
1
2
3
4
1.0
1.0
1.0
0.2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
2
33
57
95
24
30
-
-
PPh3 (2)
P(2-tol)3 (2)
n-Bu3P (1), DPPP (1)
n-Bu3P (1), DPPP (1)
8
h
64
a) All reactions were carried out under reflux in DMF. b) Molar ratio between phosphine and Pd.
c) 2 eq. of base was added. d) Isolated yield.

EXPERIMENTAL
Melting points were measured on a micro melting point hot-stage apparatus (Yanagimoto) and are uncorrected.
IR spectra were recorded on a JASCO A-102 or JASCO FT/IR 350 spectrophotometer and 1H-NMR spectra
in deuteriochloroform on a Hitachi R-1500 (60 MHz) or a Varian VXR-200 (200MHz) or -500 (500 MHz)
spectrometer unless otherwise stated. NMR spectral data are reported in parts per million downfield from
tetramethylsilane as an internal standard (δ 0.0) and coupling constants are given in Hertz. MS spectra were
obtained on a VG-70SE spectrometer. Column chromatography was carried out on silica gel (Wako gel C-
200 or Merck, silica gel 60, No. 9385). All experiments were carried out in an argon atmosphere and the
extract was washed with brine, dried over anhydrous MgSO4, then filtered, and the filtrate was evaporated to
dryness under reduced pressure, unless otherwise noted. 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.
General procedure for the preparation of N-methylcarboxmides (1) from 1-cyclohexene-
1-carboxylic acid and 2-haloaniline
A few drops of dry DMF and oxalyl chloride (1.5 mL,16.0 mmol) were added to a solution of carboxylic acid
(1.0 g, 7.93 mmol) in dry CH2Cl2 (16 mL) under ice-cooling and the mixture was stirred for 4 h under reflux.
Then, the reaction mixture was concentrated to dryness under reduced pressure. To this residue was added a
solution of 2-haloaniline (9.5 mmol) in dry CH2Cl2 (11 mL) and dry NEt3 (1.5 mL, 10.8 mmol) and the
whole was stirred for 2 h at 50℃. The reaction mixture was concentrated to dryness and diluted with CH2Cl2,
then washed with 1N HCl, aqueous 5% NaOH solution and brine. The residue dissolved in CHCl3 was
subjected to column chromatography on silica gel. Elution with hexane : AcOEt (6 : 1) gave NH-
carboxamides.
N-(2-Bromophenyl)-1-cyclohexene-1-carboxamide :
Yield : 67%. mp 72.5－73.5℃ (from petr. ether), as colorless needles. IR (KBr) cm-1: 3220, 1655,
1630.1H-NMR (60 MHz, CDCl3) δ: 1.55－1.91 (4H, m), 2.10－2.52 (4H, m), 6.80－7.62 (4H, m, Ar-H),
8.00－8.07 (1H, br s, NH), 8.47 (1H, dd, J=8, 2 Hz, Ar-H). Anal. Calcd for C13H14NOBr: C, 55.73; H,
5.04; N, 5.00. Found: C, 55.72; H, 5.18, N, 4.92.
N-(2-Iodophenyl)-1-cyclohexene-1-carboxamide :
Yield : 57%. mp 68－70℃ (from hexane), as colorless needles. IR (KBr) cm-1: 3240, 1655, 1635.1H-NMR
(200 MHz, CDCl3) δ: 1.62－1.83 (4H, m), 2.22－2.32 (2H, m), 2.38－2.46 (2H, m), 6.83 (1H, ddd,
J=7.9, 7.9, 1.5 Hz), 6.89－6.93 (1H, m, C2-H), 7.35 (1H, ddd, J=7.9, 7.9, 1.5 Hz, Ar-H), 7.77 (1H, dd,
J=7.9, 1.5 Hz, Ar-H), 7.85 (1H, br s, NH), 8.36 (1H, dd, J=7.9, 1.5 Hz, Ar-H). Anal. Calcd for
C13H14NOI: C, 47.73; H, 4.28; N, 5.00. Found: C, 47.92; H, 4.40, N, 4.19.
A suspension of NH-carboxamide (1.79 mmol) and NaH (203 mg, 63% dispersion in mineral oil, 5.35
mmol) in dry DMF (30 mL) was stirred for 30 min at rt and then a solution of methyl iodide (0.11 mL, 1.79
mmol) in dry DMF (20 mL) was added to the reaction mixture. After stirring for 30 min at rt, the reaction
mixture was diluted with ether and washed with brine. The residue dissolved in CHCl3 was subjected to

column chromatography on silica gel. Elution with hexane : AcOEt (4 : 1) gave N-methylcarboxamides (1).
N-(2-Bromophenyl)-N-methyl-1-cyclohexene-1-carboxamide (1a)
Yield : 92%. mp 98－100℃ (from hexane), as colorless plates. IR (KBr) cm-1: 1630.1H-NMR (60 MHz,
CDCl3) δ: 1.34－1.54 (4H, m), 1.79－2.16 (4H, m), 3.24 (3H, s, NCH3), 5.85 (1H, m, C2-H), 7.14－
7.55 (4H, m, Ar-H). Anal. Calcd for C14H16NOBr: C, 57.15; H, 5.48; N, 4.76. Found: C, 57.08; H, 5.73,
N, 4.69.
N-(2-Iodophenyl)-N-methyl-1-cyclohexene-1-carboxamide (1b)
Yield : 91%. mp 95－96.5℃ (from hexane), as colorless needles. IR (KBr) cm-1: 1625.1H-NMR (60 MHz,
CDCl3) δ: 1.45－2.18 (8H, m), 3.23 (3H, s, NCH3), 5.91 (1H, m, C2-H), 6.99－7.96 (4H, m, Ar-H).
Anal. Calcd for C14H16NOI: C, 49.28; H, 4.73; N, 4.11. Found: C, 49.45; H, 4.72, N, 3.97.
2-Bromo-N-methyl-N-phenyl-1-cyclohexene-1-carboxamide (4)
A solution of methyl 2-bromo-1-cyclohexene-1-carboxylate6 (4.80 g, 21.9 mmol) in MeOH (130 mL) was
added to an aqueous 10% NaOH solution (80 mL) and was stirred for 4 h at rt. The reaction mixture was
acidified with 1N HCl and extracted with AcOEt. The residue was recrystallized from hexane to give 2-
bromo-1-cyclohexene-1-carboxylic acid (4.11 g, 92%) mp 102－103.5℃, as colorless needles, (lit.,7 103
－104℃).
A few drops of dry DMF and oxalyl chloride (0.17 mL, 2.0 mmol) were added to a solution of 2-bromo-
1-cyclohexene-1-carboxylic acid (200 mg, 0.98 mmol) in dry CH2Cl2 (16 mL) under ice-cooling and the
mixture was stirred for 4 h under reflux. Then, the reaction mixture was concentrated to dryness under
reduced pressure. To this residue was added a solution of aniline (0.20 mL, 2.16 mmol) in dry CH2Cl2 (2
mL) and dry NEt3 (0.176 mL, 1.23 mmol) and the whole was stirred for 2 h at 40℃. The reaction mixture
was concentrated to dryness and diluted with CH2Cl2, then washed with 10% HCl, aqueous 5% NaOH
solution and brine. The residue dissolved in CHCl3 was subjected to column chromatography on silica gel.
Elution with hexane : AcOEt (6 : 1) gave 2-bromo-N-phenyl-1-cyclohexene-1-carboxamide (204 mg,
1
75%) as colorless needles, mp 135－137.5℃ (from ether). IR (KBr) cm-1: 3280, 1660, 1640. H-NMR
(60 MHz, CDCl3) δ: 1.63－1.84 (4H, m), 2.45－2.59 (4H, m), 7.10－7.67 (6H, m, Ar-H and NH).
Anal. Calcd for C13H14NOBr: C, 55.73; H, 5.04; N, 5.00. Found: C, 55.78; H, 5.04, N, 4.89.
A suspension of 2-bromo-N-phenyl-1-cyclohexene-1-carboxamide (200 mg, 0.71 mmol) prepared above
and NaH (82 mg, 63% dispersion in mineral oil, 2.1 mmol) in dry DMF (14 mL) was stirred for 30 min at rt
and then a solution of methyl iodide (0.04 mL, 0.71 mmol) in dry DMF (9 mL) was added to the reaction
mixture. After stirring for 30 min at rt, the reaction mixture was diluted with ether and washed with brine. The
residue dissolved in ether was subjected to column chromatography on silica gel. Elution with hexane :
AcOEt (3 : 1) gave 4 (138 mg, 65%), mp 53.5－55.5℃ (from petr. ether) as colorless plates. IR (KBr)
1
cm-1: 1630. H-NMR (60 MHz, CDCl3) δ: 1.37－1.53 (4H, m), 2.06－2.33 (4H, m), 3.35 (3H, s, NCH3),

7.34 (5H, m, Ar-H). Anal. Calcd for C14H16NOBr: C, 57.15; H, 5.48; N,4.76. Found: C, 57.26; H, 5.41,
N, 4.61.
General procedure for the coupling reaction of N-methylanilides (1 or 4) by palladium
reagent (see Tables 1 and 2 )
The coupling reaction of N-methylanilides (1 or 4) (0.24 mmol) in dry DMF (3 mL) was carried out using
Pd(OAc)2 and a phosphine ligand in the ratios indicated in Table 2, and 2 mol equivalents of base for the time
and at the temperature indicated in Table 2. The reaction mixture was diluted with ether and the precipitates
were removed by filtration. The filtrate was washed with brine. The residue was dissolved in AcOEt and
subjected to column chromatography on silica gel. Elution with benzene-AcOEt (8 : 1) gave coupling
product(s) (a mixture of 2 and 3, or 4) and successive elution with the same solvent gave the starting
material.
1’-Methylspiro[2-cyclohexene-1, 3-[3H]indol]-2’(1’H)-one (2)5a and 1’-methylspiro[3-
cyclohexene-1, 3-[3H]indol]-2’(1’H)-one (3)5a : the ratio of products (2 and 3) was determined by
HPLC (column, chemsorb 5Si; eluent, hexane : AcOEt (20 : 1); flow rate, 2.0 mL/min; wave length, 254 nm;
tR for 2 = 19.3 min; tR for 3 = 16.5 min).
7, 8, 9, 10-Tetrahydro-5-methylphenanthridin-6(5H)-one (5) : mp 99－101˚C (from hexane)
1
(lit. ,8a 98－98.5℃, 8b 100－101℃) as colorless needles. IR (KBr) cm-1: 1640. H-NMR (500 MHz, CDCl3)
δ : 1.78－1.89 (4H, m), 2.66－2.69 (2H, m), 2.85－2.88 (2H, m), 3.75 (3H, s, NCH3), 7.24 (1H, ddd,
J=8.1, 7.0, 1.0 Hz, Ar-H), 7.36 (1H, dd, J=8.5, 1.0 Hz, Ar-H), 7.51 (1H, ddd, J=8.5, 7.0, 1.5 Hz, Ar-
H), 7.71 (1H, dd, J=8.1, 1.5 Hz, Ar-H). Anal. Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C,
78.85; H, 7.20, N, 6.54.
ACKNOWLEDGEMENT
This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology. The authors are indebted to the SC-NMR Laboratory of Okayama
University for the NMR experiments.
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