Palladium-assisted biaryl coupling reaction of 1-(2-iodobenzoyl)-1,2,3,4-tetrahydroquinoline

Article abstract of DOI:10.3987/COM-05-S(K)2

The biaryl coupling reaction of 1-(2-iodobenzoyl)-1,2,3,4-tetrahydroquinoline using Pd reagent was examined. The reaction proceeded smoothly to produce, 5,6-dihydro-4H,8H-pyrido[3,2,1-de]phenanthridin-8-one in excellent yield.

Full text of DOI:10.3987/COM-05-S(K)2

HETEROCYCLES, Vol. 66, 2005
527
HETEROCYCLES, Vol. 66, 2005, pp. 527 – 530. © The Japan Institute of Heterocyclic Chemistry
Received, 18th March, 2005, Accepted, 15th April, 2005, Published online, 18th April, 2005. COM-05-S(K)2
PALLADIUM-ASSISTED BIARYL COUPLING REACTION OF 1-(2-
IODOBENZOYL)-1,2,3,4-TETRAHYDROQUINOLINE
Takashi Harayama,* Tomonori Sato, Akihiro Hori, 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 – The biaryl coupling reaction of 1-(2-iodobenzoyl)-1,2,3,4-
tetrahydroquinoline using Pd reagent was examined. The reaction proceeded
smoothly to produce 5,6-dihydro-4H,8H-pyrido[3,2,1-de]phenanthridin-8-one in
excellent yield.
In a preliminary study of the synthesis of pyrrolophenanthridine alkaloids, the intramolecular biaryl
coupling reaction of 1-(2-iodobenzoyl)-2,3-dihydroindole (1) using Pd(OAc) and K CO in DMF was
2
2
3
1
examined, and the reaction produced the desired dihydropyrrolophenanthridone (2) in only 8% yield.
The yield was improved to 20% after re-examination. See run 11 in Table 1.) However, Cai et al.
(
reported that the reaction of 1-[(6-bromo-1,3-benzodioxol-5-yl)carbonyl]-2,3-dihydroindole (3) using
Pd(OAc) and K CO in DMA in the absence of phosphine ligand afforded pyrrolophenanthridone (4) in
2
2
3
2
5
5% yield. Thus, we examined the reaction of 1-[(6-iodo-1,3-benzodioxol-5-yl)carbonyl]-2,3-
dihydroindole (5), which should be more reactive than 3, under their reaction conditions, but we could not
3
obtain 4, even in the presence of a phosphine ligand. Miki et al. reported that the reaction of 1-(2-bromo-
4
4
,5-dimethoxybenzoyl)indole-2,3-dicarboxylate (6) with Pd(PPh ) gave no coupling product. These
3
4
results seem to be in conflict. Therefore, we re-examined the biaryl coupling reaction of 1. Subsequently,
we investigated the reaction of 1-(2-iodobenzoyl)tetrahydroquinoline (7) using Pd reagent in order to
examine the effect of ring size, i.e., dihydroindole has a five-membered ring, and tetrahydroquinoline has
a six-membered ring. When it works well, the method will provide a new and concise synthesis of 5,6-
5
dihydro-4H,8H-pyrido[3,2,1-de]phenanthridin-8-one (8), which is an isomer of aporphine alkaloid, using
6
, 7
the Pd-assisted biaryl coupling reaction.
First, the coupling reaction of 7 was examined. The starting materials (7) for the coupling reaction were
This paper is dedicated to the memory of the late Professor Kenji Koga.

528
HETEROCYCLES, Vol. 66, 2005
R1
R1
X
MeO
MeO
Br
CO Me
2
N
N
N
R2
R2
CO Me
2
O
O
O
1
2
1
2
2 : R =R =H
1
3
5
: R =R =H, X=I
: R + R =OCH O, X=Br
: R + R =OCH O, X=I
6
1
2
1
2
4 : R + R =OCH O
2
2
1
2
2
I
N
N
O
O
8
7
Table 1. Results of coupling reaction of 1-(2-iodobenzoyl)terahydroquinoline (7) and 1-(2-
a)
iodobenzoyl)dihydroindole (1).
starting
material
phosphine (P/Pd)b)
P(o-tol) (2)
time( h)
yield (%)
run Pd regent (10 mol%)
base
K CO3
1.0
2.0
0.5
0.5
3.0
2.0
2.0
98
91
90
90
88
88
89
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
3
2
PBu (2)
3
K CO3
2
PdCl ( PPh )
-
AcONa
2
3 2
7
Pd(OAc)2
PCy (2)
K CO3
3
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
K CO3
2
PPh (2)
3
K CO3
2
c)
n-Bu P (1), DPPP (1)
3
K CO3
2
8
9
10
1
2
3
4
Pd(OAc)2
Pd(OAc)2
P(o-tol) (2)
K CO3
4.0
4.0
4.0
4.0
4.0
4.0
4.0
-
22
-
20
20
-
-
3
2
PBu (2)
K CO3
3
2
1
PdCl ( PPh )
-
-
-
AcONa
2
3 2
d)
1
1
1
1
Pd(OAc)2
K CO3
2
e)
f)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K CO3
2
e)
PPh (2)
K CO3
3
2
c, e)
n-Bu P (1), DPPP (1) K CO
3
2
3
a) The reaction was carried out using Pd(OAc) (10 mol%), base (200 mol%) in DMF
2
under reflux. b) Molar ratio between phosphine and Pd. c) See reference 6e). d) Sc(OTf)3
(
100 mol%) was added. e) See reference 1. f) Yield was improved,
prepared from tetrahydroquinoline and 2-iodobenzoyl chloride in 80% yield. The results of the coupling
reaction of 7 are summarized in Table 1. In general, the reaction proceeded smoothly to produce
5
pyrido[3,2,1-de]phenanthridin-8-one (8) in excellent yield. In addition, the reactions of 1 under several
1
reaction conditions, including previously reported conditions, were (re)examined. However, the cyclized
product (2) was obtained in at most 22% yield using Pd(OAc) , Bu P, and K CO (see run 9 in Table 1)
2
3
2
3
even using the reaction conditions under which the cyclization reaction of 7 worked well. A similar
difference in the behaviors of benzoyltetrahydroquinoline (7) and benzoyldihydroindole (1) was reported
for the Pshorr reactions of 1-(2-aminobenzoyl)tetrahydroquinoline and 1-(2-aminobenzoyl)dihydroindole,
in which authors suggested that the difference could be attributable to the favorable conformation of
5
a
tetrahydroquinoline to the cyclization and/or the less strained structure of 8 than 2. The results using

HETEROCYCLES, Vol. 66, 2005
529
palladium reagents were similar to those of the Pshorr reactions.
In conclusion, the Pd-assisted biaryl coupling reaction of 1-(2-halobenzoyl)tetrahydroquinoline is a
concise and versatile procedure for synthesizing pyridophenanthridone derivatives.
EXPERIMENTAL
Melting points were measured on a micro-melting point hot-stage apparatus (Yanagimoto) and are
1
uncorrected. IR spectra were recorded on a JASCO FT/IR 350 spectrophotometer and H-NMR spectra in
an indicated sovent on Varian VXR-300 (300 MHz) spectrometers, unless otherwise stated. NMR
spectral data are reported in parts per million downfield from tetramethylsilane as an internal standard (δ
0
.0), and the coupling constants are given in Hertz. Column chromatography was carried out on a Merck
silica gel (230-400 mesh). All the extracts were washed with brine, dried over anhydrous MgSO , and
4
filtered; the filtrate was concentrated to dryness under reduced pressure. Pd(OAc) was treated with
2
boiling benzene, and the mixture was filtered while hot. The hot filtrate was then concentrated to dryness
to give purified Pd(OAc)2.
1
-(2-Iodobenzoyl)-1,2,3,4-tetrahydroquinoline (7)
A solution of 2-iodobenzoic acid (9.92 g, 40 mmol) in a few drops of dry DMF and thionyl chloride (4.4
mL, 60 mmol) was refluxed for 30 min and concentrated to dryness under reduced pressure. To this
residue was added a solution of tetrahydroquinoline (6.39 g, 48 mmol) in dry CH Cl (60 mL) and dry
2
2
NEt (7.3 mL), and the mixture was stirred for 40 min at rt. The reaction mixture was poured into
3
1
0% HCl and extracted with CHCl . The organic layer was washed with 1 N HCl, aqueous sat. NaHCO3
3
solution, and brine. The residue was recrystallized from ether to give 7 (11.55 g, 80%) as colorless plates,
-1
1
mp 137-139˚C. IR (KBr) cm : 1625. H-NMR (300 MHz, DMSO-d at 80˚C ) δ: 1.99 (2H, tt J=6.6, 6.6
6
Hz), 2.83 (2H, t, J=6.6 Hz), 3.64 (2H, br s), 6.99 (2H, m), 7.14 (3H, m),7.29 (1H, br d, J=7.2 Hz), 7.41
(
1H, dd, J=7.5, 7.5 Hz), 7.82 (1H, br d, J=8.1 Hz). Anal. Calcd for C H NOI: C, 52.91; H, 3.89; N,3.86.
16 14
Found: C, 52.83; H, 3.84; N, 3.85.
General Procedure for the Coupling Reaction of 1-(2-Iodobenzoyl)-1,2,3,4-tetrahydroquinoline (7)
runs 1 ~ 7 in Table 1)
-(2-Iodobenzoyl)tetrahydroquinoline (7) (105 mg, 0.3 mmol) was reacted with Pd(OAc) , a phosphine
(
1
2
ligand, and 200 mol% of base in dry DMF (8 mL) under reflux for the time 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. The residue dissolved in CHCl was subjected to column chromatography on
3
silica gel. Elution with hexane-AcOEt (4:1) gave 5,6-dihydro-4H,8H-pyrido[3,2,1-de]phenanthridin-8-
5
a
5b
-1
one (8) as colorless pillars (ether), mp 94-96˚C (lit., 94-95˚C, lit., 180-182˚C). IR (KBr) cm : 1646.
1
H-NMR (300 MHz, CDCl ) δ: 2.13 (2H, tt J=6.1, 6.1 Hz), 3.02 (2H, t, J=6.1 Hz), 4.32 (2H, t, J=6.1 Hz),
3

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HETEROCYCLES, Vol. 66, 2005
7
.21 (1H, dd, J=7.5, 7.5 Hz), 7.30 (1H, dd, J=0.6, 7.5 Hz), 7.58 (1H, ddd, J=1.0, 7.5, 7.5 Hz), 7.75 (1H,
ddd, J=1.5, 7.5, 7.8 Hz), 8.13 (1H, dd, J=1.0, 7.8 Hz), 8.27 (1H, dd, J=0.6, 7.5 Hz), 8.54 (1H, dd, J=1.5,
.5 Hz). Anal. Calcd for C H NO: C, 81.68; H, 5.57; N,5.95. Found: C, 81.89; H, 5.66; N, 5.93.
7
1
6
13
The Coupling Reaction of 1-benzoyl-7-iodo-2,3-dihydroindole (1) using Pd reagent (runs 8 ~ 11 in
Table 1)
1
The reactions and work-up were carried out according to the reported procedure. Only the yields of 2 are
given in the Table.
ACKNOWLEDGEMENTS
The authors are indebted to the SC-NMR Laboratory of Okayama University for performing the NMR
spectral experiments.
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