Regioselectivity in the biaryl coupling reactions of 1-[(1,3-benzodioxol-5-yl)methyl]-7-iodo-2,3-dihydroindole using palladium reagent

Article abstract of DOI:10.3987/COM-05-S(T)5

The biaryl coupling reaction of 1-[(1,3-benzodioxol-5-yl)methyl]-7-iodo-2,3-dihydroindole (1) using Pd(OAc)₂ gave selectively 4,5-dihydro-7H-[1,3]dioxolo[4,5-k]pyrrolo[3,2,1-de]phenanthridine (4), which was formed by connection to a more hindered carbon, in 3.4～4.2:1 ratios.

Full text of DOI:10.3987/COM-05-S(T)5

HETEROCYCLES, Vol. 67, No. 1, 2006
385
HETEROCYCLES, Vol. 67, No. 1, 2006, pp. 385 - 390. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd February, 2005, Accepted, 23rd March, 2005, Published online, 24th March, 2005. COM-05-S(T)5
REGIOSELECTIVITY IN THE BIARYL COUPLING REACTIONS OF 1-
[(1,3-BENZODIOXOL-5-YL)METHYL]-7-IODO-2,3-DIHYDROINDOLE
USING PALLADIUM REAGENT
Takashi Harayama,* 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-[(1,3-benzodioxol-5-yl)methyl]-7-
iodo-2,3-dihydroindole (1) using Pd(OAc)2 gave selectively 4,5-dihydro-7H-
[1,3]dioxolo[4,5-k]pyrrolo[3,2,1-de]phenanthridine (4), which was formed by
connection to a more hindered carbon, in 3.4~4.2:1 ratios.
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 and versatile method to synthesize condensed
aromatic lactams, some of which can be transformed into polycyclic aromatic alkaloids.2 Moreover, we
successfully synthesized pyrrolophenanthridine and quinazoline alkaloids via an intramolecular
palladium-assisted aryl-aryl coupling reaction.3
In studies of the synthesis of trisphaeridine and pyrrolophenanthridine alkaloids, we found a palladium-
assisted biaryl coupling reaction of amides possessing a methylenedioxy group on the benzoyl part and an
iodo group as the leaving group on the aniline part, such that A and B, produced ortho-products such as C
and D as major products, in 4~6:1 ratios. 2d, 4 These results indicate that the biaryl coupling of amides (A
and B) occurred selectively at the more hindered position and that the methylenedioxy group would affect
the regioselectivity at the cyclization position. By contrast, the cyclopalladation of benzylamine (E) gave
the palladacycle (F), the para-product.5 Moreover, we reported that the coupling reaction of N-
benzylnaphthylamine (G) produced a seven-membered compound (H) via a coordinated intermediate (I)
of benzylamine to PdII.6 Therefore, we were interested in investigating whether similar selectivity

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HETEROCYCLES, Vol. 67, No. 1, 2006
O
O
O
O
O
O
I
O
O
I
N
N
N
N
MOM
MOM
O
R
O
O
D = 5 : R=O
4 : R=H2
A
B
C
PdII
PdII
NR2
O
O
O
NR2
O
E
F
R2
R2
R2
Pd0
– Pd0
PdII
Br
R1
R1
R1
N
Me
N
N
Me
Me
G
H
I
O
O
O
O
O
O
X
Br
I
N
N
HN
R
1 : X=I
8 : X=H
2
3
6 : R = H2 : anhydrolycorine
7 : R = O : anhydrolycorin-7-one
Scheme 1. Pyrrolophenanthridine alkaloids and related compounds
Table 1. Results of biaryl coupling reaction of 1-[(1,3-benzodioxol-5-yl)methyl]-7-iodo-2,3-
dihydroindole (1)a)
yeild (%)
ligand
run
(L/Pd) b)
time
5+7 (5:7)c)
8
(4+5) :(6+7)
temp.
4
6
1
A P(o-tol)3 (2) 125oC 2.5 h
55
14
3 (3.5:1)
17
3.9:1
4.0:1
4.2:1
3.4:1
125oC 2 h
trace trace 75 (4.0:1) 12
2
B P(o-tol)3 (2)
125oC 1 h
115oC 3 h
40
52
9
4 (3.2:1)
4 (2.5:1)
17
5
3
4d)
A
A
n-Bu3P (2)
-
15
a) The reaction was carried out using Pd(OAc)2(5 mol%), K2CO3 (200 mol%) in degassed DMF
under the conditions indicated (A: Ar, B: air). b) The molar ratio of the ligand and Pd. c) The
ratio was determined by 1H-NMR spectral(200 MHz) and HPLC (Chemcosorb 5Si-U, ! =254
nm, flow rate = 0.5 ml/min, IPA:hexane = 1:6, tR = 15.5 and 17.7 min.) analysis. d)100 mol% of
n-Bu4NCl and 300 mol% of K2CO3 were added.

HETEROCYCLES, Vol. 67, No. 1, 2006
387
occurred in the palladium-assisted coupling reaction of 1-[(1,3-benzodioxol-5-yl)methyl-7-iodo-2,3-
dihydroindole (1), possessing a methylenedioxy group, in which coordination of benzylamine to
palladium was expected.
The amine (1) was prepared by benzylation of 7-iododihydroindole (2)7 with 5-bromomethyl-1,3-
benzodioxole (3)8 in 83% yield. The results of the coupling reaction of 1 using a palladium reagent are
summarized in Table 1. The reaction of 1 with Pd(OAc)2, P(o-tol)3, and K2CO3 under an argon
atmosphere afforded the ortho- (4 and 5) and para- (6 and 7) coupled products in a ratio of 3.9:1 with a
total yield of 72%, along with a 17% yield of the deiodo amine (8) (run 1 in Table 1). The reaction of 1
under air gave a mixture of the oxidized ortho- (5) and para-(7) coupled products, in a 4.0:1 ratio (run 2
in Table 1).3b The reaction of 1 under butylphosphine produced the ortho-coupled products selectively in
4.2:1 ratio (run 3 in Table 1). Interestingly, the reaction under Jeffery’s conditions in the absence of
phosphine ligand9 gave the ortho-products selectively in 3.4:1 ratio, which was compatible to those in the
presence of phosphine ligand (run 4 in Table 1). Minor compounds (6 and 7) were identified with
authentic samples of pyrrolophenenthridine alkaloids (anhydrolycorin3b and anhydrolycorin-7-one,3b
respectively) by comparison with the 1H-NMR spectra and retention times on HPLC.
In the Pd-assisted biaryl coupling reaction of benzylamine (1), the methylenedioxy group on the benzyl
part would influence the coupling position. The coupling reactions of benzamides and benzylamines,
which possess other oxygen substituents, are now under investigation.
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 VXR-200 (200 MHz) or -500 (500 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) and Wako activated alumina (300 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.
1-[(1,3-Benzodioxol-5-yl)methyl]-7-iodo-2,3-dihydroindole (1) :
To a solution of 7-iododihydroindole (735 mg, 3.00 mmol) in dry MeCN (8 mL) were added 5-bromo-
methyl-1,3-benzodioxole (3)8 (710 mg, 3.30 mmol), Et4NI (77 mg, 0.30 mmol), and i-Pr2NEt (2.1 mL,
12.0 mmol), and the reaction mixture was stirred for 1 h at rt. The mixture was diluted with AcOEt, and

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the organic layer was washed with aqueous 5% NaOH solution and brine. The residue was dissolved in
CHCl3 and was subjected to column chromatography through silica gel. Elution with hexane-AcOEt
(15:1) gave 1 (945 mg, 83%) as a pale yellow oil.1H-NMR (500 MHz, CDCl3) δ: 2.94 (2H, t, J=8.5 Hz),
3.38 (2H, t, J=8.5 Hz), 4.57 (2H, s, Ar-CH2-N), 5.95 (2H, s, OCH2O), 6.47 (1H, dd, J=7.0, 8.0 Hz), 6.77
(1H, d, J=7.5 Hz), 6.81 (1H, dd, J=7.5, 1.5 Hz), 6.95 (1H, d, J=1.5 Hz), 7.06 (1H, dd, J=7.0, 1.5 Hz),
7.53 (1H, dd, J=8.0, 1.5 Hz). Anal. Calcd for C16H14NO2I: C, 50.68; H, 3.72; N,3.69. Found: C, 50.65; H,
4.11; N, 3.45.
General Procedure for the Coupling Reaction of 1-[(1,3-Benzodioxol-5-yl)methyl]-7-iodo-2,3-
dihydroindole (1) (runs 1~3 in Table 1)
1-[(1,3-Benzodioxol-5-yl)methyl]-7-iodo-2,3-dihydroindole (1) (0.3 mmol) was reacted with Pd(OAc)2 (5
mol%), a phosphine ligand (10 mol%), and K2CO3 (200 mol%) in dry DMF (8 mL) at 125˚C for the times
indicated in Table 1. Then, 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 CHCl3 and was subjected
to column chromatography on alumina. Elution with hexane-AcOEt (50:1) gave 8, and successive elution
with the same solvent gave 4 and 6. Elution with AcOEt afforded a mixture of 5 and 7. The mixture was
1
recrystallized from CHCl3–MeOH to give 5. The ratio of 5 to 7 was determined by H-NMR (200MHz)
and HPLC (Chemcosorb 5Si-U) by comparison with authentic samples.3b
The Coupling Reaction of 1-[(1,3-benzodioxol-5-yl)methyl]-7-iodo-2,3-dihydroindole (1) under
Jeffery’s Conditions (run 4 in Table 1)9
1-[(1,3-Benzodioxol-5-yl)methyl]-7-iodo-2,3-dihydroindole (1) (0.3 mmol) was reacted with Pd(OAc)2 (5
mol%), n-Bu4NCl (100 mol%), and K2CO3 (300 mol%) in dry DMF (8 mL) at 115˚C for 3 h. Then, 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 CHCl3 and was subjected to column chromatography on
alumina. The products were separated using the procedure mentioned above.
4,5-Dihydro-7H-[1,3]dioxolo[4,5-k]pyrrolo[3,2,1-de]phenanthridine (4) : pale yellow prisms (EtOH),
1
mp 110-114˚C. IR (KBr) cm-1: 1245, 1045. H-NMR (500 MHz, CDCl3) δ: 3.03 (2H, t, J=8.0 Hz), 3.35
(2H, t, J=8.0 Hz), 4.07 (2H, s), 6.06 (2H, s), 6.64 (1H, d, J=8.0 Hz), 6.67 (1H, d, J=8.0 Hz), 6.78 (1H, dd,
J=7.5, 7.5 Hz), 7.05 (1H, dd, J=7.5, 1.0 Hz), 7.70 (1H, dd, J=7.5, 1.0 Hz). Anal. Calcd for C16H13NO2: C,
76.48; H, 5.21; N,5.57. Found: C, 76.51; H, 5.36; N, 5.57.
4,5-Dihydro-7H-[1,3]dioxolo[4,5-k]pyrrolo[3,2,1-de]phenanthridin-7-one (5) : colorless needles
1
(CHCl3-MeOH), mp 243.5-246˚C. IR (KBr) cm-1: 1655. H-NMR (500 MHz, CDCl3) δ: 3.43 (2H, t,
J=8.0 Hz), 4.73 (2H, t, J=8.0 Hz), 6.23 (2H, s), 7.09 (1H, d, J=8.5 Hz), 7.20 (1H, dd, J=8.0, 7.0 Hz), 7.33
(1H, dd, J=7.0, 1.0 Hz), 8.16 (1H, dd, J=8.0, 1.0 Hz), 8.18 (1H, d, J=8.5 Hz). Anal. Calcd for C16H11NO3:
C, 72.45; H, 4.18; N,5.28. Found: C, 72.48; H, 4.43; N, 5.37.

HETEROCYCLES, Vol. 67, No. 1, 2006
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1-[(1,3-Benzodioxol-5-yl)methyl]-2,3-dihydroindole (8), anhydrolycorin (6), and anhydrolycorin-7-one
1
(7) were identified by comparison with the H-NMR (200 MHz) spectra and HPLC retention times of
authentic samples.3b
ACKNOWLEDGEMENTS
The authors are indebted to the SC-NMR Laboratory of Okayama University for performing the NMR
experiments.
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