Synthesis of phenanthridinones using Cu- or Pd-mediated C[sbnd]N bond formation

Article abstract of DOI:10.1016/j.tet.2016.12.051

The chemoselective synthesis of phenanthridinones was studied using copper(I)- and palladium(II)-catalyzed C[sbnd]N bond formation with various bases, ligands, and solvents. Phenanthridinones were obtained from 2-halobiarylcarboxylates and amines in a one

Full text of DOI:10.1016/j.tet.2016.12.051

Accepted Manuscript
Synthesis of phenanthridinones using Cu- or Pd-mediated C–N bond formation
Prattya Nealmongkol, Jordan Calmes, Somsak Ruchirawat, Nopporn Thasana
PII:
S0040-4020(16)31349-7
10.1016/j.tet.2016.12.051
TET 28343
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 May 2016
Revised Date: 13 December 2016
Accepted Date: 22 December 2016
Please cite this article as: Nealmongkol P, Calmes J, Ruchirawat S, Thasana N, Synthesis of
phenanthridinones using Cu- or Pd-mediated C–N bond formation, Tetrahedron (2017), doi: 10.1016/
j.tet.2016.12.051.
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Synthesis of Phenanthridinones Using Cu- or
Pd-mediated C-N Bond Formation
Leave this area blank for abstract info.
Prattya Nealmongkol,a Jordan Calmes,b Somsak Ruchirawat,a,b,c Nopporn Thasanaa,b,c,
*
aProgram on Chemical Biology, Chulabhorn Graduate Institute, Laksi, Bangkok 10210, Thailand. bLaboratory
of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand. cCenter of Excellence
on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok, Thailand

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Phenanthridinones Using Cu- or Pd-mediated C-N Bond Formation
Prattya Nealmongkol,a Jordan Calmes,b Somsak Ruchirawat,a,b,c Nopporn Thasana,a,b,c,
*
a Chemical Biology Program, Chulabhorn Graduate Institute, Kamphaeng Phet 6, Bangkok 10210, Thailand
b Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Kamphaeng Phet 6, Bangkok 10210, Thailand
c Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10210, Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The chemoselective synthesis of phenanthridinones was studied using copper(I)- and
palladium(II)-catalyzed C-N bond formation with various bases, ligands, and solvents.
Phenanthridinones were obtained from 2-halobiarylcarboxylates and amines in a one-pot
reaction. The phenanthridinones and heterocyclic-fused lactam derivatives were accomplished
using developed methods.
Available online
2016 Elsevier Ltd. All rights reserved
.
Keywords:
copper
palladium
C-N bond formation
phenanthridinone
lactam
1. Introduction
Phenanthridinone scaffold has been found widely in various
biologically active compounds.1-4 In 1893, phenanthridinone was
first synthesized by Grabe and Wander using Hofmann reaction
of 2,2’-amidobiphenylcarboxylic acid but the unsatisfied yield
was obtained.5 The Curtius degradation of diphenic monoazide in
alcoholic solvent under the acid condition was then developed,
leading to the phenanthridinone derivative but there remained
limitations of variation of its analog.6-7 The syntheses of
phenanthridinones have been further studied for more effective
routes.8-12 Since the C-N bond formations have been conducted
by Buchwald and Hartwig groups, palladium-catalyzed C-N bond
formations using the necessary ligand and base were reported for
more efficient conditions to construct the nitrogen containing
compounds.13-18
Reported herein is a methodology for the one-pot synthesis of
a small-molecule lactam model that is analogous to the core of
many pharmacologically active compounds. Developing an
efficient synthesis for this lactam will aid in optimizing reaction
conditions for biologically active phenanthridinone derivatives,
with a heterocyclic-fused lactam.
Phenanthridinone is a common moiety found in bioactive
alkaloids from many sources as shown in Fig. 1. Oxynitidine (1),
a phenanthridinone derived from Xanthoxylum, is a potential
antitumor and antiviral agent.19 Pancratistatin (2), shows a high
level of inhibition of in vivo cancer cell growth.20
Indenoisoquinoline (3) acts as a non-camptothecin topoisomerase
I inhibitor.21 Azalamellarin D (4) is an extension of lamellarin D
(5) investigated in our group.22 The lactam within the B-ring of
an azalamellarin replaces the lactone structure of lamellarin,
improving the compound’s stability.22 Lamellarin D (5) has
received attention from many research groups, including ours.23
Biological and synthetic studies of lamellarin D in particular
have been reported.24
Figure 1. Structures of oxynitidine (1), pancratistatin (2),
indenoisoquinoline (3), azalamellarin D (4), and lamellarin D (5).

2
Tetrahedron
Table 1. Reaction of methyl-2-bromocarboxylate 6a and
2. Results and discussion
ACCEPTED MANUSCRIPT
homoveratylamine 7 mediated by CuTC in the subcritical
water condition, use various bases and ligands.a
2.1. Cu(I)-mediated lactone and lactam formation:
Completion of C-O and C-N bond formation
Methyl 2-bromocarboxylate (6) and homoveratylamine (7)
were used to study the Cu(I)-catalyzed C-N bond formation of
the corresponding phenanthridinone 8.22,25 Various bases and
bidentate ligands (a to e in Fig. 2) were screened with the
subcritical water under the benign conditions to conform with the
green chemistry aspect.26 The competition of intermolecular C-N
bond formation and intramolecular C-O bond formation was
observed and afforded a mixture of the target compound 8 and
benzopyranone 9 in moderate to good yields as summarized in
the Table 1.
Entry
1
7 (equiv)
Base
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Ligand
Yield 8 (%)b
Yield 9 (%)b
5
5
-
a
b
c
d
e
a
a
-
23
31
9
36
18
41
50
37
38
33
34
60
36
36
49
First, we examined the possibility of Cu(I)-catalyzed C-N
2
bond formation of compounds 6 and 7 with subcritical water at
o
3
5
300 C using copper thiophenecarboxylate (CuTC) as catalyst in
the presence of Cs2CO3 as a base.26 The C-N bond formation
product, lactam 8 and C-O bond formation product, lactone 9
were obtained in 23% and 36% yields, respectively (Table 1,
entry 1). The bidentate ligands a-e were screened and it was
found that TMEDA (ligand a) gave the C-N bond formation
product 8 in higher yield (Table 1, entry 2) compared with other
bidentate ligands b-e which gave lactone 9 in higher yield (Table
1, entries 3 to 6). Some bases were then screened in the presence
of TMEDA (ligand a), and gave lower yield of the corresponding
lactam 8 (Table 1, entries 7 and 8). Interestingly, using
phosphazine base t-Bu-P4 as base in the absence of ligand, the
highest overall yield was obtained in a 1:2 ratio of lactam 8:
lactone 9 (Table 1, entry 9). Adjusting the amounts of amine 7 (3
to 10 equivalents) under basic conditions and TMEDA as ligand,
both lactam 8 and lactone 9 yields relatively increased (Table 1,
entries 10 to 12). It was summarized that the intramolecular C-O
bond formation occurred faster than the intermolecular C-N bond
formation using subcritical water; this is in good accordance with
our previous report.26
4
5
23
10
11
26
16
31
20
34
34
5
5
6
5
7
5
8
5
NaOt-Bu
t-Bu-P4
Cs2CO3
Cs2CO3
Cs2CO3
9
5
10
11
12
3
a
a
a
7
10
a Unless otherwise noted, the reactions were performed in a 10 mL microwave
vessel: 0.5 equiv of CuTC, 300 oC, 10 min. The 300 oC reactions should only
be performed by a trained chemist using a dedicated, scientific reactor with
adequate safety features.
b Isolated yields of pure product after PTLC on silica.
Table 2. Screening of solvents and alkyl groups.a
In an attempt to synthesize phenanthridione as the major
product, the chemoselectivity of C-N bond formation was studied
based on the result of entry 2 Table 1 that gave compound 8 as a
major product using 0.5 equiv CuTC, in the presence of Cs2CO3
and TMEDA. We then optimized the conditions by screening
other solvents with the different dielectric constant for
microwave irradiation. To our delight, the ratio of compounds
8:9 increased to 1.7:1 ratio using dioxane as solvent (Table 2,
entry 1). When the solvent was changed to DMF, the yield of
mixture 8 and 9 increased, in a 1:1 ratio (Table 2, entry 2). A
mixture of water and DMF or toluene in a 1:1 ratio resulted in the
decrease in the ratio of C-N bond formation product (Table 2,
entries 3 to 4). Interestingly, reaction carried out in toluene gave
C-O bond formation in excellent yield (Table 2, entry 5) whereas
using dichloromethane, methanol or solvent free condition gave
no reaction (Table 2, entries 6 to 8). Among different size of
alkyl groups, methyl ester gave the best result (Table 2, entries 9
and 10).
Entry
compound
Solvent
Yield 8
Yield 9
(%)b
(%)b
1
2
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
Dioxane
DMF
17
25
10
24
3
H2O:DMF 1:1
H2O:Toluene 1:1
Toluene
25
51
4
18
31
5
trace
NRc
NRc
NRc
23
95
6
DCM
NRc
NRc
NRc
39
O
O
O
7
MeOH
OH
NHBz
OH
OH
NHAc
N
N
NH2
N
N
d
8
-
d
e
t-Bu
a
b
c
: Glycine : N-Acetylglycine
: TMEDA
: Phenanthroline : Hipuric acid
9
H2O
H2O
N
P
N
P
Me2N
Me2N
Me2N
NMe2
NMe2
NMe2
N
P
N
N P
10
19
18
N
O
Me2N
NMe2
a Unless otherwise noted, the reactions were performed in a 10 mL microwave
vessel: 5 equiv of homoveratrylamine, 0.5 equiv of CuTC, 300 C, 10 min.
PPh2
PPh2
NMe2
o
f: Xantphos
g
h
: t-Bu-P4
: Sparteine
o
The 300 C reactions should only be performed by a trained chemist using a
dedicated, scientific reactor with adequate safety features.
b Isolated yields of pure product after PTLC on silica.
Figure 2. Screened ligands a-g and phophazine base h in this study.

3
c NR: no reaction.
d Solvent-free reaction.
moderate yields (Table 5, entries 1-4). The results of conditions
ACCEPTED MANUSCRIPT
A, with PdCl2 as catalyst, gave the products 24 and 25 in higher
yield than condition B. Heteroaromatic-fused lactam, tetracyclic
7-methyl-5H-indolo[2,3-c]quinolin-6(7H)-one 26 and 11-methyl-
5H-indolo[3,2-c]quinolin-6(11H)-one 27 were successfully
obtained from the corresponding 2-arylindole-3-carboxylate 20
and 3-arylindole-2-carboxylate 21 in poor to moderate yields
using conditions A (Table 5, entries 5-6). Benzo[h][1,6]-
naphthyridin-5(6H)-one 28 was prepared from 2-arylnicotinate
22 in moderate yield (Table 5, entries 7-8). Synthesis of the last
heterocyclic compound, furo[2,3-c]quinolin-4(5H)-one 29 was
achieved from 2-arylfuran-3-carboxylate 23 in poor yield under
both conditions (Table 5, entries 9 and 10).
2.2. Pd(II)-mediated C-N bond formation
The competition of Cu(I)-mediated C-N and C-O bond
formation gave
a
mixture of phenanthridinone
8
and
benzopyranone 9 under microwave irradiation. To study the
selectivity of C-N bond formation, we then turned our interest to
the palladium catalyst. The reaction of methyl 2-
bromocarboxylate (6a) and homoveratylamine (7) was studied
using Pd(II)-catalyzed C-N bond formation with various bases
and ligands as shown in Table 3.
We initially attempted to use 5 mol% Pd(OAc)2, 10 mol%
Xantphos (ligand f) and Cs2CO3 in 1,4-dioxane under microwave
irradiation at 300 C for 10 min and obtained only the C-O bond
Table 3. Screening of palladium(II), bases and ligands.
o
formation of benzopyranone 9 in 60% yield (Table 3, entry 1). A
dramatic change took place when using conventional heating at
o
115 C for 23 h; thus, the double C-N bond formation product 8
was obtained in moderate yield (55% yield) together with the
undesired product, carbazole 10 in 35% yield (Table 3, entry 2).
Increasing the amount of catalyst gave no significant increase in
the yield of product 8 and carbazole 10 (Table 3, entry 3) as well
as using Pd(TFA)2 as a catalyst, instead of Pd(OAc)2 (Table 3,
entry 4). The yield of 8 increased to 76% yield using 5 mol%
PdCl2, 10 mol% Xantphos and Cs2CO3 in refluxing 1,4-dioxane
Entry
Pd(II) (mol%)
Base
Ligand
(mol%) (h)
Time
8b
(%)
9(10)b
(%)
1a
2
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Cs2CO3
Cs2CO3
f (10)
f (10)
f (20)
f (20)
f (10)
f (10)
f (10)
f (10)
f (10)
g (10)
0.16
-
9, 60
o
at 115 C (Table 3, entry 5). A detailed screening of different
23
23
23
23
23
23
23
23
23
55
10, 35
bases revealed that using Cs2CO3 gave the highest yield of
phenanthridinone 8. Sparteine (ligand g) was also studied instead
of Xantphos (ligand f) and gave lower yield (Table 3, entry 10).
The tentative mechanism of C-N bond formation of
compounds 8 and 10 is proposed as shown in Scheme 1. The
oxidative addition of a palladium complex inserted into the C-Br
bond of 6a and followed by reacting with amine to form the
intermediate B. The reductive elimination of B afforded the C-N
bond formation product C which was further lactamized to give
the target product 8.27 The carbazole 10 was obtained by the
tandem decarboxylative palladium-catalyzed intramolecular C-N
bond formation.28-29 It may arise from palladium complex E
produced by the palladium-catalyzed decarboxylation and initial
oxidative addition of carboxylate D followed by either the second
oxidative addition to form palladacycle30 F or palladium complex
G which underwent reductive elimination to give carbazole 10.
With the effective conditions for the synthesis of
phenanthridinone 8 in hand, we then directed our attention to the
synthesis of a small library of phenanthridinone analogues using
both 5 mol% PdCl2 (condition A) and 10 mol% Pd(TFA)2
(condition B) as the catalyst, Xantphos as ligand, and Cs2CO3 as
3
Pd(OAc)2 (10) Cs2CO3
Pd(TFA)2 (10) Cs2CO3
53
10, 32
4
45
10, 31
5
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
Cs2CO3
Na2CO3
K2CO3
Ag2CO3
K3PO4
76
NRc
trace
6
-
-
-
-
-
7
25
8
NRc
NRc
45
9
10
Cs2CO3
a The reactions were performed in a 10 mL microwave vessel, 300 oC, 10 min.
The 300 C reactions should only be performed by a trained chemist using a
dedicated, scientific reactor with adequate safety features.
b Isolated yields of pure product after PTLC on silica.
c NR: no reaction.
o
o
base in refluxing 1,4-dioxane at 115 C. The phenanthridinone
analogues 11-17 were obtained in 12-86% yields as shown in
Table 4. The N-benzylated phenanthridinone 11 was obtained in
45% and 86% yields using PdCl2 and Pd(OAc)2 as catalyst,
respectively (Table 4, entries 1 to 2). The electron donating group
such as methoxy group in the benzylamine derivative affected to
the yield of Pd-catalyzed C-N bond formation products (Table 4,
entries 3 to 6).
2.3. Pd(II)-mediated C-N bond formation: Synthesis of
phenanthridinone derivatives
In order to demonstrate our strategy in the synthesis of a
heterocyclic-fused lactam, we synthesized a small group of
phenanthridinone derivatives using the optimized condition as
shown in Table 5. The polyoxygenated phenanthridinones 24 and
Scheme 1. A proposed mechanism.
25
were prepared
from methyl tri- and tetra-
methoxybiarylcarboxylates 18 and 19, respectively, in poor to

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 4. Synthesis of phenanthridin-4-one derivatives.
3. Conclusion
In summary, we have developed a new method using a Pd(II)-
catalyzed coupling/lactamization process to construct
phenanthridinones from various 2-halobiarylcarboxylates. The
efficiency and functional group effects were studied and applied
to
a number of phenanthridinones and heterocyclic-fused
quinolinone derivatives. This approach is a particularly efficient
route to heterocyclic and polycyclic quinolinone scaffolds.
Entry
1
R
Pd(II) (mol%)
PdCl2 (5)
Time (h)
23
Product (%)a
11, 45
11, 86
12, 34
12, 75
13, 12
13, 29
14, 11
14, 26
15, 65
15, 6
4. Experimental section
4.1. General methods
2
Pd(OAc)2 (10)
PdCl2 (5)
23
3
57
4
Pd(OAc)2 (10)
PdCl2 (5)
23
Melting points were measured with a Thermo Fisher
Scientific IA920 digital melting point apparatus and reported
5
23
1
without correction. H-Nuclear magnetic resonance (1H NMR)
6
Pd(OAc)2 (10)
PdCl2 (5)
23
spectra were recorded on a Varian Gemini2000, a Bruker AV-
300, and a Bruker Avance-600 NMR instruments at 200, 300,
and 600 MHz, respectively, using deuterochloroform as solvents
with tetramethylsilane as an internal standard. 13C-Nuclear
magnetic resonance (13C NMR) spectra were recorded on a
Varian Gemini2000, a Bruker AV-300, and a Bruker Avance-600
NMR instruments at 50, 75, and 150 MHz, respectively, using
deuterochloroform with tetramethylsilane as an internal standard.
7
23
8
Pd(OAc)2 (10)
PdCl2 (5)
28
9
23
10
11
12
13
14
Pd(OAc)2 (10)
PdCl2 (5)
29
69
16, 32
16, 2
Pd(OAc)2 (10)
PdCl2 (5)
55
FTIR spectra were obtained on
a Spectrum One FTIR
23
17, 32
17, 64
spectrometer, a Perkin Elmer System with the universal ATR
(UATR) accessory. Mass spectra were performed with an AEI-
MS-902. High-resolution mass spectra were performed with a
MicroTOFLC, Bruker Daltonics. Column chromatography was
carried out using Fluka aluminum oxide (type 507 C neutral; 100-
125 mesh) and Merck silica gel (70-230 mesh ASTM). Thin
layer chromatography (TLC) and preparative thin layer
chromatography (PTLC) were carried out on precoated silica gel
(E. Merck PF 254). All reagents were purified and dried
according to the standard procedures.
Pd(OAc)2 (20)
23
a Isolated yields of pure product after PTLC on silica.
Table 5. Synthesis of various lactam derivatives.
4.2. General Procedure for the Preparation of Biarylcarboxylate
Esters 6a - 6c and 18 - 23
Entry
Substrate
Product
conda
Time
Yield
(%)b
(h)
12
30
A solution of 2-halophenylboronic acid (2.0 equiv), alkyl 2-
bromophenylcarboxylate (1.0 equiv) and 10 mol% Pd(PPh3)4 in three
portion of toluene:EtOH:10%Na2CO3 (5:1:2) solution was refluxed
overnight. After the complete reaction was observed by TLC, water
was added to quench and partition with EtOAc to obtain the crude
product. The crude product was then purified by flash column
chromatography or the preparative thin layer chromatography (10%
EtOAc:hexanes) to obtain the product. Spectroscopic data of the
biarylcarboxylate esters including compounds 6a, 18 – 21,24 22 and
2325 were previously reported in the literature.
1
2
18
24
A
B
48
8c
OMe
3
4
19
MeO
MeO
25
26
27
28
29
A
B
17
60
40
26
OMe
Br
CO2Me
5
6
20
21
22
23
A
A
17
17
55
13
4.2.1.
Ethyl
2'-bromo-[1,1'-biphenyl]-2-carboxylate
(6b).
Employing the general procedure with ethyl 2-bromobenzoate (0.10
g, 0.32 mmol) with 2-bromophenylboronic acid (0.13 g, 0.65 mmol)
under the general condition above gave 6b as pale colorless oil (0.07
g, 78% yield). Rf 0.45 (20% EtOAc:hexanes). IR (UATR): νmax 3053,
2981, 1714, 1600, 1465, 1443, 1365, 1287, 1255, 1131, 752 cm-1. 1H
NMR (300 MHz, CDCl3): δ 7.95 (dd, J = 7.5, 1.2 Hz, 1H), 7.52 (dd,
J = 8.1, 1.2 Hz, 1H), 7.48 (dt, J = 7.5, 1.5 Hz, 1H), 7.38 (dt, J = 8.7,
1.5 Hz, 1H), 7.25 (dt, J = 7.0, 1.2 Hz, 1H), 7.17 – 7.09 (m, 3H), 4.00
(q, J = 6.0 Hz, 2H), 0.92 (t, J = 6.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 167.0, 142.9, 142.0, 132.0, 131.6, 130.8, 130.4, 130.2,
130.0, 128.5, 127.8, 126.9, 123.0, 60.8, 13.6. HRMS (microTOF):
m/z calcd for C15H1381BrO2Na (M[81Br]+Na+): 328.9972, found
328.9972; for C15H1379BrO2Na (M[79Br]+Na+): 326.9983; found
326.9991.
7
8
A
B
17
17
26
53
9
A
B
85
40
4
9
10
a All reactions were performed with palladium(II) catalyst (0.1 equiv), PdCl2
for condition A and Pd(OAc)2 for condition B, with biaryl ester (1.0 equiv),
amine (5.0 equiv), Cs2CO3 (2.0 equiv), Xantphos (0.2 equiv) in 1,4-dioxane
(5 mL).
b Isolated product yields after PTLC on silica gel.
c Recovered starting material 81%.
4.2.2.
Isopropyl 2'-bromo-[1,1'-biphenyl]-2-carboxylate (6c).
Employing the General Procedure with isopropyl 2-bromobenzoate
(0.10 g, 0.41 mmol) with 2-bromophenylboronic acid (0.16 g, 0.82
mmol) under the general condition above gave 6c as a colorless oil

5
137.3, 133.8, 132.6, 129.5, 129.1, 128.6, 128.0, 127.9 (2C), 125.5,
(0.02 g, 22% yield). Rf 0.42 (20% EtOAc:hexanes). IR (UATR): νmax
ACCEPTED MANUSCRIPT
123.2, 122.5, 121.6, 119.5, 116.0, 114.2 (2C), 55.2, 45.9. EI-MS: m/z
(%) 316 (M+, 7), 315 (32), 166 (7), 149 (8), 121 (100). HRMS
(microTOF): m/z calcd for C21H17NO2Na (M + Na+) 338.1150; found
338.1151.
3058, 2979, 2934, 1708, 1600, 1464, 1414, 1350, 1285, 1257, 1106,
1
750 cm-1. H NMR (300 MHz, CDCl3): δ 8.02 (dd, J = 7.8, 1.2 Hz,
1H), 7.59 (d, J = 8.1 Hz, 1H), 7.54 (dt, J = 7.5, 1.5 Hz, 1H), 7.45 (dt,
J = 7.6, 1.2 Hz, 1H), 7.32 (dt, J = 6.9, 1.2 Hz, 1H), 7.24 – 7.17 (m,
3H), 4.97 (sept, J = 6.3 Hz, 1H), 1.04 (d, J = 6.3 Hz, 3H), 0.95 (d, J
= 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 166.7, 143.2, 141.9,
132.1, 131.5, 131.0, 130.8, 130.2 (2C), 128.6, 127.9, 126.9, 123.2,
68.3, 21.4, 21.3. HRMS (microTOF): m/z calcd for C16H1581BrO2Na
(M[81Br]+Na+): 343.0132, found 343.0128; for C16H1579BrO2Na
(M[79Br]+Na+): 341.0143; found 341.0147.
4.3.4.
5-(3,4-Dimethoxybenzyl)phenanthridin-6(5H)-one
(13).
Employing the general procedure with compound 6a (0.06 g, 0.20
mmol), 3,4-dimethoxybenzylamine (0.15 mL, 1.03 mmol), Xantphos
(0.01 g, 0.02 mmol), PdCl2 (0.003 g, 0.01 mmol) and Cs2CO3 (0.13
g, 0.41 mmol) in 1,4-dioxane (5 mL) for 23 h gave a yellow solid
(0.008 g, 12% yield). Rf 0.25 (20% EtOAc:hexanes). Mp: 118 – 120
oC. IR (UATR): νmax 2934, 1722, 1646, 1608, 1514, 1437, 1258,
4.3.
General
Procedure
for
the
Preparation
of
1139, 1025 cm-1. 1H NMR (300 MHz, CDCl3):
δ 8.62 (d, J = 7.8 Hz,
Phenanthridinones 8, 11 – 17 and 24 – 29
1H), 8.32 – 8.25 (m, 2H), 7.79 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.5
A mixture of methyl 2-halobiarylcarboxylate (0.2 mmol, 1.0 equiv),
amine (1.0 mmol, 5.0 equiv), PdCl2 (0.02 mmol, 0.1 equiv),
xantphos (0.02 mmol, 0.1 eqiuv), and Cs2CO3 (0.4 mmol, 2.0 eqiuv)
in 1,4-dioxane (5 mL) was heated at 115 oC under Ar atmosphere for
12 to 85 h. The reaction was monitored by TLC. After completion,
the reaction was partitioned with water (25 mL) and EtOAc (4 x 25
mL). The solvent was removed under reduced pressure to give a
crude product which was then purified by PTLC (30%
EtOAc/hexane) to give the product.
Hz, 1H), 7.44 – 7.28 (m, 3H), 6.86 (s, 1H), 6.77 (m, 2H), 5.60 (s,
2H), 3.81 (s, 6H). 13C NMR (75 MHz, CDCl3):
δ 161.9, 154.5,
149.4, 148.2, 137.4, 133.8, 132.7, 129.5, 129.1, 128.0, 125.4, 123.3,
122.6, 121.7, 119.5, 118.8, 116.0, 111.4, 110.1, 55.9 (2C), 46.3. EI-
MS: m/z (%) 345 (M+, 33), 167 (24), 151 (100), 127 (11), 97 (19), 71
(28). HRMS (microTOF): m/z calcd for C22H19NO3Na (M + Na+)
368.1249; found 368.1257.
4.3.5.
5-(Pyridin-2-ylmethyl)phenanthridin-6(5H)-one
(14).
4.3.1.
5-(3,4-Dimethoxybenzyl)phenanthridin-6(5H)-one
(8).
Employing the general procedure with compound 6a (0.06 g, 0.20
mmol), pyridine-2-ylmethanamine (0.10 mL, 1.03 mmol), Xantphos
(0.01 g, 0.02 mmol), PdCl2 (0.003 g, 0.01 mmol) and Cs2CO3 (0.13
g, 0.41 mmol) in 1,4-dioxane (5 mL) for 23 h gave a white solid
(0.013 g, 11 % yield). Rf 0.25 (20% EtOAc:hexanes). Mp: 137 – 139
Employing the general procedure with compound 6a (0.10 g, 0.34
mmol), homoveratrylamine (7) (0.20 mL, 1.71 mmol), Xantphos
(0.02 g, 0.03 mmol), PdCl2 (0.005 g, 0.02 mmol) and Cs2CO3 (0.22
g, 0.68 mmol) in 1,4-dioxane (5 mL) for 23 h gave a yellow solid
(0.09 g, 76 % yield). Rf 0.28 (30% EtOAc:hexanes). Mp: 94 – 97 oC.
1
oC. IR (UATR): νmax 3066, 1650, 1608, 1587, 1436, 1316 cm-1. H
IR (UATR): νmax 2935, 2827, 1645, 1608, 1587, 1514, 1438, 1259,
NMR (300 MHz, CDCl3):
δ 8.63 – 8.61 (m, 2H), 8.29 (m, 2H), 7.79
1
1237, 1155, 1027 cm-1. H NMR (300 MHz, CDCl3):
δ
8.52 (d, J =
(td, J = 7.6, 1.5 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.54 (td, J = 7.6,
1.5 Hz, 1H), 7.47 – 7.37 (m, 2H), 7.27 (td, J = 7.8, 1.5 Hz, 1H), 7.17
7.8 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.69
(t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H),
7.40 (d, J = 8.1 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H), 6.91 – 6.80 (m,
3H), 4.52 (t, J = 7.8 Hz, 2H), 3.85 (s, 6H), 2.99 (t, J = 7.8 Hz, 2H).
13C NMR (75 MHz, CDCl3): δ 161.0, 148.9, 147.6, 136.7, 133.3,
132.2, 130.9, 129.4, 128.4, 127.7, 125.2, 123.3, 122.1, 121.3, 120.5,
119.2, 114.6, 111.9, 111.3, 55.7 (2C), 44.2, 33.0. EI-MS: m/z (%)
359 (M+, 3), 178 (31), 164 (100), 151 (11), 149 (24). HRMS
(microTOF): m/z calcd for C23H21NO3Na (M + Na+) 382.1411; found
382.1413.
– 7.14 (m, 2H), 5.78 (s, 2H). 13C NMR (75 MHz, CDCl3):
δ 161.8,
156.9, 149.3, 137.3, 137.0, 133.9, 132.7, 129.6, 129.1, 128.0, 125.3,
123.2, 122.7, 122.3, 121.7, 121.4, 119.4, 116.2, 48.6. EI-MS: m/z
(%) 286 (M+, 100), 269 (73), 180 (81), 149 (66). HRMS
(microTOF): m/z calcd for C19H15N2O (M + H+) 287.1176; found
287.1178.
4.3.6.
5-(Pyridin-3-ylmethyl)phenanthridin-6(5H)-one
(15).
Employing the general procedure with compound 6a (0.08 g, 0.29
mmol), pyridine-3-ylmethanamine (0.10 mL, 1.47 mmol), Xantphos
(0.01 g, 0.02 mmol), PdCl2 (0.004 g, 0.01 mmol) and Cs2CO3 (0.19
g, 0.59 mmol) in 1,4-dioxane (5 mL) for 23 h gave a yellow solid
(0.05 g, 65% yield). Rf 0.17 (20% EtOAc:hexanes). Mp: 104 – 106
4.3.2.
5-(Benzyl)phenanthridin-6(5H)-one (11). Employing the
general procedure with compound 6a (0.06 g, 0.20 mmol),
benzylamine (0.10 mL, 1.03 mmol), Xantphos (0.01 g, 0.02 mmol),
PdCl2 (0.003 g, 0.01 mmol) and Cs2CO3 (0.13 g, 0.41 mmol) in 1,4-
dioxane (5 mL) for 23 h gave a yellow solid (0.02 g, 45% yield). Rf
oC. IR (UATR): νmax 2920, 2851, 1649, 1608, 1436, 1366, 1335,
1
1313, 749, 742 cm-1. H NMR (300 MHz, CDCl3):
δ 8.66 (s, 1H),
o
0.34 (20% EtOAc:hexanes). Mp: 115 – 117 C. IR (UATR): νmax
8.60 (d, J = 8.1 Hz, 1H), 8.49 (br s, 1H), 8.30 (d, J = 7.8 Hz,, 2H),
7.80 (t, J = 7.8 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.54 (d, J = 7.8 Hz,
1H), 7.42 (t, J = 7.5 Hz, 1H), 7.32 – 7.18 (m, 3H), 5.68 (s, 2H). 13C
1
3027, 1650, 1608, 747, 723 cm-1. H NMR (300 MHz, CDCl3):
δ
8.53 (d, J = 7.8 Hz, 1H), 8.20 (m, 2H), 7.69 (t, J = 7.8 Hz, 1H), 7.52
(t, J = 7.8 Hz, 1H), 7.32 – 7.18 (m, 8H), 5.57 (s, 2H). 13C NMR (75
MHz, CDCl3): δ 161.9, 137.3, 136.6, 133.8, 132.7, 129.5, 129.1,
128.8 (2C), 128.0, 127.1, 126.5 (2C), 125.4, 123.3, 122.5, 121.7,
119.5, 116.0, 46.5. EI-MS: m/z (%) 286 (M+H+, 7), 285 (34), 284
(19), 179 (22), 167 (27), 97 (29), 83 (24). HRMS (microTOF): m/z
calcd for C20H15NONa (M + Na+) 308.1055; found 308.1045.
NMR (75 MHz, CDCl3):
δ 169.9, 148.8, 148.5, 137.1, 134.5, 133.8,
132.9, 132.4, 129.7, 129.1, 128.2, 125.2, 123.6, 123.5, 122.8, 121.8,
119.6, 115.5, 44.1. EI-MS: m/z (%) 286 (M+, 92), 285 (100), 269
(49), 179 (36), 166 (17), 149 (11), 92 (41). HRMS (microTOF): m/z
calcd for C19H15N2O (M + H+) 287.1174; found 287.1178.
4.3.7.
5-(Pyridin-4-ylmethyl)phenanthridin-6(5H)-one
(16).
4.3.3.
5-(4-Methoxybenzyl)phenanthridin-6(5H)-one
(12).
Employing the general procedure with compound 6a (0.06 g, 0.20
mmol), pyridine-4-ylmethanamine (0.10 mL, 1.03 mmol), Xantphos
(0.01 g, 0.02 mmol), PdCl2 (0.003 g, 0.01 mmol) and Cs2CO3 (0.13
g, 0.41 mmol) in 1,4-dioxane (5 mL) for 69 h gave a white solid
(0.018 g, 32% yield). Rf 0.22 (20% EtOAc:hexanes). Mp: 96 – 99 oC.
IR (UATR): νmax 3524, 3034, 2946, 1646, 1608, 1584, 1587, 1435,
1362, 749 cm-1. 1H NMR (300 MHz, CDCl3): δ 8.67 (br s, 1H), 8.59
(dd, J = 7.9, 1.2 Hz, 1H), 8.51 (br s, 1H), 8.28 (d, J = 8.1 Hz, 2H),
7.79 (td, J = 7.6, 1.5 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.54 (d, J =
7.8 Hz, 1H), 7.41 (td, J = 7.8, 1.2 Hz, 1H), 7.30 – 7.18 (m, 3H), 5.66
(s, 2H). 13C NMR (75 MHz, CDCl3): δ 161.8, 148.6, 148.4, 136.8,
Employing the general procedure with compound 6a (0.06 g, 0.20
mmol), 4-methoxybenzylamine (0.13 mL, 1.03 mmol), Xantphos
(0.01 g, 0.02 mmol), PdCl2 (0.003 g, 0.0.01 mmol) and Cs2CO3 (0.13
g, 0.41 mmol) in 1,4-dioxane (5 mL) for 57 h gave a yellow solid
(0.02 g, 34% yield). Rf 0.20 (10% EtOAc:hexanes). Mp: 129 – 131
oC. IR (UATR): νmax 2956, 2925, 2852, 1646, 1608, 1512, 1437,
1246, 1031, 724 cm-1. H NMR (300 MHz, CDCl3): δ 8.61 (d, J =
8.1 Hz, 1H), 8.29 – 8.10 (m, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.60 (t, J
= 7.8 Hz, 1H), 7.42 – 7.19 (m, 5H), 6.81 (d, J = 8.1 Hz, 2H), 5.59 (s,
2H), 3.73 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 161.9, 158.7,
1

6
Tetrahedron
ACCEPTED MANUSCRIPT
134.6, 133.7, 132.9, 129.7, 129.0, 128.1, 125.1, 123.8, 123.5, 122.8
135.1, 131.1, 126.2, 126.1, 125.9, 124.0, 122.6, 122.4, 121.6, 121.0,
(2C), 121.7, 119.5, 115.4, 44.0. EI-MS: m/z (%) 286 (M+, 12), 279
(12), 167 (27), 149 (98), 97 (40), 69 (100). HRMS (microTOF): m/z
calcd for C19H14N2ONa (M + Na+) 309.0993; found 309.0998.
120.7, 119.9, 118.6, 114.7, 112.1, 111.5, 110.5, 55.9 (2C), 43.9,
33.6, 31.5. EI-MS: m/z (%) 412 (M+, 7), 248 (42), 129 (28), 97 (66),
69 (100). HRMS (microTOF): m/z calcd for C26H24N2O3Na (M +
Na+) 435.1673; found 435.1679.
4.3.8.
5-(3-Methylpyridin-2-yl)phenanthridin-6(5H)-one
(17).
Employing the general procedure with compound 6a (0.08 g, 0.29
mmol), 3-methylpyridin-2-ylamine (0.11 mL, 1.47 mmol), Xantphos
(0.01 g, 0.02 mmol), PdCl2 (0.004 g, 0.01 mmol) and Cs2CO3 (0.19
g, 0.59 mmol) in 1,4-dioxane (5 mL) for 23 h gave a yellow solid
(0.025 g, 32% yield). Rf 0.11 (20% EtOAc:hexanes). Mp: 178 – 180
oC. IR (UATR): νmax 3059, 2920, 2815, 1654, 1607, 1435, 1319,
4.3.12.
5-(3,4-Dimethoxyphenethyl)-11-methyl-5H-indolo[3,2-
c]quinolin-6(11H)-one (27). Employing the general procedure with
compound 21 (0.02 g, 0.05 mmol), homoveratrylamine (7) (0.05 mL,
0.24 mmol), Xantphos (0.006 g, 0.01 mmol), PdCl2 (0.002 g, 0.006
mmol) and Cs2CO3 (0.13 g, 0.40 mmol) in 1,4-dioxane (5 mL) for 17
h gave a brown solid (0.003 g, 13% yield). Rf 0.14 (30% EtOAc :
hexane). Rf 0.14 (30% EtOAc:hexanes). Mp: 69 – 71 oC. IR
(UATR): νmax 3746, 3053, 2917, 2849, 1643, 1512, 1463, 743 cm-1.
1H NMR (600 MHz, CDCl3): 8.62 (d, J = 7.7 Hz, 1H), 8.45 (d, J =
8.1 Hz, 1H), 7.63 – 7.61 (m, 2H), 7.54 - 7.53 (m, 1H), 7.50 (t, J = 7.9
Hz, 1H), 7.41 (t, J = 8.9 Hz, 1H), 7.39 – 7.34 (m, 1H), 6.97 – 6.91
(m, 2H), 6.87 (d, J = 7.9 Hz, 1H), 4.67 (t, J = 8.4 Hz, 2H), 4.32 (s,
3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.07 (t, J = 8.4 Hz, 2H). 13C NMR
(150 MHz, CDCl3): 159.7, 149.3, 148.0, 140.0, 139.4, 138.6, 131.4,
130.1, 128.9, 124.6, 124.4, 123.2, 122.3, 122.0, 121.3, 120.8, 115.6,
114.9, 112.5, 111.7, 108.9, 56.0 (2C), 43.7, 33.7 (2C). EI-MS: m/z
(%) 413 (M+H+, 0), 88 (11), 86 (65), 84 (100), 83 (10). HRMS
(microTOF): m/z calcd for C26H24N2O3Na (M + Na+) 435.1673;
found 435.1679.
748, 724 cm-1. 1H NMR (200 MHz, CDCl3):
δ 8.83 – 8.75 (m, 2H),
8.58 – 8.50 (m, 2H), 8.06 – 8.00 (m, 2H), 7.82 (t, J = 8.0 Hz, 1H),
7.63 (dd, J = 7.7, 4.6 Hz, 1H), 7.53 – 7.47 (m, 2H), 6.65 – 6.60 (m,
1H), 2.36 (s, 3H). 13C NMR (50 MHz, CDCl3):
δ 160.9, 150.7,
148.1, 140.2, 137.4, 134.2, 132.9, 132.7, 129.3, 128.8, 128.0, 125.7,
124.5, 123.2, 122.9, 121.8, 119.1, 115.6, 17.0. EI-MS: m/z (%) 286
(M+, 46), 285 (100), 271 (12), 255 (9). HRMS (microTOF): m/z
calcd for C19H15N2O (M + H+) 287.1174; found 287.1178.
4.3.9.
5-(3,4-Dimethoxyphenethyl)-8,9,10-trimethoxyphenan
thridin-6(5H)-one (24). Employing the general procedure with
compound 18 (0.02 g, 0.06 mmol), homoveratrylamine (7) (0.11 mL,
0.65 mmol), Xantphos (0.007 g, 0.01 mmol), PdCl2 (0.002 g, 0.006
mmol) and Cs2CO3 (0.15 g, 0.45 mmol) in 1,4-dioxane (5 mL) for 12
h gave a yellow solid (0.01 g, 48% yield). Rf 0.48 (20%
EtOAc:hexanes). Mp: 102 – 104 oC. IR (UATR): νmax 3498, 2928,
2850, 1714, 1642, 1606, 1582, 1515, 1454, 1143, 1085, 754 cm-1. 1H
4.3.13.
6-(3,4-Dimethoxyphenethyl)benzo[h][1,6]naphthyridin-
5(6H)-one (28). Employing the general procedure with compound 22
(0.10 g, 0.40 mmol), homoveratrylamine (7) (0.30 mL, 2.0 mmol),
Xantphos (0.05 g, 0.08 mmol), PdCl2 (0.007 g, 0.08 mmol) and
Cs2CO3 (0.92 g, 2.82 mmol) in 1,4-dioxane (5 mL) for 17 h gave a
white solid (0.04 g, 26% yield). Rf 0.20 (30% EtOAc:hexanes). Rf
0.20 (30% EtOAc : Hexane). Mp: 146 – 148 oC. IR (UATR): νmax
NMR (300 MHz, CDCl3):
δ 9.23 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H),
7.60 – 7.45 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 6.96 – 6.85 (m, 3H),
4.58 (t, J = 8.2 Hz, 2H), 4.04 (s, 3H), 4.03 (s, 3H), 3.97 (s, 3H), 3.89
(s, 2 x 3H), 3.04 (t, J = 8.2 Hz, 2H). 13C NMR (75 MHz, CDCl3):
δ
2992, 2932, 2830, 1650, 1609, 1595, 1515, 756 cm-1. H NMR (600
1
160.7, 153.3, 151.4, 149.1, 147.8, 147.3, 136.0, 131.1, 128.4, 127.3,
122.7, 122.4, 121.6, 120.7, 119.2, 114.4, 112.0, 111.4, 106.1, 61.2,
60.4, 56.1, 55.9 (2C), 44.9, 33.2. EI-MS: m/z (%) 449 (M+, 5), 298
(8), 286 (17), 185 (100), 164 (50), 149 (50). HRMS (microTOF): m/z
calcd for C26H27NO6Na (M + Na+) 472.1735; found 472.1730.
MHz, CDCl3): 9.02 (dd, J = 4.5, 1.7 Hz, 1H), 8.95 (dd, J = 7.9, 1.4
Hz, 1H), 8.77 (dd, J = 7.9, 1.7 Hz, 1H), 7.66 (td, J = 7.7, 1.5 Hz,
1H), 7.53 (dd, J = 7.9, 4.5 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 (t,
J = 7.5 Hz, 1H), 6.92 – 6.84 (m, 3H), 4.59 (t, J = 8.3 Hz, 2H), 3.88
(s, 3H), 3.04 (t, J = 8.3 Hz, 2H). 13C NMR (150 MHz, CDCl3):
161.3, 153.8, 150.3, 149.3, 148.1, 138.3, 136.6, 131.3, 131.0, 125.7,
123.0, 122.8, 120.9 (2C), 120.8, 114.4, 112.4, 111.7, 56.0 (2C), 44.3,
33.2. EI-MS: m/z (%) 361 (M+H+, 0), 360 (M+, 2), 179 (19), 165
(13), 164 (98), 149 (39), 88 (10), 84 (100). HRMS (microTOF): m/z
calcd for C22H21NO3 (M + H+) 361.1546; found 361.1546.
4.3.10. 5-(3,4-Dimethoxyphenethyl)-2,3,8,9-tetramethoxy
phenanthridin-6(5H)-one (25). Employing the general procedure
with compound 19 (0.02 g, 0.06 mmol), homoveratrylamine (7)
(0.10 mL, 0.60 mmol), Xantphos (0.007 g, 0.01 mmol), PdCl2 (0.002
g, 0.006 mmol) and Cs2CO3 (0.13 g, 0.42 mmol) in 1,4-dioxane (5
mL) for 17 h gave a yellow solid (0.01 g, 40% yield). Rf 0.08 (20%
EtOAc:hexanes). Mp: 180 – 182 oC. IR (UATR): νmax 2997, 2936,
2830, 1633, 1611, 1588, 1509, 1257, 1028 cm-1. 1H NMR (300 MHz,
4.3.14. 5-(3,4-Dimethoxyphenethyl)furo[2,3-c]quinolin-4(5H)-one
(29). Employing the general procedure with compound 23 (0.02 g,
0.10 mmol), homoveratrylamine (7) (0.08 mL, 0.52 mmol),
Xantphos (0.006 g, 0.01 mmol), PdCl2 (0.005 g, 0.01 mmol) and
Cs2CO3 (0.07 g, 0.21 mmol) in 1,4-dioxane (5 mL) for 85 h gave a
brown (1 mg, 4% yield). Rf 0.11 (30% EtOAc:hexanes). Mp: 77 – 79
CDCl3):
δ 7.95 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 6.82 – 6.88 (m,
4H), 4.59 (t, J = 8.1 Hz, 2H), 4.11 (s, 3H), 4.05 (s, 6H), 3.98 (s, 3H),
3.87 (s, 3H), 3.84 (s, 3H), 3.06 (t, J = 8.1 Hz, 2H). 13C NMR (75
MHz, CDCl3):
δ 160.7, 153.3, 150.3, 149.2 (2C), 147.9, 145.0,
oC. IR (UATR): νmax 2918, 2849, 1646, 1515, 1145, 757 cm-1. H
1
131.5, 131.3, 128.3, 120.5, 118.5, 112.1 (2C), 111.5, 108.9, 105.4,
102.0, 98.7, 56.6, 56.1 (2C), 55.9 (2C), 55.8, 44.9, 33.5. EI-MS: m/z
(%) 479 (M+, 0), 279 (12), 167 (26), 149 (100), 97 (10). HRMS
(microTOF): m/z calcd for C27H29NO7Na (M + Na+) 502.1841; found
502.1836.
NMR (600 MHz, CDCl3): 8.06 (dd, J = 7.8, 1.5 Hz, 1H), 7.64 (d, J =
1.9 Hz, 1H), 7.57 (dt, J = 7.8, 1.6 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H),
7.33 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.91 – 6.82 (m,
3H), 4.57 (t, J = 8.1 Hz, 2H), 3.87 (s, 2 x 3H), 2.99 (t, J = 8.8 Hz,
2H). 13C NMR (150 MHz, CDCl3): 159.2, 155.3, 144.0, 131.1, 129.5,
126.2, 122.2, 121.5, 120.8, 115.4, 114.9, 113.5, 112.4, 111.7, 108.3,
56.0 (2C), 43.9, 33.7, two quaternary carbons were not observed on
the spectrum. EI-MS: m/z (%) 350 (M+H+, 0), 164 (11), 149 (27), 88
(10), 86 (65), 84 (100). HRMS (microTOF): m/z calcd for
C21H20NO4 (M + Na+) 350.1383; found 350.1386.
4.3.11.
5-(3,4-Dimethoxyphenethyl)-7-methyl-5H-indolo[2,3-
c]quinolin-6(7H)-one (26). Employing the general procedure with
compound 20 (0.05 g, 0.14 mmol), homoveratrylamine (7) (0.10 mL,
0.72 mmol), Xantphos (0.008 g, 0.01 mmol), PdCl2 (0.002 g, 0.007
mmol) and Cs2CO3 (0.09 g, 0.29 mmol) in 1,4-dioxane (5 mL) for 17
h gave a yellow solid (0.032 g, 55% yield). Rf 0.34 (30%
o
Acknowledgements
EtOAc:hexanes). Mp: 136 – 140 C. IR (UATR): νma1x 3053, 2929,
2850, 1643, 1514, 1463, 1260, 1155, 1028, 744 cm-1. H NMR (300
This research was supported by the Thailand Research Fund
(TRF; RMU5380021 and BRG5680005 for N.T.) and Mahidol
University. Center of Excellent on Environmental Health and
Toxicology, Science & Technology Postgraduate Education and
MHz, CDCl3):
δ 8.48 (d, J = 7.8 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H),
7.59 – 7.49 (m, 4H), 7.45 – 7.30 (m, 2H), 7.45 – 6.86 (m, 3H), 4.61
(t, J = 7.9 Hz, 2H), 4.38 (s, 3H), 3.90 (s, 6H), 3.05 (t, J = 7.9 Hz,
2H). 13C NMR (75 MHz, CDCl3):
δ 156.6, 149.1, 147.8, 140.7,

7
Ploypradith, P; Mahidol, C.; Sahakitpichan, S.; Wongbudit, S.;
Research Development Office (PERDO), Ministry of Education is
gratefully acknowledged.
ACCEPTED MANUSCRIPT
Ruchirawat, S. Angew. Chem. Int. Ed. Engl. 2004, 43, 866–868.
(d) Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas,
N.D.; Ruchirawat, S. J. Org. Chem. 2006, 71, 9440–9448.
24. Kluza, J.; Gallego, M. A.; Loyens, A.; Beauvillain, J. C.; Sousa-
Faro, J. M. F.; Cuevas, C.; Marchetti, P.; Bailly, C. Cancer
Research 2006, 66, 3177–3187.
References and notes
1. Xiao, X.; Morrell, A.; Fanwick, P. E.; Cushmana, M. Tetrahedron
2006, 62, 9705–9712.
2. Rosa, M.; Lobe, A. M.; Branco, P. S.; Prabhakar, S. Tetrahedron
1997, 53, 299–306.
3. Harayama, T.; Hori, A.; Abe, H.; Takeuchi, Y. Tetrahedron 2004,
60, 1611–1616.
4. Nakamura, M.; Aoyama, A.; Salim, M. T. A.; Okamoto, M.; Baba,
M.; Miyachi, H.; Hashimoto, Y.; Aoyama, H. Bioorg. Med. Chem.
2010, 18, 2402–2411.
5. Graebe, D.; Wander, A. Liebigs Ann. Chem. 1893, 276, 245–253.
6. Labriola, R. A. J. Org. Chem. 1940, 6, 329–333.
7. Labriola, R. A.; Felitte, A. J. Org. Chem. 1943, 8, 536–539.
8. Yang, W.; Wang, J.; Wei, Z.; Xu, Xianxiu. J. Org. Chem. 2016,
81, 1675–1680.
9. Liu, H.; Han, W.; Li, C.; Ma, Z.; Li, R.; Zheng, X.; Fu, H., Chen,
H. Eur. J. Org. Chem. 2016, 389–393.
10. Feng, M.; Tang, B.; Wang, N.; Xu, H.-X.; Jiang, X. Angew. Chem.
Int. Ed. 2015, 54, 14960–14964.
11. Calder, E. D. D.; McGonagle, F. I.; Harkiss, A. H.; McGonagle,
G. A.; Sutherland, A. J. Org. Chem. 2004, 79, 7633–7648.
12. Peng, X.; Wang, W.; Jiang, C.; Sun, D.; Xu, Z.; Tung, C.-H. Org.
Lett. 2014, 16, 5354–5357.
13. Wolfe, J. P.; Wagaw, S.; Marcoux, J.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805–818.
14. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852–860.
15. Guram, S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed.
1995, 34, 1348–1350.
25. Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young,
L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379−9382.
26. Nealmongkol, P.; Tangdenpaisal, K.; Sitthimonchai, S.;
Ruchirawat, S., Thasana, N. Tetrahedron 2013, 69, 9277–9283.
see also Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863−3867.
27. (a) Poondra, R. R.; Turner, N. J. Org. Lett. 2005, 7, 863−866. (b)
Luo, X.; Chenard, E.; Martens, P.; Cheng, Y.-X.; Tomaszewski,
M. J. Org. Lett. 2010, 12, 3574−3577. (c) Gollner, A.; Koutentis,
P. A. Org. Lett. 2010, 12, 1352−1355. (d) Furuta, T.; Yamamoto,
J.; Kitamura, Y.; Hashimoto, A.; Masu, H.; Azumaya, I.; Kan, T.;
Kawabata, T. J. Org. Chem. 2010, 75, 7010−7013. (e) Yang, B.
H.; Buchwald, S. L. Org. Lett. 1999, 1, 35−37.
28. (a) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131,
4194−4195. (b) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias,
M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130,
16184−16186.
29. (a) Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng,
G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824−4833. (b)
Becht, J.-M.; Catala, C.; Le Drian, C.; Wabner, A. Org. Lett.
2007, 9, 1781−1783. (c) Goossen, L. J.; Rodriguez, N.; Linder, C.
J. Am. Chem. Soc. 2008, 130, 15248−15249. (d) Becht, J.-M.; Le
Drian, C.; Org. Lett. 2008, 10, 3161−3164. (e) Myers, A. G.;
Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124,
11250−11251.
30. Karig, G.; Moon, M.-T.; Thasana, N.; Gallagher, T. Org. Lett.
2002, 4, 3115–3118.
16. Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609–3612.
17. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144–1157.
18. Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 7215–7216.
Supplementary Material
19. Hesse, M. Alkaloids Nature’s Curse or Blessing?, Eds.
Wallimann, P. M.; Kisakurek, M. V., Wiley-VCH, Zurich, 2002.
20. Da Silva, A. J. M.; Melo, P. A.; Silva, N. M. V.; Brito, F. V.;
Buarque, C. D.; De Souza, D. V.; Rodrigues, V. P.; Pocas, E. S.
C.; Noel, F.; Albuquerque, E. X.; Costa, P. R. R. Bioorg. Med.
Chem. Lett. 2001, 11, 283–286.
Supplementary material that may be helpful in the review process
should be prepared and provided as a separate electronic file.
That file can then be transformed into PDF format and submitted
along with the manuscript and graphic files to the appropriate
editorial office.
21. Xiao, X.; Morrell, A.; Fanwick, P. E.; Cushman, M. Tetrahedron
2006, 62, 9705–9712.
22. Boonya-Udthayan, S.; Yotapan, N.; Woo, C.; Bruns, C. J.;
Ruchirawat, S.; Thasana, N. Chem. Asian J. 2010, 5, 3113−3123.
23. (a) Ruchirawat, S.; Mutarapat, M. Tetrahedron Lett. 2001, 42,
1205–1208. (b) Ploypradith, P.; Jinaglueng, W.; Pavaro, C.;
Ruchirawat, S. Tetrahedron Lett. 2003, 44, 1363–1366. (c)
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