Synthesis of coumarin- and quinolone-annulated benzazocinone frameworks by a palladium-catalyzed intramolecular heck reaction

Article abstract of DOI:10.1055/s-0031-1290970

A synthetic strategy based on the sequential application of an aromatic aza-Claisen rearrangement and an intramolecular Heck reaction as the key steps has been developed for the synthesis of various new coumarin- and quinolone-annulated benzazocinone deri

Full text of DOI:10.1055/s-0031-1290970

PAPER
▌1711
paper
Synthesis of Coumarin- and Quinolone-Annulated Benzazocinone
Frameworks by a Palladium-Catalyzed Intramolecular Heck Reaction
Coumarin- and Quinolone-Annulated Benzazocinone Frameworks
K. C. Majumdar,* Srikanta Samanta, Tapas Ghosh
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B., India
E-mail: kcm@klyuniv.ac.in
Received: 30.01.2012; Accepted after revision: 28.03.2012
no[6,5-c][2]benzazocine and quino[6,5-c][2]benzazocine
derivatives by means of an aza-Claisen rearrangement and
a palladium-catalyzed intramolecular Heck reaction.
Abstract: A synthetic strategy based on the sequential application
of an aromatic aza-Claisen rearrangement and an intramolecular
Heck reaction as the key steps has been developed for the synthesis
of various new coumarin- and quinolone-annulated benzazocinone
derivatives in 60–70% yields.
The substrates 1a–f20k,m,21 and 422 were prepared accord-
ing to published procedures. Treatment of chromenone 1a
with 2-iodobenzoyl chloride (prepared by refluxing 2-io-
dobenzoic acid with a slight excess of thionyl chloride) in
the presence of potassium carbonate as a base and tetrabu-
tylammonium hydrogen sulfate as a phase-transfer cata-
lyst in a mixture of dichloromethane and water at room
temperature for six hours gave the Heck precursor 3a
(Scheme 1). The other Heck precursors 3b–f and 5 were
prepared similarly.
Key words: heterocycles, annulations, ring closure, rearrange-
ments, catalysis, Heck reactions
Bicyclic and tricyclic fused N-heterocycles form the core
structures of many medicinally and clinically important
substances.1 Nitrogen-rich medium-size heterocycles are
found in many drugs, preclinical lead substances, and bio-
active natural products. Eight-membered nitrogen-con-
taining frameworks are found in several alkaloids such as
manzamine A2,3 and keramamine A.4 Peesapati et al.5 syn-
thesized several benzazocinone derivatives that show an-
algesic, anti-inflammatory, or antimicrobial activities.
Furthermore, azocinone derivatives are attractive building
blocks for peptides, as they mimic the dipeptide β-turn.6
Despite the wide range of applications of benzazocinones,
there are few reports of efficient syntheses of these com-
pounds. Rings with seven or more members are generally
difficult to prepare because of the presence of torsional,
transannular, and large-angle strain and of enthalpic and
entropic constraints on ring closure.7 Such compounds
therefore pose a major synthetic challenge, and the con-
struction of their basic skeletons by using conventional
methods such as lactamization and reduction is relatively
difficult.8–10
I
COCl
R
N
NHR
+
I
i
O
O
X
O
X
1a–f
3a–f
2
1a: X = O, R = Et
1d: X = NMe, R = Me
1b: X = O, R = Me 1e: X = NEt, R = Et
1c: X = NMe, R = Et 1f: X = NEt, R = Me
I
NTs
O
NHTs
COCl
I
i
+
4
2
5
Scheme 1 Preparation of Heck precursors. Reagents and conditions:
(i) K2CO3 (2 equiv), Bu4NHSO4 (10 mol%), CH2Cl2/H2O, r.t.
Palladium-catalyzed cyclization is a very powerful and
useful tool for the construction of C–C or carbon–hetero-
atom bonds.11–17 Generally, palladium-catalyzed coupling
reaction of nitrogen-containing compounds18 require
harsh conditions. Donets and Eycken19 recently devel-
oped a microwave-assisted cyclization procedure for the
synthesis of extended alkyl chains containing a dibenzaz-
ocinone framework; unfortunately, this procedure gave
low yields and was applicable only to two-electron-donat-
ing substrates. Our continuing efforts in palladium-medi-
ated synthesis of heterocycles20,21 encouraged us to accept
the challenge of synthesizing a dibenzazocinone frame-
work by means of a palladium-catalyzed intramolecular
Heck reaction. Here, we report the synthesis of chrome-
We then performed an intramolecular Heck reaction with
substrate 3a by adopting Jeffery’s two-phase protocol23
by using palladium(II) acetate as the catalyst, anhydrous
N,N-dimethylformamide as the solvent, potassium acetate
as the base, and tetrabutylammonium iodide (TBAI) as
the additive. The reaction was allowed to proceed for six
hours under a nitrogen atmosphere. We selected palladi-
um(II) acetate as the catalyst because it is widely used in
this type of intramolecular Heck reaction. Compound 6a,
the eight-membered 8-exo-Heck product, was obtained in
39% yield without any contamination from the 9-endo-
Heck product 5a or from the 8-exo-isomerized product 4a
(Scheme 2).
Increasing the reaction time did not improve the yield of
SYNTHESIS 2012, 44, 1711–1717
Advanced online publication: 09.05.2012
DOI: 10.1055/s-0031-1290970; Art ID: SS-2012-Z0092-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
the reaction. The exo-Heck product 6a was easily charac-
1
terized from its H NMR spectrum, which indicated the

1712
K. C. Majumdar et al.
PAPER
I
Et
N
O
O
i
i
NEt
NEt
O
O
O
O
O
3a
O
O
4a
i
O
NEt
O
O
6a
Scheme 2 Probable cyclization scope of the palladium-catalyzed Heck reaction. Reagents and conditions: i) Pd(OAc)2 (10 mol%), TBAI (1.2
equiv), KOAc (2.5 equiv), DMF, 90 °C, N2.
presence of two exo-methylene protons belonging to the Heck cyclization, was a more effective additive than
azocinone ring at δH = 5.44 (d, J = 2.4 Hz, 2 H). The 13
C
TBAI. Among the various palladium catalysts tested, pal-
NMR and mass spectra also supported the structural as- ladium tetrakis(triphenylphosphine) was found to be the
signment.
best choice. The optimal solvent was N,N-dimethylform-
amide, and potassium acetate was the optimal base.
Therefore, the optimal reaction conditions were identified
as palladium tetrakis(triphenylphosphine) as the catalyst,
N,N-dimethylformamide as the solvent, potassium acetate
as the base, tributylammonium bromide as the additive,
and temperature of 90 °C; under these conditions the reac-
tion took eight hours to reach completion and gave the
Heck product 6a in a yield of 67%.
The Heck product 6a was obtained as a sole product and
has not been reported in the literature, so the method is
quite important. However, the product was obtained in a
low yield (39%). We therefore concentrated on improving
the yield of the reaction by carrying out a series of exper-
iments to optimize the catalyst, base, additive, and sol-
vent. The results are summarized in Table 1.
The optimization study showed that the catalyst, base, ad-
ditive, and solvent all have considerable effects on the re-
action yield. TBAB, which plays an important role in the
To examine the tolerance of this intramolecular palladi-
um-catalyzed arylation reaction toward substituents, we
Table 1 Optimization of the Conditions for the Heck Reaction
Entrya
Catalyst
Solvent
Base
Additive
Yield (%)
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
PdCl2
DMF
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
NaOAc
KOAc
KOAc
KOAc
Cs2CO3
KOAc
TBAI
TBAI
TBAI
TBAI
TBAI
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
–
39
30
26
35
60
67
58
41
43
37
19
DMA
DMF
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
DMF
DMF
6b
7
DMF
DMF
8
MeCN
1,4-dioxane
THF
9
10
11
12
DMF
c
DMF
–
a All the reactions were carried out at 90 °C.
b Optimal reaction conditions.
c No reaction.
Synthesis 2012, 44, 1711–1717
© Georg Thieme Verlag Stuttgart · New York

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Coumarin- and Quinolone-Annulated Benzazocinone Frameworks
1713
treated a number of iodobenzamides 3b–f under opti- The formation of the 8-exo-Heck product is favored be-
mized reaction condition and we obtained the correspond- cause of the lower steric and transannular interactions.24
ing tetracyclic azocinone derivatives 6b–f in 60–70% Coumarin and quinolone moieties are found in many nat-
yield (Table 2). The 1-naphthylamine-derived Heck pre- ural products with a broad spectrum of biological activi-
cursor 5 similarly gave the corresponding benzazocinone ties.25–28 Because benzazocinone moieties are also known
derivative 7 in 61% yield.
to display pharmaceutical and medicinal activities, our
Table 2 Synthesis of Benzazocinone Derivatives by a Heck Reaction
Entry
Substrate
Product
Time (h)
Yield (%)
Et
N
O
1
3a
6a
8
67
O
NEt
I
O
O
O
O
Me
N
O
2
3
3b
6b
6c
8
70
70
O
NMe
I
O
O
O
O
Et
N
O
O
O
O
O
3c
7.25
NEt
I
O
O
O
O
N
Me
O
N
Me
Me
N
O
O
O
4
5
3d
6d
7.5
68
60
NMe
I
N
Me
O
O
O
N
Me
Et
N
3e
6e
10.5
NEt
I
N
Et
N
Et
Me
N
6
7
3f
6f
10
62
61
NMe
I
N
Et
N
Et
I
O
O
TsN
TsN
5
7
8
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1711–1717

1714
K. C. Majumdar et al.
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13C NMR (125 MHz, CDCl3): δ = 31.8, 37.7, 93.8, 116.4, 116.7,
117.7, 118.4, 127.2, 128.6, 130.1, 131.2, 132.1, 134.9, 138.5, 139.6,
140.4, 141.4, 153.7, 160.0, 170.3.
newly formed coumarin- and quinolone-annulated benza-
zocinones are also expected to show bioactivities.
In conclusion, we have developed an efficient method for
the construction of coumarin- and quinolone-fused benz-
azocinone derivatives by a palladium-catalyzed, ligand-
free, Heck coupling reaction. The method is relatively
simple, straightforward, and highly regioselective.
MS (ESI): m/z = 468 [M + Na]+.
Anal. Calcd for C20H16INO3: C, 53.95; H, 3.62; N, 3.15. Found: C,
53.97; H, 3.60; N, 3.14.
N-(5-Allyl-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-N-ethyl-
2-iodobenzamide (3c)
Yellow gummy liquid; yield: 339.2 mg (87%).
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded by using KBr disks or neat liquid
samples on a Perkin-Elmer 120–000A spectrometer. NMR spectra
were recorded for solns in CDCl3 with TMS as the internal standard
on a Bruker Ultrashield-400 spectrometer. 13C-NMR spectra were
recorded for solns in CDCl3 on Bruker Ultrashield-400 and Bruker
Ultrashield-500 spectrometers. Mass spectra were recorded on a
Qtof Micro instrument. CHN analyses were performed on a Perkin-
Elmer 2400 series II CHN-analyzer. Silica gel (60–120 mesh) was
used for chromatographic separation. Silica gel-G (E-Mark, India)
was used for TLC. The PE fraction that we used boiled at 60–80 °C.
IR (KBr): 1612, 1645, 1658, 2929 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.37 (t, J = 7.2 Hz, 3 H), 3.17–3.23
(m, 2 H), 3.77 (s, 3 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.84 (d, J = 17.2
Hz, 2 H), 5.97–6.06 (m, 1 H), 6.69 (d, J = 10.0 Hz, 1 H), 6.82 (td,
J = 1.6, 7.6 Hz, 1 H), 6.87 (dd, J = 1.6, 7.6 Hz, 1 H), 7.00 (t, J = 7.2
Hz, 1 H), 7.10 (d, J = 9.2 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.79
(d, J = 10.0 Hz, 1 H), 7.95 (d, J = 10.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.7, 31.9, 37.6, 44.2, 94.0, 113.2,
117.6, 121.9, 126.6, 127.3, 129.8, 130.3, 132.1, 134.4, 134.7, 135.2,
135.8, 139.0, 139.4, 141.8, 161.1, 170.0.
Substrates 1a–f 20k,m,21 and 422 were prepared according to the pub-
lished procedures.
MS (ESI): m/z = 473 [M + H]+.
Anal. Calcd for C22H21IN2O2: C, 55.94; H, 4.48; N, 5.93. Found: C,
55.90; H, 4.49; N, 5.91.
N-(5-Allyl-2-oxo-2H-chromen-6-yl)-N-ethyl-2-iodobenzamide
(3a); Typical Procedure
N-(5-Allyl-1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-iodo-N-
methylbenzamide (3d)
Yellow solid; yield: 361.2 mg (86%); mp 149–150 °C (MeCN).
IR (KBr): 1610, 1642, 1657, 2929 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.41 (s, 3 H), 3.78 (s, 3 H), 4.10
(q, J = 6.8 Hz, 2 H), 4.84 (d, J = 17.2 Hz, 1 H), 5.16 (dd, J = 10.4,
17.6 Hz, 1 H), 5.99–6.07 (m, 1 H), 6.69 (d, J = 10.0 Hz, 1 H), 6.83
(td, J = 1.6, 7.6 Hz, 1 H), 6.92 (dd, J = 1.2, 7.6 Hz, 1 H), 7.03 (t,
J = 7.6 Hz, 1 H), 7.12 (d, J = 9.2 Hz, 1 H), 7.56 (d, J = 9.2 Hz, 1 H),
7.78 (d, J = 9.6 Hz, 1 H), 7.93 (d, J = 10.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 29.5, 31.8, 37.6, 93.7, 113.8,
117.4, 121.8, 126.9, 127.1, 129.9, 130.3, 130.6, 135.1, 135.6, 136.5,
139.3, 139.8, 140.0, 141.5, 161.4, 170.3.
A mixture of 2-iodobenzoic acid (251 mg, 0.87 mmol) and SOCl2
was refluxed for 3 h. Excess SOCl2 was removed and the residue
was dissolved in CH2Cl2 (10 mL). A soln of amine 1a (200 mg, 0.87
mmol) in CH2Cl2 (20 mL) and Bu4NHSO4 (cat.) was added to the
stirred soln of the acid chloride. Aq K2CO3 (241.4 mg, 1.74 mmol)
was then added slowly and the mixture was stirred for 6 h at r.t. The
soln was then washed sequentially with 5% aq HCl (2 × 20 mL) and
5% aq NaOH (2 × 20 mL). The organic layer was dried (Na2SO4)
and the solvent was evaporated under reduced pressure. The residue
was purified by column chromatography [silica gel, PE–EtOAc
(7:3)] to give a pale yellow gummy liquid; yield: 336.6 mg (84%).
Compounds 3b–f and 5 were similarly prepared. All the amidation
reactions were performed by using 200 mg of the appropriate
amine.
IR (KBr): 1596, 1652, 1731, 2934 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.03 (t, J = 6.8 Hz, 3 H), 3.16–3.25
(m, 1 H), 3.65 (dt, J = 2.4, 17.2 Hz, 1 H), 3.85 (dt, J = 2.4, 16.8 Hz,
1 H), 4.51–4.60 (m, 1 H), 4.83 (d, J = 17.2 Hz, 1 H), 5.19 (dd,
J = 10.8, 15.2 Hz, 1 H), 5.96–6.06 (m, 1 H), 6.39 (d, J = 10.0 Hz, 1
H), 6.86 (d, J = 8.0 Hz, 1 H), 7.01–7.06 (m, 2 H), 7.43–7.51 (m, 2
H), 7.71 (d, J = 7.6 Hz, 1 H), 7.79 (d, J = 10.0 Hz, 1 H).
MS (ESI): m/z = 481 [M + Na]+.
Anal. Calcd for C21H19IN2O2: C, 55.04; H, 4.18; N, 6.11. Found: C,
55.08; H, 4.17; N, 6.14.
N-(5-Allyl-1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl)-N-ethyl-2-
iodobenzamide (3e)
Pale yellow solid; yield: 318.9 mg (84%); mp 161–162 °C (MeCN–
hexane).
13C NMR (100 MHz, CDCl3): δ = 12.4, 31.8, 44.2, 94.1, 116.4,
116.7, 117.8, 118.6, 126.7, 127.4, 128.4, 130.5, 133.5, 135.0, 136.9,
139.6, 140.9, 141.5, 153.8, 159.8, 169.9.
IR (KBr): 1599, 1648, 1662, 2930 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.04 (t, J = 7.2 Hz, 3 H), 1.40 (t,
J = 7.2 Hz, 3 H), 3.17–3.26 (m, 1 H), 3.72 (dt, J = 2.4, 16.8 Hz, 1
H), 3.89 (dt, J = 2.4, 16.8 Hz, 1 H), 4.10- 4.19 (m, 2 H), 4.54–4.63
(m, 1 H), 4.87 (d, J = 16.8 Hz, 1 H), 5.17 (dd, J = 10.4, 15.2 Hz, 1
H), 5.96–6.06 (m, 1 H), 6.68 (d, J = 10.0 Hz, 1 H), 6.82 (td, J = 1.6,
7.6 Hz, 1 H), 6.87 (dd, J = 1.6, 7.6 Hz, 1 H), 7.00 (t, J = 7.2 Hz, 1
H), 7.10 (d, J = 9.2 Hz, 1 H), 7.51 (d, J = 9.2 Hz, 1 H), 7.70 (d,
J = 8.0 Hz, 1 H), 7.79 (d, J = 10.0 Hz, 1 H).
MS (ESI): m/z = 460 [M + H]+.
Anal. Calcd for C21H18INO3: C, 54.92; H, 3.95; N, 3.05. Found: C,
54.93; H, 3.91; N, 3.01.
N-(5-Allyl-2-oxo-2H-chromen-6-yl)-2-iodo-N-methylbenz-
amide (3b)
Yellow gummy liquid; yield: 351.7 mg (85%).
IR (KBr): 1598, 1668, 1724, 2931 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.40 (s, 3 H), 3.68 (dt, J = 2.4, 17.2
Hz, 1 H), 3.89 (dt, J = 2.4, 16.8 Hz, 1 H), 4.90 (d, J = 17.2 Hz, 1 H),
5.18 (dd, J = 10.4, 15.6 Hz, 1 H), 5.97–6.10 (m, 1 H), 6.46 (d,
J = 9.6 Hz, 1 H), 6.84–6.95 (m, 1 H), 7.06 (t, J = 8.0 Hz, 1 H), 7.15
(td, J = 1.2, 8.0 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.47–7.58 (m, 1
H), 7.78 (d, J = 9.6 Hz, 1 H), 7.94 (d, J = 10.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.4, 12.8, 32.0, 37.6, 44.3, 94.1,
113.2, 117.6, 120.3, 121.8, 122.0, 127.3, 129.8, 130.4, 132.1, 134.4,
134.8, 135.2, 135.8, 139.4, 141.8, 161.1, 170.0.
MS (ESI): m/z = 487 [M + H]+.
Anal. Calcd for C23H23IN2O2: C, 56.80; H, 4.77; N, 5.76. Found: C,
56.82; H, 4.74; N, 5.71.
N-(5-Allyl-1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-iodo-N-
methylbenzamide (3f)
Yellow gummy liquid; yield: 319.8 mg (82%).
Synthesis 2012, 44, 1711–1717
© Georg Thieme Verlag Stuttgart · New York

PAPER
Coumarin- and Quinolone-Annulated Benzazocinone Frameworks
IR (KBr): 1589, 1639, 1730, 2932 cm–1.
1715
IR (KBr): 1611, 1645, 1659, 2929 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.38 (t, J = 7.2 Hz, 3 H), 3.17–3.23
(m, 2 H), 3.78 (s, 3 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.85 (d, J = 17.2
Hz, 2 H), 5.97–6.06 (m, 1 H), 6.69 (d, J = 10.0 Hz, 1 H), 6.82 (td,
J = 1.6, 7.6 Hz, 1 H), 6.87 (dd, J = 1.6, 7.6 Hz, 1 H), 7.00 (t, J = 7.2
Hz, 1 H), 7.10 (d, J = 9.2 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.79
(d, J = 10.0 Hz, 1 H), 7.95 (d, J = 10.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.7, 31.9, 37.6, 44.3, 93.9, 113.3,
117.6, 121.9, 126.7, 127.3, 129.9, 130.4, 132.1, 134.4, 134.8, 135.2,
135.8, 139.1, 139.4, 141.8, 161.1, 170.0.
1H NMR (400 MHz, CDCl3): δ = 3.45 (m, 3 H), 4.05–4.15 (m, 2 H),
5.45 (s, 2 H), 6.45 (d, J = 10.0 Hz, 1 H), 7.12–7.25 (m, 4 H), 7.44–
7.49 (m, 2 H), 7.88 (d, J = 10.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 34.2, 45.8, 115.6, 116.6, 117.3,
119.8, 127.5, 128.2, 129.1, 130.0, 134.8, 134.9, 135.8, 137.6, 139.4,
140.8, 145.2, 153.4, 160.0, 171.6.
MS (ESI): m/z = 340 [M + Na]+.
Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76; N, 4.41. Found: C,
75.74; H, 4.74; N, 4.40.
MS (ESI): m/z = 473 [M + H]+.
7-Ethyl-4-methyl-13-methylene-4,7,13,14-tetrahydroquino[6,5-
c][2]benzazocine-3,8-dione (6c)
Anal. Calcd for C22H21IN2O2: C, 55.94; H, 4.48; N, 5.93. Found: C,
55.90; H, 4.48; N, 5.92.
Brown gummy liquid; yield: 76.5 mg (70%).
(5):
IR (KBr): 1568, 1645, 1662, 2922 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.2 Hz, 3 H), 3.22 (d,
J = 12.0 Hz, 1 H), 3.24 (d, J = 12.0 Hz, 1 H), 3.28–3.48 (m, 1 H),
3.77 (s, 3 H), 4.37–4.45 (m, 1 H), 5.45 (d, J = 2.4 Hz, 2 H), 6.82 (d,
J = 10.0 Hz, 1 H), 7.38 (d, J = 10.4 Hz, 2 H), 7.69 (t, J = 8.8 Hz, 1
H), 7.82–7.84 (m, 2 H), 8.34 (d, J = 10.0 Hz, 1 H), 8.51 (d, J = 10.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.8, 29.7, 34.5, 44.2, 115.2,
119.1, 119.8, 122.5, 125.2, 127.5, 127.8, 128.6, 134.6, 134.8, 135.0,
135.4, 135.9, 137.8, 139.6, 145.5, 161.6, 171.8.
N-(2-Allyl-1-naphthyl)-2-iodo-N-tosylbenzamide (5)
Off-white gummy liquid; yield: 282.8 mg (84%).
IR (KBr): 1598, 1645, 2858, 2929 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 3 H), 3.64–3.81 (m, 1 H),
4.96 (dd, J = 1.6, 17.2 Hz, 1 H), 5.08 (dd, J = 1.2, 11.2 Hz, 1 H),
5.20 (d, J = 13.6 Hz, 1 H), 5.75–5.91 (m, 1 H), 6.39 (s, 1 H), 6.78
(s, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 7.29–7.37 (m, 3 H), 7.39–7.51
(m, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.70 (t, J = 8.8 Hz, 2 H), 7.89 (d,
J = 8.8 Hz, 1 H), 7.96 (d, J = 8.8 Hz, 1 H).
MS (ESI): m/z = 345 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 21.8, 37.0, 93.5, 117.7, 124.2,
126.0, 126.4, 127.4, 127.5, 128.0, 128.2, 129.1, 129.7, 129.8, 130.7,
130.9, 132.9, 135.1, 135.6, 140.0, 145.5, 168.7.
Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C,
76.77; H, 5.84; N, 8.05.
MS (ESI): m/z = 568 [M + H]+.
4,7-Dimethyl-13-methylene-4,7,13,14-tetrahydroquino[6,5-
c][2]benzazocine-3,8-dione (6d)
Brown gummy liquid; yield: 70.3 mg (68%).
Anal. Calcd for C27H22INO3S: C, 57.15; H, 3.91; N, 2.47. Found: C,
57.10; H, 3.93; N, 2.46.
IR (KBr): 1570, 1641, 1668, 2923 cm–1.
7-Ethyl-13-methylene-13,14-dihydro-3H-chromeno[6,5-
c][2]benzazocine-3,8(7H)-dione (6a); Typical Procedure
N2 was bubbled through a mixture of amide 3a (150 mg, 0.33
mmol), TBAB (126 mg, 0.39 mmol), and fused KOAc (80 mg, 0.82
mmol) in anhyd DMF (10 mL). Pd(PPh3)4 (37.6 mg, 10 mol%) was
then added and the mixture was stirred at 90 °C for 8 h. The mixture
was cooled, mixed with H2O (20 mL), and extracted with EtOAc (3
× 20 mL). The organic extracts were washed successively with H2O
(4 × 10 mL) and brine (10 mL) then dried (Na2SO4) and concentrat-
ed under reduced pressure to give a viscous mass that was purified
by column chromatography [silica gel, PE–EtOAc (7:3)] to give an
orange solid; yield: 72.5 mg (67%); mp 161–162 °C (MeCN–hex-
ane).
1H NMR (400 MHz, CDCl3): δ = 3.30 (d, J = 13.6 Hz, 1 H), 3.31 (d,
J = 13.6 Hz, 1 H), 3.63 (s, 3 H), 3.64 (s, 3 H), 5.44 (d, J = 2.4 Hz, 2
H), 6.80 (d, J = 8.8 Hz, 1 H), 7.67 (t, J = 6.8 Hz, 1 H), 7.82 (d,
J = 9.6 Hz, 2 H), 7.84 (d, J = 10.0 Hz, 2 H), 8.32 (d, J = 10.0 Hz, 1
H), 8.56 (d, J = 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.9, 39.9, 45.1, 116.6, 116.9,
117.9, 118.4, 126.2, 126.9, 127.6, 128.1, 129.8, 131.4, 132.4, 137.8,
140.0, 141.3, 146.8, 155.1, 160.2, 171.9.
MS (ESI): m/z = 353 [M + Na]+
.
Anal. Calcd for C21H18N2O2: C, 76.34; H, 5.49; N, 8.48. Found: C,
76.35; H, 5.47; N, 8.44.
Products 6b–f and 7 were similarly prepared from the correspond-
ing Heck precursors (150 mg).
IR (KBr): 1597, 1648, 1734, 2931 cm–1.
4,7-Diethyl-13-methylene-4,7,13,14-tetrahydroquino[6,5-
c][2]benzazocine-3,8-dione (6e)
Light brown solid; yield: 66.3 mg (60%); mp 154–155 °C (MeCN–
hexane).
1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 6.8 Hz, 3 H), 3.66–3.75
(m, 1 H), 4.03 (d, J = 16.4 Hz, 1 H), 4.16 (dt, J = 2.4, 16.0 Hz, 1 H),
4.26–4.35 (m, 1 H), 5.44 (d, J = 2.4 Hz, 2 H), 6.45 (d, J = 10.0 Hz,
1 H), 7.11–7.18 (m, 4 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.89 (d, J = 9.6
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.5, 34.3, 44.3, 115.4, 116.7,
117.3, 119.9, 127.5, 128.2, 129.1, 129.3, 134.7, 134.9, 135.7, 137.6,
139.4, 140.7, 145.2, 153.4, 159.9, 171.6.
IR (KBr): 1561, 1651, 1662, 2926 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 7.2 Hz, 6 H), 3.67–3.76
(m, 1 H), 4.14–4.17 (m, 2 H), 4.24–4.38 (m, 2 H), 4.49–4.57 (m, 1
H), 5.44 (d, J = 2.0 Hz, 2 H), 6.73 (d, J = 10.0 Hz, 1 H), 7.11 (d,
J = 7.2 Hz, 2 H), 7.44–7.49 (m, 2 H), 7.64–7.69 (m, 2 H), 7.89 (d,
J = 10.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.8, 29.7, 34.6, 44.3, 114.0,
115.2, 119.4, 121.1, 122.5, 127.3, 127.5, 128.0, 128.6, 128.7, 132.0,
133.9, 135.6, 137.9, 138.6, 145.5, 161.2, 171.8.
MS (ESI): m/z = 332 [M + H]+.
Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17; N, 4.23. Found: C,
76.14; H, 5.16; N, 4.20.
MS (ESI): m/z = 359 [M + H]+.
Anal. Calcd for C23H22N2O2: C, 77.07; H, 6.19; N, 7.82. Found: C,
77.11; H, 6.19; N, 7.80.
7-Methyl-13-methylene-13,14-dihydro-3H-chromeno[6,5-
c][2]benzazocine-3,8(7H)-dione (6b)
Orange solid; yield: 74.8 mg (70%); mp 126–127 °C (MeCN–hex-
ane).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1711–1717

1716
K. C. Majumdar et al.
PAPER
4-Ethyl-7-methyl-13-methylene-4,7,13,14-tetrahydroquino[6,5-
c][2]benzazocine-3,8-dione (6f)
(6) (a) Derrer, S.; Feeder, N.; Teat, S. J.; Davies, J. E.; Holmes,
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Der Eycken, E. Org. Lett. 2005, 7, 2723. (d) Majumdar, K.
C.; Ansary, I.; Sinha, B.; Chattopadhyay, B. Synthesis 2009,
3593.
Brown gummy liquid; yield: 67.8 mg (62%).
IR (KBr): 1565, 1645, 1664, 2922 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.2 Hz, 3 H), 3.23 (d,
J = 12.0 Hz, 1 H), 3.24 (d, J = 12.0 Hz, 1 H), 3.28–3.48 (m, 1 H),
3.77 (s, 3 H), 4.37–4.44 (m, 1 H), 5.45 (d, J = 2.4 Hz, 2 H), 6.82 (d,
J = 10.0 Hz, 1 H), 7.38 (d, J = 10.4 Hz, 2 H), 7.69 (t, J = 8.8 Hz, 1
H), 7.82–7.85 (m, 2 H), 8.34 (d, J = 10.0 Hz, 1 H), 8.51 (d, J = 10.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.8, 29.7, 34.5, 44.3, 115.2,
119.1, 119.8, 122.5, 125.2, 127.5, 127.8, 128.6, 134.6, 134.8, 135.0,
135.4, 135.9, 137.8, 139.6, 145.6, 161.6, 171.8.
MS (ESI): m/z = 367 [M + Na]+.
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Watanabe, H.; Wakitani, K.; Aisaka, K. J. Med. Chem. 2004,
47, 101. (b) Cho, H.; Murakami, K.; Fujisawa, A.; Niwa, M.;
Nakanishi, H.; Uchida, I. Heterocycles 1998, 48, 1555.
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61, 11771. (b) Li, C. J. Chem. Rev. 2005, 105, 3095.
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review on the chiral Heck reaction, see: Shibaski, M.; Vogel,
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(13) (a) Metal Catalyzed Cross Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(b) Tsuji, J. Palladium Reagents and Catalysts, Innovations
in Organic Synthesis; Wiley: New York, 1995.
Anal. Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C,
76.75; H, 5.86; N, 8.12.
8-Methylene-14-tosyl-7,14-dihydrobenzo[f]naphtho[1,2-b]azo-
cin-13(8H)-one (7)
Orange gummy liquid; yield: 70.8 mg (61%).
IR (KBr): 1596, 1622, 1695, 2923 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26 (s, 3 H), 3.74 (d, J = 16.8 Hz,
1 H), 4.11 (d, J = 16.4 Hz, 1 H), 5.15 (s, 1 H), 5.26 (s, 1 H), 6.98 (d,
J = 7.2 Hz, 1 H), 7.15 (d, J = 6.8 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 2 H),
7.37–7.47 (m, 4 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.69–7.74 (m, 3 H),
7.88 (d, J = 8.0 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.8, 39.8, 116.5, 123.7, 125.9,
126.1, 126.3, 126.7, 127.5, 127.7, 128.0, 128.5, 129.0, 129.2, 129.4,
129.6, 130.2, 130.5, 131.9, 134.0, 135.2, 137.4, 144.8, 145.5, 171.3.
MS (ESI): m/z = 440 [M + H]+.
(14) (a) Trzeciak, A. M.; Ziόłkowski, J. J. Coord. Chem. Rev.
2007, 251, 1281. (b) Biffis, A.; Zecca, M.; Basato, M. J.
Mol. Catal. A: Chem. 2001, 173, 249. (c) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (d) Heck, R.
F. In Comprehensive Organic Synthesis, Vol. 4; Trost, B.
M., Ed.; Pergamon: New York, 1991, Chap. 4.3, 833.
(15) (a) Mizutani, T.; Honzawa, S.; Tosaki, S.; Shibasaki, M.
Angew. Chem. Int. Ed. 2002, 41, 4680. (b) Link, J. T.;
Overman, L. E. In Metal-Catalyzed Cross-Coupling
Reaction; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998, Chap. 6, 231.
Anal. Calcd for C27H21NO3S: C, 73.78; H, 4.82; N, 3.19. Found: C,
73.79; H, 4.76; N, 3.22.
Acknowledgment
We thank the CSIR (New Delhi) for financial assistance. T.G. is
grateful to the CSIR (New Delhi) for a senior research fellowship.
We also thank the DST (New Delhi) for providing NMR, IR, and
UV–vis spectrometers under the DST-FIST program.
(16) (a) Tietze, L. F.; Kettschau, G.; Heuschert, U.; Nordmann,
G. Chem.–Eur. J. 2001, 7, 368. (b) Percec, V.; Hill, D. H.
Step-Polymerization Reactions via Nickel- and Palladium-
Catalyzed Carbon-Carbon Bond Formation, In Step-
Growth Polymers for High-Performance Materials: New
Synthetic Methods, ACS Symposium Series 624; Hedrick, J.
K.; Labadie, J. W., Eds.; American Chemical Society:
Washington DC, 1996, Chap. 1, 29. (c) Heitz, W. From
ArylX to ArylH Activation in Metal-Catalyzed
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