Palladium-catalyzed tethered intramolecular arylation: An unusual synthesis of linearly fused pyridocoumarin derivatives

Article abstract of DOI:10.1055/s-0030-1258246

A new synthetic protocol has been developed by the implementation of the palladium-mediated benzylic C-H activation followed by tethered intramolecular arylation strategy to give linearly fused and unusually oxidized pyridocoumarin derivatives. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258246

3918
PAPER
Palladium-Catalyzed Tethered Intramolecular Arylation: An Unusual
Synthesis of Linearly Fused Pyridocoumarin Derivatives
K. C. Majumdar,* Sanjay Nath, Buddhadeb Chattopadhyay, Biswajit Sinha
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B., India
E-mail: kcm_ku@yahoo.co.in
Received 26 July 2010; revised 2 August 2010
observed under the applied reaction conditions. Further
C–H activation/oxidation of the product is most likely in-
hibited due to steric hindrance at the more substituted ben-
zylic position. Moreover Murahashi et al. have reported
that tertiary amines undergo hydride elimination adjacent
to the nitrogen atom upon binding to palladium(II), giving
rise to an iminium ion that, upon hydrolysis, produced
carbonyl compounds and secondary amines.16 Additional
interest is derived from our long-standing efforts17 in the
synthesis of coumarin-annulated heterocyclic com-
pounds, as coumarins fused with heterocycles and aza an-
alogues of coumarins have received increasing attention
due to their potential biological activity.18 In particular,
coumarins fused to pyridines have been reported to pos-
sess antiallergic,19 antidiabetic,20 and analgesic proper-
ties.21 Recently, we successfully synthesized22 some
interesting regular aza-heterocycles by application of the
intramolecular Heck reaction. Therefore, with an interest
in synthesizing new coumarin-fused heterocycles for pos-
sible evaluation as biologically active compounds23 or any
other useful compounds such as fluorogenic probes,24
laser dyes25 etc., we have undertaken a study on the
intramolecular arylation of 7-[(alkyl)(2-bromoben-
zyl)amino]-4-methylcoumarins, which also offers the
scope to investigate palladium-mediated C–H activation
accompanied by tethered intramolecular arylation. Herein
we report the results of our investigation.
Abstract: A new synthetic protocol has been developed by the im-
plementation of the palladium-mediated benzylic C–H activation
followed by tethered intramolecular arylation strategy to give lin-
early fused and unusually oxidized pyridocoumarin derivatives.
Key words: oxidation, C–H activation, biaryl coupling, intramo-
lecular cyclization, palladium acetate
The development of new and mild methods for the regio-
selective functionalization of C–H bonds in complex
molecules remains a significant challenge in organic syn-
thesis.1–3 It is desirable to utilize reactions that require a
minimal amount of labor and allow the construction of
complex molecules in a time- and cost-effective manner.
The past decade has seen the development of intermolec-
ular palladium-catalyzed organic reactions, which by vir-
tue of their ease of operation, complexity, and diversity,
constitute highly effective transformations.4 In recent
years, palladium-catalyzed ligand-directed C–H bond
functionalization has become a valuable synthetic method
for the selective oxidation of organic molecules.5 Accord-
ingly numerous palladium-catalyzed ligand-directed reac-
tions have been developed for the directed oxygenation,6
halogenation,7 and sulfonylation8 of both sp2 and sp3 C–H
bonds. Several of such C–H bond activations leading to
catalytic oxidation have been reported based on the cat-
ions Hg(II),9 Pd(II),10 Pt(II),11 Au(I) and Au(III).12 How-
ever, these transformations are generally limited by their
modest substrate scope and harsh reaction conditions.10
Methane and ethane were found to be oxidized to formic
acid and acetic acid, respectively, by metallic palladium
as the catalyst, dioxygen as the oxidant, and in presence of
carbon monoxide.13 Recently Sanford et al.14 reported
some interesting examples of ligand-directed oxidative
sp2 C–H bond functionalization reactions, though these
types of reactions sometimes suffer from significant dis-
advantages, i.e. the iodine(III) oxidant is expensive and
forms stoichiometric quantities of iodobenzene with each
catalytic turnover. They have also reported15 that the sp3
C–H bond of 8-methylquinoline reacts readily with (di-
acetoxyiodo)benzene (1.1 equiv) with palladium(II) acetate
(1–2 mol%) in acetic acid or methanol to afford benzyl es-
ters or benzyl ethers in good yields; despite the presence
of additional benzylic hydrogens, no over-oxidation was
The requisite starting materials 3a–j were prepared in
good to excellent yields by refluxing 4-methyl-7-(substi-
tuted-amino)coumarins 1a–f with either 2-bromobenzyl
bromide (2a) or 2-bromo-5-methoxybenzyl bromide (2b)
in dry acetone in the presence of anhydrous potassium
carbonate and a small amount of sodium iodide
(Scheme 1).
Consequently, with a view to synthesizing the cyclized
product, the intramolecular arylation was carried out with
3a in the presence of palladium(II) acetate as the catalyst,
anhydrous potassium acetate as the base, and tetrabutyl-
ammonium bromide as an additive in dry N,N-dimethyl-
formamide at 140 °C under a nitrogen atmosphere for 13
hours. A new compound was obtained in 40% yield. This
was characterized from its elemental analysis and spectral
data as the corresponding unusually oxidized cyclized
product, i.e. pyridocoumarin derivative, 4a.
It is interesting to note that oxidation of the benzylic
methylene occurs during the regioselective Heck cycliza-
tion under the applied reaction conditions. This reaction
SYNTHESIS 2010, No. 22, pp 3918–3926
Advanced online publication: 07.09.2010
DOI: 10.1055/s-0030-1258246; Art ID: Z19110SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

PAPER
Palladium-Catalyzed Tethered Intramolecular Arylation
3919
R2
Br
Br
Br
(i)
+
R2
O
O
NHR1
O
O
N
1a–f
R1
2a,b
3a–j
R
R
1 = Pr, Et, Pent, Me, Ac, H
2 = H, OMe
Scheme 1 Reagents and conditions: (i) acetone, K2CO3, NaI, reflux.
Br
(i)
+
+
O
O
N
O
O
N
O
O
N
O
O
O
N
3a
4a
unexpected but observed
5a
expected but not found
6a
not found
Scheme 2 Reagents and conditions: Pd(OAc)2, TBAB, KOAc, DMF, 140 °C.
seems to be quite unusual as no externally added oxidiz-
ing agent was used for this purpose (Scheme 2) The other
substrates 3b–f on similar treatment under optimized reac-
tion conditions gave the linearly fused oxidized cyclized
products 4b–f (Table 1, entries 2–6). Unexpectedly differ-
ent results were obtained when the reaction was carried
out with the substrates 3g,h following the same reaction
conditions. In these cases, only for (methylamino)cou-
marin derivatives, oxidation of benzylic CH2 group was
not observed; rather the expected unoxidized cyclized
products 5g,h were obtained as the sole isolable products
Me
Me
N
N
Br
(i)
5k (10%)
Et
N
Et
N
Et
N
O
(i)
Br
3l
5l (8%)
4l (10%)
(entries 7 and 8).
The conflicting results obtained so far prompted us to
study the reaction with other substrates. We tried the reac-
tion with N-(2-bromobenzyl)-N-methylaniline (3k) and
N-(2-bromobenzyl)-N-ethylaniline (3l). The expected cy-
clization product 5k was obtained in only 10% yield from
the substrate 3k without any oxidation of the benzylic
CH2 group; most of the starting material remained unaf-
fected. For 3l both cyclized products, unoxidized product
5l (8%) and oxidized product 4l (10%) were obtained un-
der the same reaction conditions at 120 °C (Scheme 3).
When the unoxidized product 5l was subjected to further
reaction under the same conditions, 5l was slowly oxi-
dized to give the product 4l.
Scheme 3 Reagents and conditions: (i) Pd(OAc)2, TBAB, KOAc,
DMF, 120 °C.
formed at 100 °C, no reaction occurred. However, with in-
creasing the temperature, the reaction slowly begins and it
is its maximum when temperature reaches to 140 °C.
Continuing the reaction for a long time at elevated tem-
peratures decreases the yield rapidly due to the decompo-
sition of the cyclized product. An examination of the
influence of various solvents, such as N,N-dimethylform-
amide, acetonitrile, dioxane, and toluene, suggested that
N,N-dimethylformamide is the best choice and the opti-
mized reaction conditions are: Pd(OAc)2, KOAc, TBAB,
DMF, 140 °C. To study the effect of externally added ox-
idizing agent to increase the rate of C–H activation, 2-io-
doxybenzoic acid (IBX) was added to the reaction mixture
and the reaction was carried out under the same optimized
conditions. However, complete decomposition of the
starting material was observed.
To optimize the reaction conditions a series of experi-
ments were performed where sequential changes were
made to the catalyst, base, additive, and solvent used and
these are summarized in Table 2. The use of palladium(II)
chloride as catalyst was also found to be effective, but the
yield of the cyclized product was low (14%). The catalysts
PdCl2(PPh3)2 and Pd(PPh3)4 were found to be inactive in
the reaction. We have also studied the effects of various
bases and it was found that triethylamine and potassium
carbonate were also effective, but the yield of the product
was lower than that of the aforesaid catalytic system. Tet-
rabutylammonium hydrogen sulfate (TBAHS) as additive
was found to be totally ineffective. Temperature plays an
important role in the reaction. When the reaction was per-
The structures of the cyclized products were determined
from their analytical and spectral data. IR spectrum of the
cyclized product 4c showed two carbonyl peaks at 1650
and 1731 cm–1 while the required unoxidized cyclized
product should contain only one carbonyl peak at ~1731
1
cm–1. The H NMR spectrum revealed three singlets at
d = 6.30 (H3coumarin), 7.31 (H8coumarin), and 8.44 (H5coumarin
)
Synthesis 2010, No. 22, 3918–3926 © Thieme Stuttgart · New York

3920
K. C. Majumdar et al.
PAPER
indicating the linearly fused structure of the cyclized d = 3.55 (q, J = 7.1 Hz) in the uncyclized starting material
product instead of the expected angularly fused product. 3c, whereas the signal is shifted to d = 4.44 (q, J = 7.2 Hz)
13
At the same time the signal at d = 4.56 (s) for benzylic in the cyclized product 4c (Figure 1). The C NMR and
protons in the starting material 3c was absent in the cy- DEPT (135) spectra also supported the unusual oxidation
clized product 4c. The absence of the two benzylic pro- of the benzylic methylene during the Heck reaction of the
tons suggests that there is some structural change in the substrate 3c. The 13C NMR spectrum showed two signals
cyclized product; and this is possible only when the ben- at d = 161.5 and 160.8 indicating the presence of two car-
zylic methylene is oxidized to carbonyl under the applied bonyl groups in the final product 4c. This is further sup-
reaction conditions. The unusual oxidation is further sup- ported by the fact that the peaks at d = 161.5 and 160.8 in
ported by the fact that in the 1H NMR spectrum downfield the 13C NMR spectrum are absent in the DEPT spectra.
shift occurs in case of NCH2CH3 protons in the cyclized The oxidation phenomenon was also confirmed by its mo-
product. 1H NMR signal for NCH2CH3 protons appear at lecular ion at m/z = 306.1 [M+ + H] in the mass spectrum.
Table 1 Examples of the Synthesis of Linearly Fused Pyridocoumarin Derivativesa
Entry
1
Substrate
Product
Time (h)
13
Yield (%)
40
Br
O
O
O
N
O
O
N
Pr
Pr
3a
4a
OMe
OMe
OMe
OMe
Br
2
3
4
5
6
14
12
14
13
13
24
45
28
31
25
O
O
N
O
O
O
N
Pr
Pr
3b
4b
Br
O
O
N
O
O
N
O
Et
Et
3c
4c
OMe
Br
O
O
N
O
O
N
O
Et
Et
4d
3d
Br
O
O
N
O
O
N
O
Pent
Pent
3e
4e
OMe
Br
O
O
N
O
O
N
O
Pent
Pent
3f
4f
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PAPER
Palladium-Catalyzed Tethered Intramolecular Arylation
3921
Table 1 Examples of the Synthesis of Linearly Fused Pyridocoumarin Derivativesa (continued)
Entry
7
Substrate
Product
Time (h)
14
Yield (%)
Br
50
45
O
O
N
O
O
N
Me
Me
3g
5g
MeO
OMe
Br
Br
Br
8
15
O
O
N
O
O
N
Me
Me
5h
3h
b
9
4i/5i
50
50
–
O
O
N
Ac
3i
b
10
4j/5j
–
O
O
N
H
3j
a Reaction conditions: Pd(OAc)2, TBAB, KOAc, DMF, 140 °C.
b No reaction.
Table 2 Optimization of the Palladium-Catalyzed Cyclizationa of
3a
Entry Catalystb
Basec
Aditived
Solvent Yield
(%)
Br
1H NMR: δ = 4.56 (s)
13C NMR: δ = 55.1
O
O
N
CH2CH3
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
KOAc
Et3N
TBAB
TBAB
TBAB
TBAB
TBAHS
TBAB, IBX
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
DMF
toluene
40
25
10
14
3c
1H NMR: δ = 3.55 (q, J = 7.1 Hz)
13C NMR: δ = 46.3 Hz
3
K2CO3
Et3N
4
e
5
Pd(OAc)2
Pd(OAc)2
PdCl2
KOAc
KOAc
Et3N
–
f
13C NMR: δ = 160.8
6
–
O
O
N
O
CH2CH3
4c
e
7
–
1H NMR: δ = 4.44 (q, J = 7.2 Hz)
13C NMR: δ = 38.8
e
8
Pd(PPh3)4
Et3N
–
–
e
9
Pd(PPh3)2Cl2 KOAc
Pd(OAc)2 KOAc
TBAB
TBAB
–
Figure 1
e
10
–
a All reactions were performed at 140 °C.
b 10 mol% catalyst was used in the reaction.
c Base (2.75 equiv) was used.
d Additive (1.2 equiv) was used.
e No reaction.
The spectral and analytical data of compounds 4 indicate
that two different reactions may occur, i.e., palladium-
mediated intramolecular arylation and benzylic CH2 oxi-
dation. The formation of products 4 from the substrates 3
indicates that the palladium catalyst serves two functions
viz. palladium-mediated intramolecular arylation and oxi-
dation of N(R1)CH2Ph to N(R1)COPh (Scheme 4). It is
f Decomposed product.
Synthesis 2010, No. 22, 3918–3926 © Thieme Stuttgart · New York

3922
K. C. Majumdar et al.
PAPER
not clear whether the cyclization is followed by oxidation tron-donating groups on nitrogen supports the participa-
(path a) or vice versa (path b). Only in one case (from sub- tion of nitrogen in step (i). The oxidation reaction fails
strate 3l) the cyclized unoxidized product 5l was obtained when the nitrogen is substituted by methyl may perhaps
along with the cyclized oxidized product 4l. The cyclized be due to the lower +I effect of the methyl group than that
unoxidized product 5l on further treatment with palladi- of other alkyl groups.
um(II) acetate under the same optimized reaction condi-
Sanford et al.14 reported that after the oxidation of one of
tions afforded the oxidized product 4l. From this result,
benzylic C–H, the other benzylic C–H is not oxidized un-
however, it is difficult to conclude that the same sequence
der their applied reaction conditions. On the other hand
is followed in all the cases. Path a is assumed to involve at
Murahashi et. al.16 observed that tertiary amines readily
first a palladium-mediated intramolecular Heck cycliza-
hydrolyzed to secondary amines and ketones during the
tion, which is followed by oxidation of the benzylic meth-
palladium-catalyzed hydrolysis reaction, i.e., breaking of
C–N bond takes place. However, in our present study we
ylene occurring through a number of steps.
have observed the oxidation of the benzylic CH2 to the
carbonyl (C=O) group accompanied by regioselective cy-
clization without any rupture of the C–N bond to give the
(i) normal intramolecular
cyclization
(ii) Pd(II)
Br
linearly fused pyridocoumarin derivatives. This reaction
'path a' step (i)
O
O
N
R
seems to be quite unusual as no externally added oxidiz-
ing agent was used in the reaction mixture unlike Sanford
et al. Oxidation of both the benzylic hydrogen and in-
tramolecular arylation occur simultaneously under the ap-
plied reaction conditions.
O
O
N
R
3
Pd
7
may follow suggested
oxidation pathway
as in 'path a'
'path b'
In conclusion, we have demonstrated an efficient method
for palladium-catalyzed oxygenation of unactivated sp3
C–H bonds without using an externally added oxidizing
agent. This reaction is highly selective. The reaction also
offers an easy access to linearly fused pyridocoumarin de-
rivatives. To our knowledge, this type of oxidation of
N(R1)CH2Ph to N(R1)COPh reaction has not been report-
ed previously.
Br
O
O
N
8
H
R
Pd
O
O
N
R
O
11
normal intramolecular
cyclization
H
Pd
O
O
N
H–
9
R
KOAc
Melting points were determined in an open capillary and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer L 120-000A
spectrophotometer on KBr disks. 1H and 13C NMR spectra were re-
corded on Bruker DPX-400 and Bruker DPX-300 spectrometers in
CDCl3 with TMS as internal standard. CHN was recorded on a
Perkin-Elmer 2400 series II CHN analyzer. Silica gel [(60–120
mesh) and (230–400 mesh) Spectrochem, India] were used for chro-
matographic separation. Silica gel G and silica gel GF-254
[Spectrochem (India)] were used for TLC. Petroleum ether (PE) re-
fers to the fraction boiling between 60–80 °C.
second oxidation
H
O
O
N
R
O
O
O
N
OAc
4
10
R
Scheme 4 Probable mechanism of palladium-catalyzed C–H acti-
vation
The mechanism requires initial coordination of the nitro-
gen lone pair to palladium(0) followed by a metal inser-
tion into the adjacent C–H bond to form 8,16,26 which is in
rapid equilibrium with the iminium ion 9.27 The interme-
diate 10 may be formed from 9 by the reaction of potassi-
um acetate in the reaction medium. The intermediate 10
may finally afford the product 4 by a second oxidation fol-
lowed by hydrolysis. On the other hand, path b may at first
follow the suggested oxidation pathway followed by the
normal intramolecular arylation to afford the products 4.
The presence of an electron-withdrawing acetyl group on
the nitrogen, i.e. 3i (Table 1, entry 9), prohibits the reac-
tion to give unreacted starting material. This observation
was also obtained when the nitrogen was unsubstituted,
i.e. 3j (Table 1, entry 10). The reaction only occurs with
7-[(2-Bromobenzyl)(propyl)amino]-4-methyl-2H-1-benzopyr-
an-2-one (3a); Typical Procedure
A mixture of 1a (400 mg, 1.84 mmol) and 2-bromobenzyl bromide
2a (460 mg, 1.84 mmol) in anhyd acetone (60 ml) in the presence
of anhyd K2CO3 and NaI was refluxed for 10–12 h. After cooling
the mixture was filtered and the solvent was removed by distillation.
The residual mass was extracted with CH2Cl2 (3 × 20 mL); the com-
bined organic extracts were washed successively with H2O (2 × 25
mL) and brine (30 mL) and dried (Na2SO4). CH2Cl2 was distilled off
to give the crude product which was purified by chromatography
(PE–EtOAc, 4:1) to afford 3a as a colorless solid; yield: 90%; mp
120 °C.
IR (KBr): 1705, 1617 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.98 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.75 (sextet, J = 7.4 Hz, 2 H, NCH2CH2), 2.31 (s, 3 H, CH3), 3.42
(t, J = 7.8 Hz, 2 H, NCH2CH2), 4.58 (s, 2 H, NCH2), 5.95 (s, 1 H,
electron-donating groups (except methyl) on nitrogen. H3coumarin), 6.46–6.51 (m, 2 H, HAr), 6.97 (d, J = 7.4 Hz, 1 H, HAr),
7.12 (t, J = 7.3 Hz, 1 H, HAr), 7.19 (t, J = 7.3 Hz, 1 H, HAr), 7.34 (d,
J = 8.7 Hz, 1 H, HAr), 7.59 (d, J = 7.8 Hz, 1 H, HAr).
The success of the reaction with the substrates with elec-
Synthesis 2010, No. 22, 3918–3926 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Tethered Intramolecular Arylation
3923
13C NMR (125 MHz, CDCl3): d = 11.2, 18.3, 20.4, 53.4, 55.1, 98.3,
108.7, 109.3, 109.8, 122.6, 125.4, 127.2, 127.5, 128.6, 132.9, 135.5,
150.9, 152.7, 155.6, 161.8.
HRMS: m/z [M + Na]+ calcd for C20H20BrNNaO2: 408.0575; found:
408.0575; m/z [M + 2 Na]+ calcd for C20H20BrNNa2O2: 410.0557;
found: 410.0575.
MS: m/z = 413 [M+], 415 [M+ + 2].
Anal. Calcd for C22H24BrNO2: C, 63.77; H, 5.84; N, 3.38. Found: C,
63.50; H, 5.90; N, 3.45.
Compound 3f
Colorless solid; yield: 82%; mp 110 °C.
IR (KBr): 1720, 1615 cm–1.
Compound 3b
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 6.7 Hz, 3 H, CH2CH3),
1.35–1.38 (m, 4 H, CH2CH2CH3), 1.73 (quintet, J = 7.7 Hz, 2 H,
NCH2CH2), 2.31 (s, 3 H, CH3), 3.44 (t, J = 7.8 Hz, 2 H, NCH2CH2),
3.65 (s, 3 H, OCH3), 4.51 (s, 2 H, NCH2), 5.95 (s, 1 H, H3coumarin),
6.45–6.48 (m, 2 H, HAr), 6.54 (d, J = 2.4 Hz, 1 H, HAr), 6.68 (dd,
J = 2.7, 8.7 Hz, 1 H, HAr), 7.34 (d, J = 8.8 Hz, 1 H, HAr), 7.48 (d,
J = 8.7 Hz, 1 H, HAr).
Viscous liquid; yield: 85%.
IR (neat): 1715, 1619 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.98 (t, J = 7.3 Hz, 3 H, CH2CH3),
1.74 (sextet, J = 7.6 Hz, 2 H, NCH2CH2), 2.31 (s, 3 H, CH3), 3.41
(t, J = 7.8 Hz, 2 H, NCH2CH2), 3.65 (s, 3 H, OCH3), 4.52 (s, 2 H,
NCH2), 5.95 (s, 1 H, H3coumarin), 6.46 (d, J = 5.5 Hz, 1 H, HAr), 6.49
(d, J = 2.0 Hz, 1 H, HAr), 6.55 (d, J = 2.6 Hz, 1 H, HAr), 6.67 (dd,
J = 2.6, 8.7 Hz, 1 H, HAr), 7.33 (d, J = 8.8 Hz, 1 H, HAr), 7.49 (d,
J = 7.4 Hz, 1 H, HAr).
MS: m/z = 443 [M+], 445 [M+ + 2].
Anal. Calcd for C23H26BrNO3: C, 62.17; H, 5.90; N, 3.15. Found: C,
62.33; H, 6.02; N, 3.10.
MS: m/z = 415 [M+], 417 [M+ + 2].
Anal. Calcd for C21H22BrNO3: C, 60.59; H, 5.33; N, 3.36. Found: C,
60.31; H, 5.41; N, 3.41.
Compound 3g
Yellow solid; yield: 90%; mp 99–100 °C.
IR (KBr): 1715, 1608 cm–1.
Compound 3c
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H, CH3), 3.18 (s, 3 H,
NCH3), 4.61 (s, 2 H, NCH2), 5.97 (s, 1 H, H3coumarin), 6.50 (d, J = 2.4
Hz, 1 H, HAr), 6.55 (dd, J = 8.9, 2.5 Hz, 1 H, HAr), 6.97 (d, J = 7.4
Hz, 1 H, HAr), 7.14 (t, J = 7.0 Hz, 1 H, HAr), 7.21 (t, J = 7.4 Hz, 1 H,
HAr), 7.37 (d, J = 8.8 Hz, 1 H, HAr), 7.59 (d, J = 7.8 Hz, 1 H, HAr).
Yellow solid; yield: 85%; mp 90 °C.
IR (KBr): 1717, 1618 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H,
NCH2CH3), 2.36 (s, 3 H, CH3), 3.55 (q, J = 7.1 Hz, 2 H, NCH2CH3),
4.56 (s, 2 H, NCH2), 5.95 (s, 1 H, H3coumarin), 6.50 (dt, J = 8.9, 2.5
Hz, 2 H, HAr), 7.01 (d, J = 7.4 Hz, 1 H, HAr), 7.13 (t, J = 6.9 Hz, 1
H, HAr), 7.20 (t, J = 7.2 Hz, 1 H, HAr), 7.35 (d, J = 8.8 Hz, 1 H, HAr),
7.60 (d, J = 7.7 Hz, 1 H, HAr).
MS: m/z = 357 [M+], 359 [M+ + 2].
Anal. Calcd for C18H16BrNO2: C, 60.35; H, 4.50; N, 3.91. Found: C,
60.11; H, 4.61; N, 4.09.
13C NMR (125 MHz, CDCl3): d = 12.6, 18.8, 46.3, 55.1, 98.9,
109.1, 109.9, 110.4, 123.1, 125.9, 127.7, 128.0, 129.2, 133.5, 136.2,
151.3, 153.1, 156.2, 162.3.
Compound 3h
Yellow solid; yield: 82%; mp 160–161 °C.
IR (KBr): 1714, 1605 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H, CH3), 3.17 (s, 3 H,
NCH3), 3.67 (s, 3 H, OCH3), 4.56 (s, 2 H, NCH2), 5.97 (s, 1 H,
H3coumarin), 6.49 (d, J = 2.5 Hz, 1 H, HAr), 6.54 (dt, J = 4.7, 2.6 Hz,
2 H, HAr), 6.68 (dd, J = 8.7, 3.0 Hz, 1 H, HAr), 7.37 (d, J = 8.8 Hz,
1 H, HAr), 7.48 (d, J = 8.6 Hz, 1 H, HAr).
MS: m/z = 371 [M+], 373 [M+ + 2].
Anal. Calcd for C19H18BrNO2: C, 61.30; H, 4.87; N, 3.76. Found: C,
61.06; H, 4.65; N, 4.01.
Compound 3d
Yellow solid; yield: 80%; mp 60 °C.
IR (KBr): 1717, 1619 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H,
NCH2CH3), 2.31 (s, 3 H, CH3), 3.54 (q, J = 7.1 Hz, 2 H, NCH2CH3),
3.66 (s, 3 H, OCH3), 4.50 (s, 2 H, NCH2), 5.95 (d, J = 1.0 Hz, 1 H,
H3coumarin), 6.45 (d, J = 2.5 Hz, 1 H, HAr), 6.50 (dd, J = 8.9, 2.5 Hz,
1 H, HAr), 6.58 (d, J = 2.9 Hz, 1 H, HAr), 6.69 (dd, J = 8.7, 3.0 Hz,
1 H, HAr), 7.35 (d, J = 8.8 Hz, 1 H, HAr), 7.48 (d, J = 8.6 Hz, 1 H,
HAr).
MS: m/z = 387 [M+], 389 [M+ + 2].
Anal. Calcd for C19H18BrNO3: C, 58.78; H, 4.67; N, 3.61. Found: C,
58.85; H, 4.63; N, 3.77.
Compound 3l
Viscous liquid; yield: 90%.
IR (neat): 2933 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.24 (t, J = 7.0 Hz, 3 H,
NCH2CH3), 3.49 (q, J = 7.0 Hz, 2 H, NCH2CH3), 4.49 (s, 2 H,
NCH2), 6.60 (d, J = 8.2 Hz, 2 H, HAr), 6.66 (t, J = 7.2 Hz, 1 H, HAr),
7.08–7.21 (m, 5 H, HAr), 7.56 (d, J = 7.8 Hz, 1 H, HAr).
MS: m/z = 401 [M+], 403 [M+ + 2].
Anal. Calcd for C20H20BrNO3: C, 59.71; H, 5.01; N, 3.48. Found: C,
59.98; H, 4.78; N, 3.73.
MS: m/z = 289 [M+], 291 [M+ + 2].
Compound 3e
Viscous liquid; yield: 88%.
IR (KBr): 1705, 1617 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 6.7 Hz, 3 H, CH2CH3),
1.32–1.38 (m, 4 H, CH2CH2CH3), 1.71 (quintet, J = 7.3 Hz, 2 H,
NCH2CH2), 2.31 (s, 3 H, CH3), 3.44 (t, J = 7.8 Hz, 2 H, NCH2CH2),
4.57 (s, 2 H, NCH2), 5.95 (s, 1 H, H3coumarin), 6.47 (d, J = 8.7 Hz, 2
H, HAr), 6.98 (d, J = 7.3 Hz, 1 H, HAr), 7.13 (t, J = 7.2 Hz, 1 H, HAr),
7.19 (t, J = 7.3 Hz, 1 H, HAr), 7.34 (d, J = 8.5 Hz, 1 H, HAr), 7.59 (d,
J = 7.8 Hz, 1 H, HAr).
Anal. Calcd for C15H16BrN: C, 62.08; H, 5.56; N, 4.83. Found: C,
62.29; H, 5.60; N, 4.90.
11-Methyl-6-propyl-9H-pyrano[2,3-c]phenanthridine-5,9(6H)-
dione (4a); Typical Procedure
A mixture of 3a (100 mg, 0.26 mmol), anhyd KOAc (26 mg, 0.26
mmol), TBAB (100 mg, 0.31 mmol), and Pd(OAc)2 (5.8 mg, 10
mol%) was heated in anhyd DMF under N2 at 140 °C for 13 h with
continuous stirring. After completion of the reaction (TLC monitor-
ing), the mixture was cooled and H2O (3 mL) was added. It was re-
peatedly extracted with EtOAc (3 × 25 mL) and the combined
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K. C. Majumdar et al.
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organic extracts were washed successively with H2O (3 × 15 mL)
followed by brine (20 mL). The organic layer was dried (Na2SO4).
Evaporation of EtOAc furnished a crude mass that was purified by
column chromatography (silica gel, 25% EtOAc–PE) to afford the
product 4a as a yellow solid; yield: 40%; mp 255 °C.
1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 6.4 Hz, 3 H, CH2CH3),
1.42–1.49 (m, 4 H, CH2CH2CH2CH3), 1.80 (quintet, J = 7.2 Hz, 2
H, NCH2CH2), 2.59 (s, 3 H, CH3), 4.35 (t, J = 7.2 Hz, 2 H,
NCH2CH2), 6.31 (s, 1 H, H3coumarin), 7.30 (s, 1 H, HAr), 7.62 (t,
J = 7.6 Hz, 1 H, HAr), 7.80 (t, J = 7.6 Hz, 1 H, HAr), 8.26 (d, J = 8.0
Hz, 1 H, HAr), 8.44 (s, 1 H, HAr), 8.54 (d, J = 7.6Hz, 1 H, HAr).
13C NMR (125 MHz, CDCl3): d = 14.0, 18.6, 22.4, 26.8, 29.1, 43.4,
102.6, 114.0, 114.9, 116.3, 119.5, 121.3, 125.0, 128.3, 129.1, 132.6,
132.8, 140.0, 151.9, 154.1, 160.4, 161.2.
IR (KBr): 1650, 1730 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.08 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.83 (sextet, J = 7.6 Hz, 2 H, CH2CH2CH3), 2.58 (s, 3 H, CH3), 4.32
(t, J = 7.8 Hz, 2 H, NCH2CH2), 6.30 (s, 1 H, H3coumarin), 7.29 (s, 1 H,
HAr), 7.61 (t, J = 7.6 Hz, 1 H, HAr), 7.80 (t, J = 7.3 Hz, 1 H, HAr),
8.26 (d, J = 8.2 Hz, 1 H, HAr), 8.44 (s, 1 H, HAr), 8.54 (d, J = 8.0 Hz,
1 H, HAr).
MS: m/z = 348 [M+ + H].
Anal. Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C,
76.33; H, 6.16; N, 3.94.
HRMS: m/z [M + Na]+ calcd for C20H17NNaO3: 342.1106; found:
342.1106.
Compound 4f
Yellow solid; yield: 25%; mp 240 °C.
Compound 4b
Yellow solid; yield: 24%; mp 240 °C.
IR (KBr): 1632, 1728 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.95 (t, J = 6.6 Hz, 3 H, CH2CH3),
1.46–1.53 (m, 4 H, CH2CH2CH2CH3), 1.79–1.81 (m, 2 H,
NCH2CH2), 2.58 (s, 3 H, CH3), 3.97 (s, 3 H, OCH3), 4.37 (t, J = 7.35
Hz, 2 H, NCH2CH2), 6.30 (s, 1 H, H3coumarin), 7.31 (s, 1 H, HAr), 7.38
(d, J = 9.0 Hz, 1 H, HAr), 7.96 (s, 1 H, HAr), 8.20 (d, J = 9.0 Hz, 1 H,
HAr), 8.35 (s, 1 H, HAr).
IR (KBr): 1655, 1725 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.08 (t, J = 7.3 Hz, 3 H, CH2CH3),
1.83 (m, 2 H, CH2CH2CH3), 2.56 (s, 3 H, CH3), 3.96 (s, 3 H, OCH3),
4.33 (t, J = 7.7 Hz, 2 H, NCH2CH2), 6.29 (s, 1 H, H3coumarin), 7.29 (s,
1 H, HAr), 7.37 (d, J = 8.8 Hz, 1 H, HAr), 7.95 (d, J = 2.6 Hz, 1 H,
HAr), 8.18 (d, J = 8.9 Hz, 1 H, HAr), 8.34 (s, 1 H, HAr).
MS: m/z = 377 [M+].
MS: m/z = 349 [M+].
Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found: C,
72.93; H, 6.26; N, 3.79.
Anal. Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found: C,
72.40; H, 5.56; N, 3.96.
Compound 5g
Yellow solid; yield: 50%; mp 200–201 °C.
Compound 4c
Yellow solid; yield: 45%; mp 205 °C.
IR (KBr): 1650, 1731 cm–1.
IR (KBr): 1710 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H, CH3), 3.00 (s, 3 H,
NCH3), 4.38 (s, 2 H, NCH2), 6.05 (s, 1 H, H3coumarin), 6.57 (s, 1 H,
HAr), 7.14 (d, J = 7.3 Hz, 1 H, HAr), 7.29 (s, 1 H, HAr), 7.35 (t,
J = 7.6 Hz, 1 H, HAr), 7.73 (d, J = 7.8 Hz, 1 H, HAr), 7.82 (s, 1 H,
HAr).
1H NMR (400 MHz, CDCl3): d = 1.42 (t, J = 7.2 Hz, 3 H,
NCH2CH3), 2.58 (s, 3 H, CH3), 4.44 (q, J = 7.2 Hz, 2 H, NCH2CH3),
6.30 (s, 1 H, H3coumarin), 7.31 (s, 1 H, HAr), 7.61 (t, J = 7.2 Hz, 1 H,
HAr), 7.80 (t, J = 7.1 Hz, 1 H, HAr), 8.26 (d, J = 8.2 Hz, 1 H, HAr),
8.44 (s, 1 H, HAr), 8.54 (d, J = 7.9 Hz, 1 H, HAr).
13C NMR (125 MHz, CDCl3): d = 12.8, 19.0, 38.8, 102.9, 114.5,
115.4, 116.9, 120.1, 121.7, 125.6, 128.8, 129.6, 133.1, 133.2, 140.2,
152.2, 154.7, 160.8, 161.5.
MS: m/z = 278 [M+ + H].
Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C,
78.09; H, 5.38; N, 4.89.
13C NMR DEPT (125 MHz, CDCl3): d = 12.8, 19.0, 38.8, 103.0,
114.5, 120.1, 121.7, 128.8, 129.6, 133.2.
Compound 5h
Yellow solid; yield: 45%; mp 260–261 °C.
MS: m/z = 306.1 [M+ + H].
IR (KBr): 1715 cm–1.
Anal. Calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C,
75.02; H, 5.03; N, 4.50.
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H, CH3), 3.02 (s, 3 H,
NCH3), 3.73 (s, 3 H, OCH3), 4.34 (s, 2 H, NCH2), 6.03 (s, 1 H,
H3coumarin), 6.55 (s, 1 H, HAr), 6.66 (d, J = 2.5 Hz, 1 H, HAr), 6.90
(dd, J = 8.6, 2.6 Hz, 1 H, HAr), 7.66 (d, J = 8.6 Hz, 1 H, HAr), 7.71
(s, 1 H, HAr).
Compound 4d
Yellow solid; yield: 28%; mp 250 °C.
IR (KBr): 1652, 1727 cm–1.
MS: m/z = 307 [M+].
1H NMR (400 MHz, CDCl3): d = 1.42 (t, J = 7.2 Hz, 3 H,
NCH2CH3), 2.56 (s, 3 H, CH3), 3.97 (s, 3 H, OCH3), 4.44 (q, J = 7.2
Hz, 2 H, NCH2CH3), 6.29 (d, J = 1.0 Hz, 1 H, H3coumarin), 7.32 (s, 1
H, HAr), 7.38 (dd, J = 8.9, 2.8 Hz, 1 H, HAr), 7.95 (d, J = 2.8 Hz, 1
H, HAr), 8.18 (d, J = 9.0 Hz, 1 H, HAr), 8.34 (s, 1 H, HAr).
Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C,
74.43; H, 5.78; N, 4.44.
Compound 5k
Yellow viscous liquid; yield: 10%.
MS: m/z = 335 [M+].
IR (neat): 2925 cm–1.
Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C,
71.39; H, 5.20; N, 4.25.
1H NMR (400 MHz, CDCl3): d = 2.97 (s, 3 H, NCH3), 4.52 (s, 2 H,
NCH2), 6.68–6.75 (m, 3 H, HAr), 7.18–7.22 (m, 4 H, HAr), 7.28–7.32
(m, 1 H, HAr).
Compound 4e
Yellow solid; yield: 31%; mp 220 °C.
MS: m/z = 195 [M+].
Anal. Calcd for C14H13N: C, 86.12; H, 6.71; N, 7.17. Found: C,
86.01; H, 6.92; N, 7.40.
IR (KBr): 1624, 1720 cm–1.
Synthesis 2010, No. 22, 3918–3926 © Thieme Stuttgart · New York

PAPER
Palladium-Catalyzed Tethered Intramolecular Arylation
3925
Compound 4l
Yellow viscous liquid; yield: 10%.
IR (neat): 2928, 1650 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.42 (t, J = 7.0 Hz, 3 H,
NCH2CH3), 4.47 (q, J = 7.0 Hz, 2 H, NCH2CH3), 7.31 (t, J = 7.5 Hz,
1 H, HAr), 7.44 (d, J = 8.3 Hz, 1 H, HAr), 7.56 (quintet, J = 6.9 Hz,
2 H, HAr), 7.75 (t, J = 7.5 Hz, 1 H, HAr), 8.29 (t, J = 9.8 Hz, 2 H,
HAr), 8.55 (d, J = 7.9 Hz, 1 H, HAr).
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Compound 5l
Yellow viscous liquid; yield: 8%.
IR (neat): 2920 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.19 (t, J = 7.0 Hz, 3 H,
NCH2CH3), 3.46 (q, J = 7.0 Hz, 2 H, NCH2CH3), 4.50 (s, 2 H,
NCH2), 6.66 (q, J = 8.7 Hz, 3 H, HAr), 7.17 (t, J = 7.8 Hz, 2 H, HAr),
7.22 (m, 1 H, HAr), 7.28 (d, J = 7.24 Hz, 2 H, HAr).
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Anal. Calcd for C15H15N: C, 86.08; H, 7.22; N, 6.69. Found: C,
85.80; H, 7.28; N, 6.57.
Acknowledgment
We thank the CSIR (New Delhi) and DST (New Delhi) for financial
assistance. One of us (B.S.) is grateful to the CSIR (New Delhi) for
a fellowship.
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