A short route to the synthesis of pyrrolocoumarin and pyrroloquinolone derivatives by sonogashira cross-coupling and gold-catalyzed cycloisomerization of acetylenic amines

Article abstract of DOI:10.1055/s-0028-1083295

The syntheses of pyrrolocoumarin and pyrroloquinolone derivatives have been achieved in excellent yields from the acetylenic amines by gold-catalyzed cycloisomerization in the absence of any silver salts or any other bases. The acetylenic amines were in t

Full text of DOI:10.1055/s-0028-1083295

PAPER
311
A Short Route to the Synthesis of Pyrrolocoumarin and Pyrroloquinolone
Derivatives by Sonogashira Cross-Coupling and Gold-Catalyzed
Cycloisomerization of Acetylenic Amines
S
ynthesis of Pyrro
r
locouma
i
rin
a
nd
s
Pyrroloqu
h
inolone
D
er
n
ivative
s
a C. Majumdar,* Buddhadeb Chattopadhyay, Srikanta Samanta
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
E-mail: kcm_ku@yahoo.co.in
Received 11 September 2008; revised 18 September 2008
AuL
R1
LAu+
R1
Abstract: The syntheses of pyrrolocoumarin and pyrroloquinolone
derivatives have been achieved in excellent yields from the acety-
lenic amines by gold-catalyzed cycloisomerization in the absence of
any silver salts or any other bases. The acetylenic amines were in
turn obtained by Sonogashira coupling of the corresponding cou-
marin and quinolone derivatives.
R2
R2
Nu+
B
Nu
A
Scheme 1
Key words: coumarin, quinolone, Sonogashira coupling, gold ca-
talysis, intramolecular cyclization, cycloisomerization
exhibit, for example, antifungal, antibacterial, antiviral,
and antimicrobial properties.6–9 In particular, pyrano-
indole-tethered heterocycles have been used for their an-
tibacterial, monoamine oxidase (MAO) inhibitory, and
anthelmintic activities.10 We recently reported11 the first
example of a [1,3] shift of an aryloxy group and a cyclo-
isomerization process of an alkyne via the palladium-cat-
alyzed reaction. In addition, we also reported12 the
regioselective synthesis of pyrrolocoumarins by aza-
Claisen rearrangement. Our recent interest in transition-
metal-catalyzed heterocyclization13 has prompted us to
study gold-catalyzed cycloisomerization reactions lead-
ing to highly functionalized pyrrolocoumarin and pyrrolo-
quinolone derivatives. Herein, we report the results of our
investigation.
In organic chemistry, heterocycles have a central position
owing to their useful properties.1 A number of synthetic
methodologies have been developed for their synthesis by
ring-closing reactions. A new carbon–heteroatom bond is
formed in a common approach, whether it be intra- or
intermolecular cyclization. The intramolecular addition of
a nitrogen functionality to an alkyne or alkene is a partic-
ularly important strategy. In general, the intramolecular
addition of heteroatom-centered nucleophiles to unsatur-
ated carbon–carbon bonds are important reactions. These
often need harsh reaction conditions if the carbon–carbon
double or triple bond is not sufficiently polarized.2 The in-
tramolecular version of such an addition is usually rela-
tively much faster. Among the various metal-catalyzed
synthetic protocols that have been developed, palladium is
one of the most widely used and accepted metals, and is
employed in different types of synthetic transformations
for intramolecular cyclization. Very recently, gold salts
and complexes have emerged as the most powerful cata-
lysts for the electrophilic activation of alkynes toward a
variety of nucleophiles under homogeneous conditions.
The development of atom-economical reactions by gold
catalysis is one of the primary challenges for synthetic
chemists. In a simplified form of the gold-catalyzed reac-
tion, the nucleophilic attack on the [AuL]+-activated
alkyne proceeds via p-complexes A to give trans-alke-
nyl–gold complexes B as intermediates3–5 (Scheme 1).
The requisite starting materials 3a–f and 4a–f for the cy-
cloisomerization were synthesized in moderate to good
yields by the Sonogashira coupling reaction (Scheme 2).
Compounds 3a–f were prepared by the reaction of 2a–f
with phenylacetylene in the presence of [Pd(PPh3)2Cl2] as
catalyst and copper(I) iodide as co-catalyst in anhydrous
triethylamine–N,N-dimethylformamide (2:5) as mixed
solvent at 120 °C for 1.5 hours. Compounds 4a–f were
prepared by the reaction of 2a–f with (trimethylsilyl)acet-
ylene in the presence of the same catalyst and co-catalyst
at 80 °C in triethylamine–tetrahydrofuran–N,N-dimethyl-
formamide (2:2:5) in a sealed tube for nine hours. Com-
pounds 2a–f were, in turn, prepared by bromination of the
corresponding amines, by stirring with N-bromosuccin-
imide in anhydrous acetonitrile at room temperature for
15 minutes (Scheme 2). Amino compounds 1 were pre-
pared by a reported procedure.14
This type of coordination is a common theme in gold-cat-
alyzed cycloisomerization of enynes, in which the alkene
function acts as a nucleophile. Coumarin and quinolone
moieties are found in a large number of natural products,
which have a broad spectrum of biological activity, and
The cycloisomerization of coumarin 3a to form pyrrolo-
coumarin 5a was studied to find the optimal reaction con-
ditions (Table 1). No change was detected by TLC when
the cycloisomerization reaction of alkyne 3a was carried
out in the presence of 1 mol% of gold(III) chloride as a
catalyst in toluene at 100 °C in a sealed tube (Table 1, en-
SYNTHESIS 2009, No. 2, pp 0311–0317
x
x
.
x
x
.2
0
0
8
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083295; Art ID: Z21108SS
© Georg Thieme Verlag Stuttgart · New York

312
K. C. Majumdar et al.
PAPER
Ph
Br
NHR1
NHR1
NHR1
i
ii
O
X
O
X
O
X
1
2
3
a X = O, R1 = Et
TMS
iii
b X = O, R1 = Me
c X = O, R1 = H
d X = NMe, R1 = Et
e X = NMe, R1 = Me
f X = NMe, R1 = H
NHR1
O
X
4
Scheme 2 Reagents and conditions: (i) NBS, MeCN, r.t., 15 min; (ii) phenylacetylene, [Pd(PPh3)2Cl2], CuI, Et3N–DMF (2:5), 120 °C, 1.5 h;
(iii) (trimethylsilyl)acetylene, [Pd(PPh3)2Cl2], CuI, Et3N–THF–DMF (2:2:5), sealed tube, 80 °C, 9 h.
try 1). Increasing the catalytic load of the reaction also
failed to cause any cycloisomerization, leaving the start-
ing material unchanged (entry 2). However, when aceto-
nitrile, a highly polar solvent, was used instead of the low-
polarity solvent toluene, the reaction proceeded smoothly
to give cyclized product 5a in 83% yield (entry 3). Aiming
for quantitative conversion of alkyne 3a into product 5a,
we carried out a series of experiments, in which the cata-
lytic loading, solvent, and temperature were changed se-
quentially. From the optimization experiments it was
found that ethanol is the best solvent and that at 80 °C, 1
mol% catalyst is sufficient to bring about the highest yield
in this transformation (Table 1, entry 8). We also conduct-
ed the reaction in the absence of solvent, but the results
were not satisfactory (entries 10 and 11). Therefore, the
optimized reaction conditions consist of the following:
gold(III) chloride (1 mol%), ethanol, 80 °C, 3.5 hours.
The optimization experiments are summarized in Table 1.
Table 1 Optimization of the Cycloisomerization Reaction of 3a To
Form 5a
Ph
Ph
NEt
NHEt
AuCl3 (cat.), solvent
O
O
O
O
3a
5a
Entry
AuCl3
(mol%)
Solvent
Temp
(°C)
Time
(h)
Yielda,b
(%)
1
2
1
5
1
2
2
1
1
1
5
1
1
1
1
toluene
100
110
80
10
10
4
n.r.
n.r.
83
toluene
MeCN
MeCN
MeCN
EtOH
EtOH
EtOH
EtOH
neat
3
4
80
4
~85
<5
5
r.t.
r.t.
50
10
10
5
Generally, in this type of gold-catalyzed cyclization, sil-
ver(I) trifluoromethanesulfonate is usually used in con-
junction with the gold catalyst. But in the reaction
reported above, the isomerization proceeds smoothly in
the absence of any silver salt. In the light of this prelimi-
nary result, the optimized experimental conditions shown
in Table 1 (entry 8) were adopted for the study of the
scope of the reaction with other alkynes 3b–f. It was grat-
ifying that alkynes 3b–f also afforded the corresponding
cyclized products 5b–f in excellent yields under these op-
timized conditions.
6
n.r.
50
7
8c
9
80
3.5
10
20
10
10
10
94
r.t.
r.t.
80
~3.5
n.r.
21
10
11
12
13
neat
dioxane
DMF
80
n.r.
n.r.
It is important to note that an electron-withdrawing group
is required for the cycloisomerization of acetylenic
amines to increase the nucleophilicity of the nitrogen,15–19
and a few examples of the cycloisomerization of acetylen-
ic amines with free amines have been reported.20–22 More-
over, to our knowledge, there is no report of the cyclo-
isomerization of acetylenic amines with electron-donating
substituents. Here we have shown that acetylenic amines
without electron-withdrawing groups as well as acetylen-
ic amines with electron-donating groups readily undergo
80
a Isolated yields.
b n.r. = no reaction.
c Optimized reaction conditions.
cycloisomerization to give the pyrrolocoumarin and pyr-
roloquinolone derivatives.
After synthesizing pyrrolocoumarin derivatives 5a–c as
well as pyrroloquinolone derivatives 5d–f starting from
the corresponding phenyl-substituted alkynes 3a–f, we
Synthesis 2009, No. 2, 311–317 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolocoumarin and Pyrroloquinolone Derivatives
313
TMS
NEt
NEt
NHEt
iii
i
X
O
N
O
N
O
N
Me
Me
Me
4d
6d
6d
i
ii
NHEt
O
N
Me
7d
Scheme 3 Reagents and conditions: (i) AuCl3, EtOH, 80 °C; (ii) K2CO3, MeOH, 30 °C, 4 h; (iii) AuCl3, K2CO3, EtOH.
wanted to extend the reaction to the terminally trimethyl-
silyl-substituted alkynes 4a–f. When trimethylsilyl-sub-
stituted alkyne 4d was subjected to the optimized reaction
conditions described above for the cycloisomerization of
compounds 3, no product was obtained (Scheme 3). We
then attempted the reaction with toluene, dioxane, N,N-
dimethylformamide, or acetonitrile as solvent, increased
the catalytic load to 5 mol%, and increased the tempera-
ture. No cycloisomerized product was obtained. This fail-
ure of alkynes 4a–f to cycloisomerize may be due to the
presence of the bulky trimethylsilyl group, sterically pre-
venting the cyclization. Therefore, we had to change the
strategy. When substrate 4d was treated with gold(III)
chloride in conjunction with potassium carbonate in etha-
nol at 70 °C, the reaction proceeded smoothly to afford
the corresponding cyclized product 6d (Scheme 3).
Table 2 Cycloisomerization of Alkynes 3a–f and 4a–f
Entry Substratea X
R1
R2
Time Producta Yieldsb
(h)
(%)
94
91
87
89
93
90
84
87
91
88
91
89
1c 3a
2c 3b
3c 3c
4c 3d
5c 3e
6c 3f
O
O
O
Et
Ph
3.5 5a
Me Ph
4
5
5b
5c
H
Ph
Ph
NMe Et
4.5 5d
NMe Me Ph
4
7
5e
5f
NMe
O
H
Ph
7d 4a
8d 4b
9d 4c
10d 4d
11d 4e
12d 4f
Et
TMS (H)e 11
6a
6b
6c
6d
O
Me TMS (H)e
9
O
H
TMS (H)e 12
TMS (H)e 10
Thus, it was quite clear to us that during the course of the
reaction the trimethylsilyl group was initially eliminated
by the reaction of potassium carbonate, and then the cy-
clization proceeded with the unsubstituted alkyne moiety
in one pot (Scheme 3). This was again verified by the re-
action of the unsubstituted alkyne substrate 7d. When
compound 4d was treated with potassium carbonate in
NMe Et
NMe Me TMS (H)e
8.5 6e
TMS (H)e 10
6f
NMe
H
a See Scheme 4 for structures of 3–6.
methanol at 30 °C for four hours, it gave the correspond- b Isolated yields.
ing trimethylsilyl-eliminated product 7d (Scheme 3).
c Optimized reaction conditions A: AuCl3 (1 mol%), EtOH, 80 °C,
3.5–7 h.
d Optimized reaction conditions B: AuCl3 (1 mol%), EtOH, 70 °C,
sealed tube, K2CO3, 8.5–12 h.
Similarly, other substrates 4 were reacted to give the cy-
clized products 6 in one pot. Here it is notable that the time
required for the cyclization of compounds 4 to 6 is rela-
tively long; this is because the triple bond at the terminal
position is not substituted (not activated). The results are
summarized in Table 2.
e R2 = TMS in substrate 4; R2 = H in product 6.
In conclusion, we have achieved the synthesis of pyrrolo-
coumarin and pyrroloquinolone derivatives by a gold-cat-
alyzed intramolecular cycloisomerization strategy in the
absence of any silver salts in conjunction with the gold
catalyst. We have also shown that in the absence of an
electron-withdrawing group and in the presence of an
electron-donating group the acetylenic amines are
smoothly cycloisomerized to afford the biologically ac-
tive coumarin- and quinolone-fused pyrrole derivatives.
The method is simple, straightforward, and high yielding.
The mechanistic rationalization of the reaction is depicted
in Scheme 4. Initially, the Lewis acidic gold(III) coordi-
nates to the alkynyl moiety of 3 or 4. The resulting
electron-deficient triple bond of 3 or 4 undergoes intramo-
lecular nucleophilic attack by the less basic nitrogen atom
of the amine group, leading to intermediate 9. For the in-
termediate to form, a 5-endo-dig cyclization occurs be-
cause 4-exo-dig is energetically unfavorable. Finally,
protodemetalation of 9 affords the final product 5 or 6.
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314
K. C. Majumdar et al.
PAPER
MS (EI): m/z = 275 [M+].
R2
R2
Anal. Calcd for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C,
78.71; H, 4.90; N, 5.21.
NR1
NHR1
Compound 3c
Yellow solid; yield: 75%; mp 157–158 °C.
IR (KBr): 1713, 3362, 3472 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.35 (s, 2 H, NH2), 6.45 (d, J = 9.6
Hz, 1 H, C3-H of coumarin), 6.90 (d, J = 8.8 Hz, 1 H, ArH), 7.13 (d,
J = 8.8 Hz, 1 H, ArH), 7.38–7.39 (m, 3 H, ArH), 7.55–7.56 (m, 2 H,
ArH), 8.12 (d, J = 9.6 Hz, 1 H, C4-H of coumarin).
O
X
5,6
AuCl3
O
X
3,4
π-coordination
R2
protodemetalation
[Au]
R2
[Au]
NR1
NHR1
MS (EI): m/z = 261 [M+].
cyclization
O
X
O
X
8
Anal. Calcd for C17H11NO2: C, 78.15; H, 4.24; N, 5.36. Found: C,
78.34; H, 4.04; N, 5.39.
9
Scheme 4 Probable mechanistic pathway of the gold-catalyzed cy-
cloisomerization
Compound 3d
Yellow solid; yield: 64%; mp 192–193 °C.
IR (KBr): 1682, 3381 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H, Me), 3.01
(s, 3 H, NMe), 3.69 (q, J = 7.1 Hz, 2 H, NCH2), 4.69 (s, 1 H, NH),
6.76 (d, J = 9.5 Hz, 1 H, C3-H of quinolone), 6.91 (d, J = 8.9 Hz, 1
H, ArH), 7.31 (d, J = 8.6 Hz, 1 H, ArH), 7.38–7.40 (m, 3 H, ArH),
7.58–7.59 (m, 2 H, ArH), 8.14 (d, J = 9.5 Hz, 1 H, C4-H of quinol-
one).
Melting points were determined in open capillaries and are uncor-
rected. IR spectra of samples prepared as KBr discs were recorded
on a Perkin-Elmer L120-000A IR spectrometer. NMR spectra of
samples as solns in CDCl3 with TMS as internal standard were re-
corded on a Bruker DPX-400 NMR spectrometer. MS (TOF ES+,
El) analysis was carried out on QTOF Micro YA 263 and Jeol
JMS600 spectrometers. Silica gel (60–120 mesh) was used for chro-
matographic separation. Silica gel-G [E-Mark (India)] was used for
TLC. PE refers to the fraction boiling between 60 and 80 °C.
MS (EI): m/z = 302 [M+].
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.13; H, 5.98; N, 9.49.
Compound 3a from Compound 2a; Typical Procedure
A mixture of 2a (180 mg, 0.70 mmol) and phenylacetylene (0.09
mL, 0.80 mmol) in DMF–Et3N (5:2, 7 mL) was degassed with N2.
[Pd(PPh3)2Cl2] (23.50 mg, 0.04 mmol) and CuI (15.28 mg, 0.08
mmol) were then added to the well-stirred soln. The mixture was
heated with stirring at 120 °C for 1.5 h. The solvent was removed
under reduced pressure and CH2Cl2 (20 mL) was added to the re-
sulting residue. After filtration of the mixture over Celite, the fil-
trate was washed with H2O (10 mL) followed by brine (10 mL) and
dried (Na2SO4). The solvent was removed to give the crude product,
which was chromatographed (silica gel, EtOAc–PE, 15:85); this
furnished product 3a. Other compounds 3b–f were prepared simi-
larly.
Compound 3e
Yellow solid; yield: 75%; mp 230–231 °C.
IR (KBr): 1688, 3144 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.98 (s, 3 H, Me), 3.70 (s, 3 H,
NMe), 4.70 (s, 1 H, NH), 6.75 (d, J = 9.5 Hz, 1 H, C3-H of quinol-
one), 6.93 (d, J = 9.0 Hz, 1 H, ArH), 7.29 (d, J = 9.1 Hz, 1 H, ArH),
7.38–7.39 (m, 3 H, ArH), 7.57–7.58 (m, 2 H, ArH), 8.14 (d, J = 9.5
Hz, 1 H, C4-H of quinolone).
MS (EI): m/z = 288 [M+].
Anal. Calcd for C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C,
79.32; H, 5.66; N, 9.83.
Compound 3a
Yellow solid; yield: 76%; mp 108–109 °C.
IR (KBr): 1716, 3397 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.0 Hz, 3 H, Me), 3.27
(q, J = 7.0 Hz, 2 H, NCH2), 4.58 (s, 1 H, NH), 6.44 (d, J = 9.6 Hz,
1 H, C3-H of coumarin), 6.82 (d, J = 9.1 Hz, 1 H, ArH), 7.20 (d,
J = 9.1 Hz, 1 H, ArH), 7.39–7.40 (m, 3 H, ArH), 7.55–7.56 (m, 2 H,
ArH), 8.12 (d, J = 9.6 Hz, 1 H, C4-H of coumarin).
Compound 3f
Yellow solid; yield: 80%; mp 130–132 °C.
IR (KBr): 1681, 3268, 3397 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.75 (s, 3 H, NMe), 4.88 (s, 2 H,
NH2), 6.83 (d, J = 9.6 Hz, 1 H, C3-H of quinolone), 7.40–7.43 (m, 2
H, ArH), 7.47–7.50 (m, 3 H, ArH), 7.76 (d, J = 8.9 Hz, 2 H, ArH),
8.12 (d, J = 9.6 Hz, 1 H, C4-H of quinolone).
MS (EI): m/z = 274 [M+].
MS (EI): m/z = 289 [M+].
Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C,
78.63; H, 5.22; N, 10.45.
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.98; H, 5.11; N, 5.03.
Compound 5a from Compound 3a; Typical Procedure
AuCl3 (0.52 mg, 1 mol%) was added to a magnetically stirred soln
of 3a (50 mg, 0.173 mmol) in EtOH, and the mixture was heated on
an oil bath at 80 °C for 3.5 h. The mixture was cooled to r.t. and the
EtOH was removed under reduced pressure. The crude mass was
then purified by flash column chromatography (silica gel, 230–400
mesh, EtOAc–PE, 20:80); this gave product 5a. Substrates 3b–f
were subjected to the same reaction conditions to afford products
5b–f.
Compound 3b
Yellow solid; yield: 70%; mp 129–130 °C.
IR (KBr): 1710, 3406 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.96 (s, 3 H, NMe), 4.71 (s, 1 H,
NH), 6.44 (d, J = 9.6 Hz, 1 H, C3-H of coumarin), 6.82 (d, J = 9.0
Hz, 1 H, ArH), 7.22 (d, J = 9.3 Hz, 1 H, ArH), 7.39–7.40 (m, 3 H,
ArH), 7.56–7.57 (m, 2 H, ArH), 8.12 (d, J = 9.6 Hz, 1 H, C4-H of
coumarin).
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Synthesis of Pyrrolocoumarin and Pyrroloquinolone Derivatives
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Compound 5a
MS (EI): m/z = 288 [M+].
Yellow solid; yield: 94%; mp 148–149 °C.
IR (KBr): 1712 cm–1.
Anal. Calcd for C19H16N2O: C, 79.14; H, 5.59; N, 9.72. Found: C,
79.31; H, 5.38; N, 9.81.
1H NMR (400 MHz, CDCl3): d = 1.32 (t, J = 6.8 Hz, 3 H, Me), 4.24
(q, J = 6.8 Hz, 2 H, NCH2), 6.46 (d, J = 9.5 Hz, 1 H, C3-H of cou-
marin), 6.73 (s, 1 H, =CH), 7.22 (d, J = 8.8 Hz, 1 H, ArH), 7.45–
7.54 (m, 6 H, ArH), 8.12 (d, J = 9.5 Hz, 1 H, C4-H of coumarin).
Compound 5f
Yellow solid; yield: 90%; mp 140–141 °C.
IR (KBr): 1670, 3149 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.1, 32.7, 99.7, 110.7, 110.8,
113.9, 114.9, 128.6, 128.7, 129.7, 129.8, 130.3, 132.3, 140.8, 143.3,
150.0, 160.1.
1H NMR (400 MHz, CDCl3): d = 3.82 (s, 3 H, NMe), 6.73 (d,
J = 9.6 Hz, 1 H, C3-H of quinolone), 6.92 (s, 1 H, =CH), 7.42 (d,
J = 8.0 Hz, 1 H, ArH), 7.49–7.55 (m, 6 H, ArH), 8.31 (d, J = 9.6 Hz,
1 H, C4-H of quinolone), 8.64 (s, 1 H, NH)
MS (EI): m/z = 289 [M+].
MS (EI): m/z = 274 [M+].
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.69; H, 4.99; N, 4.91.
Anal. Calcd for C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C,
78.99; H, 4.97; N, 9.98.
Compound 5b
Yellow solid; yield: 91%; mp 136–137 °C.
IR (KBr): 1709 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.80 (s, 3 H, NMe), 6.46 (d,
J = 9.5 Hz, 1 H, C3-H of coumarin), 6.77 (s, 1 H, =CH), 7.22 (d,
J = 8.9 Hz, 1 H, ArH), 7.43–7.51 (m, 6 H, ArH), 8.13 (d, J = 9.5 Hz,
1 H, C4-H of coumarin).
13C NMR (75 MHz, CDCl3): d = 31.4, 99.3, 110.5, 110.9, 113.6,
114.9, 124.2, 128.5, 128.7, 129.4, 131.9, 134.4, 140.8, 143.8, 150.1,
161.9.
Compound 4a from Compound 2a; Typical Procedure
A mixture of 2a (180 mg, 0.70 mmol) and (trimethylsilyl)acetylene
(98.56 mg, 1.0035 mmol) in DMF–THF–Et3N (5:2:2, 9 mL) was
degassed with N2. [Pd(PPh3)2Cl2] (23.50 mg, 0.0334 mmol) and CuI
(15.28 mg, 0.0802 mmol) were then added to the well-stirred soln.
The mixture was heated with stirring in a sealed tube at 80 °C for 9
h. The solvent was removed under reduced pressure and CH2Cl2 (20
mL) was added to the resulting residue. After filtration of the mix-
ture over Celite, the filtrate was washed with H2O (10 mL) followed
by brine (10 mL) and dried (Na2SO4). The solvent was removed to
give the crude product, which was chromatographed (silica gel,
EtOAc–PE, 15:85); this furnished product 4a. Other compounds 4
were prepared similarly.
MS (EI): m/z = 275 [M+].
Anal. Calcd for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C,
78.44; H, 4.93; N, 5.28.
Compound 4a
Yellow solid; yield: 80%; mp 124–126 °C.
Compound 5c
Yellow solid; yield: 87%; mp 252–253 °C.
IR (KBr): 1721, 3129 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.48 (d, J = 9.5 Hz, 1 H, C3-H of
coumarin), 7.05 (s, 1 H, =CH), 7.17 (d, J = 8.8 Hz, 1 H, ArH), 7.38
(t, J = 7.2 Hz, 1 H, ArH), 7.48 (t, J = 7.8 Hz, 2 H, ArH), 7.54 (d,
J = 8.8 Hz, 1 H, ArH), 7.69 (d, J = 7.4 Hz, 2 H, ArH), 8.15 (d,
J = 9.5 Hz, 1 H, C4-H of coumarin), 8.60 (s, 1 H, NH).
IR (KBr): 1716, 3397 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.31 (s, 9 H, SiMe3), 1.31 (t,
J = 7.2 Hz, 3 H, Me), 3.19–3.26 (m, 2 H, CH2), 4.52 (s, 1 H, NH),
6.42 (d, J = 9.5 Hz, 1 H, C3-H of coumarin), 6.78 (d, J = 9.0 Hz, 1
H, ArH), 7.17 (d, J = 9.1 Hz, 1 H, ArH), 8.01 (d, J = 9.5 Hz, 1 H,
C4-H of coumarin).
13C NMR (125 MHz, CDCl3): d = 0.7, 15.1, 38.8, 98.3, 103.2,
107.7, 114, 117.6, 118.5, 120.1, 142.3, 146.1, 147.4, 161.4.
MS (EI): m/z = 261 [M+].
HRMS (TOF, ES+): m/z [M + Na] calcd for C16H19NO2Si:
308.1080; found: 308.1094.
Anal. Calcd for C17H11NO2: C, 78.15; H, 4.24; N, 5.36. Found: C,
77.91; H, 4.39; N, 5.51.
Compound 5d
Yellow solid; yield: 89%; mp 244–245 °C.
Compound 4b
Yellow solid; yield: 79%; mp 118–120 °C.
IR (KBr): 1681 cm–1.
IR (KBr): 1711, 3406 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 6.9 Hz, 3 H, Me), 3.79
(s, 3 H, NMe), 3.83 (q, J = 6.9 Hz, 2 H, NCH2), 6.81 (d, J = 9.5 Hz,
1 H, C3-H of quinolone), 6.84 (s, 1 H, =CH), 7.27 (d, J = 9.0 Hz, 1
H, ArH), 7.45 (d, J = 7.2 Hz, 1 H, ArH), 7.48–7.58 (m, 5 H, ArH),
8.15 (d, J = 9.5 Hz, 1 H, C4-H of quinolone).
1H NMR (400 MHz, CDCl3): d = 0.31 (s, 9 H, SiMe3), 2.93 (d,
J = 5.2 Hz, 3 H, Me), 4.52 (d, J = 4.8 Hz, 1 H, NH), 6.43 (d, J = 9.5
Hz, 1 H, C3-H of coumarin), 6.78 (d, J = 9.1 Hz, 1 H, ArH), 7.19 (d,
J = 9.7 Hz, 1 H, ArH), 8.00 (d, J = 9.5 Hz, 1 H, C4-H of coumarin).
13C NMR (100 MHz, CDCl3): d = 0.4, 30.6, 97.7, 102.8, 107.2,
112.9, 117.2, 118.1, 119.8, 141.8, 145.7, 147.6, 160.9.
MS (EI): m/z = 302 [M+].
HRMS (TOF, ES+): m/z [M + H] calcd for C15H17NO2Si: 272.1186;
found: 272.1172.
Anal. Calcd for C20H18N2O: C, 79.44; H, 6.00; N, 9.26. Found: C,
79.59; H, 6.19; N, 9.09.
Compound 5e
Yellow solid; yield: 93%; mp 217–218 °C.
Compound 4c
Yellow solid; yield: 70%; mp 118–120 °C.
IR (KBr): 1686 cm–1.
IR (KBr): 1707, 3472 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.82 (s, 6 H, NMe), 6.79 (d,
J = 9.5 Hz, 1 H, C3-H of quinolone), 6.84 (s, 1 H, =CH), 7.28 (d,
J = 9.1 Hz, 1 H, ArH), 7.44 (d, J = 7.0 Hz, 1 H, ArH), 7.50–7.58 (m,
5 H, ArH), 8.14 (d, J = 9.5 Hz, 1 H, C4-H of quinolone).
1H NMR (500 MHz, CDCl3): d = 0.31 (s, 9 H, SiMe3), 4.29 (s, 2 H,
NH2), 6.44 (d, J = 9.5 Hz, 1 H, C3-H of coumarin), 6.87 (d, J = 7.1
Hz, 1 H, ArH), 7.12 (d, J = 7.1 Hz, 1 H, ArH), 8.01 (d, J = 9.5 Hz,
1 H, C4-H of coumarin).
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MS (EI): m/z = 280 [M + Na].
Compound 6a
This compound was reported earlier.13f
Anal. Calcd for C14H15NO2Si: C, 65.34; H, 5.87; N, 5.44. Found: C,
65.11; H, 5.99; N, 5.63.
Compound 6b
Yellow solid; yield: 87%; mp 124–126 °C.
IR (KBr): 1698 cm–1.
Compound 4d
Yellow solid; yield: 75%; mp 70–72 °C.
IR (KBr): 1653, 3409 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3 H, Me), 6.45 (d, J = 9.5
Hz, 1 H, C3-H of coumarin), 6.69 (d, J = 3.8 Hz, 1 H, ArH), 7.18–
7.21 (m, 2 H, ArH), 7.45 (d, J = 8.8 Hz, 1 H, ArH), 8.11 (d, J = 9.5
Hz, 1 H, C4-H of coumarin).
HRMS (TOF, ES+): m/z [M + H] calcd for C12H9NO2: 200.0706;
found: 200.0703.
1H NMR (400 MHz, CDCl3): d = 0.31 (s, 9 H, SiMe3), 1.32 (t,
J = 7.1 Hz, 3 H, Me), 3.24–3.27 (m, 2 H, CH2), 3.67 (s, 3 H, NMe),
4.51 (s, 1 H, NH), 6.72 (d, J = 9.6 Hz, 1 H, C3-H of quinolone), 6.89
(d, J = 9.2 Hz, 1 H, ArH), 7.23 (d, J = 9.1 Hz, 1 H, ArH), 8.03 (d,
J = 9.6 Hz, 1 H, C4-H of quinolone).
HRMS (TOF, ES+): m/z [M + H] calcd for C17H22N2OSi: 299.1574;
found: 299.1563.
Compound 6c
Yellow solid; yield: 91%; mp 190–192 °C.
Compound 4e
IR (KBr): 1687, 3188 cm–1.
Yellow solid; yield: 72%, mp 180–182 °C.
IR (KBr): 1648, 3389 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.31 (s, 9 H, SiMe3), 2.96 (d,
J = 5.2 Hz, 3 H, NMe), 3.68 (s, 3 H, NMe), 4.64 (s, 1 H, NH), 6.73
(d, J = 9.6 Hz, 1 H, C3-H of quinolone), 6.89 (d, J = 9.2 Hz, 1 H,
ArH), 7.27 (d, J = 9.8 Hz, 1 H, ArH), 8.03 (d, J = 9.6 Hz, 1 H, C4-
H of quinolone).
1H NMR (400 MHz, CDCl3): d = 6.47 (d, J = 9.5 Hz, 1 H, C3-H of
coumarin), 6.79 (d, J = 2.9 Hz, 1 H, ArH), 7.18 (d, J = 8.8 Hz, 1 H,
ArH), 7.38 (t, J = 2.6 Hz, 1 H, ArH), 7.45 (d, J = 8.8 Hz, 1 H, ArH),
8.13 (d, J = 9.5 Hz, 1 H, C4-H of coumarin).
HRMS (TOF, ES+): m/z [M + H] calcd for C11H7NO2: 186.0550;
found: 186.0547.
Compound 6e
Yellow solid; yield: 91%; mp 220–222 °C.
IR (KBr): 1655 cm–1.
HRMS (TOF, ES+): m/z [M + H] calcd for C16H20N2OSi: 285.1418;
found: 285.1406.
Compound 4f
Yellow solid; yield: 63%; mp 211–212 °C.
IR (KBr): 1668, 3341, 3399 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.31 (s, 9 H, SiMe3), 4.66 (s, 2 H,
NH2), 6.73 (d, J = 9.6 Hz, 1 H, C3-H of quinolone), 6.93 (d, J = 7.2
Hz, 1 H, ArH), 7.28 (d, J = 8.9 Hz, 1 H, ArH), 8.06 (d, J = 9.6 Hz,
1 H, C4-H of quinolone).
1H NMR (400 MHz, CDCl3): d = 3.82 (s, 3 H, NMe), 3.87 (s, 3 H,
NMe), 6.76–6.81 (m, 2 H, ArH), 7.18 (d, J = 2.8 Hz, 1 H, ArH),
7.53 (d, J = 9.0 Hz, 2 H, ArH), 8.13 (d, J = 9.6 Hz, 1 H, C4-H of qui-
nolone).
HRMS (TOF, ES+): m/z [M + H] calcd for C13H12N2O: 213.1022;
found: 213.1016.
Compound 6f
Yellow solid; yield: 89%; mp 152–153 °C.
IR (KBr): 1676, 3144 cm–1.
MS (EI): m/z = 270 [M+].
Anal. Calcd for C15H18N2OSi: C, 66.63; H, 6.71; N, 10.36. Found:
C, 66.91; H, 6.49; N, 10.53.
1H NMR (400 MHz, CDCl3): d = 3.82 (s, 3 H, NMe), 3.88 (s, 3 H,
NMe), 6.77–6.82 (m, 2 H, ArH), 7.18 (d, J = 2.7 Hz, 1 H, ArH),
7.55 (d, J = 8.9 Hz, 2 H, ArH), 8.13 (d, J = 9.6 Hz, 1 H, C4-H of qui-
nolone).
Compound 6d from Compound 4d; Typical Procedure
AuCl3 (0.5 mg, 1 mol%) and K2CO3 (115.23 mg, 0.83 mmol) were
added to a magnetically stirred soln of 4d (50 mg, 0.167 mmol) in
EtOH (10 mL), and the mixture in a sealed tube was then heated on
an oil bath for 10 h. The mixture was cooled to r.t. and EtOH was
removed under reduced pressure. The mixture was extracted with
EtOAc (2 × 15 mL), washed with H2O (15 mL) and brine (15 mL),
and dried (Na2SO4). The EtOAc layer was evaporated to give the
crude mass. This was then purified by flash column chromatogra-
phy (silica gel, EtOAc–PE, 30.70); this gave product 6d. Other sub-
strates 4 were similarly subjected to the same reaction conditions to
afford the corresponding products 6.
Acknowledgment
We thank the CSIR (New Delhi) and the DST (New Delhi) for fi-
nancial assistance. Two of us (B.C. and S.S.) are grateful to the
CSIR (New Delhi) for research fellowships.
References
(1) (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic
Chemistry; Stanley Thornes: Cheltenham, 1998. (b)Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry;
Elsevier Science: Oxford, 2000.
(2) (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.
(b) Beller, M.; Riermeier, T. H. In Transition Metals for
Organic Synthesis, 2nd ed., Vol. 2; Beller, M.; Bolm, C.,
Eds.; Wiley-VCH: New York, 1998. (c) Teles, J. H.; Brode,
S.; Chabanas, M. Angew. Chem. Int. Ed. 1998, 37, 1415.
(d) Kukharev, B. F.; Stankevich, V. K.; Klimenko, G. R.
Russ. J. Org. Chem. 1993, 29, 2005. (e) Taube, R. Applied
Homogeneous Catalysis with Organometallic Compounds,
Compound 6d
Yellow solid; yield: 88%; mp 198–200 °C.
IR (KBr): 1640 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.50 (t, J = 7.3 Hz, 3 H, Me), 3.84
(s, 3 H, NMe), 4.22–4.27 (q, J = 7.3 Hz, 2 H, NCH2), 6.78 (d,
J = 2.9 Hz, 1 H, ArH), 6.85 (d, J = 9.2 Hz, 1 H, C3-H of quinolone),
7.27 (t, J = 5.4 Hz, 2 H, ArH), 7.57 (d, J = 9.0 Hz, 1 H, ArH), 8.18
(d, J = 9.2 Hz, 1 H, C4-H of quinolone).
HRMS (TOF, ES+): m/z [M + H] calcd for C14H14N2O: 227.1179;
found: 227.1172.
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PAPER
Synthesis of Pyrrolocoumarin and Pyrroloquinolone Derivatives
317
Vol. 1; Cornils, B.; Herrmann, W. A., Eds.; Wiley-VCH:
New York, 1996, 507.
(12) Majumdar, K. C.; Chattopadhyay, B. Synthesis 2008, 921.
(13) (a) Majumdar, K. C.; Chattopadhyay, B. Synlett 2008, 979.
(b) Majumdar, K. C.; Chattopadhyay, B.; Sinha, B.
Tetrahedron Lett. 2008, 49, 1319. (c) Majumdar, K. C.;
Chattopadhyay, B.; Nath, S. Tetrahedron Lett. 2008, 49,
1609. (d) Majumdar, K. C.; Chattopadhyay, B.; Ray, K.
Tetrahedron Lett. 2007, 48, 7633. (e) Majumdar, K. C.;
Chattopadhyay, B.; Taher, A. Synthesis 2007, 3647.
(f) Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2008, 49,
2418. (g) Majumdar, K. C.; Chattopadhyay, B.; Pal, A. K.
Lett. Org. Chem. 2008, 5, 276.
(14) (a) Majumdar, K. C.; Ghosh, S. J. Chem. Soc., Perkin Trans.
1 1994, 2889. (b) Majumdar, K. C.; Biswas, P.; Jana, G. H.
J. Chem. Res. 1997, 310.
(15) Hiroya, K.; Matsumoto, S.; Sakamoto, T. Org. Lett. 2004, 6,
2953.
(3) (a) Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002,
102, 813. (b) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004,
104, 1317. (c) Bruneau, C. Angew. Chem. Int. Ed. 2005, 44,
2328. (d) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2006, 45, 7079. (e) Terrason, V.; Michaux,
J.; Gaucher, A.; Wehbe, J.; Marque, S.; Prim, D.; Campagne,
J.-M. Eur. J. Org. Chem. 2007, 5332.
(4) (a) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem. Int. Ed.
2006, 45, 7896. (b) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180. (c) Echavarren, A. M.; Nevado, C. Chem. Soc. Rev.
2004, 33, 431.
(5) (a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
(b) Furstner, A.; Davies, P. W. Angew. Chem. Int. Ed. 2007,
46, 3410. (c) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth.
Catal. 2006, 348, 2271.
(6) Boyd, D. R.; Sharma, N. D.; Barr, S. A.; Carroll, J. G.;
Mackerracher, D.; Malone, J. F. J. Chem. Soc., Perkin Trans.
1 2000, 3397.
(16) Cacchi, S.; Fabrizi, G.; Parisi, L. M.; Bernini, R. Synlett
2004, 287.
(17) Hiroya, K.; Itoh, S.; Skakamoto, T. Tetrahedron Lett. 2005,
61, 10958.
(7) (a) Bar, G.; Parson, A. F.; Thomas, C. B. Tetrahedron 2001,
57, 4719. (b) Lee, Y. R.; Kim, B. S.; Kweon, H. I.
Tetrahedron 2000, 56, 3867.
(8) Pirrung, M. C.; Blume, F. J. Org. Chem. 1999, 64, 3642.
(9) Dickinson, J. M. Nat. Prod. Rep. 1993, 10, 71.
(10) Hiremath, S. P.; Badiger, G. R.; Jivanagi, A. S.; Purohit, M.
G. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
1992, 31, 583.
(18) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata, A.;
Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
1999, 529.
(19) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004, 610.
(20) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmidt, B.;
Knochel, P. Tetrahedron 2003, 1571.
(21) Zhang, Y.; Donahue, J. P.; Li, C. J. Org. Lett. 2007, 9, 627.
(22) Trost, B. M.; McClory, A. Angew. Chem. Int. Ed. 2007, 46,
2074.
(11) Majumdar, K. C.; Sinha, B.; Chattopadhyay, B.; Ray, K.
Tetrahedron Lett. 2008, 49, 4405.
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