Palladium-catalyzed regioselective oxidative amination of alkenes: An efficient route to the synthesis of pyrrolocoumarin and pyrroloquinolone derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.05.068

Palladium-catalyzed IBX-induced intramolecular oxidative amination of alkenes has been utilized for the synthesis of pyrrolocoumarin and pyrroloquinolone derivatives in excellent yields in a short reaction time.

Full text of DOI:10.1016/j.tetlet.2010.05.068

Tetrahedron Letters 51 (2010) 3807–3810
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Palladium-catalyzed regioselective oxidative amination of alkenes: an
efficient route to the synthesis of pyrrolocoumarin and pyrroloquinolone
derivatives
*
K. C. Majumdar , Srikanta Samanta, Raj Kumar Nandi, Buddhadeb Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741 235, WB, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed IBX-induced intramolecular oxidative amination of alkenes has been utilized for the
synthesis of pyrrolocoumarin and pyrroloquinolone derivatives in excellent yields in a short reaction
time.
Received 13 March 2010
Revised 10 May 2010
Accepted 17 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalyst
Oxidative amination
IBX (2-iodoxybenzoic acid)
Pyrrolocoumarin
Pyrroloquinolone
The prominence of five-membered nitrogen-containing hetero-
cycles in natural products and biologically active molecules1 has
evoked considerable interest toward their synthesis. Natural prod-
ucts possessing coumarin and quinolone sub-units show broad-
spectrum biological activities.2–6 Various pyrrolocoumarins possess
anti bacterial, monoamine oxidase (MAO) inhibitory, and anthel-
mintic activities.7 They have also been used as fluorogenic probes.8
A number of synthetic methodologies9a–d have been developed for
the synthesis of coumarin- and quinolone-fused pyrroles by ring-
closing reaction. The intramolecular addition of nitrogen functional-
ity to an alkyne or an alkene is an important strategy. This often
needs harsh reaction conditions if the carbon–carbon multiple bond
is not sufficiently polarized.10 Intramolecular oxidative amina-
tion11,12 of olefins represents a powerful synthetic strategy for the
synthesis of nitrogen heterocycles. Among the various metal-cata-
lyzed (Ag, Cu) synthetic protocols developed, palladium is one of
the widely used and accepted metal that is employed in different
types of intramolecular oxidative amination of olefins. In principle,
the reaction may be initiated by palladium–amine interaction fol-
lowed by simultaneous transfer to the alkene, which may also be
considered as alkene insertion into the amine–palladium bond
(Fig. 1).13
different terminal enimides and intramolecular14b oxidative ami-
nation of olefins to produce pyrrolidine and pyrroline heterocycles
efficiently using molecular oxygen. Liu and co-workers reported15
a Brønsted base-modulated regioselective Pd-catalyzed intramo-
lecular aerobic oxidative amination of alkenes for the formation
of seven-membered amides. Palladium-catalyzed intramolecular
amination of olefins has been reported for the formation of
2-methyl-1-tosyl indole under different conditions16 in only
21–28% yields in a complex mixture. But there is no such report
on the synthesis of pyrrolo-fused heterocycles by Pd-catalyzed oxi-
dative amination starting from unactivated olefinic amine precur-
sors. This has prompted us to undertake a study on the synthesis of
pyrrolocoumarins and pyrroloquinolones by the intramolecular
oxidative amination.
The starting materials 1a–f, 2(a,b), 3 for this study were pre-
pared according to our earlier published procedure.17,18 We had
earlier demonstrated9b the gold (III)-catalyzed amination of al-
kynes to synthesize pyrrolo-pyridine derivatives. Therefore, ini-
tially we have attempted Au(III) catalyst for the alkene–amine
coupling. However, when 5-allyl-6-(ethylamino)-1-methylquino-
lone 1a was subjected to react with AuCl3 in acetonitrile, the de-
sired cyclization to give pyrroloquinolone derivative did not
occur even after refluxing for 14 h. The catalyst system was chan-
ged and Pd(OAc)2 was tried in anhydrous DMF in the presence of
Na2CO3 as base at 100 °C for 10 h. Pleasantly the cyclized product
pyrrolo[3,2-f]quinolinone was obtained in good yield (71%)
(Scheme 1).
Stahl and co-workers reported the palladium-catalyzed inter-
molecular14a aerobic oxidative amination of alkenes to synthesize
* Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582 8282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.068

3808
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 3807–3810
PdII
R
HN
reaction
condition
R
N
()n
PdII
NHR
()n
products
R
N
()n
PdII
PdII
()n
Figure 1. Mechanistic background of aminopalladation for heterocycle synthesis.
none (BQ) as a reoxidant. When the reaction was carried out at 70 °C
for 1.5 h without IBX the product obtained was just 28% (entry 4)
and on increasing the reaction time up to a stage that the reaction
hardly proceeded anymore, the yield was 69% (entry 5). So the opti-
mized reaction conditions are 10 mol % Pd(OAc)2/1 equiv IBX/
3 equiv Na2CO3/DMF/70 °C. All the other starting materials 1(b–f),
2(a,b), and 3 were treated under the optimized reaction conditions
to afford the corresponding cyclized products 4(b–f), 5(a,b), and 6 in
85–97% yields. The results are given in Table 2.
We have been particularly interested in the oxidative amination
reactions, and a simplified catalytic cycle for a representative reac-
tion is shown in Scheme 2: aminopalladation of the alkene, fol-
lowed by b-hydride elimination, generates the heterocyclic
product 4a0, which subsequently isomerizes to form the desired
product 4a and the reduced Pd catalyst (step IV, Scheme 2). The re-
duced catalyst then gets reoxidized directly by the oxidant IBX to
regenerate the catalyst PdII (step V).
NHEt
3 mol% AuCl3
CH3CN, reflux, 14h
no reaction
O
O
NMe
1a
10 mol% Pd(OAc)2,
3 eq. Na2CO3, anh. DMF,
100 oC, 10h, 71%
NEt
NHEt
10 mol% Pd(OAc)2,
1 eq. IBX, 3 eq. Na2CO3,
anh. DMF, 70 oC, 1.5 h. 95%
O
NMe
NMe
or
1a
4a
Scheme 1.
In order to improve the yield of the reaction we have then used
IBX as an oxidant in the reaction. In the presence of IBX (2-iodoxy-
benzoic acid) surprisingly the yield of the product, pyrroloquino-
lone 4a19, was increased to 95% at 70 °C in only 1.5 h. We have
carried out a series of experiments by sequential changes of cata-
lyst, solvent, base, and oxidant. The results are summarized in
Table 1.
From Table 1 it is clear that Pd(OAc)2 is much more efficient
than Pd(PPh3)4 and Cu(OAc)2. In the absence of any catalyst the
reaction did not proceed at all (entry 8). Among the different sol-
vents tried, DMF is the best choice compared to CH3CN and DMA.
In aqueous medium the reaction was sluggish (yield 15%, entry
13). IBX is preferable to iodobenzenediacetate (IBD) and benzoqui-
The past few years have seen an explosive growth in the dem-
onstration and use of IBX as a selective reagent for unique oxida-
tive transformations20 including oxidation of benzylic carbons,
oxidation of amines, dehydrogenation of carbonyl to the corre-
sponding
a,b-unsaturated analogues, dehydrogenation of N-het-
erocycles to heteroaromatics, and oxidative cleavage of
dithioacetals and dithioketals. But its use as a reoxidant [Pd(0) to
Pd(II)] is perhaps the first report.
It is relevant to mention that we failed to get the corresponding
pyrroloquinolone and pyrrolocoumarin derivatives by the radical
cyclization.17c It is interesting to note that here we have succeeded
in developing a more generalized approach which overcomes the
Table 1
Study under different conditions
NHEt
NEt
N
O
N
Me
O
Me
1a
4a
Entries
Catalysta
Solvent
Baseb
Oxidantc
Temp (°C)
Time (h)
Yieldd (%)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
CH3CN
DMF
DMF
H2O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
KOAc
—
—
IBX
—
—
100
100
70
70
70
70
90
100
100
80
10
15
1.5
1.5
16
1.5
5
12
12
4
71
48
95
28
69
79
70
NRg
15
73
90
80
15
77
3e
4
5
6
7
8
IBDf
IBX
IBX
IBX
IBX
IBX
BQh
IBX
IBX
Na2CO3
KOAc
9
10
11
12
13
14
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
80
80
70
80
5
2.5
1.5
5
DMF
a = catalyst used 10 mol %, b = base used 3 equiv, c = oxidant used 1 equiv; d = isolated yield; e = optimized reaction condition; f = iodobenzenediacetate; g = no reaction;
h = benzoquinone.

K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 3807–3810
3809
Table 2
Intramolecular oxidative amination of olefinic substrates
Entries
Starting
Product
Time (h)
Yielda (%)
NHEt
NEt
1
1.5
95
91
O
N
O
N
Me
1a18
Me
4a19
NHMe
NMe
2
2
O
1b
N
O
4b
N
Me
Me
NHEt
NHMe
NH2
NEt
NMe
NH
3
4
5
1.5
1.5
2
97
95
96
O
O
O
O
O
O
O
1c
4c
O
1d17a
4d
O
O
O
1e17a
O
O
O
O
4e
6
7
2.5
89
91
O
NHMe
NMe
1f
4f
NHEt
Et
N
3
2a
5a
NHMe
NMe
8
3
85
96
2b
5b
O
N
O
H
NH2
N
MeN
MeN
O
9
1.5
O
617c
N
Me
317c
Me
a = isolated yield.
earlier drawbacks and limitations. The protocol has also been uti-
lized for the transformation of 2 and 3 to 5 and 6, respectively.
It has been mentioned earlier that intramolecular oxidative
amination was also achieved by aerobic oxidation.14b,15 The reac-
tions when carried out in air is very slow giving a lower yield of
the product. However, the yield of the reaction can be improved
by passing molecular oxygen into the reaction mixture giving a
60% yield of the N-tosylindole in 16 h14b and in some cases mix-
tures of exo-methylene and internal olefin products were obtained.
It is remarkable that we could achieve 85–97% yield of the internal
olefin products regioselectively by simply using Pd(OAc)2 with IBX
as additives within a much shorter reaction time.
In conclusion, we have developed a novel protocol catalyzed by
palladium (II) under mild conditions using IBX as a reoxidant. By
the successful implementation of this protocol, a variety of pyrrol-
o-fused heterocycles and carbocycles have been prepared in excel-
lent yields from the unactivated olefins. The starting materials for
these reactions can readily be obtained via aza-Claisen rearrange-

3810
K. C. Majumdar et al. / Tetrahedron Letters 51 (2010) 3807–3810
O
EtHN
O
+ H2O
I
IBA
OH
N
O
Me
PdII(OAc)2
1a
O
V
I
+ 2HOAc
O
I
Pd0
HO
IBX
O
NHEt
IV
HOAc
O
N
Me
PdH(OAc)
II
PdOAc
NEt
III
O
N
Me
NEt
NEt
HOAc
4a
O
N
O
N
Me
4a/
Me
Scheme 2. Probable mechanistic pathway of the oxidative cyclization.
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Acknowledgments
We thank the CSIR (New Delhi) and the DST (New Delhi) for
financial assistance and two of us (S.S. and R.K.N.) are grateful to
the CSIR (New Delhi) for their fellowships. We also thank the
DST (New Delhi) for providing Brucker NMR (400 Mz) and
Perkin–Elmer CHN analyzer.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.068.
18. 5-Allyl-6-(ethylamino)-1-methylquinolin-2(1H)-one (1a): This substrate was
prepared according to earlier published procedure.17 Compound 1a obtained
as a solid; mp 102–104 °C; yield 85%. IR (KBr): 3358, 1648, 1304 cmꢀ1 1H
.
NMR(CDCl3, 300 MHz): dH = 1.29 (t, 3H, J = 6.9 Hz, NCH2CH3), 3.21 (q, 2H,
J = 6.9 Hz, NCH2CH3), 3.57 (d, 2H, J = 4.5 Hz, CH2), 3.71 (s, 3H, NCH3), 4.91 (d,
1H, J = 17.1 Hz, @CHaHb), 5.10 (d, 1H, J = 10.2 Hz, @CHaHb), 5.90–6.01 (m, 1H,
@CH), 6.70 (d, 1H, J = 9.9 Hz, C3-H of quinolone), 7.04 (d, 1H, J = 9.3 Hz, ArH),
References and notes
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7.25 (d, 1H, J = 9.3 Hz, ArH), 7.81 (d, 1H, J = 9.9 Hz, C4-H of quinolone) ppm. 13
C
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120.0, 121.7, 133.1, 134.4, 134.8, 141.7, 161.3 ppm. HRMS (ESI): Calcd:
265.1317 (M+Na)+. Found: 265.1317 (M+Na)+.
19. 3-Ethyl-2,6-dimethyl-3H-pyrrolo[3,2-f]quinolin-7(6H)-one (4a): Typical proce-
dure:
A mixture of 1a (100 mg, 0.41 mmol), Pd(OAc)2 (9.2 mg, 10 mol %),
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anhyd Na2CO3 (130.4 mg, 1.23 mmol), and IBX (115 mg, 0.41 mmol) was taken
in dry N,N-dimethylformamide (DMF) (10 mL) and was stirred at 70 °C for
1.5 h. The reaction mixture was cooled, water (20 mL) was added, extracted
with ethyl acetate (3 ꢁ 20 mL), and the ethylacetate extract was washed with
water (4 ꢁ 10 mL), brine (10 mL), dried (Na2SO4), and the solvent was distilled
off to furnish a viscous mass which was purified by column chromatography
over silica gel. Elution of the column with 45% (ethyl acetate/pet) afforded the
product 4a as
a solid; mp 126–128 °C, yield 95%. IR (KBr): 2922, 1643,
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.
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