Pd(OAc)2-catalyzed dehydrogenative C-H activation: An expedient synthesis of uracil-annulated β-carbolinones

Article abstract of DOI:10.3762/bjoc.11.146

An intramolecular dehydrogenative C-H activation enabled an efficient synthesis of an uracil-annulated β-carbolinone ring system. The reaction is simple, efficient and high yielding (85-92%).

Full text of DOI:10.3762/bjoc.11.146

Pd(OAc)2-catalyzed dehydrogenative C–H activation:
An expedient synthesis of uracil-annulated β-carbolinones
Biplab Mondal1, Somjit Hazra1, Tarun K. Panda2 and Brindaban Roy*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1360–1366.
1Department of Chemistry, University of Kalyani, Kalyani,
Nadia-741235, West Bengal, India and 2Department of Chemistry,
Indian Institute of Technology Hyderabad, Ordnance Factory Estate,
Yeddumailaram - 502205, Telangana, India
doi:10.3762/bjoc.11.146
Received: 12 March 2015
Accepted: 24 July 2015
Published: 04 August 2015
Email:
Brindaban Roy* - broybsku@gmail.com
Associate Editor: J. Aubé
* Corresponding author
© 2015 Mondal et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
β-carbolinones; cyclization; dehydrogenative C–H activation;
Pd(OAc)2; uracil
Abstract
An intramolecular dehydrogenative C–H activation enabled an efficient synthesis of an uracil-annulated β-carbolinone ring system.
The reaction is simple, efficient and high yielding (85–92%).
Introduction
The presence of a β-carbolinone skeleton in various natural research on bioenzyme inhibitors, such as the inhibition of HLE
products, such as secofascaplysin A (I), SL651498 (II) (human leukocyte elastase) [15-18].
(Figure 1), and their remarkable biological and pharmacolog-
ical properties make them stand out amongst all the carboline Uracil, on the other hand, is one of the four nucleobases of
class of compounds [1-12]. For example, SL651498 was docu- RNA. It holds immense importance from a pharmaceutical and
mented as a potential drug development candidate in a research
program designed to discover subtype-selective GABAA
receptor agonists for the treatment of muscle spasms and gener-
alized anxiety disorder [13]. β-Carbolinones such as strychno-
carpine, the alkaloid from Alstonia venenata, and substituted
1-oxo-13-carbolines were also shown to have serotonin-
receptor-binding activity (5-HT receptor) [14]. Moreover the
natural and synthetic β-carbolines are also known to show anti-
cancer activity against colon and lung cancers, and some
Figure 1: Naturally occurring β-carbolinones.
β-carbolinones act as biological control agents for receptor
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biological point of view [19]. For example, 5-fluorouracil [20] (Scheme 1). The acids were treated with oxalyl chloride at room
and other uracil-based molecules [21-23] such as 3’-azido-3’- temperature [33] and the resulting acid chloride obtained was
deoxythymidine (AZT), 2’,3’-dideoxycytidine (DDC), (E)-5-[2- transformed to the amide by the reaction with amine 3 in dry
(bromovinyl)-2’-deoxyuridine] (BVDU), are active against THF using NaH as a base.
cancer and the HI virus [24-31].
The amide precursor was then subjected to a series of reactions
Diverse approaches towards the synthesis of β-carbolinones in pursuit of the best reaction conditions for the dehydrogena-
have been developed [32-36], such as an intramolecular Heck tive cross-coupling process. Assuming that the reaction goes
reaction strategy of 2- and 3-iodoindoles for the synthesis of β- through an electrophilic metallation pathway, it was projected
or γ-carbolinones by Beccalli et al. [32], AuCl3 and that Pd(OAc)2 would be an excellent starting point for catalyst
Pd-catalyzed cycloisomerization of indole-2-carboxamides to screening. The amide 4a (R1 = R2 = R3 = R4 = Me) was used as
β-carbolinones [33-35], Pd-catalyzed dehydrogenative annula- a model substrate for this dehydrogenative coupling reaction.
tion of indole-carboxamides with alkynes etc [36]. The develop- The reaction was set up in the presence of Pd(OAc)2
ment of metal-catalyzed C–H activation reaction has revolution- (10 mol %), Cu(OAc)2 (2 equiv) in DMF under open air at
ized the way a synthetic chemist now approaches a traditional 70 °C (Table 1, entry 1). After 8 h we obtained 35% yield of 5a
C–C bond disconnection [32-44]. Dehydrogenative C–H acti- with 52% conversion of starting material. Increasing the
vation [45-52] is the most elegant alternative in this endeavor as temperature to 90 °C (Table 1, entry 2) afforded 63% yield of
it avoids pre-functionalization of any C–H bond beforehand. 5a with 80% conversion of 4a. Then different oxidants
But regioselectivity is the main problem in this type of reaction [Cu(OTf)2, PhI(OAc)2, K2S2O8, (NH4)2S2O8, p-benzoquinone
due to the ubiquitous presence of various C–H bonds in a (BQ), oxone, AgOAc, molecular oxygen] were examined under
simple organic molecule. However, sometimes the issue of these reaction conditions. With Cu(OTf)2 (Table 1, entry 3) and
regioselectivity can be resolved by the electronic property of the oxone (Table 1, entry 8), total recovery of starting material was
substrate itself. Pioneering work published by Fagnou et al. observed while PhI(OAc)2 (Table 1, entry 4), (NH4)2S2O8
shows how a catalyst inverts its selectivity and reactivity (Table 1, entry 6) showed total decomposition of starting ma-
between the coupling partners to achieve indole C3-arylation in terial. With BQ the yield was almost the same (65%) as with
a cross coupling reaction of an unactivated arene and Cu(OAc)2 (Table 1, entry 7). The use of K2S2O8 increased the
N-acetylindole [53]. Driven by the same logic and guided by yield of 5a to 83% (Table 1, entry 5) with complete conversion
our previous work we envisioned that an intramolecular dehy- of starting material; AgOAc further increased the yield to 91%
drogenative cross coupling reaction could be achievable (Table 1, entry 9). Molecular oxygen also used as an oxidant
between the electron deficient uracil C6–H bond adjacent to the resulted in a low 30% yield of 5a (Table 1, entry 10) with 51%
nitogen atom and the electron rich indole C3–H bond for the conversion of 4a. Examination of different solvents led to deter-
synthesis of uracil annulated β-carbolinones [54-56]. Herein, we mining that the polar solvents (DMF/DMSO (9:1), DMSO,
report our novel approach towards the synthesis of uracil annu- DMAc, Table 1, entries 11, 12, 13) were far superior compared
lated β-carbolinones via an intramolecular dehydrogenative to non-polar solvent toluene (Table 1, entry 14). But the optimal
coupling reaction of indole-2-carboxamides.
result was obtained with the use of DMF (Table 1, entry 9).
Testing the efficiency of other Pd catalysts for this reaction
revealed that Pd2dba3, i.e., Pd(0) did not show any catalytic
Results and Discussion
We started our investigation with the preparation of amide activity (Table 1, entry 17). The yield decreased sharply for
precursors 4 from N-substituted indole-2-carboxylic acids 1 other Pd catalysts such as PdCl2, Pd(CH3CN)2Cl2 and
Scheme 1: Preparation of starting substrate.
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Table 1: Optimization of intramolecular dehydrogenative coupling.
Entry
Catalyst
Oxidant
Solvent
Temp (°C)
Conversion (%)a
Yield (%)b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
PhI(OAc)2
K2S2O8
(NH4)2S2O8
BQ
DMF
70
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
52
80
0
35
63
0
2
DMF
3
DMF
4
DMF
0
0
5
DMF
100
0
83
0
6
DMF
7
DMF
78
0
65
0
8
oxone
DMF
9
AgOAc
O2
DMF
100
51
100
100
100
40
83
70
0
91
30
82
78
80
30
52
35
0
10
11
12
13
14
15
16
17
18
DMF
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
DMF/DMSO (9:1)
DMSO
DMAc
toluene
DMF
Pd(CH3CN)2Cl2
Pd2(dba)3
Pd(PPh3)2Cl2
DMF
DMF
DMF
40
32
All reactions were performed with 1 equiv starting material (4), 10 mol % Pd-catalyst, 2 equiv oxidant in 5 mL solvent at mentioned tempetature, 8 h
under open air. aCalculation on the basis of isolation of starting material. bIsolated yield.
Pd(PPh3)2Cl2 presumably be due to the less electrophilic nature
of these catalysts (Table 1, entries 15, 16, 18).
With the optimized reaction conditions in hand (10 mol %
Pd(OAc)2, 2 equiv AgOAc in DMF at 90 °C for 8 h), we further
explored the substrate scope of the reaction (Scheme 2).
All the reactions went very smoothly giving excellent yields in
the range of (85–92%). No distinct steric influence was noticed
when the indole-N-methyl group was replaced by ethyl, butyl or
benzyl groups. However, the reaction did not proceed at all with
the unsubstituted indole precursor (R1 = H, 4m), this result may
be explained with potential coordination of the Pd catalyst
between the indole nitrogen and amide carbonyl oxygen. A
representative X-ray crystal structure of β-carbolinone deriva-
Figure 2: ORTEP diagram of 5h.
tive 5h was obtained [57] (Figure 2).
The inactivity of Pd(0) (Table 1, entry 17), and inferior reactiv- the indole C3 postion. The nucleophilicity of indole at C3 is
ity of other less electrophilic Pd catalysts indicates a mecha- well known [58] and a similar kind of electrophilic reaction
nistic pathway that commence with electrophilic metalation at leads to the intermediate A (Scheme 3). We believe this inter-
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Scheme 2: Synthesis of various β-carbolinone derivatives.
mediate then undergoes a σ-bond metathesis reaction to form a Conclusion
seven membered palladacycle B which in turn produces the In conclusion we have developed an elegant method for the
product β-carbolinones after reductive elimination from the preparation of uracil annulated β-carbolinones via a high
7-membered palladacycle B. The catalytic cycle is completed yielding dehydrogenative C–H activation process. The
by AgOAc.
key to the success of this reaction is the complementary elec-
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Beilstein J. Org. Chem. 2015, 11, 1360–1366.
Scheme 3: Proposed mechanistic pathway.
tronic properties of the indole C3–H bond and the uracil C6–H Acknowledgements
bond. It is anticipated this efficient and atom economic ap- We thank DST (New Delhi, India) for financial assistance
proach can be emulated for the preparation of other β-carboli- through the DST-PURSE programme, DST fast track scheme,
nones as well, and further results in this regard will be reported UGC-SAP programme and University of Kalyani. B.M. & S.H.
in due course.
are thankful to University of Kalyani and CSIR (New Delhi,
India) respectively for research fellowships. We also thank DST
(New Delhi, India) for providing NMR (400 MHz) and mass
Experimental
Representative procedure for the preparation of uracil annu- spectrometer instruments.
lated β-carbolinones (5a–m):
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