Palladium (II)-catalysed intramolecular C–H functionalizations: Efficient synthesis of kealiinine C and analogues

Article abstract of DOI:10.1016/j.mcat.2018.06.007

An efficient palladium-catalysed C–H functionalization sequence has been developed for the synthesis of 2-aminoimidazole alkaloids (Kealiinine C) and its analogues. This protocol proceeds via iodocyclisation of propargylguanidines followed by intramolecul

Full text of DOI:10.1016/j.mcat.2018.06.007

MolecularCatalysis455(2018)233–238
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Palladium (II)-catalysed intramolecular CeH functionalizations: Efficient
synthesis of kealiinine C and analogues
Debasmita Sahaa,c,1, Izabela Stolarzewicza,1, Vijay Bahadura,b, Upendra K. Sharmaa,⁎⁎
,
⁎
Leonid G. Voskressenskyd, Anuj Sharmac, Brajendra K. Singhb, Erik V. Van der Eyckena,d,
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven,
Belgium
b
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India
Medicinal Chemistry Lab, Department of Chemistry, Indian Institute of Technology Roorkee, Uttarakhand, 247667, India
Peoples Friendship University of Russia (RUDN University) Miklukho-Maklaya Street 6, 117198 Moscow, Russia
c
d
A R T I C L E I N F O
A B S T R A C T
Keywords:
Kealiinines
2-aminoimidazoles
CeH functionalization
Guanylation
An efficient palladium-catalysed CeH functionalization sequence has been developed for the synthesis of 2-
aminoimidazole alkaloids (Kealiinine C) and its analogues. This protocol proceeds via iodocyclisation of pro-
pargylguanidines followed by intramolecular Pd-catalysed cyclisation.
Iodocyclization
1. Introduction
and its hydrogenation provided the final kealiinine framework [12].
Simultaneously, Looper et al. reported the synthesis of kealiinines B and
The potential benefits of maneuvering an inert CeH bond have been
repeatedly discussed over the years and is a challenging and intensive
topic of research [1]. The significance of such direct transformation of
CeH bonds is exemplified by their incorporation into the synthesis of
complex molecules from their desired CeH precursors [2–4]. As a re-
sult, such strategies have made revolutionary accomplishments towards
the total synthesis of natural products [5].
2-Amino imidazole alkaloids isolated from the sponges of Leucetta
and Clathrina families exhibit a range of biological activities namely
human β-secretase (BACE-1) inhibitors and tubulin-binding agents
[6,7]. A subgroup of these alkaloids containing a naphthimidazole
moiety viz. kealiiquinone I and its 2-amino congener (2-amino-2-
deoxykealiiquinone II) were reported to possess cytotoxic and antic-
ancer activities (Fig. 1) [8,9]. Moreover, naturally occurring analogues
of kealiiquinone and the kealiinines were isolated and suggested to
serve as biosynthetic precursors of I and II.
C via an electrophilic activation/cyclization sequence of the ene-gua-
nidine intermediate with NBS [13].
In 2010, our group has synthesized polysubstituted 2-aminoimida-
zoles by a Ag-mediated guanylation–cyclization protocol [14] followed
by a metal free, phenyliodonium diacetate (PIDA) mediated oxidative
cascade cyclization of propargylguanidines to obtain the kealiinine
framework [15]. Broadening our existing methodologies, we herein
report a transition metal catalyzed CeH activation sequence for the
synthesis of kealiinine C and analogues. It was envisioned that iodo-
cyclisation of guanylated propargylamines followed by an in-
tramolecular Pd-catalyzed cyclisation might be a suitable alternative
(Scheme 1).
2. Experimental
2.1. Materials
Over the past years, the total synthesis of kealiinine alkaloids [10]
have been reported by Lovely and co-workers [11]. They organized the
All the starting materials, reagents and catalysts were purchased
from Sigma-Aldrich or Acros or TCI Europe and used as such. For thin
layer chromatography, analytical TLC plates (Alugram SIL G/UV254
and 70–230 mesh silica gel (E. M. Merck) were used). Column
synthesis of kealiinine A-C, through
a series of position-specific
Grignard reactions followed by an intramolecular Friedel-Crafts-dehy-
dration sequence of the formed bis benzylic diol. Further, C2-azidation
⁎
Corresponding author at: Peoples Friendship University of Russia (RUDN University) Miklukho-Maklaya Street 6, 117198 Moscow, Russia.
Corresponding author.
⁎⁎
E-mail addresses: usharma81@gmail.com (U.K. Sharma), erik.vandereycken@kuleuven.be (E.V. Van der Eycken).
Equal contribution by both authors.
1
https://doi.org/10.1016/j.mcat.2018.06.007
Received 24 April 2018; Received in revised form 4 June 2018; Accepted 5 June 2018
2468-8231/©2018ElsevierB.V.Allrightsreserved.

D. Saha et al.
MolecularCatalysis455(2018)233–238
Fig. 1. Structures of kealiinine family analogues.
Scheme 1. Plausible retrosynthetic strategy.
chromatography was performed using silica gel (Merck, 60–120 mesh
size). Anhydrous solvents were purchased from Acros Organics and
stored over molecular sieves. The chromatographic solvents used for
isolation/purification of compounds were distilled prior to use. The
chromatographic solvents are mentioned as volume: volume ratios.
Microwave reactions were typically run in microwave CEM-Discover or
oven dried screw-cap vials.
2.3. Synthesis of intermediates and deprotection
Synthesis of iodocyclised propargylguanidines (9) as well as the
synthesis of kealiinine C and analogues (Boc-deprotection) is described
in supporting information in details via the reported procedures and has
been mentioned in the Scheme 2.
2.4. General procedure for palladium–catalysed CeH activation step
2.2. Apparatus
To a reaction vial were added, iodocyclized compound (0.04 mmol),
palladium acetate (10 mol %), Cs2CO3 (1.5 equiv.), pivalic acid (30 mol
%) and triphenyl phosphine (20 mol %) in anhydrous chlorobenzene
(1.0 mL). The mixture was degassed with N2. The reaction vessel was
sealed and heated at 120 °C for 24 h. Then the mixture was diluted with
EtOAc (5 ml) and washed with water (2 × 3 mL), dried over Na2SO4
and concentrated on rotary evaporator gave the crude product. Elution
of the column with 35% ethyl acetate/heptane mixture gave the desired
product as solid which was confirmed by 1H and 13C NMR spectroscopy.
1H and 13C NMR spectra were recorded on a 300 and 400 MHz in-
strument using CDCl3/DMSO as a solvent. The 1H and 13C chemical
shifts are reported in parts per million relative to tetramethylsilane
(TMS) using the residual solvent signal as the internal reference. The
following abbreviations were used to designate chemical shift multi-
plicities: s = singlet, bs = broad singlet, d = doublet, dd = double
doublet, q = quartet, t = triplet, m = multiplet. The 13C NMR spectra
are proton decoupled. The melting points were determined on a digital
Barnsted Electrothermal 9200 apparatus and are uncorrected. Mass
spectra were recorded by using a Kratos MS50TC and a Kratos Mach III
system. The ion source temperature was 150–250 °C, as required. High
resolution EI-mass spectra were performed with a resolution of 10,000.
The low-resolution spectra were obtained with a HP5989 A MS instru-
ment. The low resolution ESI-MS were obtained with a Thermo
Scientific instrument.
2.5. Characterization of the products
All compounds were fully characterized with 1H and 13C NMR,
melting points and HR-MS analysis. The detailed synthetic procedures,
spectral characterization of the compounds, as well as the NMR spectra
can be found in the supplementary material.
234

D. Saha et al.
MolecularCatalysis455(2018)233–238
Scheme 2. Synthetic strategy towards 9a.
Reagents and conditions : a) CH3OCH2PPh3Cl,
(1.5 equiv), tBuOK (2.5 equiv), THF, rt, 12 h; b)
TFA:H2O (1:1), DCM, rt, 12 h; c) CuBr (20 mol
%), toluene, MW (100 °C, 1 h); d) Pd(PPh3)4
(5 mol%), DMBA (1.5 equiv), DCM, reflux, 6 h;
e) DBTU (1.5 equiv), DIPEA (3 equiv), EDCl (2
equiv), DCM, rt, 8 h; f) I2 (2 equiv), K2CO3,
DCM, rt, 5 h.
Table 1
Optimization of reaction conditions.a
Entry
Catalyst
Ligand
Additive
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
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
Pd(OAc)2(PPh3)2
Pd(dba)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
–
–
–
–
–
–
–
–
–
–
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOAc
TEA
Toluene
CH3CN
MeOH
DMSO
Chlorobenzene
DMF
26
nd
nd
13
46
nd
nd
nd
17
nd
nd
nd
62
nd
nd
nd
nd
38
30
31
nd
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
9
K2CO3
DABCO
K3PO4
10
11
12
13
14
15
16
17
18
19
20
21
DIPEA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PPh3
Davephos
P(o-tolyl)3
CyJohnPhos
P(tBu)3
a
All reactions were run with 1a (0.04 mmol), catalyst (10 mol%), ligand (20 mol%), additive (30 mol%), base (1.5 equiv) in the indicated solvent (1.0 mL) at
120 °C for 24 h under nitrogen atmosphere in a closed vessel.
b
isolated yields.
3. Result and discussion
chemistry earlier described by our group [14]. It was initiated with a Cu
(I)-catalyzed three-component iminium acetylide addition (A3-cou-
pling) of 4-ethynylanisole, N-methylallylamine and the aryl
The required substrate, propargylguanidine 8a was synthesized via
235

D. Saha et al.
MolecularCatalysis455(2018)233–238
Table 2
Follow-up reactions with Pd catalysts other than Pd(OAc)2 such as
PdCl2, Pd(OAc)2(PPh3)2, Pd(dba)2 and Pd(PPh3)4 did not deliver the
desired product (Table 1, entries 14-17). Further altering the ligands,
for instance, Davephos, P(o-totyl)3 and CyJohnphos, yielded 38%, 30%
and 31% of the required product respectively, whereas P(tBu)3 did not
form any product (Table 1, entries 18-21). This revealed that only tri-
phenylphosphine provided the best yield of the desired product
(Table 1, entry 13). Also, performing the reaction at lower temperatures
(50 °C, 100 °C) or longer duration did not result in any improvements in
the yields (Table 2, entries 1-3). Moreover, reaction was also performed
under microwave conditions at 120 °C for 1 h but the alternative de-
halogenated product was obtained as the major product (Table 2, en-
tries 4). Further varying the molar ratio of catalyst, ligand, additive and
base ascertain that the use of 10 mol% of Pd(OAc)2, 20 mol% of PPh3,
30 mol% of pivalic acid and 1.5 equiv of Cs2CO3 provided the best
yields of the desired product 10a (Table 2, entries 5-9). The structure of
10a was confirmed by 1H and 13C NMR analysis as well as mass spec-
trometry.
To check the capacity of the CeH activation cyclisation step, we
decided to prepare other analogues of the kealiinine family (Scheme 3,
10b-10e). Their syntheses follow the similar strategy by simply sub-
stituting the appropriate benzaldehyde, alkyne or amine in the A3-
coupling step. It was found that the conditions are specific for tri-
methoxy benzaldehyde only, as in case the di-methoxy benzaldehyde,
only the de-halogenated product was obtained as the major one instead
of the desired cyclised product. However, when the aryl substituent on
the alkyne part was an electron-deficient (eF) or an electron-donating
(eCH3), the cyclised product was obtained in good to moderate yields
(Scheme 3: 10b, 62%; 10c, 58%; 10d, 64%).
Altering the standard conditions.a
Entry
Catalyst
Ligand
Additive
Base
Solvent
Yield (%)b
Effect of time, temperature and microwave irradiation
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PivOH
PivOH
PivOH
PivOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
ndc
21d
61e
ndf
Change in molar equivalents
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PivOH
PivOH
PivOH
PivOH
PivOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
40g
21h
24i
30j
34k
a
All reactions were run with 1a (0.04 mmol) under nitrogen atmosphere in a
closed vessel.
b
isolated yields.
at 50 °C.
at 100 °C.
reaction time 48 h.
microwave irradiation at 120 °C for 1 h.
Pd(OAc)2 5 mol%.
Pd(OAc)2 20 mol%.
PPh3 10 mol%.
c
d
e
f
g
h
i
j
PivOH 20 mol%.
Cs2CO3 (2 equiv).
k
acetaldehydes (obtained via Wittig reaction) (Scheme 2). Further
deallylation of these intermediates with Pd(PPh3)4 and N,N-di-
methylbarbituric acid (DMBA) provided the secondary propargyla-
mines 7a. Guanylation of these intermediates with bis Boc protected
isothiourea and base yielded the propargylguanidines 8a in good yield.
For investigation of our intramolecular cyclization studies, we se-
lected kealiinine C as our prime target, thereby avoiding regioselec-
tivity issues to assemble the naphthimidazole system. For the rapid and
efficient construction of the kealiinine ring structure, we initiated our
investigations by exploring the intramolecular cyclization of iodocy-
clised propargylguanidines 9a under Pd(II)-catalysis in the presence of
PPh3 as ligand and Cs2CO3 as the base in various solvents such as to-
luene, CH3CN, MeOH, DMSO, chlorobenzene and DMF and by heating
the reaction at 120 °C for 24 h (Table 1, entries 1-6). Among all,
chlorobenzene proved to be the best choice, affording the cyclised
product 10a in 46% yield (Table 1, entry 5). The de-halogenated pro-
duct 10a' has been the obvious major product in most of the cases. To
direct the reaction towards intramolecular cyclization, a toolbox of
bases, catalysts, ligands and additives were tested.
As per the earlier reports, the mechanistic details of the CeH acti-
vation step can be explained with initial oxidative addition of the io-
docyclised compound 9a on a ligated Pd(0)-species to generate the Pd
(II)-complex A. This is followed by a base-assisted formation of pivalate
which on coordination to the Pd(II)-center generates intermediate B.
This acts as a proton shuttle within concerted metalation-deprotonation
(CMD) transition state C to form intermediate D. Finally, a reductive
elimination of the intermediate D will lead to the desired kealiinine
framework and regenerates the Pd(0) species which enters into the next
catalytic cycle (Scheme 4).
Next, we carried out the deprotection of the cyclized product 10a
upon treatment with a 1:1 mixture of TFA:DCM to afford fully ar-
omatized kealiinine C 11a upon oxidation in good yields along with
other analogues (Scheme 5, 11b-11d).
Accordingly, varying the base such as NaOAc, Et3N, K2CO3, DABCO,
K3PO4 and DIPEA (Table 1, entries 7-12), it was found that, none of
them succeeded in providing the desired product except K2CO3 in 17%
yield (Table 1, entry 9). However, the yield of the isolated product was
surprisingly increased to 62% by performing the reaction in the pre-
sence of pivalic acid as an additive (30 mol%) indicating that the re-
action might be going through a concerted metalation deprotonation
(CMD) pathway (Table 1, entry 11-13).
4. Conclusions
In summary, we have developed a palladium-catalysed CeH func-
tionalization protocol to obtain the tricyclic kealiinine framework in
moderate to good yields. The total syntheses of kealiinine C and its
analogues was accomplished in a concise way with moderate to good
yields.
Scheme 3. Scope of the C–H activation step.
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D. Saha et al.
MolecularCatalysis455(2018)233–238
Scheme 4. Proposed mechanistic pathway for the C–H activation step.
Scheme 5. Synthesis of kealiinine analogues.
237

D. Saha et al.
MolecularCatalysis455(2018)233–238
Acknowlegdements
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DS and UKS are thankful to the University of Leuven (KU Leuven)
for a postdoctoral fellowship and research associateship respectively.
VB is thankful to the Erasmus Mundus Expert III consortium for ob-
taining a visiting scholarship for the stay in KU Leuven. The authors
wish to thank the FWO [Fund for Scientific Research-Flanders
(Belgium)] and the Research Fund of the University of Leuven (KU
Leuven) for financial support. The publication was prepared with the
support of the “RUDN University Program 5-100”.
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Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2018.06.007.
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