Pd(II)-Catalyzed [4 + 2] Heterocyclization Sequence for Polyheterocycle Generation

Article abstract of DOI:10.1021/acs.orglett.8b02543

A new Pd(II)-catalyzed cascade sequence for the formation of polyheterocycles, from simple starting materials, is reported. The sequence is applicable to both indole and pyrrole substrates, and a range of substituents are tolerated. The reaction is thought to proceed by a Pd(II)-catalyzed C-H activated Heck reaction followed by a second Pd(II)-catalyzed aza-Wacker reaction with two Cu(II)-mediated Pd(0) turnovers per sequence. The sequence can be considered a formal [4 + 2] heterocyclization.

Full text of DOI:10.1021/acs.orglett.8b02543

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd(II)-Catalyzed [4 + 2] Heterocyclization Sequence for
Polyheterocycle Generation
Elizabeth L. Glaisyer, Michael S. Watt, and Kevin I. Booker-Milburn*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: A new Pd(II)-catalyzed cascade sequence for the formation of
polyheterocycles, from simple starting materials, is reported. The sequence is
applicable to both indole and pyrrole substrates, and a range of substituents
are tolerated. The reaction is thought to proceed by a Pd(II)-catalyzed C−H
activated Heck reaction followed by a second Pd(II)-catalyzed aza-Wacker
reaction with two Cu(II)-mediated Pd(0) turnovers per sequence. The
sequence can be considered a formal [4 + 2] heterocyclization.
simple heterocyclic tethered alkenes by way of a novel C−H
olyheterocycles are commonly found in a wide range of
1
2
Pmolecules as privileged structures in drug discovery, in activated Heck/aza-Wacker sequence (Scheme 1B).
the cores of many natural products,3 synthetic dyes4 and
While investigating the first step of the mechanism involved
with reaction of 1, and related processes with dienes, we
organic light-emitting diodes (OLEDs).5 It is important
synthesized the simple alkenyl-tethered indole carboxylate 4 (R
= Ts). It was assumed that the straightforward oxidative Heck
cyclized product 5 (R = Ts) would be obtained as no π-allyl
intermediate would be formed (cf. 2) and the reaction would
therefore proceed by β-hydride elimination to 5. However,
when 4 (R = Ts) was subjected to the cyclization conditions
using 10 mol % of Pd(OAc)2 and 2.5 equiv of Cu(OAc)2 as an
oxidant the cascade product 6 (R = Ts) was observed in 25%
yield. It was proposed that this was due to the putative Heck
intermediate 5 (R = Ts) undergoing an adventitious Pd(II)-
catalyzed aza-Wacker-type reaction with the CONHTs group.
Previous studies10 have demonstrated cascade reactions of O-
hydroxamic acid ethers under Rh(III) catalysis. Here, the
preformed N−O bond served as an internal oxidant for the
Rh(I) redox cycle. In our case, with Pd(II)/Cu(II), the
formation of the cascade product 6 was a very surprising result
and was therefore explored further as an attractive proposition
for replacing synthetically demanding dienes with simple
alkenes in these cascade processes.
therefore that efficient new methodologies for the construction
of such structures are developed to aid advances in medicines
and materials. In recent years, there has been intense activity in
the development of new transition-metal-catalyzed C−H
activation reactions6 due to their potential to reduce step
count and waste generated by conventional cross-coupling
reactions involving aryl halides. The use of such direct
reactions in a cascade sequence allows complex drug- and
natural product-like molecules to be constructed rapidly from
simple starting materials.7 We have previously shown that an
indole or pyrrole core bearing an N-tethered diene 1 can, by
way of Heck cyclization, be used to generate π-allyl
intermediates such as 2, which in turn can be trapped by a
variety of internal heterocyclic nucleophiles (Scheme 1A).8
This work was later extended by switching the heterocyclic
nucleophile to an internal heteroatom nucleophile, forming
diaza-heterocyclic systems.9 Herein, we describe how complex
polyheterocyles such as 6 can be assembled in one step from
Preliminary optimization studies (Table 1) saw an increase
in yield from 25% to 50% on increasing the equivalence of
K2CO3 to 2.5 equiv with both Pd(OAc)2 and Pd(TFA)2
(Table 1, entries 1−3). The tosylamide product 6a proved
to be insoluble in common laboratory solvents, hindering
purification and analysis, and so a change in directing group
(R) was investigated. The N-benzoyl amide substrate 4b was
surprisingly unreactive when subjected to the cyclization
conditions, and no product 6b was observed (Table 1, entry
4). This result suggests that N−H pKa was an important factor,
and so the N-mesylamide 4c was also evaluated, as this should
have similar electronic properties to 4a. Pleasingly, this
Scheme 1. Generation of Complex Polycyclic Heterocycles
via Pd(II)-Catalyzed Cascade Sequences8,9
Received: August 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02543
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Preliminary Optimization Studies
Scheme 3. Pd(II)-Catalyzed C−H-Activated Heck/aza-
Wacker Cascade Reactions of Indoles
entry
catalyst
base equiv
product
yield (%)
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
1
6a
6a
6a
6b
6c
25
50
50
0
2.5
2.5
2.5
2.5
52
performed equally well to the N-tosylamide 4a, giving the
much more soluble 6c in 52% yield (Table 1, entry 4).
Further optimization of this reaction by a traditional iterative
approach proved frustrating, as yields remained at the 50%
mark. We therefore embarked on a basic design of experiments
(DoE) study to identify the optimum conditions. The use of
DoE has become increasingly important over recent years due
to its ability to derive expansive information on reaction
conditions from a condensed subset of defined experiments.11
Using MODDE software, 7 variables were chosen, and (using a
linear model) 22 experiments were run, including three center
points (see Supporting Information (SI) for details). It was
found that the type of catalyst used was the most significant
factor, with Pd(OAc)2 giving the best results. It was also found
that a higher temperature and a higher catalyst loading were
beneficial, whereas a larger excess of base had a negative effect.
The optimum conditions (A, Scheme 2) from the DoE study
Scheme 2. Results of Optimization Studies Using DoE and
Additives
Conversely, gem-dimethyl substitution at the carbon adjacent
to the alkene was significantly detrimental to the yield of 8c.
This could be a result of the change in direction of β-hydride
elimination (see Scheme 5) or due to steric effects. A
surprising result was observed when a methyl group was
added to the terminal position of the alkene (7d), where
instead of the usual [6,6] ring formation the [6,7] product 8d
was observed (see Scheme 5).
Phenyl substitution at the terminal alkene carbon gave the
expected alkene product 8e in good yield. For the cascade
methodologies developed previously, extension of the chain to
enable 7-membered ring formation proved unsuccessful.8,9 It
was pleasing therefore to observe the formation of 8f in
moderate yield.
Substitution of the indole ring was also investigated
(Scheme 3, examples 8g−o). The reaction showed little
preference for either electron-rich or electron-poor groups. For
example, substituents at positions 4, 5, and 6 were all well
tolerated (8g−m) and included halide (8i,m), nitrile (8j), and
ether (8h,l) groups. Substitution at the 7-position was less
successful (8n), although this was likely due to the high
insolubility of the nitro substrate 7n. It was expected that the
7-aza indole 7o would perform poorly due to the basic pyridine
nitrogen and its potential ability to act as a deactivating ligand,
but pleasingly even this cascade sequence proceeded to give
novel heterocycle 8o in 58% yield.
were as follows: Pd(OAc)2 (20 mol %), AgOAc (4 equiv),
K2CO3 (2 equiv). Unfortunately, these conditions have clear
limitations, such as the high catalyst loading and large excess of
expensive AgOAc oxidant required. There are many literature
precedents from Yu on the use of mono N-protected amino
acids12 and other organic acids13 as additives for C−H
activation methodology. Inspired by this, an additional screen
of organic acids was undertaken using the optimized DoE
results, yielding further improvements in the experimental
procedure. Although a number of acids yielded positive results
(see SI), ultimately PivOH (30 mol %) was chosen as the most
readily available of the additives. Equally importantly this
allowed for a lower Pd loading (10 mol %) and use of 3 equiv
of Cu(OAc)2 in place of AgOAc (conditions B, Scheme 2).
With these optimized conditions in hand, the scope of the
reaction was investigated. Initially, we explored substitution of
the alkene and carbon chain of the starting substrate (Scheme
3, 8a−f). Chain branching was well tolerated and gave the
methyl isomers 8a,b in similar yields to the parent compound.
The scope of this methodology was expanded further by
switching from an indole substrate to a pyrrole substrate
(Scheme 4). Unfortunately, the yields for these systems were
B
DOI: 10.1021/acs.orglett.8b02543
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Pd(II)-Catalyzed C−H-Activated Heck/aza-
Wacker Cascade Reactions of Pyrroles
Scheme 5. Proposed Mechanism for the C−H-Activated
Heck/aza-Wacker Sequence
less than that seen for indoles. It is thought that this is due to a
lower catalytic turnover. We were however able to synthesize a
range of such compounds and demonstrate the tolerance to
substitution at both the 4 and 5 positions of the pyrrole ring
(9b−f). Moderate yields were obtained for all pyrrole
cyclizations, although these substrates/products all appeared
to be more sensitive to decomposition under the reaction
conditions.
A plausible mechanistic description of this complex cascade
is presented in Scheme 5. Initially, 4c undergoes base-catalyzed
N-metalation with Pd(II)Ln (I), followed by directed C−H
activation of the indole C2 (II).9 Cyclization of 12 by
carbometalation (III) followed by β-hydride elimination (IV)
gives 14. Redox with Cu(II) then regenerates the active
Pd(II)Ln species (V). Intermediate 14 then enters the second
catalytic cycle involving base-catalyzed N-metalation (VI) and
amino-palladation (VII/VIII) to 17, which after β-hydride
elimination (IX) gives product 6c and Pd(0)Ln which can
enter a second redox cycle with Cu(II). Stahl14 has undertaken
a number of elegant studies supporting a syn-amino palladation
mechanism for such aza-Wacker processes.
This double catalytic cycle is supported by a number of
experimental observations. First, the reaction requires at least 2
equiv of Cu(II) oxidant, thus providing evidence of two
palladium turnovers per cascade sequence. Further methylation
of the N-mesylamide results in a substrate 18 that is inert to
the reaction conditions (100% starting material recovered),
indicating that the first step I involves metalation of the N-
mesylamide. We were able to prepare the proposed
intermediate 19 (as tosylamidesee SI), and when subjected
to reaction conditions B, we obtained the product 6c in 83%
yield, thus strongly supporting its role as an intermediate in the
cascade sequence. Finally, the interesting 7-membered ring
formation when the methyl substrate 7d was used is likely a
result of the cyclized Pd species 20 undergoing an entropically
more favored elimination to the terminal alkene 21 followed by
a 7-endo aza-Wacker cyclization to 8d.
Current work is underway to extend the methodology to
nonaromatic scaffolds, which could serve as a key step toward
the total synthesis of naturally occurring alkaloids and potential
drug discovery scaffolds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02543.
Experimental procedures and spectroscopic data (PDF)
In conclusion, we have developed a novel Pd(II)-catalyzed
sequence for the rapid formation of polyheterocycles from
simple substrates in a cascade procedure that can be
considered a [4 + 2] heterocyclization. Evidence has been
presented to suggest that the overall sequence proceeds by a
C−H activated, oxidative Heck cyclization followed by an aza-
Wacker cyclization. The reaction has been shown to be
tolerant of a range of substitutions on both the carbon chain
and heterocyclic core and works for both substituted indoles
and pyrroles.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: k.booker-milburn@bristol.ac.uk.
ORCID
Kevin I. Booker-Milburn: 0000-0001-6789-6882
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b02543
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Int. Ed. 2013, 52, 1245−1247. (e) Engle, K. M.; Wang, D.-H.; Yu, J.-
Q. J. Am. Chem. Soc. 2010, 132, 14137−14151.
ACKNOWLEDGMENTS
■
We thank the EPSRC Bristol Chemical Synthesis Doctoral
Training Centre (EP/G036764/1) for PhD studentship
funding to ELG and MSW.
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DOI: 10.1021/acs.orglett.8b02543
Org. Lett. XXXX, XXX, XXX−XXX