Catalytic Isohypsic-Redox Sequences for the Rapid Generation of Csp3-Containing Heterocycles

Article abstract of DOI:10.1002/chem.201804131

Cross-coupling reactions catalyzed by transition metals are among the most influential in modern synthetic chemistry. The vast majority of transition-metal-catalyzed cross-couplings rely on a catalytic cycle involving alternating oxidation and reduction o

Full text of DOI:10.1002/chem.201804131

A Journal of
Accepted Article
Title: Catalytic Isohypsic-Redox Sequences for the rapid generation of
Csp3-containing heterocycles
Authors: Craig D Smith, David Phillips, Alina Tirla, and David J France
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To be cited as: Chem. Eur. J. 10.1002/chem.201804131
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Catalytic Isohypsic–Redox Sequences for the rapid generation of
sp3-containing heterocycles
C
Craig D. Smith, David Phillips, Alina Tirla, and David J. France*[a]
7
Abstract: Cross-coupling reactions catalyzed by transition metals are
among the most influential in modern synthetic chemistry. The vast
majority of transition metal catalyzed cross-couplings rely on a
catalytic cycle involving alternating oxidation and reduction of the
metal center and are generally limited to forging just one type of new
bond per reaction (e.g. the biaryl linkage formed during a Suzuki
cross-coupling). Here we present an Isohypsic–Redox Sequence
reactions of -diazocarbonyls), and the chain propagation phase
of metal-catalyzed alkene polymerization.8
,9
The preference for redox-active catalytic cycles is
maintained in the wide field of Pd-catalyzed fine chemical
synthesis. Most processes occur by some variant of the well-
known iterative sequence of oxidative addition, transmetallation,
and reductive elimination. Nevertheless, many isohypsic Pd-
catalyzed processes are known, such as the addition of
organoboronates to activated -bonds,10 cycloisomerization
(IRS) that uses one metal to effect two catalytic cycles, thereby
generating multiple new types of bonds from a single catalyst source.
We show that the IRS strategy is amenable to several widely used
transformations including the Suzuki–Miyaura coupling, Buchwald–
Hartwig amination, and Wacker oxidation. Furthermore, each of these
reactions generates value-added heterocycles with significant sp3-C
1
1
processes that terminate by protonation or -halide elimination,
allylic rearrangements of esters or imidates,12 and the halo-
allylation of alkynes,13 among others.14
The mechanistic distinction between redox-active and
isohypsic catalysis carries an important consequence from a
synthetic perspective, namely that functionality that is inert to the
metal oxidation state present in the isohypsic process (such as
the aryl halides typically involved in oxidative addition to Pd )
should be tolerated during an isohypsic reaction at a different
(3-dimensional) content. Our results provide a general framework for
generating complex products by using a single metal to fulfill multiple
roles. By uniting different combinations of reactions in the isohypsic
and redox phases of the process, this type of catalytic multiple bond-
forming platform has the potential for wide applicability in the efficient
synthesis of functional organic molecules.
0
II
oxidation state (e.g. Pd ). Subsequent alteration of the metal
oxidation state (for example by the addition of a new reagent)
allows for a second catalytic bond formation to occur using the
same metal (Fig. 1).
Transition metal catalysis is among the most common strategies
in organic synthesis for the formation of C–C and C–X bonds.1
The vast majority of organometallic reactions rely on a single
This type of transition from isohypsic to redox manifolds is
an example of assisted tandem catalysis where one precatalyst
effects two distinct catalytic processes using sequential reagent
2
catalytic cycle to generate one new bond. Although the power of
transition metal catalysis to effect previously unknown reactions
has proved to be tremendously enabling, this “one reaction–one
bond” limitation fails to maximize the complexity of the products
generated using these methods. Catalytic multiple bond-forming
strategies carry vast potential to impact the “economies of
synthesis” through the rapid evolution of molecular complexity.3
We set out to develop a multiple bond-forming reaction sequence
that would use a single metal to effect multiple catalytic cycles by
uniting an isohypsic reaction manifold with more common redox
catalytic cycles.4
15
combinations to control the change in mechanism. Despite its
potential for broad utility (based on the number of well elucidated
catalytic cycles), this isohypsic–redox strategy has seldom been
used in the field of Pd-catalysis, and never in the context of alkene
16
difunctionalization.
We have previously developed a Pd-catalyzed alkene
difunctionalization reaction that forms
concomitant creation of an sp –sp C–C bond (Fig. 2b). This
a
heterocycle with
3
3
17
methodology was specifically designed to generate heterocycles
3
with significant sp -C content, as studies of clinical success rates
Most transition metal catalyzed reactions form a single new
bond via a mechanistic cycle that involves alternating oxidative
and reductive steps with respect to the metal catalyst. A smaller,
but still widely used, set of metal-catalyzed processes occurs
without changes in the metal oxidation state, i.e. in an isohypsic
manifold. Common examples of such catalytic cycles include the
indicate a correlation between the progress of drug candidates
through clinical trials and enhanced three-dimensionality.18 An
isotopic labeling study suggested the alkene heteroallylation
process proceeds via an isohypsic mechanism involving a
somewhat unusual -halide elimination step.17,19 Here, we
describe the development of an Isohypsic–Redox Sequence
conjugate addition of organoboronates to ,-unsaturated
(
IRS) based on the unification of alkene heteroallylation with
5
carbonyl compounds,
Au(I) or Co(III)-catalyzed alkyne
transformative Pd-catalyzed redox-active processes such as the
Suzuki–Miyaura coupling, Buchwald–Hartwig amination, and both
6
activations, metallocarbenoid reactions (e.g. Rh(II)-catalyzed
the Wacker and Feringa–Grubbs aldehyde-selective Wacker
oxidation protocols (Fig. 2c).1
6d,20
This IRS approach enhances
[
a]
WestChem School of Chemistry
University of Glasgow
University Avenue, Glasgow
G12 8QQ
molecular complexity by generating three new bonds in a single
process while also forming a heterocycle and a new sp –sp C–C
bond.
3
3
UK
E-mail: david.france@glasgow.ac.uk
Supporting information for this article is given via a link at the end of
the document.
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Once the heteroallylation in the presence of an aryl bromide
had been demonstrated, we set out to establish our first IRS using
the Suzuki–Miyaura cross-coupling, the most common C–C bond
forming reaction used by medicinal chemists.21 In this process, we
were relying on the well-precedented reduction of Pd(II) to Pd(0)
Figure 1. Overview of the isohypsic–redox sequence (IRS) as an approach to
complex molecule synthesis.
2
2
by boronic acids to initiate the redox catalytic cycle. After
optimization,23 including use of Buchwald dialkylbiaryl phosphine
ligands,24 we were able to generate the desired biaryl coupling
products in good yield through the two catalytic cycles (Fig. 4).
Substrate scoping studies demonstrated that both electron-
withdrawing and electron-donating substituents were tolerated.
By modifying the phosphine ligand to XPhos in the case of
thiophene (3e),25 and PPhos in the case of pyridine (3f),26 we
were able to effectively couple these heterocycles.
Figure 2. (a) Widely used cross-coupling strategy (b) Alkene heteroallylation
reaction proceeding through isohypsic mechanism (c) Postulated isohypsic–
redox tandem catalysis.
Our first task in achieving the planned IRS was to identify
an appropriate substrate for the alkene heteroallylation process
that contained a functional handle for use in a diverse array of
subsequent redox reactions. As aryl halides are the most
commonly used coupling partners in standard Pd-catalyzed
processes, bromophenol 1 was selected as our initial test case
(
Fig 3). Gratifyingly, this alkenyl phenol underwent the desired
heteroallylation reaction to generate benzofuran 2 in good yield
under our previously optimized conditions without engaging the
aryl bromide, as expected by the all Pd(II) catalytic cycle.17
Figure 4. Tandem Heteroallylation–Suzuki coupling. Isolated yields based on 1.
*
SPhos replaced by XPhos, ^ SPhos replaced by PPhos.
Figure 3. Heteroallylation of alkenyl phenol 1. Isohypsic mechanism tolerates
aryl bromide.
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Having demonstrated the capacity to form C–C bonds in the
redox phase of the IRS process, we next chose to study C–N
bond formation using the Buchwald–Hartwig amination.27 In this
instance, reduction of the Pd(II) was envisaged to occur via a -
hydride elimination from a Pd(II)–amine complex.28 Use of a
dialkylbiaryl phosphine was again found to be advantageous in
coupling with hexyl amine (Fig. 5). In addition to primary amines,
the coupling proceeded well with secondary amines to generate
morpholine 4c, piperazine 4d and aniline 4e.
Figure 6. Tandem Heteroallylation–Wacker-type oxidations. Isolated yields
based on 1. (a) Isolated yield. (b) Yield determined by 1H NMR integration,
additional 19% yield of methyl ketone also observed. See SI for details.
Figure 5. Tandem Heteroallylation–Buchwald–Hartwig amination. Isolated
yields based on 1.
In summary, we have developed a suite of tandem catalytic
processes based around the concept of linking the isohypsic
(
redox neutral) alkene heteroallylation reaction with well-known
In order to extend the scope of the IRS platform beyond
functionalized benzofurans, as well as to make use of the double
bond that is installed by the isohypsic heteroallylation, we set out
to combine the synthesis of N-containing heterocycles with
oxidation of the double bond as a redox step (Fig. 6).29 The Pd(0)
generated at the end of the Wacker process would be re-oxidized
by an external oxidant to complete a redox cycle. After screening
a range of conditions for the standard Wacker oxidation such as
varying the re-oxidant system,23 we found that benzoquinone was
the most effective (5 to 6). A methyl ketone was successfully
installed in compounds containing both the isoquinolone and
pyrrolopyrazinone ring systems. We then turned our attention to
the possible aldehyde-selective Wacker-type alkene oxidation
developed by Feringa and Grubbs et al. 16d,20 Using silver nitrite
and copper(II) chloride as co-catalysts resulted in formation of the
expected aldehyde as the major product in a modest overall yield
consistent with the yields reported for these two processes in
isolation (5 to 7).20e Interestingly, the presence of a nitrile ligand
redox catalytic cycles including the Suzuki–Miyaura, Buchwald–
Hartwig, and Wacker transformations. In all cases, one metal is
used to effect two different catalytic cycles, thereby providing a
strategy for the rapid evolution of molecular complexity in the
context of forming 3D heterocycles. Given the number of well-
elucidated catalytic cycles, expansion of the IRS concept has vast
potential both within the field of Pd-catalysis and beyond.
Experimental Section
Representative procedure: A 4 mL screw-top glass vial was charged with
4
-bromo-2-(2’-methylallyl)phenol (1) (45.0 mg, 0.200 mmol), toluene (0.65
mL), allyl chloride (80.0 μL, 1.00 mmol), NaHCO (34.0 mg, 0.400 mmol)
and Pd(hfacac) (5.00 mg, 0.0100 mmol) and the vial was sealed under
3
2
ambient atmosphere. The resulting mixture was heated to 50 °C by
immersion of the entire vial into a preheated aluminium block until the
substrate had been consumed, as judged by TLC analysis. The reaction
mixture was cooled to room temperature and the volatile components were
evaporated in vacuo. To the vial was added toluene (0.4 mL), SPhos (8.00
(
as used in earlier work by Feringa and Grubbs et al.) was found
to be essential for the reaction to proceed.
3 4
mg, 0.0200 mmol), freshly ground K PO (127 mg, 0.600 mmol) and
phenylboronic acid (73.0 mg, 0.600 mmol) and the vial was sealed under
ambient atmosphere. The mixture was then heated at 50 °C for 16 h. The
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reaction mixture was cooled to room temperature then purified directly by
flash chromatography on silica gel (petroleum ether, then petroleum
ether/EtOAc; 98:2) to give 3a (36 mg, 68%).
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Acknowledgements
Funding from the University of Glasgow and EPSRC to CDS (DTA
award ref: EP/J500434/1), DP (DTA award ref: EP/K503058/1)
and DJF (award ref: EP/I027165/1) is gratefully acknowledged.
We also thank GlaxoSmithKline for samples from the New
Methodology Expansion Set. Dr. Alistair Boyer (University of
Glasgow) and Prof. Nicholas C. O. Tomkinson (University of
Strathclyde) provided helpful discussions.
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Keywords: Heterocycles; Homogeneous Catalysis; Isohypsic;
Palladium; Tandem Catalysis
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Entry for the Table of Contents
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Craig D. Smith, David Phillips, Alina
Tirla, and David J. France*
Page No. – Page No.
Catalytic Isohypsic–Redox
Sequences for the rapid generation of
3D heterocycles
Coupling reactions catalyzed by transition metals are tremendously influential in
modern synthetic chemistry. These reactions typically involve redox cycling at the
metal center and are generally limited to forging just one type of new bond per
reaction. Here we present an Isohypsic–Redox Sequence (IRS) that uses one
metal to effect two catalytic cycles, thereby generating multiple new types of bonds
from a single catalyst source.
This article is protected by copyright. All rights reserved.