Modular Access to Eight-Membered N-Heterocycles by Directed Carbonylative C?C Bond Activation of Aminocyclopropanes

Article abstract of DOI:10.1002/anie.201910276

Aminocyclopropanes equipped with pendant nucleophiles undergo carbonylative heterocyclization triggered by C?C bond activation to generate eight-membered N-heterocycles. In these processes, intramolecular “capture” of a rhodacyclopentanone intermediate by an aryl or N-based nucleophile is followed by C?C or C?N bond-forming “collapse” to the targets. These studies demonstrate how the combination of cyclopropane strain release and the templating effect of catalytically generated metallacycles can be harnessed to enable otherwise challenging medium ring closures.

Full text of DOI:10.1002/anie.201910276

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Accepted Article
Title: Modular Access to Eight-Membered N-Heterocycles by Directed
Carbonylative C-C Bond Activation of Aminocyclopropanes
Authors: Olivia Boyd, Gangwei Wang, Olga Sokolova, Adam Calow,
Sophie Bertrand, and John Bower
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910276
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10.1002/anie.201910276
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Modular Access to Eight-Membered N-Heterocycles by Directed
Carbonylative C-C Bond Activation of Aminocyclopropanes
Olivia Boyd+, Gang-Wei Wang+, Olga O. Sokolova, Adam D. J. Calow, Sophie M. Bertrand, and John F.
Bower*
Abstract: Aminocyclopropanes equipped with pendant nucleophiles
undergo C-C bond activation triggered carbonylative heterocyclization
to provide 8-membered N-heterocycles. In these processes,
intramolecular “capture” of a rhodacyclopentanone intermediate by an
aryl or N-based nucleophile is followed by C-C or C-N bond forming
“collapse” to the targets. These studies demonstrate how the
combination of cyclopropane strain release and the templating effect
of catalytically generated metallacycles can be harnessed to enable
otherwise challenging medium ring closures.
(“capture”) in advance of C-Nu bond forming reductive elimination
and protodemetallation (“collapse”) to the targets. “Capture-
collapse” heterocyclizations of this type are, in principle, well
suited to the synthesis of medium rings (8 to 11-membered)
because the templating effect of the metallabicycle and the
release of cyclopropane ring strain address the kinetic and
thermodynamic impediments typical of conventional medium ring
closures.[9] However, the success of the strategy is intimately
linked to the facility of C-Nu reductive elimination, a process
posited as the first irreversible step in methodologies that access
7-membered rings.[6] Indeed, prior efforts to extend the approach
to 8-membered rings (Scheme 1B, right) were unsuccessful,
presumably due to (a) an increased barrier for C-Nu reductive
elimination from III (formation of a more challenging ring size)[9]
and/or (b) diminished equilibrium access to this 5,6-metallabicycle
(larger chelate size vs II). As outlined below, we have been able
to overcome these issues, such that a wide range of 8-membered
heterocycles, including systems bearing stereodefined
substituents, are now accessible in a step and atom economical
manner.
Nitrogen heterocycles are prevalent in natural products and
pharmaceuticals, but medium rings (8 to 11-membered) remain
underrepresented in drug design.[1] Nevertheless, this region of
chemical space is appealing because medium rings limit
conformational flexibility,
a
feature that can increase
bioavailability and minimize entropic penalties during the binding
of a drug molecule to a receptor.[2] For example, medium ring
heterocycles have been incorporated into the design of protein
kinase D, protein-tyrosine phosphatase 1B and Rho kinase
inhibitors (Scheme 1A).[3] The key problem preventing further
application is the shortage of methodologies for accessing
medium rings, and this issue is well recognized.[1] Although
progress has been made in the development of catalytic
cycloadditions that access medium sized carbocycles,[4]
complementary processes that provide more pharmaceutically
relevant N-based variants have emerged slowly.[5] Ideally, new
methods would access such structures in a direct, atom
economical and stereocontrolled manner.
Previously, we outlined a metallacycle-based blueprint for
accessing 7-membered heterocycles (Scheme 1B, left).[6,7] Under
carbonylative conditions, carbonyl directed C-C bond activation of
aminocyclopropanes
1
by
Rh(I)-catalysts
leads
to
rhodacyclopentanones I.[8] From here, directing group
dissociation enables metallation of a pendant nucleophile by the
Rh(III)-center to form 5,5-metallabicyclic intermediate II
O. Boyd,[+] Dr. G.-W. Wang,[+] O. O. Sokolova, Dr. A. D. J. Calow,
Prof. J. F. Bower
School of Chemistry, University of Bristol,
Bristol, BS8 1TS, United Kingdom
E-mail: john.bower@bris.ac.uk
Dr. Sophie M. Bertrand
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels
Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom
[+] These authors contributed equally.
Supporting information for this article is given via a link at the end
of the document. X-ray data is available under CCDC 1946652-
1946655.
Scheme 1. Introduction
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Table 1. 8-Membered rings by carbonylative heterocyclization.a
Our initial studies sought an 8-membered ring synthesis involving
C-C reductive elimination from the key rhodacyclopentanone
intermediate (III). To this end, we opted for systems 1 possessing
electron rich arene nucleophiles at the R3 position such that
nucleophilic capture of the Rh(III)-center (I to III) would be
facilitated. An additional consideration in placing the arene at R3
(rather than as part of R2) is that the amide directing group
becomes part of the ring system of III; thus, the conformational
bias (restricted rotation) of the amide unit should enhance access
to this intermediate. Based on this, optimization studies were
conducted on the cyclization of indole system 1a (prepared in two
steps) to 8-membered ring 2a (Table 1). Here, we found that,
under a balloon of CO, the combination of [Rh(cod)OMe]2 and
P(4-FC6H4)3 delivered 2a in 77% yield. These conditions were the
result of extensive efforts to gain high selectivity over C7-8
unsaturated product 3a (>12:1; see the SI).[10] The process is
critically dependent on the presence of an acid additive (2-
NO2C6H4CO2H) and minimal product was observed in its
absence. [Rh(cod)2]OTf was a marginally less efficient pre-
catalyst, whereas [Rh(cod)Cl]2 was ineffective. The use of PhCN
as a coordinating (stabilizing) solvent was also important, with
other solvents, such as 1,2-DCB, proving ineffective. Competing
C-N bond formation, via the NH unit of 1a, was not observed.
Interestingly, 2a exhibited a broadened 1H NMR spectrum at room
temperature; variable temperature studies suggest that this is due
to slow conformational interconversion of the strained 8-
membered ring system (see the SI). This behavior was evident for
other products described below.
The scope of the optimized conditions has been evaluated with a
range of heteroarene nucleophiles (Table 1A). Cyclization via the
C3 position of electronically distinct indoles provided adducts 2a-
f in moderate to excellent yield. The yields refer to pure C7-8
saturated product, and these were formed with uniformly good
selectivity (8:1 to >15:1) over the corresponding C7-8 unsaturated
variants (3a-f). Importantly, other classes of heteroarene also
participate: pyrrole (1g), furan (1h), thiophene (1i) and
benzofuran (1j) systems cyclized to generate targets 2g-j in 24-
69% yield and with good selectivity over 3g-j. It is notable that the
yield of the process corresponds with the nucleophilicity of
heteroaromatic unit (pyrrole>furan>thiophene)[11] (vide infra).
Systems with less nucleophilic arenes (e.g. phenyl groups) do not
participate (see the SI).
Five-membered heteroaromatics are nucleophilic via C3 and C2;
consequently, we reasoned that complementary processes might
be achieved by attaching the cyclopropylamide unit to the C3
position. Indeed, heterocyclization of indole 1k proceeded
smoothly to provide adduct 2k in 58% yield (Table 1B). The
process extended to a range of heteroaromatics, with 2l-o all
formed in useful yields. For 1m-o, competing cyclization via C4
was not observed. The structures of 2k and 2m were confirmed
by single crystal X-ray diffraction. The processes in Table 1B offer
distinct regioselectivity versus those in Table 1A, such that the
position of the N-center can easily be switched in the final ring
system. To extend scope we explored an ambitious carbonylative
heterocyclization of pyrrole 1p, where the C2 position is blocked
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(Table 1C). Although the process was chemically efficient, 2p was
generated in a 4:3 ratio with its unsaturated variant 3p (not
depicted). To circumvent this, we exposed the crude mixture to
Rh-catalyzed hydrogenation conditions[12] which promoted
smooth reduction of the enamide of 3p. Using this modification,
2p was isolated in 58% yield for the two-step process.
deuterium incorporation was observed at C6 and C8 of deuterio-
2k (Equation 1); the latter is consistent with the proposed
protodemetallation step (Scheme 1B).[14] At partial conversion,
less deuterium incorporation was observed at C6 (deuterio-2k’),
supporting the idea that exchange at this position occurs via
enolization of the product (see the SI for further evidence)
(Equation 2). In this experiment deuterium incorporation was also
observed at C2 of the recovered starting material (deuterio-1k).
Equation 3 indicates that exchange at this position does not occur
at the stage of the 1k. Based on previous studies, we suggest that
reversible carbonylative C-C bond activation to the
rhodacyclopentanone (III)[7b] precedes reversible C2-H
metallation. Kinetic profiles for the heterocyclization of 1k vs
deuterio-1k’ revealed a small KIE (kH/kD = 1.14) (Equation 4).[15]
An acid-base reaction between the Rh-precatalyst and the acid
additive likely generates a Rh-carboxylate complex[16] that can
facilitate CMD-type metallation of C2-H.[17] The acid plays a two-
fold role because it also facilitates the protodemetallation step.
Overall, the collective observations are consistent with C-C
reductive elimination being the first irreversible step, and, in part,
this may be demanding due to the ring size being formed.[9,14]
More nucleophilic arenes might enhance this by providing greater
equilibrium access to III;[18] this would account for (a) the efficiency
trends seen for 2g-i and (b) the failure of phenyl-based systems.
We have confirmed the importance of an endocyclic amide
Table 2. Heterocyclizations using substituted cyclopropanes.a
directing group by exposing “exo-variant”
6 to optimized
conditions (Equation 5); here, only decomposition occurred and
azocane 7 was not observed. The minor amounts of C7-8
unsaturated products (3) observed throughout the studies in
Table 1 could result from β-hydride elimination after C-C reductive
elimination from III; here, turnover may be achieved by
protonation of the resulting Rh(I)-hydride in advance of reductive
elimination of dihydrogen.[6a,19]
Extension of the method to disubstituted cyclopropanes was
challenging because the increased steric demands of these
systems impede C-C bond activation. Using the conditions in
Table 1, heterocyclization of C2-linked system 1q provided C7-8
unsaturated product 3q in only 24% yield. Extensive studies were
undertaken to improve efficiency, resulting in the conditions
shown in Table 2, which deliver C7-8 saturated system 2q in 61%
yield (14:1 2q:3q).[13] The key changes vs Table 1 were the
omission of P(4-FC6H4)3 and the replacement of 2-NO2C6H4CO2H
with (E)-(CHCOOH)2 (further optimization studies are in the SI).
The studies outlined so far form the 8-membered ring by C-C
reductive elimination. Access to the metallabicyclic precursors
(III) is facilitated by (a) the restriction of conformational freedom
imposed by the endocyclic amide and (b) the use of relatively
nucleophilic arenes. To explore further the scope of the strategy,
we examined processes that involve C-N reductive elimination
from III, because such intermediates should be accessible by
“capture” of I with good N-based nucleophiles. To this end, we
prepared 1v-x, which incorporate a tethered aniline (Scheme 3).
The basic nature of this functionality meant that acidic
heterocyclization conditions were not suitable (cf. Table 1), but a
preliminary protocol was identified that uses dimethyl fumarate as
a π-acidic ligand.[7b] Under these conditions, C7-8 unsaturated
1,4-diazocanes 3v-x were generated in 17-46% yield and the
corresponding C7-8 saturated products (2v-x, not depicted) were
not observed. The lowest efficiency was for 4-CF3 system 3x,
which supports the importance of using a relatively nucleophilic
aniline. The processes are oxidative, and GCMS analysis
revealed that turnover is achieved by reduction of dimethyl
fumarate to dimethyl succinate.
Substituted
cyclopropanes
are
easily
accessed
in
enantioenriched form, and so the method allows stereospecific
introduction of substituents at C7. This is demonstrated by the
enantioretentive conversion of cyclopropane 1r (98.5:1.5 e.r.) to
heterocycle 2r (98.5:1.5 e.r.). The conditions extended to systems
with different substitution on the cyclopropane (2s), and to
substrates with different aromatic nucleophiles (2t).
A
regiochemically distinct cyclization via C2 of a pyrrole generated
2u. More highly substituted rings can be accessed
diastereoselectively via α-functionalization of the ketone, as
demonstrated by the conversion of 2q to 4.
A mechanistic study was performed using substrate 1k (Scheme
2). When the cyclization was run using 2-NO2C6H4CO2D,
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Scheme 2. Mechanistic studies.
ACKNOWLEDGMENTS
We thank the Royal Society (URF to J.F.B. and a K. C. Wong
Fellowship to G.-W.W.), EPSRC and GSK (studentship to O.B.),
the European Research Council (grant no. 639594 CatHet), the
Leverhulme Trust (Philip Leverhulme Prize to J.F.B.) and the
School of Chemistry X-ray Crystallographic Service.
Keywords: rhodium, cyclopropane, C-C activation, azocane
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In conclusion, we demonstrate the first examples of “capture-
collapse” heterocyclizations that provide 8-membered rings. Our
strategy hinges on the tandem exploitation of strain relief and
metallabicycle templating to overcome the usual enthalpic and
entropic barriers associated with medium ring closures.
Significantly, this is achieved within the context of a step and atom
economical reaction design that is also well suited to the
introduction of stereodefined substituents. These studies add to a
growing body of processes that exploit catalytic C-C bond
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The present method is unusual in the flexibility and stereocontrol
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present level of development, cis-1,2-disubstituted and trisubstituted
cyclopropanes are not suitable substrates.
[14] In principle, C8-protodemetallation could occur before or after C-C
reductive elimination; we favor the latter option based on previous
studies (see reference 6b).
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[18] This interpretation must be treated with caution (see reference 17c). An
alternate explanation could be that more electron rich arenes facilitate
C-C reductive elimination by enhancing the developing cross-
conjugation of the arene with the ketone.
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cannot be discounted on the basis of available data.
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Olivia Boyd+, Gang-Wei Wang+, Olga O.
Sokolova, Adam D. J. Calow, Sophie M.
Bertrand, and John F. Bower*
Page No. – Page No.
Modular Access to Eight-Membered
N-Heterocycles by Directed
Carbonylative C-C Bond Activation of
Aminocyclopropanes
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