A Simple and Broadly Applicable C?N Bond Forming Dearomatization Protocol Enabled by Bifunctional Amino Reagents

Article abstract of DOI:10.1002/anie.201708176

A C?N bond forming dearomatization protocol with broad scope is outlined. Specifically, bifunctional amino reagents are used for sequential nucleophilic and electrophilic C?N bond formations, with the latter effecting the key dearomatization step. Using t

Full text of DOI:10.1002/anie.201708176

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Accepted Article
Title: A Simple and Broadly Applicable C-N Bond Forming
Dearomatization Protocol Enabled by Bifunctional Amino-
Reagents
Authors: Xiaofeng Ma, Joshua Farndon, Tom Young, Natalie Fey, and
John Bower
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708176
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10.1002/anie.201708176
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COMMUNICATION
A Simple and Broadly Applicable C-N Bond Forming
Dearomatization Protocol Enabled by Bifunctional Amino-
Reagents
Xiaofeng Ma, Joshua J. Farndon, Tom A. Young, Natalie Fey, and John F. Bower*
Abstract: A C-N bond forming dearomatization protocol with broad
scope is outlined. Specifically, bifunctional amino-reagents are used
for sequential nucleophilic and electrophilic C-N bond formations, with
the latter effecting the key dearomatization step. Using this approach,
γ-arylated alcohols are converted to a wide range of differentially
protected spirocyclic pyrrolidines in just two or three steps.
arene and N-protecting group. The spirocyclic pyrrolidine
products obtained by this method are core motifs in many natural
products and are also recognized as privileged scaffolds in drug
discovery.[6] Accordingly, we anticipate that the strategy described
herein will find broad utility in synthetic settings.
Electrophile-triggered dearomatization processes enable the
direct conversion of readily prepared planar molecules to
synthetically valuable three-dimensional scaffolds,[1] often with the
concomitant provision of functionality primed for diversification. C-
C bond forming processes of this type now offer exceptional
utility,[1,2] but related C-N bond forming dearomatizations have not
reached the same level of sophistication (Scheme 1A). Within this
context, predominant methods rely on nitrenium ions and are
limited to lactam products equipped with specific N-protecting
groups.[3] Oxime-based processes, which provide dihydropyrroles,
are also of note, although competing Beckmann rearrangement is
often problematic.[4] As far as we are aware, the direct synthesis
of
dearomatizations has not been achieved. Ciufolini and co-
workers have pioneered conceptually distinct approach
pyrrolidines
using electrophilic nitrogen triggered
a
involving oxidation of an arene to its corresponding cation in
advance of trapping by a nitrogen nucleophile.[5] Although often
effective, the process requires specific N-protecting groups
(carbamates are not tolerated), is most efficient under strongly
acidic conditions (e.g. TFA as solvent) and can suffer from
competing oxidation processes involving the arene.[5e] Given the
limitations associated with the state-of-the-art, we reasoned that
the development of a C-N bond forming dearomatization platform
with broad scope would represent a significant and useful
advance. Specifically, we sought to circumvent the requirement of
a strong external oxidant, and, at the same time, provide a
pyrrolidine synthesis that can accommodate a variety of N-
protecting groups (especially synthetically flexible carbamates)
and a range of nucleophilic arenes (e.g. phenols, naphthols,
indoles). As outlined below, we have been able to achieve this by
developing a suite of bifunctional amino-reagents 2 that allow the
two or three-step conversion of γ-aryl alcohols (e.g. 1) to
protected pyrrolidines (e.g. 4) (Scheme 1B). This unique
approach is efficient, mild (no external oxidant) and operationally
simple, offering exceptionally wide scope with respect to both the
Scheme 1.
Our studies in this area stemmed from ongoing efforts to
exploit electrophilic nitrogen sources for N-heterocycle
synthesis.[7] Specifically, we envisaged that initial exploitation of
the nucleophilic character of 2 for Mitsunobu alkylation with
alcohols 1 would provide precursors 3. At this stage, the
electrophilic character of the nitrogen center would be harnessed
to trigger the dearomatization step (to 4). The overall approach
offers several distinct advantages: (1) pre-installation of the O-
based leaving group on nitrogen facilitates the Mitsunobu step
and avoids protecting group manipulations,[8] (2) readily prepared
enantiopure secondary alcohols can potentially be used as a
starting point,[7] (3) the use of an N-O bond as a mild internal
oxidant should minimize competing oxidation processes involving
the arene, (4) the leaving group derived byproduct (HOR) should
be easy to remove during work-up, and (5) a wide range of N-
protecting groups should be tolerated because the
Dr X. Ma, J. J. Farndon, T. A. Young, Dr N. Fey, Prof. Dr J. F. Bower,
School of Chemistry,
University of Bristol,
Bristol, BS8 1TS, United Kingdom
E-mail: john.bower@bris.ac.uk
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10.1002/anie.201708176
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dearomatization step relies on the electrophilicity of the nitrogen
center, rather than on its nucleophilicity.
beneficial in certain cases as the substrates are more stable, and
this increased stability can translate into enhanced
dearomatization yields. Indeed, OFBz precursor 3c was more
efficient than OTs precursor 3c’ for accessing N-Cbz system 4c
(82% vs 70% yield). Conversely, an OTs leaving group was most
effective for the formation of methyl and tert-butyl carbamate
products 4d and 4e. Satisfactory results were achieved for Alloc-
protected system 4f using Conditions B. The results in Table 1
are significant as they show that the method tolerates a wide
range of synthetically useful N-protecting groups and that it is also
mild enough for efficient dearomatization of the oxidatively
sensitive indole core; C-N bond forming dearomatizations of this
unit to provide spirocyclic pyrrolidine products have not been
reported previously.[4,10-12]
Table 1. Evaluation of electrophilic aminating agents for the C-N bond forming
dearomatization process (FBz
methoxybenzenesulfonyl).
=
pentafluorobenzoyl, Mbs
=
p-
To evaluate the feasibility of the approach outlined in Scheme
1B, we targeted initially a range of differentially protected reagents
2a-f, equipped with either OTs or OFBz leaving groups (vide infra)
(see Table 1, box). In the event, these reagents were easily
prepared on multi-gram scale and showed good levels of stability
(see the Supporting Information). Mitsunobu alkylation of 2a-f’,
with 3-(1H-indol-3-yl)propan-1-ol as the pro-electrophile, provided
targets 3a-f’ in an efficient manner (57-86% yield, see the
Supporting Information). Despite the lack of direct precedence, C-
N bond forming dearomatization of OFBz system 3a was achieved
using a very simple protocol: exposure to catalytic quantities of
K2HPO4 (15 mol%) at 140 oC in n-BuCN resulted in
spirocyclization to provide 4a in 44% yield (Conditions A). Under
the same conditions, spirocyclization of Mbs protected system 3b
generated 4b in 65% yield. With the aim of accessing N-tosyl
protected pyrrolidines more efficiently, we investigated the
cyclization of OTs system 3a’. Optimization studies revealed that
the desired process could be achieved under much milder
conditions (K2CO3, TFE, 80 oC) than for 3a, and this enabled
access to 4a in 75% yield (Conditions B). The relative facility of
Conditions A vs B is reflective of the leaving group ability of
Table 2. C-N bond forming dearomatizations of indole-based systems (aK2HPO4
(200 mol%) was used. bSynthesized from enantioenriched 3s (92% e.e.).
With efficient protocols in hand, we chose initially to evaluate
scope with respect to indole-based systems, primarily because of
the lack of complementary methods for achieving this type of
dearomatization. The method is largely insensitive to substitution
o
pentafluorobenzoate vs tosylate (pKa values in H2O at 25 C:
FBzOH 1.75, TsOH 0.7).[9] Although OTs systems offer higher
reactivity, we have found that an OFBz leaving group can be
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10.1002/anie.201708176
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on the indole ring, with a variety of substrates 3g-p undergoing
dearomatization to provide spirocyclic imines 4g-p in moderate to
excellent yield. The exact reaction conditions were selected on a
case-by-case basis, although, in general, Conditions B were
preferable for processes involving Boc-protected amines. The
method also provides access to systems with additional
substitution on the pyrrolidine ring. Modest diastereocontrol was
observed for C-3 substituted system 4q, but high levels of
diastereoselectivity were achieved for C-2 (4r) and C-4 (4s-u)
substituted variants. The alcohol precursor for 3s was accessed
in high enantiopurity via chiral iminium ion catalyzed
enantioselective addition of indole to crotonaldehyde (see the
Supporting Information),[13] and this allowed access to product 4s
in 92% e.e. The stereochemical assignments of the major
diastereomers of 4r-u were determined by nOe experiments, and
the structure of 4u was confirmed unambiguously by single crystal
X-ray diffraction.[14]
observed for C-N bond forming dearomatizations of ortho-phenols
and naphthols; this provides access to enone products where the
spirocyclic pyrrolidine is located adjacent to the newly unveiled
ketone (Table 3B). Thus, the method is generally applicable to the
dearomatization of a key range of aromatic nucleophiles, with
excellent efficiencies observed in all cases.
The spirocyclic products accessed in this study are diverse,
with each embodying electrophilic functionality that can be
modified further (Figure 1). For example, reduction (NaBH4) of the
imine moiety of 4u proceeded smoothly to provide indoline 7 in
quantitative yield. C-C bond formations are also readily achieved;
allyl-Grignard addition to imine 4u occurred primarily from the face
opposite the N-Boc moiety to deliver 8 in 6:1 d.r. Vinyl-cuprate
addition to 6e was also diastereoselective (5:1 d.r.) and generated
9 in 77% yield. The processes in Figure 1 are representative, and
many other diversity oriented transformations can easily be
envisaged. Note that in each case the products are accessed in
only a few steps from the corresponding “planar” alcohol (see
Scheme 1B), which highlights the rapid complexity generation
that can achieved by harnessing bifunctional amino-reagents 2 for
dearomatizing heteroannulations.
Figure 1. Derivatizations of the dearomatization products.
Our proposed mechanism for the processes described here is
supported by a series of observations. Cross-over experiments
have confirmed that the N-O unit must be tethered to the aromatic
undergoing dearomatization (Scheme 2A); cyclization of N-OTs
system 3j in the presence of NH system 10 led to the formation of
4j, and 4e was not observed. Thus, the N-O bond acts as an
internal oxidant only, and is not effective as an external oxidant.
The conversion of 3e’ to 4e is not affected by addition of TEMPO
or BHT, which suggests that potential radical-based pathways
involving initial N-O homolysis are not operative.[16] Additionally,
we examined the behavior of alkenyl systems 11a and 11b
because N-centered radicals are known to undergo fast 5-exo
cyclization onto alkene acceptors (Scheme 2B).[16,17] When 11a
and 11b were exposed to optimized dearomatization conditions
(in the presence or absence of 1,4-cyclohexadiene (CHD) as a
hydrogen atom donor) pyrrolidine product 12 was not observed.
Although these results seemingly discount the intermediacy of an
N-centered radical, it is important to note that 11a and 11b lack a
pendant arene, and so the results in Scheme 2B do not rule out
the possibility of N-O homolysis by intramolecular electron
transfer from the indole or phenol unit.[17a,18] Nevertheless, at the
current stage we favor a mechanistic pathway in line with that
depicted in Scheme 1B, wherein dearomatization occurs by direct
nucleophilic attack of the arene onto the electrophilic nitrogen
Table 3. C-N bond forming dearomatizations of phenols and naphthols (aK2CO3
(150 mol%) used in 1,2-DCE).
Further scope studies revealed that the approach can be
extended to para-phenol and para-naphthol systems 5a-e,
providing carbamate protected products 6a-e that are not
accessible using the oxidative C-N bond forming dearomatization
approach of Ciufolini and co-workers (Table 3A).[5a-e,15] In each
case, dearomatizing spirocyclization occurred cleanly and 6a-e
were isolated in uniformly high yields. Similar efficiencies were
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10.1002/anie.201708176
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COMMUNICATION
allows catalytic quantities of this component to be used. We have
confirmed the formation of pentafluorobenzene by GCMS
analysis of crude reaction mixtures, and our previous studies have
shown that the protodecarboxylation process is facile.[21] Under
both Conditions A and B, minimal conversions are observed in the
absence of base and hindered organic variants (e.g. 2,6-di-tert-
butylpyridine) are not suitable. These observations suggest an
involved role for the base beyond simply sequestering the acid
byproduct (TsOH, FBzOH) and this may provide an avenue for the
future realization of enantioselective processes.
In summary, we outline a conceptually simple approach to
C-N bond forming dearomatization, wherein nucleophilic attack of
an arene onto an electrophilic nitrogen center generates
differentially protected spirocyclic pyrrolidines. The protocol offers
unprecedented scope, encompassing indoles, phenols and
naphthols as the nucleophilic component, and tolerating a range
of N-protecting groups; the ability to use synthetically flexible
carbamates is particularly significant. The substrates are
accessed directly using bifunctional amino-reagents that
incorporate the functionality required for the subsequent
dearomatization step; this occurs under mildly basic conditions
and avoids external oxidants. The spirocyclic pyrrolidine products
obtained by this method are well recognized as privileged
scaffolds in drug discovery, and the ability to access them in a
flexible and direct manner is likely to be of wide interest.
25.1
TS
TsO-
0.0
Acknowledgements
5a-Me
1.81
2.64
We thank the Bristol Chemical Synthesis CDT, funded by EPSRC
(EP/G036764/1) for a studentship (J. J. F.), the Royal Society for
a URF (J. F. B.) and the European Research Council for financial
support via the EU’s Horizon 2020 Programme (ERC grant
639594 CatHet). The Centre for Computational Chemistry is
thanked for computational resources.
-60.9
6a-Me
Reaction coordinate
Keywords: dearomatization, C-N bond, spirocyclic pyrrolidine
Scheme 2. Preliminary mechanistic studies.
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equivalent of 5a) to 6a-Me was modelled and the computed free
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reaction time required for complete conversion under Conditions
B (93% yield after 9 hours at 60 oC, see the Supporting
Information) (Scheme 2C).[20] For Conditions A, fast
protodecarboxylation of the pentafluorobenzoate leaving group to
afford pentafluorobenzene regenerates the base (K2HPO4) and
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10.1002/anie.201708176
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[14] CCDC 1565891-1565892 contain crystallographic data for this paper.
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[20] Solvated Gibbs free energies are quoted at the B2PLYP-D3/6-
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COMMUNICATION
Xiaofeng Ma, Joshua J. Farndon, Tom
A. Young, Natalie Fey, and John F.
Bower*
Page No. – Page No.
A Simple and Broadly Applicable C-N
Bond Forming Dearomatization
Protocol Enabled by Bifunctional
Amino-Reagents
A C-N bond forming dearomatization protocol with broad scope is outlined.
Specifically, bifunctional amino-reagents are used for sequential nucleophilic and
electrophilic C-N bond formations, with the latter effecting the key dearomatization
step. Using this approach, γ-arylated alcohols are converted to a wide range of
differentially protected spirocyclic pyrrolidines in just two or three steps.
This article is protected by copyright. All rights reserved.