Synthesis of 2-Aryl- and 2-Vinylpyrrolidines via Copper-Catalyzed Coupling of Styrenes and Dienes with Potassium β-Aminoethyl Trifluoroborates

Article abstract of DOI:10.1021/acs.orglett.6b01259

2-Arylpyrrolidines occur frequently in bioactive compounds, and thus, methods to access them from readily available reagents are valuable. We report a copper-catalyzed intermolecular carboamination of vinylarenes with potassium N-carbamoyl-β-aminoethyltrifluoroborates. The reaction occurs with terminal, 1,2-disubstituted, and 1,1-disubstituted vinylarenes bearing a number of functional groups. 1,3-Dienes are also good substrates, and their reactions give 2-vinylpyrrolidines. Radical clock mechanistic experiments are consistent with the presence of carbon radical intermediates and do not support participation of carbocations.

Full text of DOI:10.1021/acs.orglett.6b01259

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑Aryl- and 2‑Vinylpyrrolidines via Copper-Catalyzed
Coupling of Styrenes and Dienes with Potassium β‑Aminoethyl
Trifluoroborates
Chanchamnan Um and Sherry R. Chemler*
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, United States
S
* Supporting Information
ABSTRACT: 2-Arylpyrrolidines occur frequently in bioactive
compounds, and thus, methods to access them from readily
available reagents are valuable. We report a copper-catalyzed
intermolecular carboamination of vinylarenes with potassium
N-carbamoyl-β-aminoethyltrifluoroborates. The reaction occurs with terminal, 1,2-disubstituted, and 1,1-disubstituted
vinylarenes bearing a number of functional groups. 1,3-Dienes are also good substrates, and their reactions give 2-
vinylpyrrolidines. Radical clock mechanistic experiments are consistent with the presence of carbon radical intermediates and do
not support participation of carbocations.
Scheme 1. Polar/Radical Pyrrolidine Syntheses
unctionalized pyrrolidines are important nitrogen hetero-
Fcycles found in numerous bioactive compounds of both
natural and synthetic origin. 2-Arylpyrrolidines, in particular,
are ubiquitous.1−3 The need to access these important moieties
and related heterocycles has inspired the development of a
number of methods.4−26 Many of these methods, however,
utilize strong bases5 and water-sensitive organometallic
reagents.7,8 Additional intermolecular metal-catalyzed cou-
plings18−20 and intramolecular metal-catalyzed and Bronsted
acid catalyzed cyclizations21−25 have been developed, providing
various routes to 2-arylpyrrolidines and related products. These
latter methods, however, are mainly limited to sulfonamides.
More recently, readily available vinylarenes have been used to
directly access 2-arylpyrrolidines and related saturated hetero-
cycles via intermolecular coupling with bifunctional heter-
oatom-substituted reagents that can undergo polar/radical [3 +
2]-type bond-forming reaction sequences under mild reaction
conditions.26−31 The products of these reactions, by virtue of
the required substrates, often contain additional functional
groups (Schemes 1a,b) that may not be desired in all
applications, and primarily N-sulfonyl pyrrolidine synthesis
has been reported.
To address the existing limitations as well as to explore an
orthogonal reactivity mode, we envisaged that a β-aminoethyl
carbon radical could serve as a bifunctional three-atom unit to
effect a net intermolecular carboamination in the presence of an
oxidant (Scheme 1c). The resulting products of the coupling
with vinylarenes are simple 2-arylpyrrolidines whose applica-
tions in medicinal chemistry endeavors can be readily
envisioned. Herein is presented our development of this
method and its extension to 1,3-dienes. The method is ideal for
the synthesis of N-carbamoylpyrrolidines. Carbamates are
generally considered to be more attractive than sulfonamides
as the latter are higher molecular weight and often require more
strenuous conditions to reveal the parent amine. The utility of
carbamates in medicinal chemistry has been noted.32
We recently disclosed an oxidative alkyl Heck-type reaction
between alkylboron reagents and vinylarenes.33 In this
transformation, alkyl radicals, generated in situ from [Cu(II)]
oxidation of the alkylboron reagent, add to vinylarenes.
Oxidation of the resulting benzyl radical then provides the
observed higher substituted vinylarene products. We hypothe-
sized that under the reaction conditions the benzylic radical, or
carbocation derived thereof, could be intercepted with an
amine, resulting in 2-arylpyrrolidine formation (Scheme 1c).
The ready availability of N-carbamoyl-β-aminoethylboron
reagents, due to the respective contributions of Overman and
Molander,34,35 presented an excellent opportunity to test this
hypothesis.
Copper(II) 2-ethylhexanoate [Cu(eh)2] is a readily available
copper salt that has previously been shown to activate
potassium alkyltrifluoroborates in coupling reactions with
Received: April 29, 2016
© XXXX American Chemical Society
A
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Letter
radical acceptors.33,36 However, an attempt at the copper(II) 2-
ethylhexanoate-catalyzed coupling of potassium N-Cbz-β-
aminoethyltrifluoroborate 1a with 4-methoxystyrene in the
presence of MnO2 (2.55 equiv) as stoichiometric oxidant did
not result in pyrrolidine formation (Table 1, entry 1). Upon
changing the catalyst to [Cu(1,10-phenanthroline)](OTf)2,33
oxidative coupling readily occurred to give 82% yield of 2-
arylpyrrolidine 2a (Table 1, entry 2). The Boc analogue 1b also
provided the coupling product 2b, but in lower yield (49%,
entry 3). The boronic acid analogue 1c underwent the coupling
reaction but also less efficiently (Table 1, entry 4, 52% yield).37
Lowering the copper loading from 20 mol % to 15 mol % led to
a less efficient reaction with N-Cbz-β-aminoethyltrifluoroborate
1a (Table 1, entry 5, 67% yield). Ag2CO3 (2 equiv) could also
serve as a stoichiometric oxidant in place of MnO2 (Table 1,
entry 6).
Scheme 2. Annulation with Terminal Styrenes
Table 1. Effect of Alkylborane Structure, Catalyst Loading,
a
and Oxidant on Reaction Efficiency
c
yield
entry
PG
BXn
oxidant
MnO2
CuX2 (mol %)
(%)
b
1
Cbz BF3K 1a
Cbz BF3K 1a
Boc BF3K 1b
Cu(eh)2
(20 mol %)
NR
(2.55 equiv)
MnO2
(2.55 equiv)
MnO2
(2.55 equiv)
MnO2
(2.55 equiv)
a
b
c
2
3
4
Cu(OTf)2
(20 mol %)
82
46
52
67
63
Two equiv of styrene was used. Reaction run for 48 h. Reaction run
at 95 °C.
Cu(OTf)2
(20 mol %)
Scheme 3. Annulation with Disubstituted Styrenes
Cbz B(OH)2
Cu(OTf)2
(20 mol %)
1c
d
5
Cbz BF3K 1b
MnO2
(2.55 equiv)
Cu(OTf)2
(15 mol %)
6
Cbz BF3K 1b
Ag2CO3
(2 equiv)
Cu(OTf)2
(20 mol %)
a
25 mol % of 1,1-phenanthroline was used unless otherwise noted.
1,10-Phenanthroline was not used. Isolated yield. 20 mol % of 1,10-
b
c
d
phenanthroline was used. MnO2 (85% by weight) was used in these
reactions.
A number of styrenes underwent this reaction (Scheme 2).
Styrenes with electron-donating substituents were most
reactive. While most reactions were performed at the 0.125
mmol scale of 1a (Scheme 2), a 1.25 mmol scale for the
efficient (70% yield) production of 2f was also performed.
Ethers, alkyl substitutents, sulfonamides and amides were
tolerated. Halide-substituted styrenes underwent the reaction,
but longer reaction times were required. Substrates bearing two
potentially reactive alkenes (terminal styrene, indole, terminal
alkyl-substituted alkene) favored reaction at the terminal
styrene. A styrene bearing a methyl ester also underwent the
reaction but with lower efficiency. A 2-fluoropyridyl in place of
a substituted phenyl was also tolerated, although the reaction
was less efficient. 1-Phenyl-4-pentene, lacking conjugation, did
not react.
Disubstituted styrenes were next evaluated (Scheme 3). 1-
Alkyl- and 1-arylstyrenes provided tertiary amines and spiro-
cycles 3a−e. Coupling with indene gave cis-fused bicyclic
pyrrolidine 3f. Both trans and cis-stilbene gave the same trans-
pyrrolidine adduct 3g. 1-Phenyl-1-cyclohexene, a trisubstituted
alkene, was unreactive (not shown).
a
b
Reaction run in anhydrous 1,4-dioxane at 120 °C. Reaction run for
36 h.
Dienes and an enyne also underwent the coupling reaction to
give the corresponding 2-vinyl- and 2-propargylpyrrolidines 4
and 5 (Scheme 4). trans-Ethyl cinnamate and an α,β-
unsaturated diene provided β-amino acid esters 6 and 7 with
good diastereoselectivity for the 2,3-trans pyrrolidines (Scheme
4).
Bexarotene methyl ester, the methyl ester of a retinoid
anticancer agent that has recently shown promise in the
treatment and prevention of Alzheimer’s disease,38 provided
pyrrolidine 8 from the coupling reaction along with two alkyl
Heck-type diastereomers 9 (Scheme 5).
B
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entiate between path I and path II because, on the basis of
oxidation potentials, MnO2 is capable of oxidizing both [Cu(I)]
and a benzylic radical, although [Cu(I)] is the more easily
oxidized species.41
Scheme 4. Reactions of Dienes and a Dienoate
To investigate the mechanism further, a series of vinyl-
cyclopropanes were submitted to the coupling reaction with N-
Cbz-β-aminoethyltrifluoroborate 1a (Scheme 7). Reaction with
Scheme 7. Radical Clock Mechanism Probes
Scheme 5. Reaction of Bexarotene Methyl Ester
2-(buta-1,3-dienyl)cyclopropylbenzene provided a mixture of
pyrrolidine diastereomers 10, and no cyclopropane ring-opened
products were detected (Scheme 7). Reaction with 2-
((phenylcyclopropyl)vinyl)benzene provided both pyrrolidine
diastereomers 11 and dihydronaphthalene 12.33 The regio-
chemistry of 12 indicates that cyclopropane ring opening
occurred at the phenyl-bearing carbon. This supports a radical
cyclopropane ring-opening mechanism over a metal-mediated
ring opening where the less substituted organometallic would
have been preferred.42 To differentiate between a carbocation
and a radical cyclopropane opening, the 2-tert-butoxy-3-(1-
phenylvinyl)cyclopropyl)benzene radical clock was applied
(Scheme 7). Newcomb has demonstrated this kind of radical
clock will open at the oxygen-bearing carbon in carbocationic
mechanisms and at the phenyl-bearing carbon in radical
mechanisms.43 In the event, a mixture of 4-phenylnaphthylene
13 and dihydronaphthalene 14 were obtained in this reaction.
Naphthalene 13 is likely formed by elimination of t-BuOH
from 14. The regioselectivity in these reactions support
involvement of radical intermediates and do not provide
evidence for carbocation intermediates. The lack of ring-opened
product from reaction with the cyclopropyl diene probe could
indicate that C−N bond formation is favored over ring-opening
and/or radical addition to the arene when the carbon is less
hindered. With increased steric hindrance at carbon, ring-
opening and/or radical addition to the arene becomes
competitive. While pyrrolidine formation without ring-opening
is feasible, it is also possible the ring could open and
subsequently close prior to pyrrolidine formation.44
These intermolecular coupling reactions appear to occur
through copper-catalyzed/MnO2 mediated stepwise oxidative
coupling sequence (Scheme 6). Copper(II)-catalyzed oxidation
Scheme 6. Proposed Reaction Mechanism
of the alkylborane to its corresponding alkyl radical initiates the
process.33,36,39 The alkyl radical then adds to the styrene to
produce a stabilized benzylic radical intermediate. This
intermediate can combine with [Cu(II)] to form an
alkylcopper(III) intermediate capable of undergoing C−N
bond formation via reductive elimination (path I).40 Alter-
natively, the benzylic radical could be further oxidized by MnO2
to provide a benzylic carbocation that is then trapped by the
pendant amine (path II).31 Oxidation of [Cu(I)] back to
[Cu(II)] with MnO2 then closes the catalytic cycle. At the
onset of our mechanistic investigation, we could not differ-
In summary, we have developed new conditions for the
synthesis of simple 2-arylpyrrolidines from vinylarenes and
dienes. The scope of the alkene partner is broad. Radical clock
experiments support a purely radical mechanism, likely
C
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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.6b01259.
Experimental procedures and characterization of new
compounds (PDF)
NMR spectra (PDF)
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Y. J. Am. Chem. Soc. 2011, 133, 20890.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: schemler@buffalo.edu.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institute of General Medical Science for
support of this work (R01 078383) and the Bureau of
Educational and Cultural Affairs of the U.S. Department of
States for a Fullbright fellowship to C.U. We thank Mr.
Shuklendu Karyakarte (UB chemistry) for assistance with some
NMR spectra.
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