SmI2-Catalyzed Intermolecular Coupling of Cyclopropyl Ketones and Alkynes: A Link between Ketone Conformation and Reactivity

Article abstract of DOI:10.1021/jacs.1c01356

The archetypal single electron transfer reductant, samarium(II) diiodide (SmI2, Kagan's reagent), remains one of the most important reducing agents and mediators of radical chemistry after four decades of widespread use in synthesis. While the chemistry of SmI2 is very often unique, and thus the reagent is indispensable, it is almost invariably used in superstoichiometric amounts, thus raising issues of cost and waste. Of the few reports of the use of catalytic SmI2, all require the use of superstoichiometric amounts of a metal coreductant to regenerate Sm(II). Here, we describe a SmI2-catalyzed intermolecular radical coupling of aryl cyclopropyl ketones and alkynes. The process shows broad substrate scope and delivers a library of decorated cyclopentenes with loadings of SmI2 as low as 15 mol %. The radical relay strategy negates the need for a superstoichiometric coreductant and additives to regenerate SmI2. Crucially, our study uncovers an intriguing link between ketone conformation and efficient cross-coupling and thus provides an insight into the mechanism of radical relays involving SmI2. The study lays further groundwork for the future use of the classical reagent SmI2 in contemporary radical catalysis.

Full text of DOI:10.1021/jacs.1c01356

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Article
SmI2‑Catalyzed Intermolecular Coupling of Cyclopropyl Ketones and
Alkynes: A Link between Ketone Conformation and Reactivity
Soumitra Agasti, Nicholas A. Beattie, Joseph J. W. McDouall, and David J. Procter*
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ABSTRACT: The archetypal single electron transfer reductant,
samarium(II) diiodide (SmI2, Kagan’s reagent), remains one of the
most important reducing agents and mediators of radical chemistry
after four decades of widespread use in synthesis. While the
chemistry of SmI2 is very often unique, and thus the reagent is
indispensable, it is almost invariably used in superstoichiometric
amounts, thus raising issues of cost and waste. Of the few reports
of the use of catalytic SmI2, all require the use of super-
stoichiometric amounts of a metal coreductant to regenerate
Sm(II). Here, we describe a SmI2-catalyzed intermolecular radical
coupling of aryl cyclopropyl ketones and alkynes. The process
shows broad substrate scope and delivers a library of decorated
cyclopentenes with loadings of SmI2 as low as 15 mol %. The
radical relay strategy negates the need for a superstoichiometric coreductant and additives to regenerate SmI2. Crucially, our study
uncovers an intriguing link between ketone conformation and efficient cross-coupling and thus provides an insight into the
mechanism of radical relays involving SmI2. The study lays further groundwork for the future use of the classical reagent SmI2 in
contemporary radical catalysis.
intermediates A would be less-problematic at lower concen-
trations of the reagent.
INTRODUCTION
■
The archetypal single electron transfer (SET)1 reductant,
samarium(II) diiodide (SmI2, Kagan’s reagent),2 remains one
of the most important reducing agents and mediators of radical
chemistry after four decades of widespread use in synthesis.3
Intramolecular processes using the commercially available
reagent are particularly popular, and SmI2-mediated radical
cyclizations feature in the total synthesis of numerous high
profile and complex natural products.4 Intermolecular
processes using SmI2 are inherently more challenging as
intermolecular radical C−C bond formation must outrun the
competing reduction of radicals to carbanions. While the
chemistry of SmI2 is very often unique, and thus the reagent is
indispensable,2−4 it is almost invariably used in super-
stoichiometric amounts, thus raising issues of cost and waste.
Of the few reports of the use of catalytic SmI2, all require the
use of superstoichiometric amounts of a metal coreductant to
regenerate Sm(II).5 For example, Corey described one of the
very few SmI2-catalyzed intermolecular coupling processes:5b
Unfortunately, the catalytic system requires 15 equiv of Zn/Hg
amalgam (Scheme 1A).
Herein, we disclose an efficient method for the construction
of decorated cyclopentenes using an intermolecular radical
coupling of aryl cyclopropyl ketones and alkynes catalyzed by
SmI2. Prior to this study, the only previous intermolecular
radical coupling of cyclopropyl ketones and alkynes was an
enantioselective process utilizing a noncommercial, chiral-at-
rhodium complex and requiring imidazolyl cyclopropyl ketones
capable of two-point binding to the metal.8f Crucially, our
studies uncover an intriguing link between ketone conforma-
tion and efficient coupling and thus provide an insight into the
mechanism of radical relays7,8 involving SmI2 (Scheme 1B).
RESULTS AND DISCUSSION
■
Optimization studies began with the SmI2-mediated coupling
of readily available cyclopropyl phenyl ketones 1a−c and
phenylacetylene 2a (Table 1). While the use of 25 mol % of
SmI2 with phenyl ketone 1a resulted in low conversion and a
Received: February 3, 2021
Published: February 25, 2021
We recently reported a radical-relay approach to catalysis
with SmI2 that negates the need for coreductants and additives:
cyclopropyl ketones underwent catalytic radical cyclization to
give complex bicyclic ketones.6 We envisaged that unprece-
dented and more-challenging, intermolecular couplings might
be possible using catalytic SmI2, as the reduction of radical
© 2021 The Authors. Published by
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due to reversible reduction of the carbonyl and/or reversible
fragmentation.
Scheme 1. SmI2-Catalyzed Intermolecular Radical
Couplings
a
The scope of the reaction with regard to the aryl alkyne was
explored using 2-methylphenyl ketone 1b (Figure 1). The
presence of electron-releasing alkyl, alkoxy, amino, and
trifluoromethoxy groups on the aryl substituent of the alkyne
was tolerated (3e-3q). In line with the intermolecular addition
of a nucleophilic radical (cf. A in Scheme 1B) to the alkyne,
aryl alkynes bearing electron-withdrawing groups (e.g., bromo,
fluoro, trifluoromethyl, phenyl, nitrile, and carbomethoxy)
a
(A) Using a stoichiometric coreductant to regenerate Sm(II). (B)
This work. Using a radical relay to regenerate Sm(II). The crucial link
between conformation and the efficiency of the coupling. TMS =
trimethylsilyl.
a
Table 1. Screening of Catalytic Conditions
a
entry ketone temp. (°C) SmI2 loading Conversion Yield of 3
b
1
2
3
4
5
6
7
1a
1b
1b
1b
1b
1c
1d
55
55
RT
55
55
55
55
25 mol %
25 mol %
25 mol %
20 mol %
15 mol %
15 mol %
25 mol %
40%
100%
85%
85%
63%
89%
0%
35%
99%
82%
79%
50%
87%
0%
b
c
d
a
Reaction conditions: 1a−c (1 equiv), 2a (5 equiv), SmI2 (0.1 M in
THF), in THF (0.5 mL/0.1 mmol of substrate) under nitrogen.
b
aNMR yield using nitromethane as internal standard. Isolated yield
c
d
given. Reaction time, 16 h. Cyclohexyl 2,2-dimethylcyclopropylke-
tone 1d was used. THF = tetrahydrofuran.
35% yield of 3a (entry 1), byproduct 4 was also observed in
the product mixture (9%). In an attempt to block competing
intramolecular radical addition, the use of 2-methylphenyl
ketone 1b was investigated; under identical conditions, 1b gave
3b in 99% isolated yield after 45 min (entry 2). Lowering the
reaction temperature (entry 3) or the catalytic loading of SmI2
to 20 mol % (entry 4) and 15 mol % (entry 5) led to lower
conversion. However, switching to 2,6-dimethylphenyl ketone
1c and using 15 mol % SmI2 gave 3c in 87% yield (entry 6).
The use of the corresponding cyclohexyl cyclopropyl ketone
1d resulted in no product formation, and starting materials
were recovered unchanged (entry 7) (vide infra). This is likely
Figure 1. Scope with respect to the aryl alkyne. Reaction conditions:
1b (1 equiv), 2 (typically 5 equiv), 25 mol % SmI2 (0.1 M in THF),
in THF (0.5 mL/0.1 mmol of substrate) under nitrogen. Isolated
a
b
yields; using 2.5 equiv of 2; using 40 mol % SmI2.
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generally gave higher yields of 3 (3r−3ad). Diynes and a triyne
underwent monocoupling to give 3ae-3ag in high yield.
Naphthyl (3ah), phenanthrenyl (3ai), and pyrenyl (3aj) motifs
were tolerated, as was the important heteroaromatic, thiophene
(3ak). Crucially, functional groups that are typically reduced
by SmI2 (e.g., carbomethoxy, nitrile and bromo) are unreactive
under the catalytic conditions. The alkyl substituted alkyne,
prop-2-yn-1-ylcyclopentane, was unreactive, as was phenyl
propiolate. Attempted coupling with benzofuran was un-
successful, and starting materials were recovered.6 For
ineffective coupling partners, it appears that trapping of the
radical formed upon reversible fragmentation of the cyclo-
propyl ring is inefficient and starting ketone is recovered. See
the Supporting Information for further details and a table of
unsuccessful coupling partners.
We next varied the aryl cyclopropyl ketone partner 1 (Figure
2). As noted during optimization studies, the presence of an
ortho-methyl substituent on the aryl ring had a marked,
beneficial effect on the efficiency of the catalytic radical
coupling. In addition, ethyl (3al), fluoro (3am, 3at), chloro
(3ao), phenyl (3as), and iodo (3au) substituents on the aryl
ring of the ketone were compatible with the catalytic coupling.
Ortho substitution was again seen to have a clear, beneficial
impact on the efficiency of coupling; compare the yield of 3c
with that of 3ap. The use of conveniently prepared spirocyclic
cyclopropylketones gave spirocycles 3av and 3aw in 73% and
52%, respectively.
Finally, the importance of gem-dialkyl substitution on the
cyclopropane ring in 1 was probed; monomethyl substrate 1q
gave 3ax in moderate yield and as a 2:1 mixture of
diastereoisomers, while the use of the simple, unsubstituted
cyclopropyl ketone failed to deliver 3ay. Cyclopropyl ketone
1s, bearing a phenyl substituent on the cyclopropane ring,
failed to deliver 3az and starting ketone was recovered;
although the radical anion intermediate derived from 1s is
likely to undergo facile ring-opening,9a the benzylic radical
from cyclopropane fragmentation appears to be insufficiently
reactive to be trapped by the alkyne. Pleasingly, 3c was
prepared on a 1 g scale in 86% while 3ar and 3c were prepared
on a 1 mmol scale in 90% yield and 82% yield, respectively,
with a reduced 15 mol % loading of SmI2.
In line with our previous mechanistic studies,6 we propose a
radical-relay mechanism for the SmI2-catalyzed, intermolecular
radical coupling (Scheme 2): Note that exposure of 1b and 2a
Scheme 2. Proposed Radical Relay for the Intermolecular
Radical Coupling
to various Lewis acids (e.g., SmI3, Yb(OTf)3, La(OTf)3) gave
no trace of 3b, thus ruling out a Lewis acid-mediated
coupling.10 Reversible SET from SmI2 to ketone 1 gives
ketyl radical I11 which fragments9b to give enolate/radical II.
Intermolecular coupling with 2a then generates radical III
which rebounds by addition to the Sm(III)-enolate moiety,
generating new ketyl radical IV. Back electron transfer to
Sm(III) regenerates the SmI2 catalyst and liberates product 3.
It is also possible that ketyl radical IV directly reduces starting
ketone 1.12 Calculations (vide infra) suggest that product ketyl
radical IV has a similar reducing ability to the starting ketyl
radical I. Thus, rather than a case of “reductant upconver-
sion”,12b in which a more reducing radical is formed from a
less-reducing radical and an electron-transfer chain process
results, we believe it is the instability of the starting ketyl
radical I and the formation of a more stable product ketyl
radical IV that is key to the catalytic process.
Figure 2. Scope with respect to the aryl cyclopropyl ketone. Reaction
conditions: 1 (1 equiv), 2 (typically 5 equiv), 25 mol % SmI2 (0.1 M
in THF), in THF (0.5 mL/0.1 mmol of substrate) under nitrogen.
Isolated yields. a Using 1.01 g of ketone partner. b Using 15 mol % of
SmI2. c Using 40 mol % SmI2. d 4-Ethynylbenzonitrile was used as the
Computational studies (PBE0/Def2-TZVP/PCM(THF)/
D3(B-J)//Def2-SVP) have been used to probe the mechanism
of the catalytic, intermolecular, radical coupling and, in
e
alkyne partner. Starting ketone was recovered.
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particular, the crucial impact that ortho-substitution in the aryl
ketones 1 has on the efficiency of coupling (Figure 3). First, we
examined the conformation of the samarium ketyl radicals
derived from ketones 1a−c (cf. I in Scheme 2) and the
distribution of spin density in the radicals (Figure 3A). The
main impact of the ortho-methyl substituents in ketones 1b
and 1c is that the aryl rings are twisted out of the plane of the
ketone carbonyl. This can be seen for ketyl radicals I-1b and I-
1c, in which the aryl rings are 13° and 44°, respectively, out of
plane. This renders the ketyl radicals I-1b and I-1c less stable,
with less spin density in the aromatic ring and more of the spin
density localized on what was the ketone carbonyl carbon
(31% spin density on the aryl ring I-1a, 28% in I-1b and 18%
in I-1c) (Figure 3A).
Crucially, the destabilization of the ketyl radical I appears to
lower the barrier for ring-opening of the cyclopropyl ring to
give radicals II; the computed barrier for ring opening of I-1a
is 14.8 kcal mol−1, while those for I-1b and I-1c are 13.8 and
13.7 kcal mol−1, respectively (Figure 3B). It is interesting to
note that the TS(I−II) is also destabilized, as ortho
substituents are introduced to the aryl ring, but to a slighter
lesser extent, while the stability of the radical product of ring-
opening II is largely unaffected by the nature of the aryl ring as
the spin density is now remote from the aryl substituent. It is
important to note that destabilization of ketyl radical I makes
SET from Sm(II) to the ketone a higher energy process (20.9
kcal mol−1 for 1a; 25.1 kcal mol−1 for 1b, and; 26.9 kcal mol−1
for 1c); however, this energy cost is repaid in full at the end of
the relay during the favorable reduction of Sm(III) by the ketyl
radical.
Building on our proposal that aryl cyclopropyl ketones are
more effective substrates when their aryl rings are twisted out
of the plane, thus rendering the ketyl radicals formed upon
reduction less stable, we revisited the use of alkyl cyclopropyl
ketones in the reaction. As discussed previously, cyclohexyl
cyclopropyl ketone 1d was unreactive and the use of other
bulky alkyl cyclopropyl ketones resulted in low yields or the
return of only starting material. However, i-butyl and methyl
cyclopropyl ketones underwent smooth coupling, to give 3aac
and 3aad, respectively (Figure 3C). Attempts to switch alkyne
partners for alkenes showed that the use of simple alkenes was
not effective (e.g., oct-1-ene), although coupling was seen with
the activated acceptors, styrene and acrylonitrile, to give 3aaf
and 3aah, respectively (Figure 3D).
The products of the SmI2-catalyzed cross-coupling are
versatile building blocks for synthesis. For example, cyclo-
pentene 3c can be selectively oxidized and reduced to give
epoxide 5 and ketone 6, respectively (Figure 4). Furthermore,
the product of cross-coupling 3ar, bearing the pentamethyl-
phenyl ketone motif, can be efficiently converted to the
corresponding alcohol 7, acid 8, and ester 9.13
CONCLUSION
■
In summary, SmI2 catalyzes the radical cross-coupling of aryl
cyclopropyl ketones and alkynes. The process shows broad
substrate scope and delivers a library of decorated cyclo-
pentenes with loadings down to 15 mol % of SmI2. We invoke
the operation of a radical relay mechanism that negates the
need for a superstoichiometric coreductant and additives to
regenerate Sm(II). Crucially, our study uncovers an intriguing
link between ketone conformation and efficient cross-coupling
and thus provides an insight into the mechanism of radical
relays involving SmI2. The study lays further groundwork for
Figure 3. Computational studies. (A) Probing the importance of
conformation on ketyl radical stability. (B) Mechanism of the catalytic
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chromatography on silica gel (100- 200 mesh size) with hexane/ethyl
acetate as eluent.
Figure 3. continued
radical coupling and the influence of the aryl substituent. Level of
theory; PBE0/Def2-TZVP/PCM(THF)/D3(B-J)//Def2-SVP. (C)
Scope with respect to alkyl cyclopropyl ketones. Reaction conditions:
1 (1 equiv), 2a (5 equiv), 25 mol % SmI2 (0.1 M in THF), in THF
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications Web site. The Supporting Information is
available free of charge at https://pubs.acs.org/doi/10.1021/
jacs.1c01356.
■
sı
a
(0.5 mL/0.1 mmol of substrate) under nitrogen. Isolated yields.
Starting ketone was recovered. b Starting ketone was recovered in 81%
c
yield. Starting ketone was recovered in 22% yield. (D) Survey of
alkene partners. Reaction conditions: 1 (1 equiv), alkene (5 equiv),
Experiments, experimental procedures, characterization
data, CCDC numbers for X-ray crystal structures, details
of computational studies, and spectra for all new
compounds (PDF)
25 mol % SmI2 (0.1 M in THF), in THF (0.5 mL/0.1 mmol of
d
substrate) under nitrogen. Isolated yields. Starting ketone was
recovered.
Accession Codes
CCDC 2039352−2039355 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
David J. Procter − Department of Chemistry, The University
of Manchester, Manchester M13 9PL, U.K.; orcid.org/
0000-0003-3179-2509; Email: david.j.procter@
manchester.ac.uk
Authors
Soumitra Agasti − Department of Chemistry, The University
of Manchester, Manchester M13 9PL, U.K.
Nicholas A. Beattie − Department of Chemistry, The
University of Manchester, Manchester M13 9PL, U.K.
Joseph J. W. McDouall − Department of Chemistry, The
University of Manchester, Manchester M13 9PL, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01356
Figure 4. Selective manipulation of the products of SmI2-catalyzed
intermolecular coupling.
Notes
The authors declare no competing financial interest.
the future use of the classical SET reagent SmI2 in
contemporary radical catalysis.
ACKNOWLEDGMENTS
■
We thank the EPSRC (PDRA to S.A. and PDRA to N.A.B.;
EP/R029938/1), the European Union Horizon 2020 (Fellow-
ship to S.A.; Marie Sklodowska-Curie IF, EU project 891623 -
SmART), and the University of Manchester.
EXPERIMENTAL SECTION
■
Preparation of SmI2. An oven-dried round-bottom flask,
equipped with a stirrer bar, was flushed with a strong flow of N2
for 30 min. The flask was then loaded with samarium metal (∼40
mesh, 1.4 equiv), washed diiodoethane (1 equiv), and the flask was
flushed for another 30 min with N2. Freshly distilled and degassed
THF (0.1 M) was added, and the mixture was stirred overnight at
room temperature. Finally, the mixture was allowed to settle for at
least 1 h and titrated prior to use.14
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