Radical Cyclization of Alkene-Tethered Ketones Initiated by Hydrogen-Atom Transfer

Article abstract of DOI:10.1002/anie.201709659

An unprecedented C?C coupling reaction between alkenes and ketones by hydrogen-atom transfer, using Fe(acac)₃ and PhSiH₃ in EtOH, is described. This mild protocol features high site selectivity and allows the construction of sterically congested structures containing tertiary alcohols and quaternary centers. The overall process introduces a novel strategic bond disconnection for ring-closing reactions.

Full text of DOI:10.1002/anie.201709659

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Hydrogen Atom Transfer-Initiated Radical Cyclization of Alkene-
Tethered Ketones
Authors: Josep Bonjoch, BEN BRADSHAW, MAR SALADRIGAS,
Caroline Bosch, and Gisela V. Saborit
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709659
Angew. Chem. 10.1002/ange.201709659
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10.1002/anie.201709659
Angewandte Chemie International Edition
COMMUNICATION
Hydrogen Atom Transfer-Initiated Radical Cyclization of Alkene-
Tethered Ketones
Mar Saladrigas, Caroline Bosch, Gisela V. Saborit, Josep Bonjoch*, and Ben Bradshaw*
Abstract: An unprecedented hydrogen atom transfer-based C-C
coupling reaction between alkenes and ketones using Fe(acac)3 and
PhSiH3 in EtOH is described. This mild protocol features high site-
selectivity and allows for the construction of sterically congested
structures containing tertiary alcohols and quaternary centers. The
overall process introduces a novel strategic bond disconnection for
ring-closing reactions.
(a) HAT C-C Coupling precedents
(i) Shenvi
Mn(dpm)3
PhSiH3
TBHP, iPrOH
R1
R1
R2
Me
R2
alkene-
alkene
Me
(1)
(2)
n
n
R2
Fe(dipm)3
R3
R2
(ii) Baran
PhSiH3, EtOH
R1
R1
alkene-
Michael
acceptor
R3
EWG
Radical reactions are important tools for the construction of
carbon-carbon bonds, mainly via the addition of carbon-centered
radicals to unsaturated bonds.1 Such reactions often exhibit high
chemoselectivity, lead to a particular stereochemical outcome,
and are able to generate complex structures via tandem
reactions.2 Among the plethora of carboradical precursors,
alkenes offer many advantages: they are generally stable under
a wide range of conditions and are ubiquitous functional groups
found in a variety of feedstock chemicals.
EWG
H
R2
Me
Co(acac)3
TBHP, Et3SiH
CH2Cl2
(iii) Herzon
R1
alkene-
pyridinium
salt
R1
(3)
(4)
R2
H3C
N
R3
H
CH3
H3C
CH3SO3
N
CH3
OMe
(b) This work
O
OH
Due to these inherent advantages, the application of hydrogen
atom transfer (HAT) to generate carbon-centered radicals from
alkenes has become an active area of research.3 Drago4a and
Mukaiyama4b were pioneers in the use of alkenes as radical
precursors via HAT, combining cobalt complexes with oxygen to
access Markovnikov hydration products,4c although Norton5 was
the first to identify Halpern’s HAT mechanism6 in these reactions.
In this century, many researchers have expanded the scope of
the process to include other electrophiles or metals.7 However, it
was not until relatively recently that this methodology was shown
to have potential as a general approach to C-C bond formation.
In his hydrogenation studies,8 Shenvi proved it was possible to
intramolecularly couple two alkene units under HAT conditions
(Scheme 1a, Eq. 1).9 Baran´s group was the first to develop a
general coupling reaction using electron-deficient alkenes as the
electrophilic component in both intra- and intermolecular variants
using iron catalysis (Scheme 1a, Eq. 2).10 A number of other
methodological procedures (e.g. Scheme 1a, Eq 3)11 as well as
applications in natural product synthesis12 of HAT-promoted C-C
bond formation have been subsequently reported. Nevertheless,
to date the HAT-initiated process has not been applied to
reductively couple alkenes to ketones, despite the carbonyl
group being one of the most common unsaturated groups. While
radical cyclization onto a C=O π-bond is facile, rate studies have
shown that ring closure of radicals on carbonyl groups is slower
than the ring opening of the alkoxy radical counterparts,13
rendering carbonyl groups generally unfavorable as radical
acceptors. This is reflected by the scarce usage of radical
cyclizations to access cycloalkanols with ketones as radical
HAT conditions
R3
R2
[M]
R2
R1
alkene-
ketone
PhSiH3, solvent
R1
H
Key challenges of using a carbonyl as a radical acceptor:
Reverse reaction is faster (via alkoxy radical)
Competing abstraction, reduction and ring expansion pathways
Scheme 1. General context of C-C bond formation from alkenes via HAT and
the new challenge of using ketones as radical acceptors
acceptors, although in isolated examples haloalkanes,14
vinylbromide,15 alkynes,16 and epoxides17 have been used as
proradicals.
In this work, we expand the scope of the HAT process to
include ketones as radical acceptors (Scheme 1b, Eq 4).
Notably, this procedure overturns the character of the radical
donor in classical keto alkene cyclizations, in which an initial
ketyl radical is formed using either tributyltin hydride18 or
samarium iodide.19 In the new approach the carbonyl group
would play the role of the radical acceptor, allowing a new
procedure for the radical cyclization of keto alkenes.20
As part of our search for a stereodivergent process for the
hydrogenation of complex alkenes toward a unified synthesis of
phlegmarine alkaloids,21 we investigated a number of HAT
reductive conditions and developed an alternative protocol22
using stoichiometric Mn(dpm)3, PhSiH3 in DCE as the solvent,
which allowed clean quantitative conversion to the desired
products. While studying the scope of these hydrogenation
reaction conditions, we observed that if the substrate bore a
proximal carbonyl group, the radical intermediate was trapped,
affecting a coupling rather than a reduction reaction. Unusually,
in a process expected to be reversible, the starting keto alkene
could be channeled to the reduced tertiary alcohol product. Thus,
when keto alkene 123 was treated with Mn(dpm)3, and PhSiH3 in
DCE, the radical intermediate II did not evolve to the reduced
compound all-cis-trimethyldecalin I,24 but instead led to the
unexpected formation of tricyclic alcohol 2 (Scheme 2 and Table
1, entry 1).
a
[a]
M. Saladrigas, Caroline Bosch, G. V. Saborit, Prof. Dr. J. Bonjoch,
Dr. Ben Bradshaw
Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB,
Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona
(Spain)
E-mail: josep.bonjoch@ub.edu; benbradshaw@ub.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201709659
Angewandte Chemie International Edition
COMMUNICATION
mechanistic interest (Table 2). The related compound 3a with an
endocyclic double bond also gave 2. Compound 3b with the
alkene and ketone groups reversed in relation to compound 1
gave clean cyclization to tricyclic compound 4. The decalone
3c26 bearing an allyl side chain was coupled in good yield to give
5 (entry 2). Notably, the allyl group remained unreacted while
the formation of the radical took place exclusively at the
exocyclic methylene. Thus, this constitutes a clear example of in
situ selectivity dictated by the radical stability in HAT reactions
upon isolated alkenes.27 Similarly, the analogous dialkene 3d
gave clean cyclization from the methylene group onto the
carbonyl, leading to alcohol 6. To evaluate if our cyclization
reaction could compete with radical cross coupling reactions, we
performed the reaction of 1 in the presence of methyl vinyl
ketone.10a Although intramolecular reactions are normally much
faster, we wondered whether the formation of 7 might be favored
by the potential reversibility of the reaction or by a competitive
process. Indeed, a mixture of 2 and 7 (3:1) was isolated from the
reaction mixture.
O
Me
Mn(dpm)3
O
I
PhSiH3
Me
Me
Me
DCE
Me
O
Me
II
1
OH
2
Scheme 2. Intramolecular coupling vs reduction under HAT reaction
conditions.
This serendipitous observation opened the gates to the
underexplored field of carbon-carbon bond formation by HAT,
using the reaction of radical-centered carbons on ketone
carbonyl groups. To further explore the parameters of the
alkene-ketone coupling protocol (metal, solvent, temperature,
time), compound 1 was used as a test substrate, the key results
being summarized in Table 1 (see also SI). When using EtOH as
a solvent, the reaction was relatively high yielding (86%), but
less so than with DCE, and it also gave a small amount of by-
products (entry 2). After evaluating a series of modifications, we
found that an inert atmosphere was essential for a good yield,
which dropped to 73% in open air (entry 3). The reaction could
also be performed with catalytic quantities of Mn(dpm)3, albeit
with a slightly reduced yield compared to the stoichiometric
version (entry 4). Switching to Fe(acac)3 initially gave poor
results, with the yield dropping to just 30% (entry 5). However,
when EtOH was used as the solvent, the yield was not only
better than with DCE, but it also matched that observed with
Mn(dpm)3 when used in stoichiometric quantities (entry 6). It
was possible to shorten the reaction time to just 3 h or operate
at room temperature (entries 7 and 8), but both modifications
could not be combined without worsening the yield (entry 9).
Table 2. Substrate scope for HAT-triggered cyclization of alkenes onto
ketones.
O
OH
Fe(acac)3 (20 mol%)
PhSiH3 (2.5 equiv)
R3
H
R3
R2
R2
R1
EtOH
60 ºC, 3-24 h
R1
substrate
H
substrate
adduct
adduct
Me
Me
O
O
Me
OH
Me
OH
Me
3a
2 (74%)
3c
5 (80%)
Table 1. Screening of conditions for the radical cyclization of alkene-ketone 1
Me
Me
O
Me
Me
O
[M]
PhSiH3, solvent
Me
Me
OH
O
OH
Me
OH
Me
4 (68%)
3b
3d
6 (73%)
1
2
Entry[a]
Metal (equiv)
Solvent
T (ºC)
Time (h)
Yield
Competition experiment: Intermolecular vs intramolecular coupling
Me
Fe(acac)3 (30 mol%)
PhSiH3 (2.5 equiv)
1
Mn(dpm)3 (1)
Mn(dpm)3 (1)
Mn(dpm)3 (1)
DCE
EtOH
DCE
DCE
DCE
EtOH
EtOH
EtOH
EtOH
60
60
24
24
24
24
24
24
3
92%
86%
73%
79%
30%
95%
92%
95%
59%
O
O
2
Me
EtOH/(CH2OH)2 (5:1)
60 ˚C, 12 h
3[b]
60
60
60
60
60
25
25
1
OH
Me
O
O
4
Mn(dpm)3 (0.2)
Fe(acac)3 (0.2)
Fe(acac)3 (0.2)
Fe(acac)3 (0.2)
Fe(acac)3 (0.2)
Fe(acac)3 (0.2)
7 (23%)
2 (67%)
(3.0 equiv)
5
After studying the tricyclic series, we decided to extend the iron-
promoted intramolecular coupling of alkenes and ketones to
another set of molecules. Starting from γ,δ-unsaturated ketones
8a-8c, cis-ring fused hydrindane compounds28 9-11 were
obtained in 76-87% yield. In the presence of the radical
scavenger TEMPO (3 equiv) the reaction from 8c was not
promoted. Interestingly, although the cyclization of 8a-8c took
place onto a β-keto ester, the competitive Dowd-Beckwith ring
expansion13 was not observed. However, when keto alkene 8d
6
7
8
24
3
9
[a] PhSiH3 (2.5 equiv) was used. [b] Reaction carried out open to air.
With optimum conditions in hand, we evaluated this iron-
triggered radical cyclization25 in related substrates of synthetic or
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10.1002/anie.201709659
Angewandte Chemie International Edition
COMMUNICATION
the bridged compound 15 and perhydroindole 16 was obtained
starting from 8g, although in only moderate yield. The cyclization
of the open-chain ketone 8h was not diastereoselective,
Table 3. Extended substrate scope for the HAT-triggered cyclization of
alkenes onto ketones.[a]
cyclopentane 1714a being isolated as
a mixture of three
O
OH
Fe(acac)3 (20-100mol%)
PhSiH3 (2.5 equiv)
R3
H
R3
R2
diastereoisomers (dr 3:2.5:1).
R2
R1
Cyclization of compounds 8i and 8j gave the corresponding
hydrindanols 18 and 19 in comparable yields (54% vs. 60%).
This indicated that although a R1R2C=CH2 gem-disubstituted
alkene is likely a better carboradical source in the HAT process
than a monosubstituted alkene, this is counterbalanced by the
resulting increased steric crowding in the cyclization.
EtOH
60 ºC, 3-24 h
R1
H
substrate
substrate
adduct
adduct
OH
O
Me
HO
O
Me
CO2Me
O
Finally, the HAT alkene coupling reaction was applied to the
synthesis of a 12-demethyl analog of presilphiperfolan-8-ol.30,31
With cyclohexane 8i in hand, and following the reported
procedure of Ito,32 bridged compound 8k was easily synthesized.
The radical cyclization to form the 5,5-membered ring embedded
in tricyclic compound 20 was achieved in very good yield, its
structure being unequivocally confirmed by X-ray analysis.33 The
formation of the thermodynamically preferred stereoisomer is
due to the intermediacy of a pyramidalized C-radical.8a This
approach constitutes a straightforward synthetic entry to the
CO2Me
CO2Et
CO2Et
8a
O
9 (87%)[b,c]
8f
15 (50%)
Me
HO
O
Me
OH
O
CO2Me
O
CO2Me
N
N
Ts
H
O
O
Ts
O
characteristic
presilphiperfolanol sequiterpenes.34
tricyclo[5.3.1.04,1]undecane
skeleton
of
8b
10 (83%)[b]
8g
16 (40%)[b]
The reaction mechanism for the related radical C-C
formation between non-activated alkenes and Michael acceptors
in similar reaction conditions has been studied by Baran and
Holland, who provided considerable evidence for the different
Me
O
Me
OH
O
O
HO
Me
Ph
Me
CO2Me
intermediates.10c Based on this precedent,
a
simplified
CO2Me
Ph
mechanism for reductive coupling of alkenes to ketones is
outlined in Scheme 3. HAT from the HFe(acac)2, generated in
situ, to the olefin acts as the rate-determining step. Addition of
the carbon-centered radical to the ketone provides an alkoxy
radical, which, while being less favorable than the ring-opened
product, is converted to an alkoxide via a SET process from the
Fe(II) species with concomitant reoxidation to Fe(III). The latter
allows the catalytic cycle to continue via Fe(acac)2(OEt)
(Scheme 3, bottom right).
O
17 (81%)[b]
8c
11 (76%)
8h
R
Me
HO
O
CO2Me
R
OH
Me
O
Me
Me
Me
Me
CO2Me
O
H
O
O
H
O
Me
Me
8d
12 (64%)[b,d]
8i (R = H)
8j (R = Me)
18 (54%)[b]
19 (60%)[b]
Fe(acac)3
PhSiH3
Me
R2
Me
R2
R1
n
n
EtOH
n
O
O
R2
R1
Me
Me
CO2Me
CO2Me
R3
R3
H
R1
OH
R3
HFeIII(acac)2
H
H
H
O
Me
O
O
Me
Me
Me
O
Me
Me
O
Me
Me
R2
R1
O
O
O
FeIII(acac)2
EtOH
Me
R2
R1
Me
FeII(acac)2
n
EtOH
H
n
20 (83%)[b,c]
8k
R3
8e
14 (26%)
R3
EtO FeIII(acac)2
O
OH
Scheme 3. Overview of the proposed reaction mechanism.
[a] Yield for combined diastereomers (see SI for details) showing the major
isomer. 20 mol% Fe(acac)3 used. [b] 100 mol% Fe(acac)3 used. [c] Ethylene
glycol was added as a cosolvent to facilitate the removal of silyl by-products.
[d] 26% of ring-expanded product was also isolated.
Summary: In summary, we have shown that an iron-mediated
HAT reaction can be successfully employed to reductively
couple different types of unactivated alkenes with ketones. As
well as presenting a novel strategic bond disconnection for the
construction of sterically congested cyclic compounds, the
reaction exhibits site-selectivity between different alkenes
present in the same molecule. Both factors should find
application in the context of complex molecule synthesis.
Studies to apply this method to natural product synthesis and
expand this work to other related acceptor groups are currently
ongoing.35
was used as the starting material, in addition to the expected
decalin 12, the 10-membered ring expansion product 1329 was
isolated as a minor compound (26%). For compound 8e, bearing
an isopentenyl side chain, no cyclization was observed and only
a small amount of the reduced compound 14 was isolated,
presumably due to steric crowding, which would involve the
formation of a tertiary alcohol with two adjacent quaternary
centers. Compound 8f, bearing two carbonyls, selectively gave
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10.1002/anie.201709659
Angewandte Chemie International Edition
COMMUNICATION
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[35] After submission of this manuscript, Glorius has published the
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10.1002/anie.201709659
Angewandte Chemie International Edition
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Mar Saladrigas, Caroline Bosch, Gisela
V. Saborit, Josep Bonjoch*, and Ben
Bradshaw*
Page No. – Page No.
Hydrogen Atom Transfer-Initiated
Radical Cyclization of Alkene-
Tethered Ketones
A new HAT: An unprecedented hydrogen atom transfer (HAT)-based C-C coupling
reaction between unactivated alkenes and ketones using Fe(acac)3 and PhSiH3 in
EtOH is reported. As well as introducing a new strategic bond disconnection for the
construction of sterically congested cyclic structures, it allows differentially
substituted olefin types to be reacted in a site-selective manner.
This article is protected by copyright. All rights reserved.