Free-Radical Carbo-Alkenylation of Olefins: Scope, Limitations and Mechanistic Insights

Article abstract of DOI:10.1002/chem.201605043

The three-component free-radical carbo-alkenylation of electron-rich olefins has been studied, varying the substitution pattern in the alkene, in the radical precursor and in the final acceptor. New vinylsulfones were also prepared and their reactivity investigated. The scope and limitations of the process was established, and the reaction mechanism clarified using selected dienes as radical clocks. It was thus recognised that the reversible addition onto the olefin of the released sulfonyl group is an important event, which should not be overlooked when using such multicomponent carbo-alkenylation reactions.

Full text of DOI:10.1002/chem.201605043

A Journal of
Accepted Article
Title: Free-radical Carbo-alkenylation of Olefins. Scope, Limitations
and Mechanistic Insights
Authors: Yannick Landais, Redouane Beniazza, Virginie Liautard,
Clément Poittevin, Benjamin Ovadia, Shireen Mohammed,
and Frédéric Robert
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201605043
Link to VoR: http://dx.doi.org/10.1002/chem.201605043
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10.1002/chem.201605043
Chemistry - A European Journal
FULL PAPER
Free-radical Carbo-alkenylation of Olefins. Scope, Limitations and
Mechanistic Insights
R. Beniazza,[a] V. Liautard,[a] C. Poittevin,[a] B. Ovadia,[a] S. Mohammed,[a] F. Robert,[a] and Y. Landais*[a]
Abstract: The 3-component free-radical carbo-alkenylation of
electron-rich olefins has been studied, varying the substitution pattern
in the alkene, in the radical precursor and in the final acceptor. New
vinylsulfones were also prepared and their reactivity investigated. The
scope and limitations of the process was established, and the reaction
mechanism clarified using selected dienes as radical clocks. It was
thus recognised that the reversible addition onto the olefin of the
released sulfonyl group is an important event, which should not be
overlooked when using such multicomponent carbo-alkenylation
reactions.
fluorinated alkyl radicals,7 has for instance enjoyed recently a
strong growth, using photocatalytic processes promoted by visible
light.8 Polarity effects are important in such transformations, and
consequently the nature of the added radical and that of the olefin
greatly influences the outcome of the reaction.9 Electron-poor
radical species, such as fluorinated alkyl radicals, but also alkyl
radicals flanked by electron-withdrawing substituents (CN, CO2R,
PO(OR)2,….) have been shown to add efficiently to electron-rich
olefins (Figure 1).9d Electron-releasing substituents on the olefinic
backbone are also critical in these additions as to ensure high
rates. Consequently, enol ethers and thioethers, but also enamine,
enamides8j,k and strained olefins are substrates of choice for
these reactions. Addition of the first radical onto the olefin can
then be followed by the reaction of the resulting nucleophilic
radical with a radical trap (e.g. A-X) or simply oxidized into a
carbocation which may eventually be trapped in situ with a
nucleophile (Figure 1).8j,k Both outcome have been reported and
give access to a broad range of functionalities in a single pot
operation. Amongst A-X reagents, allyl-, vinyl- and
alkynylsulfones are reagents of choice, which have been studied
extensively.10
Introduction
Olefins are readily available feedstock, the functionalization of
which offers an easy access to a variety of important building
blocks for organic synthesis. The addition of carbon fragments
across the olefinic π-system has thus attracted a considerable
interest and is still the subject of an intense research nowadays.1
Transition-metal carbo-functionalization of olefins is
a
straightforward option to elaborate olefinic precursors.2 Free-
radical processes are also receiving a constant attention due to
mild reaction conditions and the large variety of substituents,
which can be added onto the olefinic backbone.1,3 The addition of
an alkyl radical onto a C=C bond is energetically favorable.
However, intermolecular radical additions to olefins often suffer
from low rates and are slowed down by steric hindrance and often
plagued by competing processes.3 Intramolecular radical
reactions onto unsaturated systems are in contrast much faster
and largely employed in synthetic sequences, including complex
radical cascades.4 Intermolecular addition to activated olefins
(acrylates and more generally electron-poor olefins), as in the
Giese reaction, have however been developed successfully and
found many useful applications in the synthesis of complex
substrates.5 The addition of electron-deficient radical species onto
electron-rich unsaturated systems, has also been investigated
and is currently receiving an increasing interest.6 The addition of
A
EDG
EDG
EDG
A
X
+
R
R
R
- X
R'
R'
R'
A : allyl, vinyl, alkynyl, Cl, CN,...
X : RSO2, RS, R3Sn,...
EDG : Electron-Donating-Group
Ox
(-e-)
Nu
Nu-
EDG
EDG
+
R
R
R'
R'
Figure 1. Free-radical addition onto electron-rich olefins.
In this context, our laboratory has developed three-component
radical functionalization of olefins, relying on the addition of two
carbon fragments across the olefinic skeleton, providing adducts
with two new C-C bonds along with two additional functional
groups.11 Carbo-alkynylation, carbo-oximation and carbo-
aminomethylation were thus devised, using various sulfones III to
trap the radical species issued from the addition of the radical
precursor I onto the olefinic partner II (Figure 2).12 More recently,
we extended this chemistry to the development of a one-pot
carbo-alkenylation of olefins including useful enamides and ene-
carbamates.13 We report here further studies in this context, which
not only expand notably the scope of the carbo-alkenylation
reaction, varying the nature of the olefinic pattern and that of the
sulfonyl acceptor, but also provide additional insights into the
mechanism of the process. Some functionalizations of the
[a]
Dr. R. Beniazza, Dr. V. Liautard, Dr. C. Poittevin, Dr. B. Ovadia, Dr.
S. Mohammed, Dr. F. Robert, Prof. Dr. Y. Landais
Institute of Molecular Sciences, UMR-CNRS 5255
University of Bordeaux
351, Cours de la libération
33405 Talence cedex, France
E-mail: y.landais@ism.u-bordeaux1.fr
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/chem.201605043
Chemistry - A European Journal
FULL PAPER
R3
R4
obtained radical adducts are also described showing the utility of
this one-pot process for synthetic purposes.
(Bu3Sn)2
R4
O
R2
R1
R5
PhO2S
DTBHN
X
R5
+
+
R1
1,2-DCE
65°C
R3
O
R2
SO2Ph
SO2Ph
R1
(1 equiv)
2 (4-10 equiv) 3-E (1 equiv)
4a-v
R1
R2
1a, R1 = OEt, R2 = H, X = S(C=S)OEt
R2
3-CR
EWG
X
I
II
, R1 = Me, R2 = H, X = S(C=S)OEt
1b
EWG
A
A
SO2Ph
1c, R1 = Ph, R2 = H, X = Br
III
New -bonds
, R1 = OPh, R2 = H, X = I
, R1 = Ph, R2 = Me, X = Br
1d
R1
R1
R2
1e
R2
SO2Ph
SO2Ph
NOBn
R
EWG
EWG
N
SiMe2Ph
EtO2C
PO(OEt)2
CN
SC(S)OEt
OBn
R
EtO2C
Ph
O
carbo-alkynylation
carbo-oximation
EWG
R1
SO2Ph
R
R
SO2Ph
SO2Ph
4b,75%
SO2Ph
4c, 58%
R2
4a
R1
R1
R2
NOBn
, 88%, d.r. 50:50
R2
R
EWG
OEt
OEt
O
EWG
HN
OBn
carbo-aminomethylation
EtO2C
PhO2S
R
EtO2C
EtO2C
carbo-alkenylation
4f, 59%, dr : 1:1
SO2Ph
4e, 65%
SO2Ph
4d, 76%
EtO2C
Figure 2. Three-component radical functionalization processes.
SiMe3
EtO2C
SO2Ph
O
OEt
O
Results and Discussion
PhO2S
SO2Ph
4h
, 51%, d.r. 45:55
O
4i, 79%, d.r. 3 : 1
4g
, 60%
The scope of the carbo-alkenylation was first extended to a series
of olefins 2, using xanthates, iodides and bromides 1a-e as radical
precursors in DCE, tBuON=NOtBu (DTBHN) as an initiator and
(Bu3Sn)2 to sustain the radical chain. Results are summarized in
Scheme 1 and 2. Simple esters and ketones were shown to be
efficient radical precursors, adding smoothly to olefins. We
observed little difference in reactivity between xanthates, iodides
and bromides. In most reactions, 4 equivalents of olefins were
required, but up to 10 equivalents were needed with less reactive
olefins (1-octene for instance). 1.2 Equivalents of disulfone 3-E
was used, whatever the nature of the olefin. Generally good yields
were obtained with allylsilanes as shown with the formation of
sulfone 4a. Functional groups in olefins 2, such as ketone, nitrile,
phosphonate or acetal were found to be compatible with reaction
conditions (i.e. 4b-e). Norbornene also reacted as expected
providing 4f, albeit with no diastereocontrol. Addition onto 1,1-
disubstituted olefins provided sulfones with an allylic all-carbon
quaternary center as in 4g and 4o. Electron-rich enol ethers were
found to be reactive with the electrophilic radical issued from 1a,
allowing additions onto 1,2-disubstituted double bonds as
illustrated with the formation of 4h-l. If one except the case of 4j
and 4k, which were formed as single trans isomers, low
stereocontrol was generally observed with prochiral enol ethers
as for example in 4h, 4i and 4l. Similarly, thioenol ethers also
reacted to give thioethers 4m and 4n in good yields. Other classes
of olefins, containing useful amino substituents, were also studied.
Enamides and ene-carbamates were shown to be reactive under
above conditions, as exemplified with the preparation of 4p-s in
moderate to excellent yields. As above for enol ethers, Addition
onto 1,2-disubstituted electron-rich olefins is not an issue as
shown with the preparation of 4p-q from the corresponding ene-
carbamates. Monoprotected allylamine and fully protected amino-
olefins were also found to react, affording the desired adducts 4t-
v in reasonable yields.
EtO2C
EtO2C
O
O
O
O
O
EtO2C
OBn
SO2Ph
PhO2S
PhO2S
4j, 37%, d.r. > 95:5
4k, 79%, d.r. > 95:5
4l, 55%, d.r. 4 : 1
OTBDMS
SEt
SEt
PhO2C
Ph
O
Ph
O
SO2Ph
4m, 66%
SO2Ph
4n, 61%, d.r. 49:51
SO2Ph
4o, 64%
OMe
OMe
NHCO2Me
MeO2C
EtO2C
N
O
N
EtO2C
R1
SO2Ph
SO2Ph
SO2Ph
4s, 86%
O
4r
, 48%
, R1 = Me, 82%, d.r. 55:45
, R1 = OEt, 62%, d.r. 55:45
4p
4q
NHBoc
NPhBoc
EtO2C
EtO2C
N(COMe)2
EtO2C
SO2Ph
4u, 65%
SO2Ph
SO2Ph
4t, 52%
4v, 56%
Scheme 1. Carbo-alkenylation of olefins using disulfone 3-E.
Readily available bromides are also potent radical precursors as
illustrated below with some reactions using -bromonitrile 5a or
fluorinated -bromo esters 5c-d14 (Scheme 2). Reactions were
performed using conditions above and 3-Z as the sulfone
acceptor, leading exclusively to E-vinylsulfones 6a-i in reasonable
yields. This is in good agreement with previous studies,15 which
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10.1002/chem.201605043
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established that the E-olefin was always obtained, irrespective of
the geometry of the starting sulfone (vide infra). Slightly lower
yields were obtained with fluoro or difluoroesters, while precusor
5e led to the 3-component adducts 6h-i in excellent yields. Aryl
iodides were also reacted under similar conditions, but all our
efforts to obtain useful amount of product were unsuccessful.16
(Bu3Sn)2
DTBHN
EtO2C
S(C=S)OEt
1a
PhO2S
EtO2C
1,2-DCE
65°C
3-E
SO2Ph
SO2Ph
10, 48%, d.r. 1:1
9
(Bu3Sn)2
DTBHN
EtO2C
S(C=S)OEt
1a
EtO2C
R4
(Bu3Sn)2
DTBHN
R5
SO2Ph
R5
PhO2S
R1
R2
R6
R3
Br
R2
R1
1,2-DCE
65°C
SO2Ph
SO2Ph
R6
3-E
+
+
SO2Ph
R3
R4
1,2-DCE
65°C
12, 65%, d.r. 8 : 2
2
11
5a, R1 = CN, R2 = R3 = H
Z
SO2Ph
3-
5b, R1 = R2 = CO2Me, R3 = H
5c, R1 = CO2Et, R2 = F, R3 = H
5d, R1 = CO2Et, R2 = R3 = F
6a-i
Scheme 4. Carbo-alkenylation of limonene 9 and norbornadiene 11.
5e, R1 = MeO2C(CH2)2CO, R2 = R3 = H
Dienes 13 and 17 behaved somewhat differently from simple
alkenes and produced a mixture of products, depending on the
ratio between the olefin and the tin mediator (Scheme 5). For
instance, treatment of an excess of diene 13 (4 eq.) as above, led
to a mixture of 14, 15 and 16. The former results from the addition
of the electrophilic phenylsulfonyl radical onto one of the C=C
bond of 13,19 while 15 and 16 are issued from the trapping of the
final primary radical, respectively by the xanthate 1a and sulfone
3-E. Similarly, cycloocta-1,5-diene 17, which has been used
previously as a radical clock,20 also afforded a mixture of
bicyclo[3.3.0]octane systems 18 and 19 depending on the ratio
between 17 and (Bu3Sn)2. In both cases, an excess of olefin was
shown to favor the addition of the PhSO2 radical. The best results
were finally obtained when the three components and the tin
mediator were present in a (quasi) equimolar ratio. In each case,
a major diastereomer was formed, the structure and relative
OtBu
NC
NC
NC
N
Boc
SO2Ph
SO2Ph
PhO2S
6a, 52%
6b, 62%, d.r. > 95:5
6c, 57%
MeO2C
MeO2C
MeO2C
MeO2C
F
SiMe2Ph
EtO2C
Cl
SO2Ph
6e, 43%
SO2Ph
6d, 48%
SO2Ph
6f
, 49%, d.r. 55:45
F
F
SiMe2Ph
SiMe2Ph
EtO2C
O
EtO2C
O
N
Boc
SO2Ph
SO2Ph
6g, 32%
CO2Me
PhO2S
6h
6i
, 63%, d.r. > 95:5
, 85%
1
configuration of which were assigned using H NMR and X-ray
diffraction studies (for X-ray of 18, see supporting information).
Scheme 2. Carbo-alkenylation using bromide precursors 5a-e.
SO2Ph
EtO2C
-Pinene 7 was also treated under the same conditions than
above and afforded, after rearrangement,17 sulfone 8 in moderate
yield (Scheme 3), indicating that ring opening is faster than the
intermolecular trapping of the secondary radical by disulfone 3
(vide infra).
1a
(1 eq.)
S(C=S)OEt
EtO2C
14
3-E (1.2 eq.)
(Bu3Sn)2
EtO2C
EtO2C
(d.r. 86:14)
CO2Et
DTBHN
1,2-DCE
65°C
13
EtO2C
EtO2C
R
14 15 16
13
/
/
/ (Bu3Sn)2
CO2Et
(Bu3Sn)2
EtO2C
S(C=S)OEt
1a
15
4 : 1.2
1 : 1.2
(72%) 29 : 51 : 20
(64%) 0 : 0 : 100
, R = S(C=S)OEt (d.r. 80:20)
DTBHN
16, R = CH=CHSO2Ph (d.r. 95:5)
PhO2S
1,2-DCE
65°C
8
51%
PhO2S
H
3-E
SO2Ph
SO2Ph
1a
(1 eq.)
7
3-E
(1.2 eq.)
H
(Bu3Sn)2
Scheme 3. Carbo-alkenylation of -pinene 7.
18
(d.r. 95:5)
SO2Ph
DTBHN
1,2-DCE
65°C
EtO2C
H
17
17 / (Bu3Sn)2
Extension of the three-component carbo-alkenylation to dienes
led to important observations from a mechanistic point of view.
Regioselective addition of the radical precursor to the 1,1-
disubstituted double bond of limonene 9 led to the sulfone 10, the
subsequent cyclization onto the endocyclic double bond being
unfavored (Scheme 4). Norbornadiene 11 led to 12 as a mixture
of two diastereomers after cyclization of the radical resulting from
the addition of xanthate 1a.18
18 / 19
H
4 : 1.2
4 : 2
(79%) 35 : 65
(81%) 30 : 70
(79%) 6 : 94
19
(d.r. 95:5)
SO2Ph
1 : 1.2
Scheme 5. Carbo-alkenylation of diene 13 and cyclocta-1,5-diene 17.
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These last results led us reconsidering the radical chain
mechanism, by including the addition of the released PhSO2
radical onto the olefin component, a crucial step in the process.
The study on dienes was also extended to systems having
electronically differentiated C=C bonds, as for instance in 20 and
24a-b (Scheme 6). In the former, addition of xanthate 1a occurred
preferentially onto the electron-richer ene-carbamate moiety to
provide a nucleophilic radical which was trapped by disulfone 3-
E, thus underlining the importance of polar effects in such
processes. Interestingly, when sulfonyloxime 22 was used
instead of 3-E, the addition of 1a was followed by a 5-exo-trig
cyclization and final trapping of the primary C-centered radical by
22. This clearly indicates that 3-E is a very efficient radical trap,
as addition of primary alkyl radicals onto 22 is known to proceed
with a rate constant of 9.6 x l05 M-1s-1 (25 °C).24 The high reactivity
of 3-E was further supported by the absence of 5-exo-trig
cyclization products during addition of 1a onto dienes 24a-b,
which afforded instead 25a-b, resulting from the addition onto the
enamide moiety. Interestingly, we also observed the formation of
by-products 26a-b, resulting from the addition of the tBuO radical
generated from DTBHN. The addition of this radical onto the olefin
in these 3-component processes has never been observed before,
but is not so surprising considering the electrophilic nature of the
alkoxy radicals.25,26
Figure
3 below summarizes a reasonable radical chain
mechanism, incorporating the reversible phenylsulfonyl addition.
The tin radical, generated through reaction of (Bu3Sn)2 with
DTBHN, abstracts the xanthate or the halogen atom from I to form
the electrophilic radical A, which adds to the olefin II. The new
nucleophilic radical B may then react with the sulfonyl derivative
III (i.e. 3) to afford the final product. Depending on the nature of
the olefin, the atom transfer product may also be isolated.21
Usually, it is further consumed in the reaction medium by adding
an additional amount of the initiator (DTBHN) as long as sufficient
ditin reagent is present. With electron-rich enamides, the atom
transfer product is not formed under these conditions, the
nucleophilic radical B ( to nitrogen) reacting faster with the
electron-deficient disulfone 3.13 The released PhSO2 radical then
sustains the radical chain by reacting with ditin to furnish
PhSO2SnBu3 and a new tin radical. The addition of the PhSO2
radical onto the olefin also occurs, generating radical C, whatever
the nature of the olefin, but this step is reversible and -
fragmentation of the -sulfonyl radical is known to be fast with
most olefins.22 With dienes such as 13 or 17, 5-exo-trig cyclization
of the -sulfonyl radical C competes with -fragmentation, thus
generating radical D. Rate constants for such cyclizations are
estimated to be in the range 105 s-1 and 106 s-1 respectively.23 As
a comparison, -fragmentation rate constants are in the range of
105 s-1.22 The cyclization step leading to radical D is irreversible
and leads to products 14 or 18, depending on the relative
reactivity between xanthate 1a and sulfone 3. Using an excess of
olefin thus favors, in these cases, the addition of the electrophilic
sulfonyl radical and leads to an increase of the concentration of
radical C. We already observed a similar phenomenon during our
study on carboalkynylation of olefins, using vinyl pivalate as an
olefin. In this case, the -fragmentation was reported to be slow
and large amount of sulfonyl addition intermediate C was
formed.12b
3-E (1.2 eq.)
(Bu3Sn)2
DTBHN
Boc
N
Boc
N
EtO2C
S(C=S)OEt
+
EtO2C
1,2-DCE
65°C
20
1a
PhO2S
21
, 59%
NOBn
22
PhO2S
(1.2 eq.)
(Bu3Sn)2, DTBHN
1,2-DCE, 65°C
Boc
N
EtO2C
BnON
23, 40%
CO2Et
O
N
SO2Ph
R
3-E (1.2 eq.)
PhSO2
25a, R = H (24%)
25b, R = Me (41%)
(d.r. > 95:5)
(Bu3Sn)2
DTBHN
R1
R1
R
PhO2S
1a
+
+
Products
O
N
1,2-DCE
Ot-Bu
C
D
R
65°C
R1
R2
X
R1
R
O
N
SO2Ph
R2
EWG
R
24a, R = H
Bu3Sn-SnBu3
24b, R = Me
26a
26b
, R = H (7%)
PhSO2
R
, R = Me (16%)
PhSO2-SnBu 3
(d.r. > 95:5)
SO2Ph
III
X
tBuO
R1
R2
Bu3Sn
Bu3Sn-SnBu3
Scheme 6. Carbo-alkenylation of dienes 20 and 24a-b.
EWG
B
EWG
Y
I
EWG
Y
Finally, while most electron-rich olefins reacted efficiently under
the above conditions, such was not the case with allylic alcohols
and ethers (Scheme 7). Unprotected allylic alcohols did not react
at all.27 Protection of the alcohol function as in allylic ethers 27
restored the desired reactivity, but led to the expected compound
28 in low yield and no stereocontrol. Phenylallyl ethers 29a-b
reacted under the standard conditions, but furnished in both cases
the corresponding phenols as main isolable products, likely as a
result of the -fragmentation of the phenoxy radical.28 Recent
atom-transfer
process
EWG
A
Bu3SnY
R1
R1
R2
R2 II
EWG
Y
Figure 3. Radical chain mechanism of the carbo-alkenylation of olefins.
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10.1002/chem.201605043
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studies by Zard et al. have shown that related allylic ethers are
precursor in the presence of (Bu3Sn)2 and DTBHN in 1,2-DCE.
Results are summarized in Table 1 below. Carbo-alkenylation
generally occurs with high yields and in most cases with excellent
stereocontrol, the E-isomer largely predominating. As shown
above, E- and Z-acceptors 315a-c led selectively to adduct 33a with
excellent yields and E-configuration (Entries 1-2, Table 1).
Replacing one of the sulfonyl groups with an ester as in 32a-b
(Entries 3-4) surprisingly led to much lower yields. Styrrylsulfone
32c15a-c (Entry 5) provided good yield of the sulfone adduct 33c,
while the silylsulfone analogue 32d proved unreactive (Entry 6). It
is worth adding that 32c was however much less reactive than 3-
E or 3-Z, requiring several additions of DTBHN to afford 33c.
Chlorosulfone 32e reacted smoothly, giving vinyl chloride 33e,
albeit with low stereocontrol (entry 7). Electronic effects were also
studied using model acceptors 32f-i32,33 (entries 8-11). Reactions
on these acceptors occurred on the less hindered site, providing
adducts 33f-i in good yields and variable stereocontrol,
depending on the nature of the para-substituent on the aromatic
ring, but always favouring the retention of configuration.33 Olefins
32j-n34 proved to be excellent Michael acceptors, leading to
adducts 33j-l in good yield, in fast reactions usually requiring a
single addition of DTBHN. In good agreement with previous work
by Russel et al.,15a-c chlorine and bromine were also shown to be
good leaving groups in these reactions, as illustrated with the
formation, in high yields, of addition products 33j-l from
precursors 32j-n (Entries 12-16).15a-c Finally, -nitrostyrene35
(Entry 18) was not reactive under our reaction conditions, only
leading to traces of 33c.
efficient allylating agents.29
3-E
(1.2 eq.)
OTBDMS
(Bu3Sn)2
DTBHN
OTBDMS
1a
+
EtO2C
1,2-DCE
65°C
PhO2S
28
27
, 30%, d.r. 1:1
1a
conditions
OPh
29a
PhOH
HO
above
1a
O
OMe
OMe
OMe
conditions
above
OMe
29b
Scheme 7. Carbo-alkenylation of allylic ethers 27 and 29a-b.
The treatment of vinyltrifluoroborate 30 under the three-
component reaction conditions in the presence of 1a and 3-E
surprisingly and reproducibly (in 1,2-DCE or benzene) furnished
the adduct 31 in moderate yield (Scheme 8). When the reaction
was repeated with -bromoacetate instead of 1a, adduct 31 was
again obtained, albeit in only 19% yield. Changing xanthate 1a for
the benzoyl xanthate led to a complex mixture of products, but no
trace of addition product. Interestingly, the formation of 31 in low
amount was also observed during 3-component reaction between
1a, 3-E and unreactive olefins such as sterically hindered
triacetyl-D-glucal, therefore indicating that 30 is not the olefinic
partner during the formation of 31 in the reaction below. Although
definitive conclusions cannot be drawn at that stage, it may be
hypothesized that the formation of 31 is the result of the carbo-
alkenylation of but-1-ene. The latter might be formed through-
elimination of a -stannylalkyl radical, generated from a Bu3SnX
species present in the medium. This radical might result from an
abstraction, by a tbutoxy radical (DTBHN), of an hydrogen of one
of the butyl chains in Bu3SnX. -elimination of such -stannylalkyl
radicals was invoked to explain the formation of but-1-ene during
thermolysis of Bu3SnCl at 200-300°C, occurring through
disproportionation into Bu2SnCl2 and Bu4Sn.30 Although much
milder conditions are used here, decomposition of Bu3SnOt-Bu
(formed during initiation, Figure 3) or/and Bu3SnSO2Ph might thus
lead to sufficient concentration of but-1-ene to allow for the
formation of 31. Interestingly, when the reaction was carried out
using (Me3Sn)2 instead of (Bu3Sn)2, compound 31 was not formed,
supporting the above hypothesis.
Table 1. Carbo-alkenylation of allylsilane 2a with acceptors 3 and 32a-p.
1a
(1 equiv)
SiMe2Ph
(Bu3Sn)2
DTBHN
SiMe2Ph
R2
2a
EtO2C
R1
1,2-DCE
65°C
X
R1
R2
32a-o
33a-l
Entry Acceptor[a]
R1
R2
X
33
E/Z [b]
Yield
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3-E
3-Z
32a
32b
32c
32d
32e
32f
32g
32h
32i
32j
32k
32l
SO2Ph
H
CO2Et
H
Ph
Me3Si
Cl
Cl
Cl
Cl
Cl
CO2Et
CO2Et
CO2Et
CN
SO2Ph
Ph
H
SO2Ph
H
CO2Et
H
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
33a
33a
33b
33b
33c
33d
33e
33f
33g
33h
33i
33j
33j
95:5
95:5
95:5
95:5
95:5
-
65:35
82:18
90:10
92:8
95:5
95:5
95:5
95:5
95:5
95:5
95:5
-
88
78
27
20
74
-
75
71
68
65
75
71
73
79
76
56
49
traces
H
H
Ph
pTol
pMeOPh
pMeO2CPh SO2Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
SO2Ph
Cl
Br
Cl
Cl
3-E (1.2 eq.)
(Bu3Sn)2
33j
33k
33l
33c
33c
DTBHN
1a
32m
32n
32o
32p
+
EtO2C
BF3K
30
1,2-DCE
65°C
SO2Ph
, 43%
Br
NO2
31
Ph
H
[a] E/Z ratio in acceptors 32a-p is > 95:5. [b] E/Z ratio estimated by 1H NMR. [c]
Yield of isolated products.
Scheme 8. Carbo-alkenylation of vinyltrifluoroborate 30.
In order to extend the scope of the carbo-alkenylation reaction,
various acceptors were then studied.31 A survey on the effect of
the substitution pattern on the vinyl acceptor was thus performed
using allylsilane 2a as a model olefin and xanthate 1a as a radical
This study finally allowed us drawing a general picture to
rationalize both the reactivity of these radical traps and the
stereocontrol of the addition-elimination process (Figure 4). When
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10.1002/chem.201605043
Chemistry - A European Journal
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using trisubstituted olefins, addition of the radical species occurs
on the less sterically hindered position, - to the acceptors, as
shown with 32f-n. With disubstituted systems, the picture is less
clear-cut and depends on the steric and electronic nature of both
substituents and attacking radical species. For instance,
stabilization of the radical intermediate is important as shown in
32c and 32o where a stabilized benzylic radical is formed upon
radical addition. In systems having two conjugate acceptors
acting in opposition as in 32a and 32b with PhSO2 and CO2Me
substituents, the nucleophilic radical may add on both centers,
explaining the low yield observed in this case. With
chlorovinylsulfone 32e, the addition occurs with high selectivity -
to the sulfonyl group, yet the more powerful acceptor. This
regioselectivity is in good agreement with pioneering studies by
Russel et al.15c who showed that addition of secondary alkyl
radicals occurred preferentially  to PhSO2 (e.g. a 85:15
selectivity was observed with a cyclohexyl radical). This was
explained by the interplay between steric factors and polar effects.
Stabilization of the resulting radical by the -chlorine atom may
also explain this selectivity. Stereocontrol is another issue in this
process. In most cases, the reaction proceeds with retention of
configuration.15c With trisubstituted sulfones 32f-i, retention of
configuration was generally observed, with a level of stereocontrol
depending on the nature of the para substituent of the aromatic
moiety, and increasing in the order H < Me < OMe < CO2Me. This
order is consistent with the radical stabilizing effect of these
substituents. Addition of a nucleophilic alkyl radical (R) onto these
olefins generates a benzylic radical intermediate, eventually
leading to conformations IVa-b in which the C-SO2Ph bond and the
radical orbital are suitably aligned for-elimination (Figure 4).
Barrier to rotation (IVa  IVb) is likely higher with more stabilizing
substituents (X = CO2Me) thus leading to more retention. In
disubstituted systems, the radical intermediate is not stabilized by
resonance. For instance, with disulfone 3-Z, interconversion
between conformations such as IVa and IVb must be fast relative
to -elimination, the latter occurring from a conformation
minimizing interactions between the attacking R group and the
remaining PhSO2 substituent.
Based on the above observations, best acceptors were used
varying the nature of olefins. Results of these investigations are
summarized in Scheme 9 below. Vinylsulfone 32j provided the
desired adducts with yields similar to those obtained with the vinyl
chloride analogue 32k. As above, the reaction was compatible
with a wide range of olefins. Noteworthy, reactions with these
acceptors were fast processes, requiring the addition of smaller
amount of initiator as compared to those needed for acceptors
such as 3-E and 3-Z (0.15 to 0.3 equiv. of DTBHN).
R2
R3
R3
DTBHN
EtO2C
EtO2C
R4
CO2Et
1a
or
1d
(0.15-0.3 eq)
+
R4
+
(Bu3Sn)2
1,2-DCE
R2
R1
O
X
2
32j
CO2Et
34a-h
, X = SO2Ph
32k, X = Cl
OAc
OMe
CO2Et
Cl
CO2Et
EtO2C
EtO2C
EtO2C
CO2Et
CO2Et
CO2Et
CO2Et
34a, 72% (from 32j)
34a, 39% (from 32k)
34b, 41% (from 32j)
34b, 41% (from 32k)
34c, 58% (from 32k)
MeO
MeO
Br
EtO2C
Boc
CO2Et
Boc
N
N
N
CO2Et
Boc
EtO2C
CO2Et
EtO2C
CO2Et
EtO2C
CO2Et
34d, 56% (from 32j) d.r. > 95:5
34e, 73% (from 32j)
34f, 53% (from 32j)
OTBDMS
CO2Et
BocHN
CO2Et
CO2Et
NHBoc
EtO2C
CO2Et
PhO2C
EtO2C
CO2Et
34h, 56% (from 32j)
CO2Et
34i, 72% (from 32j and 1d)
34g
32j
)
, 87% (from
Scheme 9. Carbo-alkenylation of olefins 2 with Michael acceptors 32j-k.
The reaction was also performed starting from -bromo
acylsilane12b 35 and 2-methoxypropene, which led in the
presence of Michael acceptor 32j, to the corresponding
unsaturated acylsilane 36 in good yield (Scheme 10).
acceptor
EWG
X
Ar
EWG
acceptor
acceptor
(32f-n)
(32c, 32o)
X
X = SO2Ph, Br
32j
acceptor
(Bu3Sn)2
OMe
CO2Et
O
CO2R
Cl
PhO2S
acceptor
PhO2S
acceptor
DTBHN
+
32a,b
(
32e
( )
tBuMe2Si
)
OMe
tBuMe2Si
O
1,2-DCE
Br
CO2Et
36, 62%
65°C, 1.5 h
SO2Ph
35
R
p-XAr
H
p-XAr
Cl
Cl
Scheme 10. Carbo-alkenylation of 2-methoxypropene with -bromo acylsilane
35.
R
H
SO2Ph
IVa
IVb
Three-component adducts may be elaborated further as
illustrated below with the transformation of diester 34i into the
fused tetrahydrofuran 37 (Scheme 11). Treatment of 34i with
(tris(dimethylamino)sulfonium difluorotrimethylsilicate) (TASF)
led to a tandem desilylation/oxa-Michael process affording 38 as
a mixture of diastereomers. Deprotonation of 38 with NaH then
triggered a Dieckmann-type cyclization, which was followed by
the saponification of one of the ester group, then decarboxylation,
R
R
p-XAr
Cl
Cl
Arp-X
E (retention)
Z (inversion)
Figure 4. Radical addition to acceptors (arrows indicates the regioselectivity of
the process).
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10.1002/chem.201605043
Chemistry - A European Journal
FULL PAPER
to eventually give the fused tetrahydrofuran 37 in 41% overall
yield. Formation of a single isomer of 37, starting from a 72:28
mixture of 38 indicates that the oxa-Michael process is reversible.
This was confirmed when the cyclisation of 34i was carried out in
a single pot, using dry TBAF, leading to 37 in 65% overall yield
with complete diastereocontrol.
conjugated dienes. In this case, the reaction only requires the use
of an equimolar amount of diene and precursor 1a, as to avoid
competing reactions such as the addition of the sulfonyl radical,
released from the vinylsulfone acceptor. This addition occurs
irrespective of the nature of the olefin, but is reversible, except
with dienes where a fast 5-exo-trig cyclization competes. The
study on dienes thus showed that the addition of the electrophilic
sulfonyl radical is an important step which should not be
overlooked when designing such 3-component carbo-alkenylation
reactions. These studies allowed a better understanding of the
reaction mechanism, which will however await for further kinetic
studies regarding for instance addition onto sulfonyl acceptors,
where kinetic data are scarce.22 Variation of the substitution
pattern of these acceptors have led to the development of new
Michael acceptors, which were elaborated further, demonstrating
that useful intermediates for organic synthetic purposes may be
assembled in no more than two steps in a straightforward manner.
Dry TBAF
OSiMe2tBu
CO2Et
CO2Et
°
MS, THF
4A
PhO2C
O
HO
20°C, 3 h
65%, d.r. > 95:5
CO2Et
34i
37
TASF, THF
20°C, 24 h
NaH, THF
20°C, 24 h
PhO2C
63%, d.r. 72:28
65%, d.r. > 95:5
EtO2C
EtO2C
O
38
Scheme 11. Elaboration of diester 34i into fused tetrahydrofuran 37 through a
desilylation/oxa-Michael/Dieckmann/saponification/decarboxylation process.
Experimental Section
General procedure for the carbo-alkenylation of olefins. To a solution
of xanthate, bromide or iodide 1 (1 equiv.) in dry 1,2-DCE (2.5 to 5 mL)
were added olefin 2 (1 to 4 equiv.), sulfone 3 (1.2 equiv.) and di(tributyltin)
(1 to 1.5 equiv.). The reaction mixture was degassed and then stirred at
65°C. Then 15 mol% of DTBHN was added and the reaction mixture stirred
for 1.5 h. The reaction progress was monitored by TLC and further
additions of DTBHN (15 mol %) were carried out (up to 3 times every 1.5
h) depending on the quantity of precursor 1 remaining. The yellow reaction
mixture was then concentrated under reduced pressure and the residue
purified by chromatography on silica gel (Petroleum Ether / EtOAc).
Michael addition was also performed using unsaturated sulfones
as illustrated in Scheme 12.36 For instance, pyrrolidine was able
to initiate the intramolecular conjugate addition in 39, leading to
spiroketone 40 in good yield. Intramolecular Michael addition in
41 led similarly to cyclohexanone 42 as a single diastereoisomer.
In the last case, it is worthy of note that the second cyclization
onto the ester group does not take place under these conditions,
and 43 can be isolated as a single trans-diastereoisomer.
Full synthetic details and characterization data is available in the
Supporting Information. The crystal structure of compound 18 was
deposited at the Cambridge Crystallographic Data Centre.
The data have been assigned to the following deposition number: CCDC
1508782.
O
, THF
20°C, 12 h
N
H
NBoc
O
NBoc
PhO2S
PhO2S
40, 61%
39
Acknowledgements
SO2Ph
O
O
, THF
N
H
We thank CNRS, MNERT, ANR (RAD-MCR N°11-BS07-010-01) for
generous support. We are grateful to B. Stinus, J. Lusseau and C. Davies
for preliminary experiments, N. Pinaud, and J.M. Lasnier (CESAMO, ISM,
University of Bordeaux) for NMR experiments and to Dr. B. Kauffmann and
S. Massip (IECB, Bordeaux) for X-ray diffraction studies.
SO2Ph
20°C, 24 h
N
N
O
O
O
O
41
42
, 79%, d.r. > 95:5
O
, THF
N
H
Keywords: Radicals • Addition-elimination • multicomponent reactions •
-fragmentation •
EtO2C
O
EtO2C
20°C, 72 h
SO2Ph
SO2Ph
4d
43, 61%, d.r. > 95:5
[1]
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10.1002/chem.201605043
Chemistry - A European Journal
FULL PAPER
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3-E (1 eq.)
(Bu3Sn)2
[7]
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I
DTBHN
SiMe2Ph
+
SiMe2Ph
1,2-DCE
65°C
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R
SO2Ph
i-a
i-b
ii-a
ii-b
, R = H
, R = H, 32%
, R = Cl
, R = Cl, 40%
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3-E (1 eq.)
(Bu3Sn)2
OtBu
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DTBHN
N
Boc
N
SO2Ph
1,2-DCE
65°C
Boc
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10.1002/chem.201605043
Chemistry - A European Journal
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[28] The product resulting from the addition of the xanthate 1a onto 29a-b
was not observed and only the phenols were recovered.
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[37] Compounds 39 and 41 were prepared through carbo-alkenylation of the
corresponding olefins with xanthate 1b and sulfone 3-E in 41% and 67%
yield respectively (see supporting information).
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Entry for the Table of Contents
FULL PAPER
Radical and fast. Free-radical carbo-
alkenylation of electron-rich olefins
has been studied, varying the
substitution pattern on the alkene, the
radical precursor and on the final
sulfonyl acceptor. The scope and
limitations of the process was
established, and the reaction
mechanism precised using selected
dienes as radical clocks. It was shown
that the reversible addition of the
released sulfonyl group onto the olefin
is important and should not be
overlooked when using such
R. Beniazza, V. Liautard, C. Poittevin, B.
Ovadia, S. Mohammed, F. Robert, and
Y. Landais*
Page No. – Page No.
Free-radical Carbo-alkenylation of
Olefins. Scope, Limitations and
Mechanistic Insights
processes.
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