Free-radical carboalkynylation and carboalkenylation of olefins

Article abstract of DOI:10.1021/ol2007633

Free-radical three-component carboalkynylation and -alkenylation of olefins have been developed. These involve the addition, across the double bond of an unactivated olefin, of a radical species α- to an electron-withdrawing group and an alkenyl or alkynyl moiety, derived from the corresponding sulfones.

Full text of DOI:10.1021/ol2007633

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2658–2661
Free-Radical Carboalkynylation
and Carboalkenylation of Olefins
ꢀ ꢀ
Virginie Liautard, Frederic Robert, and Yannick Landais*
ꢀ
University of Bordeaux, Institut des Sciences Moleculaires, 351, cours de la liberation,
ꢀ
33405 Talence Cedex, France
y.landais@ism.u-bordeaux1.fr
Received March 22, 2011
ABSTRACT
Free-radical three-component carboalkynylation and -alkenylation of olefins have been developed. These involve the addition, across the double
bond of an unactivated olefin, of a radical species R- to an electron-withdrawing group and an alkenyl or alkynyl moiety, derived from the
corresponding sulfones.
Intermolecular addition of two functionalized carbon
fragments across an electron-rich olefinic π-system re-
mains a challenging transformation and still the subject of
intense scrutiny. Several transition metal complexes are able
to mediate such a process, in a single pot, but the versatility
of the method is somewhat restricted by the limited func-
tional group tolerance on both the olefin and the added
fragments.1 Radical chemistry is potentially able to mediate
such a transformation with more flexibility. Several exam-
ples of one-pot functionalization of conjugated olefins
under mild radical conditions have thus been reported.2 In
contrast, little has been done on the analogous transforma-
tion involving electron-rich olefins.3 Pioneering studies by
Fuchs et al.4 have shown that carboalkynylation using
trifluoromethylsulfonylalkyne derivatives is effective, allow-
ing the addition of CF3 and alkyne moieties across the π-
system. However, this method is limited to the introduction
of a CF3 group as the initial electrophilic component.
Multicomponent reactions may offer an attractive solution,
extending the nature of the fragments that may be added
onto the olefinic backbone. Multicomponent processes5 rely
on the matched polarity between the different partners.6 The
free-radical addition onto an electron-rich olefin thus im-
plies that an electrophilic radical component is added first
on the olefin, affording a nucleophilic radical intermediate
that should in turn be trapped by an electrophilic partner.
These three-component reactions were recently defined as
ADA-processes involving the intermolecular assembly be-
tween an acceptor (A), a donor (D), i.e. an olefin, and an
€
(1) Carbopalladation: (a) Brase, S.; De Meijere, A. Palladium-cata-
lyzed cascade carbo-palladation: Termination by nucleophilic reagents in
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-I., Ed.; John Wiley & Sons, Inc: 2002; pp 1405ꢀ1429. (b) Oda, H.;
Hamataka, K.; Fugami, K.; Kosugi, M.; Migita, T. Synlett 1995, 1225.
Pt-catalyzed diboration: (c) Kilman, L. T.; Mlynarski, S. N.; Morken,
J. P. J. Am. Chem. Soc. 2009, 131, 13210. Zr-catalyzed carboalumina-
tion: (d) Zhu, G.; Liang, B.; Negishi, E.-I. Org. Lett. 2008, 10, 1099 and
references cited therein.
(2) (a) Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed. 1996, 118,
1209. (b) Miura, K.; Fujisawa, N.; Saito, H.; Wang, D.; Hosomi, A. Org.
Lett. 2001, 3, 2591. (c) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem.
Res. 1991, 24, 296. (d) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32,
163. (e) Schaffner, A. P.; Sarkunam, K.; Renaud, P. Helv. Chim. Acta
2006, 89, 2450.
(4) (a) Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 4486.
(b) Xiang, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 11986. (c) Xiang,
J.; Jiang, W.; Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1997, 119, 4123.
(d) Xiang, J.; Fuchs, P. L. Tetrahedron Lett. 1996, 37, 5269. (e) Xiang, J.;
Jiang, W.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 6635. (f) Xiang, J.;
Fuchs, P. L. Tetrahedron Lett. 1998, 39, 8597.
(5) (a) Ryu, I. Multicomponent radical reactions. In Multicomponent
ꢀ
Radical Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
2005. (b) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177.
(6) (a) DeVleeschouwer, F.; VanSpeybroeck, V.; Waroquier, M.;
Geerlings, P.; DeProft, F. Org. Lett. 2007, 9, 2721. (b) Arthur, N. L.;
Potzinger, P. Organometallics 2002, 21, 2874. (c) Giese, B. Radical
Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press:
Oxford, 1986; Chapter 2, pp 4ꢀ35.
(3) (a) Ryu, I.; Sonoda, N. Angew. Chem. 1996, 35, 1050. (b) Ryu, I.;
Muraoka, H.; Kambe, N.; Komatsu, M.; Sonoda, N. J. Org. Chem.
1996, 61, 6396. (c) Kim, S.; Lee, I. Y.; Yoon, J. Y.; Oh, D. H. J. Am.
Chem. Soc. 1996, 118, 5138. (d) Godineau, E.; Landais, Y. J. Am. Chem.
Soc. 2007, 129, 12662.
(7) Godineau, E.; Landais, Y. Chem.;Eur. J. 2009, 15, 3044.
r
10.1021/ol2007633
Published on Web 04/19/2011
2011 American Chemical Society

acceptor (A).7 Based on this concept, we describe here the
development of a new free-radical carboalkenylation and -
alkynylation of olefins, which result in the formation of two
CꢀC bonds and the addition of two functional groups
across the double bond of an unactivated olefin. The
three-component reaction (3-CR) proceeds through the
addition of a radical species R- to an electron-withdrawing
group, attached to A (ester, ketone, amide, etc.), onto the
less hindered end of an olefin B, followed by the coupling
of the resulting electron-rich radical with an unsaturated
sulfonyl acceptor C (Figure 1).3d,8 A scope and limitation of
the method was defined that emphasizes on the importance
of the electronic nature of the sulfonyl acceptor C.
Table 1. Three-Component Carboalkynylation
olefin
sulfone
yielda
(%)
entry (equiv)
R1
R2 (equiv) product
1
2
3
4
5
6
7
8
9
2a (2)
2a (4)
2a (4)
2b (4)
2b (4)
2c (4)
OPiv
OPiv
H
H
H
H
H
H
3a (1.5)
3a (1.2)
3a (1.5)
3a (1.2)
3b (1.2)
3b (1.2)
4a
4a
4a
4b
4c
4d
4e
4f
24
35b
38c
43
76
60
86
54
59
OPiv
CH2SiMe2Ph
CH2SiMe2Ph
OEt
2d (4) (CH2)2OTBDPS Me 3b (1.2)
2e (4)
2f (4)
-(CH2)5-
3b (1.2)
3b (1.2)
(CH2)5CH3
H
4g
Figure 1. Three-component carboalkynylation and -alkenyla-
tion of olefins.
a Isolated yield. b Ratio 4/5/6 1:0.2:0.3. c Ratio 4/5/6 1:0.4:0.6.
Preliminary experiments were carried out using xanthate
1a, as an electrophilic radical precursor, vinyl pivalate 2,
and alkynylsulfone 3a as a final acceptor. When 1.5 equiv
of (Bu3Sn)2 and 0.15 equiv of di-tert-butyl hyponitrite
(DTBHN) were used to initiate the process, we were pleased
to find that the carboalkynylation product 4a was obtained,
albeit in poor yield (Table 1, entry 1). Increasing the amount
of olefin led to a slightly better yield of 4a, along with the
unexpected formation of alkynes 5 and 6 (entry 2). Increas-
ing the amount of sulfone to 1.5 equiv slightly improved the
yield of 4a but also increased in the meantime the amount of
5 and 6 (entry 3), illustrating the high reactivity of sulfone 3
(vide infra). Under similar conditions, a good radical
acceptor such as allylsilane 2b9 also provided 4b, albeit in
a modest 43% yield (entry 4). The high reactivity of 3a was
then altered by introducing a SiMe3 group onto the
alkyne.4e Pleasingly, this modification led to a significant
yield improvement. 2b and enol ether 2c thus led to 4c and 4d
respectively in satisfying yields (entry 5ꢀ6). Generation of a
quaternary center was also possible as shown by the forma-
tion of alkyne 4eꢀf (entries 7ꢀ8). Finally, less nucleophilic
oct-1-ene 2f also reacted to provide the alkyne ester 4g in
reasonable yield (entry 9).
We then extended the three-component process to the
analogous carboalkenylation. Vinyl bisphenylsulfone 78b
was designed as a sulfone candidate. It was first reacted
with xanthate 1a and allylsilane 2b. Pleasingly, the desired
vinylsulfone 8a was obtained in an excellent 96% yield
(Table 2, entry 1). While xanthates provide the best results,
simple bromide 1b was also shown to react efficiently with
2b (entry 2). Monosubstituted alkene 2f was found to be
less reactive (entry 3) and led to 8b in moderate yield. Not
only increasing the amount of sulfone to 2 equiv (entry 4)
but also changing the nature of the solvent, using 1,2-DCE
(entry 5), significantly improved the yield. The increased
amount of sulfone was only required when using poorly
activated olefins (entries 5, 11ꢀ12). The three-component
reaction was particularly efficient with electron-rich olefins
(entries 1ꢀ2, 7ꢀ8), emphasizing again the crucial role of
polar effects in these processes. Quaternary centers could also
be generated using 1,1-disubstituted olefins 2dꢀ2e (entries
6, 9). Vinyl acetate 2h led to the expected product 8g in
moderate yield (entry 10), along with a diacetate 9 (as a 1:1
mixture of two diastereomers). A similar behavior was
observed with olefin 2a. The formation of 9 may be rationa-
lized invoking the dual reactivity of vinyl acetate 2h toward
nucleophilic and electrophilic radical species.10 Silyl protected
allylic alcohol 2j (entry 12) led to the 3-CR product 8i in
reasonable yield, while the corresponding free alcohol pro-
vided only traces of the desired vinylsulfone, showing that
free hydroxyl groups are not compatible with reaction con-
ditions. Finally, styrenes, vinylsilanes, and enamines were
(8) For reactions using sulfone acceptors under radical conditions,
see: (a) Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J.-Y.;
Kim, S. J. Am. Chem. Soc. 1999, 121, 12190. (b) Kim, S.; Kim, S. Bull.
Chem. Soc. Jpn. 2007, 80, 809. (c) Kim, S.; Song, H.-J.; Choi, T.-L.;
Yoon, J.-Y. Angew. Chem., Int. Ed. 2001, 40, 2524. (d) Kim, S.; Yoon
J.-Y. J. Am. Chem. Soc. 1997, 119, 5982. (e) Bertrand, F.; Le Guyader,
F.; Liguori, L.; Ouvry, G.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. C. R.
Acad. Sci. 2001, 4, 547. (f) Russell, G. A.; Ngoviwatchai, P.; Tashtoush,
H. L.; Pla-Dalmau, A.; Khanna, R. J. J. Am. Chem. Soc. 1988, 110, 3530.
(g) Schaffner, A.-P.; Darmency, V.; Renaud, P. Angew. Chem., Int. Ed.
2006, 45, 5847.
(9) Allylsilanes as radical traps; see: (a) Porter, N. A.; Zhang, G.;
Reed, A. D. Tetrahedron Lett. 2000, 41, 5773. (b) Chabaud, L.; Landais,
Y.; Renaud, P.; Robert, F.; Castet, F.; Lucarini, M.; Schenk, K.
Chem.;Eur. J. 2008, 14, 2744.
(10) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264, 201.
Org. Lett., Vol. 13, No. 10, 2011
2659

Table 2. Three-Component Carboalkenylation
Scheme 2. Three-Component Carboalkenylation: Variation of
the Nature of the Electrophilic Radical
olefin
yielda,b
(%)
entry ester (equiv)
R1
R2 product
1
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2b (4) CH2SiMe2Ph
2b (4) CH2SiMe2Ph
H
H
H
H
H
8a
8a
8b
8b
8b
8c
8d
8e
8f
96c
82
2
3
2f (4)
2f (4)
2f (4)
(CH2)5CH3
(CH2)5CH3
(CH2)5CH3
53c
68c,d
83d
59d
72c
82
4
5
6
2d (4) (CH2)2OTBDPS Me
7
2c (4) OEt
H
H
8
2g (4) Ot-Bu
2e (4) -(CH2)5-
2h (4) OAc
9
76
10
11
12
H
H
H
8g
8h
8i
56e
79
2i (4)
2j (4)
(CH2)3Cl
CH2OTBDMS
53
a Isolated yield. b Conditions: 1,2-dichloroethane (1,2-DCE) as sol-
vent and sulfone 7 (1.2 equiv). c Benzene as solvent. d Sulfone 7 (2 equiv).
e 12% of diacetate 9 was also formed.
nitrile 13c was prepared efficiently from the corre-
sponding xanthate 12c or bromide. Dimethyl malonate
13d and Weinreb amide 13e were finally accessible in
satisfying and reproducible yields under the same
conditions.
found to be poor substrates for this reaction, providing no
product or complex mixtures.
Scheme 3. Three-Component Carboalkenylation with Acylsi-
lanes
Incontrastto sulfone3a, styrylsulfone10exhibitedgood
reactivity, providing, in the presence of electronically
differentiated olefins, three-component reaction products
11aꢀc in moderate to excellent yields (Scheme 1).
Scheme 1. Three-Component Carboalkenylation Using
Sulfone 10
We finally studied these radical processes using acylsi-
lanes as electrophilic radical precursors. While acylsilane
enolates are well-known and behave similarly to ester
enolates,11 R-acylsilyl radicals have not been reported so
far. These were easily generated from the corresponding R-
bromoacylsilane 14, prepared in two steps from ethylvinyl
ether.12 The three-component process with sulfone 7 and
olefin 2b provided good yields of acylsilane 15 (Scheme 3).
Such difunctional building blocks are attractive, consider-
ing the dual electrophilic and nucleophilic reactivity of the
acylsilane functional group.13
The nature of the radical precursor could also be varied
as shown in Scheme 2. Using 1.2 equiv of sulfone 7 and
allylsilane 2b (4 equiv), methyl- and benzylketones
13aꢀb were obtained in good yields, starting from the
corresponding xanthates 12aꢀb or bromide. Similarly,
(11) (a) Kuwajima, I.; Abe, T.; Minami, N. Chem. Lett. 1976, 993.
(b) Yoshida, J.; Matsunaga, S.; Ishichi, Y.; Maekawa, T.; Isoe, S. J. Org.
Chem. 1991, 56, 1307. (c) Verlhac, J. B.; Kwon, H.; Pereyre, M. J.
Organomet. Chem. 1992, 437, C13.
(12) Nowick, J. S.; Danheiser, R. L. Tetrahedron 1988, 44, 4113.
2660
Org. Lett., Vol. 13, No. 10, 2011

H, R2 = OPiv), explaining the formation of alkyne 5 as a
byproduct. The relatively slow β-fragmentation of III,
likely at the origin of the formation of 5, is worth
noticing.15 DFT calculations at the B3LYP 6-311þG(d,
p)//B3LYP 6-31G(d) level were also carried out, as to gain
further insights into the reactivity of alkynylsulfones, and
particularly that of 3aꢀb. Calculations of the energy of the
LUMOfor3aand 3c(ananalogue of 3b) revealedthatthey
are almost identical. In contrast, a significant polarization
of the alkyne triple bond was observed in 3a, the Mulliken
population analysis16 leading to a partial negative charge
on the alkyne carbon center R- to the sulfone (Figure 2),
thus explaining the apparent mismatch reactivity of 3a
toward electron-poor radical species such as I, and the
formation of 6. In contrast, little or no polarization was
observed on silylalkyne 3c, likely as a result of the strong
πꢀd interaction between silicon (a π-acceptor) and the
carbon center.17,18
In summary, we reported here novel free-radical
mediated carboalkynylation and alkenylation processes,
starting from readily available bromides or xanthates,
olefins, and sulfone acceptors. Addition across the olefin
double bond gives rise to the formation of two new
carbonꢀcarbon bonds and the incorporation of two func-
tional groups in systems that should find useful applica-
tions, for instance in the preparation of polysubstituted
cyclic building blocks. Further investigations in this direc-
tion are underway and will be reported in due course.
Figure 2. Three-component carboalkynylation and alkenylation
radical chain.
As mentioned above, the success of such three-compo-
nent reactions heavily relies on the matched polarity
between the three partners.7 A possible radical chain is
depicted in Figure 2,3 taking into account the electrophilic
nature of radical precursor I and the nucleophilic character
of II, generated through the addition of I onto the olefinic
partner. An electrophilic PhSO2 radical readily adds to
electron-rich olefins14 including 2a to generate III (R1 =
Acknowledgment. ANR (No. 07-3195-931), CNRS,
and the Region Aquitaine are gratefully acknowledged
for financial support.
Supporting Information Available. Experimental pro-
cedures and product characterization data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(13) (a) Page, P. C. B.; McKenzie, M. J. Acylsilanes in Science of
Synthesis; Fleming, I., Ed.; Georg Thieme Verlag: 2002; Vol. 4, p 513.
(b) Moser, W. H. Tetrahedron 2001, 57, 2065. (c) Tsai, Y.-M.; Tang
K.-H.; Jiaang, W.-T. Tetrahedron Lett. 1996, 37, 7767.
(14) For instance, addition of a MeSO2 radical to hexene is nearly
diffusion controlled (k = 1 ꢁ 109 sꢀ1 Mꢀ1). See: Gozdz, A.; Maslak, P. J.
Org. Chem. 1991, 56, 2179.
(16) Similar results were obtained by performing Natural Bond
Orbital (NBO) analysis (see Supporting Information).
(17) Steric effects of the bulky SiMe3 group should also favor the
approach of the radical R- to the sulfone.
(18) (a) Rubin, M.; Trofimov, A.; Gevorgyan, V. J. Am. Chem. Soc.
2005, 127, 10243. (b) Vasilevsky, S. F.; Baranov, D. S.; Mamatyuk, V. I.;
Gatilov, Y. V.; Alabugin, I. V. J. Org. Chem. 2009, 74, 6143.
(15) The rate constant for the β-fragmentation of a closely related β-
tosyl benzoyl radical was determined to be 2.7 ꢁ 105 sꢀ1
M
ꢀ1. See:
Timokhin, V. L.; Gastaldi, S.; Bertrand, M. P.; Chatgilialoglu, C. J. Org.
Chem. 2003, 68, 3532.
Org. Lett., Vol. 13, No. 10, 2011
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