Free-radical carbo-alkenylation of enamides and ene-carbamates

Article abstract of DOI:10.1021/ol401147w

The addition of xanthates and vinyldisulfones across the double bond of enamides and ene-carbamates provides access to the corresponding three-component adducts in good to excellent yields with a high level of diastereocontrol in cyclic systems. This strategy illustrates a complementary reactivity for these versatile olefins and extends their scope of application.

Full text of DOI:10.1021/ol401147w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Free-Radical Carbo-alkenylation of
Enamides and Ene-carbamates
ꢀ
ꢀ ꢀ
Clement Poittevin, Virginie Liautard, Redouane Beniazza, Frederic Robert, and
Yannick Landais*
ꢀ
Institut des Sciences Moleculaires, Universite de Bordeaux, UMR-CNRS 5255, 351,
cours de la liberation, 33405 Talence Cedex, France
ꢀ
ꢀ
y.landais@ism.u-bordeaux1.fr
Received April 24, 2013
ABSTRACT
The addition of xanthates and vinyldisulfones across the double bond of enamides and ene-carbamates provides access to the corresponding three-
component adducts in good to excellent yields with a high level of diastereocontrol in cyclic systems. This strategy illustrates a complementary
reactivity for these versatile olefins and extends their scope of application.
Enamides and ene-carbamates are versatile intermediates
for the synthesis of heterocycles, amino acids, and other
useful building blocks. Their functionalization using organic
Scheme 1. Reactivity of Enamides and Ene-carbamates under
Ionic and Radical Conditions
and organometallic catalysis has led to intensive research due
to their unique reactivity.1 The presence of an electron-with-
drawing carbonyl group on the nitrogen center somewhat
reduces the nucleophilicity of the olefinic moiety, as com-
pared to that of their enamine analogues, thus expanding the
reactivity scope of this class of olefins. Reactions of enamides
and ene-carbamates I under ionic conditions generally follow
route (a), where the C2 and C1 carbons exhibit, respectively,
nucleophilic and electrophilic reactivities (Scheme 1).2
In a similar fashion, radical species are known to add effi-
ciently to enamides3 and ene-carbamates4 both in intra- and
(1) (a) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352,
753–819. (b) Gopalaiah, K.; Kagan, H. B. Chem. Rev. 2011, 111, 4599–
4657. (c) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41, 292–
301. (d) Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 3304–3307. (e) Lu,
intermolecular fashions (path (b)). The resulting electron-
M.; Lu, Y.; Zhu, D.; Zeng, X.; Li, X.; Zhong, G. Angew. Chem., Int. Ed.
2010, 49, 8588–8592. (f) Dagousset, G.; Zhu, J.; Masson, G. J. Am.
Chem. Soc. 2011, 133, 14804–14813.
(2) Drouet, F.; Lalli, C.; Liu, H.; Masson, G.; Zhu, J. Org. Lett. 2011,
13, 94–97 and references cited therein.
(3) (a) Ripa, L.; Hallberg, A. J. Org. Chem. 1998, 63, 84–91.
(b) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.;
Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922–1925. (c) Taniguchi,
T.; Ishibashi, H. Tetrahedron 2008, 64, 8773–8779.
rich radical IIb may simply react with a reducing agent (e.g.,
Bu3SnH) or trap an halogen or a xanthate from the radical
precursor in an atom-transfer process.5 Recent studies have
shown that IIb may also be oxidized to generate an iminium
such as IIa, which then reacts following route (a).6 On the
(4) (a) Parsons, A. F.; Williams, D. A. J. Tetrahedron 2000, 56, 7217–
7228. (b) Parsons, A. F.; Williams, D. A. J. Tetrahedron 1998, 54, 13405–
13420. (c) Curran, D. P.; Guthrie, D. B.; Geib, S. J. J. Am. Chem. Soc.
2008, 130, 8437–8445. (d) Miranda, L. D.; Zard, S. Z. Org. Lett. 2002, 7,
1135–1138.
(5) (a) Curran, D. P.; Eichenberger, E.; Collis, M.; Roepel, M. G.;
Thoma, G. J. Am. Chem. Soc. 1994, 116, 4279–4288. (b) Bryans, J. S.;
Chessum, N. E. A.; Huther, N.; Parsons, A. F.; Ghelfi, F. Tetrahedron
2003, 59, 6221–6231. (c) Gagosz, F.; Zard, S. Z. Org. Lett. 2003, 5, 2655–
2657.
r
10.1021/ol401147w
XXXX American Chemical Society

basis of these premises, it was foreseen that, under suitable
(non-oxidative) conditions, the intermediate radical spe-
cies IIb could also react with a third component, e.g., an
electron-poor olefin, to generate an addition product IIIb in
a process where the enamide or the ene-carbamate would
exhibit formal polarity as in B, thus complementing
the polarity A generally observed in reactions of these
olefins.2,6 Following our continuous interest in radical multi-
component processes7 and guided by recent progress in this
field,6,7b we wish to report here on the development of a
carbo-alkenylation of various acyclic and cyclic enamides
and ene-carbamates, the reactivity of which follows pathway
(b) above.
The study began with the examination of the three-com-
ponent reactions (3-CR) starting from xanthate 1a,b and
acyclic ene-carbamates 2aꢀfin the presence of vinyldisulfone
38 (Table 1). The reaction was initiated using di-tert-butyl
hyponitrite (DTBHN) and (Bu3Sn)2 in 1,2-dichloroethane.7c
Preliminary experiments showed that better results were
obtained using 1 equiv of xanthate,9 4 equiv of the olefin,
and 1.2 equiv of the disulfone. Yields of the 3-CR process
were generally good but decreased with the presence of bulky
and/or electron-withdrawing substituents on the carbamate
moiety (entries 5 and 6, Table 1). Introduction of a sub-
stituent R to the nitrogen center as in trisubstituted ene-
carbamate 2g led to no reaction, illustrating the detrimental
effect of steric hindrance R to the carbamate moiety.10 In all
cases, the diastereocontrol was very low, contrasting with
the observations made during addition of similar radicals to
enamines (vide infra).11
The study was then extended to vinyloxazolidinones and
-pyrrolidinones 5aꢀf (Scheme 2). We were pleased to observe
that the three-component reaction led to the expected products
6aꢀh in good yields, whatever the substitution pattern of the
olefinic backbone, in contrast with observations made with
acyclic systems above (e.g., 2g). For instance, reaction between
1a, 3 and 5a,b led to 6a and 6b in 60 and 75% yield,
respectively, indicating that the steric hindrance at the proxi-
mity of the nitrogen center was reduced with oxazolidinones
and pyrrolidinones. As above, no stereocontrol was observed
during the formation of 6dꢀe. The presence of a bulky SiMe3
as in 5d slightly improved the diastereocontrol with the for-
mation of the major anti diastereomer 6f, whose relative con-
figuration was determined on the basis of X-ray diffraction
studies on the minor syn-isomer (Supporting Information).
The reaction was also applied to cyclohexenecarbamates 5e
and amides 5f, which afforded the corresponding disubstituted
cyclohexanes 6gꢀh in moderate yields and low stereocontrol.
Scheme 2. Carbo-alkenylation of Vinyloxazolidinones
and -pyrrolidinones 5aꢀf
Table 1. Radical Carbo-alkenylation of Ene-carbamates 2aꢀf
entry
R1
R2
R3
R4
4a
yieldb (%)
1
2
3
4
5
6
7
8
OEt
OEt
OEt
Me
H
H
H
OEt
4a
4b
4c
4d
4e
4f
86
80
91
88
38
0
Me
Me
Me
Me
Me
Me
Me
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
(6) (a) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1–11. (b) Friestad,
G. K.; Wu, Y. Org. Lett. 2009, 11, 819–821. (c) Courant, T.; Masson, G.
Chem.;Eur. J. 2012, 18, 423–427. (d) Jiang, J.; Huang, C.; Zeng, C.;
Zhang, Y.; Yu, S. Chem.;Eur. J. 2012, 18, 15158–15166.
(7) (a) Godineau, E.; Landais, Y. J. Am. Chem. Soc. 2007, 129,
12662–12663. (b) Godineau, E.; Landais, Y. Chem.;Eur. J. 2009, 15,
3044–3055. (c) Liautard, V.; Robert, F.; Landais, Y. Org. Lett. 2011, 10,
2658–2661 and references cited therein.
(8) (a) Kim, S.; Kim, S. Bull. Chem. Soc. Jpn. 2007, 80, 809–822.
(b) Bertrand, F.; Le Guyader, F.; Liguori, L.; Ouvry, G.; Quiclet-Sire,
B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci. 2001, 4, 547–555.
(9) Quiclet-Sire, B.; Zard, Z. S. Top. Curr. Chem. 2006, 264, 201–236.
Me
OEt
OEt
OEt
Me
Boc
COPh
Phenc
Phenc
4g
4h
62
82
a Compounds 4 were obtained essentially as a 1:1 mixture of diaste-
reomers (measured by 1H NMR of the crude reaction mixture). b Isolated
yield after column chromatography. c Phen: 2-phenylethyl.
B
Org. Lett., Vol. XX, No. XX, XXXX

The methodology was extended to the functionalization
of cyclic enamides 7aꢀd (Scheme 3). In contrast with the
three-component reaction involving acyclic precursors, a
high level of diastereocontrol was observed (1H NMR)
with the trans-isomer generally predominating, as shown
by the X-ray structure determination of compound 8e
obtained from xanthate 1b and amide 7b. In line with
previous observations, yields dropped with the introduc-
tion of a chain R to the nitrogen center (e.g., 8d).
Reaction with amides 7aꢀd allowed various substituents
on the nitrogen. Reaction of amide 7c afforded the addi-
tion product 8c, albeit in modest yield but high diaste-
reocontrol, without a trace of the 5-exo-trig cyclization
product, indicating that the intermolecular trapping of
the radical intermediate IIb (Scheme 1) by sulfone 3 is
faster than the cyclization onto the butenyl fragment. The
matched polarity between radical IIb and vinylsulfone 3 is
likely at the origin of this reactivity (vide infra).
overbalance the natural tendency of the C-centered radical
to react at the less hindered site.
Scheme 4. Carbo-alkenylation of Cyclic Ene-carbamates 9aꢀe
Carbo-alkenylation of cyclic ene-carbamates led to si-
milar observations (Scheme 4). For instance, the presence
of an alkyl chain R to nitrogen in 9a,b led to modest yields
of the three-component adducts 10a,b, having the trans-
relative configuration (1H NMR). Varying the size of the
ene-carbamate ring led to contrasting results.
As mentioned above, enamides and ene-carbamates are
electron-rich olefins that favor the addition of electron-
deficient radical species such as those derived from
xanthates 1a,b. These additions generate a reactive radical
such as IIb,12 which possesses an allylic character13 as
shown by the canonical forms below (Scheme 5). Ab initio
calculations at the DFT level14 indicates that spin density
in IIb is mainly concentrated R to the nitrogen as in IIb-i.
Scheme 3. Carbo-alkenylation of Cyclic Enamides 7aꢀd
·
The free rotation around the C ꢀN bond and thus the
absence of allylic strain (A1,3), as in resonance form IIb-ii,
would thus explain the low level of stererocontrol observed
in acyclic series (Table 1 and Scheme 2). This contrasts
with the high stereocontrol observed in radical addition
to related enamine systems,11 where A1,3 was invoked.
Computational studies have also been performed on
the reaction between radical intermediate IV (arising from
the addition of 1b onto olefin 9d) and vinylsulfone 3
(Scheme 5). The lowest energy conformation, which ex-
·
hibits a nearly planar C NCdO system, clearly shows that
While excellent yield was obtained with 6-membered
ring carbamate 9d, modest and low yields were observed
respectively for the 7- and 5-membered ring systems 9e and
9c. The formation of 10f indicates that the presence of a
substituent (Me) at C5 is not sufficient to control the
diastereofacial selectivity during the attack of the xanthate
precursor, while the trans-configuration between C2 and
C3 is again observed. Finally, the formation of 10g, albeit
in low yield, is noteworthy and is the result of the addition
of a radical species at the most sterically hindered site of a
trisubstituted olefin, indicating that a strong driving force
the top face is hindered by the ketone chain (pseudoaxial),
forcing the sulfone to approach through the bottom face.
This transition state proved to be in excellent agreement
with experiment, as 10h arising from the three-component
reaction between 9d, 1b, and 3 was formed with complete
diastereocontrol (Scheme 6).
(12) Electron-rich radicals such as IIb react very rapidly with vinyl-
sulfone 3, leading to the expected adduct, without a trace of the xanthate
transfer product (e.g., quenching the reaction between 1a, 3 and 9d after
10 min led to 30% of the expected 10d and no xanthate transfer product;
see the Supporting Information). Such transfer products are occasion-
ally found7c and are likely intermediates in these reactions when using
less reactive olefins.
(13) Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2008, 10, 3279–3282.
(14) DFT calculations were performed with the Gaussian09 software
package (Supporting Information). The M06-2X exchange correlation
functional was used with a standard double-ζ 6-31þG(d,p) basis set.
(10) Olefin 2g may have also lost its enamide character (overlap
between the olefin and the nitrogen lone pair) as a result of A1,3 strain
(we thank a reviewer for this comment).
(11) (a) Renaud, P.; Schubert, S. Angew. Chem., Int. Ed. Engl. 1990,
29, 433–435. (b) Schubert, S.; Renaud, P.; Carrupt, P.-A.; Schenk, K.
Helv. Chim. Acta 1993, 76, 2473–2489.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Canonical Forms of Radical IIb and Transition State
for the Addition of Radical Intermediate IV onto Sulfone 3
Scheme 6. Functionalization of Carbamate 10h and Amide 12
The compounds resulting from the free-radical carbo-
alkenylation are valuable intermediates in organic synth-
esis, as illustrated by the pyrrolidine-mediated cycliza-
tion of ketone 10h into aza-decalone 11, which was
obtained as a single diastereomer and may be regarded
as a potent building block in the synthesis of alkaloids
of the lycopodium family (Scheme 6).15 Similarly, cycli-
zation of amide 12, whose structure was unambiguously
determined through X-ray diffraction studies, led to
the corresponding bicyclic amide 13 with complete
diastereocontrol.
As a summary, we reported here the carbo-alkenylation
of enamides and ene-carbamates. This three-component
reaction proceeds through the addition of a radical species
derived from a xanthate, and a vinylsulfone across the
olefinic backbone of enamides and ene-carbamates. Good
yieldsand highlevel ofsterecocontrol inthe cyclicseriesare
observed, leading to valuable intermediates for organic
synthesis. This study illustrates a new reactivity pattern for
enamides and ene-carbamates and demonstrates that these
olefins are efficient traps for electron-poor radical species.
Further elaboration of cyclic sulfones such as 8, 10, and 12
into advanced intermediates for alkaloid synthesis is now
underway and will be reported in due course.
Acknowledgment. We thank the CNRS, MNERT,
and the ANR (MCR-RAD No. 11-BS07-010-01) for
generous support. We gratefully acknowledge Dr. B.
Kauffman (IECB, UBx1) and A. Lacoudre (ISM, UBx1)
for X-ray diffraction studies.
Supporting Information Available. Representative ex-
perimental procedures including product characterization
and CIF. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Ma, X.; Gang, D. R. Nat Prod. Rep. 2004, 21, 752–772.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX