A novel C-C bond formation by Baylis-Hillman type reaction mediated by SmI2: An effective approach to α-hydroxyalkylacrylamide synthesis

Article abstract of DOI:10.1039/b006495p

α-Bromoacrylamides (1) reacted with aldehydes or ketones, in the presence of SmI₂ at - 78 °C in THF, within 5 min to produce Baylis-Hillman type reaction products (2) through an anionic process using vinylsamarium Grignard species in good yield

Full text of DOI:10.1039/b006495p

A novel C–C bond formation by Baylis–Hillman type reaction mediated by
SmI2: an effective approach to a-hydroxyalkylacrylamide synthesis
So Won Youn, Heui Sul Park and Yong Hae Kim*
Center for Molecular Design & Synthesis and Department of Chemistry, Korea Advanced Institute of Science and
Technology, 373-1, Kusong Dong, Yusong Gu, Taejon, 305-701, Korea. E-mail: kimyh@sorak.kaist.ac.kr
Received (in Cambridge, UK) 15th August 2000, Accepted 5th September 2000
First published as an Advance Article on the web 28th September 2000
Table 1 The reactions of acrylamides with various aldehydes and
a-Bromoacrylamides (1) reacted with aldehydes or ketones,
ketonesa
in the presence of SmI2 at 278 °C in THF, within 5 min to
produce Baylis–Hillman type reaction products (2) through
an anionic process using vinylsamarium Grignard species in
good yields (52–89%).
The construction of C–C bonds has been one of the most
fundamental reactions in organic synthesis. The Baylis–
Hillman reaction1 produces multifunctional molecules that can
be used for the synthesis of natural and unnatural products2
through C–C bond formation between the a-position of
activated alkene and carbon electrophiles having an electron-
deficient sp2 carbon atom under a basic catalyst, in particular a
tertiary amine. But the reaction suffers from being inconven-
iently slow.1 Furthermore, under normal circumstances acryla-
mides, crotonic derivatives, and ketones are inert substrates for
the Baylis–Hillman reaction.1,3 Therefore a number of at-
tempts2g,4,5 have been made to provide the corresponding
adduct including the use of microwave irradiation and high
pressure.6
Samarium diiodide has become a useful reagent for various
organic reactions.7 Especially, SmI2 can be used to generate
radicals and to reduce alkyl radicals to alkylsamarium reagents
that can be trapped by a variety of electrophiles to form a new
C–C bond.7–9 However, there have been arguments that in
general, vinyl- and aryl radicals do not usually undergo further
reduction to vinyl- or arylsamarium reagents.9 We report here
the first example of reactions via vinylsamarium species.
It has been found that a-bromoacrylamides (1) reacted with a
variety of aldehydes or ketones in the presence of SmI2 to give
a-hydroxyalkylacrylamides (Baylis–Hillman adducts, 2) within
5 min at 278 °C in THF in good yields (Scheme 1).
The reaction works best when 1 eq. of aldehyde and 3 eq. of
SmI2 are used in THF (run 2–5, Table 1). The crotonic
derivative gave only the (Z)-isomer which was readily con-
firmed by 1H NMR spectroscopy5a,b,d,f and a variety of
aldehydes and enolizable ketones also proceeded successfully
in good yields. The results obtained are summarized in Table 1.
Here a question is raised as to whether the reaction proceeds
via anionic or radical species. Treatment of 1a with SmI2 (3
eq.)–CD3OD (1 eq.) in THF afforded 3a (67%, 80% deuterated
product) as the main product as shown in eqn. 1. The amount of
Benzaldehyde and a,b-unsaturated carbonyl compounds are
reduced to the corresponding alcohols without undergoing
Baylis–Hillman type reaction: reduction of carbonyl groups
must be faster than Baylis–Hillman type reaction.
(1)
deuterium incorporation was determined by 1H NMR and mass
spectroscopy. On the other hand, when 1a was treated with
SmI2 (1 eq.) and THF-d8 as a solvent, no deuterated acrylamide
was detected, whereas a-bromoacrylamides acted as an electro-
phile to form 4a (eqn. 2).7a,10 If the vinyl radical species (A)
exists for long time it should abstract one D from THF-d8. If the
reaction undergoes samarium Grignard type reaction, it should
require more than 2 eq. of SmI2 to consume the starting
Scheme 1
acrylamide.
DOI: 10.1039/b006495p
Chem. Commun., 2000, 2005–2006
This journal is © The Royal Society of Chemistry 2000
2005

tertiary amine as a catalyst and its scope is limited to aldehydes
as acrylamides, crotonic derivatives and ketones are not
reactive. However, a Baylis–Hillman type reaction mediated by
SmI2 is available for both aldehydes and ketones under mild
reaction conditions and with short reaction times.
This work was partially supported by graduate School of
Molecular Science of MOE.
Notes and references
(2)
1 Reviews: (a) D. Basavaiah, P. D. Rao and R. S. Hyma, Tetrahedron,
1996, 52, 8001; (b) S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988,
44, 4653; (c) E. Ciganek, in Organic Reactions, ed. L. A. Paquette, John
Wiley & Sons, New York, 1997, vol. 51, pp. 201 and references cited
therein.
Judging from the three observations, an anion species (B)
appears to be involved in the reaction (Fig. 1). The reaction
might proceed via an allenoate intermediate (C).5,11 Ethyl a-
bromoacrylate or 2-bromocyclohex-2-en-1-one did not give the
desired products. A phenyl group in the amide seems to enable
the formation of the vinylsamarium intermediate (B). The a-
carbon of the acrylamide bearing phenyl group is more electron-
deficient than other moieties bearing alkyl or hydrogen.
Therefore, the vinyl radical can undergo further reduction to
vinylsamarium reagent B by a further mole of SmI2. These
results imply that the reduction of the vinyl radical should be
faster than hydrogen abstraction from THF. To our knowledge,
this is the first example of the generation of the vinyl samarium
intermediate by means of the reduction of bromovinyl com-
pounds! It is noteworthy that the reaction with enolizable
ketones also affords the Baylis–Hillman products.
2 (a) J. M. Brown, Angew. Chem., Int. Ed. Engl., 1987, 26, 190; (b) A. H.
Hoveyda, D. A. Evans and G. C. Fu, Chem. Rev., 1993, 93, 1307; (c) T.
Jenn and D. Heissler, Synlett, 1995, 607; (d) R. Annunziata, M.
Benaglia, M. Cinquini, F. Cozzi and L. Raimond, J. Org. Chem., 1995,
60, 4697; (e) P. Perlmutter and M. Tabone, J. Org. Chem., 1995, 60,
6515; (f) C. M. Marson, J. H. Pink and C. Smith, Tetrahedron Lett.,
1995, 36, 8107; (g) Y. Génisson, C. Massardier, I. Gantier-Luneau and
A. E. Greene, J. Chem. Soc., Perkin Trans. 1, 1996, 2869; (h) D.
Basavaiah, M. Bakthadoss and S. Pandiaraju, Chem. Commun., 1998,
1639.
3 M. L. Bode and P. T. Kaye, J. Chem. Soc., Perkin Trans. 1, 1993,
1809.
4 (a) M. Brand, S. E. Drewes, N. D. Emslie and A. A. Khan, Synth.
Commun., 1991, 21, 727; (b) J. Auge, N. Lubin and A. Lubineau,
Tetrahedron Lett., 1994, 35, 7947; (c) V. K. Aggarwal, G. J. Tarver and
R. McCague, Chem. Commun., 1996, 2713; (d) S. Rafel and J. W.
Leahy, J. Org. Chem., 1997, 62, 1521; (e) T. Kataoka, T. Iwama and S.
Tsujiyama, Chem. Commun., 1998, 197; (f) V. K. Aggarwal, A. Mereu,
G. J. Tarver and R. McCague, J. Org. Chem., 1998, 63, 7183.
5 For methods using Al, Cu, and others: (a) Y. Sato and S. Takeuchi,
Synthesis, 1983, 734; (b) J. P. Marino and R. J. Linderman, J. Org.
Chem., 1983, 48, 4621; (c) T. Tsuda, T. Yoshida and T. Saegusa, J. Org.
Chem., 1988, 53, 1037; (d) G. Li, H.-X. Wei and S. Willis, Tetrahedron
Lett., 1998, 39, 4607; (e) H.-X. Wei, S. Willis and G. Li, Tetrahedron
Lett., 1998, 39, 8203; (f) P. V. Ramachandran, M. V. R. Reddy, M. T.
Rudd and J. R. De Alaniz, Tetrahedron Lett., 1998, 39, 8791; (g) G. Li,
H.-X. Wei, B. R. Whittlesey and N. N. Batrice, J. Org. Chem., 1999, 64,
1061; (h) H.-X. Wei, J. D. Hook and K. A. Fitzgerald, Tetrahedron:
Asymmetry, 1999, 10, 661.
In summary, it has been demonstrated that the reaction of a-
bromoacrylamides with aldehydes or ketones in the presence of
SmI2 can provide Baylis–Hillman adducts through an anionic
process, solving several problems of Baylis–Hillman reaction.
Baylis–Hillman reactions require long reaction times and a
6 (a) J. S. Hill and N. S. Isaacs, Tetrahedron Lett., 1986, 27, 5007; (b) J.
S. Hill and N. S. Isaacs, J. Chem. Res. (S), 1988, 330; (c) G. H. P. Roos
and P. Rampersadh, Synth. Commun., 1993, 23, 1261; (d) M. K. Kunda,
S. B. Mukherjee, N. Balu, R. Padmakumar and S. V. Bhat, Synlett,
1994, 444.
7 Recent reviews: (a) G. A. Molander, Chem. Rev., 1992, 92, 29; (b) D. P.
Curran, T. L. Fevig, C. P. Jasperse and M. J. Totleben, Synlett, 1992,
943; (c) G. A. Molander, in Organic Reactions, ed. L. A. Paquette, John
Wiley & Sons, New York, 1994, vol. 46, pp. 211; (d) G. A. Molander
and C. R. Harris, Chem. Rev., 1996, 96, 307; (e) T. Skrydstrup, Angew.
Chem., Int. Ed. Engl., 1997, 36, 345; (f) G. A. Molander and C. R.
Harris, Tetrahedron, 1998, 54, 3321; (g) A. Krief and A.-M. Laval,
Chem. Rev., 1999, 99, 745 and references cited therein.
8 (a) G. A. Molander and C. Kenny, J. Am. Chem. Soc., 1989, 111, 8236;
(b) G. A. Hasegawa and D. P. Curran, Tetrahedron Lett., 1993, 34,
1717.
9 (a) M. Matsukawa, J. Inagana and M. Yamaguchi, Tetrahedron Lett.,
1987, 28, 5877; (b) J. Inagana, M. Ishikawa and M. Yamaguchi, Chem.
Lett., 1987, 1485; (c) T. L. Fevig, R. L. Elliott and D. P. Curran, J. Am.
Chem. Soc., 1988, 110, 5064; (d) D. P. Curran and B. Yoo, Tetrahedron
Lett., 1992, 33, 6931; (e) D. P. Curran and M. J. Totleben, J. Am. Chem.
Soc., 1992, 114, 6050; (f) M. Kunishima, K. Hioki, S. Tani and A. Kato,
Tetrahedron Lett., 1994, 35, 7253; (g) L. Capella and P. C. Mon-
tevecchi, Tetrahedron Lett., 1994, 35, 8445; (h) L. Capella, P. C.
Montevecchi and M. L. Navacchia, J. Org. Chem., 1995, 60, 7424; (i)
X. H. Du and R. W. Armstrong, Tetrahedron Lett., 1998, 39, 2281.
10 Organosamarium intermediates appear to be initiated but unstable in
solution.7 In the absence of electrophiles such as aldehydes or ketones,
the organosamarium species reacted with the substrate itself to form 4a
together with the dehalogenated byproduct 3aA.
11 (a) J. P. Marino and R. J. Linderman, J. Org. Chem., 1981, 46, 3696; (b)
T. Tsuda, T. Yoshida, T. Kawamoto and T. Saegusa, J. Org. Chem.,
1987, 52, 1624.
Fig. 1 Possible mechanism.
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Chem. Commun., 2000, 2005–2006