Rhodium-catalyzed functionalization of sterically hindered alkenes

Article abstract of DOI:10.1021/ol902646j

(Figure presented) For the first time the rhodium-catalyzed 1,4-addition of organoboranes to hindered Baylis-Hillman adducts, trisubstituted alkenes, affording highly functionalized alkenes, via addition of the organoboranes and hydroxyelimination, Is reported. Moreover, preliminary results have shown that, thanks to the use of a monosubstituted chiral diene ligand, enantio-enriched products were easily accessible, while chiral phosphane ligands were completely inappropriate in this reaction.

Full text of DOI:10.1021/ol902646j

ORGANIC
LETTERS
2010
Vol. 12, No. 2
308-310
Rhodium-Catalyzed Functionalization of
Sterically Hindered Alkenes
Thomas Gendrineau, Jean-Pierre Genet, and Sylvain Darses*
Laboratoire Charles Friedel (UMR 7223, CNRS), Ecole Nationale Supe´rieure de
Chimie de Paris, 11 rue P&M Curie, 75231 Paris Cedex 05, France
sylVain-darses@chimie-paristech.fr
Received November 17, 2009
ABSTRACT
For the first time the rhodium-catalyzed 1,4-addition of organoboranes to hindered Baylis-Hillman adducts, trisubstituted alkenes, affording
highly functionalized alkenes, via addition of the organoboranes and hydroxyelimination, is reported. Moreover, preliminary results have
shown that, thanks to the use of a monosubstituted chiral diene ligand, enantio-enriched products were easily accessible, while chiral phosphane
ligands were completely inappropriate in this reaction.
The stereoselective and catalytic 1,4-addition reactions of
organometallic reagents, mainly boron and zinc, to R,ꢀ-
unsaturated substrates have provided new synthetic tools in
organic synthesis.1 If the rhodium- or copper-catalyzed
additions to disubstituted activated alkenes can be readily
achieved under various conditions, the reaction with trisub-
stituted alkenes is still a challenge. It is only very recently
that catalyzed additions to trisubstituted activated alkenes
have appeared in the literature.2,3 In the copper-catalyzed
1,4-addition of organometallic reagents, the groups of
Alexakis and Hoveyda have developed efficient catalytic
systems for the generation of all-carbon stereogenic centers,
upon the addition to ꢀ,ꢀ-disubstituted Michael acceptors.4
On the other hand, in the case of rhodium-catalyzed 1,4-
addition reactions, examples are rare of reactions involving
trisubstituted activated alkenes. Indeed, construction of
stereogenic quaternary centers has been described recently
by the groups of Carretero5 and Hayashi6 upon the addition
of organometallics to ꢀ,ꢀ-disubstituted Michael acceptors.7
Some examples of addition to activated arylmethylene
cyanoacetates8 and alkylidene Meldrum’s acids have ap-
peared in the literature.9 However, to our knowledge,
(1) Reviews: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(b) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (c) Guo, H.-
C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354. (d) Miura, T.;
Murakami, M. Chem. Commun. 2007, 217. (e) Yamamoto, Y.; Nishikata,
T.; Miyaura, N. Pure Appl. Chem. 2008, 80, 807. (f) Alexakis, A.; Ba¨ckvall,
J.-E.; Krause, N.; Pa`mies, O.; Die´guez, M. Chem. ReV. 2008, 108, 2796.
(g) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa,
B. L. Chem. ReV. 2008, 108, 2824. (h) von Zezschwitz, P. Synthesis 2008,
1809. (i) Gutnov, A. Eur. J. Org. Chem. 2008, 4547.
(3) For some recent examples of stoichiometric addition of organome-
tallics to R,ꢀ-unsaturated tri- or tetrasubstituted alkenes, see: (a) Toyooka,
N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Tetrahedron 2004, 60, 6197.
(b) Becheanu, A.; Baro, A.; Laschat, S.; Frey, W. Eur. J. Org. Chem. 2006,
2215. (c) Oueslati, F.; Perrio, C.; Dupas, G.; Barre´, L. Org. Lett. 2007, 9,
153. (d) Zimmerman, H. E.; Suryanarayan, V. Eur. J. Org. Chem. 2007,
4091, and references cited therein.
(2) (a) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc.
2005, 127, 4584. (b) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem.,
Int. Ed. 2005, 44, 1376. (c) Hird, A. W.; Hoveyda, A. H. J. Am. Chem.
Soc. 2005, 127, 14988. (d) Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier,
H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416. (e) Lee,
K.-s.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006,
128, 7182. (f) Palais, L.; Mikhel, I. S.; Bournaud, C.; Micouin, L.; Falciola,
C. A.; Vuagnoux-d’Augustin, M.; Rosset, S.; Bernardinelli, G.; Alexakis,
A. Angew. Chem., Int. Ed. 2007, 46, 7462. (g) Brown, M. K.; May, T. L.;
Baxter, C. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 1097. (h)
Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A. Angew. Chem., Int. Ed. 2008,
(4) (a) Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774. (b)
Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801.
(5) Mauleo´n, P.; Carretero, J. C. Chem. Commun. 2005, 4961.
(6) (a) Shintani, R.; Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc. 2006,
128, 5628. (b) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.;
Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588.
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Lett. 2008, 10, 589.
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2008, 10, 437.
10.1021/ol902646j  2010 American Chemical Society
Published on Web 12/17/2009

examples of rhodium-catalyzed additions to nonactivated
R,R,ꢀ-trisubstituted alkenes are rather limited. Indeed, Csa´ky¨
and co-workers have described the diastereoselective con-
jugate additions of boronic acids to R-substituted hydroxy-
cyclopentenones,10 and Belyk et al. reported the synthesis
of 1,3,4-trisubstituted pyrrolidines via the rhodium-catalyzed
addition of boronic acids.11
In our continuous interest in rhodium-catalyzed reactions
with organoboron derivatives,12 we recently showed that they
add to readily available Baylis-Hillman (BH) adducts in
the presence of a rhodium complex, affording stereodefined
trisubstituted (E)-alkenes under mild conditions via an
unusual mechanism.13 We want to report now the 1,4-
addition of boron reagents to R,R,ꢀ-trisubstituted BH deriva-
tives, allowing access to highly functionalized cyclic sub-
strates (Scheme 1). Moreover, the use of chiral diene ligands
Table 1. Rhodium-Catalyzed Addition of Boronic Acids to
Hindered BH Adductsa
entry
1
2 (Ar ))
product (3)
yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1d
1e
1e
1f
C6H5 (2a)
4-MeOC6H4 (2b)
4-CF3C6H4 (2c)
2-naphthyl (2d)
3aa
3ab
3ac
3ad
3ba
3bb
3be
3bf
3cb
3da
3ea
3eb
3fa
91
82c
33c
39
82
96
2a
2b
4-MeC6H4 (2e)
3,5-Me2C6H3 (2f)
81
57c
71c
65
9
2b
2a
2a
2b
10
11
12
13
14
15
35
33c
76
2a
3-MeOC6H4 (2g)
2a
1f
1g
3fg
3ga
52c
74c
a Reactions conducted with 0.5 mmol of 1, 2 equiv of 2 with 1 mol %
of [RhOH(cod)]2 at rt in 1 mL of methanol. b Isolated yields of alkene, the
isomeric ratio E/Z being above 95:5. c Reaction conducted at 50 °C.
Scheme 1
.
1,4-Addition/ꢀ-Hydroxy Elimination on
Trisubstituted BH Adducts
and 9). Under these conditions, electron-deficient or ortho-
substituted boronic acids afforded only moderate yields due
to competitive proto-deboronation (entries 3 and 4). Other
cyclic substrates also reacted (entries 11-15), even if the
observed yields were lower with 5-membered methyl-
substituted BH substrate 1e (entries 11 and 12) compared to
the phenyl-substituted one 1f (entries 13 and 14). In all the
examined reactions, stereodefined (E) trisubstituted alkenes
(E/Z > 98:2) were produced as confirmed by NOE experi-
ments. These substrates, bearing R,ꢀ-unsaturated ketone
functionality, can be further functionalized by Michael-type
addition reactions, providing further opportunities to access,
in a straightforward way, more complex structures.14
We also evaluated the reactivity of potassium trifluoro-
(organo)borates15 because of their attractiveness in terms of
higher stability and ease of preparation and purification
compared to trivalent organoboranes, and also because these
compounds have been shown to be highly suited to rhodium-
catalyzed processes.12 Under quite similar conditions, and
with triethylamine as an additive,16 potassium aryltrifluo-
roborates 4 added to trisubstituted BH adduct at room
temperature (Scheme 2). Indeed, the addition of potassium
trifluoro(phenyl)borate to 1a afforded a 76% yield of the
expected product 3aa. Interestingly, potassium 4-bromophe-
nyltrifluoroborate also underwent 1,4-addition to 1a, afford-
allowed the stereoselective control of the generated stereo-
genic center, affording enantio-enriched substrates.
Preliminary experiments have established that the reaction
of BH adduct 1a with phenylboronic acid (2a) was best
conducted with [RhOH(cod)]2 as rhodium catalyst
precursor.13c We were pleased to find that, under these
conditions, the reaction occurred smoothly, even at room
temperature, using methanol as solvent, affording the adduct
3aa resulting from the 1,4-addition of the organometallic
reagent followed by ꢀ-hydroxyelimination with good yields
(Table 1, entry 1), even in the presence of 1 mol % of
rhodium catalyst. Other six-membered substituted BH ad-
ducts reacted equally well with various arylboronic acids
(entries 1-10). Most of the reactions were finished in less
than 1 h at room temperature, but for some less reactive BH
adducts or boronic acids, faster reaction rates were achieved
at slightly higher reaction temperature (50 °C, entries 2, 3,
´
(10) de la Herran, G.; Mba, M.; Murcia, M. C.; Plumet, J.; Csaky¨, A. G.
Org. Lett. 2005, 7, 1669.
(11) Belyk, K. M.; Beguin, C. D.; Palucki, M.; Grinberg, N.; Da Silva,
J.; Askin, D.; Yasuda, N. Tetrahedron Lett. 2004, 45, 3265.
(12) (a) Pucheault, M.; Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2002,
3552. (b) Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004,
43, 719. (c) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc. 2004,
126, 15356. (d) Pucheault, M.; Darses, S.; Genet, J.-P. Chem. Commun.
2005, 4714. (e) Mora, G.; Darses, S.; Genet, J.-P. AdV. Synth. Catal. 2007,
349, 1180. (f) Martinez, R. m.; Voica, F.; Genet, J.-P.; Darses, S. Org.
Lett. 2007, 9, 3213. (g) Navarre, L.; Martinez, R. m.; Genet, J.-P.; Darses,
S. J. Am. Chem. Soc. 2008, 130, 6159.
(14) (a) Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005, 61, 10377.
(b) Yamamoto, Y.; Nishikata, T.; Miyaura, N. J. Synth. Org. Chem. Jpn.
2006, 64, 1112. (c) Yamamoto, Y.; Nishikata, T.; Miyaura, N. Pure Appl.
Chem. 2008, 80, 807.
(15) Reviews: (a) Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2003, 4313.
(b) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49. (c)
Molander, G. A.; Ellis, N. M. Acc. Chem. Res. 2007, 40, 275. (d) Stefani,
H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623. (e) Darses, S.;
Genet, J.-P. Chem. ReV. 2008, 108, 288.
(13) (a) Navarre, L.; Darses, S.; Genet, J.-P. Chem. Commun. 2004, 1108.
(b) Navarre, L.; Darses, S.; Genet, J.-P. AdV. Synth. Catal. 2006, 348, 317.
(c) Gendrineau, T.; Demoulin, N.; Navarre, L.; Genet, J.-P.; Darses, S.
Chem.sEur. J. 2009, 15, 4710.
(16) For improved reactivity of RBF3K with Et3N, see: (a) Lalic, G.;
Corey, E. J. Org. Lett. 2007, 9, 4921. (b) Lalic, G.; Corey, E. J. Tetrahedron
Lett. 2008, 49, 4894. (c) Gendrineau, T.; Genet, J.-P.; Darses, S. Org. Lett.
2009, 11, 3486.
Org. Lett., Vol. 12, No. 2, 2010
309

Scheme 2
.
Rhodium-Catalyzed Addition of Potassium
Scheme 3. Toward an Asymmetric Version
Trifluoro(organo)borates to Hindered BH Adducts
It is important to note that the high reactivity of these
trisubstituted BH adducts is quite unusual. Indeed, when the
same reaction conditions were applied to R-alkyl-substituted
cyclic enones, lacking the hydroxy substituent in the ꢀ
position of the ketone, no reaction occurred. The main
difference in the reactivity of this substrate compared to BH
adduct relies on the presence of the hydroxy substituent: for
the later, the catalytic cycle is terminated by a ꢀ-hydroxye-
limination,13 while for the former a protonation of a rhodium
enolate must occur.19 Indeed, it appeared that the rate-
determining step with such hindered alkenes is not the olefin
insertion, but the protonation step. In the described reaction,
the protonation step is bypassed by a more efficient ꢀ-hy-
droxyelimination step.
We have described for the first time a rhodium-catalyzed
1,4-addition of organoboranes to hindered BH adducts.
Moreover, preliminary results have shown that, thanks to
the use of chiral diene ligands, enantioenriched substrates
were easily accessible, while chiral phosphane ligands were
completely ineffective.
ing highly functionalized substrate 3ah, that can be further
functionalized either by 1,4-addition or palladium-catalyzed
cross-coupling.
As a potential stereogenic center is generated during the
reaction, we evaluated the possibility to produce enantioen-
riched substrates using this 1,4-addition/ꢀ-hydroxyelimina-
tion process. Several chiral phosphane ligands, which have
been found to be useful in rhodium-catalyzed 1,4-additions,1
were evaluated. However, whatever the reaction conditions
used, the reaction of 1a with 2a was totally inhibited in the
presence of phosphane ligand, whatever the reaction tem-
perature. On the other hand, we were pleased to find that
the use of our recently developed C1-symmetric chiral diene
ligand17,18 allowed the production of enantioenriched sub-
strates. Indeed, preliminary results have shown that, among
the evaluated chiral monosubstituted dienes, ligand 5 was
the most suited in terms of enantioselection level (Scheme
3). Under otherwise identical conditions, the addition of
phenylboronic acid (2a) to BH adduct 1a afforded enan-
tioenriched 3aa with an enantiomeric excess of 84%. In the
same way, reaction of 2a with phenyl-substituted BH adduct
1b afforded the expected adduct 3ba with an identical
enantioselectivity, despite a moderate 25% yield. Further
developments are actually underway in order to improve both
the reaction yield and enantioselectivity.
Acknowledgment. T.G. thanks the Ministe`re de l’Education
et de la Recherche for a grant. The authors thank Diverchim
SA for the generous gift of rhodium catalyst precursor.
Supporting Information Available: Experimental pro-
cedures and compounds description. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S.
Angew. Chem., Int. Ed. 2008, 47, 7669, and references cited therein
.
(18) For the use of chiral dienes in catalysis, see: (a) Hayashi, T.;
Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125,
11508. (b) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1628. (c) Review: Defieber, C.; Gru¨tzmacher, H.;
OL902646J
(19) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052.
Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482
.
310
Org. Lett., Vol. 12, No. 2, 2010