Rhodium-catalyzed enantioselective conjugate addition of organoboronic acids to α,β-unsaturated sulfones

Article abstract of DOI:10.1021/ol048690p

(Chemical Equation Presented) A general method for the enantioselective catalytic conjugate addition to acyclic α,β-unsaturated sulfones is described. Using metal-chelating α,β-unsaturated pyridyl sulfones as substrates, the rhodium-catalyzed chiraphos-me

Full text of DOI:10.1021/ol048690p

ORGANIC
LETTERS
2
004
Vol. 6, No. 18
195-3198
Rhodium-Catalyzed Enantioselective
Conjugate Addition of Organoboronic
Acids to r,â-Unsaturated Sulfones
3
Pablo Maule o´ n and Juan C. Carretero*
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias,
UniVersidad Aut o´ noma de Madrid, Cantoblanco 28049 Madrid, Spain
juancarlos.carretero@uam.es
Received July 8, 2004
ABSTRACT
A general method for the enantioselective catalytic conjugate addition to acyclic r,â-unsaturated sulfones is described. Using metal-chelating
r,â-unsaturated pyridyl sulfones as substrates, the rhodium-catalyzed chiraphos-mediated addition of organoboric acids takes place in excellent
yield and high enantioselectivity. The subsequent elimination of the pyridylsulfonyl group by Julia−Kociensky olefination provides a novel
approach to the enantioselective synthesis of allylic substituted alkenes.
Conjugate addition is undoubtedly among the most general
and versatile tools in organic synthesis. Thus, it is not
surprising that the development of enantioselective catalytic
procedures for this cornerstone reaction has attracted much
been extended to other types of electron-deficient olefins such
4
5
6
as R,â-unsaturated esters, amides, phosphonates, and nitro
7
compounds.
However, despite the great versatility of sulfones in organic
1
8
attention in recent years. In this field the rhodium-catalyzed
synthesis, the development of enantioselective catalytic
asymmetric 1,4-addition of aryl and alkenylboronic acids to
enones, developed by Miyaura and Hayashi, is one of the
conjugate addition reactions to R,â-unsaturated sulfones
remains an exciting challenge in asymmetric catalysis. As
the closest precedent, Hayashi et al. have recently reported
that R,â-unsaturated phenyl sulfones do not react with
organoboron reagents under the usual rhodium-catalyzed
conditions, whereas, interestingly, the reaction with the more
nucleophilic aryltitanium reagents occurs with concomitant
2
most practical methods due to the stability and availability
of the boronic acid used as a nucleophile and the high
enantioselectivity typically associated with this process,
3
especially when binap is used as a chiral ligand. Since the
2a
first paper published in 1997, this strategy has successfully
*
Fax: 34914973966.
(4) (a) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi,
T. Tetrahedron: Asymmetry 1999, 10, 4047-4056. (b) Sakuma, S.; Sakai,
M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951-5955.
(5) (a) Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66,
6852-6856. (b) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944-
8946.
(6) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 1999, 121, 11591-11592.
(7) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716-10717.
(8) Simpkins, N. S. In Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. For some reviews on sulfone chemistry, see: (a)
Simpkins, N. S. Tetrahedron 1990, 46, 6951-6984. (b) Rayner, C. M.
Contemp. Org. Synth. 1996, 3, 499-533. (c) N a´ jera, C.; Yus, M.
Tetrahedron 1999, 55, 10547-10658.
(1) Recent reviews on enantioselective conjugate additions: (a) Tomioka,
K.; Nagaoka, Y. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 3, Chapter
3
1.1. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061. (c)
Krause, N.; Hoffmann-R o¨ der, A. Synthesis 2001, 171-196.
2) Leading references: (a) Sakai, M.; Hayashi, H.; Miyaura, N.
(
Organometallics 1997, 16, 4229-4231. (b) Takaya, Y.; Ogasawara, M.;
Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579-
5
3
580. (c) Takaya, Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1998,
9, 8479-8482.
(
3) For recent reviews, see: (a) Hayashi, T. Synlett 2001, 879-887. (b)
Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844. For a very
recent reference, see: (c) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T.
J. Am. Chem. Soc. 2004, 126, 6240-6241.
1
0.1021/ol048690p CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/31/2004

elimination of the sulfonyl group after the conjugate addition
step, leading to desulfonylated alkenes as final products.
reactivity was observed from the nitrogen-tethered sulfones
bearing 2-(dimethylamino)phenyl (1b), 1,3-pyrimidinyl (1c),
tetrazoyl (1d), and benzimidazoyl (1e) moieties. On the
contrary, to our delight, the imidazoyl sulfone 1f and the
2-pyridyl sulfone 1g smoothly evolved under the reaction
conditions to give the expected â-phenyl-substituted sulfone
2 as the only detected product. The pyridyl derivative 1g
showed the highest reactivity and provided nearly quantita-
tive yield in pure isolated addition product (98%). Convinced
that the high reactivity of this substrate was due to the
coordination of the rhodium catalyst with the appropriately
placed nitrogen atom and not merely to electronic effects,
we studied the behavior of the isomer 4-pyridyl sulfone 1h.
In accordance with the impossibility of an intramolecular
rhodium-chelating effect, we found that this substrate was
completely unreactive.
Having established the best substitution at sulfur in
sulfones 1, we next studied the enantioselectivity of the
rhodium-catalyzed addition of phenylboronic acid to the
sulfone 1g in the presence of 3 mol % of a number of
structurally varied chiral ligands (Table 2). To establish
appropriate reactivity comparisons, all the reactions were
stopped after 12 h under identical reaction conditions.
Interestingly, complete conversions were only obtained in
the case of the P,P-bidentate ligands binap, tol-binap, and
chiraphos (entries 1-3, respectively). The rest of the ligands
with either P,P- (entries 4-7), P,N- (entries 8 and 9), or P,S-
bidentate coordination (entries 10 and 11) proved to be much
less efficient, especially the nitrogen-based ligands. An
unsatisfactory reactivity was also observed in the case of
using the monodentate Feringa’s phosphoramidite ligand13
9
By using an appropriately rhodium-coordinating hetero-
aromatic sulfone as the key controlling moiety and chiraphos
as the optimal chiral ligand, we report herein that R,â-
unsaturated sulfones are excellent substrates for the rhodium-
catalyzed enantioselective conjugate addition of arylboronic
acids, providing â-substituted sulfones in very high yields
and enantioselectivities ranging 76-92% ee.10
We have recently reported that the palladium-coordinating
ortho-(dimethylamino)phenyl sulfonyl group is essential to
perform intermolecular Heck reactions on R,â-unsaturated
1
2
1
1
sulfones. With this precedent in mind, we envisaged that
this type of metal-chelating effect could be used to enhance
the reactivity of R,â-unsaturated sulfones in the rhodium-
catalyzed addition of organoboron reagents, as well as to
suppress any possible desulfonylation process.
As a model reaction we studied the behavior of a variety
of propenyl sulfones 1, having different aromatic substitution
at sulfur, under the usual experimental conditions described
for the rhodium-catalyzed conjugate addition of organo-
3
boronic acids to enones: Rh(acac)(C
2 4
H )
2
(3 mol %), (()-
binap (3 mol %), PhB(OH)
00 °C (Table 1).
2
(excess), dioxane/H O (10:1),
2
1
Table 1. Rhodium-Catalyzed Reaction of Differently
Substituted Propenyl Sulfones with Phenyl Boronic Acida
(entry 12).
Concerning the enantioselectivity of the process, unlike
the reported results on the rhodium-catalyzed enantioselective
conjugate addition to other types of electron deficient
2-7
alkenes, in which binap proved to be the ligand of choice,
in our case the highest enantioselectivity was reached using
1
4
chiraphos (81% ee, entry 3). It is worthy of note that the
planar chiral Fesulphos P,S-ligands, recently developed by
15
us, also provided enantioselectivity similar to that obtained
from chiraphos (76-81% ee), albeit the reactivity was much
lower.
Having found that (S,S)-chiraphos displayed the optimal
reactivity/enantioselectivity profile on the model reaction,
the structural scope of this enantioselective reaction was
studied (Table 3). We considered both the substitution at
a
Reaction conditions: PhB(OH)2 (5 equiv), Rh(acac)(C2H4)2 (3 mol %),
()-binap (3 mol %), dioxane/H2O (10:1), 100 °C, 12 h. a In isolated
product.
(
(
12) For the use of the pyridyl group as a controlling chelating group in
We found not only that the phenyl sulfone 1a was inert
under the reaction conditions but also that the same lack of
metal-mediated reactions of R,â-unsaturated pyridyl silanes, see: Itami, K.;
Mitsudo, K.; Nokami, T.; Kamei, T.; Koike, T.; Yoshida, J. J. Organomet.
Chem. 2002, 653, 105-113 and references therein.
(13) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2003,
68, 9481-9484.
(
9) Yoshida, K.; Hayashi, T. J. Am. Chem. Soc. 2003, 125, 2872-2873.
(
10) For a chiral auxiliary approach on the addition of chiral nitrogen
nucleophiles to R,â-unsaturated sulfones, see: (a) Enders, D.; M u¨ ller, S.
F.; Raabe, G. Angew. Chem., Int. Ed. 1999, 38, 195-197. (b) Enders, D.;
M u¨ ller, S. F.; Raabe, G. Synlett 1999, 741-743. For enantioselective radical
addition-allylation reactions and cyclizations of vinyl sulfones, see: (c)
Watanabe, Y.; Mase, N.; Furue, R.; Toru, T. Tetrahedron Lett. 2001, 42,
(14) Superiority of chiraphos over binap as a chiral ligand was confirmed
with other pairs of pyridyl sulfones and arylboronic acids, showing the
generality of this ligand effect. For instance, the binap-mediated reaction
of sulfone 1g with p-fluorophenylboronic acid gave product 3 in 76% ee
(84% ee using chiraphos) and the addition of phenylboronic acid to sulfone
1k afforded 4 in 76% ee (87% ee using chiraphos).
(15) (a) Priego, J.; Garc ´ı a Manche n˜ o, O.; Cabrera, S.; G o´ mez Array a´ s,
R.; Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679-3686. (b)
Garc ´ı a Manche n˜ o, O.; G o´ mez Array a´ s, R.; Carretero, J. C. J. Am. Chem.
Soc. 2004, 125, 456-457.
2
981-2984. (d) Sugimoto, H.; Kobayashi, M.; Nakamura, S.; Toru, T.
Tetrahedron Lett. 2004, 45, 4213-4216.
11) (a) Maule o´ n, P.; Alonso, I.; Carretero, J. C. Angew. Chem., Int. Ed.
001, 40, 1291-1293. (b) Maule o´ n, P.; Nu n˜ ez, A. A.; Alonso, I.; Carretero,
J. C. Chem. Eur. J. 2003, 9, 1511-1520.
(
2
3196
Org. Lett., Vol. 6, No. 18, 2004

Table 2. Enantioselective Rhodium-Catalyzed Addition of
Phenyl Boronic Acid to Pyridyl Sulfone 1g
Table 3. Enantioselective Rhodium-Catalyzed Addition of
Boronic Acids to R,â-Unsaturated 2-Pyridyl Sulfones
conversionb yield of
ee (%)d
entrya
1
R1
R2
product yield (%)b ee (%)c
entrya
ligand (L*)
(R)-binap
(R)-tol-binap
(S,S)-chiraphos
(S,S)-norphos
(S)-phanephos
josiphos 1
josiphos 2
tanyaphos
mandyphos
Fesulphos 1
Fesulphos 2
phosphoramidite
(%)
2g (%) (configuration)e
c
1
2
1g Me
1g Me
1g Me
1i nPent
1i nPent
1i nPent
1j iPr
1j iPr
1j iPr
Ph
2g
3
97
98
81
84
77
84
87
81
78
85
76
87
92
85
1
2
3
4
5
6
7
8
9
>98
>98
>98
10
97
92
97
73 (R)
60 (R)
81 (S)
pFC6H4
pMeOC6H4
Ph
pFC6H4
pMeOC6H4
Ph
3d
4d
5d
6d
7e
8e
9e
4
89
5
98
6
94
<10
73
7
92
68
41 (R)
8
93
<10
<10
<10
87
70
39
pFC6H4
pMeOC6H4
9
93
10
11
12
13
74 (94)f
1
1
1
0e
1e
2e
1k â-Naph Ph
1k â-Naph pFC6H4
1k â-Naph pMeOC6H4
96
97
84 (94)f
1 f
1 f
0
78
66
31
76 (S)
81 (S)
73 (S)
1
1
2
a
2
Reaction conditions: R B(OH)2 (5 equiv), Rh(acac)(C2H4)2 (3 mol %),
a
Reaction conditions: PhB(OH)2 (5 equiv), Rh(acac)(C2H4)2 (3 mol %),
b
chiraphos (3 mol %), dioxane/H2O (10:1), 100 °C, 12 h. In pure isolated
b
1
L* (3 mol %), dioxane/H2O (10:1), 100 °C, 12 h. Determined by H NMR
after 12 h. In pure isolated product. Determined by HPLC (Chiralpak
AD). Configuration determined by chemical correlation with the known
compound (R)-14. Performed with 6 mol % ligand and rhodium catalyst.
product. c Determined by HPLC (Chiralpak AD or Chiralcel OD). d Reaction
c
d
e
time ) 24 h. Performed with 5 mol % ligand and rhodium catalyst (48 h
reaction time). Converted product.
e
f
f
the p-methoxyphenyl boronic acid provided the lowest
asymmetric induction. (d) With the exception of substrate
1j, a slight enhancement in the enantioselectivity is observed
with the increasing steric bulk of the â-substituent.
Interestingly, the 2-pyridylsulfonyl group not only is
essential for achieving the rhodium-catalyzed conjugate
addition, but its basic elimination by Julia-Kociensky
olefination reaction provides a practical alternative for the
1
6
introduction of a C-C double bond. As shown in Table 4,
the treatment of several enantioenriched â-substituted pyridyl
Table 4. Elimination of the Pyridylsulfonyl Group by
Julia-Kocienski Olefination
the aryl boronic acid (three electronically different reagents)
and the steric bulk at the â-position on the R,â-unsaturated
pyridyl sulfone (substrates 1g, 1i, 1j, and 1k).
Several conclusions are drawn from this study: (a)
Complete conversions and chemical yields higher than 90%
in pure isolated product were obtained in most reactions.
Only the bulkier substrates 1j and 1k led to incomplete
conversions when treated with p-methoxyphenyl boronic acid
E/ Z
ratioa
(E)-isomer
b
entry
sulfone
R3
alkene
yield (%)
1
2
3
4
5
6
2g
2g
2g
2g
3
Ph
14
15
16
17
18
19
>99/<1
90/10
87/13
65/35
>99/<1
>99/<1
93
81
89c
48
92
91
pFC6H4
PhC2H2
iPr
(>90% yield in converted product, entries 9 and 12). (b)
Ph
Ph
Reasonably high and rather homogeneous asymmetric induc-
tion, ranging from 76 to 92% ee, was obtained in all
reactions. (c) For each tested sulfone, the p-fluorophenyl
boronic acid always gave the highest enantioselectivity, while
5
a
1
b
Determined by H NMR from the crude mixtures. In pure (E)-alkene
after silica gel chromatography. c As an 87:13 mixture of E/Z isomers.
Org. Lett., Vol. 6, No. 18, 2004
3197

sulfones with KHMDS in DME at -78 °C, followed by
addition of an aromatic (entries 1, 2, 5, and 6), aliphatic
chemical uncertainty in the formation of the C-C double
bond. For instance, this point is well illustrated in Table 4
by the unambiguous synthesis of the regioisomers 15 and
18 (entries 2 and 5).
(
entry 4), or R,â-unsaturated aldehyde (entry 3), afforded
the corresponding alkene in excellent yield, usually with high
E)-stereoselectivity. The enantiopurity of alkene 14 was
(
In conclusion, we have developed, to the best of our
knowledge, the first catalytic procedure of enantioselective
conjugate addition of carbon nucleophiles to R,â-unsaturated
sulfones. The success of this Rh-catalyzed addition of boronic
acids relies heavily on the use of R,â-unsaturated 2-pyridyl
sulfones as key rhodium-coordinating substrates and chira-
phos as the optimal chiral ligand. This methodology has a
broad scope regarding both the arylboronic acid and the
sulfone substrate, affording the conjugate addition products
in excellent yields (usually >90%) and high enantioselec-
tivities (76-92% ee). The efficient elimination of the
pyridylsulfonyl group by Julia-Kocienski olefination offers
a new approach to the enantioselective synthesis of allylic
substituted alkenes.
confirmed by HPLC (Chiralcel OD) to be identical to that
of the sulfone precursor 2g (81% ee) proving that, as
1
6a
expected, this olefination process occurs without racem-
ization at the â-stereogenic carbon. On the other hand, since
(
R)-14 is a known compound,17 this chemical correlation
allowed us to establish the (S)-configuration of the chiral
sulfone 2g obtained in the Rh-chiraphos-catalyzed addition
1
8
step.
From a synthetic point of view, this two-step enantio-
selective synthesis of allylic substituted alkenes constitutes
an interesting alternative to the direct enantioselective metal-
catalyzed allylic substitution of allylic alcohols derivatives
19
with stabilized enolates. On the other hand, unlike processes
involving π-allylic species, this approach avoids any regio-
Acknowledgment. This work was supported by the
MCyT (Projects BQU2000-0226 and BQU2003-0508). P.M.
thanks the MCyT for a predoctoral fellowship. Prof. Jos e´ L.
Garc ´ı a-Ruano is gratefully acknowledged for unrestricted
access to the HPLC equipment of his group. We also thank
Solvias for the generous gift of several chiral ligands.
(16) For a recent review on modified Julia olefination, see: (a)
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563-2585. See
also: (b) Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett.
2
001, 42, 5149-5153. Corrigendum: Charette, A. B.; Berthelette, C.; St-
Martin, D. Tetrahedron Lett. 2001, 42, 6619. (c) Alonso, D. A.; N a´ jera,
C.; Varea, M. Tetrahedron Lett. 2004, 45, 573-577.
(
17) Knochel, P.; Schwink, L. Chem. Eur. J. 1998, 4, 950-968.
(
18) By chemical analogy, the rest of chiral sulfones obtained using (S,S)-
Supporting Information Available: Experimental details
chiraphos as a ligand (compounds 3-13) are also supposed to have the
same configuration, as shown in Table 3.
1
13
and copies of H NMR and C NMR spectra of representa-
tive compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(19) For some recent reviews on enantioselective metal-catalyzed allylic
substitution: (a) Trost, B. M.; Van Kraken, D. L. Chem. ReV. 1996, 96,
395-422. (b) Trost, B. M.; Carawheg, M. L. Chem. ReV. 2003, 103, 2921-
2944. (c) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2003, 42,
2580-2584.
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Org. Lett., Vol. 6, No. 18, 2004