Catalytic asymmetric conjugate boration of α,β-unsaturated sulfones

Article abstract of DOI:10.1039/c1cc11949d

The α,β-unsaturated sulfones are suitable activated olefins in catalytic asymmetric conjugate β-boration. These substrates undergo smooth conjugate addition of bis(pinacolato)diboron [B₂(pin)₂] catalyzed by nonracemic Cu^I-diphosphine complexes to provide, upon subsequent oxidation, β-hydroxy sulfones in good yields and high enantiocontrol.

Full text of DOI:10.1039/c1cc11949d

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Catalytic asymmetric conjugate boration of a,b-unsaturated sulfonesw
´ ´ ´
Abraham L. Moure, Ramon Gomez Arrayas* and Juan C. Carretero*
Received 6th April 2011, Accepted 26th April 2011
DOI: 10.1039/c1cc11949d
The a,b-unsaturated sulfones are suitable activated olefins in
catalytic asymmetric conjugate b-boration. These substrates
undergo smooth conjugate addition of bis(pinacolato)diboron
[B2(pin)2] catalyzed by nonracemic CuI-diphosphine complexes
to provide, upon subsequent oxidation, b-hydroxy sulfones in
good yields and high enantiocontrol.
The reactivity of a,b-unsaturated sulfones was first investi-
gated by running model reactions of a small set of representa-
tive aryl 1-alkenyl sulfones. To test the influence of the nature
of the arylsulfonyl group and the aromatic/aliphatic nature of
the substituent at the b-position, substrates 1a–b and 2a–b
were subjected to the reaction with B2(pin)2 (1.1 equiv.)
following typical conditions reported using (Æ)-Binap as
the diphosphine ligand: CuCl/(Æ)-Binap (10 mol%), NaOt-Bu
(15 mol%), MeOH (2 equiv.) in THF at room temperature
(Table 1). The isolation of the resulting b-boryl sulfone
intermediate was not successful because of its instability
during chromatography. Therefore, it was quantitatively
transformed into the corresponding b-hydroxy sulfone by
oxidation with NaBO3 of the crude reaction mixture.
In accordance with previous findings,4a–c the very low
conversion observed in the absence of MeOH confirmed its
important role for catalytic turnover in this reaction (entry 1).
However, even in the presence of this additive the reactivity of
1a was very low to be practical (57% conversion after 72 h,
entry 2), showing the reluctance of vinyl sulfones to undergo
conjugate boration compared to other activated olefins.
Organoboronic acids and their derivatives exhibit remarkable
versatility due to their functional group tolerance and the
ability of the boron atom to be readily converted into a wide
variety of functionalities in a stereospecific manner and under
mild reaction conditions.1 Therefore, the development of
novel protocols for the enantioselective construction of chiral
organoboronates is of growing importance in asymmetric
synthesis.2 The asymmetric CuI-catalyzed boration of
electron-deficient alkenes with B2(pin)2 via catalytic generation
of chiral Cu–B species as ‘‘formal boryl nucleophiles’’ has
recently emerged as a powerful synthetic tool to provide
functionalized chiral boronates.3–5 Stunning progress in this
area has been achieved mainly through two approaches:
g-boration of allylic or propargylic carbonates3 and b-boration
of electron-deficient alkenes.4 The pioneering racemic work
on Cu-catalyzed conjugate addition of B2pin2 to a,b-enones,
independently reported by Hosomi et al.6 and Miyaura et al.,7
spurred the development of the catalytic asymmetric variant
of this reaction and its application to a variety of activated
olefins including a,b-unsaturated cyclic4h,j and acyclic4i,o,q
ketones, acyclic esters4e–g,n–p and lactones,4j,k amides4l,m and
nitriles,4d,e,n as well as imines,4r to afford optically active
b-boryl carbonyl derivatives and nitriles.8 However, despite
the great versatility of sulfones in organic synthesis,9
a,b-unsaturated sulfones remain yet to be incorporated into
the arsenal of activated olefins with general application in
Cu-catalyzed asymmetric direct b-boration. We describe herein a
novel procedure for such asymmetric transformation affording,
upon oxidation, enantioenriched b-hydroxy sulfones10 in good
yields and high enantiocontrol.
Table 1 Reactivity of a,b-unsaturated sulfones in the Cu-catalyzed
conjugate boration
Entrya Ar
R (substrate) Methodb T/h
Product Yieldc (%)
1d
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph (1a)
Ph (1a)
Ph (1a)
Me (2a)
Me (2a)
A
A
B
A
B
B
B
72
72
2
0.75 4a
0.75 4a
3a
3a
3a
28
57
82
52
100 (85)
33
100 (87)
2-Py Ph (1b)
2-Py Me (2b)
2 3b
0.75 4b
a
Conditions: substrate 1 or 2 (0.2 mmol), B2pin2 (0.22 mmol,
1.1 equiv.), CuCl (10 mol%), (Æ)-Binap (12 mol%), NaOt-Bu (15 mol%),
´
´
´
Departamento de Quımica Organica, Universidad Autonoma de
Madrid (UAM), Cantoblanco, 28049 Madrid, Spain.
E-mail: juancarlos.carretero@uam.es, ramon.gomez@uam.es;
Fax: +34 914973966
b
MeOH (2 equiv.), THF (0.4 mL), rt. Method A: copper salt, ligand
and base were aged for 30 min before addition of B2pin2 and then, after
10 min, addition of substrate and MeOH; Method B: MeOH was added
dropwise to a solution of copper salt, ligand, base, substrate and B2pin2
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data of new compounds, copies of
NMR spectra, and X-ray crystallography data. CCDC 818353. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1cc11949d
c
in THF at rt. Conversion yield. In parentheses, isolated yield after
d
chromatography. Reaction performed in the absence of MeOH.
c
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Chem. Commun., 2011, 47, 6701–6703 6701

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A survey of reaction conditions led us to find that a change in
the mode of addition of the reagents produced a dramatic
increase of reactivity (Method B, entry 3). Thus, 82% conversion
after just 2 h was observed when MeOH was directly added to
the solution containing all the species (copper salt, base,
ligand, substrate, and diborane) in THF at room temperature
(Method B), rather than the typical reported procedure
consisting of aging the copper source, the base and the ligand
for 30 min before the addition of the B2(pin)2 and then, after
further stirring for 10 min, the addition of the olefin and the
MeOH (Method A). This enhancement of reactivity when
using the mode of addition B was also observed in the case
of the methyl-substituted sulfone 2a (compare entries 4 and 5).
Interestingly, this substrate 2a showed higher reactivity than
the phenyl-substituted substrate 1a (complete conversion after
45 min at room temperature, entry 5). Heteroarylsulfones such
as 1b and 2b, both bearing a (2-pyridyl)sulfonyl group, were also
suitable substrates, providing comparable reactivity in the case
of the b-methyl-substituted substrate 2b (entry 7).11 However,
the lower reactivity associated to aromatic substituents at the
b-position of the a,b-unsaturated sulfone moiety observed in
the couple 1a/2a was even more pronounced in the case of the
substrate 1b (R = Ph, 33% conversion after 2 h, entry 6).11
With the optimized conditions for the racemic reaction in
hand, a broad survey of chiral phosphines was undertaken to
realize an enantioselective variant of the conjugate boration of
the model substrate 2a (Table 2). The nature of the ligand
Table 3 Catalytic enantioselective conjugate boration of b-alkyl-
substituted a,b-unsaturated sulfonesa
a
Conditions: sulfone (0.2 mmol), B2pin2 (0.22 mmol, 1.1 equiv.), CuCl
(10 mol%), Taniaphos or Josiphos (12 mol%), NaOt-Bu (15 mol%),
MeOH (2 equiv.), THF (0.4 mL), rt. b Using Taniaphos as the chiral
ligand. c Using Josiphos as the chiral ligand.
Table 2 Enantioselective CuI-catalyzed b-boration of vinyl sulfone 2a
slightly influenced the reactivity (90–100% conversion in
most cases), compared with the deep impact observed in
enantiocontrol. The ferrocene-based (R,R)-Josiphos and
(R,S)-Taniaphos provided the alcohol (R)-4a12 with excellent
values of asymmetric induction (490% ee, entries 9 and 10),
and were chosen as optimal chiral ligands. Catalyst loading
and the amount of base were reduced to 5 mol% and
7.5 mol%, respectively, without affecting enantioselectivity,
although the chemical yield was slightly lower (entries 9
and 10).
Entry Liganda (L*)
Conversionb (%) Yieldc (%) eed (%)
1
2
3
4
5
6
7
8
9
10
Binap
100
90
100
85
—
80
82
—
—
—
—
60
53
60
86
33
40
1
40
Tol-Binap
Segphos
DTBM-Segphos 100
Quinox
Quinap
Mandyphos
Walphos
Josiphos
Taniaphos
We next investigated the substrate scope under the
optimized conditions. As shown in Table 3, the reaction
tolerates a series of b-alkyl substituents, which furnished
the corresponding b-hydroxy sulfones of (R)-configuration12
generally in good yields and enantiocontrol. Substrates with
linear alkyl chain substituents displayed high reactivity and
enantioselectivity (products 4a–b and 5b, 89–94% ee), regardless
of the nature of the sulfonyl group. Side chains branched at
the b-position were also well tolerated (product 6a), while
branching at the a-position (e.g., cyclohexyl or i-Pr) had a
strong detrimental impact on the reactivity (products 8a, 9a
and 9b, 34–40% yield), yet maintaining a good asymmetric
induction (84–87% ee). On the other hand, the less sterically
encumbered cyclopropyl group did not affect the reactivity
(product 7a, 79% yield), albeit it produced slightly lower
enantioselectivity (77% ee). Substrates containing several
functional groups such as bromoaryl (product 11b), chloride
(12b), acetoxy (13b), acetal (14b) and alkynes (15b) also
behaved very well in this transformation (87–97% ee),
highlighting the wide functional tolerance of this method, as well
as opening attractive possibilities for further functionalization.
100
89
100
76
100 (100)e
100 (90)e
90 (81)e
72 (62)e
91 (91)e
94 (94)e
a
See ESIw for the complete ligand screening (16 ligands tested).
b
c
Determined by 1H NMR on the crude reaction mixture. In pure
d
product after chromatography. Determined by HPLC on a chiral
e
stationary phase. In parentheses, values for the reaction performed
with 5 mol% of catalyst loading (CuCl/L*) and 7.5 mol% of
NaOt-Bu.
c
6702 Chem. Commun., 2011, 47, 6701–6703
This journal is The Royal Society of Chemistry 2011

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S. Kunii and M. Sawamura, Nat. Chem., 2010, 2, 972;
(c) J. K. Park, H. H. Lackey, B. A. Ondrusek and
D. T. McQuade, J. Am. Chem. Soc., 2011, 133, 2410.
4 For reviews, see: (a) J. A. Schiffner, K. Muther and M. Oestreich,
¨
Angew. Chem., Int. Ed., 2010, 49, 1194; (b) A. Bonet, C. Sole,
H. Gulyas and E. Fernandez, Curr. Org. Chem., 2010, 14, 2531;
´
(c) L. Mantini and C. Mazet, ChemCatChem, 2010, 2, 501. For
catalytic asymmetric conjugate borations, see: ; (d) S. Mun,
J.-E. Lee and J. Yun, Org. Lett., 2006, 8, 4887; (e) J.-E. Lee
and J. Yun, Angew. Chem., Int. Ed., 2008, 47, 145;
Scheme 1 Catalytic asymmetric b-boration of b-aryl-substituted
a,b-unsaturated sulfones.
(f) W. J. Fleming, H. Muller-Bunz, V. Lillo, E. Ferna
´
ndez and
P. J. Guiry, Org. Biomol. Chem., 2009, 7, 2520; (g) V. Lillo, A. Prieto,
A. Bonet, M. M. Dıaz-Requejo, J. Ramırez, P. J. Perez and
E. Fernandez, Organometallics, 2009, 28, 659; (h) I.-H. Chen,
¨
Despite b-aryl-substituted a,b-unsaturated sulfones showing
poorer reactivity in the model b-boration reaction of 1a, and
especially 1b, with the catalyst system CuCl/(Æ)-Binap, we
briefly explored the reactivity of this type of substrates under
the enantioselective version conditions (Scheme 1). The negative
influence of aromatic substituents at the b-position on the
reactivity was confirmed in the reaction of 1a with the
CuI/Josiphos (10 mol%) catalyst system. The product (R)-3a
was isolated in moderate yield (50%) due to incomplete
conversion (70%), but with high asymmetric induction
(91% ee). Noteworthily, electron-rich aromatic substituents at
the b-position tend to give higher yields, while maintaining the
high enantiocontrol, as exemplified by the substrate 16a bearing a
4-methoxyphenyl group (product 18a, 72% yield, 89% ee). In
contrast, electron-poor aromatic substituents such as a 4-trifluoro-
methylphenyl group (substrate 17a) seem to make the substrate
inert in this reaction (product 19a, not detected).
´
´
´
´
L. Yin, W. Itano, M. Kanai and M. Shibasaki, J. Am. Chem. Soc.,
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2009, 15, 1939; (j) X. Feng and J. Yun, Chem. Commun., 2009, 6577;
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13609; (o) J. M. O’Brien, K.-s. Lee and A. H. Hoveyda, J. Am. Chem.
Soc., 2010, 132, 10630; (p) J. K. Park, H. H. Lackey, M. D. Rexford,
K. Kovnir, M. Shatruk and D. T. McQuade, Org. Lett., 2010, 12,
5008; (q) I.-H. Chen, M. Kanai and M. Shibasaki, Org. Lett., 2010,
12, 4098; (r) C. Sole, A. Whiting, H. Gulyas and E. Ferna
Synth. Catal., 2011, 353, 376.
´
ndez, Adv.
5 For NHC-copper-catalyzed boron–copper addition to unactivated
olefins and alkynes with B2pin2, see, respectively: (a) Y. Lee and
A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131, 3160; (b) Y. Lee,
H. Jang and A. H. Hoveyda, J. Am. Chem. Soc., 2009, 131, 18234.
6 H. Ito, H. Yamanaka, J.-i. Tateiwa and A. Hosomi, Tetrahedron
Lett., 2000, 41, 6821.
7 (a) K. Takahashi, T. Ishiyama and N. Miyaura, Chem. Lett., 2000,
982; (b) K. Takahashi, T. Ishiyama and N. Miyaura, J. Organomet.
Chem., 2001, 625, 47.
8 For the rhodium-catalyzed enantioselective b-boration of a,b-
unsaturated carbonyl compounds, see: (a) T. Shiomi, T. Adachi,
K. Toribatake, L. Zhou and H. Nishiyama, Chem. Commun., 2009,
5987. For metal-free catalytic asymmetric b-borations, see:
In conclusion, this work provides the first methodology
for the asymmetric b-boration of a,b-unsaturated sulfones
via conjugate addition of bis(pinacolato)diboron catalyzed
by CuI/Josiphos complexes. Upon in situ oxidation of the
boronate, the corresponding b-hydroxy sulfones are produced
in good yields and high enantioselectivities (typically in the
range 85–95% ee). Broad structural scope and wide functional
group tolerance have been demonstrated, especially with
b-alkyl-substituted substrates. Novel applications and extension
of this chemistry are currently underway in our laboratory.
(b) A. Bonet, H. Gulya
Int. Ed., 2010, 49, 5130.
9 (a) N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon
Press, Oxford, 1993; (b) J. C. Carretero, R. Gomez Arrayas and
s and E. Fernandez, Angew. Chem.,
´ ´
´
´
J. Adrio, in Sulfones in Asymmetric Catalysis, ed. T. Toru and
C. Bolm, Wiley-VCH, Weinheim, 2008, ch. 9, pp. 291–320.
10 Enantioenriched b-hydroxy sulfones are typically accessed by
asymmetric reduction of b-ketosulfones. See for instance:
(a) B. T. Cho and D. J. Kim, Tetrahedron: Asymmetry, 2001, 12,
2043; (b) V. Gotor, F. Rebolledo and R. Liz, Tetrahedron:
Asymmetry, 2001, 12, 513; (c) G. Zhao, J.-B. Hu, Z.-S. Quian
and W.-X. Yin, Tetrahedron: Asymmetry, 2002, 13, 2095;
(d) H.-L. Zhang, X.-L. Hou, L.-X. Dai and Z.-B. Luo, Tetra-
hedron: Asymmetry, 2007, 18, 224.
´
e Innovacion
We thank the Ministerio de Ciencia
´
´
(MICINN, CTQ2009-07791) and the Consejerıa de Educacion
de la Comunidad de Madrid (programme AVANCAT, S2009/
PPQ-1634) for financial support. A.L.M. thanks the
UAM for a predoctoral fellowship. We thank Solvias AG
(Dr H.-U. Blaser and Dr B. Pugin, Solvias ligand-kit) and
Takasago (Dr T. Touge, Segphos and DTBM-Segphos) for
generous loans of chiral ligands.
11 A competitive experiment, in which an equimolar mixture of
substrates 2a and 2b was subjected to the reaction with B2pin2
under the optimized conditions with the Cu–Josiphos catalyst
system, revealed that the 2-pyridylsulfone 2b displayed a slightly
Notes and references
1 For recent general reviews, see: (a) Contemporary Boron Chemistry,
ed. M. Davidson, A. K. Hughes, T. B. Marder and K. Wade, RSC,
Cambridge, 2000; (b) C. M. Crudden, B. W. Glasspoole and
C. J. Lata, Chem. Commun., 2009, 6704.
2 For examples on recent applications of chiral boronates:
(a) D. Imao, B. W. Glasspoole, V. S. Laberge and
C. M. Crudden, J. Am. Chem. Soc., 2009, 131, 5024; (b) S. Nave,
R. P. Sonawane, T. G. Elford and V. K. Aggarwal, J. Am. Chem.
Soc., 2010, 132, 17096; (c) S. M. Winbush and W. R. Roush, Org.
Lett., 2010, 12, 4344; (d) J. Chang, H. Lee and D. G. Hall, J. Am.
Chem. Soc., 2010, 132, 5544.
higher rate than the parent 2a (k
/k
= 1.2). In contrast,
2-PySO2 PhSO2
the opposite tendency was observed when this experiment was
performed with an equimolar mixture of the b-phenyl-substituted
substrates 1a and 1b under identical conditions (k2-PySO /kPhSO = 0.4).
2
2
These values are in concordance with the results shown in Table 1.
12 The absolute configuration of the b-hydroxy phenyl sulfones was
determined by comparison of the [a]D values with those of known
compounds. The same absolute stereochemistry of the 2-pyridyl
sulfones was confirmed by X-ray crystallographic analysis of a
recrystallized 97% ee sample of compound (R)-10b. See ESIw for
details. CCDC 818353 contains the supplementary crystallo-
graphic data for this paper.
3 Recent examples: (a) H. Ito, T. Okura, K. Matsuura and
M. Sawamura, Angew. Chem., Int. Ed., 2010, 49, 560; (b) H. Ito,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6701–6703 6703