Highly regio- and enantioselective catalytic asymmetric hydroboration of α-substituted styrenyl derivatives

Article abstract of DOI:10.1039/c0cc01547d

The catalytic asymmetric hydroboration of a variety of 1,1-disubstituted olefins has been achieved with excellent yields, perfect regioselectivity and in some cases, high levels of enantioselectivity using readily accessible iridium catalyst.

Full text of DOI:10.1039/c0cc01547d

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Highly regio- and enantioselective catalytic asymmetric hydroboration
of a-substituted styrenyl derivativeswz
´ ´
Clement Mazet* and David Gerard
Received 24th May 2010, Accepted 7th July 2010
DOI: 10.1039/c0cc01547d
The catalytic asymmetric hydroboration of
a
variety of
Building on an early report by Marder and Baker,9
Crudden10 and Miyaura11 have concomitantly established that
iridium catalysts display a complementary regioselectivity to
that of rhodium catalysts in the hydroboration of styrenyl
derivatives.4,8,12 Interestingly, chiral hydrogenation iridium
catalysts rank among the very rare successful examples that
impart high levels of enantioselectivity in an asymmetric
process employing terminal prochiral alkenes.13 Owing to
the mechanistic similarities between hydrogenation and hydro-
boration, which share the same elementary steps (i.e. oxidative
addition, migratory insertion, reductive elimination), we reasoned
that iridium would be the transition metal of choice to develop
highly regio- and enantioselective catalysts for the asymmetric
hydroboration of 1,1-disubstituted olefins.
1,1-disubstituted olefins has been achieved with excellent yields,
perfect regioselectivity and in some cases, high levels of enantio-
selectivity using readily accessible iridium catalyst.
Whether the process is mediated or catalyzed, in most asymmetric
transformations involving olefins as prochiral reagents, 1,1-
disubstituted olefins systematically stand out as a particularly
more challenging substrate subclass.1 This has been attributed
to the difficulty of a chiral auxiliary or a chiral catalyst to
discriminate between two relatively similar substituents at a
geminal position. Consequently, enantioselectivities for these
substrates are usually lower than those obtained for the
corresponding 1,2-disubstituted, trisubstituted or even tetra-
substituted analogues. Asymmetric hydroboration of terminal
olefins is no exception and, for several decades, even the
most selective and general chiral hydroborating agents were
revealed to be incapable of unraveling this long-standing
synthetic problem.2 Recently, Soderquist and coworkers
designed chiral variants of 9-borabicyclononane (9-BBN) that
mediated the hydroboration of four different terminal olefins
displaying unprecedented enantioselectivity levels for the most
biased substrates (28–92% ee).3 As a next step in this direc-
tion, the development of transition metal-catalyzed hydro-
boration reactions would provide an attractive alternative
to the use of expensive and sacrificial stoichiometric chiral
auxiliaries. The strongly favored Markovinov regioselectivity
observed with most chiral transition metal catalysts investi-
gated to date has certainly precluded the development of a
catalytic asymmetric hydroboration of terminal olefins.4
Suzuki,5 Burgess,6 and Ito and Hayashi7 have independently
demonstrated the difficulty of obtaining specific boration at
the terminal position (b) rather than at the more substi-
tuted position (a) using chiral rhodium catalysts. Moderate
b-regioselectivities along with low enantioselectivities were obtained
in the best cases. Perhaps not surprisingly, subsequent studies
have focused on developing highly a-regioselective chiral rhodium
catalysts using monosubstituted styrenyl derivatives as prochiral
substrates.8 We present herein the approach we followed towards
the discovery of a highly regio- and enantioselective iridium-
catalyzed hydroboration of terminal olefins.
We began our investigations by evaluating the potential of
chiral ligands that have proven successful in the context of iridium-
catalyzed asymmetric hydrogenation of various classes of olefins,
using a-methylstyrene as test substrate and commercially available
[Ir(Cl)(COD)]2 (COD = 1,5-cyclooctadiene). The air-stable pinacol-
borane (HBpin) was preferred over catecholborane (HBcat) as
hydroborating agent, not only because its higher steric demand
intrinsically favors b-selectivity but also because it gives access to
more robust products.14 Reactions were performed at room
temperature, in THF, using 2.5 mol% of in situ generated catalyst
(Table 1). Remarkably, only the C1-symmetric phosphino-
oxazoline ligands (Phox) L7 and L8 provided 2a with encouraging
levels of enantioselectivity (32 and 48% ee respectively; Table 1,
entries 6 and 7). The use of a cationic iridium precursor led to
polymerization of the styrenyl derivative suggesting that the
ancillary anionic ligand may play an important role in the
hydroboration reaction (Table 1, entry 10).
We next decided to evaluate the influence of a variety of
halides and oxyanions on the outcome of the reaction using
ligand L8 (Table 2, entries 1–8).15 In all cases, the regio-
selectivity remained excellent in favor of the b-boration product
2a (2a/3a, >99 : 1). Except for X = Br (entry 2), all other
anions surveyed led to better enantioselectivities. Although no
clear trend is visible with respect to the steric and electronic
properties of the anions, notable improvements were obtained
in the oxyanions series, with X = OMe offering the best balance
in terms of reactivity, regioselectivity and enantioselectivity
(Table 2, entry 5). Subsequent solvent optimization studies
showed hexanes was the candidate of choice, delivering quanti-
tatively and regioselectively 2a in 92% ee (Table 2, entry 13).
Electronic effects were further investigated by subjecting two
additional Phox ligands L10 and L11 to the optimized reac-
tion conditions. Introduction of either electron-donating or
electron-withdrawing substituents on the para position of
the P-aryl rings led to substantially diminished yields and/or
enantioselectivities in both cases (Table 2, entries 14 and 15).
University of Geneva, Organic Chemistry Department,
Quai Ernest Ansermet 30, 1211-Geneva, Switzerland.
E-mail: clement.mazet@unige.ch; Fax: +41 (0)22 3793215;
Tel: +41 (0)22 3796288
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Full experi-
mental data and characterization for all new compounds. See DOI:
10.1039/c0cc01547d
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Table 1 Optimization studies
Table 3 Substrate scope
Entrya Olefin R1
R2 2/3b
Yieldc (%) eed (%)
Entrya
L*
Metal precursor
2a/3ab
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
Me >99 : 1 92
Me >99 : 1 83
Me >99 : 1 93
Me >99 : 1 94
Me >99 : 1 91
Me >99 : 1 98
92 (S)
50 (S)
77 (S)
80 (S)
79 (S)
76 (S)
76 (S)
32 (S)
44 (S)
55 (S)
o5
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
4-IC6H4
4-(CF3)C6H4 Me >99 : 1 92
4-(MeO)C6H4 Me >99 : 1 64
4-MeC6H4
3-MeC6H4
2-MeC6H4
C6H5
1
2
3
4
5
6
7
8
9
10
L1
L2
L3
L4
L6
L7
L8
L9
L8
L8
[Ir(Cl)(COD)]2
[Ir(Cl)(COD)]2
[Ir(Cl)(COD)]2
[Ir(Cl)(COD)]2
[[Ir(Cl)(COD)]2
[Ir(Cl)(COD)]2
[Ir(Cl)(COD)]2
[Ir(Cl)(COD)]2
[Rh(Cl)(COD)]2
[Ir(COD)2]BArF
nd
nd
o5
o5
75
>99
99
89
95
55
90
nd
nd
nd
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
90 : 10
nd
o5
o5
o5
32 (S)
48 (S)
6 (S)
o5
9
Me >99 : 1 81
Me >99 : 1 88
Me >99 : 1 66
Et >99 : 1 98
Cy >99 : 1 55
10
11
12
13
1j
1k
1l
ndd
31 (S)
6 (S)e
1m
C6H5
a
b
Average of at least two experiments on a 1.0 mmol scale. Determined
by 1H NMR. Isolated yield after chromatography. Determined by
e
HPLC after conversion to the corresponding alcohol. Reaction
c
d
performed at 40 1C.
not only the enantioselectivity, but also the yields are reduced
(Table 3, entries 8–10). Increasing the steric demand at the
vicinity of the benzylic position by using larger R2 alkyl groups
(R2 = Et, Cy) or by replacing the phenyl ring with either an
o-tolyl or a cyclohexyl drastically reduces the enantioselectivity
(Table 3, entries 11–13).
a
b
Average of at least two experiments on a 1.0 mmol scale. Deter-
mined by 1H NMR. Determined by HPLC after conversion to the
d
corresponding alcohol. Polymerization of 1a was observed.
c
To delineate the scope and limitation of our catalytic system,
we applied the optimized reaction conditions to a representa-
tive set of diversely substituted terminal olefins (Table 3).
Introduction of electron-withdrawing substituents on the
para or meta positions of model substrate 1a induces a slight
but measurable erosion in enantioselectivity (76–80% ee for
substrates 1c–1g, Table 3, entries 3–7). A fluorine atom has a
stronger negative impact (50% ee, Table 3, entry 2), as much
as the introduction of electron-donating substituents for which
Hydroboration of a-methylstyrene using L8 under the
optimized reaction conditions and D-Bpin as the hydroborating
agent provided interesting preliminary mechanistic insights
(Fig. 1). The distribution of deuterium in the product was
assessed after oxidation to the corresponding alcohol.16 The
high extent of deuterium incorporation in the benzylic position
accounts for the expected C(1)-migratory insertion/reductive
elimination sequence (A - B). Incorporation of deuterium
both in the terminal position and in the methyl group of the
substrate is evidence for reversible C(2)-migratory insertion
(A - C).
Table 2 Counter-anion and solvent effect
The higher extent of incorporation in the terminal position in
C can be attributed to the lower entropic cost associated with
poising the C(1)-protons rather than the methyl protons in a
position favorable for a subsequent b-H-elimination. According
to the perfect regioselectivities observed in the hydroboration
reactions, reductive elimination from C is virtually not feasible.17
These results also suggest that initial hydride insertion followed
by reductive elimination occurs preferentially to boron insertion
followed by reductive elimination.
Entrya L*
X
Solvent
2a/3ab
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
Cl
Br
I
THF
THF
THF
THF
THF
THF
>99 : 1
>99 : 1
>99 : 1
>99 : 1 >99
>99 : 1 >99
>99 : 1 >99
>99 : 1
>99 : 1 >99
>99 : 1 >99
95
68
63
48 (S)
30 (S)
72 (S)
60 (S)
85 (S)
66 (S)
82 (S)
72 (S)
88 (S)
71 (S)
60 (S)
87 (S)
92 (S)
35 (S)
76 (S)
OH
OMe
Oi-Pr
Ot-Bu THF
OPh
OMe
OMe
OMe
OMe
OMe
The synthetic applicability of the iridium-catalyzed asymmetric
hydroboration of terminal olefins was demonstrated by
75
THF
TBME
Acetone >99 : 1
CH2Cl2 >99 : 1
Toluene >99 : 1
Hexanes >99 : 1 >99
Hexanes >99 : 1
Hexanes >99 : 1
9
10
11
12
13
14
15
28
66
97
L10 OMe
L11 OMe
99
84
a
b
Average of at least two experiments on a 1.0 mmol scale. Deter-
mined by 1H NMR. Determined by HPLC after conversion to the
corresponding alcohol.
c
Fig. 1 Labelling experiments and mechanistic implications.
Chem. Commun., 2011, 47, 298–300 | 299
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Notes and references
1 S. P. Thomas and V. K. Aggarwal, Angew. Chem., 2009, 121, 1928
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Scheme 1 (i) See Table 2 entry 4 (1.0 g scale); (ii) Pd(OAc)2
(10 mol%), dppf (12 mol%), PhB(OH)2 (1.5 equiv.), K3PO4 (3.0 equiv.),
THF, 80 1C, 48 h; (iii) NaOH, H2O2, 23 1C, 2 h; (iv) DMP (1.7 equiv.)
CH2Cl2, 23 1C, 20 min; (v) KHF2, H2O : MeOH, 23 1C, 30 min; (vi)
Pd(OAc)2 (5 mol%), RuPhos (10 mol%), 4-bromoanisole (1.0 equiv.),
K2CO3 (3.0 equiv.), toluene : H2O (10 : 1), 80 1C, 24 h.
5 M. Sato, N. Miyaura and A. Suzuki, Tetrahedron Lett., 1990, 31,
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performing a series of fundamental derivatizations relying on
challenging orthogonal functionalization through successive
Suzuki cross-coupling reactions (Scheme 1).18
Asymmetric hydroboration of 1d was performed on a 1.0 g
scale delivering 4d exclusively with excellent yield and good
enantioselectivity (90% yield, 79% ee). Using a standard
protocol, selective Suzuki cross-coupling between the electro-
philic site of 2d and phenylboronic acid was successfully
achieved, leaving the boronic ester untouched. No traces of
cross-product could be detected and the coupling product 4d
was obtained in 65% yield without any extensive optimiza-
tions of the reaction conditions. From this pivotal intermediate,
successive oxidations, first to the corresponding alcohol 5d and
next to the potentially stereo-labile a-chiral aldehyde 6d, were
performed without noticeable epimerization of the stereogenic
center (93% yield over 2 steps, 79% ee).19 The relatively inert
boronate ester 4d was converted to the corresponding potassium
trifluoroborate salt 7d in quantitative yield.20 A second Suzuki
cross-coupling was conducted exploiting conditions developed
by Molander21 and coworkers. Using 5 mol% of Pd(OAc)2
and 10 mol% of Buchwald’s RuPhos ligand,22 4-bromoanisole
was coupled with 7d under aqueous conditions. The expected
chiral polyaromatic product 8d was obtained in 70% yield
without erosion of the enantiomeric purity, demonstrating
that competing reversible b-hydride elimination does not
occur under these conditions.23
7 T. Hayashi, Y. Matsumoto and Y. Ito, Tetrahedron: Asymmetry,
1991, 2, 601.
8 (a) T. Hayashi, in Comprehensive Asymmetric Catalysis, ed.
E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin,
1999, vol. 1, pp. 351–366; (b) J. M. Brown, in Modern Rhodium-
Catalyzed Organic reactions, Wiley-VCH, Weinheim, 2005.
9 S. A. Westcott, T. B. Marder and R. T. Baker, Organometallics,
1993, 12, 975.
10 C. M. Crudden, Y. B. Hleba and A. C. Chen, J. Am. Chem. Soc.,
2004, 126, 9200.
11 Y. Yamamoto, R. Fujikawa, T. Umemoto and N. Miyaura,
Tetrahedron, 2004, 60, 10695.
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C. M. Crudden, J. Am. Chem. Soc., 2010, 132, 131.
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A. Pfaltz, Adv. Synth. Catal., 2005, 347, 282; (b) M. Dieguez,
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¨
¨
M. Dieguez, J. Am. Chem. Soc., 2009, 131, 12344.
14 A. C. Chen, L. Ren and C. M. Crudden, J. Org. Chem., 1999, 64,
9704.
15 K. Fagnou and M. Lautens, Angew. Chem., 2002, 114, 26 (Angew.
Chem., Int. Ed., 2002, 41, 26).
16 D. A. Evans, G. C. Fu and B. A. Anderson, J. Am. Chem. Soc.,
1992, 114, 6679.
17 The formation of p-allyl iridium intermediates can be ruled out
becauseit would imply the formation of coordinatively over-
saturated iridium complexes. An achiral ligand gives the same
isotopic distribution.
18 (a) M. Tobisu and N. Chatani, Angew. Chem., 2009, 121, 3617
(Angew. Chem., Int. Ed., 2009, 48, 3565); (b) N. Iwadate and
M. Suginome, J. Am. Chem. Soc., 2010, 132, 2548.
19 C. Botuha, M. Haddad and M. Larcheveque, Tetrahedron:
Asymmetry, 1998, 9, 1929.
20 (a) S. Darses and J.-P. Genet, Eur. J. Org. Chem., 2003, 4313;
(b) V. Bagutski, A. Ros and V. K. Aggarwal, Tetrahedron, 2009,
65, 9956.
In conclusion, we have developed an efficient protocol for the
catalytic asymmetric hydroboration of terminal olefins. High
catalytic activity, perfect regioselectivity and enantioselectivities
up to 92% were obtained using (phosphinooxazoline)–iridium
catalysts. The applicability of this method was further high-
lighted by orthogonal functionalization through successive
Suzuki cross-coupling reactions.
This work was supported by the State Secretariat for Educa-
tion and Research. Solvias is acknowledged for the gift of
ligand L2 and Johnson Matthey for the loan of iridium
21 G. A. Molander and L. Jean-Ge
´
5446.
22 R. Martı
rard, J. Org. Chem., 2009, 74,
´
n and S. L. Buchwald, Acc. Chem. Res., 2008, 41,
precursors. Professor E.-P. Kundig is warmly thanked for
¨
giving us access to his analytical facilities. L. Mantilli, S. Torche
and D. Grassi are acknowledged for practical assistance.
1461.
23 Y. Iwai, K. M. Gligorich and M. S. Sigman, Angew. Chem., 2008,
120, 3263 (Angew. Chem., Int. Ed., 2008, 47, 3219).
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This journal is The Royal Society of Chemistry 2011
300 | Chem. Commun., 2011, 47, 298–300