Regio- and enantiocontrol in the room-temperature hydroboration of vinyl arenes with pinacol borane

Article abstract of DOI:10.1021/ja049761i

The catalyzed hydroboration of vinyl arenes was carried out using pinacol borane instead of catechol borane, as the former reagent and the product boronates are significantly easier to handle. By careful choice of catalyst, either the branched or the linear product can be obtained in greater than 96% selectivity. Interestingly, common ligands such as BINAP and Josiphos give opposite asymmetric induction with pinacol borane as compared with catechol borane, while P,N-ligands such as Quinap gave the same sense of induction. The hydroboration of 6-methoxynaphthalene proceeded with the greatest regio- (95:5) and enantioselectivity (94:6) of all vinyl arenes examined. The hydroboration product was then employed in a concise synthesis of the nonsteroidal antiinflammatory agent, Naproxen. Copyright

Full text of DOI:10.1021/ja049761i

Published on Web 07/14/2004
Regio- and Enantiocontrol in the Room-Temperature Hydroboration of Vinyl
Arenes with Pinacol Borane
Cathleen M. Crudden,* Yonek B. Hleba, and Austin C. Chen
Department of Chemistry, Queen’s UniVersity, Kingston, Ontario, Canada K7L 3N6
Received January 14, 2004; E-mail: cruddenc@chem.queensu.ca
Table 1. Hydroboration of Styrene with Pinacol Boranea
The Rh-catalyzed hydroboration1 of vinyl arenes is a valuable
reaction for the preparation of highly enantiomerically enriched
alcohols,2 amines,3 and carboxylic acids.4 The Rh catalyst serves
to introduce asymmetry by means of the attached chiral ligands
and also to invert the usual preference of the uncatalyzed hydro-
boration to occur in an anti-Markovnikov sense (eq 1).1
c
entry
catalyst
ligand
(L:M)b
2:3
yield
1
2
3
4
5
6
7
8
9
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)Cl]2
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)2]BF4
[Rh(COD)DPPE]BF4
DPPB
DPPB
DPPB
DPPB
DPPP
DPPP
DPPE
DPPE
1:1
2:1
1.2:1
1:1
1:1
2:1
98:2
95:5
96:4
84:16
70:30
98:2
72%d
70%
84%
63%
86%e
56%f
82%
nr
1:1
2:1
73:27
67:33
65:35
68%g
99%g
The use of catechol borane (HBCat) in the metal-catalyzed
reaction is critical since the oxygen substituents on boron decrease
the rate of the uncatalyzed (background) reaction substantially.
However, catechol borane is air sensitive, difficult to handle, and
decomposes in the presence of Rh complexes, phosphines, and other
nucleophiles.5
10
1:1
a Reactions were performed with 5% catalyst in an N2 glovebox. b Molar
ratio. c Isolated yields after chromatography. d NMR yield ) 62%, 1% cat.
e NMR yield ) 79%, 1% cat. f Yield ) 18%, 1% cat. g NMR yield (1 h).
in a 1:1 mixture with bisphosphines such as DPPB or DPPP (Table
1). Under these conditions, the branched boronate ester (2) was
obtained as the major product with greater than 96% selectivity
(Table 1, entry 1).
Therefore, we became interested in the use of pinacol borane
(HBPin) as a substitute, since it is significantly more stable in air
and to nucleophiles than HBCat.6 The boronate ester products are
also stable species that can be handled in air and purified by chro-
matography.4,7 However, the greater steric bulk of pinacol borane
makes achieving high branched selectivity more challenging. With
use of ClRh(PPh3)3 as the catalyst, HBPin has been reported to
give an unattractive mixture of products with 2 as a minor
component (eq 2).8 When [Rh(COD)Cl]2 is employed, dehydro-
genative borylation is the major pathway, giving compound 4 in
96% yield.9
As shown in Table 1, high branched-to-linear ratios are always
obtained in the case of DPPB and only a slight reduction in yield
is observed running the reaction at 1% catalyst loading. Excess
phosphine significantly improves the selectivity using DPPP as the
ligand (compare entries 5 and 6); however, use of a full 2 equiv
leads to a decrease in yield. This is especially obvious at low catalyst
loadings, such that the 56% yield obtained in entry 6 is decreased
to 18% at 1% catalyst loading. With DPPE, the addition of 2 equiv
shuts down the reaction completely (entry 8). Since the selectivity
in this case was similar to that obtained with cationic Rh alone
(entry 9), we attemped the reaction with preformed [Rh(DPPE)-
(COD)]+ complex (entry 10). As expected, the selectivity was
similar, but the yield was higher with the preformed complex.
Although we cannot exclude the possibility that dissociation of
DPPE leads to the active catalyst, this is certainly not the case with
DPPB, where significantly different B:L ratios are observed. With
PPh3 or P(OPh)3, the regioselectivity was poor and vinylboronate
4 was observed in small amounts.
Remarkably, when iridium is employed as the catalyst, a
complete reVersal in selectiVity is obtained, with the linear isomer
being the only obserVed product (Table 2).11 A variety of vinyl
arenes reacted with >99% selectivity and greater than 90% yields.
The change in regioselectivity likely stems from a change in
mechanism from Rh-H insertion to Ir-B insertion, as proposed
by Bonin and Micoun in their seminal paper on Ir-catalyzed
hydroborations of diazines.12a
Although pinacol borane has received very limited attention,
recent results from the labs of Gevorgyan,10a Westcott,10b and
Ramachandran10c have shown that it can be superior to catechol
borane in the hydroboration of cyclopropenes, allylamines, and
fluoroolefins.10d We find that under appropriate conditions, vinyl
arenes can also react with high selectivities for either 2 or 3 using
this reagent. Boronate esters such as 2 are important targets since
they can be converted into a variety of NSAIDs such as Ibuprofen4
and Naproxen. Thus, we report that the use of cationic Rh com-
plexes modified by chelating phosphines gives high selectivities
for 2, while iridium catalysts give 3 as the only observable product.
In the presence of chiral ligands for Rh, hydroboration with HBPin
leads to high enantioselectivities at room temperature and a reVersal
in the sense of enantioselection is obserVed compared to catechol
borane.
The asymmetric hydroboration of styrene was attempted using
a variety of commonly employed chiral ligands (Table 3). Much
to our surprise, with pinacol borane as the hydroborating reagent,
The hydroboration of styrene with HBPin was effectively
-
catalyzed by cationic Rh complexes such as [Rh(COD)2]+BF4
9
9200
J. AM. CHEM. SOC. 2004, 126, 9200-9201
10.1021/ja049761i CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Iridium-Catalyzed Hydroboration of Vinyl Arenesa
Table 4. Enantioselective Hydroboration of Vinyl Arenes with
Pinacol Borane and Rh‚Josiphosa
er
(%)
entry
substrate
2:3
yieldb
entry
substrate
styrene (1a)
p-methylstyrene (1b)
p-chlorostyrene (1c)
p-bromostyrene (1d)
p-methoxystyrene (1e)
L:B
yieldb
1
2
3
4
5
6
7
8
styrene (1a)
p-methylstyrene (1b)
p-chlorostyrene (1c)
p-bromostyrene (1d)
p-methoxystyrene (1e)
6-methoxy-2-vinylnaphthalene (1f)
2-vinylnaphthalene (1g)
83:17 92:8
82:18 94:6
72:28 90:10 90%
83:17 92:8 87%
83:17 88:12 69%
87%
39%
1
2
3
4
5
>99:1
>99:1
>99:1
>99:1
>99:1
99%
95%
99%
90%
98%
95:5
95:5
94:6
93:7
92:8
83%
67%
51%
6-methoxy-5-nitro-2-vinylnaphthalene (1h) 91:9
a See Table 1. b Isolated yields after chromatography.
a See footnote to Table 1. b Isolated yields after chromatography
Table 3. Asymmetric Hydroboration of Styrene with HBPin and
HBCata
temp
(°C)
erb
R:S
yield
(%)
entry
ligand
reagent
B:L
Depending on the choice of catalyst (Rh or Ir), either the branched
or the linear product can be obtained with greater than 95%
selectivity. Reversals in enantioselectivity are observed with chiral
bisphosphine-ligated catalysts when pinacol borane is employed
in place of catechol borane.
1
2
3
4
5
6
7
8
(R)-Binap
(R)-Binap
(R)-Binap
(R,S)-Josiphos
(R,S)-Josiphos
(R,S)-Josiphos
(S) Quinap
HBCat
HBCat
HBPin
HBCat
HBCat
HBPin
HBCat
HBPin
-65
25
25
-70
25
25
25
25
99:1
99:1
96:4
992a/4a
902a
30
79:21
30:70
96:4
80:20
8:92
6:94
56:44
99:1
65
N.A.c
72:28
97:3
N.A.c
53(87)d
69
Acknowledgment. We acknowledge support from the Natural
Sciences and Engineering Research Council of Canada.
(S) Quinap
65:35
9:91
30
Supporting Information Available: Experimental procedures,
conditions for determination of the enantiomeric ratio, and selected
spectra (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
a See footnote to Table 1. b Enantiomeric ratio; R and S refers to 2a.
Note that the R/S designation does not change after oxidation. c Not
available.2c d Yield in parentheses corresponds to optimized case in dichlo-
roethane.
the opposite enantiomer of the product was obtained using the same
antipode of Binap (compare entries 2 and 3). Josiphos also gave
the opposite enantiomer when HBPin was employed (entries 5 and
6). In this case, the reaction with HBPin was more enantioselectiVe
than with HBCat at 25 °C and approached the results obtained with
HBCat at -78 °C. Reversals in asymmetric induction have been
reported for hydrogenation12b and hydroboration12a reactions when
different metals are employed, although in our case, the switch is
caused merely by a change in the achiral reagent.
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Quinap, a less sterically demanding ligand, reacts with good
enantioselectivity, but the reversal in stereoinduction is not observed,
suggesting that unfavorable steric interactions between the bulky
BPin and PPh2 substituents are indeed responsible for the change
in enantioselectivity. The larger BPin group does not stack
effectively with the aryl rings of the chiral ligand and substrate.13a
Chelation of Rh to an oxygen on boron, which is predicted to be
stabilizing,13b may also be disrupted with the bulkier pinacol borane.
Under optimized conditions, (dichloroethane, Rh/Josiphos 1:1.2
ratio), the hydroboration of a variety of vinyl arenes was effected
at 25 °C (Table 4). High enantioselectivies were observed in all
cases. After hydroboration of 6-methoxy-2-vinylnaphthalene (1f),
homologation and oxidation gives Naproxen in 66% yield (5, eq
3). This substrate gave the highest branched to linear selectivity
and the highest enantioselectivity of any of olefins examined (entry
6). Other vinyl naphthalenes also react with high regio- and
enantioselectivities (entries 7 and 8).
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borated with high regio- and enantiocontrol at 25 °C with HBPin.
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