The rhodium-catalysed 1,2-addition of arylboronic acids to aldehydes and ketones with sulfonated S-Phos

Article abstract of DOI:10.1016/j.tetlet.2009.10.082

The rhodium-catalysed 1,2-addition of arylboronic acids to aryl aldehydes has been accomplished in high yield using sulfonated S-Phos, a water-soluble biaryl phosphine ligand which allows for catalyst recycling. The catalytic protocol has also been successful in the challenging arylation of ketones.

Full text of DOI:10.1016/j.tetlet.2009.10.082

Tetrahedron Letters 50 (2009) 7365–7368
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The rhodium-catalysed 1,2-addition of arylboronic acids to aldehydes
and ketones with sulfonated S-Phos
James R. White a, Gareth J. Price a, Pawel K. Plucinski b, Christopher G. Frost a,
*
a Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
b Department of Chemical Engineering, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The rhodium-catalysed 1,2-addition of arylboronic acids to aryl aldehydes has been accomplished in high
yield using sulfonated S-Phos, a water-soluble biaryl phosphine ligand which allows for catalyst recy-
cling. The catalytic protocol has also been successful in the challenging arylation of ketones.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 September 2009
Revised 5 October 2009
Accepted 16 October 2009
Available online 22 October 2009
The synthesis of alcohols by the insertion of aldehydes into the
metal–carbon bonds of rhodium complexes has emerged as a use-
ful method for organic synthesis.1 Miyaura and co-workers first de-
scribed the efficient addition of arylboronic acids to aldehydes in
aqueous solution employing phosphine complexes having a large
P-Rh-P angle and also with bulky and donating trialkyl phos-
phines.2 A number of other ligands have been used to prepare rho-
dium complexes with excellent activity for this important
synthetic process.3 The use of enantiopure ligands has afforded
good levels of enantioselectivity.2a,4 An appealing advance in this
area is the report of enantioenriched secondary and tertiary
alkylboron derivatives adding to aldehydes with complete stereor-
etention in the presence of an appropriate rhodium complex.5 The
rhodium-catalysed addition of arylboronic acids to aldehydes is
noted to tolerate aqueous reaction conditions which can offer dis-
tinct benefits in terms of reactivity and the prospect of catalyst
recycling.6 In this context, Shaughnessy and co-workers reported
that a combination of t-Bu-Amphos 8 and RhCl3ꢀ3H2O provides a
recyclable catalyst for the coupling of aryl- and vinylboronic acids
with aldehydes in aqueous solvents.7 In this Letter, we report the
application of a sulfonated biaryl phosphine ligand in rhodium-cat-
alysed additions of arylboronic acids to aldehydes and, remarkably,
ketones. S-Phos 5 is a key member of a family of rationally de-
signed biaryl phosphine ligands introduced by Buchwald and co-
workers that have shown immense potential in the Suzuki–Miya-
ura couplings of challenging substrates.8 The ready availability of
a sulfonated S-Phos 6 inspired us to investigate the possibility of
developing a robust and recyclable catalyst system for the aryla-
tion of aldehydes.9
Extraction of the organic product using diethyl ether and subse-
quent addition of more reagents to recycle the catalyst species
yielded continued conversion (Table 1, entries 1–3). Also the room
temperature activity of the catalyst suggested high activity (Table
1, entry 4). However the use of an alternative phosphine, TPPMS-Li
(7), containing the easily prepared backbone common to many
industrially applied water-soluble phosphine ligands,10 showed
significantly lower ability to turnover the reaction in recycling
experiments (Table 1, entries 5–7). These results prompted us to
attempt additions to related ketone substrates, progress in this
area is not so advanced due to the lower reactivity in part due to
the increased steric demands imposed in these systems.11 So far,
only highly activated ketones have been shown to undergo the
1,2-addition reaction with arylboronic acids using transition metal
catalysts.12 These typically include electronically activated sub-
(HO)2B
2
(1.5 eq.)
O
[Rh(cod)Cl]2 4 (2 mol%)
Ligand 6 (4 mol%)
OH
H
1.1 eq. NaOH, N2
H2O, 80 ºC, 2 h
1
3
100% conversion
Ph2P
SO3Li
PCy2
O
PCy2
Initial results were immediately promising, with p-tolualde-
hyde 1 being completely converted into the diaryl-carbinol prod-
uct 3 (isolated in 86% yield) in two hours at 80 °C (Scheme 1).
TPPMS-Li 7
O
O
O
NMe3Cl
(t-Bu)2P
SO3Na
SS-Phos 6
t-Bu-Amphos 8
S-Phos 5
* Corresponding author. Tel.: +44 (0)1225 386142; fax: +44 (0)1225 386231.
E-mail address: c.g.frost@bath.ac.uk (C.G. Frost).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.082

7366
J. R. White et al. / Tetrahedron Letters 50 (2009) 7365–7368
Table 1
is often a hydroxy-rhodium intermediate, which can be produced
in situ using aqueous alkali-metal hydroxides and a suitable pre-
catalyst.16 The use of smaller amounts of base also retarded con-
version, probably due to the presence of increasing amounts of
boric acid as by-product, which results in an unfavourable environ-
ment for catalyst turnover.17
Our attempts to increase conversion employing a 1:1 ratio of
water and co-solvent to improve mixing were unsuccessful (Table
3, entries 2–5). The use of polar aprotic solvents gave poor results,
possibly due to complexation with the metal centre and subse-
quent deactivation. The only improvement came with increasing
the concentration of the reaction mixture in water, this resulted
in a useful 51% conversion (Table 3, entry 8). Unfortunately, vary-
ing the temperature at this higher concentration showed no fur-
ther improvement.
Activity and recycling of rhodium complexes with water-soluble ligands
[Rh(cod)Cl]2 (4) (2 mol%)
OH
O
Ligand (4 mol%)
1.5 eq. 2
H
1.1 eq. NaOH, N2
H2O, 80 ºC, 2 h
1
3
Entry
Ligand
% Conv.a
1
6
6
6
6
7
7
7
100
81
66
100
46
Trace
83
2b
3c
4d
5b
6c
7
Using this optimised set of conditions we revisited the aldehyde
substrates to improve the catalyst recycling. Importantly, we noted
that the addition of a portion of base for each recycle of the catalyst
allowed high activity to be maintained over five reactions of 1 (Ta-
ble 4). This indicated that the drop-off in catalytic activity we ob-
served previously (Table 1, entries 1–3) was not due to
degradation of the catalytically active species during the recycling
All reactions performed on 1.0 mmol of aldehyde in water (1.5 ml).
a
As determined by 1H NMR spectroscopy.
b
Second run. Recycle via extraction of organic components, followed by the
addition of a further 1.0 equiv of aldehyde and 1.5 equiv of boronic acid per cycle to
the aqueous catalyst and designated ligand.
c
Third run.
Reaction performed at rt for 48 h.
d
strates such as trifluoromethylketones,13 and various 1,2-dicar-
bonyl derivatives.14 The reaction has also been shown to work with
tethered ketone/boronic acid systems in an intramolecular
fashion.15
Table 3
Effect of co-solvent and temperature on ketone arylation
[Rh(cod)Cl]2 (4) (2 mol%)
O
HO Me
Ligand 6 (4 mol%)
We therefore selected p-nitroacetophenone (9) and p-meth-
oxyphenylboronic acid (10) to use in a more challenging addition.
The initial conditions gave an encouraging 41% conversion as
determined by 1H NMR (Table 2, entry 1). Purification by column
chromatography afforded diaryl-methylcarbinol 11 in a 39% yield.
With this convenient model system we then proceeded to further
investigate the reaction parameters. A brief base screen showed
metal hydroxides to be most effective (Table 2, entries 3 and 11),
and a hydroxy-rhodium species or appropriate precatalyst was
found to be essential (Table 2, entries 3–8). This is consistent with
literature precedent, where the active species for transmetallation
1.5 eq. p-MeO-PhB(OH)2 (10)
Me
1.1 eq. NaOH, N2
1:1 H2O/co-solvent, Temp., 24 h
O2N
O
O2N
9
11
Entry
Co-solvent
Temp (°C)
% Conv.a
1
2
3
4
5
6
7
8
9
(H2O)
MeCN
DMSO
1,4-Dioxane
IPA
None
None
None
None
80
80
80
80
80
40
60
80
100
40
5
8
9
30
32
39
51
46
Table 2
Initial results for the ketone arylation
All reactions performed on 0.125 mmol of ketone in water (0.75 ml) with co-solvent
(0.75 ml). Where no co-solvent was used the total volume of water remained at
0.75 ml.
[Rh] (4 mol%)
Ligand 6 (4 mol%)
1.5 eq. p-MeO-PhB(OH)2 (10)
O
HO Me
a
As determined by 1H NMR spectroscopy.
Me
Base, N2
H2O, 80 °C, 24 h
O2N
O
O2
N
9
11
Table 4
Optimised aldehyde arylations and catalyst recycling
Entry
Catalyst
Basea
% Conv.b
[Rh(cod)Cl]2 (4) (2 mol%)
Ligand 6 (4 mol%)
OH
O
1
2
3
4
5
6
7
8
[Rh(cod)Cl]2 (4)
4
4
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
K2CO3
NEt3
41 (39)c
(HO)2B
43 (29)d
H
40
0
0
0
0
40
17
30
41
21
1.1 eq. NaOH, N2
H2O, 80 ºC, 2 h
(None)
R
R
(1.5 eq.)
Cycle
RhCl3ꢀ3H2O
[Rh(acac)(C2H4)2]2
Entry
R
% Conv.a
Rh2(tfa)4
[Rh(cod)OH]2
4
4
4
4
1
2
3
4
5
6
7
—
—
1
p-F
100 (91)
97b
>99 (96)
>99
>99
>99
p-OMe
p-Me
p-Me
p-Me
p-Me
p-Me
9
10
11
12
2c
3c
4c
5c
KOH
None
All reactions performed on 0.125 mmol of ketone in water (1.5 ml), except entries 1
and 2 where 1.0 mmol of ketone was used in water (3.0 ml).
>99 (97)
a
All reactions performed on 1.0 mmol of aldehyde in water (1.5 ml).
1.1 equiv of base.
a
As determined by 1H NMR spectroscopy, isolated yield in parentheses.
Degradation, primarily to the diaryl ketone, occurred during purification.
1.0 equiv of aldehyde, 1.5 equiv of boronic acid and 1.1 equiv of base added per
As determined by 1H NMR spectroscopy, isolated yields in parentheses.
b
b
c
c
Reaction time of 2 h.
Without ligand, reaction time extended to 48 h; purification was complicated
d
cycle. Products removed after cooling via extraction with diethyl ether.
by product colouration suggesting metal contamination.

J. R. White et al. / Tetrahedron Letters 50 (2009) 7365–7368
7367
Table 5
logues due to the changes in electronic character of the
phosphorus centre.6b,18 We have shown that sulfonated S-Phos li-
gand 6, with a phosphine remote sulfonate group, to be highly
effective in rhodium-catalysed 1,2-additions of arylboronic acids
in aqueous media. The superiority of 6 over 7 is attributed to the
electron-donating dicyclohexylphosphine group enhancing the
nucleophilicity of the aryl donor on rhodium. The results from
the solvent study suggest an ‘on-water’ reaction may be occurring,
where the reactants are dispersed as small droplets leading to a
large increase in the surface area between the reactants and the
aqueous phase. The effective high concentrations of reactants, cou-
pled with the continued availability of ions from bulk solution con-
tribute to an enhanced rate of transmetallation and ensuing
insertion.19 The aqueous solubility of the sulfonated S-Phos ligand
enabled the rhodium complex to be recycled in five successive
aldehyde arylations affording quantitative conversions and a 97%
isolated yield of product in the final run.
Trifluoromethyl ketone arylations
[Rh(cod)Cl]2 (4) (2 mol%)
Ligand 6 (4 mol%)
HO CF3
O
(HO)2B
CF3
1.1 eq. NaOH, N2
H2O, 80 ºC, 24 h
R'
(1.5 eq.)
R'
% Yielda
R
R
Entry
R
R0
1
2
3
4
5
6
7
8
H
H
H
H
87
90
89
p-Me
p-OMe
p-Me
H
p-Me
m-Me
o-Me
2-Naphthyl
p-OMe
m-OMe
p-Cl
2,4,6-Me
p-Cl
p-Cl
p-Cl
p-Cl
p-Cl
p-Cl
p-Cl
p-Cl
0b
78
94
95
92
93
95
96
87
82
9
10
11
12
13
p-Cl
m-Cl
Acknowledgements
All reactions performed on 1.0 mmol of ketone in water (1.5 ml).
a
This work was supported by the EPSRC. Dr. Anneke Lubben
(Mass Spectrometry) and Dr. John Lowe (NMR) are also thanked
for their valuable assistance.
Isolated yield after column chromatography.
b
The starting ketone was recovered quantitatively.
process, but rather the resultant conditions (no added base) were
unfavourable for continued transmetallation of the boronic acid.
The scope of the catalytic additions employing ligand 6 was ex-
tended to include trifluoromethylketones (Table 5). The corre-
sponding products were obtained in very good yields with a
range of boronic acids. The reaction was tolerant of different sub-
stitution patterns on the donor (Table 5, entries 6–8) and even
deactivating halogen substituents afforded excellent isolated
yields of product (Table 5, entries 12 and 13). Unsurprisingly, the
sterically demanding mesitylketone substrate proved unreactive
(Table 5, entry 4).
Supplementary data
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.082.
References and notes
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c Le Notre, J.; Frost, C.G. Science of
Finally, investigating the scope of the arylation of simple ke-
tones showed electronic effects consistent with those seen for
aldehyde substrates (Table 6). Electron-withdrawing groups on
the carbonyl compound are beneficial for reactivity, as are comple-
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It also appears that the nature of the ketone is of greater impor-
tance in determining the reactivity, with only the p-nitroacetophe-
none substrate offering reasonable conversion into product (Table
6, entries 4–6). The addition of further equivalents of boronic acid
wasfoundtoprovidea68%yieldofisolatedproduct(Table6, entry7).
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Table 6
Aryl-methyl ketone reactivity patterns
[Rh(cod)Cl]2 (4) (2 mol%)
Ligand 6 (4 mol%)
HO Me
O
(HO)2B
Me
1.1 eq. NaOH, N2
H2O, 80 ºC, 24 h
R'
R'
R
R
(1.5 eq.)
11. Miyaura et al., in their original report, noted ketones were unreactive, see Ref.
2a. Ref. 3a also notes chemoselectivity for the aldehyde in the presence of a
ketone.
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Miyamura, S.; Satoh, T.; Miura, M. J. Organomet. Chem. 2006, 691, 2821–
2826.
Entry
R
R0
% Conv.a
1
2
3
4
5
6
7
p-OMe
p-Me
p-F
p-NO2
p-NO2
p-NO2
p-NO2
p-OMe
p-OMe
p-OMe
p-F
p-Me
p-OMe
p-OMe
6
13
19
41
49
60
13. Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Chem.
Commun. 2006, 4093–4095.
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3356; (b) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.
Org. Lett. 2006, 8, 2715–2718; (c) Miyamura, S.; Satoh, T.; Miura, M. J. Org.
Chem. 2007, 72, 2255–2257; (d) Ganci, G. R.; Chisholm, J. D. Tetrahedron Lett.
2007, 48, 8266–8269; (e) Duan, H.-F.; Xie, J.-H.; Qiao, X.-C.; Wang, L.-X.; Zhou,
Q.-L. Angew. Chem., Int. Ed. 2008, 47, 4351–4353.
70 (68)b
All reactions performed on 1.0 mmol of ketone in water (1.5 ml).
As determined by 1H NMR spectroscopy, isolated yields in parentheses.
Using 5.0 equiv of boronic acid.
a
b

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J. R. White et al. / Tetrahedron Letters 50 (2009) 7365–7368
15. (a) Takezawa, A.; Yamaguchi, K.; Ohmura, T.; Yamamoto, Y.; Miyaura, N. Synlett
2002, 10, 1733–1735; Also using palladium catalysis: (b) Liu, G.; Lu, X.
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16. Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169–196.
17. Addition of boric acid was found to retard the reaction.
18. Shaughnessy, K. H.; Booth, R. S. Org. Lett. 2001, 3, 2757–2759.
19. (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
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