Angewandte
Chemie
Thus, while addition of tetrazole provided an active
hydroformylation catalyst system, the regioselectivity was low
À
(Table 1, entry 1). Previous studies on C H activation
employing phosphinites had identified Cs2CO3 and K3PO4
as efficient promoters for transesterification.[8] Unfortunately,
under the conditions of hydroformylation, low activity and
poor regioselectivity were detected (Table 1, entries 2,3). We
wondered whether a mild Lewis acid, such as LiCl, could
promote transesterification. Thus, addition of 10 mol% LiCl
furnished a reasonably active catalyst which proceeded with
excellent regioselectivity (99:1, Table 1, entry 4). Lowering
the amount of LiCl to 1 mol% and changing the solvent to
THF to increase the solubility of the lithium salt led to a
decreased catalyst activity while the regioselectivity remained
high (Table 1, entry 5). Lowering the amount of LiCl further
and addition of molecular sieves to remove traces of water
furnished a very active catalyst, albeit with a slightly reduced
regioselectivity (97:3, Table 1, entry 6). Interestingly, the
reaction proceeded even in the absence of LiCl furnishing
the best catalyst system. Thus, employing 1 mol% of rhodium
catalyst and 10 mol% of the directing ligand 3, in THF
solvent at 408C and with a syngas pressure of 20 bar, were
found to be the optimal conditions. After 6 h, complete
conversion was reached and a perfect regioselectivity towards
the branched regioisomer, the g-lactol, was detected (Table 1,
entry 7).[16]
With these optimized conditions in hand we next checked
whether this catalyst system would allow also for regioselec-
tive hydroformylation of an internal alkene, which is one of
the great challenges in hydroformylation chemistry.[17] We
were pleased to find that in all cases the reaction proceeded
smoothly with exceptional levels of regiocontrol to afford
(after oxidation) the corresponding g-lactones in good-to-
excellent yields. Either Z- or E-configured alkenes could thus
be employed with similar results (Table 2, entries 2 and 3). A
sterically more demanding secondary alkyl substituent in 4-
position was tolerated as well (Table 2, entry 4). Remarkably,
reaction of a substrate functionalized with an additional 1,2-
disubstituted alkene function (Table 2, entry 6) displayed a
completely regioselective hydroformylation of the homoal-
lylic alkene function. Furthermore, the reaction tolerates
functional groups, such as thioethers, ethers, and free hydroxy
groups (Table 2, entries 7, 9, and10).
Scheme 1. Hydroformylation of homoallylic alcohol 1 with and without
a covalently bound catalyst-directing phosphinite group (2). acac=ace-
tylacetonoate.
expected, the alcohol substrate 1 reacted with the standard
triphenylphosphine/rhodium catalyst to give a mixture of the
regioisomeric g- and d-lactols (27:73). Once more this result
illustrates that a hydroxy group is unsuited to function as a
directing group in the course of the hydroformylation.[14]
Conversely, the reaction of phosphinite 2 proceeded com-
pletely regioselectively, in favor of the branched regioisomer.
The primary reaction products were the lactol phosphinites.
Liberation of the lactols was easily achieved upon reaction
with methanol in the presence of catalytic amounts of
tetrazole.[15] Hence, a transesterification of a phosphinite
from the reaction product to another alcohol substrate is
possible, and may work under hydroformylation conditions.
Hydroformylation of homoallylic alcohol 1 was probed
using catalytic amounts (10 mol%) of phosphinite 2 in the
presence of potential transesterification catalysts tetrazole,
cesium carbonate, potassium phosphate, and lithium chloride
(Table 1).
Table 1: Development of the hydroformylation procedure with a catalytic
amount of the directing group.
Entry
Ligand
Additive
Solvent
Conv.
[%][a]
Regioselectivity[a]
Hydroformylation of the homoallylic alcohols with the
standard rhodium/triphenylphosphine catalyst were also
performed for comparison purposes, to give an insight into
the role of the phosphinite ligand. In all cases mixtures of
regioisomers were obtained (see Table 2, regioselectivity
values in parentheses). Furthermore, hydroformylation of
the methyl ether of (E)-3-hexenol with the phosphinite 3/
rhodium catalyst was studied (Table 2, entry 11). In this case
the reaction was very slow (6% conversion after 12 h) while
under the same conditions the corresponding homoallylic
alcohol was quantitatively consumed after 8 h (Table 2,
entry 2). Furthermore, the methyl ether furnishes a mixture
of regiosomers (53:47, Table 2, entry 11) while in the case of
the corresponding homoallylic alcohol, the g-lactols were
formed exclusively (Table 2, entry 2). These results are in
accord with a directed reaction, and suggest that the role of 3
(g:d)
1
2
3
4
5
6
2
2
2
2
2
2
tetrazole
10 mol%
Cs2CO3
10 mol%
K3PO4
10 mol%
LiCl
10 mol%
LiCl
toluene
toluene
toluene
toluene
THF
66[b]
46:54
45:55
41:59
99:1
24
36
62
11
99:1
1 mol%
LiCl
THF
99
97:3
0.1 mol%
MS (4 )[d]
MS (4 )
7
3
THF
99[c]
99:1
[a] Determined by GC. [b] Conversion after 6 h. [c] Complete conversion
was reached after 6 h. [d] MS=molecular sieve.
Angew. Chem. Int. Ed. 2008, 47, 7346 –7349
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7347