Direct asymmetric α-allylation of aldehydes with simple allylic alcohols enabled by the concerted action of three different catalysts

Article abstract of DOI:10.1002/anie.201103263

Triple catalysis: The title reaction between α-branched aldehydes and allylic alcohols, which generates all-carbon quaternary stereogenic centers, constitutes the first asymmetric Tsuji-Trost-type α-allylation of carbonyl compounds with allylic alcohol (s

Full text of DOI:10.1002/anie.201103263

DOI: 10.1002/anie.201103263
Triple Catalysis
Direct Asymmetric a-Allylation of Aldehydes with Simple Allylic
Alcohols Enabled by the Concerted Action of Three Different
Catalysts**
Gaoxi Jiang and Benjamin List*
Tsuji–Trost allylations are Pd0-catalyzed reactions in which
diverse nucleophiles are allylated with allylic alcohol deriv-
atives such as allylic acetates.[1] Asymmetric catalysis of these
reactions is commonly achieved by the use of chiral neutral
ligands.[1,2] We have recently described a different approach
that is based on the use of chiral counteranions, which are
introduced to the reaction in catalytic amounts.[3,4] We
discovered an asymmetric a-allylation of a-branched alde-
hydes using benzhydryl allyl amine as the allylating reagent
and a combination of [Pd(PPh3)4] and the chiral Brønsted acid
TRIP as catalysts.[4a] Herein, we report the first example of a
highly enantioselective a-allylation of aldehydes with simple
allylic alcohols [Eq. (1)]. This reaction is catalyzed by the
concerted action of three different species, [Pd(PPh3)4],
benzhydryl amine, and TRIP, and constitutes another exam-
ple of asymmetric counteranion-directed catalysis (ACDC).[4]
improving our previous protocol by directly utilizing simple
allylic alcohols rather than benzhydryl allyl amines, which
have to be synthesized individually in a separate step.
In our previous allylation studies, we have suggested that
our reaction involves the generation of the equivalent of a p-
allyl-Pd-TRIP ion pair as the critical intermediate, which
reacts with an enamine generated from the released benzhy-
dryl amine and the aldehyde. We reasoned that the same p-
allyl-Pd complex should also be generable from allylic alcohol
and the combined action of TRIP and [Pd(PPh3)4]. Indeed,
very recently we have shown that a simple achiral Brønsted
acid and [Pd(PPh3)4] constitutes a powerful catalyst pair for
nonasymmetric a-allylations of aldehydes,[8] suggesting that
the concentration and nucleophilicity of the aldehyde-derived
enol is sufficient for the reaction to occur. This transformation
proceeds via a mass-spectrometrically detectable p-allyl-Pd
intermediate and not through a Claisen mechanism,[6a,b] and
no reaction occurs in the absence of Pd. However, while we
were delighted to find that TRIP and [Pd(PPh3)4] indeed
readily catalyze the a-allylation of hydratropic aldehyde (2-
phenylpropanal, 1a) with allylic alcohol (2a), the enantio-
meric ratio of product 3a was disappointingly minuscule
[Eq. (2)].
We hypothesized that the low enantioselectivity can be
attributed to the fact that both E- and Z-enol isomers are
generated under our reaction conditions but lead to opposite
enantiomeric products (Figure 1). In our previous and highly
enantioselective variant, a benzhydryl amine derived enam-
ine was invoked, of which we expect the preferred E isomer to
predominantly engage in the transition state. Consequently,
While great progress in the asymmetric catalysis of Tsuji–
Trost-type allylations has been made in recent years, the
direct use of allylic alcohols as allylating reagents is extremely
rare[5] and even entirely unprecedented with carbonyl nucle-
ophiles.[6,7] Continuing our studies on the use of chiral
counteranions in asymmetric Pd catalysis,[4a] we recently
became interested in further simplifying and potentially
[*] Dr. G. Jiang, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
[**] We thank A. Lee for kindly donating several racemic aldehydes and
M. W. Alachraf for MS studies. Generous funding by the Max Planck
Society is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103263.
Figure 1. Developing a working hypothesis.
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Table 2: Asymmetric a-allylation of different aldehydes.[a]
our initial result immediately suggested a solution to the
enantioselectivity problem of the aldehyde a-allylation with
allylic alcohols: If an amine would be added as the third
catalyst, the resulting enamine, because of its higher nucle-
ophilicity, could potentially outperform the corresponding
enol in the allylation, and provide the product with high
enantioselectivity (Figure 1).
Entry
R1
R2
Prod.
Yield [%][b]
e.r.[f]
1
2
3
4
5
6
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a
3b
3c
3d
3e
3 f
3g
3h
3i
97
95
94
94
98
98
94
97
96
77
90
97:3
97:3
99.8:0.2
96:4
96:4
95:5
96:4
96:4
96:4
81:19
84.5:15.5
Indeed, this hypothesis served as the guideline of our
initial screening experiments. Accordingly, a mixture of
substrates 1a and 2a was treated with a catalytic amount of
[Pd(PPh3)4] (1.5 mol%) and (S)-TRIP (3.0 mol%) at 408C
for 12 h in the presence or absence of different amines to give
aldehyde 3a in varying yields and enantioselectivities
(Table 1). Gratifyingly, adding 40 mol% of different amines
to the reaction mixture dramatically increased the enantio-
selectivity. For example, with amine A1, an e.r. of 88:12 was
obtained (Table 1, entry 2). As expected from our previous
studies, of the different amines (Table 1, entries 2–6), benz-
hydryl amine A5 gave the best result and afforded product 3a
in 97% yield and with an excellent enantioselectivity of 97:3
e.r. (Table 1, entry 6). It is noteworthy that 40 mol% of amine
A5 is necessary to ensure high enantioselectivity. Reducing
the amount of the cocatalyst leads to lower yield and
enantioselectivity (Table 1, entry 7). This seems to mainly
result from product inhibition leading to the corresponding
benzhydryl imine of 3a, which undergoes relatively slow
hydrolysis under the reaction conditions. In fact, acidic
workup of the reaction is required to ensure complete
hydrolysis of this imine.
4-MeO-C6H4
4-Me-C6H4
3-Me-C6H4
4-Ph-C6H4
4-Cl-C6H4
2-F-C6H4
3-F-C6H4
6-MeO-2-naph
C6H5
7[c]
8
9
10[d]
11[d,e]
3j
3k
Cyclohexyl
Me
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [Pd(PPh3)4]
(1.5 mol%), (S)-TRIP (3.0 mol%), A5 (40 mol%), M.S. 5 ꢁ (100 mg),
toluene (1.0 mL), 408C, 12 h. [b] Isolated product. [c] For 24 h.
[d] [Pd(PPh3)4] (5.0 mol%), (S)-TRIP (10 mol%), A5 (80 mol%), 72 h.
[e] 80 mol% of (S)-1-phenylethylamine instead of A5, 1108C, 24 h.
[f] Determined by HPLC after reduction to the alcohol with NaBH4, or by
GC with a chiral stationary phase.
methyl-branched aromatic aldehydes bearing electron-donat-
ing and electron-withdrawing groups at different positions.
Treating various aldehydes (1a–i) with allylic alcohol (2a,
2 equiv) in the presence of [Pd(PPh3)4] (1.5 mol%), (S)-TRIP
(3.0 mol%), A5 (40 mol%), and 5 ꢀ molecular sieves at 408C
in toluene for 12 h readily furnished the corresponding a-
allylated aldehydes 3a–i in 94–98% yields and excellent
enantioselectivities (up to e.r. 99.8:0.2; Table 2, entries 1–9).
In comparison, our previous protocol gave similar enantiose-
lectivities but slightly lower yields.[4a] For the a-ethyl-sub-
stituted substrate 1j slightly higher catalyst loading was
required to obtain the corresponding product 3j in 77% yield
and 81:19 e.r. Remarkably, while aliphatic aldehydes failed to
give reasonable conversion with this protocol, we found that
when aldehyde 1k was treated with [Pd(PPh3)4], (S)-TRIP,
and 80 mol% of (S)-1-phenylethylamine instead of benzhy-
dryl amine (A5) at 1108C, the allylated product 3k was
obtained smoothly and in high yield and promising enantio-
selectivity (Table 2, entry 11).
Having established optimized conditions for the asym-
metric a-allylation of aldehydes with allylic alcohol, we next
examined the scope and limitations of our new reaction. As
shown in Table 2, the reaction is quite general and tolerates a-
Table 1: Developing a highly enantioselective reaction.[a]
Importantly, we were pleased to find that our new method
can be easily extended to a range of substituted allylic
alcohols (Table 3). Accordingly, treating aldehyde 1a with
four different substituted allylic alcohols (2b–e) readily
furnishes the desired products 3l–o in excellent enantiose-
lectivities (up to 99.3:0.7).
We currently propose the mechanism of our reaction to
involve three intertwined catalytic cycles (Figure 2). First,
there is an enamine catalytic cycle, in which the aldehyde is
activated via an enamine formed with the primary amine
catalyst A5. The enamine is allylated by the p-allyl-Pd-
phosphate via an intermediate that involves all three catalysts
and leads to the formation of the product imine and the
regeneration of Pd0 and TRIP. Imine hydrolysis then gives the
final product. The p-allyl-Pd-phosphate is generated in the
Entry
Amine
Conv. [%][b]
e.r.[d]
1
2
3
4
–
96
83
94
55:45
88:12
92.5:7.5
91:9
55:45
97:3
A1
A2
A3
A4
A5
A5
>99 (96)[c]
19
5
6
>99 (97)[c]
88
7[e]
92:8
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Pd(PPh3)4]
(1.5 mol%), (S)-TRIP (3.0 mol%), amine (40 mol%), M.S. 5 ꢁ (100 mg),
toluene (1.0 mL), 408C, 12 h. [b] Determined by GC–MS or H NMR
spectroscopy. [c] Yield of isolated product in parenthesis. [d] Determined
by HPLC after reduction to the alcohol with NaBH4. [e] 30 mol% of A5
used.
1
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Angew. Chem. Int. Ed. 2011, 50, 9471 –9474

Table 3: Asymmetric a-allylation with diverse allylic alcohols.[a]
=
allylic alcohol (CH2 CHCD2OH), which leads to the product
mixture expected from a p-allyl-Pd-mechanism (see the
Supporting Information).[6a]
In summary, we have developed the first highly enantio-
selective direct a-allylation of a-branched aldehydes with
allylic alcohols. Effective asymmetric induction is realized
through the incorporation of a chiral anion within the
activated complex following an ACDC strategy. Our reaction
efficiently creates all-carbon quaternary stereogenic centers
in a single step from readily available precursors. Most
importantly, simple allylic alcohols can be used directly and
do not require derivatization in an additional chemical step.
Entry
Product
Yield [%][f]
e.r.[g]
1[b,c]
2[b]
3[d]
4[e]
R1 =Ph, R2 =H
R1 =H, R2 =Ph
R1 =Me, R2 =H
R1 =H, R2 =Me
3l
3m
3n
3o
96
96
66
95
94:6
99.3:0.7
96:4
94:6
Received: May 12, 2011
Revised: June 7, 2011
Published online: September 13, 2011
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), [Pd(PPh3)4]
(1.5 mol%), (S)-TRIP (3.0 mol%), A5 (40 mol%), M.S. 5 ꢁ (100 mg),
toluene (1.0 mL), 408C, 12 h. [b] 0.21 mmol of 2. [c] 60 mol% of A5,
24 h. [d] [Pd(PPh3)4] (3.0 mol%), (S)-TRIP (6.0 mol%). [e] [Pd(PPh3)4]
(5.0 mol%), (S)-TRIP (10 mol%), 60 h. [f] Yield of isolated product.
[g] Determined by HPLC after reduction to the alcohol with NaBH4.
Keywords: allylation · allylic alcohol · chiral counteranions ·
.
palladium · phosphates
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