Journal of the American Chemical Society
Article
although regioselectivity and yields varied. For instance, the
reactions in the presence of dppf−PdI2 or DPEphos−PdI2
provided similar regioselectivity and yields as the reaction with
xantphos−PdI2 (95−99% yield, 54−58% n-regioselectivity),
while regioselectivity was higher with rac-BINAP−PdI2 (82%),
albeit at lower alkene conversion (21%). Noteworthy,
monodentate PPh3 and PdI2 formed an active catalyst that
furnished the model aldehydes in 93% yield and 49% n-
selectivity.
Optimization of Reaction Conditions. We then evaluated
reactions of functionalized alkenes that are prone to undergo
side reactions (e.g., (co)polymerization, hydrogenation pro-
cesses).8 In the presence of 1 mol % xantphos−PdI2 and syngas,
styrene (1a) was consumed completely (>99% conv.), but there
was only 11% of aldehyde 2a formed with 76:24 β:α selectivity
(Figure 2b). The remaining starting material was converted to a
complex mixture of products as the result of oligomerization and
hydrogenation side reactions. Varying the reaction conditions
(e.g., solvent, temperature, or pressure) did not lead to a
significant improvement of the yield of 2a.31
conditions of previous Pd-based hydroformylation protocols,
but are compatible with the new method (81−94% β selectivity
and 33−81% yields). Linear and cyclic aliphatic alkenes (1y−
1z) were compatible as well; albeit the reactions required higher
temperature (100 °C). Notably, alkene substrates containing
unprotected N−H or O−H bonds or strongly coordinating
groups, such as pyridyl moiety, failed to deliver the aldehyde
product, illustrating current limitations of the method (Scheme
S1).
Because 1,2-disubstituted aryl olefins, such as trans-
isomethyleugenol 1o or trans-β-methylstyrene 1p are prone to
undergo isomerization, especially at elevated temperatures,
hydroformylation typically results in a mixture of aldehydes with
either the α or γ isomer being the main product.34 With the new
conditions, however, 1o−1p reacted to form β aldehydes
predominantly (62−69% β selectivity; Figure 2d). Remarkably,
β selectivity was partially maintained at higher temperatures,
albeit hydrogenation diminished the yield of aldehydes.
Interestingly, methyleugenol 1o′ and allylbenzene 1p′, the
terminal alkene analogues of 1o−1p, reacted to form aldehyde
products with similar regioselectivity, suggesting facile isomer-
ization and an inherent (moderate) β-selectivity under these
conditions. Likewise, hydroformylation reactions of monosub-
stituted 1aa as well as Z-1,2-disubstituted aliphatic olefin 1ab
produce the same linear aldehyde product (Figure 2e).
Hydroformylation of Alkynes. Next, we turned our attention
to alkynes. The hydroformylation of alkynes constitutes an
appealing strategy to produce enals, which are valuable building
blocks in synthesis and occur as structural motives in natural or
synthetic products (e.g., fragrances or flavors). However, despite
many efforts, the hydroformylation protocols for their
generation remain largely undeveloped.35−41 Besides controlling
regioselectivity, a key challenge is to prevent undesired side
reactions, which mainly include hydrogenation of both starting
materials and products. Previous efforts have shown that the
chemoselectivity of the reaction can be adjusted by carefully
designed catalysts and optimized reaction conditions;35−39
however, control over regioselectivity remains largely unsolved.
For instance, under state-of-the-art Rh-based35 or Pd-based36
protocols, methylphenylacetylene (4a) reacted to form a
mixture of regioisomeric aldehydes 5a:6a in 62:38 ratio, 78%
combined yield along with 10% hydrogenation products, or in
21:79 ratio, 70% combined yield at 100% conversion of starting
material, respectively (Figure 3a).
We found that in the presence of xantphos−PdI2 and
Pd(OAc)2, the reaction of 4a furnished enals with an
unprecedented selectivity of 5a:6a 95:5, 99:1 E:Z (5a), and
96% yield (Figure 3a). Control experiments confirmed that the
presence of an iodide as well as the use of Pd(OAc)2 as a
cocatalyst are critical for activity and chemoselectivity. No
reaction occurred when xantphos−PdI2 was substituted by an
analogue containing a different anion, or when Pd(OAc)2 (or
PdI2) was absent.31 Furthermore, the iodide also appears to be
instrumental in controlling regioselectivity. This feature is
highlighted by the control reaction in the presence of xantphos−
Pd(acac)2 and p-TsOH, which only led to formation of enals in
low regioselectivity and yield (5a:6a 68:32, 14% yield). These
results suggest an active role of the iodide in the product-
forming step.
Next we turned to Lewis acid additives, which have been
demonstrated by Dobereiner and Becica to accelerate amide N-
aryl formation catalyzed by a xantphos−Pd complex.32 The rate
enhancement was proposed to originate from reversible ligand
abstraction to create an open ligation site for substrate
coordination. We indeed observed an increase in activity of
xantphos−PdI2 in the presence of 0.2 mol % Al(OTf)3 or
In(OTf)3 (Figure 2b). In sharp contrast, and in line with our
+ −
mechanistic assumptions, the addition of 0.2 mol % PPh4 I or
excess xantphos (0.2 mol %) slowed down or completely
inhibited the reaction. Furthermore, the addition of Brønsted
acids lowered yields of aldehydes to <10% and promoted
hydrogenation processes (66% or 71% yield of ethylbenzene
formed, in the presence of AcOH or TsOH, respectively).
To eliminate the need for the presence of a strong Lewis acid
that may trigger side reactions, we tested whether excess PdI2
(without dative ligands) could also serve to reversibly abstract
ligands. Indeed, with 0.2 mol % PdI2 instead of a Lewis acid, the
reaction was also accelerated (Figure 2b). Similar enhancement
was observed by the addition of Pd(OAc)2 (the latter is soluble
in organic solvents, alike xantphos−PdI2, allowing for ease of
manipulation in solution). In addition, 1 mol % xantphos−PdI2
and 0.2 mol % Pd(OAc)2 also allow for the transformations to be
carried out efficiently at lower temperature. At 70 °C, 1a was
converted to the aldehydes in nearly quantitative yield, with 78%
β selectivity. At 50 °C, the reaction was slower (65% conversion,
using double the standard catalyst loading), but the aldehyde
was formed with higher regioselectivity (85% β-aldehyde).
Evaluation of Substrate Scope of Alkenes. The method
proved to be broadly applicable (Figure 2c). Styrene derivatives
containing an electron-withdrawing (1b−1f) or an electron-
donating group (1g−1j), as well as those with a sizable aromatic
moiety (1k) were compatible substrates, generating the product
with up to 90% β selectivity. Reactions with 1,1-disubstituted
olefins (1l−1n) were similarly efficient and highly regioselective
(93−99% β). A range of vinyl and allyl substrates 1q−1u also
underwent hydroformylation to form aldehydes with high β
selectivities (90%−99%). Notably, acrylates 1v-1w, which have
been reported to copolymerize with CO in the presence of Pd-
based hydroformylation catalysts,33 reacted smoothly (94−99%
β selectivity and 81−99% yield). Remarkable are also trans-
formations involving acid-sensitive N-Boc-N-vinylformamide
1u and acetal 1x, which are incompatible with the acidic
Evaluation of Substrate Scope of Alkynes. The catalytic
protocol can be applied to a broad range of alkynes to form β-
aryl enals, which were inaccessible through previous hydro-
formylation protocols (Figure 3b). Reactions with alkynes 4b-
E
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX