at 160 to 300°C ( 20). In contrast, an Fe-peroxo
complex cleaves aldehyde C–C bonds at room
temperature, but this complex must be used in
stoichiometric amounts and can lead to olefin
epoxidation ( 21, 22).
Given this challenge, we designed a strategy in
which dehydroformylation of an aldehyde substrate is driven by the concomitant hydroformylation of a strained olefin acceptor (Fig. 1C) ( 23, 24).
This transfer hydroformylation avoids the ac-
cumulation of CO gas, which acts as a catalyst
poison in related aldehyde dehomologations. Thus,
formyl group transfer should proceed under mild
conditions. Brookhart’s study on the linear-to-
branched isomerization of aldehydes with Rh
catalysis supports the feasibility of this approach
( 25). Moreover, Morimoto developed hydroformyla-
tions of monosubstituted olefins using formal-
dehyde as a source of CO and H2 ( 26). Here, we
report a Rh catalyst for transfer hydroformyla-
tion that operates in the 22° to 80°C temperature
range, with loadings as low as 0.3 mole percent
(mol %). This mild protocol for dehydroformyla-
tion can be applied to a wide range of aldehydes,
including those derived from alkaloid, terpene,
steroid, and macrolide natural products.
During initial studies, we obtained promising
results by investigating nontraditional counter-
ions for Rh(Xantphos) complexes (Fig. 2). The
Xantphos ligand was chosen given its success in
related hydroacylations, hydroformylations, and
decarbonylations ( 13, 16). Using citronellal (1a)
and norbornadiene (5a) as the model substrate
and acceptor, respectively, we observed that typ-
ical counterions such as BF4– and Cl– yielded
trace decarbonylation products, whereas a softer
counterion, I–, led to mixed dehydroformylation
and decarbonylation reactivity. An increase in re-
activity and selectivity was obtained by switching
to organic counterions such as phenolates and
sulfonamidates. The use of a benzoate counterion
provided a breakthrough in efficiency. Against
expectations, further tuning of the counterion
revealed few trends related to acidity, Hammett
parameters, or coordinating ability. This obser-
vation suggests that the counterion plays a crit-
ical role in the mechanism. 3-Methoxybenzoate
provided a fivefold increase in initial rate compared
with benzoate. We also identified 5-norbornene-
2-carboxaldehyde (6a) as a stoichiometric prod-
uct in each of these reactions indicating that a
transfer hydroformylation mechanism operates.
The choice of olefin acceptor influences both
catalyst loading and reaction temperature (Fig. 2).
Because norbornadiene (5a) gave selectivity greater
than 99:1 2a:3a, the catalyst loading could be lowered to 0.3 mol at 80°C or 1 mol at 60°C using
this acceptor. The reaction temperature could be
further reduced by using olefin acceptors that
cannot chelate to Rh. For instance, norbornene (5b)
displayed excellent reactivity at 40°C, whereas a
slightly more strained acceptor, benzonorbornadiene
(5c), provided reactivity at ambient temperature.
To examine the scope of this strategy, we chose
norbornadiene (5a) as the acceptor because it
afforded the highest chemoselectivity with the
lowest catalyst loadings.
This transfer hydroformylation protocol enables
access to olefins from a wide range of aldehyde
precursors (Fig. 3, A and B). The Diels-Alder cyclo-addition was used to generate cyclohexene-4-
carboxaldehdye substrates 1b through 1d. The
trans adduct 1b underwent dehydroformylation
to yield the conjugated 1,3-diene, whereas 1c
gave a mixture of 1,3- and 1,4-dienes. The cis
Diels-Alder adduct 1d yielded the 1,3-diene exclusively, most likely as a result of a syn-selective
b-hydride elimination. We reason that the observed regioselectivities are controlled by kinetics because 4-phenylbutanal (1e) yields the
terminal olefin (2e) without any isomerization
to the styrene derivative. In general, Lewis basic
functionality, such as ethers, esters, amines,
phthalimides, and indoles, were tolerated (1f
to 1i and 1l). A vinylindole was derived by dehydroformylation of 1g, which was ultimately
prepared from commercial indole and acrolein.
Although 4-pentenals are prototypical substrates
for intramolecular olefin hydroacylation, the
a-allylated aldehyde 1h underwent chemoselective dehydroformylation to yield the conjugated diene. Disubstituted olefins enriched in
the E stereoisomer (>20:1 E/Z) were accessed
from the corresponding a-arylated aldehydes (1i).
Substrates that do not form conjugated products
Fig. 2. Effects of counterion structure and ring strain. Yields were determined by gas chromatographic
analysis of the reaction mixtures using durene as an internal standard. nbd, norbornadiene; nbe,
norbornene; bnbd, benzonorbornadiene.
Fig. 1. Dehydroformylation in nature and organic synthesis. (A) Dehydroformylation during sterol
biosynthesis. (B) Reactivity of acyl-RhIII-hydrides. (C) Proposed transfer hydroformylation.