Nickel-catalyzed, carbonyl-ene-type reactions: Selective for alpha olefins and more efficient with electron-rich aldehydes

Article abstract of DOI:10.1021/ja061471+

Described are several classes of unusual or unprecedented carbonyl-ene-type reactions, including those between alpha olefins and aromatic aldehydes. Catalyzed by nickel, these processes complement existing Lewis acid-catalyzed methods in several respects.

Full text of DOI:10.1021/ja061471+

Published on Web 04/04/2006
Nickel-Catalyzed, Carbonyl-Ene-Type Reactions: Selective for Alpha Olefins
and More Efficient with Electron-Rich Aldehydes
Chun-Yu Ho, Sze-Sze Ng, and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received March 2, 2006; E-mail: tfj@mit.edu
Table 1. Nickel-Catalyzed, Carbonyl-Ene-Type Reactions of
Carbonyl addition reactions are among the most utilized carbon-
Monosubstituted Alkenesa
carbon bond-forming transformations. In many of these, the
nucleophile is an organometallic reagent, whereas an alkene serves
in this capacity in the carbonyl-ene reaction.1 Although alkenes
are among the most readily available classes of organic molecules,
the full potential of this advantage has yet to be realized in the
context of this transformation. Despite decades of research, the chief
limitation of this otherwise versatile process is still one of scope.
The most efficient reactants are electron-rich olefins (e.g., 1,1-
disubstituted alkenes or 2-methoxypropene) and small and/or highly
electron-deficient aldehydes (e.g., chloral, formaldehyde, or gly-
oxylate esters). Few carbonyl-ene reactions of aromatic2,3 or
sterically demanding aldehydes4 have been reported. Equally rare
are those of monosubstituted alkenes, and the vast majority of these
are with electron-deficient aldehydes.5 In short, current carbonyl-
ene technology is effective for only a small subset of the plethora
of possible coupling partners.
Herein we describe a general means for catalyzing carbonyl-
ene-type reactions (eq 1) of several types of compounds that
heretofore were of very limited or nonexistent utility, including
the most readily available alkenes (alpha olefins6) and several
important families of aldehydes (aromatic, heteroaromatic, and
tertiary aliphatic aldehydes). Catalyzed by a nickel-phosphine
complex,7 these not only are the first intermolecular carbonyl-ene
reactions between alpha olefins and aromatic aldehydes3 but also
the first between these alkenes and tert-alkyl aldehydes4 (t-BuCHO).
These are also the first catalytic carbonyl-ene reactions in which a
monosubstituted alkene reacts preferentially over a more substituted
double bond,8 and the first in which electron-rich aldehydes are
more efficient than those bearing electron-withdrawing substituents.
We recently reported that allylic alcohol derivatives can be
prepared directly from alpha olefins, aldehydes, silyl triflates, and
an amine base under nickel catalysis, and that homoallylic byprod-
ucts are formed in some cases.9,10 We have since found that certain
organophosphorus additives (Ph3P or EtOPPh2) invert the selectivity,
providing an efficient entry into synthetically valuable homoallylic
alcohols that previously were unavailable by way of carbonyl-ene
processes.
a See Supporting Information and eq 1. Standard conditions (entries 1-7,
15-17): To a solution of Ni(cod)2 (0.1 mmol) and EtOPPh2 (0.2 mmol) in
toluene (2.5 mL) at 23 °C under Ar were added the alkene (0.5 mL),
triethylamine (3.0 mmol), the aldehyde (0.5 mmol), and triethylsilyltriflate
(0.875 mmol). The mixture was stirred for 48 h at room temperature and
purified by chromatography (SiO2). Entries 8-14: Ph3P was used in place
Under these conditions, propene (1a) itself undergoes a nickel-
catalyzed, carbonyl-ene reaction (Table 1, entry 1), yielding the
triethylsilyl ether of allyl phenyl carbinol (2a). The minor product
in this case is an allylic alcohol derivative (3a, not shown11), but
when the alpha olefin 1-octene (1b) is used, the analogous allylic
byproducts are formed in only trace amounts (entries 2-8). The E
1
of EtOPPh2. b Determined by H NMR. c See Supporting Information for
structures of allylic products (3a-3o). d Propene (1a, 1 atm) was used in
place of Ar. e Reaction time 18 h. f Reaction temperature 35 °C. g Five-
fold larger reaction scale (see text). h Three equiv of 1d was employed.
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10.1021/ja061471+ CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
configuration of the double bond is favored over the Z by a factor
of 3-5 in all cases examined in this series.
The analogous reactions of allylbenzene (1c) are highly selective
with respect to both product distribution and olefin geometry (entries
9-13). Identical results (nearly quantitative yield) are obtained when
the reaction is performed on a 5-fold larger scale and with only
1.5 equiv of allylbenzene relative to p-anisaldehyde (entries 10 and
11). Imide carbonyl groups are tolerated in the reaction (entry 14),
as are those bearing â- or R-branching (entries 15 and 16-17,
respectively).
Several observations concerning several of the aldehydes deserve
further comment. Heteroaromatic aldehydes, such as 1-methyl-2-
indolecarboxaldehyde, are tolerated (entries 7 and 13), despite the
fact that the silyl triflate used in the reaction is highly electrophilic.
Noteworthy also is the fact that pivaldehyde (t-BuCHO) may be
employed in this transformation (entry 8).12 Silyl ethers of homoal-
lylic alcohols derived from these very sterically demanding alde-
hydes may thus be accessed directly from the alkene, without
preparation of an allylsilane reagent.13 Moreover, we are aware of
no other examples of intermolecular carbonyl-ene reactions involv-
ing a tertiary aliphatic aldehyde.4
While reactions of benzaldehyde require 48 h at room temper-
ature to reach completion (compare entries 2 (48 h) and 3 (18 h)),
those involving p-anisaldehyde can be complete within 18 h (entry
4) and are generally higher yielding (compare entries 3 and 4 and
entries 9 and 10). Furthermore, aromatic aldehydes bearing electron-
withdrawing substituents are much less efficient (entry 5).14 While
we have yet to conduct an exhaustive Hammett analysis, all
evidence thus far points to the likelihood that there is a strong
dependence of reaction rate upon the electronic nature of the
aldehyde. Whatever the cause, we are unaware of other cases of
carbonyl-ene reactions in which electron-rich aldehydes are more
efficient than electron-poor.
In a similar vein, we have observed that substitution on the alkene
has a profound impact on the efficiency of the transformation.
Whereas 1,1-disubstituted alkenes are among the most effective
olefins in Lewis acid-catalyzed carbonyl-ene reactions, they do not
undergo coupling to any noticeable degree with the nickel-catalyzed
system. Similarly unreactive are trans- and cis-disubstituted alk-
enes.15
A profound demonstration of this complementary selectivity is
illustrated in Scheme 1. When citronellene (1h) and benzaldehyde
are treated with Me2AlCl, only the trisubstituted alkene reacts, and
no detectable amount of reaction of the terminal olefin is observed.
On the other hand, under nickel-catalyzed conditions, this selectivity
is completely reVersed. Products corresponding to reaction of the
terminal alkene (2p) are the only ones detectable. To the best of
our knowledge, this is the first example of a catalytic carbonyl-
ene-like reaction that is faster for a monosubstituted alkene than
for one more highly substituted.8
In summary, the nickel-catalyzed carbonyl-ene reactions de-
scribed here complement Lewis acid-catalyzed methods in several
respects (Figure 1). In particular, alpha olefins, aromatic aldehydes,
and tert-alkyl aldehydes are excellent starting materials, whereas
previously they had not been utilized at all or only to a limited
extent. That is, using only off-the-shelf reagents and catalysts, this
Figure 1. Complementarity of catalytic carbonyl-ene reactions.
process effects several classes of unprecedented carbonyl-ene
reactions and expands the scope of this venerable transformation
significantly. Currently, we are investigating the mechanistic basis
of the unusual selectivity and reactivity patterns, as well as further
demonstration of the general concept of simple, unactivated alkenes
functioning as nucleophiles in carbon-carbon bond-forming reac-
tions.9
Acknowledgment. Support for this work was provided by the
National Institute of General Medical Sciences (GM-063755). C.-
Y.H. thanks The Croucher Foundation for a postdoctoral fellowship.
We are grateful to Dr. Li Li for obtaining mass spectrometric data
for all compounds (MIT Department of Chemistry Instrumentation
Facility, which is supported in part by the NSF (CHE-9809061 and
DBI-9729592) and the NIH (1S10RR13886-01)).
Supporting Information Available: Experimental procedures and
data for all new compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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(14) Reactions of p-nitrobenzaldehyde afforded no trace of coupling product.
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