The Diels-Alder cyclization of ketenimines

Article abstract of DOI:10.1021/ol300742t

A Diels-Alder reaction between cyclopentadiene and a variety of ketenimines is reported. A copper(I)-bis(phosphine complex catalyzes the cycloaddition across the C - N bond of the ketenimine in a [4 + 2] reaction to give an enamine intermediate that is hy

Full text of DOI:10.1021/ol300742t

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2191–2193
The DielsꢀAlder Cyclization of
Ketenimines
Jeremy Erb, Jessica Strull, David Miller, Jean He, and Thomas Lectka*
Department of Chemistry, Johns Hopkins University, 3400 North Charles Street,
Baltimore, Maryland 21218, United States
lectka@jhu.edu
Received March 22, 2012
ABSTRACT
A DielsꢀAlder reaction between cyclopentadiene and a variety of ketenimines is reported. A copper(I)-bis(phosphine complex catalyzes the cycloaddition
across the CdN bond of the ketenimine in a [4 þ 2] reaction to give an enamine intermediate that is hydrolyzed upon purification to generate aminoketones.
The DielsꢀAlder reaction of ketenes and dienes has
achieved a mythical status in organic chemistry due to its
problematic nature and the unusual mechanistic pathways
it follows. For example, ketenes are known to react by
parallel [4 þ 2] and/or subsequent [2 þ 2] manifolds, often
in complex ways (Scheme 1).1 In contrast, keteniminium
salts are known to add dienes across their CdC bonds in a
[4 þ 2] manner.2 However, the corresponding DielsꢀAlder
reaction involving ketenimines is scarcely known3,4 in the
literature; the basic documentation of such a reaction
would provide an important mechanistic counterpoint to
the seminal ketene cycloaddition reaction. In this commu-
nication, we present a Lewis acid catalyzed DielsꢀAlder
reaction between dienes with ketenimines and elucidate the
similarities and differences of this unique reaction to the
corresponding process involving ketenes. What is more,
this reaction represents a different approach to the catalyt-
ic synthesis of enamine intermediates,5 whose importance
to synthetic chemistry grows with each passing year.6
In contrast to other catalytic enamine syntheses, the amino
group is retained in the product, affording potential appeal
(3) While the DielsꢀAlder reaction of ketenimines is rare, other
cycloaddition variants are known for ketenimines, especially those in
which they act as four-electron components. For [4 þ 2] cycloadditions
ꢀ
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r
10.1021/ol300742t
2012 American Chemical Society
Published on Web 04/05/2012

for the synthesis of amine building blocks and pharmaco-
logically relevant targets.7
that were previously shown to catalyze the cyclization of
dienes with imines,10 such as Sc(OTf)3, AgOTf, and
BF3•etherate; all of these candidates gave (at most)
trace amounts of product, with the notable exception of
(Ph3P)2CuClO4 (MeCN)2,11 which resulted in 3a (60%
3
Scheme 1. DielsꢀAlder Cyclization Pathways
yield) after aqueous workup (Scheme 2). The other possible
products listed in Scheme 1 were ruled out based on NMR
data, and only 3a was isolated from each reaction.
Scheme 2. DielsꢀAlder Cyclization of 1,3-Diphenylketenimine
Rather than an imine or enamine, spectroscopic evi-
dence surprisingly revealed 3a to be an amino ketone
possessing a five-membered ring core. This product would
be most likely derived from the hydrolysis of strained
enamine 2aupon workup conditions after the DielsꢀAlder
cyclization had occurred. To examine this possibility, we
performed an in situ NMR experiment in order to observe
the enamine directly. A standard catalyzed reaction was
conducted in CDCl3 and monitored by 1H and 13C NMR.
Two 1H resonances at δ 4.15 and 4.60 ppm (area 1:2) grew
in over time and disappeared upon the introduction of
aqueous acid, replacing the vinyl proton of the enamine in
monotonic fashion. These peaks, putatively due to the
vinyl hydrogens, are consistent with diastereomers of the
enamine product. Likewise, two 13C resonances (both
enamine isomers) were observed at 102.6 and 101.9 ppm.
A calculation12,13 of the 13C NMR chemical shift of the
enamine vinyl carbon (B3LYP/6-311þþG**) shows excel-
lent agreement with experiment as well, producing chemical
shifts of 101.5 and 100.8 ppm. It is important to note that in
contrast to the very complex ketene-diene cycloaddition
potential energy surface, Cope rearrangement of the initially
formed enamine to the cyclobutanimine does not occur,
even at elevated temperatures.
At the beginning of our study, the first question we
addressed was in the nature of the products that would
form during the reaction of a ketenimine and a diene
(Scheme 1). For example, would the reaction follow the
ketene precedent and afford the corresponding mixture
of enamine or cyclobutanimine products from [4 þ 2] and
[2 þ 2] reactions? Would the iminium salt precedents2 be
followed instead to yield [4 þ 2] adducts across the CdC
bond? Would the ketenimine operate as an imine and
undergo a [4 þ 2] Povarov8 if provided with an N-substituted
aromatic ring? Or would it follow its own unique variation?
In analogy with the reaction of cyclopentadiene (CpH)
and disubstituted ketenes,1a we first attempted a reaction of
CpH with 1,3,3-trisubstituted ketenimines. Under all condi-
tions, we observed at most trace amounts of cycloadducts.
Next we examined potentially more reactive (but much harder
to handle) 1,3-disubstituted ketenimines.9 For example,
we first investigated the reaction of 1,3-diphenylketenimine
with CpH. We found that the thermal pathway proceeds
in a sealed tube under elevated temperatures (180 °C)
to afford a modest amount of cycloadduct (20%). At
that time, we turned instead to screening potential Lewis
acid catalysts for the reaction. We first tried Lewis acids
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However, placement of one m-methyoxy substituent on each
ring gave the best yield. It may be the case that increasing the
electronegative character of the ketenimine would result in
higher yields for cycloaddition products were it not for the
basic instability of the ketenimines themselves.
Table 1. Cyclization Product Table
Additionally, if the reaction progresses as envisaged, we
should observe a negligible secondary kinetic isotope
effect15 upon cycloaddition of 1D with enamine formation.
In fact, that is exactly what we see when we submit the label
1
isomer 1D to the reaction and monitor it by H NMR
(Scheme 3). Of course, any rate determining pathway
involving addition across the CdC bond should exert a
normal secondary KIE. A KIE of 1.01 was observed under
standard conditions, consistent with a maintenance of
hybridization at the vinylic carbon.
Scheme 3. Secondary Isotope Effect Study
In conclusion, we have developed a copper(I) catalyzed
DielsꢀAlder reaction between ketenimines and dienes that
proceeds at room temperature. We have observed an
enamine intermediate by spectroscopic means that is best
explained by a [4 þ 2] cycloaddition between the diene and
the CdN bond of the ketenimine. Hydrolysis of the
enamine upon workup yields products in good yield.
Future work will concern an expansion of scope and a
detailed mechanistic study.
a Reaction conditions: PPh3 (0.1 mmol), CuClO4 (0.05 mmol), 1 mL
of CH2Cl2, rt, 1 h; then 0 °C, 5 mL of CH2Cl2, ketenimine (0.5 mmol),
0.2 mL of cyclopentadiene (3.24 mmol), rt, overnight. b All yields are
isolated yields.
The ketenimines proved to be fairly unstable and are best
prepared immediately before use.14 Electron withdrawing
substituents on the N-aromatic ring give products in good
yield (entries 2, 5, 6, and 7, Table 1), although when the
electron withdrawing character is too potent (i.e., ꢀNO2
groups) the ketenimine becomes quite unstable and con-
denses with itself. Some electron donating groups can be
used with success (entry 3). Interestingly, electron donating
groups such as 4-methoxy substituents give products in
trace amounts regardless of placement on either ring. This
result suggests that a “pushꢀpull“ mechanism is unlikely.
Acknowledgment. J.E. thanks JHU for a Gary H. Posner
Graduate Fellowship.
Supporting Information Available. Experimental proce-
dures, spectroscopic characterization of new compounds,
and DFT calculations. This material is available free of
charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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