The development of a catalytic synthesis of Muenchnones: A simple four-component coupling approach to α-amino acid derivatives

Article abstract of DOI:10.1021/ja027474d

A new palladium-catalyzed route to prepare 1,3-oxazolium-5-oxides (i.e., Muenchnones) directly from imine, carbon monoxide, and acid chloride building blocks has been developed. This provides a straightforward catalytic synthesis of Muenchnones and is ame

Full text of DOI:10.1021/ja027474d

Published on Web 01/18/2003
1
The Development of a Catalytic Synthesis of Munchnones: A Simple
Four-Component Coupling Approach to r-Amino Acid Derivatives
Rajiv Dhawan, Rania D. Dghaym, and Bruce A. Arndtsen*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Received June 26, 2002 ; E-mail: bruce.arndtsen@mcgill.ca
Scheme 1. Mechanistic Rationale for Mu¨nchnone Formation
Mesoionic 1,3-oxazolium-5-oxides (e.g., Mu¨nchnones, 1), and
their R-amide substituted ketene tautomer (1′), are an important
family of substrates for the synthesis of biologically relevant
molecules.1 Mu¨nchnones are versatile 1,3-dipolar addition substrates
and have proven key in the construction of a range of natural
products and pharmacologically relevant heterocycles, including
pyrroles,1,2a,b imidazoles,2c,d pyrrolines,2e and indole derivatives.2f
Alternatively, the less stable ketene 1′ can serve as a precursor to
R-amino acid and peptide derivatives, via reaction with alcohols
or N-terminated peptides,3a and their cycloaddition with imines
provides access to peptide-based â-lactams.3b While the diversity
of products accessible from 1 makes them attractive synthetic
targets, their preparation to date has typically involved multistep
processes. For example, the most common approach involves the
dehydration of the appropriately substituted N-acyl amino acid
derivative.1 This route limits the utility of these compounds in the
actual synthesis of amino acids and also imposes a necessary initial
preparation of the amino acid precursor. As such, alternative
transition metal-based syntheses of these compounds have become
of growing relevance.4 Perhaps the most well-established of these
is the carbonylation of presynthesized chromium-carbenes,4a,5,6
which has been employed to develop stoichiometric syntheses of a
variety of R-amino acid derivatives, peptides, â-lactams, and
pyrroles.
HCdNBn, PhCOCl, and 1 atm of CO with 5 mol % Pd2(dba)3‚
CHCl3, bipyridine, and NEt(iPr)2 base leads to the disappearance
of starting materials over 4 days and to the generation of 1a as a
minor product (5% yield, Table 1, entry 1). The formation of 1a,
albeit in very low yield, suggested this approach might indeed allow
for the development of a one-pot catalytic synthesis of Mu¨nchnones
from three basic building blocks (eq 1), which could be employed
in a range of further transformations. With a working hypothesis
for the mechanism of this transformation, we set out to improve
the efficiency of this process.
First, it was noted that the imine and acid chloride are consumed
during the catalysis, implying that the low yields of 1a may result
from the decomposition of the reactive Mu¨nchnone product,1,10
rather than incomplete reaction. Our attention therefore turned
toward tuning the palladium catalyst to allow for a more selective
and mild reaction. In principle, this might be accomplished by
allowing more facile access to CO-coordinated intermediate 3 (C),
because steps A and B are known to be rapid.7a Consistent with
this, the removal of bipy from the catalytic reaction increased the
rate of Mu¨nchnone formation (from 4 days to 24 h) and led to a
doubling of the yield (ca. 10%, entry 3).11 Increasing the pressure
of CO further facilitates the generation of 3 and increases the yield
of 1a to 13% (entry 4). However, this also led to the incomplete
conversion of imine and acid chloride, due to the precipitation of
palladium from the reaction.
The formation of palladium sediments can be inhibited by the
addition of Cl- and Br- sources, as previously noted in “ligandless”
catalysis,12 and leads to a dramatic increase in the yield of 1a
(entries 5-7). In the case of Bu4N+Br-, this allows for the formation
of 1a in a synthetically useful 69% yield.11 The efficiency of the
catalysis can be further improved by removal of the potentially
coordinating dba ligand from the Pd(0) source via the use of [Pd-
(Cl)[η2-CH(p-tolyl)NBn(COPh)]2 (4a), generated by pretreating Pd2-
(dba)3‚CHCl3 with imine and acid chloride.13 The use of catalyst
4a leads to the formation of 1a as essentially the only significant
reaction product (83% yield, entry 8). Overall, this optimized
protocol (Table 1) provides a straightforward and high yield
catalytic route to prepare stable Mu¨nchnones.
Despite the obvious potential advantages of a metal-catalyzed
method to form Mu¨nchnones directly from readily available
materials, to date this has not been reported. We7 and others8 have
recently suggested the possibility of preparing peptide-based
products from simple imine and carbon monoxide units, rather than
the traditional routes employing R-amino acids. As described below,
these investigations have led to the discovery of a metal-catalyzed
method to prepare stable Mu¨nchnones, via a catalytic coupling of
imines, carbon monoxide, and acid chlorides. The utility of this
transformation is demonstrated in the design of a new one-pot
catalytic synthesis of diprotected R-amino acid derivatives.
Our approach to the catalytic synthesis of Mu¨nchnones is shown
in eq 1 and is based upon our recently observed palladium-catalyzed
synthesis of imidazolines, the postulated mechanism for which is
in Scheme 1.7a,9 In particular, we surmised that oxidative addition
of imine and acid chloride to Pd(0) (steps A, B), CO coordination
(C), insertion (D), and â-hydride elimination (E) might provide a
pathway to construct 1, provided subsequent cycloaddition (F) to
form 2 could be inhibited. During the course of these studies, it
was observed that the HCl generated during catalysis is critical for
the Mu¨nchnone cycloaddition step (F), implying that its removal
might allow the build-up of 1. Indeed, the reaction of (p-tolyl)-
9
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J. AM. CHEM. SOC. 2003, 125, 1474-1475
10.1021/ja027474d CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalytic Synthesis of 1aa
illustration of this feature, we have used this catalytic Mu¨nchnone
synthesis, followed by the addition of methanol, to design a new
one-pot, four-component coupling route to diprotected R-amino acid
derivatives (eq 2). R-Aryl amino acids have been demonstrated to
be of utility in antimicrobial agents and enzyme inhibitors.15 As
shown in Table 2, diversely substituted amino acid derivatives can
be prepared by modification of the starting imine and acid chloride.
In addition to its simplicity, this transformation also provides what
is to our knowledge the first example of the catalytic construction
of R-amino acids from imines and carbon monoxide.
In summary, this report has described the development of the
first catalytic synthesis of Mu¨nchnones, providing direct access to
this general class of compounds from basic building blocks.
Experiments directed toward the development of multicomponent
catalytic syntheses of other peptidic and/or heterocyclic products
based on 1 are currently underway.
#
[CO]
Pd catalyst
base
additive
%1a (%2)b
1
2
3
4
5
6
7
8
1 atm
1 atm
1 atm
4 atm
4 atm
4 atm
4 atm
4 atm
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3
4a
NEt(iPr)2
bipy, 5%
bipy, 5%
5% (-)c
- (82%)c
10%
13%
30%
50%
69%
83%
NEt(iPr)2
NEt(iPr)2
NEt(iPr)2
NEt(iPr)2
NEt(iPr)2
NEt(iPr)2
LiCl
LiBr
Bu4NBr
Bu4NBr
a 0.48 mmol of imine and additive, 0.67 mmol of acid chloride, 0.74
mmol of base, and 5 mol % catalyst for 24-30 h at 55 °C. b NMR yield.
c 4 days.
Table 2. Scope of Palladium-Catalyzed Mu¨nchnone Synthesisa
Acknowledgment. We thank NSERC and FCAR for their
financial support. R.D. thanks McGill and NSERC for postgraduate
fellowships.
Supporting Information Available: Synthesis details on 1, 4, and
5 (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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a Analogous to Table 1, # 8.13 b NMR. c Pd2(dba)3‚CHCl3 cat. d 96 h.
A useful feature of this catalytic reaction is the simplicity of the
three separate building blocks, which are either commercially
available (CO) or easily prepared (imines and acid chlorides). As
such, this chemistry can be generalized to prepare a range of
Mu¨nchnones, many of which have not been previously reported.
Notably, functionalities such as aryl-halides, esters, ethers, and
thioethers are tolerant to the catalysis conditions (Table 2), and
both alkyl and aryl acid chloride and N-substituted imines can be
employed. However, C-alkyl substituted imines do not yield
Mu¨nchnones under these conditions. This is likely related to the
established lower stability of these products1,14 and may be
addressable in the future with the use of in situ traps.
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(13) See the Supporting Information for the synthesis of 1, 4, and 5.
(14) Side reactions of these N-acyl iminium salts may also inhibit 1 formation;
enamides are observed in these reactions in ca. 30% yield.
Considering the wide scope of products available from 1 and 1′,
this procedure should prove useful in the design of new catalytic
syntheses for a range of Mu¨nchnone-based targets. As a preliminary
(15) Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889.
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