Palladium catalyzed synthesis of muenchnones from α-amidoethers: A mild route to pyrroles

Article abstract of DOI:10.1002/anie.200801385

(Chemical Equation Presented) Having the munchies: A mild palladiumcatalyzed method to activate the carbon-oxygen bond of α-amidoethers has been developed and applied to carbonylation chemistry (see scheme). A muenchnone intermediate is generated in situ and undergoes a 1,3-dipolar cycloaddition with alkynes to give diversely substituted pyrroles.

Full text of DOI:10.1002/anie.200801385

Communications
DOI: 10.1002/anie.200801385
Cycloaddition
Palladium Catalyzed Synthesis of Münchnones from a-Amidoethers:
A Mild Route to Pyrroles**
Yingdong Lu and Bruce A. Arndtsen*
The metal-catalyzed carbonylation of a-amido-
alcohols (1; e.g. aldehyde amidocarbonylation) has
become an important method to construct a amino
acids and related products (Scheme 1).[1] One
useful feature of this reaction is the accessibility
of the substrates (1),or their ether analogues,for
use in carbonylation reactions. The preparation of
1 includes the in situ condensation of aldehydes
and amides,the electrochemical oxidation of
amides,the reduction of imides or imidates,or
the acylation of imines.[2] The coupling of this
synthesis with catalytic carbonylation allows the
formation of amino acid derivatives,which have
various substitutions,in a minimal number of steps
and on large scale.[1] While effective,this reaction
typically requires high reaction temperatures,high
CO pressures (ca. 1008C,60 bar),and the use of
strong acid additives. These are presumably related
Scheme 2. Postulated mechanism for the palladium-catalyzed carbonylation of 1.
to the poor ability of palladium to directly activate
Considering the availability of a-amidoethers as building
blocks,we became interested in the potential use of this
chemistry to access other classes of products. In particular,we
recently reported that the multicomponent coupling of
imines,acid chlorides,and carbon monoxide with unsaturated
substrates can provide a route to assemble various useful
heterocycles (pyrroles,imidazoles,imidazolines,or b-lactams)
by the formation of the münchnones (3).[6] Notably,this
chemistry proceeds through carbonylative intermediates that
are similar to those observed with a-amidoalcohols
Scheme 1. Formation of dipolar cycloaddition reagents from 1.
(Scheme 2,path B),but it occurs under mild conditions
À
the C O bond of 1,which instead is believed to be converted
into a more reactive iminium salt intermediate (4) under the
reaction conditions (Scheme 2).[1,3] Whereas we have noted
(4 atm CO,55 8C) and does not require an acid to activate the
intermediate a-chloroamide towards oxidative addition.
These data suggested the potential of using the carbonylation
of structurally versatile a-amidoethers to access a 1,3-dipolar
cycloaddition manifold (Scheme 1) to synthesize heterocy-
cles,rather than amino acid derivatives. We report herein the
discovery of a mild method to directly activate the carbon–
oxygen bond of a-amidoethers towards oxidative addition
and carbonylation. This method has allowed the use of a-
amidoethers in 1,3-dipolar cycloaddition chemistry by the
formation of münchnones. In addition to demonstrating a new
reactivity mode for the carbonylation of 1,this process has
been used to design a palladium-catalyzed synthesis of
pyrroles.
À
mild routes to C O carbonylation with a-phenoxyamides,the
reaction still employs relatively strong Lewis acids (e.g. AlF3)
to activate the substrate toward oxidative addition.[4,5]
[*] Y. Lu, Prof. B. A. Arndtsen
Department of Chemistry
McGill University
801 Sherbrooke Street W., Montreal QC H3A 2K6 (Canada)
Fax: (+1)514-398-3797
E-mail: bruce.arndtsen@mcgill.ca
Homepage: http://arndtsen-group.mcgill.ca/
In considering approaches to utilize a-amidoethers to
access dipolar cycloaddition intermediates (Scheme 2,path
B),a number of mechanistic challenges arise. Firstly,the
reaction of 1 to form CO insertion intermediate 5 would
formally generate a nucleophilic ROÀ anion (X = OR),which
[**] We thank the National Science and Engineering Research Council
(Canada) Discovery and AGENO programs for support of this
research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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could react with the acyl-palladium ligand,or münchnone 3,
influence on the reaction (1d, 1e),the replacement of the
to form an a-amidoester rather than undergo cycloaddition
phenyl group with a 3-pyridyl unit did indeed allow carbon-
[7,8]
(Scheme 2,path A,typical amidocarbonylation).
Addi-
ylation to occur,forming an a-amidoester in moderate yield
[10]
tionally,even before this trapping,the diversion of complex 5
down path B requires a formal deprotonation of the
b hydrogen to the palladium center. The latter is incompatible
with the typically forcing and acidic conditions needed for the
initial oxidative addition of 1. Thus,a mild method to activate
(1h,54%).
Notably,the position of the pyridyl unit is
critical for this reaction; neither the 2-pyridyl (1 f) nor 4-
pyridyl (1g) derivatives allow the reaction to occur. This lack
of reactivity suggests that it is the increased leaving group
capability of this substituent that is important for this
activation,although coordination of the nitrogen atom to
palladium could also be involved in the reaction pathway.[11]
The efficiency of this reaction can be additionally
enhanced by modifying the palladium catalyst. The nucleo-
philic attack of palladium on 1h should,in principle,be
facilitated by more basic phosphine ligands on palladium.
However,this ligand must also remain labile because it is
ultimately displaced by CO to generate intermediate 7. Bulky
and basic tBu2P(2-biphenyl) ligand 8 has the correct balance
of these features (Table 1,entry 12),leading to 2 in high yield.
Overall,this provides the mildest set of conditions,of which
we are aware,for the carbonylation of these substrates to give
amino acid derivatives.
À
the C O bond of 1 without acid co-catalysts is required.
As shown in Table 1,in situ generated a-hydroxyamide 1a
is inert towards palladium-catalyzed carbonylation in the
absence of an acid co-catalyst at temperatures up to 658C and
CO pressures up to 4 atm.[9] Similar results were observed
with phenoxy- and methoxy-substituted derivatives 1b and
1c,respectively. One postulated for the role of the acid in the
À
catalysis is that it creates a C O bond that is more susceptible
to nucleophilic displacement by palladium,in an S N2-type
oxidative addition mechanism (Scheme 2,structure A). This
suggests that increasing the electrophilicity of 1 could
similarly facilitate this step. Whereas the incorporation of
electron-withdrawing aromatic substituents onto 1 had no
Since this reaction requires neither a strong acid to
À
Table 1: C O bond activation and carbonylation of amidoethers under
À
activate the C O bond nor uses unstable iminium salt
mild conditions.[a]
substrates,it is tolerant of a number of substituents at each
of the positions of 1 (Table 2),including acid and base
1
sensitive substrates. For example,when R
is a small
enolizable alkyl unit,which is not compatible with our
previous acid chloride approaches employing amine bases,
the ether can be carbonylated in high yield (Table 2,entry 1).
Similarly,acid sensitive electron-rich heterocycles (furan and
indoles,Table 2,entries 2 and 3) can also be employed in the
reaction. In addition,aryl or alkyl substituents can be used at
R2 or R3,yielding several products that are not accessible by
typical amidocarbonylation procedures.
Entry
1
R2
R
Ligand
Yield
1[b]
2
3
1a
1b
1c
H
Bn
Bn
H
PhP(
Me
P(o-Tol)3
o-Tol)3
P(o-Tol)3
–
–
–
4
5
1d
1e
Bn
Bn
P(o-Tol)3
P(o-Tol)3
–
–
Table 2: Generality of palladium-catalyzed amidoester synthesis.[a]
6
1 f
Bn
Bn
Bn
Bn
Bn
Bn
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
PMe3
–
–
7
1g
1h
1h
1h
1h
Entry
R1
R2
R3
Yield
74%
68%
54%
8
(58%)[c]
1
2
Me
Bn
Bn
9
–
10
11
PtBu3
8%
50%
3
Et
38%
P(nap)3
4
5
6
Bn
86%
12
13
1h
1h
Bn
Bn
87%
58%
72%b
73%b
Bn
7
8
85%
Ph
58%[b]
[a] 1 (0.20 mmol), [{Pd(allyl)Cl}2] (0.010 mmol), Bu4NBr (0.10 mmol)
ligand (0.030 mmol), 4 atm CO, CH3CN (2 mL); Bn=CH2C6H5. [b] Ben-
zamide (0.20 mmol), p-tolualdehyde (0.20 mmol) used instead of 1.
[c] Catalyst used was [Pd(h2-CH(tol)NBnCOPh)]BF4(CH3CN)2 (6).[4]
[a] Conditions of Table 1 with0.030 mmol ligand 8. [b] Catalyst used was
[Pd(h2-CH(tol)NBnCOPh)]BF4(CH3CN)2 (6).
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Communications
Table 3: Palladium-catalyzed pyrrole synthesis from 1 and alkynes.[a]
Having developed a method for carbonylation of 1h
under mild conditions,we became interested in the potential
to use this approach to access a 1,3-dipolar cycloaddition
reaction manifold. In particular,the low nucleophilicity of the
PyOÀ group in 1h and the lack of an acid co-catalyst,suggests
that intermediate 5 could undergo in situ deprotonation and
cyclization to form münchnone 3 (Scheme 2,path B),rather
than trapping to amido acids. This was probed by performing
the carbonylation in the presence of methyl phenylpropiolate
as the münchnone trapping agent.[12] As anticipated,the
addition of the alkyne under typical amidocarbonylation
conditions (Table 3,entry 1) to phenoxy-substituted 1b with
AlF3 resulted in the formation of an amido acid rather than a
pyrrole.[13] Conversely,performing this reaction with the less
Entry R1
R2 R3
Ph
Alkyne
9 (Yield)
[b]
1
2
Me
p-Tol
H
–
[c]
Bn Ph
–
3
p-Tol
R
p-Tol
basic 3-pyridyl substituent in 1h resulted in the exclusive
[14]
formation of pyrrole 9a (Table 3,entry 3).
Notably,no
4
5
p-Tol
p-Tol
Bn p-Tol
amidoester is formed under these conditions.
This data demonstrates that münchnone intermediates are
generated upon carbonylation of these a-amidoether deriv-
atives,and that alkynes can effectively compete with 3-
hydroxypyridine trapping of 3. Considering the variety of
alkynes that react with münchnones,[12] this approach can in
principle provide access to a range of pyrroles. As a
preliminary illustration of this feature,modification of the
building blocks was used to construct a number of diversely
substituted products (Table 3). This includes base sensitive R1
Bn
6
p-Tol
Bn p-Tol
2
groups (9i),bulky or aromatic R groups (9c, 9l),as well as
base sensitive alkynes (9d),each of which are not readily
incorporated into our previous imine/acid chloride chemistry.
In addition to alkynes,electron-poor alkenes can also be
employed to trap 3,which undergo acid elimination to form
pyrroles (9 f, 9g). Together,these provide an effective
palladium-catalyzed approach to construct pyrroles,in
which the substitution at any position on the product can be
modified by changes to the alkyne or building block 1.
In conclusion,a palladium-catalyzed route to directly
7
8
p-Tol
Bn p-Tol
Bn p-Tol
Me
À
activate the C O bond of a-amidoethers has been developed,
9
Bn
and applied to carbonylation chemistry. This method provides
a mild way to construct amino acid derivatives,as well as
access to a new mode of reactivity for these reagents: 1,3-
dipolar cycloaddition. Considering that münchnones 3 can
undergo cycloaddition reactions with a range of unsaturated
10
Bn p-Tol
[11]
substrates (e.g. alkynes,alkenes,imines,aldehydes,etc.),
this reactivity provides potential access to various classes of
heterocycles. Studies towards the latter are currently in
progress.
11
p-Tol
p-Tol
[a] See experimental section for conditions. [b] Acetamide/benzaldehyde
(0.20 mmol), PdCl2 (0.020 mmol), LiBr (0.07 mmol), PPh3 (0.040 mmol),
H2SO4 (0.010 mmol), 80 bar CO, 2 mL NMP, 1208C. [c] 1b, AlF3
(0.40 mmol).[d] Collidine (0.30 mmol). An=4-C6H4OCH3; NMP=1-
methyl-2-pyrolidone.
Experimental Section
Pyrrole synthesis: a-amidoether (0.20 mmol),catalyst
6
(0.020 mmol),Bu NBr (0.10 mmol),alkyne (0.30 mmol),and P tBu2-
4
(biphenyl) (0.015 mmol) were dissolved in 2 mL CH3CN in a 50 mL
reaction bomb. The solution was degassed,carbon monoxide (60 psi)
was added,and the mixture was stirred at 65 8C (24 h). The product
was isolated after column chromatography by using silica gel 60 with
hexanes/ethyl acetate as the eluent.
À
Keywords: C O activation · dipolar cycloaddition · palladium ·
pyrrole
.
Received: March 23,2008
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À
[11] Examples of chelation assisted C O oxidative addition: a) F.
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could rapidly trap 3.
À
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[7] Cyclic structures similar to 3 have been postulated as inter-
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