From Aryl Iodides to 1,3-Dipoles: Design and Mechanism of a Palladium Catalyzed Multicomponent Synthesis of Pyrroles

Article abstract of DOI:10.1021/jacs.6b02314

A palladium-catalyzed multicomponent synthetic route to polysubstituted pyrroles from aryl iodides, imines, carbon monoxide, and alkynes is described. To develop this reaction, a series of mechanistic studies on the [Pd(allyl)Cl]₂/P^tBu₃ catalyzed synthesis of imidazolinium carboxylates from aryl iodides, imines, and carbon monoxide were first performed, including model reactions for each individual step in the transformation. These show that this reaction proceeds in a concurrent tandem catalytic fashion, and involves the in situ formation of acid chlorides, N-Acyl iminium salts, and ultimately 1,3-dipoles, i.e., Münchnones, for subsequent cycloaddition. By employing a Pd(P^tBu₃)₂/Bu₄NCl catalyst, this information was used to design the first four-component synthesis of Münchnones. Coupling the latter with 1,3-dipolar cycloaddition with electron deficient alkynes or alkenes can be used to generate diverse families of highly substituted pyrroles in good yield. This represents a modular and streamlined new approach to this class of heterocycles from readily accessible starting materials.

Full text of DOI:10.1021/jacs.6b02314

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Article
From Aryl Iodides to 1,3-Dipoles: Design and Mechanism of
a Palladium Catalyzed Multicomponent Synthesis of Pyrroles
Gerardo Martin Torres, Jeffrey S. Quesnel, Diane Bijou, and Bruce A. Arndtsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02314 • Publication Date (Web): 12 May 2016
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Journal of the American Chemical Society
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From Aryl Iodides to 1,3-Dipoles: Design and Mechanism of a
Palladium Catalyzed Multicomponent Synthesis of Pyrroles
Gerardo M. Torres, Jeffrey S. Quesnel, Diane Bijou, and Bruce A. Arndtsen*
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Department of Chemistry, McGill University, 801 Sherbrooke Street West, Quebec, H3A 0B8 (Canada)
KEYWORDS Carbonylation, Palladium Catalysis, Multicomponent, 1,3-Dipoles, Mechanism
Supporting Information Placeholder
ABSTRACT:
A palladium-catalyzed multicomponent synthetic route to polysubstituted pyrroles from aryl iodides, imines, carbon
monoxide, and alkynes is described. To develop this reaction, a series of mechanistic studies on the [Pd(allyl)Cl]2 / PtBu3 catalyzed syn-
thesis of imidazolinium carboxylates from aryl iodides, imines and carbon monoxide were first performed, including model reactions for
each individual step in the transformation. These show that this reaction proceeds in a concurrent tandem catalytic fashion, and involves
the in situ formation of acid chlorides, N-acyl iminium salts, and ultimately 1,3-dipoles, i.e. Münchnones, for subsequent cycloaddition.
By employing a Pd(PtBu3)2 / Bu4NCl catalyst, this information was used to design the first four-component synthesis of Münchnones.
Coupling the latter with 1,3-dipolar cycloaddition with electron deficient alkynes or alkenes can be used to generate diverse families of
highly substituted pyrroles in good yield. This represents a modular and streamlined new approach to this class of heterocycles from readi-
ly accessible starting materials.
Palladium-catalyzed carbonylative coupling reactions with
organic halides and pseudohalides have become an important tool
in synthetic chemistry. Since its initial discovery by Heck in the
mid-1970’s, this reaction has been applied to the synthesis of a
diverse range of carboxylic acid derivatives (esters, amides, alde-
hydes, ketones, etc.).1-3 Carbonylations have also seen rapidly
growing use in the assembly of more complex carbocyclic and
heterocyclic scaffolds.4 One approach developed by Alper,
Coates, Drent, and others involves the ring expansion of heterocy-
cles to form lactones or lactams.5 Alternatively, a range of aryl
halide carbonylations with intramolecular cyclization have been
described,6 as have sequential or cascade insertions,7 and reac-
tions involving the subsequent cyclization of the ester or amide
products of carbonylation.8 From a mechanistic perspective,
metal-catalyzed carbonylations are typically postulated to involve
the in situ formation of metal-acyl complexes (1) which subse-
quently undergo coupling with nucleophiles (Scheme 1a). The
reactivity of 1 therefore shows similarity to that of activated car-
boxylic acid derivatives such as acid chlorides. In considering
this analogy, and the broad utility of acid chlorides in synthesis,
we recently became interested in the potential use of carbonyla-
tions to access products other than carbonyl-containing deriva-
tives. As an initial study towards this reaction, aryl halide car-
bonylation in the presence of imines results in the generation of
imidazolinium carboxylates 2 (Scheme 1b).9 The latter is based
upon the established generation of iminium salts from acid chlo-
rides, and provides a rare example of a five-component coupling
reaction, as well as a modular method to assemble these heterocy-
cles.
Scheme 1. Palladium Catalyzed Carbonylation and Heter-
ocycle Synthesis
While the imidazolinium carboxylates formed above are lim-
ited to symmetrically substituted products, this reaction has
prompted us to question if aryl halide carbonylation chemistry
might open a more broadly applicable approach to construct
heterocycles from fundamental building blocks. Polysubstituted
heterocycles, and in particular the aryl-heteroaryl motif, are
among the most common structural units found in pharmaceutical
development. These products are typically generated via substitu-
tion chemistry on pre-synthesized heterocycles (e.g. cross cou-
pling reactions), or cyclization reactions, both of which require
the multistep synthesis of substituted precursors.10 In contrast, the
transformation in Scheme 1b presumably involves the in situ
generation of an interesting class of 1,3-dipole: Münchnones (3),
although these intermediates are not observed. Münchnones are
well-known 1,3-dipoles that have been exploited for the conver-
gent synthesis of various classes of heterocycles.11 One limitation
to the use of 3 in heterocycle synthesis is their own formation, as
these compounds are typically generated via the cyclization of -
amido acids, which can themselves require a multistep synthesis.
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While alternative approaches to Münchnones have been de-
Scheme 2. Mechanistic Postulate for Catalysis
scribed,12,13 including via the carbonylation of N-acyl iminium
salts, these also rely upon the use of reactive (and synthetic)
building blocks, such as acid chlorides or metal-carbenes. In
contrast to each of these reactions, the palladium catalyzed for-
mation of imidazolines suggests that Münchnones can be generat-
ed from the carbonylation of aryl iodides and imines. We there-
fore hypothesized that inhibiting imidazoline formation and gen-
erating 3 could provide a general platform to generate aryl-
substituted heterocycles from simple combinations of available
substrates (Scheme 1c). In addition to the synthetic chemistry, a
notable feature of this system would be its use of CO not to gen-
erate a carbonylated product, but instead to drive the multicompo-
nent assembly of fundamental building blocks via the ultimate
liberation of CO2.
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One challenge to the use of this carbonylation chemistry to
generate heterocycles is the lack of a complete understanding of
how imidazolinium carboxylates are generated, and indeed if
Münchnones are intermediates in this reaction. To address this,
we have undertaken a series of studies to determine the mecha-
nism of this catalytic transformation. These demonstrate the steps
by which the multicomponent coupling occurs, and conditions
that can favor the formation of 1,3-dipoles. Based upon this data,
we have designed a palladium catalyzed dicarbonylative approach
for the synthesis of polysubstituted pyrroles. In contrast to typical
procedures, this reaction provides a method to form a pyrrole unit
at the same time as the aryl-pyrrole bond, in one pot, and from
four simple components: aryl iodides, imines, CO, and alkynes or
alkenes.
with pentane.15a,b Interestingly, control experiments show no
reaction occurs between 1a and imine, the postulated next step in
o
catalysis, even upon prolonged heating at 55 C. However, the
addition of the other reagent present in catalysis, CO, initiates the
slow disappearance of 1a and generation of imidazolinium car-
boxylate 2a (32% yield). We observe no intermediates in this
reaction, indicating that subsequent steps leading to the formation
of product are faster than the reaction of imine with palladium-
aroyl complex. Although this data demonstrates that 1a is a via-
ble intermediate in the formation of 2a, it is notable that the stoi-
chiometric reaction is low yielding and slow (2 days, 55 oC). This
suggested that 1a may not be an immediate precursor to imidaz-
olines during catalysis.
RESULTS AND DISCUSSION
I. Stoichiometric Model Reactions
Our preliminary mechanistic postulate for the catalytic gener-
ation of imidazolines is shown in Scheme 2. Palladacycles of the
general form of 4 have been established to undergo cyclocar-
bonylations to generate Münchnones.14 We therefore hypothe-
sized that an in situ generated palladium-aroyl complex 1 serves
as a precursor to 4 by reacting with imine. In this scenario, the
palladium catalyst would mediate both an initial carbonylation of
aryl iodide to form 1, followed by a subsequent cyclocarbonyla-
tion to form Münchnone 3 and liberate catalyst. The bulky PtBu3
ligand is believed to facilitate catalysis due in part to its lability in
palladacycle 4, which can allow CO association and subsequent
insertion. While Münchnones are not observed in the reaction,
protonated imines are known to undergo rapid cycloaddition to 3,
and upon carbon-oxygen bond scission to form imidazolinium
salts.14
Scheme 3. Reactivity of Pd-Aroyl Complex 1a
Influence of Chloride In considering differences between the
control experiments in Scheme 3 and catalysis, we noted that the
catalytic synthesis of imidazolinium carboxylate employs
[Pd(allyl)Cl]2 / PtBu3, rather than Pd(PtBu3)2, as the catalyst pre-
cursor. While both of these are expected to generate similar
PtBu3-coordinated Pd(0) catalysts, as shown in Scheme 4, the use
of Pd(PtBu3)2 as catalyst results in minimal coupling under
identical conditions. One potentially important difference be-
tween these two systems is the presence of chloride in the
[Pd(allyl)Cl]2 catalyst precursor. To examine the role of chloride
in the reaction, 5 mol% Bu4NCl was added to the catalytic reac-
tion with Pd(PtBu3)2. This restores catalytic activity to the level
noted with Pd(allyl)Cl]2 / PtBu3 (Scheme 4). Further, increased
chloride concentration results in accelerated reaction.
In order to further probe this mechanism, we first performed a
series of model reactions for each of these individual steps.
Reaction of Pd(PtBu3)2 Aryl Iodide, CO and Imine Our ini-
tial studies examined the putative first steps in the catalytic cycle:
the formation of palladium-aroyl complex 1 and its reaction with
imine. Similar to previous reports,15 the addition of Pd(PtBu3)2,16
as a model for the in situ generated Pd(0) catalyst, to aryl iodide
and carbon monoxide leads to the rapid formation of the three-
coordinate palladium-aroyl complex 1a (Scheme 3). This com-
plex can be easily isolated in high yield upon precipitation
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Scheme 4. Influence of Chloride on Catalysis
Scheme 6. Mechanism of Imine Reaction 1
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A plausible role of chloride in catalysis would be to exchange
with iodide on palladium and therefore modulate reactivity.17 To
test this, the analogous chloride coordinated palladium-aroyl
complex 1b was generated by the oxidative addition of acid chlo-
ride to Pd(PtBu3)2 (Scheme 5). This chloride coordinated 1b also
does not directly react with imine. However, the addition of
carbon monoxide results in the room temperature formation of
imidazolinium carboxylate 2a in high yield (90%). The latter
transformation is much more rapid (6 h, rt) than that with the
iodide complex 1a, and of sufficient rate to be a viable step in the
catalytic reaction.
Notably, no reaction is noted for the analogous iodide complex
1a, nor with 1b in the absence of CO. The rapid formation of acid
chloride from 1b provides a rationale for the role of chloride in
catalysis, and a reasonable pathway for coupling with imine, as
acid chlorides are established to react rapidly with imines to form
N-acyl iminium salts (5, path C).20 The intermediacy of 5 in this
chemistry is further examined below.
Scheme 7. Generation of Acid Chlorides from 1b
Scheme 5. Reactivity of Pd-Aroyl Complex 1b
0.02
0.016
0.012
0.008
Acid Chloride Intermediates The above data suggest that both
chloride and carbon monoxide can facilitate the reaction of imines
with palladium-aroyl complexes, and in particular carbon monox-
ide is required for any reaction to occur. One rationale for these
effects is that chloride and/or carbon monoxide coordination exert
an influence on the reaction of imine with the palladium-aroyl
complex. The latter may occur via a direct nucleophilic attack on
the electrophilic aroyl ligand (Scheme 6, path A), or, in analogy to
previous reports with cationic palladium-acyl complexes, coordi-
nation and migratory insertion (path B).18 However, we have
recently noted that chloride and carbon monoxide in concert with
the PtBu3 ligand can accelerate palladium catalyzed aryl halide
carbonylations by allowing the generation of acid chlorides.19 As
such, an alternative postulate for the influence of chloride is that it
allows the in situ generation of acid chlorides for reaction with
imine (path C).
Keq = 1.1 x 10-3 mol.L-1.atm-2
0.004
0
0
5
10
15
20
[CO]2 (atm2)
N-Acyl Iminium Salts We see no evidence for the formation
of N-acyl iminium salts, or any intermediate, by monitoring the
stoichiometric reaction of 1b, imine, and carbon monoxide by 1H
NMR analysis. To probe for their intermediacy, we therefore
employed scrambling experiments with a labelled iminium salt
(5b, Scheme 8). The latter could exchange with any free iminium
salt generated from palladium complex 1b, and may allow 5a to
build-up in solution. Monitoring the reaction of palladium-aroyl
complex 1b with imine and CO in the presence of an excess of 5b
Insight into the pathway followed in this transformation can
be obtained by simply omitting the addition of imine to the reac-
tion of palladium-aroyl complex 1b. The addition of CO to 1b
leads to the rapid, equilibrium formation of acid chloride (Scheme
7a). Removal of CO from the reaction allows the quantitative re-
formation of 1b, while increasing CO pressure results in the fur-
ther favored generation of acid chloride. A plot of the ratio of
product vs. CO pressure provides a linear fit to [CO]2 (Scheme
7b), implying that two CO ligands may bind to the Pd(0) complex.
1
by in situ H NMR analysis reveals that iminium salt 5a does
indeed form in this reaction at short reaction times (50% at 35
min). Allowing the reaction to continue leads to the complete
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consumption of both iminium salts and generation of two separate
imidazolines, 2b and 2c.
Scheme 10. Stoichiometric Münchnone Generation
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Scheme 8. Intermediacy of N-Acyl Iminium Salts
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II. Postulated Mechanism of Imidazolium Formation
The above studies show that several palladium complexes and
organic products are each competent intermediates in catalysis:
palladium-aroyl complexes (1a and 1b), acid chlorides, N-acyl
iminium salts 5, palladacyclic complex 4 and Münchnones.
Based upon this data, we can formulate a reasonable mechanism
for the multicomponent formation of imidazolines (Scheme 11).
In this, the oxidative addition of aryl iodide and CO insertion is
rapid, and leads to the generation of the palladium-aroyl complex
1a. Control experiments demonstrate that complex 1a does not
react rapidly with imine (e.g. Scheme 3). The latter is consistent
with many examples in carbonylation reactions, which suggest
that palladium-aroyl ligands are only moderately electrophilic,
and typically require anionic nucleophiles that can first coordinate
to palladium for more facile reductive elimination.21 Instead, our
data is consistent with the reductive elimination of acid chloride
from the chloride-coordinated complex 1b, which can react with
the weakly nucleophilic imine away from the palladium catalyst
to generate free N-acyl iminium salts 5. The role of CO and PtBu3
in the formation of acid chloride is presumably similar to that we
have previously noted, where coordination of CO to the T-shaped
complex creates a sterically encumbered and electron-poor
Palladacycle Formation. The generation of free N-acyl imin-
ium salt 5 in this chemistry requires that this intermediate add to
palladium for a second carbonylation to ultimately generate imid-
azolinium carboxylates 2. Control experiments show that this
step is also viable. The addition of N-acyl iminium salt 5b to
Pd(PtBu3)2 leads to the near quantitative formation of palladacy-
clic complex 4b within 2h (Scheme 9). This complex displays
spectroscopic features similar to previously isolated amide-
chelated palladacycles.12a,18 Complex 4b is also a viable interme-
diate in catalysis: the addition of CO to this palladacycle results
in its rapid (3h, rt) conversion into imidazolinium carboxylate in
89% yield.
Scheme 9. Synthesis of Palladacyclic Intermediates
Scheme 11. Overall Mechanism of Imidazolium Carbox-
ylate Formation
Münchnone Formation One intermediate not observed in the
stoichiometric chemistry above is Münchnone 3. Previous studies
on 1,3-dipolar cycloadditions with Münchnones have demonstrat-
ed that protonated N-alkyl imines can undergo very rapid cy-
cloaddition to generate imidazolinium salts.14 In the chemistry
above, acid is generated upon the cyclocarbonylation of pal-
ladacycle 4 (Scheme 2), and can presumably protonate imine to
allow the generation of 2. We therefore examined the effect of
base on the stoichiometric reactions. As shown in Scheme 10a,
the addition of NEtiPr2 base to the reaction of palladium-aroyl
complex 1b, imine, and CO inhibits imidazolinium formation and
leads instead to the formation of Münchnone 3a. in 73% yield. A
similar effect of base is noted on the reaction with palladacycle 4a
(Scheme 10b).
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palladium intermediate 6 for the favored reductive elimination of
acid chloride.19 As such, both chloride and carbon monoxide are
1
critical for the build-up of iminium salts. Once N-acyl iminium
salt 5 is generated, control experiments suggest that it can undergo
rapid oxidative addition to Pd(PtBu3)2 to form palladacycle (4,
Scheme 9) for rapid subsequent cyclocarbonylation to form
Münchnone (Scheme 10b). The latter is established to react with
protonated imine to generate the observed imidazolinium salt
products.7
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4
5
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8
These data show that catalysis that proceeds via two separate
carbonylation cycles (A and B), both of which are mediated by
the same palladium catalyst. Monitoring the catalytic reaction by
NMR provides some insight into the relative rates of these two
cycles. In situ 31P NMR analysis (Figure 1) shows the generation
palladium-aroyl complex 1b as the only observable intermediate
at short reaction times. However, as catalysis proceeds, the build-
up of protic acid leads to the equilibrium protonation of the phos-
phine, and this complex can no longer be observed. The observa-
tion of complex 1b suggests that its subsequent reaction (i.e. with
imine) is at least partially rate determining in the overall cycle.
1H NMR analysis shows no evidence for any organic (e.g. N-acyl
iminium salt) intermediate during the course of the reaction, and
also implies that the consumption of acid chloride and iminium
salt (cycle B) is more rapid than their formation (cycle A).
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Figure 1. In situ 31P NMR Analysis of the Catalytic Formation of
Imidazolinium Carboxylate in Scheme 4.
considering the mechanism in Scheme 11, and the catalyst resting
state at 1b, these results are consistent with N-acyl iminium salt 5
formation from 1b (cycle A) as rate determining in catalysis.
While acid chloride reductive elimination is rapid, this reaction is
in dynamic equilibrium due to the rapid re-addition of acid chlo-
ride to Pd(0). In this scenario, both imine and aryl iodide concen-
tration can favor N-acyl iminium salt generation by trapping the
acid chloride and Pd(0), respectively, and carbon monoxide pres-
sure is established to favor this equilibrium by generating a more
stable Pd(0)-carbonyl intermediate (Scheme 7).
Kinetic analysis of the catalytic reaction provides further insight
into the rate determining step(s) in this system. As illustrated in
Figure 2, the catalytic formation of imidazolinium carboxylate
proceeds with the first order dependence on imine concentration,
aryl iodide concentration, and carbon monoxide pressure. In
-2
0.04
0.03
0.02
0.01
0
a)
0
5000 10000 15000
b)
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2
0
-4
-6
-8
Time (s)
kobs = 3.1 x 10-4 s-1
0
5000
10000
15000
0.005
0.015
0.025
0.035
0.045
Time (s)
[Imine]0 (mol/L)
c)
3.5
3
d) 3.2
2.7
2.5
2
2.2
1.7
1.5
1
1.2
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4
6
[ArI] (mol/L)
CO Pressure (atm)
Figure 2. Kinetic Analysis of Catalytic Formation of Imidazolinium Carboxylate. (a) Typical plot of imine concentration vs. time for
the reaction in Scheme 3 with 10 mol% Pd(PtBu3)2 and 1 eq. Bu4NCl at 40 oC. Inset: ln plot of data; (b) Initial rate dependence on imine
concentration; (c) Rate dependence on p-tolyl iodide concentration; (d) Rate dependence on CO pressure.
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common triaryl- or trialkylphosphines completely inhibits cataly-
III. Catalytic Münchnone Synthesis
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2
3
4
5
6
7
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sis (Table 2, entries 2, 3). This may arise from the strong binding
of these ligands to palladacycle 4, which could inhibit carbonyla-
tion. Moving to more sterically encumbered ligands leads to low
yield of Münchnones (ca. 20%, entries 7-10), or approximately
one to two catalytic turnovers of the palladacycle precatalyst (i.e.
cycle B, Scheme 10). In contrast, large bite angle phosphines can
lead to double-carbonylative catalysis (entries 11-13), with PtBu3
the most active. This ligand is also noted to be key in catalytic
acid chloride formation, where its cone angle can create sufficient
steric encumbrance on palladium to allow rapid acid chloride
formation.19 Under these combined conditions with excess aryl
iodide, the formation of Münchnone is sufficiently rapid to allow
us to lower the reaction temperature (entry 14). The latter further
suppresses -lactam formation, and allows the synthesis of
Münchnone in high yield.
We next turned our attention to the potential use of this chem-
istry as a general route to prepare Münchnones. The data in
Scheme 10 shows that amine base can inhibit imidazolinium
carboxylate formation and allow the build-up of Münchnone.
Similarly, the use of catalytic Pd(PtBu3)2 in the reaction of aryl
iodide, imine and CO in the presence of NEtiPr2 leads to the cata-
lytic formation of Münchnone 2a (Table 1, entry 1), but in low
yield (20%). Instead, we note the build-up of a second product:
-lactam 7a (32%). The generation of -lactam presumably
arises from the slow [2+2] cycloaddition of ketene tautomer of
Münchnone with imine.22 As in the stoichiometric experiments,
the omission of chloride completely shuts down catalysis (entry
2).
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Table 1. Catalytic formation of Münchnones
Table 2. Ligand Screening for Münchnone Formation
Entry
CO (atm)
Ar-I (equiv)
% 3a
20
% 7a
32
0
#
Ligand
% 3a
#
Ligand
% 3a
(% 7a)
(% 7a)
1
2a
3
1
1
1
1
3
5
1
1
1
2
-
20 (2)
0 (0)
0
PPh3
1
44
50
13
19
8
9
23 (4)
4
1
50
3
PCy3
0 (0)
5
4
58
6
10
65
4
0 (14)
4-iodotoluene (55 mg, 0.25 mmol), imine (52 mg, 0.25 mmol),
Bu4NCl (69 mg, 0.25 mmol), NEtiPr2 (49 mg, 0.375 mmol),
Pd(PtBu3)2 (13 mg, 25 µmol) and CO in MeCN (1.7 mL),
yields of 3a and 7a determined by 1H NMR analysis. aBu4NCl
not added to the reaction.
10
27 (6)
5
3 (2)
The formation of -lactam was an anticipated challenge in
this catalytic reaction, where, much like the catalytic formation of
imidazolinium carboxylates, the imine itself reacts more rapidly
with the Münchnone product than it builds up in the catalytic
reaction. One approach to avoid this product would be to acceler-
ate the catalytic formation of Münchnone, and therefore imine
consumption. The mechanistic results proved useful in this re-
gard. For example, increasing the concentration of aryl iodide
favors the formation and yield of Münchnone (entries 3, 4). The
latter is presumably related to the equilibrium formation of acid
chloride, where a higher concentration of aryl iodide can better
trap Pd(0) and favor catalysis. Similarly, increasing CO pressure
leads to the faster generation of Münchnone and significantly
limits the formation of -lactam (entries 5, 6).
6
7
8
0 (0)
18 (2)
24 (6)
11
12
57 (14)
55 (19)
P(o-Tol)3
13
PtBu3
PtBu3
62 (20)
80 (4)
14a
4-iodotoluene (33 mg, 0.15 mmol), imine (31 mg, 0.15 mmol) Pd
catalyst 4 (6.8 mg, 7.5 µmol), Ligand (30 µmol), NEtiPr2 (29 mg,
0.23 mmol), Bu4NCl (42 mg, 0.15 mmol), and CO (4 atm), in
The influence of ligands on this transformation was also probed.
In order to screen ligands uncomplicated by catalyst activation
steps, palladacycle 4 was used as the catalyst precursor, as it also
represents an intermediate in the catalytic cycle. The use of
1
a
MeCN (1 mL), yield determined by H NMR analysis. reaction
o
performed at 40 C, with 4-iodotoluene (164 mg, 0.75 mmol) and
CO (10 atm).
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into this transformation. This includes simple aryl iodides (8a), as
IV. Catalytic Synthesis of Pyrroles
1
2
3
4
5
6
7
8
well as those with electron rich (8b-d) and electron poor (8g,h,k)
substituents. Each of these leads to pyrroles in high overall yield.
Potentially palladium reactive aryl bromide functionalities can
also be incorporated (8e). Interestingly, the reaction can move
beyond simple aryl groups and incorporate heteroaryl iodides
(8i,j). Similar modulation of the imine can be performed. N-alkyl
and -benzyl protected imines are viable substrates in this chemis-
try, as are electron rich N-aryl imines (8l,m,q). On the imine
carbon, an array of electron rich (8l,q) or electron poor (8m,n)
aryl-substituents can be employed, as can heteroaryl imines (8p,u)
and t-butyl substituted reagents (8r,t). Conversely, enolizable
imines lead to enamides under the reaction conditions.24 Togeth-
er, this can allow the assembly of a range of 2,5-aryl, -heteroaryl
and/or -alkyl substituted pyrroles.
The reaction in Table 2 provides a new route to form a 1,3-
dipole via the carbonylation of aryl iodides with imines. As dis-
cussed previously, a feature of Münchnones is their ability to
participate in cycloaddition reactions to assemble heterocycles.
Coupling the catalytic formation of 3 with cycloaddition can
therefore provide an alternative to more classical multistep routes
to assemble the aryl-heteroaryl motif. As an example, the catalyt-
ic generation of Münchnone 3a followed by the addition of the
electron deficient alkyne dimethylacetylenedicarboxylate leads to
the generation of 2-aryl substituted pyrrole 8a in 84% yield (Eq.
1), where in one pot four bonds are generated from five separate
reagents (aryl iodide, imine, alkyne, and two equivalents of car-
bon monoxide).
9
10
11
12
13
14
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23
24
25
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59
60
The dipolarophile can also be tuned in this chemistry (Table
4). Examples of these include a number of substituted electron
poor alkynes incorporating ketone (8v), ester (8w,y,z) or electron
deficient arene (8x) functionalities. In the case of less electron
deficient alkynes (e.g. 8y,aa), the dipolarophile can be used in the
presence of the catalytic synthesis of Münchnone, allowing the
one step synthesis of substituted pyrroles. As previously noted,
phenyl methylpropiolate and electron poor aryl acetylenes under-
go regioselective cycloaddition to unsymmetrical Münchnones.26
Electron poor alkenes can be similarly used in this platform, and
undergo facile acid loss upon cycloaddition to generate tetra- or
trisubstituted pyrroles.27 This can be used to generate 3-
substituted pyrroles from vinyl halide derivatives (8ab,ac) and
nitroalkenes (8ad). While acetylene does not react with 3, the
The pyrrole core, and in particular aryl-substituted pyrroles,
represent a useful general class of pharmaceutically relevant
heterocycle, and have found significant utility in materials chem-
istry.23 In this regard, an aspect of this transformation the ability
to access these heterocycles from combinations of available and
easily diversified building blocks. This is highlighted in Tables 3
and 4. For example, a number of aryl iodides can be incorporated
Table 3. Multicomponent Synthesis of Pyrroles: Aryl Iodide and Imine Diversity
Imine (0.50 mmol), aryl iodide (2.50 mmol), Pd(PtBu3)2 (12.8 mg, 0.025 mmol), Bu4NCl (139.0 mg, 0.5 mmol), NEtiPr2 (97.0 mg, 0.75
mmol), MeCN (3.3 mL), CO (10 atm), 40 °C. Quench with DMAD (85.3 mg, 0.60 mmol) at ambient temperature for 15 minutes.
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Table 4. Multicomponent Synthesis of Pyrroles: Alkyne and Alkene Diversitya
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Imine (0.50 mmol), aryl iodide (2.50 mmol), Pd(PtBu3)2 (12.8 mg, 0.025 mmol), Bu4NCl (139.0 mg, 0.5 mmol), NEtiPr2(97.0 mg, 0.75
mmol), MeCN (3.3 mL), CO (10 atm), 40 °C. For specific conditions for each dipolarophile, see Supplementary Information.
electron deficient triphenylvinylphosphonium salt can act as an
acetylene equivalent upon acid loss to form 3,4-unsubstituted
pyrroles (8ae,af).
high overall yield. Studies towards the use of this reaction to
access other classes of products are currently underway.
ASSOCIATED CONTENT
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
Overall, this provides a method to assemble families of aryl-
and heteroaryl-substituted pyrroles with independent control of all
five substituents. Within the brief diversity probed in Tables 3
and 4, the combination of substrates provides the ability to gener-
ate almost 103 structurally different pyrroles in one pot reactions.
Considering the broad availability of aryl iodides, imines, and
alkynes/alkenes, many more structural combinations are also
possible. We are unaware of any other method to construct pyr-
roles with such broad diversity from aryl halides in combination
with other fundamental and stable building blocks.
AUTHOR INFORMATION
Corresponding Author
bruce.arndtsen@mcgill.ca
Notes
The authors declare no competing financial interest.
CONCLUSIONS
ACKNOWLEDGMENT
In conclusion, we have developed a multicomponent approach
for the synthesis of Münchnones from simple aryl iodides, imines,
and CO. Mechanistic studies suggest that this reaction proceeds
via a tandem catalytic pathway, with the in situ generation of acid
chlorides and N-acyl iminium salts. The PtBu3 ligand in concert
with chloride is found to be unique in allowing both of these
cycles to proceed under mild conditions. This presumably due to
the unusual ability of this large ligand to facilitate the reductive
elimination of acid chloride from palladium, as well as the lability
of this large phosphine, which can allow the carbonylation of
palladacyclic intermediates (4). Coupling the formation of
Münchnones with alkyne/alkene cycloaddition can provide a
multicomponent method to generate polysubstituted pyrroles.
Notably, this synthesis employs available, inexpensive and stable
reagents (aryl iodides, carbon monoxide imines, alkynes), pro-
ceeds with high efficiency, is modular, and generates pyrroles in
We thank NSERC, the Canadian Foundation for Innovation
(CFI), and the FQRNT supported Centre for Green Chem-
istry and Catalysis for funding this research.
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