Regioselective Synthesis of 2,3,4-Trisubstituted Pyrroles via Pd(II)-Catalyzed Three-Component Cascade Reactions of Amines, Alkyne Esters, and Alkenes

Article abstract of DOI:10.1021/acs.orglett.6b02325

A new, efficient, and versatile Pd(II)-catalyzed oxidative three-component cascade reaction of diverse amines, alkyne esters, and alkenes is disclosed for the direct synthesis of diverse 2,3,4-trisubstituted pyrroles with broad functional group tolerance and in good to excellent yields. This transformation is supposed to proceed through the cascade formation of C(sp²)-C(sp²) and C(sp²)-N bonds via Pd(II)-catalyzed regioselective alkene migratory insertion, intramolecular radical addition, and oxidation sequential processes.

Full text of DOI:10.1021/acs.orglett.6b02325

Letter
pubs.acs.org/OrgLett
Regioselective Synthesis of 2,3,4-Trisubstituted Pyrroles via Pd(II)-
Catalyzed Three-Component Cascade Reactions of Amines, Alkyne
Esters, and Alkenes
Xu Zhang,*,† Xuefeng Xu,† Gong Chen,§ and Wei Yi*,‡
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China
‡VARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai
Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
§China Gateway Pharmaceutical Development Company, Limited, Shanghai 201417, China
S
* Supporting Information
ABSTRACT: A new, efficient, and versatile Pd(II)-catalyzed
oxidative three-component cascade reaction of diverse amines,
alkyne esters, and alkenes is disclosed for the direct synthesis
of diverse 2,3,4-trisubstituted pyrroles with broad functional
group tolerance and in good to excellent yields. This
transformation is supposed to proceed through the cascade
formation of C(sp2)−C(sp2) and C(sp2)−N bonds via Pd(II)-
catalyzed regioselective alkene migratory insertion, intramolecular radical addition, and oxidation sequential processes.
Scheme 1. Transition-Metal-Catalyzed C−H Oxidative
Annulations of Enamines for the Synthesis of Pyrroles
rguably, substituted pyrroles represent one of the most
Aimportant classes of monocyclic N-heterocycles found in
numerous natural products, pharmaceutical drugs, biologically
active compounds, and functional materials.1 Consequently,
they have drawn considerable interest for synthetic chemists,
and to date, a plethora of elegant procedures including the
classical Knorr, Hantzsch, and Paal−Knorr condensation
reaction have been developed for their construction.2 However,
these reactions usually proceed with limited substitution
patterns of the substrates to give the relatively simple pyrrole
products under harsh conditions and/or in low yields, which
greatly hindered their application. Obviously, the development
of new, efficient, and general methodologies for direct synthesis
of multiple-substituted pyrroles using basic chemical materials
remains one of the hottest topics in modern synthetic
chemistry.
Recently, transition-metal-catalyzed C−H oxidative annula-
tion of the C−H/N−H bonds has emerged as a popular and
core strategy to construct the N-heterocycles.3 Indeed, a large
number of privileged N-heterocycles, such as indoles,4
pyridines,5 and isoquinolines,6 have been smoothly synthesized
in a more atom-economical and environmentally friendly
manner with excellent substrate/functional group tolerance by
employing such a versatile strategy. As one of the C−H/N−H
bond annulation reaction precursors, enamines have been
widely used for the synthesis of substituted pyrroles in various
transition-metal-catalyzed C−H functionalization reactions
(Scheme 1a).7a−l Despite this compelling progress, there is
room for innovation. For example, the coupling partners of
enamines are mostly limited to internal alkynes. Moreover, fully
substituted pyrroles were often delivered in these developed
catalytic systems, which would overshadow their further
derivatization in a certain extent. In contrast, as far as we
know, related C−H oxidative annulation of enamines with
terminal alkenes toward pyrrole synthesis is still unexplored,
and to date, only a beautiful example for the synthesis of 2,3,5-
trisubstituted pyrroles were reported using amines and β-keto
esters as enamine precursors (Scheme 1b).7m This is likely
associated with the relatively low reactivity of terminal alkenes
toward transition metals in comparison with internal alkynes.
Undoubtedly, it is very challenging but highly desirable to
develop a transition-metal-catalyzed direct C−H activation
Received: August 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02325
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Letter
strategy to build the privileged pyrroles with new substitution
patterns by using low reactive terminal alkenes as efficient
coupling partners.
Scheme 3. Scope of Amines
It is well-known that enamines could be conveniently
generated in situ from commercially available animes and
alkyne esters.8 Inspired by the above information, we envision
that the use of simple animes and alkyne esters in place of the
enamines, with alkenes in a proper transition-metal catalysis,
could potentially provide a complementary method for pyrrole
synthesis. Therefore, we herein report, for the first time, an
efficient, general, and straightforward method for the one-pot
cascade synthesis of important 2,3,4-trisubstituted pyrroles by a
three-component assembly from simple and readily available
amines, alkyne esters and alkenes (Scheme 1c). The versatile
protocol is also novel for the Pd(II)-catalyzed sequential
reactions, in which thiosulfate acts as both an radical generating
reagent and an organic oxidant.9
Given the successful history in Pd(II)-catalyzed C−H
oxidative cross-coupling reactions,10 at the outset of this
study, we chose Pd(OAc)2 as the active Pd(II) catalyst and
employed commercially available aniline (1a), dimethyl but-2-
ynedioate (2a), and styrene (3a) as the model substrates for
the reaction development (see the Supporting Information).
After several parameters were screened, the three-component
cascade reactions were optimized as follows: 5 mol % of
Pd(OAc)2, 2.0 equiv of K2S2O8, and 2.0 mL of HOAc in MeCN
at 100 °C for 20 h under an atmosphere of air (Scheme 2). It
a
Yields refer to isolated yields.
Scheme 2. Optimized Results of the Pd(II)-Catalyzed Three-
Component Cascade Reaction
tolerated, producing their corresponding products (4t−z and
5a−e) in decent isolated yields.
Next, we evaluated the substrate scope with respect to alkyne
esters (Scheme 4). To our delight, the reaction was well
Scheme 4. Scope of Alkyne Esters
a
The isolated yield was given when the reaction was performed on a
10 mmol scale.
was important to note that the reaction could be smoothly
performed on a 10 mmol scale under the optimized conditions
without a significant decrease in the product yield (83% vs
89%), which illustrated the remarkable robustness of this
Pd(II)-catalyzed system.
Having the established standard conditions in hand, we first
examined the substrate scope of this reaction with respect to
amines (Scheme 3). Pleasingly, the results demonstrated that a
wide range of aryl amine substrates reacted smoothly with 2a
and 3a to deliver the desired products in good to excellent
yields (67−94%). Both electron-donating and electron-with-
drawing substituents either at the ortho- (4a−e), meta- (4f−i),
or para- (4j−p) position were all well tolerated. Importantly,
the reaction also showed good compatibility with many
valuable functional groups such as chloro (4b,g,k,m,s), bromo
(4c,l), iodine (4d), methyl (4e,i,m,q−r), fluoro (4f), methoxy
(4n,s), trifluoromethyl (4h,o), and methylthio (4q) substitu-
ents. Moreover, disubstituted aryl amines, such as 2,6-
dimethylaniline (1q), 2,4-dimethylaniline (1r), and 3-chloro-
4-methoxyaniline (1s), are also applicable to give the pyrrole
products in good yields. Of note, replacement of the aryl
amines with various alkyl amines including phenyl- and
heteroaromatic ring-substituted alkyl amines were perfectly
a
Yields refer to isolated yields.
compatible with alkyl- as well as aryl-substituted internal alkyne
esters, such as methyl but-2-ynoate (2b), ethyl but-2-ynoate
(2c), methyl non-2-ynoate (2d), diethyl but-2-ynedioate (2e),
and methyl 3-phenylpropiolate (2f), thus providing the
corresponding pyrroles 6a−e in generally good yields. Gratify-
ingly, terminal alkyne ester (2g) also smoothly reacted with 1a
and 3a to deliver the desired product 6f in 68% yield, which
further demonstrated the versatility of this reaction.
To explore the substrate scope further, different arylethylenes
were also investigated in the three-component process (Scheme
B
DOI: 10.1021/acs.orglett.6b02325
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Letter
5). In general, we found that the developed catalytic system
proved to be broadly applicable, thus delivering the desired
Scheme 7. Plausible Reaction Mechanism
Scheme 5. Scope of Alkenes
generated from in situ nucleophilic addition of amine 1a to
alkyne ester 2a. Subsequently, regioselective alkene migratory
insertion via intermolecular nucleophilic attack by the β-
position of enamine moiety 8 to intermediate A gives the Pd
complex B. Radical intermediate C is produced by hydride
abstraction from B facilitated by the sulfate radical anion that is
generated from the heated K2S2O8.9,13 Next, an intramolecular
radical addition/cyclization leads to the formation of the six-
membered intermediate D. Protonolysis of D yields inter-
mediate E and HPdOAc (F), and the latter undergoes a
reductive elimination/oxidation sequence to regenerate the
active Pd(II) catalyst by the aid of K2S2O8. Finally, intermediate
E is oxidized by K2S2O8 to deliver the desired pyrrole product
4a.
In summary, we have successfully developed an efficient Pd-
catalyzed three-component cascade reaction of simple amines,
alkynes, and alkenes for the direct synthesis of novel 2,3,4-
trisubstituted pyrroles with high diversity, where thiosulfate
acted as both the radical generating reagent and the organic
oxidant. Through experimental investigation, a plausible
regioselective alkene migratory insertion for the formation of
a C(sp2)−C(sp2) bond−intramolecular radical addition/
oxidation for the formation of C(sp2)−N bond sequential
pathway was proposed. Further studies on the scope,
mechanism, and application of this three-component cascade
reaction are actively ongoing in our laboratories.
a
Yields refer to isolated yields.
products 7a−g in 64−92% yields. It should be emphasized that
the electron-withdrawing alkenes gave relatively lower yields
than the electron-donating substrates (e.g., 64% for 7c and 68%
for 7e vs 92% for 7a and 89% for 7f), suggesting that the
electrical property of the substituent on the benzene ring of
arylethylene had an obvious influence on the outcome of the
reaction.
Motivated by the aforementioned results and literature
precedents,7,11 we speculated that the enamines might be used
as a key intermediate for the Pd(II)-catalyzed cascade reaction
(Scheme 6a). Thus, enamine 8 were prepared and designated
Scheme 6. Experimental Investigation for the Reaction
Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02325.
Experimental procedures, characterization of products,
1
and H and 13C NMR spectra (PDF)
as substrates to probe the reaction mechanism. As expected, the
designed reaction occurred successfully under the standard
conditions to give the predicted product 7c in 65% yield.
We also conducted a radical capture experiment to unveil
both the role of K2S2O8 and the nature of the reaction
mechanism. As shown in Scheme 6b, when the Pd(II)-catalytic
system was treated with a representative radical inhibitor,
TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl), no desired
product was detected upon addition of TEMPO. The results
revealed that, in addition to the organic oxidant, K2S2O8 acted
as the radical-generating reagent9 for the catalytic cycle.
With these observations in mind, we finally proposed a
plausible reaction mechanism for the three-component cascade
sequence (Scheme 7). Initially, styrene (3a) was activated by
Pd(OAc)2 to form intermediate A.12 Moreover, enamine 8 is
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangxuedu@126.com.
*E-mail: yiwei.simm@simm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Youth Innovation Promotion Association CAS,
the National Natural Science Foundation of China (21502100
and 81502909), the Shanghai Municipal Natural Science
Foundation (15ZR1447800), and the Shanghai Rising-Star
Program (16QB1400200).
C
DOI: 10.1021/acs.orglett.6b02325
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Letter
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