Article pubs.acs.org/joc
Tandem One-Pot Synthesis of Polysubstituted NH-Pyrroles Involving the Palladium-Catalyzed Intramolecular Oxidative Amination of the Zinc Bromide Complex of β‑Enamino Esters Ju Hyun Kim, Suh Young Choi, Jean Bouffard, and Sang-gi Lee* Department of Chemistry and Nano Science (BK 21 Plus), Ewha Womans University, 120-750 Seoul, Korea S Supporting Information *
ABSTRACT: The Pd-catalyzed oxidative olefin amination of the zinc bromide complex intermediate, formed by the sequential reaction of nitriles with a Reformatsky reagent and 1-alkynes, affords pyrrole derivatives in good to excellent yields. This tandem protocol provides a simple, efficient, and atom- and poteconomical way to quickly build polysubstituted NH-pyrroles starting from readily available reagents in a regiocontrolled manner with a broad substrate scope and high functional group tolerance. In contrast, the Pd-catalyzed oxidative olefin amination of an isolated α-vinyl-β-enamino ester did not proceed effectively, but the reaction efficiency can be restored by addition of nBuZnBr or Zn(OAc)2, indicating the crucial role of the zinc complex in this transformation. The synthetic utility of this protocol is exemplified by the rapid synthesis of pyrrolophenanthrenes and pyranopyrrolones through selective Pd- and Cu-catalyzed C− C and C−O bond-forming reactions.
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INTRODUCTION The pyrrole moiety is a widespread scaffold found in natural products, biologically active compounds,1 as well as in dyes, pigments, and other functional materials.2 This broad utility has made pyrroles long-standing synthetic targets and has spurred extensive efforts toward the development of efficient methods to prepare this important heterocyclic compound.3 Recent advances in transition-metal-catalyzed reactions have provided new approaches for the construction of the pyrrole ring.4 For example, the direct pyrrole-forming annulation using 1-alkynes remained elusive until the discovery of silver-catalyzed alkyneisocyanide click reactions (Scheme 1a).5a,b Pd- or Pd/Cucatalyzed addition/cyclization/tautomerization cascades via propargyl amines were also recently reported (Scheme 1b).5c,d In spite of these advances, many of the methods can only provide N-substituted pyrroles, requiring an extra synthetic step to remove the N-substituent for further synthetic elaboration. Others offer a limited scope with respect to the accessible substitution patterns about the pyrrole ring.6 Therefore, the development of an efficient and direct method for the synthesis of regiocontrolled polysubstituted NHpyrroles starting from readily available reagents remains an incomplete task. During our continuing studies on the tandem use of the Blaise reaction,7 we have found that the Blaise reaction intermediate A, formed by reaction of nitriles 1 with Reformatsky reagents, could react chemo- and regioselectively with 1-alkynes to afford the corresponding α-vinylated βenamino esters. Mechanistic studies suggested that a zinc bromide complex of α-vinylated β-enamino ester B was formed as a second intermediate.8 We envisioned that the vinylated © XXXX American Chemical Society
intermediate B may serve as a viable substrate for palladiumcatalyzed intramolecular oxidative aminations to provide pyrroles 3, given that, under the reaction conditions, the intermediate B may be in equilibrium with the unchelated isomer B′, facilitating the cyclization step (Scheme 1). In a preliminary communication, the intermediate B (R2 = o-Cl-Ph), formed by tandem reaction of A with o-chlorophenyl acetylene, was utilized as a common precursor for palladium catalystcontrolled divergent synthesis of pyrrole and quinoline.9 Herein, we report the details and expand on our studies of this simple protocol that provides an efficient and atom- and pot-economic way to quickly build regiodefined pyrrole frameworks. Furthermore, we also report for the first time our important finding that the Pd-catalyzed oxidative olefin amination of the isolated α-vinyl-β-enamino ester does not proceed effectively, but that the reaction efficiency can be restored by addition of Zn(OAc)2 or n-BuZnBr, indicating that the use of zinc complex intermediate B is crucial for the intramolecular oxidative olefin amination reaction. Finally, we disclose here a new divergent conversion of a pyrrole having chlorophenyl and ester functionalities to pyrrolophenathrene and pyranopyrrolone derivatives, demonstrating the synthetic utility of this tandem process.
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RESULTS AND DISCUSSION While large numbers of efficient transition-metal-catalyzed intramolecular oxidative olefin aminations have been deReceived: July 24, 2014
A
dx.doi.org/10.1021/jo501672c | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Scheme 1. Examples for the Syntheses of Pyrrole Rings Using 1-Alkyne Synthons, and Our Tandem Strategy for One-Pot Synthesis of Polysubstituted NH-Pyrroles
Table 1. Optimization of the Reaction Conditionsa
entry 1 2 3 4 5 6 7c 8d 9 10 11 12
additive (equiv) Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
(2.2)/AcOH (2.2)/AcOH (3.0)/AcOH (3.0) (3.0) (3.0) (2.2)/AcOH (2.2)/AcOH
(2.0) (1.0) (2.0)
(2.0) (2.0)
AcONa (1.0) pyridine (0.2) Phen (0.2)
solvent
°C/h
yield (%)b
DMF DMF DMF DMF DMSO DMF/H2O DMF DMF DMSO DMSO toluene MeOH
90/4 90/4 90/1 110/4 110/3 110/3 90/24 90/12 110/12 110/12 110/24 110/24
85 70 88 52 48 37 48 15
Tandem One-Pot Synthesis of Polysubstituted NH-Pyrroles Involving the Palladium-Catalyzed Intramolecular Oxidative Amination of the Zinc Bromide Complex of β‑Enamino Esters Ju Hyun Kim, Suh Young Choi, Jean Bouffard, and Sang-gi Lee* Department of Chemistry and Nano Science (BK 21 Plus), Ewha Womans University, 120-750 Seoul, Korea S Supporting Information *
ABSTRACT: The Pd-catalyzed oxidative olefin amination of the zinc bromide complex intermediate, formed by the sequential reaction of nitriles with a Reformatsky reagent and 1-alkynes, affords pyrrole derivatives in good to excellent yields. This tandem protocol provides a simple, efficient, and atom- and poteconomical way to quickly build polysubstituted NH-pyrroles starting from readily available reagents in a regiocontrolled manner with a broad substrate scope and high functional group tolerance. In contrast, the Pd-catalyzed oxidative olefin amination of an isolated α-vinyl-β-enamino ester did not proceed effectively, but the reaction efficiency can be restored by addition of nBuZnBr or Zn(OAc)2, indicating the crucial role of the zinc complex in this transformation. The synthetic utility of this protocol is exemplified by the rapid synthesis of pyrrolophenanthrenes and pyranopyrrolones through selective Pd- and Cu-catalyzed C− C and C−O bond-forming reactions.
■
INTRODUCTION The pyrrole moiety is a widespread scaffold found in natural products, biologically active compounds,1 as well as in dyes, pigments, and other functional materials.2 This broad utility has made pyrroles long-standing synthetic targets and has spurred extensive efforts toward the development of efficient methods to prepare this important heterocyclic compound.3 Recent advances in transition-metal-catalyzed reactions have provided new approaches for the construction of the pyrrole ring.4 For example, the direct pyrrole-forming annulation using 1-alkynes remained elusive until the discovery of silver-catalyzed alkyneisocyanide click reactions (Scheme 1a).5a,b Pd- or Pd/Cucatalyzed addition/cyclization/tautomerization cascades via propargyl amines were also recently reported (Scheme 1b).5c,d In spite of these advances, many of the methods can only provide N-substituted pyrroles, requiring an extra synthetic step to remove the N-substituent for further synthetic elaboration. Others offer a limited scope with respect to the accessible substitution patterns about the pyrrole ring.6 Therefore, the development of an efficient and direct method for the synthesis of regiocontrolled polysubstituted NHpyrroles starting from readily available reagents remains an incomplete task. During our continuing studies on the tandem use of the Blaise reaction,7 we have found that the Blaise reaction intermediate A, formed by reaction of nitriles 1 with Reformatsky reagents, could react chemo- and regioselectively with 1-alkynes to afford the corresponding α-vinylated βenamino esters. Mechanistic studies suggested that a zinc bromide complex of α-vinylated β-enamino ester B was formed as a second intermediate.8 We envisioned that the vinylated © XXXX American Chemical Society
intermediate B may serve as a viable substrate for palladiumcatalyzed intramolecular oxidative aminations to provide pyrroles 3, given that, under the reaction conditions, the intermediate B may be in equilibrium with the unchelated isomer B′, facilitating the cyclization step (Scheme 1). In a preliminary communication, the intermediate B (R2 = o-Cl-Ph), formed by tandem reaction of A with o-chlorophenyl acetylene, was utilized as a common precursor for palladium catalystcontrolled divergent synthesis of pyrrole and quinoline.9 Herein, we report the details and expand on our studies of this simple protocol that provides an efficient and atom- and pot-economic way to quickly build regiodefined pyrrole frameworks. Furthermore, we also report for the first time our important finding that the Pd-catalyzed oxidative olefin amination of the isolated α-vinyl-β-enamino ester does not proceed effectively, but that the reaction efficiency can be restored by addition of Zn(OAc)2 or n-BuZnBr, indicating that the use of zinc complex intermediate B is crucial for the intramolecular oxidative olefin amination reaction. Finally, we disclose here a new divergent conversion of a pyrrole having chlorophenyl and ester functionalities to pyrrolophenathrene and pyranopyrrolone derivatives, demonstrating the synthetic utility of this tandem process.
■
RESULTS AND DISCUSSION While large numbers of efficient transition-metal-catalyzed intramolecular oxidative olefin aminations have been deReceived: July 24, 2014
A
dx.doi.org/10.1021/jo501672c | J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
Article
Scheme 1. Examples for the Syntheses of Pyrrole Rings Using 1-Alkyne Synthons, and Our Tandem Strategy for One-Pot Synthesis of Polysubstituted NH-Pyrroles
Table 1. Optimization of the Reaction Conditionsa
entry 1 2 3 4 5 6 7c 8d 9 10 11 12
additive (equiv) Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
(2.2)/AcOH (2.2)/AcOH (3.0)/AcOH (3.0) (3.0) (3.0) (2.2)/AcOH (2.2)/AcOH
(2.0) (1.0) (2.0)
(2.0) (2.0)
AcONa (1.0) pyridine (0.2) Phen (0.2)
solvent
°C/h
yield (%)b
DMF DMF DMF DMF DMSO DMF/H2O DMF DMF DMSO DMSO toluene MeOH
90/4 90/4 90/1 110/4 110/3 110/3 90/24 90/12 110/12 110/12 110/24 110/24
85 70 88 52 48 37 48 15
