Letter Cite This: Org. Lett. 2017, 19, 5677-5680
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One-Pot Synthesis of Indolizines via Sequential Rhodium-Catalyzed [2 + 1]-Cyclopropanation, Palladium-Catalyzed Ring Expansion, and Oxidation Reactions from Pyridotriazoles and 1,3-Dienes Hyunseok Kim,† Sanghyuck Kim,† Jiyeon Kim, Jeong-Yu Son, Yonghyeon Baek, Kyusik Um, and Phil Ho Lee* Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea S Supporting Information *
ABSTRACT: An efficient, one-pot synthetic method for producing functionalized indolizine derivatives was developed via a Rhcatalyzed [2 + 1]-cyclopropanation, Pd-catalyzed ring expansion, and subsequent oxidation using manganese dioxide from pyridotriazoles and 1,3-dienes.
D
functional group modifications on the indolizine core is highly desirable for structural and biological activity assessments. However, 3-(alkenyl)indolizine derivatives, a vital skeleton for building phosphoinositide 3-kinase inhibitors, have rarely been reported.13 In our continuing investigation into the synthesis of N-heterocyclic compounds using diazo compounds, triazoles, thiadiazoles, and pyridotriazoles,14 we developed a one-pot synthetic route to 3-(alkenyl)indolizine derivatives via sequential Rh-catalyzed [2 + 1]-cyclopropanation, Pd-catalyzed ring expansion, and oxidation reactions from pyridotriazoles and 1,3-dienes (Scheme 1). First, we examined the Rh-catalyzed cyclization of ethyl 7chloro-[1,2,3]triazolo[1,5-a]pyridine-3-carboxylate (1a) with (E)-buta-1,3-dienylbenzene [(E)-2a]. A wide range of catalysts including Rh2(esp)2, Rh2(OAc)4, Rh2(oct)4, Rh2(OPiv)4, Rh2(SDOSP)4, Rh2(S-PTAD)4, Rh2(pfb)4, Rh2(TFA)4, Rh2(TPA)4, and Cu(CH3CN)4PF6 and solvents including DCE, THF, and dioxane were screened [see the Supporting Information (SI)]. To our delight, the optimum conditions were discovered in the reaction of 1a (0.2 mmol, 1.0 equiv) with (E)-2a (1.5 equiv) using Rh2(oct)4 or Rh2(OPiv)4 (1.0 mol %) in DCE (1.0 mL) at 25 °C for 1 h, which produced 3a in a quantitative yield (Scheme 1, eq 1). It is noteworthy that the cyclopropanation proceeded smoothly under mild conditions. Surprisingly, cyclopropane 3a does not undergo further isomerization to the indolizine or dihydropyridoazepine under these conditions. Next, we attempted the preparation of dihydroindolizine via a ring expansion from 3a. A large number of Pd catalysts including
evelopment of synthetic methods for accessing a variety of functionalized N-heterocyclic compounds is a significant objective in the fields of organic and medicinal chemistry.1 Because indolizine derivatives containing nitrogens at their ring junction have been found in a number of natural products, pharmaceuticals, and bioactive compounds, the development of expeditious approaches for the construction and functionalization of indolizine derivatives has gained much attention.2 Current methods include the Tschitschibabin reaction,3 the Scholtz reaction,4 the cyclization of pyridines with alkenyldiazoacetates,5 dipolar cycloadditions of pyridinium and related heteroaromatic ylides with electron-deficient alkynes or alkenes,6 transition-metal-catalyzed cycloisomerizations of alkynylpyridine derivatives,7 and C−H functionalization reactions.8 Additionally, Gevorgyan and co-workers recently reported transitionmetal-catalyzed transannulation reactions using pyridotriazoles for the synthesis of indolizine derivatives (Scheme 1), which entail the Rh- or Cu-catalyzed rearrangement of 3-(2-pyridyl)cyclopropenes generated from pyridotriazoles and terminal alkynes in the presence of Rh2(S-DOSP)4 (pathways a, b, and c),9 Rh- or Cu-catalyzed transannulation reactions of pyridotriazoles with terminal alkynes (pathways d and e),10 or Cucatalyzed intramolecular transannulation reactions of pyridotriazoles with internal alkynes (pathway f).11 Among the current approaches to the synthesis of Nheterocyclic compounds, the preparation of functionalized Nheterocycles with analogous skeletons starting from identical reactants has many advantages, including the ability to efficiently establish a library to scrutinize and develop lead compounds.12 Because of its importance in synthetic chemistry, another method for the synthesis of indolizine derivatives that enables © 2017 American Chemical Society
Received: September 12, 2017 Published: October 9, 2017 5677
DOI: 10.1021/acs.orglett.7b02826 Org. Lett. 2017, 19, 5677−5680
Letter
Organic Letters
mixture was allowed to stir for another 2 h at 50 °C, and the reaction afforded the desired 4a in 84% yield (Scheme 2, eq 3). These results indicate that the catalytic amount of Rh remaining in the reaction mixture after the [2 + 1]-cyclopropanation step does not have a noticeable impact on the Pd-catalyzed ring expansion. Next, when 4a was treated with MnO2 (5 equiv) in DCE at 80 °C for 1 h, ethyl (E)-5-chloro-3-styrylindolizine-1carboxylate (5a) was smoothly produced in 87% yield (Scheme 2, eq 4). Finally, we attempted the direct synthesis of 5a via the one-pot three-step reaction starting from 1a and (E)-2a. To our delight, 5a was obtained in 75% yield via sequential one-pot Rhcatalyzed [2 + 1]-cyclopropanation, Pd-catalyzed ring expansion, and oxidation reactions (Scheme 2, eq 5).15 These results suggested that the oxidation of dihydroindolizine by MnO2 was not affected by any residual Rh and Pd catalysts. With the optimum reaction conditions in hand, we investigated the scope and limitations of the Rh-catalyzed [2 + 1]-cyclopropanation by screening a variety of substituents on the aryl group of (E)-2a in the reaction with pyridotriazole 1 (Table 1). When pyridotriazole 1a was reacted with 1,3-dienes having 4-
Scheme 1. Synthesis of Indolizine Derivatives via MetalCatalyzed Transannulations of Pyridotriazoles
Table 1. Substrate Scope of Pyridotriazoles and 1,3-Dienesa
entry
R1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Cl Cl Cl Cl Br H H H H H H H H H H H MeO
Pd(PPh3)4 and Pd2(dba)3CHCl3; ligands including Ph3P, (4MeO-C6H4)3P, (4-CF3-C6H4)3P, (C6F5)3P, (2-furyl)3P, DPEphos, Xantphos, DPPE, DPPP, and DPPF; and solvents including THF, dioxane, DMF, toluene, and DCE were examined. Gratifyingly, ring expansion occurred in the presence of Pd(PPh3)4 (4.0 mol %) in DCE (50 °C, 2 h) and gave 4a in 90% yield (see the SI) (Scheme 2, eq 2). With these results in hand, we attempted the direct synthesis of 4a starting from 1a and (E)-2a in one pot (Scheme 2, eq 3). After 1a was treated with Rh2(oct)4 (1.0 mol %) in DCE (1.0 mL) at 25 °C for 1 h, Pd(PPh3)4 (4.0 mol %) was added to the reaction mixture. The Scheme 2. Synthesis of Indolizinones in One Pot
1a
1b 1c
1d
R2
cyclopropane
yield (%)
Ph 4-Me-C6H4 4-MeO-C6H4 9-anthracenyl Ph Ph 2-Cl-C6H4 3,4-(Cl)2-C6H3 4-EtO2C-C6H4 4-CF3-C6H4 3-NO2-C6H4 4-NC-C6H4 2-naphthyl 9-anthracenyl Me n-hexyl Ph
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q
99 88b 85b 62b 77b 23,b 70,c 83d 64d 62d 79d 64d 69d 51d 44d 50e 50e 60e 0
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv) was reacted with (E)-2a (1.5 equiv) in the presence of Rh2(oct)4 (1.0 mol %) in DCE (2.0 mL) at 25 °C for 1 h under N2 unless otherwise noted. b(E)-2a (1.1 equiv) was used. c(E)-2a (1.5 equiv) was used at 130 °C for 0.5 h. d Rh2(OPiv)4 (1.0 mol %) and (E)-2a (2.0 equiv) were used at 130 °C for 0.5 h. eRh2(OPiv)4 (1.0 mol %) and (E)-2a (3.0 equiv) were used at 130 °C for 0.5 h.
methylphenyl or 4-methoxyphenyl groups, the desired products 3b and 3c were obtained in good yields (Table 1, entries 2 and 3). Anthracenyl-substituted 1,3-diene was reacted with 1a to give 3d in 62% yield (Table 1, entry 4). Bromo-substituted pyridotriazole 1b smoothly underwent Rh-catalyzed [2 + 1]-transannulation and produced 3e in 77% yield (Table 1, entry 5). Because 1c was less reactive than 1a and 1b, harsher conditions were required.9−11 When 1c (0.2 mmol, 1.0 equiv) was treated with (E)-2a (2.0 equiv) in the presence of Rh2(OPiv)4 (1.0 mol %) in DCE (2.0 mL) at 130 °C for 0.5 h under N2, Rh-catalyzed [2 + 5678
DOI: 10.1021/acs.orglett.7b02826 Org. Lett. 2017, 19, 5677−5680
Letter
Organic Letters
employed, the desired indolizine 5i was obtained in 61% yield (Table 2, entry 8). Alkyl-substituted cyclopropanes bearing methyl and n-hexyl groups were tolerated in the present transformation (Table 2, entries 9 and 10). On the basis of these results, the scope and limitations of substrates including pyridotriazoles 1 and 1,3-dienes (E)-2a were investigated for the one-pot synthesis of 5-chloro-3-(alkenyl)indolizine derivatives 5 via sequential Rh-catalyzed [2 + 1]cyclopropanation, Pd-catalyzed ring expansion, and oxidation reactions (Table 3). To demonstrate the utility of applying this
1]-cyclopropanation proceeded smoothly, providing cyclopropane 3f in 83% yield (Table 1, entry 6). Electronic modification of the substituents on the aryl ring of (E)-2a had an effect on the reaction efficiency. (E)-2a bearing electronwithdrawing groups including chloro, dichloro, ethoxycarbonyl, trifluoromethyl, nitro, and nitrile substituents on the aryl ring were well tolerated under the reaction conditions and afforded the corresponding cyclopropanes 3g−l in moderate to good yields ranging from 51% to 79% (Table 1, entries 7−12). Although lower reactivity was observed with 1,3-dienes bearing 2-naphthyl and 9-anthracenyl substituents, the yields were still synthetically acceptable (Table 1, entries 13 and 14, respectively). The structure of 3n was unambiguously determined by X-ray crystallography (see the SI). 1,3-Dienes having methyl and n-hexyl groups at the 1-position afforded the desired cyclopropanes 3o (50%) and 3p (60%) under slightly modified reaction conditions (Table 1, entries 15 and 16, respectively). Isomeric dihydroindolizines derived from cyclopropanes 3 via ring expansion were not observed at all. However, methoxy-substituted pyridotriazole 1d decomposed under the optimum conditions (Table 1, entry 17). The tolerance for the chloro and bromo substituents on pyridotriazole and 1,3-diene is especially useful, as they allow for synthetically useful catalytic cross-coupling reactions in later steps. Next, we examined the scope and limitations of the Pdcatalyzed ring expansion followed by oxidation using a wide range of cyclopropanes 3 generated from pyridotriazole and 1,3diene (Table 2). Treatment of cyclopropane 3f, which was
Table 3. Substrate Scope in One Pota
Table 2. Substrate Scope of Cyclopropanesa
entry
R
indolizine
yield (%)
1 2 3 4 5 6 7 8 9 10
C6H5 2-Cl-C6H4 3,4-(Cl)2-C6H3 4-EtO2C-C6H4 4-CF3-C6H4 3-NO2-C6H4 4-NC-C6H4 2-naphthyl Me n-hexyl
5b 5c 5d 5e 5f 5g 5h 5i 5j 5k
81 60 80 80 81 60 71 61 53 69
entry
R1
R2
R3
indolizine
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Et Me Et Et Et Et Et Et Et Et Et Et Et Et Et Et
H H 7-Me H H H H H H H H H H H H H
Ph Ph Ph 3-Me-C6H4 2-Cl-C6H4 4-Cl-C6H4 3,4-(Cl)2-C6H3 3-Br-C6H4 4-EtO2C-C6H4 4-CF3-C6H4 3-NO2-C6H4 2-naphthyl 4-Ph-C6H4 Me n-hexyl CO2Et
5a 5l 5m 5n 5o 5p 5q 5r 5s 5t 5u 5v 5w 5x 5y 5z
75 (61)b 72 62 62 62 70 67 73 60 63 59 58 68 60 75 42
a Reaction conditions: 1 (0.2 mmol, 1.0 equiv) was reacted with (E)-2a (1.1 equiv) in the presence of Rh2(oct)4 (1.0 mol %) in DCE (2.0 mL) under N2 at 25 °C for 1 h, and then Pd(PPh3)4 (4.0 mol %) in DCE (1.0 mL) was added to the reaction mixture, which was then stirred at 50 °C for 2 h. Finally, MnO2 (5.0 equiv) was added to the reaction mixture, which was then stirred at 80 °C for 1 h. b1a (1.0 g, 4.43 mmol) was used.
method on a larger scale, 1.0 g (4.43 mmol) of 1a was reacted with (E)-2a under the optimum conditions to afford the desired indolizine 5a (0.88 g, 2.70 mmol) in 61% yield via a three-step one-pot reaction, and the yield is comparable to that obtained in the small-scale experiment (Table 3, entry 1). Likewise, the methoxycarbony-substituted pyridotrazole was converted to the corresponding dolizine 5l in 72% yield (Table 3, entry 2). The present method worked equally well with the methyl-substituted pyridotriazole and provided 5m in 62% yield (Table 3, entry 3). Next, a large number of 1,3-diene (E)-2a derivatives were tested in the one-pot three-step reaction involving sequential Rhcatalyzed [2 + 1]-cyclopropanation, Pd-catalyzed ring expansion, and oxidation reactions. Electronic variations of the substituents on the aryl ring of (E)-2a did not affect the reaction efficiency. 1,3-Dienes with an electron-donating methyl group on the phenyl ring turned out to be compatible with the reaction conditions (Table 3, entry 4). Electron-withdrawing chloro and bromo substituents were tolerated on the substituted aryl ring, thus enabling further transformations (Table 3, entries 5−8). We were pleased to obtain the corresponding indolizines from (E)2a with ethoxycarbonyl, trifluoromethyl, and nitro groups (Table
a 3 (0.2 mmol) in DCE (1.0 mL) was treated with Pd(PPh3)4 (4.0 mol %) at 50 °C for 1 h followed by MnO2 (5.0 equiv) at 80 °C for 1 h.
obtained from pyridotrazole 1c and 1,3-diene (E)-2a, with Pd(PPh3)4 (4.0 mol %) in DCE at 50 °C for 1 h followed by MnO2 (5.0 equiv) at 80 °C for 1 h gave rise to ethyl (E)-3styrylindolizine-1-carboxylate (5b) in 81% yield (Table 2, entry 1). Electronic variation of the substituents on the aryl ring of cyclopropane 3 had little effect on the reaction efficiency. Cyclopropanes 3 bearing electron-withdrawing groups including chloro, dichloro, ethoxycarbonyl, trifluoromethyl, nitro, and nitrile substituents on the aryl ring were smoothly converted to ethyl (E)-3-alkenylindolizine-1-carboxylates 5 in good yields varying from 60% to 81% (Table 2, entries 2−7). The structure of 5e was unambiguously determined by X-ray crystallography (see the SI). When 2-naphthyl-substituted cyclopropane 3i was 5679
DOI: 10.1021/acs.orglett.7b02826 Org. Lett. 2017, 19, 5677−5680
Letter
Organic Letters Author Contributions
3, entries 9−11). 2-Naphthyl- and biaryl-substituted 1,3-dienes were well tolerated in the three-step one-pot reaction and afforded 5v and 5w in 58% and 68% yields, respectively (Table 3, entries 12 and 13). 1-Alkyl-substituted-1,3-dienes work equally well and produced 5x (60%) and 5y (75%) (Table 3, entries 14 and 15). Although ethyl (E)-penta-2,4-dienoate was less reactive than alkyl- and aryl-substituted 1,3-dienes, the desired indolizine 5z was obtained in an acceptable yield (Table 3, entry 16).16,17 Indolizine 5a with a chloro substituent at the 5-position opened the possibility for further functionalization for accessing diverse indolizine derivatives (6, 7, and 8) (Scheme 3). The
†
H.K. and S.K. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grant, funded by the Korean government (20110018355 and 2015H1C1A1035955) and BRL (2017R1A4A1015405).
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Scheme 3. Further Derivatization of 5-Chloroindolizine 5a
Suzuki reaction of 5a with 4-methylphenyl and 4-chlorophenylboronic acid provided the corresponding 5-aryl-substituted indolizines 6a and 6b in 87% and 92% yields, respectively. Treatment of 5a with 2-bromophenylboronic acid in the presence of Pd(PPh3)4 (5.0 mol %) and Na2CO3 produced indolizinoisoquinoline 7 in 66% yield via a Pd-catalyzed intermolecular Suzuki reaction followed by an intramolecular Heck reaction.18 When indolizine 5a was reacted with phenylacetylene under Sonogashira reaction conditions [PdCl2(PPh3)2, CuI, and Et3N], the alkynylated indolizine 8a was obtained in 93% yield. In summary, an efficient synthetic method for producing functionalized indolizine derivatives from pyridotriazoles and 1,3-dienes was developed via one-pot sequential Rh-catalyzed [2 + 1]-cyclopropanation, Pd-catalyzed ring expansion, and oxidation reactions using MnO2.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02826. Crystallographic data for 3n (CIF) Crystallographic data for 5e (CIF) Experimental procedures, characterization data, and copies of the NMR spectra for all products (PDF)
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
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Phil Ho Lee: 0000-0001-8377-1107 5680
DOI: 10.1021/acs.orglett.7b02826 Org. Lett. 2017, 19, 5677−5680
