Reaction of diphenylcyclopropenone with N-acylamidine derivatives. Synthetic and mechanistic implications

Article

Reaction of Diphenylcyclopropenone with N-Acylamidine Derivatives. Synthetic and Mechanistic Implications

Silvio Cunha ^* and Albert Kascheres

Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970, Campinas - SP, Brazil

A reatividade de ciclopropenonas frente a derivados de N-acilamidinas foi investigada. Difenilciclopropenona reagiu com N-benzoilacetamidina e com N-(metoxicarbonil)benzamidina formando 1,2-diidro-3H-pirrol-3-onas em rendimentos moderados, porém alquilfenilciclopropenonas não reagiram com os mesmos nucleófilos investigados. A teoria dos orbitais moleculares de fronteira foi empregada para racionalizar a formação dos produtos.

In this work, the reactivity of cyclopropenones toward N-acylamidine derivatives was investigated. Diphenylcyclopropenone reacted with N-benzoylacetamidine and N-(methoxycarbonyl)benzamidine affording 1,2-dihydro-3H-pyrrol-3-ones in moderate yields. However, alkylphenylcyclopropenone did not react. The formation of the compounds is examined mechanistically within frontier molecular orbital considerations.

Keywords: diphenylcyclopropenone, N-acylamidines, 1,2-dihydro-3H-pyrrol-3-ones

Introduction

Over the past four decades, the fascinating chemistry of cyclopropenones has attracted considerable attention both in utilization as a synthetic building block¹ and as rare naturally occurring compounds². Our systematic interest in the use of cyclopropenone chemistry in the construction of a wide variety of heterocycles³ prompted us to study the behavior of cyclopropenones towards N-acylamidine derivatives. Additionally, N-acylamidines can be envisioned as enaminone aza analogs (an "aza-enaminone"). Enaminones are versatile nucleophiles toward diphenyl-cyclopropenone (1) in the synthesis of nitrogen-containing compounds, Scheme 1^3a,d,h. Because of the ambiphilic and ambident proprieties of cyclopropenones, the reactions of this class of compound with nucleophiles is a complex matter^1b-c. Herein we present our results of the reactions of cyclopropenones with N-acylamidine derivatives with emphasis on synthetic and mechanistic implications.

Results and Discussion

Diphenylcyclopropenone (1) reacted smoothly with N-benzoylacetamidine (5) in benzene under reflux. An insoluble, crystalline solid was isolated, and this material was a 1:1 adduct as indicated by mass spectrum and NMR integration. The NMR spectrum contained two low field N-H protons (D₂O exchangeable) as sharp signals which suggests their participation in intramolecular hydrogen bonding. Moreover, the IR spectrum which showed an intense carbonyl absorption at 1640 cm^-1, ruled out the formation of a 1,5-dihydro-2H-pyrrol-2-one nucleus analogous to 2^3h, for which this absorption appears at 1695-1700 cm^-1. To accommodate these spectral features structure 6 (Scheme 2) was proposed in agreement with the carbonyl absorption (1638-1650 cm^-1) of some model 1,2-dihydro-3H-pyrrol-3-ones⁴.

The structure 6 was corroborated by analysis of a long-range heterocorrelation (COLOC) spectrum of derivative 7. This showed a correlation (³J) of the carbonyl C-4 with the methyl group at C-5 as well as the other correlations indicated in structure 7 (Scheme 2) in agreement with the regiochemistry assigned to 6. No such correlations would be observed if a 1,5-dihydro-2H-pyrrol-2-one analogous to 2 had formed.

This reaction proved to be very sensitive to substitution both in the cyclopropenone and in the "aza-enaminone". While diphenylcyclopropenone reacted with N-(methoxycarbonyl)benzamidine (8) to afford 9 in good yield, it failed to react with derivatives 10 and 11 under the conditions employed (Scheme 2). In addition, compounds 5 and 8 did not react with methylphenyl-cyclopropenone and isopropylphenylcyclopropenone, showing that formation of the 1,2-dihydro-3H-pyrrol-3-one nucleus is effective only with 1 (1 is more reactive towards nucleophiles than are alkylphenylcyclo-propenones because it has the lower-lying LUMO⁵).

Recently, we demonstrated that reactivity of cyclopropenones can be rationalized by a frontier orbital approach in combination with the hardness-softness concept⁵. The results of AM1⁶ calculations, as implemented in the SPARTAN 4.0 package⁷, are show in Scheme 3. Thus, it would appear that reaction of 1 is kinetically favored for the tautomeric forms of 5 and 8, wherein the terminal imine nitrogen has the largest HOMO coefficient. A slow and irreversible attack at the phenyl-C of 1 followed by an electrocyclic five-membered ring formation results in the regiochemistry observed for compounds 6 and 9.

The present study complements the reported^3h formation of the dihydropyrrolone nucleus from diphenylcyclopropenone and enaminones, furnishing a convenient route to 1,2-dihydro-3H-pyrrol-3-one derivatives and expands the frontier of utilization of cyclopropenones as synthetic building blocks for densely substituted heterocyclic compounds.

Experimental

Melting points were determined on a Hoover-Unimelt apparatus and are uncorrected. Infrared spectra were recorded as KBr discs on a Perkin Elmer FT-IR 1600 instrument. NMR spectra were obtained for ¹H at 300 MHz and for ¹³C at 75 MHz using a Varian Gemini 300 or a Bruker AC300P spectrometer. Chemical shifts are reported in d (ppm) units downfield from reference. HRMS were obtained on a Fisions VG Autospec. N-benzoyl-acetamidine⁸, N-(methoxycarbonyl)benzamidine⁹ and diphenylcyclopropenone¹⁰ were prepared according to known procedures.

Reaction of N-benzoylacetamidine (5) with 1: a solution of 206,5mg (1mmol) of diphenylcyclopropenone (1) and 173,8mg (1mmol) of N-benzoylacetamidine (5) in 10cm³ of benzene was heated at reflux with stirring for 1 day (the solution turned yellow and a precipitate began to form after 30 min.), after which time the reaction mixture was cooled at room temperature, petroleum ether was added and allowed to cool in the freezer (-25ºC). The solution was decanted from 6 (lemon yellow crystals, 115.1mg, 41% yield), mp 240-242ºC. IR (KBr): n_max/cm^-1 3283, 1670, 1640, 1602. ¹H NMR (DMSO-D₆): 1.54 (s, 3H), 7.15-7.20 (m, 5H), 7.42-7.55 (m, 8H); 7.88-7.91 (d, ³J 1.5Hz, 2H); 8.31 (s, 1H); 8.90 (s, 1H). ¹³C NMR (DMSO-D₆): 23.7 (CH₃), 72.1 (C), 107.6 (C), 125.1 (CH), 127.7 (CH), 127.8 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 130.8 (CH), 131.6 (CH), 132.0 (C), 133.3 (C), 133.6 (C), 165.0 (C), 168.5 (C), 198.1 (C). EM, m/z (%): 369 (M⁺ +1; 1.3%), 368 (M⁺, 13%), 235 (44%), 178 (100%), 105 (74%), 77 (81%).

Methylation of 6: To a solution of 6 (55.7mg, 0.15mmol) in 1cm³ of dimethyl sulfoxide was added approximately 170mg (3.04mmol) of powdered potassium hydroxide. The yellow solution turned dark orange, and 0.3cm³ (2.2mmol) of methyl iodide was added. The reaction mixture was left stirring for 1h, after which time water (20cm³) was added and the solution was extracted with methylene chloride (5 X 10cm³). The organic layer was washed with water (6 X 10cm³), dried over anhydrous potassium carbonate, filtered, and the solvent was evaporated. The residue was purified by column chromatography (Florisil^Ò, hexane/ethyl acetate 50% as eluant) to afford 7 (38mg, 63% yield) as a colorless solid, mp 128-130ºC (with decomposition). IR (KBr): n_max/cm^-1 1700, 1649. ¹H NMR (CDCl₃): 1.78 (s, 3H), 2.92 (s, 3H), 3.14 (s, 3H), 6.97-7.16 (m, 5H), 7.16-7.54 (m, 10H). ¹³C NMR (CDCl₃): 20.7 (CH₃), 29.1 (CH₃), 35.6 (CH₃), 79.5 (C), 109.6 (C), 125.0 (CH), 127.5 (CH), 127.7 (CH), 128.3 (CH), 128.5 (CH), 128.9 (CH), 129.9 (CH), 130.2 (CH), 131.0 (C), 132.3 (C), 136.4 (C), 170.9 (C), 172.6 (C), 198.0 (C). HRMS m/z 396.1838 (396.1838 calculated for C₂₆H₂₄N₂O₂ ).

Reaction of N-(methoxycarbonyl)bezamidine (8) with 1: A solution of 103,5mg (0,5mmol) of diphenylcyclo-propenone (1) and 91,1mg (0,5mmol) of N-(methoxy-carbonyl)benzamidina (8) in 10cm³ of acetonitrile was heated at reflux for 2 days. After this time, the reaction mixture was concentrated to half volume under reduced pressure, and the solution allowed to cool in the freezer (-25ºC). The solid that formed was separated from the solvent and was recrystallized from CH₂Cl₂/hexane affording 114.6mg (60% yield) of 9 as a lemon yellow solid, mp 227-229ºC (with decomposition). IR (KBr): n_max/cm^-1 3322, 3259, 1707, 1661. ¹H NMR (DMSO-D₆): 3.37 (s, 3H), 7.03-7.14 (m, 5H), 7.31-7.61 (m, 10H), 8.33 (sl, 1H), 9.06 (s, 1H). ¹³C NMR (DMSO-D₆): 51.6 (CH₃), 76.0 (C), 105.7 (C), 125.3 (CH), 126.1 (CH), 127.9 (CH), 128.3 (C), 128.5 (CH), 128.6 (CH), 128.8 (CH), 131.2 (CH), 131.4 (C), 132.9 (C), 137.4 (C), 155.4 (C), 171.7 (C), 195.9 (C). HRMS m/z 384.1473 (384.1474 calculated for C₂₄H₂₀N₂O₃ ).

Acknowledgments

The authors thank the Conselho Nacional de Densenvolvimento Científico e Tecnológico (CNPq) for a fellowship to SC.

References

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Received: November 17, 2000

Published on the web: April 23, 2001

FAPESP helped in meeting the publication costs of this article.

Publication Dates

• Publication in this collection
  17 Oct 2001
• Date of issue
  Aug 2001

History

• Received
  17 Nov 2000