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Master's Dissertation
DOI
Document
Author
Full name
Mônica Franco Zannini Junqueira Amaral
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2010
Supervisor
Committee
Stefani, Helio Alexandre (President)
Guadagnin, Rafael Carlos
Omori, Alvaro Takeo
Title in Portuguese
Funcionalização de 2-(S)-isopropil-pirimidinonas através de reações de Suzuki-Miyaura, Sonogashira e cicloadição azida-acetileno: síntese de derivados triazólicos e precursores de β-aminoácidos
Keywords in Portuguese
β-Aminoácidos
Organotrifluoroboratos
Pirimidinonas
Química farmacêutica
Suzuki-Miyaura
Triazóis
Abstract in Portuguese
Nesta monografia foram desenvolvidas metodologias sintéticas para a funcionalização das 2-(S)-isopropil-5-iodo-pirimidinonas, utilizando a reação de acoplamento cruzado de Suzuki-Miyaura e a reação de cicloadição azida-acetileno com cobre, através de estratégias simples e eficientes que permitiram a preparação de uma série de compostos com grande diversidade estrutural. Inicialmente descreve-se a síntese da 2-(S)-isopropil-5-iodo-pirimidinona (S)- 3, a partir da (S)-asparagina enantiomericamente pura 1, um aminoácido barato e de fácil acesso, produzindo na primeira etapa o 2-(S)-isopropil-peridropirimidinona-6- ácido carboxílico (2S,6S)-2, que reagindo com diacetoxiiodo benzeno/iodo e BF3.OEt2, gera a pirimidinona (S)-3. Em seguida, preparou-se uma série de 2-(S)-isopropil-5-aril-pirimidinonas (S)- 6a-q e 2-(S)-isopropil-5-alquinil-pirimidinonas (S)-7a-q, através da reação de acoplamento cruzado de Suzuki-Miyaura, sob catálise de paládio, utilizando aril- (4aq) e alquiniltrifluoroboratos de potássio (5a-q), respectivamente. Desta forma sintetizou-se uma variedade de pirimidinonas com alterações programadas de substituintes na posição 5 do anel, com rendimentos de 15% a 95%. Ainda a fim de obter algumas pirimidinonas com substituintes acetilênicos alquílicos 9a-f, utilizou-se a metodologia de acoplamento de Sonogashira. Em todos os casos obtiveram-se bons rendimentos. Dando sequência ao projeto, sintetizou-se as 2-(S)-isopropil-pirimidinonas funcionalizadas na posição C5 com anéis triazólicos substituídos na posição N1 (S)- 11a-k, através da reação de cicloadição azida-acetileno utilizando CuI como fonte de cobre e ondas ultra-sônicas como fonte de energia. Preparou-se diversos compostos, todos com rendimentos variando de 79% a 87% em 5 minutos de reação. Por último, através da redução da dupla ligação endocíclica dos compostos (S)-6a, 6b, 6g, 6l e 6n e posterior hidrólise utilizando radiação microondas proporcionou a obtenção de α-aril β-aminoácidos altamente enantioenriquecidos.
Title in English
Functionalization of 2-(S)-isopropyl pyrimidinones through reactions Suzuki-Miyaura, Sonogashira and azideacetylene cycloaddition: synthesis of triazole derivatives and precursors of β-amino acids
Keywords in English
β-Amino acids
Chemical pharmaceutical
Organotrifluoroborates
Pyrimidinone
Suzuki-Miyaura
Triazole
Abstract in English
This monograph shows the development of a synthetic methodology for the functionalization of 2-(S)-isopropyl-5-iodo-pyrimidinones using either Suzuki-Miyaura cross-coupling reactions or cycloaddition reactions of azide-acetylenes with copper, through a simple and efficient pathway enabling the preparation of a series of structurally diverse compounds. This paper begins by describing the synthesis of 2-(S)-isopropyl-5-iodopyrimidinones (S)-3, from enantiomerically pure (S)-asparagine 1. This inexpensive and readily available amino acid forms 2-(S)-isopropyl-perhidropyrimidinone-6- carboxylic acid (2S, 6S)-2, which is reacted with DIB / iodine and BF3·OEt2 to form pyrimidinone (S)-3. Using palladium-catalyzed Suzuki-Miyaura cross-coupling reactions, a series of 2-(S)-isopropyl-5-arylpyrimidinones (S)-6a-q and 2-(S)-isopropyl-5- alkynylpyrimidinones (S)-7a-q were prepared using potassium aryl- (4a-q) and alkynyltrifluoroborates (5a-q), respectively. With this reaction, a variety of pyrimidinones with different substituents at position 5 of the ring were synthesized, with yields ranging from 15% to 95%. The Sonogashira coupling reaction was used to prepare pyrimidinones with alkyl acetylenic substituents (S)-9a-f, giving good yields in all cases. 2-(S)-Isopropylpyrimidinones were then functionalized in the C5 position with N1 (S)-11a-k substituted triazole rings. These functionalizations were performed by the cycloaddition of azide-acetylenes using CuI and ultrasonic waves, which provided enough energy to reduce the reaction time to only five minutes. Several different variations of this compound were prepared, all with yields between 78% and 87%. Finally, the endocyclic double bonds in compounds (S)-6a, 6b, 6g, 6l and 6n were reduced, followed by a hydrolysis using microwave radiation to afford the highly enantioenriched α-aryl β-amino acids.
 
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MonicaAmaral.pdf (5.98 Mbytes)
Publishing Date
2011-06-17
 
WARNING: The material described below relates to works resulting from this thesis or dissertation. The contents of these works are the author's responsibility.
  • Caracelli, Ignez, et al. 1-Benzoyl-5-phenyl-2-(propan-2-yl)-1,2,3,4-tetrahydropyrimidin-4-one [doi:10.1107/S1600536809036356]. Acta Crystallographica. Section E [online], 2009, vol. 65, p. o2466-o2466.
  • Gueogjian, Kemilla, et al. ?-Arylation and Alkynylation of Cyclic ?-Iodoenones Using Palladium-Catalyzed Cross-Coupling Reactions with Trifluoroborate Salts [doi:10.1055/s-0029-1218580]. Synlett (Stuttgart) [online], 2010, vol. 2010, p. 427-432.
  • Singh, Fateh V., Amaral, Mônica F.Z.J., and Stefani, Hélio A. Synthesis of symmetrical 1,3-diynes via homocoupling reaction of n-butyl alkynyltellurides [doi:10.1016/j.tetlet.2009.03.078]. Tetrahedron Letters [online], 2009, vol. 50, p. 2636-2639.
  • Stefani, Hélio A., et al. Functionalization of 2-(S)-isopropyl-5-iodo-pyrimidin-4-ones through Cu(I)-mediated 1,3-dipolar azide alkyne cycloadditions [doi:10.1016/j.tetlet.2011.10.011]. Tetrahedron Letters [online], 2011, vol. 52, p. 6883-6886.
  • Stefani, Hélio A., et al. Synthesis of 5-alkynyl-2,2,6-trimethyl-1,3-dioxin-4-ones and 1,4-disubstituted-1,2,3-triazoles [doi:10.1016/j.tetlet.2011.04.072]. Tetrahedron Letters [online], 2011, vol. 52, p. 4256-4261.
  • Stefani, Hélio A., Amaral, Monica F.Z.J., and Juaristi, Eusebio. Synthesis of (2S)-isopropyl-5-alkynylpyrimidin-2-ones: precursors of ?-aminoacids [doi:10.1016/j.tetlet.2010.12.087]. Tetrahedron Letters [online], 2011, vol. 52, p. 1014-1019.
  • Fernando P. Ferreira, et al. Adição Nucleofílica estereoseletiva de alquiltrifluoroboratos de potássio a íons N-acilimínio cíclicos. Síntese de 5-alquil-pirroldin-2-onas quirais. In 32a. Reunião Anual da Sociedade Brasileira de Química, Fortaleza, Ceará, 2009. Adição Nucleofílica estereoseletiva de alquiltrifluoroboratos de potássio a íons N-acilimínio cíclicos. Síntese de 5-alquil-pirroldin-2-onas quirais., 2009. Resumo.
  • SINGH, F. V., et al. Synthesis of symmetrical 1,3-diynes via homocoupling reaction of n-butyl alkynyl tellurides. In 11th International Conference on the Chemistry of Selenium and Tellurium, Oulu, 2010. Synthesis of symmetrical 1,3-diynes via homocoupling reaction of n-butyl alkynyl tellurides., 2010. Abstract.
  • SINGH, F. V., Amaral, Mônica F. Z. J., e STEFANI, H. A. Synthesis of symmetrical 1,3-diynes via homocoupling reaction of n-butyl alkynyltellurides. In 13th Brazilian Meeting on Organic Synthesis, São Pedro, 2009. Synthesis of symmetrical 1,3-diynes via homocoupling reaction of n-butyl alkynyltellurides., 2009. Resumo.
  • VIEIRA, A. S., et al. Reação de acoplamento de Suzuki-Miyaura de sais de potássio de ariltrifluoroboratos com 5-iodo-1,3-dioxin-4-ona em meio aquoso. In 32a. Reunião Anual da Sociedade Brasileira de Química, Fortaleza, Ceará, 2009. Reação de acoplamento de Suzuki-Miyaura de sais de potássio de ariltrifluoroboratos com 5-iodo-1,3-dioxin-4-ona em meio aquoso., 2009. Resumo.
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