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Facile Access to 1,4-Disubstituted Pyrrolo[1,2-a]pyrazines from α-Aminoacetonitriles
Synthesis ( IF 2.2 ) Pub Date : 2019-10-01 , DOI: 10.1055/s-0039-1690699 Ananta Karmakar 1 , Sridharan Ramalingam 1 , Mushkin Basha 1 , Gopi Kumar Indasi 1 , Makonen Belema 2 , Nicholas A. Meanwell 2 , T. G. Murali Dhar 2 , Richard Rampulla 2 , Arvind Mathur 2 , Anuradha Gupta 1 , Arun Kumar Gupta 1
Synthesis ( IF 2.2 ) Pub Date : 2019-10-01 , DOI: 10.1055/s-0039-1690699 Ananta Karmakar 1 , Sridharan Ramalingam 1 , Mushkin Basha 1 , Gopi Kumar Indasi 1 , Makonen Belema 2 , Nicholas A. Meanwell 2 , T. G. Murali Dhar 2 , Richard Rampulla 2 , Arvind Mathur 2 , Anuradha Gupta 1 , Arun Kumar Gupta 1
Affiliation
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An efficient and practical synthetic protocol for the synthesis of 1,4-disubstituted pyrrolo[1,2-a]pyrazine derivatives is described that originates from α-substituted pyrroloacetonitriles which, in turn, are readily available from aryl and alkyl aldehydes. The α-pyrroloacetonitriles were subjected to a Friedel–Crafts acylation with methyl chlorooxoacetate followed by reduction of the nitrile group under Pd-catalyzed hydrogenation conditions and finally aromatization with DDQ leading to the desired pyrrolo[1,2-a]pyrazine derivatives. This method was generalized and successfully applied to various aryl, heteroaryl, and alkyl substrates. The developed protocol provides direct and convenient access to 1,4-disubstituted ring systems in moderate to good overall yields (51–68%) without the need for purification of the intermediates. Further functionalization via the stepwise halogenation (bromination, iodination) and nitration was also demonstrated. In addition, the potential of the ester functionality for elaboration was demonstrated by manipulating into heterocyclic ring systems, exemplified by conversion into benzoxazole derivatives.
中文翻译：
从α-氨基乙腈轻松获得1,4-二取代的吡咯并[1,2-a]吡嗪
描述了一种用于合成1，4-二取代的吡咯并[1,2- a ]吡嗪衍生物的有效且实用的合成方案，其源自α-取代的吡咯并乙腈，而α-取代的吡咯并乙腈可容易地从芳基和烷基醛获得。将α-吡咯乙腈与氯氧乙酸甲酯进行Friedel-Crafts酰化反应，然后在Pd催化的氢化条件下还原腈基，最后用DDQ进行芳构化，得到所需的吡咯并[1,2- a]吡嗪衍生物。该方法被普遍化并成功地应用于各种芳基，杂芳基和烷基底物。所开发的方案可直接且方便地以中等至良好的总收率（51–68％）访问1,4-二取代的环系统，而无需纯化中间体。还证明了通过逐步卤化（溴化，碘化）和硝化的进一步官能化。另外，通过操作成杂环系统证明了酯官能化的潜力，例如通过转化为苯并恶唑衍生物。
更新日期：2019-10-02
中文翻译：
从α-氨基乙腈轻松获得1,4-二取代的吡咯并[1,2-a]吡嗪
描述了一种用于合成1，4-二取代的吡咯并[1,2- a ]吡嗪衍生物的有效且实用的合成方案，其源自α-取代的吡咯并乙腈，而α-取代的吡咯并乙腈可容易地从芳基和烷基醛获得。将α-吡咯乙腈与氯氧乙酸甲酯进行Friedel-Crafts酰化反应，然后在Pd催化的氢化条件下还原腈基，最后用DDQ进行芳构化，得到所需的吡咯并[1,2- a]吡嗪衍生物。该方法被普遍化并成功地应用于各种芳基，杂芳基和烷基底物。所开发的方案可直接且方便地以中等至良好的总收率（51–68％）访问1,4-二取代的环系统，而无需纯化中间体。还证明了通过逐步卤化（溴化，碘化）和硝化的进一步官能化。另外，通过操作成杂环系统证明了酯官能化的潜力，例如通过转化为苯并恶唑衍生物。
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