Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives

Nilesh Bhaurao Chavhan; Shivraj Balajirao Sirsat; Anilkumar Govindrao Jadhav; Sainath Laxman Shinde; Suresh Sadanand Ardhapure; Ajay Dashrath Munde

doi:doi:10.11648/j.sjc.20251306.12

Research Article |

Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives

Nilesh Bhaurao Chavhan, Shivraj Balajirao Sirsat^*, Anilkumar Govindrao Jadhav, Sainath Laxman Shinde, Suresh Sadanand Ardhapure, Ajay Dashrath Munde

Published in Science Journal of Chemistry (Volume 13, Issue 6)

Received: 29 September 2025 Accepted: 23 October 2025 Published: 22 November 2025

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Abstract

In this study, we report a novel and efficient synthetic strategy for the construction of a fused bicyclic heterocyclic system with promising potential in medicinal chemistry. The synthesis begins with the reaction of ethyl bis(methylthio)methylene malononitrile with guanidine nitrate in the presence of potassium carbonate as a base, using dimethylformamide (DMF) as the solvent under reflux conditions. This reaction furnishes 2-amino-1,6-dihydro-6-imino-4-(methylthio)pyrimidine-5-carbonitrile as a key intermediate. Subsequent treatment of this intermediate with acetylacetone under acidic conditions initiates a Michael addition followed by a Robinson annulation, leading to intramolecular cyclization. This tandem sequence proceeds smoothly to afford the target compound, 4-imino-6,8-dimethyl-2-(methylthio)-4H-pyrimido[1,2-a]pyrimidine-3-carbonitrile in excellent yield. The synthesized compound was characterized by various spectroscopic techniques including IR, NMR, and mass spectrometry confirming its proposed structure. Notably, the target molecule contains a replaceable methylthio (-SCH₃) group at the 2-position making it a versatile precursor for further functionalization. The reactivity of this compound was explored through its reactions with different nucleophiles, such as substituted aromatic amines, aromatic phenols, heterocyclic amines, and active methylene compounds to afford a series of novel derivatives in good to excellent yields. Overall, this synthetic approach offers a convenient, efficient, and versatile route to access pyrimido[1,2-a]pyrimidine scaffolds which are of significant interest for the development of bioactive and pharmacologically relevant molecules.

Published in	Science Journal of Chemistry (Volume 13, Issue 6)
DOI	10.11648/j.sjc.20251306.12
Page(s)	179-184
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2025. Published by Science Publishing Group

Keywords

Guanidine Nitrate, Acetyl Acetone, Aromatic Amines, Phenols, MICHAEL Addition and Robinson Annulations

References

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[12]	Ram V. J., Goel A., Sarkhel S., Maulik P. R. A convenient synthesis and hepatoprotective activity of Imidazo [1, 2_c] pyrimido [5, 4_e] pyrimidine, tetraazaacenaphthene and tetraazaphenalene from cyclic ketene aminals through tandem addition cyclization reactions Bioorg. Med. Chem. 2002. (10) 1280.
[13]	Domling A. Isocyanide based multicomponent reactions in combinatorial chemistry Combinatorial Chemistry & High Throughput Screening. 1998. (1) 22.
[14]	Ugi I., Domling A., Gruber B., Almstetter M. Multicomponent reactions and their libraries a new approach to preparative organic chemistry Croatica Chem. Acta. — 1997. (70) 647. (b) Armstrong R., Combs A., Tempest P., Brown D. Keating T. Multiplecomponent condensation strategies for combinatorial library synthesis Acct. Chem. Res. 1996. (29) 131.
[15]	Yarim M., Sarac S., Kilic F. S., Erol K. I. Synthesis and in vitro calcium antagonist activity of 4_aryl_7,7_ dimethyl/1, 7, 7_trimethyl_1, 2, 3, 4, 5, 6, 7, 8_octahydro_quinazoline_2, 5_dione derivatives // Farmaco. — 2003. (58) 24.
[16]	Byk G., Gettlieb H. E., Herscovici J. Mirkin F. J. New regioselective multicomponent reaction: one pot synthesis of spiro heterobicyclic aliphatic rings Comb. Chem. 2000.(2) 735.
[17]	Shaabani A., Bazgir A. Microwave_assisted efficient synthesis of spiro_fused heterocycles under solvent_free conditions Tetrahedron Lett. 2004. (45) 2577.

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APA Style

Chavhan, N. B., Sirsat, S. B., Jadhav, A. G., Shinde, S. L., Ardhapure, S. S., et al. (2025). Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives. Science Journal of Chemistry, 13(6), 179-184. https://doi.org/10.11648/j.sjc.20251306.12

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ACS Style

Chavhan, N. B.; Sirsat, S. B.; Jadhav, A. G.; Shinde, S. L.; Ardhapure, S. S., et al. Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives. Sci. J. Chem. 2025, 13(6), 179-184. doi: 10.11648/j.sjc.20251306.12

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AMA Style

Chavhan NB, Sirsat SB, Jadhav AG, Shinde SL, Ardhapure SS, et al. Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives. Sci J Chem. 2025;13(6):179-184. doi: 10.11648/j.sjc.20251306.12

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@article{10.11648/j.sjc.20251306.12,
  author = {Nilesh Bhaurao Chavhan and Shivraj Balajirao Sirsat and Anilkumar Govindrao Jadhav and Sainath Laxman Shinde and Suresh Sadanand Ardhapure and Ajay Dashrath Munde},
  title = {Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives
},
  journal = {Science Journal of Chemistry},
  volume = {13},
  number = {6},
  pages = {179-184},
  doi = {10.11648/j.sjc.20251306.12},
  url = {https://doi.org/10.11648/j.sjc.20251306.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.sjc.20251306.12},
  abstract = {In this study, we report a novel and efficient synthetic strategy for the construction of a fused bicyclic heterocyclic system with promising potential in medicinal chemistry. The synthesis begins with the reaction of ethyl bis(methylthio)methylene malononitrile with guanidine nitrate in the presence of potassium carbonate as a base, using dimethylformamide (DMF) as the solvent under reflux conditions. This reaction furnishes 2-amino-1,6-dihydro-6-imino-4-(methylthio)pyrimidine-5-carbonitrile as a key intermediate. Subsequent treatment of this intermediate with acetylacetone under acidic conditions initiates a Michael addition followed by a Robinson annulation, leading to intramolecular cyclization. This tandem sequence proceeds smoothly to afford the target compound, 4-imino-6,8-dimethyl-2-(methylthio)-4H-pyrimido[1,2-a]pyrimidine-3-carbonitrile in excellent yield. The synthesized compound was characterized by various spectroscopic techniques including IR, NMR, and mass spectrometry confirming its proposed structure. Notably, the target molecule contains a replaceable methylthio (-SCH₃) group at the 2-position making it a versatile precursor for further functionalization. The reactivity of this compound was explored through its reactions with different nucleophiles, such as substituted aromatic amines, aromatic phenols, heterocyclic amines, and active methylene compounds to afford a series of novel derivatives in good to excellent yields. Overall, this synthetic approach offers a convenient, efficient, and versatile route to access pyrimido[1,2-a]pyrimidine scaffolds which are of significant interest for the development of bioactive and pharmacologically relevant molecules.
},
 year = {2025}
}

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TY  - JOUR
T1  - Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives

AU  - Nilesh Bhaurao Chavhan
AU  - Shivraj Balajirao Sirsat
AU  - Anilkumar Govindrao Jadhav
AU  - Sainath Laxman Shinde
AU  - Suresh Sadanand Ardhapure
AU  - Ajay Dashrath Munde
Y1  - 2025/11/22
PY  - 2025
N1  - https://doi.org/10.11648/j.sjc.20251306.12
DO  - 10.11648/j.sjc.20251306.12
T2  - Science Journal of Chemistry
JF  - Science Journal of Chemistry
JO  - Science Journal of Chemistry
SP  - 179
EP  - 184
PB  - Science Publishing Group
SN  - 2330-099X
UR  - https://doi.org/10.11648/j.sjc.20251306.12
AB  - In this study, we report a novel and efficient synthetic strategy for the construction of a fused bicyclic heterocyclic system with promising potential in medicinal chemistry. The synthesis begins with the reaction of ethyl bis(methylthio)methylene malononitrile with guanidine nitrate in the presence of potassium carbonate as a base, using dimethylformamide (DMF) as the solvent under reflux conditions. This reaction furnishes 2-amino-1,6-dihydro-6-imino-4-(methylthio)pyrimidine-5-carbonitrile as a key intermediate. Subsequent treatment of this intermediate with acetylacetone under acidic conditions initiates a Michael addition followed by a Robinson annulation, leading to intramolecular cyclization. This tandem sequence proceeds smoothly to afford the target compound, 4-imino-6,8-dimethyl-2-(methylthio)-4H-pyrimido[1,2-a]pyrimidine-3-carbonitrile in excellent yield. The synthesized compound was characterized by various spectroscopic techniques including IR, NMR, and mass spectrometry confirming its proposed structure. Notably, the target molecule contains a replaceable methylthio (-SCH₃) group at the 2-position making it a versatile precursor for further functionalization. The reactivity of this compound was explored through its reactions with different nucleophiles, such as substituted aromatic amines, aromatic phenols, heterocyclic amines, and active methylene compounds to afford a series of novel derivatives in good to excellent yields. Overall, this synthetic approach offers a convenient, efficient, and versatile route to access pyrimido[1,2-a]pyrimidine scaffolds which are of significant interest for the development of bioactive and pharmacologically relevant molecules.

VL  - 13
IS  - 6
ER  -

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Author Information

Nilesh Bhaurao Chavhan

Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, India
Shivraj Balajirao Sirsat

Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, India

Contact Email
Anilkumar Govindrao Jadhav

Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, India
Sainath Laxman Shinde

Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, India
Suresh Sadanand Ardhapure

Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, India
Ajay Dashrath Munde

Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, India

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Plain Text BibTeX RIS

APA Style

Chavhan, N. B., Sirsat, S. B., Jadhav, A. G., Shinde, S. L., Ardhapure, S. S., et al. (2025). Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives. Science Journal of Chemistry, 13(6), 179-184. https://doi.org/10.11648/j.sjc.20251306.12

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ACS Style

Chavhan, N. B.; Sirsat, S. B.; Jadhav, A. G.; Shinde, S. L.; Ardhapure, S. S., et al. Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives. Sci. J. Chem. 2025, 13(6), 179-184. doi: 10.11648/j.sjc.20251306.12

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AMA Style

Chavhan NB, Sirsat SB, Jadhav AG, Shinde SL, Ardhapure SS, et al. Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives. Sci J Chem. 2025;13(6):179-184. doi: 10.11648/j.sjc.20251306.12

Copy | Download

@article{10.11648/j.sjc.20251306.12,
  author = {Nilesh Bhaurao Chavhan and Shivraj Balajirao Sirsat and Anilkumar Govindrao Jadhav and Sainath Laxman Shinde and Suresh Sadanand Ardhapure and Ajay Dashrath Munde},
  title = {Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives
},
  journal = {Science Journal of Chemistry},
  volume = {13},
  number = {6},
  pages = {179-184},
  doi = {10.11648/j.sjc.20251306.12},
  url = {https://doi.org/10.11648/j.sjc.20251306.12},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.sjc.20251306.12},
  abstract = {In this study, we report a novel and efficient synthetic strategy for the construction of a fused bicyclic heterocyclic system with promising potential in medicinal chemistry. The synthesis begins with the reaction of ethyl bis(methylthio)methylene malononitrile with guanidine nitrate in the presence of potassium carbonate as a base, using dimethylformamide (DMF) as the solvent under reflux conditions. This reaction furnishes 2-amino-1,6-dihydro-6-imino-4-(methylthio)pyrimidine-5-carbonitrile as a key intermediate. Subsequent treatment of this intermediate with acetylacetone under acidic conditions initiates a Michael addition followed by a Robinson annulation, leading to intramolecular cyclization. This tandem sequence proceeds smoothly to afford the target compound, 4-imino-6,8-dimethyl-2-(methylthio)-4H-pyrimido[1,2-a]pyrimidine-3-carbonitrile in excellent yield. The synthesized compound was characterized by various spectroscopic techniques including IR, NMR, and mass spectrometry confirming its proposed structure. Notably, the target molecule contains a replaceable methylthio (-SCH₃) group at the 2-position making it a versatile precursor for further functionalization. The reactivity of this compound was explored through its reactions with different nucleophiles, such as substituted aromatic amines, aromatic phenols, heterocyclic amines, and active methylene compounds to afford a series of novel derivatives in good to excellent yields. Overall, this synthetic approach offers a convenient, efficient, and versatile route to access pyrimido[1,2-a]pyrimidine scaffolds which are of significant interest for the development of bioactive and pharmacologically relevant molecules.
},
 year = {2025}
}

Copy | Download

TY  - JOUR
T1  - Synthesis of Novel 4-Imino-6,8-Dimethyl-2-(Methylthio)-4H-Pyrimido [1, 2-A] Pyrimidine-3-Carbonitrile and its 2- Substituted Derivatives

AU  - Nilesh Bhaurao Chavhan
AU  - Shivraj Balajirao Sirsat
AU  - Anilkumar Govindrao Jadhav
AU  - Sainath Laxman Shinde
AU  - Suresh Sadanand Ardhapure
AU  - Ajay Dashrath Munde
Y1  - 2025/11/22
PY  - 2025
N1  - https://doi.org/10.11648/j.sjc.20251306.12
DO  - 10.11648/j.sjc.20251306.12
T2  - Science Journal of Chemistry
JF  - Science Journal of Chemistry
JO  - Science Journal of Chemistry
SP  - 179
EP  - 184
PB  - Science Publishing Group
SN  - 2330-099X
UR  - https://doi.org/10.11648/j.sjc.20251306.12
AB  - In this study, we report a novel and efficient synthetic strategy for the construction of a fused bicyclic heterocyclic system with promising potential in medicinal chemistry. The synthesis begins with the reaction of ethyl bis(methylthio)methylene malononitrile with guanidine nitrate in the presence of potassium carbonate as a base, using dimethylformamide (DMF) as the solvent under reflux conditions. This reaction furnishes 2-amino-1,6-dihydro-6-imino-4-(methylthio)pyrimidine-5-carbonitrile as a key intermediate. Subsequent treatment of this intermediate with acetylacetone under acidic conditions initiates a Michael addition followed by a Robinson annulation, leading to intramolecular cyclization. This tandem sequence proceeds smoothly to afford the target compound, 4-imino-6,8-dimethyl-2-(methylthio)-4H-pyrimido[1,2-a]pyrimidine-3-carbonitrile in excellent yield. The synthesized compound was characterized by various spectroscopic techniques including IR, NMR, and mass spectrometry confirming its proposed structure. Notably, the target molecule contains a replaceable methylthio (-SCH₃) group at the 2-position making it a versatile precursor for further functionalization. The reactivity of this compound was explored through its reactions with different nucleophiles, such as substituted aromatic amines, aromatic phenols, heterocyclic amines, and active methylene compounds to afford a series of novel derivatives in good to excellent yields. Overall, this synthetic approach offers a convenient, efficient, and versatile route to access pyrimido[1,2-a]pyrimidine scaffolds which are of significant interest for the development of bioactive and pharmacologically relevant molecules.

VL  - 13
IS  - 6
ER  -

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