1. Introduction
The modern field of green chemistry seeks to reduce or eliminate the use and generation of hazardous substances in chemical processes. A key strategy within this domain is solvent-free synthesis, which significantly reduces environmental waste and improves the safety and efficiency of chemical reactions.
Octahydroquinazolinones are an important class of fused heterocycles, known for their wide range of pharmacological activities including antimicrobial, anti-inflammatory, antihypertensive, anticonvulsant, and anticancer properties. Conventional synthesis routes typically rely on strong acids or metal catalysts, organic solvents, and energy-intensive heating processes.
Grindstone chemistry, or mechanochemistry, involves the physical grinding of reactants to facilitate reactions. It has emerged as a viable, eco-friendly method that not only improves yields but also avoids the use of harmful solvents or catalysts. Inspired by these advantages, we report a simple, efficient, and entirely green procedure for synthesizing octahydroquinazolinones via a one-pot, three-component grinding reaction using aromatic aldehydes, dimedone, and urea.
2. Materials and Methods
2.1. Chemicals and Reagents
All reagents and solvents used were of analytical grade and purchased from Sigma-Aldrich or Merck:
- Dimedone (5,5-dimethyl-1,3-cyclohexanedione)
- Urea
- Aromatic aldehydes (benzaldehyde and substituted derivatives)
2.2. Equipment
- Mortar and pestle (porcelain)
- Thin-layer chromatography (TLC) plates (silica gel)
- Melting point apparatus
- FT-IR spectrometer (Shimadzu)
- NMR Spectrometer (Bruker 400 MHz)
- Mass Spectrometer (ESI-MS)
2.3. General Procedure for the Synthesis of Octahydroquinazolinones
- Reactants:
- Aromatic aldehyde (1 mmol)
- Dimedone (1 mmol)
- Urea (1.2 mmol)
- Procedure:
- The solid reactants were introduced into a mortar and ground thoroughly for 10–15 minutes at room temperature.
- The reaction progress was monitored via TLC.
- After completion, the product was washed with cold water to remove unreacted urea.
- The crude solid was recrystallized from ethanol to obtain pure octahydroquinazolinone.
2.4. Characterization
- IR Spectroscopy (KBr): To confirm functional groups.
- ¹H NMR (400 MHz, DMSO-d₆): To identify hydrogen environments.
- ¹³C NMR (100 MHz, DMSO-d₆): To confirm carbon framework.
- Mass Spectrometry (ESI-MS): To verify molecular weight.
3. Results and Discussion
3.1. Reaction Optimization
Initial trials were conducted with benzaldehyde as the model aldehyde. The optimal reaction conditions were determined by varying:
- Molar ratios (1:1:1, 1:1:1.2, 1:1:1.5)
- Grinding time (5–20 min)
Best yield (91%) was achieved using a 1:1:1.2 molar ratio of benzaldehyde, dimedone, and urea, ground for 15 minutes at room temperature.
3.2. Substrate Scope
Various aromatic aldehydes were evaluated under optimized conditions. Both electron-donating and electron-withdrawing substituents were well tolerated.
Table 1. Synthesized Octahydroquinazolinone Derivatives
| Entry | Aldehyde | Product Code | Yield (%) | Mp (°C) |
|---|---|---|---|---|
| 1 | Benzaldehyde | 3a | 91 | 204–206 |
| 2 | 4-Nitrobenzaldehyde | 3b | 95 | 215–217 |
| 3 | 4-Chlorobenzaldehyde | 3c | 93 | 211–213 |
| 4 | 4-Methoxybenzaldehyde | 3d | 88 | 208–210 |
| 5 | 3,4-Dichlorobenzaldehyde | 3e | 90 | 218–220 |
3.3. Spectral Data (Representative Compound 3a)
FT-IR (KBr, cm⁻¹):
- 3350 (N–H stretching)
- 1685 (C=O stretching, lactam)
- 1620 (C=N)
- 1230 (C–N stretching)
- 755 (aromatic C–H bending)
¹H NMR (400 MHz, DMSO-d₆):
- δ 1.01 (s, 6H, CH₃ ×2 on dimedone)
- δ 2.05–2.40 (m, 4H, CH₂ dimedone)
- δ 4.35 (s, 1H, CH–N)
- δ 5.60 (s, 2H, NH₂)
- δ 6.95–7.45 (m, 5H, Ar–H)
- δ 8.25 (s, 1H, NH)
¹³C NMR (100 MHz, DMSO-d₆):
- δ 28.4, 33.1 (CH₂)
- δ 41.5 (C–N)
- δ 54.2 (tertiary C)
- δ 115.4–130.2 (aromatic C)
- δ 158.1 (C=N)
- δ 164.8 (C=O)
ESI-MS (m/z):
- Found: 261 [M+H]+
- Calculated for C13H17N3O2: 260.3 g/mol
3.4. Mechanistic Insight
A proposed mechanism involves:
- Knoevenagel condensation between aldehyde and dimedone.
- Michael addition of urea to the α,β-unsaturated intermediate.
- Intramolecular cyclization forming the fused octahydroquinazolinone ring.
The mechanical energy during grinding facilitates molecular collisions and energy transfer, eliminating the need for external heating or catalysts.
3.5. Green Chemistry Evaluation
- Solvent-free: Eliminates hazardous solvents.
- Catalyst-free: No toxic metals or acid/base catalysts.
- Energy-efficient: Room temperature reaction.
- Atom economy: High; most atoms from reactants are incorporated.
- E-factor: Very low; only aqueous waste generated.
4. Conclusion
We have successfully demonstrated a green, sustainable, and operationally simple method for synthesizing octahydroquinazolinones using solvent-free and catalyst-free grindstone chemistry. This one-pot, three-component reaction requires no special apparatus, yields excellent product purity and quantity, and eliminates environmental hazards. Its scalability, low cost, and eco-friendliness position this methodology as an attractive alternative for industrial and pharmaceutical applications.
5. References
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- Khurana, J. M., & Nand, B. (2011). One-pot synthesis of octahydroquinazolinones under solvent-free conditions. Tetrahedron Letters, 52(18), 2300–2302.
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