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Amides

Phthalimide

Heterocyclic Compounds

Microwave Assisted Thionation of Amides, Phthalimide, and Heterocyclic Compounds

¹Sydney Grandison; ¹Nicolle Rodriquez; ²Sebastian Lidwin; ³Esther Visingardi

Mentor: ¹Colleen Evans PhD

¹Dominican University New York, ²Bergen Community College, ³Rockland Community College

Introduction

Conclusions

Results

Sulfur containing compounds are exceedingly important in the field of medicinal chemistry and successfully employing a novel thionating substrate, 2,4,6-tris(methoxyphenyl)-1,3,5,2,4,6-trioxatripphosphinane-2,4,6-trisulfide (TMPT, 2), to thionate carbonyl functional groups in amides, phthalimide, and heterocyclic compounds, will provide another tool for synthetic chemists to expand chemical structure diversity that may be of biological or pharmaceutical molecular interest.

Figure 1. Refluxing of Lawesson's reagent (1) to produce TMPT

1 2

Under conventional methods, the long reaction times required for the thionation of amides, phthalimide, and heterocyclic may lead to product degradation.

Table 1. Conventional thionation reactions in toluene at 110℃

To avoid the lengthy reaction times under normal conditions, the use of a microwave to accelerate the times was utilized.

Figure 2. CEM Discover 2.0 Microwave

Synthesizer

Microwave synthesizers have various advantages compared to conventional methods. Microwaves can speed up reaction rates, rapidly and uniformly heat substances, save energy, lower cost of procedure/operation and higher product yields.
Regarding the results using amide substrates, all the above advantages were observed in their respective production, excluding benzamide. Benzamide had a higher percent yield using conventional methods rather than the microwave synthesizer. There are various adjustments that can be applied to benzamide to improve the percent yield using a microwave, such as reaction work up and purification process.
For the heterocyclic compounds used in this research, saccharin and uracil, microwave synthesis significantly improved the product yield and solubility of them compared to conventional methods.
It should be noted that research concerning the thionation of saccharin, phthalimide, and uracil using a microwave is still in progress.

Future Directions

Methods and Materials

Standard. To a glass vessel for the microwave synthesizer, add the reagent, TMPT, solvent, magnetic stir bar and pressure relief cap. Add the vessel to the microwave synthesizer for a set amount of time and temperature. Cool the mixture to 50℃ and purify the product using chromatography on silica gel, eluting with EtOAc/ hexanes (Rf ≈ 0.2) and evaporating under reduced pressure to isolate the product.

We plan to continue the studies of thiosaccharin, uracil and phthalimide in order to establish optimal reaction conditions. As well as to confirm the isolated product by NMR.
Examine thionation conditions of other substrate that have biological importance such as 3,3-dimethylglutarimide, Benzhydroxamic acid, Creatinine and Hypoxanthine
Optimize the reaction conditions and work up for thiobenzamide in order to increase yield.
We plan to study the synthesis, purification, and stability of TMPT with the goal in mind to produce multigram quantities for future studies.

Acknowledgements

The 2022 summer undergraduate research program is supported by the SOHLIS Project which is funded by a HSI Department of Education grant awarded to Dominican University.

We would also like thank Dominican University for their support of the Forkel Hall Chemistry Lab where all the work was conducted.

Many thanks for Dr. Dean Olson of University of Illinois NMR center for providing spectral data for our compounds.

Substrate	TMPT (equiv.)	Time (min.)	Yield (%)
Benzamide, 3	0.33	360	73
N,N-Dimethyl Benzamide, 4	0.33	960	63
2-Pyrrolidinone, 5	0.50	4320	60
1-Methyl-2-Pyrrolidinone, 6	0.66	270	100
ε-Caprolactam, 7	0.50	300	69
Phthalimide, 8	1.00	900	25
Saccharin, 9	0.66	480	N.R.
Uracil, 10	0.66	480	N.R.

Substrate	Time (min.)	Yield (%)
Phthalimide*, 8	10	42

Substrate	Time (min.)	Yield (%)
Saccharin**, 9	15	**
Uracil, 10	10	66

Substrate	Time (min.)	Yield (%)
Benzamide, 3	15	41
N,N-Dimethyl Benzamide, 4	15	87
2-Pyrrolidinone, 5	10	89
1-Methyl-2-Pyrrolidinone, 6	15	100
ε-Caprolactam, 7	15	77

Table 2. Microwave assisted thionation of simple amides in toluene at

170℃ with TMPT (0.66 eq.)

Table 3. Microwave assisted thionation of Phthalimide in acetonitrile at

140℃ with TMPT (0.66 eq.)

Table 4. Microwave assisted thionation of heterocyclic compounds in acetonitrile at 140℃ with TMPT (0.66 eq.)

Figure 6. Thiouracil ¹³C NMR (left) and ¹H NMR (right)

Figure 5. Thiophthalimide ¹³C NMR (left) and ¹H NMR (right)

Figure 3. N-Methyl-2-Thiopyrrolidinone ¹³C NMR (left) and ¹H NMR (right)

Figure 4. ε-Thiocaprolactam ¹³C NMR (left) and ¹H NMR (right)

*1 TMPT (0.66eq) and Toluene were used at 170 C for 15 minutes. Light-pink chunks

*2 TMPT (0.66eq) and Acetonitrile were used at 140 C for 10 minutes. Light pink crystals. In TLC & NMR showed monosubstituted product.

*3 TMPT (0.66eq) and Acetonitrile were used at 140 C for 15 minutes. Dark amber solution

*4 TMPT(1eq) and Acetonitrile were used at 140 C for 15 minutes. Dark red/orange solution that in TLC showed disubstituted product.

Microwave Synthesizer Discover 2.0. (2020). CEM. Retrieved July 7, 2022, from https://cem.com/media/contenttype/media/2016_products/discover-2-product-image.png.

**1 15 min. at 140℃. TLC analysis proved that it did not produce sufficient product and left starting material.

**2 20 min. at 140 ℃. Trial 2 offered similar results to trial 1.

**3 20 min. at 150℃. Mixture produced a higher concentration of product and reduced the amount of TMPT and starting material (observed with TLC analysis).

SOLHIS Summer 2022 Undergraduate Research

Researchers (left to right)

Sebastian Lidwin

Esther Visingardi

Nicolle Rodriguez

Sydney Grandison