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Synlett 2022(6): 0858-0860
DOI: 10.1055/s-2003-38734
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot Synthesis of Dihydropyrimidinones Using Iodotrimethylsilane. Facile and New Improved Protocol for the Biginelli Reaction at Room Temperature [1]

Gowravaram Sabitha*, G. S. Kiran Kumar Reddy, Ch. Srinivas Reddy, J. S. Yadav
Organic Chemical Sciences, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax: +91(40)27160512; e-Mail: sabitha@iict.ap.nic.in;

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Publication History

Received 19 December 2002
Publication Date:
17 April 2003 (online)

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Abstract

A novel one pot condensation of an aldehyde, β-ketoester and urea has been performed using TMSI in acetonitrile for the first time at room temperature affording dihydropyrimidinones in excellent yields.

Key words

Biginelli reaction - dihydropyrimidinones - iodotrimethyl silane - one-pot condensation - room temperature

Dihydropyrimidinones have emerged as the integral backbones of calcium channel blockers, [2] antihypertensive agents, [3] α-adrenergic [4] and neuropeptide Y (NPY) antagonists. [5] Several marine alkaloids containing the dihydropyrimidine core unit have shown interesting biological properties. [6] In particular, batzelladine alkaloids have been found to be potent HIV gp-120-CD4 inhibitors. [7] In addition, these compounds exhibit a broad range of biological activities [8] such as antiviral, antitumor, antibacterial and antiinflammatory properties. Therefore, the synthesis of this heterocyclic nucleus has gained a great importance in organic synthesis. A simple and direct method, reported by Biginelli [9] in 1893, involves the one-pot condensation of an aldehyde, a β-ketoester and urea or thiourea under strongly acidic conditions. However this protocol often suffers from low yields particularly in case of substituted aromatic or aliphatic aldehydes. [10] This has led to the disclosure of multi-step strategies [11] that produce somewhat higher yields but lack the simplicity of the original Biginelli one-pot synthesis. Thus, Biginelli’s reaction for the synthesis of dihydropyrimidinones has received renewed interest and as a result, several improved procedures [12] have recently been reported including various solid-phase modifications suitable for combinatorial chemistry. Many reported one-pot protocols normally require prolonged reaction times and high temperatures with moderate yields. In spite of a large number of methods reported for this transformation, there has been considerable interest to explore more milder, rapid and high yielding protocol at ambient temperature.

Iodotrimethylsilane with remarkable reactivity as a ‘hard-soft’ reagent has been known for a wide spectrum of synthetic applications. [13] In continuation of our interest [14] on the use of this reagent, herein we report a novel, highly efficient Biginelli reaction for the synthesis of dihydropyrimidinones in excellent yields using iodotrimethylsiane (TMSI) (in situ generated from chlorotrimethylsilane and sodium iodide) in acetonitrile for the first time at ambient temperature (Scheme [1] ).

Scheme 1

This is a novel one-pot condensation that not only preserves the simplicity of Biginelli’s one-pot reaction but also consistently produces excellent yields of the dihydropyrimidin-2-(1H)-ones. Thus, the addition of TMSCl to a mixture of benzaldehyde, β-ketoester, urea and sodium iodide in acetonitrile at room temperature resulted in the formation of corresponding dihydropyrimidinone 4a in a yield of 98%. [15] The reaction was spontaneous, the product precipitating immediately from the reaction medium and complete conversion being achieved within 30 minutes as monitored by TLC. Under similar conditions various substituted aromatic aldehydes were reacted with β-ketoesters, urea and converted into dihydropyrimidinones within 30-50 minutes in excellent yields with high purity. In the presence of an electron withdrawing group such as nitro, reaction longer but a high yield of product was observed in 1 hour. Aromatic aldehydes carrying electron donating substituents (entry 4e, 4o) also produced good yields of dihydropyrimidinones and thus pharmacologically relevant substitution patterns on the 4-aryl group can be introduced efficiently. Aliphatic aldehydes such as isobutanal and hexanal also reacted well with β-dicarbonyl compounds, and urea in the presence of iodotrimethylsilane, giving the corresponding dihydropyrimidinones in good yields. Such aldehydes normally show extremely poor yields in the Biginelli reaction. [16] This shows that aliphatic aldehydes exhibit analogues behavior to that of aromatic aldehydes. Several examples illustrating this novel, rapid procedure for the synthesis of dihydropyrimidinones are listed in Table [1] . Thiourea has been used with similar success to provide the corresponding dihydropyrimidin-2(1H)thiones (entry 4k and 4l) which are also of much interest with regard to biological activity. [8] In all cases, the products were obtained in pure form by simple filtration from the reaction mixture, followed by washing with 20% EtOAc in hexane. The trimethylchlorosilane-DMFA [17] system has been reported by Kulikova et al. for the synthesis of dihydropyrimidinones. However this method requires the use of more than a stoichiometric amount (2.3 equivalents) of reagent, with longer reaction times (14 h), cumbersome work-up followed by column chromatography purification using MeOH as solvent. In addition to this, it suffers from low yields (32-37%) with aliphatic aldehydes. In contrast, using our conditions, not only were the yields significantly raised and the reaction time shortened but also the products could be isolated by simple filtration from the reaction mixture. Moreover, according to original Russian report using TMSCl-DMFA system, urea was added after 12 hours, to a stirred mixture of acetoacetic ester, aldehyde and TMSCl in DMF and stirred further for another two hours. Therefore it is assumed that the benzylidene acetoacetate may be formed first by Knoevenagel reaction of acetoacetate with aldehyde before the addition of urea. Compared to this report, the three-component one-pot reaction proceeds smoothly and very fast under present reaction conditions to give the corresponding dihydropyrimidinones in high yield. Furthermore, the results showed that besides ethyl acetoacetate, acetylacetone can also be used as one of the substrates (entry 4n and 4o). Another important aspect of this procedure is survival of a variety of functional groups such as -NO2, -Cl, -OMe and conjugated double bond under present reaction conditions. The reagents employed for this process are inexpensive and anhydrous conditions were not required for the reaction, leading to the possibility of performing the reactions at large scale. All the reactions were very fast, clean and high yielding under extremely mild conditions using 0.8 equivalents of TMSCl and 0.8 equivalents of NaI at room temperature. However, in the absence of NaI, the reaction did not yield the desired product.

Table 1 TMSI-Mediated Efficient Synthesis of Dihydropyrimidinonesa
Product R R1 R2 X Time (min) Yield (%)b
4a C6H5 Me OEt O 30 98 (80)c
4b 2-NO2C6H4 Me OEt O 60 90
4c 4-NO2C6H4 Me OEt O 60 86
4d 4-MeC6H4 Me OEt O 45 89
4e 4-OMeC6H4 Me OEt O 40 90
4f 4-ClC6H4 Me OEt O 30 92
4g 2-Naphthyl Me OEt O 30 84
4h

Me OEt O 45 87
4i (CH3)2-CH Me OEt O 40 86
4j Hexyl Me OEt O 45 84 (37)c
4k C6H5 Me OEt S 30 90
4l 2-NO2C6H4 Me OEt S 60 85
4m 2-MeC6H4 Me Me O 45 90
4n 2-NO2C6H4 Me Me O 60 86
4o 4-OMeC6H4 Me Me O 40 90
4p Cinnamyl Me OEt O 45 85
4q C6H5 Ph OEt O 40 83
4r C6H5 Me Me O 50 85 (62)c
6a C6H5 - - O 45 88
6b 4-OMeC6H4 - - O 50 85
a All products were characterized by IR, 1H NMR spectroscopy and their mps compared with literature melting points.
b Isolated yields.
c Yields in parenthesis refer to the reported (TMSCl-DMFA system) method. [17]

Scheme 2

It is noteworthy that when ethyl trifluoroacetoacetate was used as the β-ketoester in this synthesis, the hexahydropyrimidine (Scheme [2] ), considered to be the intermediate in the Biginelli reaction, was isolated in high yield and characterized (entry 6a and 6b).

In conclusion, we have discovered a new, efficient and seemingly general method for the synthesis of Biginelli dihydropyrimidinones using in situ generated iodotrimethylsilane at room temperature. The salient features of the present one-pot protocol are simplicity, high yields, and direct isolation of products at room temperature in pure form.

Acknowledgment

GSKK thank CSIR, and ChSR thank UGC, New Delhi for the award of fellowships.

1

IICT Communication No. 01/10/03.

15

One-Pot Synthesis of Dihydropyrimidinone. Typical Procedure: TMSCl (8 mmol) was added to a stirred mixture of benzaldehyde (10 mmol), β-ketoester (10 mmol), urea (12 mmol), and NaI (8 mmol) in MeCN at r.t. Immediately the solid product precipitated out and the reaction was complete in 30 min as monitored by TLC. The precipitate was filtered and the product was washed with 20% EtOAc in hexane to give pure dihydropyrimidinone 4a in 98% yield. Spectral data for selected compounds. 4b: Mp 205-206 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.00 (t, 3 H, J = 8.0 Hz), 2.40 (s, 3 H), 3.90 (q, 2 H, J = 8.0 Hz), 5.80 (sd, 1 H, J = 3.0 Hz), 6.42 (br s, NH), 7.38-7.68 (m, 3 H, ArH), 7.82 (d, 1 H, J = 8.5 Hz, ArH), 9.20 (br s, NH). IR (KBr): 1592, 1652, 1705, 1720, 2983, 3238 cm-1. 4h: Mp 207-208 °C. 1H NMR (200 MHz, CDCl3): δ = 1.20 (t, 3 H, J = 8.5 Hz), 2.25 (s, 3 H), 4.10 (q, 2 H, J = 8.5 Hz), 5.55 (sd, 1 H, J = 3.5 Hz), 6.80-7.00 (m, 2 H, ArH), 7.10 (m, 1 H), 7.40 (br s, NH), 9.00 (br s, NH). IR (KBr): 1695, 1715, 3240 cm-1. 4i: Mp 195-196 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.75 (d, 3 H, J = 6.2 Hz), 0.90 (d, 3 H, J = 6.2 Hz), 1.25 (t, 3 H, J = 7.0 Hz), 1.75 (m, 1 H), 2.25 (s, 3 H), 4.0 (t, 1 H, J = 3.5 Hz), 4.05 (q, 2 H, J = 8.5 Hz), 7.0 (br s, NH), 8.80 (br s, NH).
IR (KBr): 1650, 1700, 3109, 3245 cm-1. 4k: Mp 206-207 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.15 (t, 3 H, J = 7.0 Hz), 2.30 (s, 3 H), 4.05 (q, 2 H, J = 7.0 Hz), 5.22 (sd, 1 H, J = 3.5 Hz), 7.25 (m, 4 H, ArH), 7.70 (s, 1 H), 9.30 (br s, NH), 9.95 (br s, NH). IR (KBr): 1585, 1672, 3100, 3185, 3338 cm-1. 6a: Mp 161-163 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 0.90 (t, J = 7.1 Hz, 3 H), 2.99 (d, J = 10.7 Hz, 1 H), 3.85 (q, J = 7.1 Hz, 1 H), 4.85 (d, J = 10.7 Hz, 1 H), 6.95 (br s, NH), 7.15 (br s, NH). IR (KBr): 1685, 1710, 3200, 3450 cm-1.

1

IICT Communication No. 01/10/03.

15

One-Pot Synthesis of Dihydropyrimidinone. Typical Procedure: TMSCl (8 mmol) was added to a stirred mixture of benzaldehyde (10 mmol), β-ketoester (10 mmol), urea (12 mmol), and NaI (8 mmol) in MeCN at r.t. Immediately the solid product precipitated out and the reaction was complete in 30 min as monitored by TLC. The precipitate was filtered and the product was washed with 20% EtOAc in hexane to give pure dihydropyrimidinone 4a in 98% yield. Spectral data for selected compounds. 4b: Mp 205-206 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.00 (t, 3 H, J = 8.0 Hz), 2.40 (s, 3 H), 3.90 (q, 2 H, J = 8.0 Hz), 5.80 (sd, 1 H, J = 3.0 Hz), 6.42 (br s, NH), 7.38-7.68 (m, 3 H, ArH), 7.82 (d, 1 H, J = 8.5 Hz, ArH), 9.20 (br s, NH). IR (KBr): 1592, 1652, 1705, 1720, 2983, 3238 cm-1. 4h: Mp 207-208 °C. 1H NMR (200 MHz, CDCl3): δ = 1.20 (t, 3 H, J = 8.5 Hz), 2.25 (s, 3 H), 4.10 (q, 2 H, J = 8.5 Hz), 5.55 (sd, 1 H, J = 3.5 Hz), 6.80-7.00 (m, 2 H, ArH), 7.10 (m, 1 H), 7.40 (br s, NH), 9.00 (br s, NH). IR (KBr): 1695, 1715, 3240 cm-1. 4i: Mp 195-196 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 0.75 (d, 3 H, J = 6.2 Hz), 0.90 (d, 3 H, J = 6.2 Hz), 1.25 (t, 3 H, J = 7.0 Hz), 1.75 (m, 1 H), 2.25 (s, 3 H), 4.0 (t, 1 H, J = 3.5 Hz), 4.05 (q, 2 H, J = 8.5 Hz), 7.0 (br s, NH), 8.80 (br s, NH).
IR (KBr): 1650, 1700, 3109, 3245 cm-1. 4k: Mp 206-207 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 1.15 (t, 3 H, J = 7.0 Hz), 2.30 (s, 3 H), 4.05 (q, 2 H, J = 7.0 Hz), 5.22 (sd, 1 H, J = 3.5 Hz), 7.25 (m, 4 H, ArH), 7.70 (s, 1 H), 9.30 (br s, NH), 9.95 (br s, NH). IR (KBr): 1585, 1672, 3100, 3185, 3338 cm-1. 6a: Mp 161-163 °C. 1H NMR (200 MHz, DMSO-d 6): δ = 0.90 (t, J = 7.1 Hz, 3 H), 2.99 (d, J = 10.7 Hz, 1 H), 3.85 (q, J = 7.1 Hz, 1 H), 4.85 (d, J = 10.7 Hz, 1 H), 6.95 (br s, NH), 7.15 (br s, NH). IR (KBr): 1685, 1710, 3200, 3450 cm-1.

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Scheme 1

Scheme 2