An Efficient Multicomponent Synthesis of Polysubstituted Pyrrolidines and Tetrahydropyrimidines Starting Directly from Nitro Compounds in Water [¹]

Abstract

A distinct approach for the synthesis of 1,3,3-trisubstituted 4,5-dioxopyrrolidines and 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines has been discovered, in the form of a three-component reaction of nitroarenes, formaldehyde, and dialkyl acetylenedicarboxylates using indium in dilute aqueous HCl at room temperature. The molar ratios of these substrates are 1:1:4 and 2:1:4 for the preparation of dioxopyrrolidines and tetrahydropyrimidines, respectively. The reactions involve the reduction of nitro compounds to amines, which are simultaneously attacked by dialkyl acetylenedicarboxylates and formaldehyde. The products are formed in good to high yields.

Pyrrolidines and pyrimidines are considered as important biologically active heterocycles. The former exhibit anticancer, antibacterial, and antifungal properties [²] while the latter antiviral, anti-inflammatory, and muscarinic agonist activities. [³] Tetrahydropyrimidines are also responsible for salt and heat sensitivity of protein-DNA interactions. [4] Dioxopyrrolidines and tetrahydropyrimidines can be prepared by multicomponent reactions [5] of anilines, formaldehyde, and alkynoates, but the methods involving these reactions are limited. [6] Moreover, high temperature, long reaction time, and the exchange of the functional groups of the alkynoates with the solvents are the problems in different earlier methods. Another point to mention is that the 4,5-dioxopyrrolidine derivatives prepared by Cao et al. was initially considered [6a] as 3,6-dihydro-1,3-oxazines and very recently their structures have been revised [6b] through X-ray crystallographic analysis. Here, we report a distinct approach for the synthesis of 4,5-di­oxopyrrolidine and tetrahydropyrimidine derivatives starting directly from the nitro compounds.

In continuation of our work [7] on the development of useful synthetic methodologies using aqueous medium, we have discovered that 1,3,3-trisubstituted 4,5-dioxopyrrolidines and 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines can be synthesized efficiently through the three-component reactions of nitroarenes, dialkyl acetylenedicarboxylates, and formaldehyde using indium in dilute aqueous HCl at room temperature. 4,5-Dioxopyrrolidine derivatives were formed using a molar ratio of 1:1:4 of these substrates, while tetrahydropyrimidines were produced when this ratio was 2:1:4 (Scheme  [¹] ).

Initially, nitrobenzene (1 mmol) was treated with dimethyl acetylenedicarboxylate (DMAD, 1 mmol) and formaldehyde (4 mmol) using different metals such as Sn, Zn, In, and Fe in aqueous HCl at room temperature (Table  [¹] ).

Considering the reaction time and yield, indium [8] was found to be most effective to carry out this conversion. Subsequently indium/aqueous HCl system was used to prepare a series of 1,3,3-trisubstituted 4,5-dioxopyrrolidines (Table  [²] ) following the above method (Scheme  [¹] ). Various nitroarenes were used to prepare these compounds. Both dimethyl and diethyl acetylenedicarboxylates afforded the desired products smoothly. The 4,5-dioxopyrrolidine derivatives were formed in good to high yields (65-76%) within 30-40 minutes. The reaction conditions were mild and various functionalities such as hydroxy, ether, and halogen remained intact.

When the reaction of nitroarenes (2 mmol), dialkyl acetylenedicarboxylates (1 mmol) and formaldehyde (4 mmol) was conducted under similar conditions as applied for the preparation of pyrrolidine derivatives (Scheme  [¹] ), 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines were obtained within 30-40 minutes (Table  [³] ).

In this case also various nitrobenzenes having different functionalities and both dimethyl and diethyl acetylenecarboxylates were used. The yields of the products were good to high (64-72%). The structures of dioxopyrrolidines and tetrahydropyrimidines were settled from their spectral (IR, ^¹H and ^¹³C NMR, ESIMS and HRESIMS) data.

In the present conversions, nitro compounds were initially reduced to amines, [9] which then reacted with dialkyl acetylenedicarboxylates and formaldehyde to form the desired heterocycles (Scheme  [²] ).

In conclusion, we have developed a novel efficient method for the synthesis of polysubstituted 4,5- dioxopyrrolidines and tetrahydropyrimidine derivatives through a distinct approach involving the multicomponent reaction of nitro compounds, dialkyl acetylenedicarboxylates, and formaldehyde using indium in dilute aqueous HCl at room temperature. The direct application of nitro compounds, conversion in water, and mild reaction conditions are the advantages of the present method.

The silica gel F₂₅₄ plates were used for TLC in which the spots were examined under UV light and then developed by I₂ vapor. Column chromatography was performed with silica gel (BDH 100-200 mesh). Solvents were purified according to standard procedures. The spectra were recorded with the following instruments; IR: Perkin­-Elmer RX1 FT-IR spectrophotometer; NMR: Varian Gemini 200 MHz (^¹H) and 50 MHz (^¹³C) spectrometer; ESIMS: VG-Autospec­ micromass and HRMS: QSTAR XL, Hybrid MS system (Applied Biosystems).

1,3,3-Trisubstituted 4,5-Dioxopyrrolidines 4; General Procedure

To a mixture of nitro compound 1 (1.0 mmol) and In (325 mesh, 2.0 mmol) were added aq 1 M HCl (1 mL) and H₂O (2 mL). The mixture was stirred at r.t. for 10 min followed by addition of alkynoate 2 (1 mmol). After 10 min, formaldehyde (3; 4.0 mmol) was added and the stirring was continued. The reaction was monitored by TLC. After completion, the mixture was washed with sat. aq NaHCO₃ (3 × 5 mL) and H₂O (3 × 5 mL), and extracted with EtOAc (3 × 5 mL). The combined extracts were concentrated and the residue was subjected to column chromatography (silica gel, hexanes-EtOAc) to obtain pure 4,5-dioxopyrrolidine derivative (Table  [²] ).

Tetrasubstituted Tetrahydropyrimidines 5; General Procedure

For the preparation of tetrahydropyrimidines, the similar experimental procedure as above for the 1,3,3-trisubstituted 4,5-dioxo­pyrrolidines was followed using nitro compound 1 (2.0 mmol), alkynoate 2 (1.0 mmol), and formaldehyde (3; 4.0 mmol), along with In (325 mesh, 4.0 mmol), aq 1 M HCl (2 mL), and H₂O (3 mL) (Table  [³] ).

The spectral (IR, ^¹H and ^¹³C NMR, and MS) and analytical data of the unknown products are given below.

Methyl 1-(4-Hydroxyphenyl)-3-methoxymethyl-4,5-dioxopyrrolidine-3-carboxylate (4h)

Yield: 76%.

IR (KBr): 3388, 1772, 1699, 1515, 1458 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.65 (2 H, d, J = 8.0 Hz), 6.93 (2 H, d, J = 8.0 Hz), 4.51 (1 H, d, J = 12.0 Hz), 4.22 (1 H, d, J = 12.0 Hz), 4.00 (1 H, d, J = 10.0 Hz), 3.90 (1 H, d, J = 10.0 Hz), 3.80 (3 H, s), 3.31 (3 H, s).

^¹³C NMR (50 MHz, CDCl₃): δ = 194.2, 166.2, 156.0, 155.6, 130.2, 120.8, 115.7, 72.6, 59.9, 55.1, 53.0, 49.9.

ESIMS: m/z = 294 [M + H]⁺.

HRMS (ESI): m/z calcd for C₁₄H₁₆NO₆ [M + H]⁺: 294.0977; found: 294.0978.

Methyl 3-Methoxymethyl-1-(3-methylphenyl)-4,5-dioxopyrrolidine-3-carboxylate (4i)

Yield: 68%.

IR (KBr): 1771, 1702, 1512, 1252 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.69 (1 H, d, J = 2.0 Hz), 7.62 (1 H, dd, J = 8.0 Hz), 7.31 (1 H, t, J = 8.0 Hz), 7.09 (1 H, dd, J = 8.0, 2.0 Hz), 4.49 (1 H, d, J = 12.0 Hz), 4.20 (1 H, d, J = 12.0 Hz), 3.93 (1 H, d, J = 10.0 Hz), 3.88 (1 H, d, J = 10.0 Hz), 3.76 (3 H, s), 3.22 (3 H, s), 2.43 (3 H, s).

^¹³C NMR (50 MHz, CDCl₃): δ = 192.9, 166.2, 156.1, 139.6, 139.0, 129.9, 129.2, 128.1, 120.0, 116.3, 72.8, 59.5, 55.1, 53.8, 49.0, 21.4.

ESIMS: m/z = 292 [M + H]⁺.

HRMS (ESI): m/z calcd for C₁₅H₁₈NO₅ [M + H]⁺: 292.1179; found: 292.1192.

Methyl 1-(4-Trifluoromethylphenyl)-3-methoxymethyl-4,5-dioxopyrrolidine-3-carboxylate (4j)

Yield: 70%.

IR (KBr): 1777, 1737, 1613, 1462 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 8.02 (2 H, d, J = 8.0 Hz), 7.72 (2 H, d, J = 8.0 Hz), 4.54 (1 H, d, J = 12.0 Hz), 4.22 (1 H, d, J = 12.0 Hz), 3.99 (1 H, d, J = 10.0 Hz), 3.89 (1 H, d, J = 10.0 Hz), 3.80 (3 H, s), 3.34 (3 H, s).

^¹³C NMR (50 MHz, CDCl₃): δ 193.1, 166.1, 155.9, 141.0, 135.0, 125.8 (br), 124.9, 119.4, 74.2, 60.0, 55.1, 53.8, 49.2.

ESIMS: m/z = 346 [M + H]⁺.

HRMS (ESI): m/z calcd for C₁₅H₁₄F₃NO₅ + Na [M + Na]⁺: 368.0721; found: 368.0726.

Ethyl 3-Ethoxymethyl-1-phenyl-4,5-dioxopyrrolidine-3-carboxylate (4k)

Yield: 67%.

IR (KBr): 1769, 1696, 1513, 1459 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.81 (1 H, d, J = 2.0 Hz), 7.78 (1 H, dd, J = 8.0, 2.0 Hz), 7.42 (1 H, t, J = 8.0 Hz), 7.16 (1 H, dd, J = 8.0, 2.0 Hz), 4.50 (1 H, d, J = 12.0 Hz), 4.28-4.18 (3 H, m), 3.99 (1 H, d, J = 10.0 Hz), 3.90 (1 H, d, J = 10.0 Hz), 3.48 (2 H, q, J = 7.0 Hz), 2.43 (3 H, s), 1.27 (3 H, t, J = 7.0 Hz) 1.10 (3 H, t, J = 7.0 Hz).

^¹³C NMR (50 MHz, CDCl₃): δ = 193.3, 166.2, 156.1, 139.4, 139.2, 135.0, 130.0, 128.2, 120.4, 116.0, 70.5, 67.5, 61.5, 55.6, 49.8, 23.4, 15.0, 14.3.

ESIMS: m/z = 320 [M + H]⁺.

HRMS (ESI): m/z calcd for C₁₇H₂₂NO₅ [M + H]⁺: 320.1497; found: 320.1488.

Ethyl 3-Ethoxymethyl-1-(3-methylphenyl)-4,5-dioxopyrrolidine-3-carboxylate (4l)

Yield: 70%.

IR (KBr): 1775, 1720, 1593, 1481 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.82 (1 H, dd, J = 8.0, 2.0 Hz), 7.80 (1 H, d, J = 2.0 Hz), 7.36 (1 H, t, J = 8.0 Hz), 7.21 (1 H, dd, J = 8.0, 2.0 Hz), 4.43 (1 H, d, J = 12.0 Hz), 4.28-4.16 (3 H, m), 3.95 (1 H, d, J = 10.0 Hz), 3.88 (1 H, d, J = 10.0 Hz), 3.45 (2 H, q, J = 7.0 Hz), 1.23 (3 H, t, J = 7.0 Hz) 1.08 (3 H, t, J = 7.0 Hz).

^¹³C NMR (50 MHz, CDCl₃): δ = 192.3, 165.5, 156.2, 140.0, 135.12, 130.0, 126.6, 124.8, 119.1, 117.3, 70.3, 67.5, 62.7, 55.2, 49.0, 15.1, 14.3.

ESIMS: m/z = 340, 342 [M + H]⁺.

HRMS (ESI): m/z calcd for C₁₆H₁₉ClNO₅ [M + H]⁺: 340.0951; found: 340.0963.

Dimethyl 1,3-Di( p -tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (5e)

Yield: 65%.

IR (KBr): 1743, 1698, 1578, 1514, 1436, 1260 cm^-¹.

^¹H NMR (CDCl₃, 200 MHz): δ = 7.04 (2 H, d, J = 8.0 Hz), 6.99 (2 H, d, J = 8.0 Hz), 6.82 (2 H, d, J = 8.0 Hz), 6.79 (2 H, d, J = 8.0 Hz), 4.81 (2 H, s), 4.12 (2 H, s), 3.71 (3 H, s), 3.53 (3 H, s), 2.32 (3 H, s), 2.23 (3 H, s).

^¹³C NMR (CDCl₃, 50 MHz): δ = 166.2, 164.6, 146.0, 140.8, 136.8, 130.7, 130.6, 129.8, 129.7, 125.2, 118.3, 118.1, 69.2, 52.5, 51.4, 47.6, 21.0, 20.5.

ESI-MS: m/z = 381 [M + H]⁺

HRMS (ESI): m/z calcd for C₂₂H₂₄N₂O₄ + Na [M + Na]⁺: 403.1633; found: 403.1647.

Dimethyl 1,3-Bis(4-methoxyphenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (5f)

Yield: 68%.

IR (KBr): 1742, 1695, 1582, 1438, 1249 cm^-¹.

^¹H NMR (CDCl₃, 200 MHz): δ = 6.90 (2 H, d, J = 8.0 Hz), 6.81 (2 H, d, J = 8.0 Hz), 6.74 (2 H, d, J = 8.0 Hz), 6.70 (2 H, d, J = 8.0 Hz), 4.72 (2 H, s), 4.11 (2 H, s), 3.72 (6 H, s), 3.70 (3 H, s), 3.53 (3 H, s).

^¹³C NMR (CDCl₃, 50 MHz): δ = 166.2, 164.1, 158.0, 154.2, 147.5, 142.1, 135.3, 127.1, 120.0, 114.6, 114.1, 96.9, 70.2, 55.2, 55.0, 51.9, 51.0, 47.4.

ESI-MS: m/z = 435 [M + Na]⁺.

HRMS (ESI): m/z calcd for C₂₂H₂₄N₂O₆ + Na [M + Na]⁺: 435.1532; found: 435.1516.

Dimethyl 1,3-Bis[4-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (5g)

Yield: 67%.

IR (KBr): 1742, 1706, 1610, 1437 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.58 (2 H, d, J = 8.0 Hz), 7.41 (2 H, d, J = 8.0 Hz), 7.11 (2 H, d, J = 8.0 Hz), 6.82 (2 H, d, J = 8.0 Hz), 5.00 (2 H, s), 4.31 (2 H, s), 3.75 (3 H, s), 3.62 (3 H, s).

^¹³C NMR (50 MHz, CDCl₃): δ = 165.8, 164.0, 150.2, 147.0, 145.2, 127.1 (br), 124.0, 119.5, 118.2, 116.0, 105.0, 67.2, 52.6, 52.0, 47.2.

ESIMS: m/z = 489 [M + H]⁺.

HRMS (ESI): m/z calcd for C₂₂H₁₈F₆N₂O₄ + Na [M + Na]⁺: 511.1068; found: 511.1060.

Diethyl 1,3-Bis[4-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (5i)

Yield: 67%.

IR (KBr): 1738, 1700, 1612, 1327 cm^-¹.

^¹H NMR (200 MHz, CDCl₃): δ = 7.54 (2 H, d, J = 8.0 Hz), 7.41 (2 H, d, J = 8.0 Hz), 7.12 (2 H, d, J = 8.0 Hz), 6.83 (2 H, d, J = 8.0 Hz), 4.99 (2 H, s), 4.31 (2 H, s), 4.21 (2 H, q, J = 7.0 Hz), 4.03 (2 H, q, J = 7.0 Hz), 1.31 (3 H, q, J = 7.0 Hz), 1.03 (3 H, q, J = 7.0 Hz).

^¹³C NMR (50 MHz, CDCl₃): δ = 166.0, 163.4, 150.2, 146.7, 144.9, 126.9 (br), 123.7, 119.5, 118.2, 116.7, 114.2, 105.0, 67.0, 62.1, 61.0, 47.3, 14.2, 13.6.

ESIMS: m/z = 517 [M + H]⁺.

HRMS (ESI): m/z calcd for C₂₄H₂₂F₆N₂O₄ + Na [M + Na]⁺: 539.1376068; found: 539.1395.

Acknowledgment

The authors thank CSIR and UGC, New Delhi for financial assis­tance. They are also thankful to NMR, Mass, and IR Divisions of IICT for spectral recording.

References

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  Srikrishna A., Sridharan M., Prasad K. R.; Tetrahedron; 2010, 66: in press; DOI: 10.1016/ j.tet.2010.03.084
• 7a Das B. Banerjee J. Mahender G. Majhi A. Org. Lett.  2004,  6:  3349 
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• 7b Das B. Holla H. Venkateswalu K. Majhi A. Tetrahedron Lett.  2005,  46:  8895 
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  Thieme Connect

Part 202 in the series: ‘Studies on Novel Synthetic Methodologies’.

References

• 2a Janecki T. Blaszczyk E. Studzian K. Janecka A. Krajenska U. Rozalski M. J. Med. Chem.  2005,  48:  3516 
  Search in Google Scholar
• 2b Hong CY. Kim YK. Chang JH. Kim SH. Choi H. Nam DH. Kim YZ. Kwak JH. J. Med. Chem.  1997,  40:  3584 
  Search in Google Scholar
• 2c Raj AA. Raghunathan R. Sridevi Kumari MR. Raman N. Bioorg. Med. Chem.  2003,  11:  407 
  Search in Google Scholar
• 3a Nair V. Chi G. Ptak R. Neamati N. J. Med. Chem.  2006,  49:  445 
  Search in Google Scholar
• 3b Pattarimi P. Smeyne RJ. Morgan JI. Neuroscience  2007,  145:  654 
  Search in Google Scholar
• 3c Messer WS. Abuh YF. Paryasamy S. Ngur DO. Edger MAN. Eissadi AA. Sheih S. Dunbar PG. Roknich S. Rho T. Fang Z. Ojo B. Zhang H. Huzl JJ. Nagy PI. J. Med. Chem.  1997,  40:  1230 
  Search in Google Scholar
• 4 Tozkoparan B. Yarim M. Sarac S. Ertan M. Kelicun P. Altinoc G. Demirdamar R. Arch. Pharm. Pharm. Med. Chem.  2000,  333:  415 
  CrossrefSearch in Google Scholar
• For recent examples of multicomponent reactions, see:
• 5a Ohno H. Ohta Y. Oishi S. Fujii N. Angew. Chem. Int. Ed.  2007,  46:  2295 
  Search in Google Scholar
• 5b Komagawa S. Saito S. Angew. Chem. Int. Ed.  2006,  45:  2446 
  Search in Google Scholar
• 5c Yoshida H. Fukushima H. Ohshita J. Kunai A. J. Am. Chem. Soc.  2006,  128:  11040 
  Search in Google Scholar
• 5d Dondas H. Fishwick CWG. Gai X. Grigg R. Kilner C. Dumrongchai N. Kongkathip B. Kongkathip N. Polysuk C. Sridharan V. Angew. Chem. Int. Ed.  2005,  44:  7570 
  Search in Google Scholar
• 5e Pache S. Lautens M. Org. Lett.  2003,  5:  4827 
  Search in Google Scholar
• 6a Cao H. Jiang H.-F. Qi C.-R. Yao W.-J. Chem H.-J. Tetrahedron Lett.  2009,  50:  1209 
  Search in Google Scholar
• 6b

  Srikrishna A., Sridharan M., Prasad K. R.; Tetrahedron; 2010, 66: in press; DOI: 10.1016/ j.tet.2010.03.084
• 7a Das B. Banerjee J. Mahender G. Majhi A. Org. Lett.  2004,  6:  3349 
  Search in Google Scholar
• 7b Das B. Holla H. Venkateswalu K. Majhi A. Tetrahedron Lett.  2005,  46:  8895 
  Search in Google Scholar
• 7c Das B. Satyalakshmi G. Suneel K. Shashikanth B. Tetrahedron Lett.  2008,  49:  7209 
  Search in Google Scholar
• 8 Ranu BC. Eur. J. Org. Chem.  2000,  2347 
  Crossref
• 9 Lee JC. Choi KII. Koh HY. Kang Y. Kuin Y. Kang Y. Cho YS. Synthesis  2001,  81 
  Thieme Connect

Part 202 in the series: ‘Studies on Novel Synthetic Methodologies’.