The First and Efficient Synthesis of 7-Aryl-6-methoxycarbonylquinazolines via Unexpected Reaction of 6-Arylethynylpyrimidine-5-carbaldehydes and Methyl Mercaptoacetate

Abstract

A highly concise synthesis of 7-aryl-6-methoxycarbonylquinazolines via reaction of 6-arylethynylpyrimidine-5-carbaldehydes and methyl mercaptoacetate is described.

Quinazoline are classes of fused heterocycles that are of considerable interest because of the diverse range of their biological properties, for example anticancer, diuretic, anti-inflammatory, anticonvulsant and antihypertensive activities. [¹] A number of solution- and solid-phase synthesis procedures for the construction of quinazoline heterosystem have recently been advanced. A literature survey revealed that anthranilic acid or anilines with suitable substituents are the most often used starting compound for this purpose. [²] However, to the best of our knowledge, there are only few examples of synthesis of quinazolines from pyrimidine derivatives in the literature [³] and the applicability of these methods is very limited.

Previous works of our group reported that 6-arylethynylpyrimidine-5-carbaldehydes undergo reactions with hydroxylamine, tert-butylamine or primary alcohols, therefore we have shown that these compounds are versatile and useful intermediates for the synthesis of pyrido[4,3-d]pyrimidine [4] and 5,7-dihydrofuro[3,4-d]pyrimi-dines [5] frameworks (Scheme  [¹] ).

These results logically led us to investigate the reactions of 6-arylethynylpyrimidin-5-carbaldehydes with sulfur nucleophiles. We were pleasantly surprised to find that reaction of the starting compounds with methyl mercapto­acetate led to novel benzannulation reaction. So herein we wish to report on a new, highly concise synthesis of 7-aryl-6-methoxycarbonylquinazolines.

The starting compounds 1 were synthesized by the palladium-catalyzed Sonagashira coupling of the corresponding 2,4-disubstituted 6-chloropyrimidine-5-carbalde-hydes with 1-arylacetylenes by the procedure reported earlier by us. [5] Reaction of compound 1a with an equivalent of sodium butylthiolate or sodium thiophenolate in methanol at room temperature proceeded in expected way and conjugate regio- and stereoselective addition [6] took place and the formation of yellow crystalline products 2a,b was observed (Scheme  [²] ).

We were further intrigued to observe the formation of a colorless product, while treatment of compound 1a with an equivalent of sodium salt of methyl mercaptoacetate in methanol at room temperature. Neither IR spectra nor ^¹³C NMR spectra of 3a showed the presence of CºC or formyl groups in molecules. In the ^¹H NMR spectra of obtained products two new singlets at δ = 7.45 ppm and δ = 8.64 ppm along with the singlet of methoxy group at δ = 3.62 ppm were observed. These data indicated that not only conjugate addition of thiolate moiety to the CºC bond, but also condensation of activated methylene group with formyl functionality had taken place. Thus, the obtained product seemed to be derivative of unknown heterocyclic system, thiepino[4,5-d]pyrimidine. However, slow crystallization of 3a from methanol provided single crystals suitable for the X-ray crystallographic analysis, which enabled the outcome of the reaction to be elucidated unambiguously (Figure  [¹] ). [7] We were surprised when crystallographic data of 3a showed that in reaction of the starting compound with methyl mercaptoacetate a novel benzannulation reaction had taken place and the obtained product was 6-methoxycarbonyl-2-methylthio-7-phenyl-4-pyrrolidinylquinazoline (Figure  [¹] ).

Thus, we decided to look for the best conditions to trigger the benzannulation reaction with 1a and methyl mercaptoacetate as the starting materials (Table  [¹] ). The use of potassium methoxide in methanol at room temperature gave the best result (entry 2). While sodium methoxide in methanol provided a slightly lower yield of the desired product 3a, K₂CO₃ in methanol, 2-propanol and dimethylsulfoxide proved to be far less effective (entries 3, 5 and 7). Et₃N in methanol was not successful (entry 4) and use of sodium hydride in absolute THF gave only an undefined mixture (entry 6). So, we found that the optimal reaction conditions were an equivalent of potassium methoxide and an equivalent of methyl mercaptoacetate in methanol at room temperature.

Encouraged by these results we decided to perform the reactions of the other 2,4-disubstituted 6-arylethynylpyri­midine-5-carbaldehydes 1a-o with methyl mercapto-acetate (Scheme  [³] ). The results of the synthesis of 7-aryl-6-methoxycarbonylquinazolines 3a-o by the presented method are summarized in Table  [²] .

We believe, that the reaction of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbaldehydes 1 with methyl mercaptoacetate could proceed via 2,4-disubstituted methyl 8-aryl-6-methoxycarbonylthiepino[4,5-d]pyrimidines 4. We assume, that intermediates 4 due to their unstability undergo smooth 1,6-electrocyclic ring closure and following aromatization with elimination of sulfur to form the corresponding 2,4-disubstituted 7-aryl-6-methoxycarbonylquinazolines 3a-o. Analogous transformation from benzothiepine to naphthalene derivatives has been reported earlier, [8] so our proposed mechanism seems to be reasonable.

In conclusion, we have developed a novel, simple and high-yielding synthetic method for quinazoline framework via unexpected reaction of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbaldehydes with methyl mer-captoacetate. This is the first example for the preparation of the title compounds from 6-arylethynylpyrimidine-5-carbaldehydes and the first example of methyl mercaptoacetate as a trigger for the benzannulation reaction. Taking into account that ester functionality in the molecules can undergo further transformations this method for the synthesis of the title compounds should be useful for the preparation of various biologically important quinazolines. Extension of these reactions is currently under way in our laboratory.

Acknowledgment

We express our gratitude to M. Kreneviciene and A. Karosiene for recording of the NMR and IR spectra, to M. Gavrilova for the elemental analyses data and to Dr. S. Belyakov (Institute of Organic Synthesis, Ryga, Latvia) for the X-ray measurements.

References and Notes

• 1a Smaill JB. Rewcastle GW. Bridges AJ. Zhou H. Showalter HDH. Fry DW. Nelson JM. Sherwood V. Elliott WL. Vincent PW. DeJohn DE. Loo JA. Greis KD. Chan OH. Reyner EL. Lipka E. Denny WA. J. Med. Chem.  2000,  43:  3199 
  Search in Google Scholar
• 1b Eckhardt M. Langkopf E. Mark M. Tadayyon M. Thomas L. Nar H. Pfrengle W. Guth B. Lotz R. Sieger P. Fuchs H. Himmelsbach F. J. Med. Chem.  2007,  50:  6450 
  Search in Google Scholar
• 1c Bavetsias V. Skelton LA. Yafai F. Mitchell F. Wilson SC. Allan B. Jackman AL. J. Med. Chem.  2002,  45:  3692 
  Search in Google Scholar
• 1d Tsou H.-R. Mamuya N. Johnson BD. Reich MF. Gruber BC. Ye F. Nilakantan R. Shen R. Discafani C. DeBlanc R. Davis R. Koehn FE. Greenberger LM. Wang Y.-F. Wissner A. J. Med. Chem.  2001,  44:  2719 
  Search in Google Scholar
• 1e Gackenheimer SL. Schaus JM. Gehlert DR. J. Pharmacol. Exp. Ther.  1995,  274:  1558 
  Search in Google Scholar
• 1f Dempcy RO. Skibo EB. Biochemistry  1991,  30:  8480 
  Search in Google Scholar
• 2a Connolly DJ. Cusack D. O’Sullivan TP. Guiry PJ. Tetrahedron  2005,  61:  10153 
  Search in Google Scholar
• 2b Hill MD. Movassaghi M. Chem. Eur. J.  2008,  14:  6836 
  Search in Google Scholar
• 2c Nikpour F. Paibast T. Chem. Lett.  2005,  34:  1438 
  Search in Google Scholar
• 3a Wada A. Yamamoto H. Ohki K. Nagai S. Kanatomo S. J. Heterocycl. Chem.  1992,  29:  911 
  Search in Google Scholar
• 3b Kim SK. Russel KC. J. Org. Chem.  1998,  63:  8229 
  Search in Google Scholar
• 4a Cikotiene I. Buksnaitiene R. Brukstus A. Chem. Heterocycl. Comp.  2007,  43:  515 
  Search in Google Scholar
• 4b Cikotiene I. Morkunas M. Rudys S. Buksnaitiene R. Brukstus A. Synlett  2008, 2799
• 5 Cikotiene I. Morkunas M. Motiejaitis D. Rudys S. Brukstus A. Synlett  2008,  1693 
  Thieme Connect
• 6 Cikotiene I. Pudziuvelyte E. Brukstus A. Tumkevicius S. Tetrahedron  2007,  63:  8145 
  CrossrefSearch in Google Scholar
• 8a Scott GP. J. Am. Chem. Soc.  1953,  75:  6332 
  Search in Google Scholar
• 8b Dimroth K. Lenke G. Chem. Ber.  1956,  89:  2608 
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• 11 Altomare A. Burla MC. Camalli M. Cascarano GL. Giacovazzo C. Guagliardi A. Moliterni AGG. Polidori G. Spagna R. J. Appl. Crystallogr.  1999,  32:  115 
  CrossrefSearch in Google Scholar
• 12 Sheldrick GM. SHELXL97, Program for the Refinement of Crystal Structures   University of Göttingen; Germany: 1997. 
• 13 Johnson CK. ORTEP-II, Report ORNL-5138   Oak Ridge National Laboratory; Oak Ridge TN (USA): 1976. 

Crystal structure analysis for 3a: C₂₁H₂₁N₃O₂S, M_r = 379.47 g mol^-¹, monoclinic, space group P21/a, a = 7.5916 (2), b = 19.0791 (4), c = 13.2219 (4) Å, α = 90.00˚, β = 94.3120 (9)˚, γ = 90.00˚, V = 1909.65 (9) Å^³, ρ = 1.320 g/cm^³, F(000) = 800. X-ray diffraction data were collected on a Nonius Kappa CCD diffractometer at 293 K using graphite-monochromated Mo-K_α radiation (λ = 0.71073 Å). Structure 3a was solved by direct methods with SIR97 program^¹¹ and refined by full-matrix least squares techniques with anisotropic non-hydrogen atoms. Hydrogen atoms were refined in the riding model. The refinement calculations were carried out with the help of SHELX97 program.^¹² ORTEP^¹³ view of the molecule is shown in Figure  [¹] . Crystallographic data for structure 3a have been deposited at the Cambridge Crystallographic Data Centre (CCDC number 703429).

Typical Procedure for the Preparation of 2,4-Disub-stituted 7-Aryl-6-methoxycarbonylquinazolines 3a-o: To a solution of the corresponding 6-arylethynylpyrimidine-5-carbaldehyde 1a-o (0.3 mmol) in methanol (5 mL) a solution of potassium salt of methyl mercaptoacetate, prepared from potassium (11.7 mg, 0.3 mmol), methyl mercaptoacetate (31.8 mg, 0.3 mmol) and methanol (3 mL) was added. The resulting reaction mixture was stirred for 2 h at r.t. The solvent was evaporated under reduced pressure, the residue was washed with H₂O, filtered and recrystallized to give compounds 3a-o.
6-Methoxycarbonyl-2-methylthio-7-phenyl-4-pyrroli-dinoquinazoline (3a): yield: 86%; mp 185-187 ˚C (from MeOH). IR (KBr): 1708 (C=O) cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 2.01 [br s, 4 H, (CH₂)₂], 2.54 (s, 3 H, SMe), 3.62 (s, 3 H, OMe), 3.92 [br s, 4 H, N(CH₂)₂], 7.37-7.47 (m, 5 H, ArH), 7.45 (s, 1 H, CH), 8.64 (s, 1 H, CH). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 13.4, 25.0, 50.6, 51.9, 11.9, 125.0, 127.2, 127.6, 127.9, 128.1, 129.2, 139.7, 144.8, 152.9, 157.5, 167.4, 168.7. Anal. Calcd for C₂₁H₂₁N₃O₂S: C, 66.47; H, 5.58; N, 11.07. Found: C, 66.37; H, 5.53; N, 11.11.

Compounds 2a,b and 3b-o were also fully characterized by IR, ^¹H NMR, ^¹³C NMR spectroscopic and microanalytical data.

References and Notes

• 1a Smaill JB. Rewcastle GW. Bridges AJ. Zhou H. Showalter HDH. Fry DW. Nelson JM. Sherwood V. Elliott WL. Vincent PW. DeJohn DE. Loo JA. Greis KD. Chan OH. Reyner EL. Lipka E. Denny WA. J. Med. Chem.  2000,  43:  3199 
  Search in Google Scholar
• 1b Eckhardt M. Langkopf E. Mark M. Tadayyon M. Thomas L. Nar H. Pfrengle W. Guth B. Lotz R. Sieger P. Fuchs H. Himmelsbach F. J. Med. Chem.  2007,  50:  6450 
  Search in Google Scholar
• 1c Bavetsias V. Skelton LA. Yafai F. Mitchell F. Wilson SC. Allan B. Jackman AL. J. Med. Chem.  2002,  45:  3692 
  Search in Google Scholar
• 1d Tsou H.-R. Mamuya N. Johnson BD. Reich MF. Gruber BC. Ye F. Nilakantan R. Shen R. Discafani C. DeBlanc R. Davis R. Koehn FE. Greenberger LM. Wang Y.-F. Wissner A. J. Med. Chem.  2001,  44:  2719 
  Search in Google Scholar
• 1e Gackenheimer SL. Schaus JM. Gehlert DR. J. Pharmacol. Exp. Ther.  1995,  274:  1558 
  Search in Google Scholar
• 1f Dempcy RO. Skibo EB. Biochemistry  1991,  30:  8480 
  Search in Google Scholar
• 2a Connolly DJ. Cusack D. O’Sullivan TP. Guiry PJ. Tetrahedron  2005,  61:  10153 
  Search in Google Scholar
• 2b Hill MD. Movassaghi M. Chem. Eur. J.  2008,  14:  6836 
  Search in Google Scholar
• 2c Nikpour F. Paibast T. Chem. Lett.  2005,  34:  1438 
  Search in Google Scholar
• 3a Wada A. Yamamoto H. Ohki K. Nagai S. Kanatomo S. J. Heterocycl. Chem.  1992,  29:  911 
  Search in Google Scholar
• 3b Kim SK. Russel KC. J. Org. Chem.  1998,  63:  8229 
  Search in Google Scholar
• 4a Cikotiene I. Buksnaitiene R. Brukstus A. Chem. Heterocycl. Comp.  2007,  43:  515 
  Search in Google Scholar
• 4b Cikotiene I. Morkunas M. Rudys S. Buksnaitiene R. Brukstus A. Synlett  2008, 2799
• 5 Cikotiene I. Morkunas M. Motiejaitis D. Rudys S. Brukstus A. Synlett  2008,  1693 
  Thieme Connect
• 6 Cikotiene I. Pudziuvelyte E. Brukstus A. Tumkevicius S. Tetrahedron  2007,  63:  8145 
  CrossrefSearch in Google Scholar
• 8a Scott GP. J. Am. Chem. Soc.  1953,  75:  6332 
  Search in Google Scholar
• 8b Dimroth K. Lenke G. Chem. Ber.  1956,  89:  2608 
  Search in Google Scholar
• 11 Altomare A. Burla MC. Camalli M. Cascarano GL. Giacovazzo C. Guagliardi A. Moliterni AGG. Polidori G. Spagna R. J. Appl. Crystallogr.  1999,  32:  115 
  CrossrefSearch in Google Scholar
• 12 Sheldrick GM. SHELXL97, Program for the Refinement of Crystal Structures   University of Göttingen; Germany: 1997. 
• 13 Johnson CK. ORTEP-II, Report ORNL-5138   Oak Ridge National Laboratory; Oak Ridge TN (USA): 1976. 

Crystal structure analysis for 3a: C₂₁H₂₁N₃O₂S, M_r = 379.47 g mol^-¹, monoclinic, space group P21/a, a = 7.5916 (2), b = 19.0791 (4), c = 13.2219 (4) Å, α = 90.00˚, β = 94.3120 (9)˚, γ = 90.00˚, V = 1909.65 (9) Å^³, ρ = 1.320 g/cm^³, F(000) = 800. X-ray diffraction data were collected on a Nonius Kappa CCD diffractometer at 293 K using graphite-monochromated Mo-K_α radiation (λ = 0.71073 Å). Structure 3a was solved by direct methods with SIR97 program^¹¹ and refined by full-matrix least squares techniques with anisotropic non-hydrogen atoms. Hydrogen atoms were refined in the riding model. The refinement calculations were carried out with the help of SHELX97 program.^¹² ORTEP^¹³ view of the molecule is shown in Figure  [¹] . Crystallographic data for structure 3a have been deposited at the Cambridge Crystallographic Data Centre (CCDC number 703429).

Typical Procedure for the Preparation of 2,4-Disub-stituted 7-Aryl-6-methoxycarbonylquinazolines 3a-o: To a solution of the corresponding 6-arylethynylpyrimidine-5-carbaldehyde 1a-o (0.3 mmol) in methanol (5 mL) a solution of potassium salt of methyl mercaptoacetate, prepared from potassium (11.7 mg, 0.3 mmol), methyl mercaptoacetate (31.8 mg, 0.3 mmol) and methanol (3 mL) was added. The resulting reaction mixture was stirred for 2 h at r.t. The solvent was evaporated under reduced pressure, the residue was washed with H₂O, filtered and recrystallized to give compounds 3a-o.
6-Methoxycarbonyl-2-methylthio-7-phenyl-4-pyrroli-dinoquinazoline (3a): yield: 86%; mp 185-187 ˚C (from MeOH). IR (KBr): 1708 (C=O) cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 2.01 [br s, 4 H, (CH₂)₂], 2.54 (s, 3 H, SMe), 3.62 (s, 3 H, OMe), 3.92 [br s, 4 H, N(CH₂)₂], 7.37-7.47 (m, 5 H, ArH), 7.45 (s, 1 H, CH), 8.64 (s, 1 H, CH). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 13.4, 25.0, 50.6, 51.9, 11.9, 125.0, 127.2, 127.6, 127.9, 128.1, 129.2, 139.7, 144.8, 152.9, 157.5, 167.4, 168.7. Anal. Calcd for C₂₁H₂₁N₃O₂S: C, 66.47; H, 5.58; N, 11.07. Found: C, 66.37; H, 5.53; N, 11.11.

Compounds 2a,b and 3b-o were also fully characterized by IR, ^¹H NMR, ^¹³C NMR spectroscopic and microanalytical data.