Dialkylation of Ethyl 4-(Het)aryl-3-oxobutanoates as a Route to 5-(2-Oxoethyl)cyclopentenones

Abstract

An unexplored ability of the long-known chemical transformation, Borsche’s cyclopentenone synthesis (the construction of a 1,4-diketone with subsequent base-induced cyclization), is reported. Double alkylation of ethyl 4-(het)aryl-3-oxobutanoates with 2-bromo-1-(het)arylethanones, with subsequent alkali treatment, provides access to cyclopentenones substituted with a 2-oxoethyl group at the 5-position. These products might serve as valuable synthons for heterocyclization, and this feature was demonstrated by synthesis of 4H-cyclopenta[b]thiophene derivatives.

Synthesis of 1,4-diketones followed by their cyclization is a well-established route to substituted cyclopent-2-en-1-ones.[1] The classical Borsche protocol involves the alkylation of ethyl acetoacetate or its derivatives by bromo ketones with subsequent cyclization.[2] Various modifications of this method have been reported.[3] For instance, the application of 4-(het)aryl-3-oxobutanoates and 2-bromo-1-(het)arylethenones (which was described in 1939 for unsubstituted benzene)[4] provide access to photochromic[5] and photoactive[6] 2,3-diarylcyclopent-2-en-1-ones 4 (Scheme [1]). A general protocol for these compounds is based on the alkylation of an oxo ester 1 by a bromo ketone 2 in the presence of metallic sodium in benzene, with subsequent cyclization in an aqueous ethanolic solution of potassium hydroxide.[5a]

During our studies on the synthesis of photoactive derivatives of cyclopentenone,[3e] [5] [6] we prepared more than 30 examples of di(het)arylethenes 4 from various equimolar combinations of substrates 1 and 2. Unexpectedly, in some cases we did not obtain the 1,4-diketone 3 or, correspondingly, the desired cyclopentenone 4. Instead, we isolated the cyclopentenones 5a (based on oxazole and thiazole[7] moieties) and 5b (based on thiazole and 4-nitrophenyl moieties) as the major products after the first step of the protocol (Scheme [2]).[8] The structures of these compounds were confirmed by 2D NMR spectroscopy (for details, see Supporting Information). ¹H NMR spectra of 5a and 5b featured double sets of signals for methylene groups, whereas their ¹³C NMR spectra contained a characteristic quaternary carbon at δ = 56.5–57.2 ppm. These products were formed after secondary alkylation of the corresponding intermediates 3 with subsequent cyclization.

The reaction of equimolar amounts of the appropriate substrates in the presence of metallic sodium (1.05 equiv) provided cyclopentenone 5b in 42% yield (Scheme [2]), whereas the reaction of two equivalents of bromoketone/sodium with the oxo ester provided 5b in a somewhat lower yield of 37%. The use of three equivalents of sodium resulted in an increase in the yield of 5b to 54%. To probe the influence of the nature of the substrate on the alkylation process, we replaced both thiazole and 4-nitrophenyl groups with a more electron-donating thienyl group. Alkylation of the 2,5-dimethylthiophene-based oxo ester 1 by 2-bromo-1-(4-nitrophenyl)ethanone afforded the normal product 6c in 91% yield (Scheme [2]). The use of a thienyl-based bromo ketone along with a thiazole oxo ester resulted in the normal alkylation product and, after cyclization, the cyclopentenone 4d. The reason for this dramatic influence of a (het)aryl moiety on the reaction pathway is unclear, but is probably the result of various electronic effects.

The unexpected products 5a and 5b are 1,4-diketones, which are classical substrates for heterocyclic chemistry (for example, for Paal–Knorr synthesis of five-membered heterocycles).[9] There are many efficient methods for the synthesis of 1,4-diketones, including oxidative coupling of enolates,[10] Michael-type addition,[11], and radical addition.[12] An analysis of the literature showed that the synthesis of 5-(2-oxoethyl)cyclopent-2-en-1-ones within Borsche’s protocol is an unexplored area. Furthermore, few methods have been developed for the synthesis of these potentially valuable compounds.[13]

Alkylation of certain oxo esters 1 with two equivalents of bromo ketones 2 in the presence of metallic sodium, with subsequent cyclization, gave the corresponding 5-(2-oxo­ethyl)cyclopent-2-en-1-ones 7e–h in yields of 27–47% over the two steps (Scheme [3]). Interestingly, the major isolated product after double alkylation of thiophene-based substrates in benzene were the cyclized products 5 with CO₂Et group on the ethene bridge. These compounds, 5e and 5g, are analogues of the anomalous products 5a and 5b (see above). 1,4-Diketones 7e–g were subjected to heterocyclization through interaction with Lawesson’s reagent in toluene. This reaction gave the corresponding 4H-cyclopenta[b]thiophenes 8e–g in yields of 55–70%.[14] ¹H NMR spectra of these products showed characteristic singlets of annulated cyclopentene at δ = 3.66–3.93 ppm and signals for the newly formed thiophene ring in the downfield region.

Interestingly, for benzene/oxazole pair (Scheme [3]; entry g), we isolated the unexpected byproduct 9 in 11% yield, along with the desired cyclopentenone 7g. The structure of compound 9 was confirmed by X-ray crystallography[15] (Scheme [3]). Obviously, the indanone 9 was formed after double alkylation of the corresponding oxo ester with a subsequent, unusual, base-induced cyclization, followed by oxazole cycloreversion (for a proposed mechanism, see the Supporting Information). Interestingly, a related opening of an oxazole ring has been described under light-irradiation conditions for diarylethene derivatives.[6a]

In conclusion, we have shown, for the first time, that the classical Borsche protocol for the synthesis of cyclopentenones provides access to 5-(2-oxoethyl)cyclopent-2-en-1-ones. These compounds are 1,4-diketones and might serve as valuable synthons for heterocyclization. This feature was demonstrated by the synthesis of 4H-cyclopenta[b]thiophene derivatives.

• References and Notes

• 1a Aitken DJ, Eijsberg H, Frongia A, Ollivier J, Piras PP. Synthesis 2014; 46: 1
  Thieme ConnectSearch in Google Scholar
• 1b Simeonov SP, Nunes JP. M, Guerra K, Kurteva VB, Afonso CA. M. Chem. Rev. 2016; 116: 5744
  CrossrefPubMedSearch in Google Scholar
• 2a Borsche W, Fels A. Ber. Dtsch. Chem. Ges. 1906; 39: 1922
  CrossrefSearch in Google Scholar
• 2b Borsche W, Menz W. Ber. Dtsch. Chem. Ges. 1908; 41: 190
  CrossrefSearch in Google Scholar
• 3a Finch N, Fitt JJ, Hsu IH. C. J. Org. Chem. 1971; 36: 3191
  CrossrefPubMedSearch in Google Scholar
• 3b Nam N.-H, Kim Y, You Y.-J, Hong D.-H, Kim H.-M, Ann B.-Z. Arch. Pharmacal. Res. 2002; 25: 600
  CrossrefPubMedSearch in Google Scholar
• 3c Lahmar N, Ben Ayed T, Bellassoued M, Amri H. Beilstein J. Org. Chem. 2005; 1: 11
  PubMedSearch in Google Scholar
• 3d Alhamadsheh MM, Gupta S, Hudson RA, Perera L, Tillekeratne LM. V. Chem. Eur. J. 2008; 14: 570
  CrossrefPubMedSearch in Google Scholar
• 3e Lonshakov DV, Shirinian VZ, Zavarzin IV, Lvov AG, Krayushkin MM. Dyes Pigm. 2014; 109: 105
  CrossrefSearch in Google Scholar
• 3f Yang J, Mei F, Fu S, Gu Y. Green Chem. 2018; 20: 1367
  CrossrefSearch in Google Scholar
• 4 Borsche W, Klein A. Chem. Ber. 1939; 72: 2082
  CrossrefSearch in Google Scholar
• 5a Shirinian VZ, Shimkin AA, Lonshakov DV, Lvov AG, Krayushkin MM. J. Photochem. Photobiol., A 2012; 233: 1
  CrossrefSearch in Google Scholar
• 5b Shirinian VZ, Lvov AG, Krayushkin MM, Lubuzh ED, Nabatov BV. J. Org. Chem. 2014; 79: 3440
  CrossrefPubMedSearch in Google Scholar
• 5c Shirinian VZ, Lvov AG, Bulich EYu, Zakharov AV, Krayushkin MM. Tetrahedron Lett. 2015; 56: 5477
  CrossrefSearch in Google Scholar
• 5d Lvov AG, Bulich EYu, Metelitsa AV, Shirinian VZ. RSC Adv. 2016; 6: 59016
  CrossrefSearch in Google Scholar
• 5e Shirinian VZ, Lonshakov DV, Lvov AG, Kavun AM, Yadykov AV, Krayushkin MM. Dyes Pigm. 2016; 124: 258
  CrossrefSearch in Google Scholar
• 6a Lvov AG, Shirinian VZ, Kachala VV, Kavun AM, Zavarzin IV, Krayushkin MM. Org. Lett. 2014; 16: 4532
  CrossrefPubMedSearch in Google Scholar
• 6b Lvov AG, Shirinian VZ, Zakharov AV, Krayushkin MM, Kachala VV, Zavarzin IV. J. Org. Chem. 2015; 80: 11491
  CrossrefPubMedSearch in Google Scholar
• 7a Weiß KM, Wei S, Tsogoeva SB. Org. Biomol. Chem. 2011; 9: 3457
  CrossrefPubMedSearch in Google Scholar
• 7b Wei S, Weiß KM, Tsogoeva SB. Synthesis 2012; 44: 3441
  Thieme ConnectSearch in Google Scholar
• 8 Ethyl 3-(4-Methyl-2-phenyl-1,3-thiazol-5-yl)-4-(4-nitrophenyl)-1-[2-(4-nitrophenyl)-2-oxoethyl]-2-oxocyclopent-3-ene-1-carboxylate (5b) Na (35 mg, 1.05 equiv) was added to a solution of oxo ester 1 (1.5 mmol) in anhyd benzene (5 mL) and the mixture was stirred for 2 h. Bromo ketone 2 (1.5 mmol) was then added and the mixture was kept overnight, then poured into H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with H₂O (100 mL), dried (MgSO₄), and concentrated in vacuum. The residue was purified by column chromatography [silica gel, PE–EtOAc (5:1)] to give a yellow powder; yield: 192 mg (42%); mp 156–157 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.25 (t, J = 7.1 Hz, 3 H), 2.09 (s, 3 H), 3.23 (d, J = 18.5 Hz, 1 H), 3.56 (d, J = 18.5 Hz, 1 H), 4.03 (d, J = 18.5 Hz, 1 H), 4.21–4.30 (m, 2 H), 4.28 (d, J = 18.5 Hz, 1 H), 7.70 (d, J = 8.9 Hz, 2 H), 8.19 (d, J = 8.8 Hz, 2 H), 8.26 (d, J = 8.9 H, 2 H z), 8.36 (d, J = 8.8 Hz, 2 H), 7.44–7.47 (m, 3 H), 7.93–7.96 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.0, 16.4, 41.5, 43.6, 56.5, 62.6, 119.7, 124.0 (2 C), 124.1 (2 C), 125.6, 126.5 (2 C), 128.8 (2 C), 129.0 (2 C), 129.2 (2 C), 130.4, 131.7, 133.1, 140.4, 140.7, 148.7, 150.7, 152.6, 166.4, 168.7, 168.9, 200.7. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₂H₂₆N₃O₈S: 612.1435; found: 612.1429.
• 9 Khaghaninejad S, Heravi M. Adv. Heterocycl. Chem. 2014; 111: 95
  Search in Google Scholar
• 10a Baran PS, DeMartino MP. Angew. Chem. Int. Ed. 2006; 45: 7083
  CrossrefPubMedSearch in Google Scholar
• 10b DeMartino MP, Chen K, Baran PS. J. Am. Chem. Soc. 2008; 130: 11546
  CrossrefPubMedSearch in Google Scholar
• 11 Liu Y, Li Y, Qi Y, Wan J. Synthesis 2010; 4188
  Thieme Connect
• 12a Miura K, Saito H, Wang D, Hosomi A. Org. Lett. 2001; 3: 2591
  CrossrefPubMedSearch in Google Scholar
• 12b Rössle M, Werner T, Baro A, Frey W, Christoffers J. Angew. Chem. Int. Ed. 2004; 43: 6547
  CrossrefPubMedSearch in Google Scholar
• 12c Che C, Qian Z, Wu M, Zhao Y, Zhu G. J. Org. Chem. 2018; 83: 5665
  CrossrefPubMedSearch in Google Scholar
• 13a Stetter H, Simons L. Chem. Ber. 1985; 118: 3172
  Search in Google Scholar
• 13b Palani N, Rajamannar T, Balasubramanian KK. Synlett 1997; 59
  Thieme Connect
• 13c Stepherson JR, Fronczek FR, Kartika R. Chem. Commun. 2016; 52: 2300
  CrossrefPubMedSearch in Google Scholar
• 14 2,5,6-Tri(het)aryl-4H-cyclopenta[b]thiophenes 8e–h; General Procedure The appropriate 5-(2-oxoethyl)cyclopentenone derivative 7 (0.2 mmol) was dissolved in dry toluene (3 mL), and Lawesson's reagent (0.089 g, 0.22 mmol) was added. The resulting mixture was refluxed for 0.5 h then poured into H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with H₂O (100 mL), dried (MgSO₄), and concentrated under vacuum. The residue was purified by column chromatography [silica gel, PE–EtOAc (15:1)].
• 15 CCDC 1904288 contains the supplementary crystallographic data for compound 9. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

• References and Notes

• 1a Aitken DJ, Eijsberg H, Frongia A, Ollivier J, Piras PP. Synthesis 2014; 46: 1
  Thieme ConnectSearch in Google Scholar
• 1b Simeonov SP, Nunes JP. M, Guerra K, Kurteva VB, Afonso CA. M. Chem. Rev. 2016; 116: 5744
  CrossrefPubMedSearch in Google Scholar
• 2a Borsche W, Fels A. Ber. Dtsch. Chem. Ges. 1906; 39: 1922
  CrossrefSearch in Google Scholar
• 2b Borsche W, Menz W. Ber. Dtsch. Chem. Ges. 1908; 41: 190
  CrossrefSearch in Google Scholar
• 3a Finch N, Fitt JJ, Hsu IH. C. J. Org. Chem. 1971; 36: 3191
  CrossrefPubMedSearch in Google Scholar
• 3b Nam N.-H, Kim Y, You Y.-J, Hong D.-H, Kim H.-M, Ann B.-Z. Arch. Pharmacal. Res. 2002; 25: 600
  CrossrefPubMedSearch in Google Scholar
• 3c Lahmar N, Ben Ayed T, Bellassoued M, Amri H. Beilstein J. Org. Chem. 2005; 1: 11
  PubMedSearch in Google Scholar
• 3d Alhamadsheh MM, Gupta S, Hudson RA, Perera L, Tillekeratne LM. V. Chem. Eur. J. 2008; 14: 570
  CrossrefPubMedSearch in Google Scholar
• 3e Lonshakov DV, Shirinian VZ, Zavarzin IV, Lvov AG, Krayushkin MM. Dyes Pigm. 2014; 109: 105
  CrossrefSearch in Google Scholar
• 3f Yang J, Mei F, Fu S, Gu Y. Green Chem. 2018; 20: 1367
  CrossrefSearch in Google Scholar
• 4 Borsche W, Klein A. Chem. Ber. 1939; 72: 2082
  CrossrefSearch in Google Scholar
• 5a Shirinian VZ, Shimkin AA, Lonshakov DV, Lvov AG, Krayushkin MM. J. Photochem. Photobiol., A 2012; 233: 1
  CrossrefSearch in Google Scholar
• 5b Shirinian VZ, Lvov AG, Krayushkin MM, Lubuzh ED, Nabatov BV. J. Org. Chem. 2014; 79: 3440
  CrossrefPubMedSearch in Google Scholar
• 5c Shirinian VZ, Lvov AG, Bulich EYu, Zakharov AV, Krayushkin MM. Tetrahedron Lett. 2015; 56: 5477
  CrossrefSearch in Google Scholar
• 5d Lvov AG, Bulich EYu, Metelitsa AV, Shirinian VZ. RSC Adv. 2016; 6: 59016
  CrossrefSearch in Google Scholar
• 5e Shirinian VZ, Lonshakov DV, Lvov AG, Kavun AM, Yadykov AV, Krayushkin MM. Dyes Pigm. 2016; 124: 258
  CrossrefSearch in Google Scholar
• 6a Lvov AG, Shirinian VZ, Kachala VV, Kavun AM, Zavarzin IV, Krayushkin MM. Org. Lett. 2014; 16: 4532
  CrossrefPubMedSearch in Google Scholar
• 6b Lvov AG, Shirinian VZ, Zakharov AV, Krayushkin MM, Kachala VV, Zavarzin IV. J. Org. Chem. 2015; 80: 11491
  CrossrefPubMedSearch in Google Scholar
• 7a Weiß KM, Wei S, Tsogoeva SB. Org. Biomol. Chem. 2011; 9: 3457
  CrossrefPubMedSearch in Google Scholar
• 7b Wei S, Weiß KM, Tsogoeva SB. Synthesis 2012; 44: 3441
  Thieme ConnectSearch in Google Scholar
• 8 Ethyl 3-(4-Methyl-2-phenyl-1,3-thiazol-5-yl)-4-(4-nitrophenyl)-1-[2-(4-nitrophenyl)-2-oxoethyl]-2-oxocyclopent-3-ene-1-carboxylate (5b) Na (35 mg, 1.05 equiv) was added to a solution of oxo ester 1 (1.5 mmol) in anhyd benzene (5 mL) and the mixture was stirred for 2 h. Bromo ketone 2 (1.5 mmol) was then added and the mixture was kept overnight, then poured into H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with H₂O (100 mL), dried (MgSO₄), and concentrated in vacuum. The residue was purified by column chromatography [silica gel, PE–EtOAc (5:1)] to give a yellow powder; yield: 192 mg (42%); mp 156–157 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.25 (t, J = 7.1 Hz, 3 H), 2.09 (s, 3 H), 3.23 (d, J = 18.5 Hz, 1 H), 3.56 (d, J = 18.5 Hz, 1 H), 4.03 (d, J = 18.5 Hz, 1 H), 4.21–4.30 (m, 2 H), 4.28 (d, J = 18.5 Hz, 1 H), 7.70 (d, J = 8.9 Hz, 2 H), 8.19 (d, J = 8.8 Hz, 2 H), 8.26 (d, J = 8.9 H, 2 H z), 8.36 (d, J = 8.8 Hz, 2 H), 7.44–7.47 (m, 3 H), 7.93–7.96 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.0, 16.4, 41.5, 43.6, 56.5, 62.6, 119.7, 124.0 (2 C), 124.1 (2 C), 125.6, 126.5 (2 C), 128.8 (2 C), 129.0 (2 C), 129.2 (2 C), 130.4, 131.7, 133.1, 140.4, 140.7, 148.7, 150.7, 152.6, 166.4, 168.7, 168.9, 200.7. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₂H₂₆N₃O₈S: 612.1435; found: 612.1429.
• 9 Khaghaninejad S, Heravi M. Adv. Heterocycl. Chem. 2014; 111: 95
  Search in Google Scholar
• 10a Baran PS, DeMartino MP. Angew. Chem. Int. Ed. 2006; 45: 7083
  CrossrefPubMedSearch in Google Scholar
• 10b DeMartino MP, Chen K, Baran PS. J. Am. Chem. Soc. 2008; 130: 11546
  CrossrefPubMedSearch in Google Scholar
• 11 Liu Y, Li Y, Qi Y, Wan J. Synthesis 2010; 4188
  Thieme Connect
• 12a Miura K, Saito H, Wang D, Hosomi A. Org. Lett. 2001; 3: 2591
  CrossrefPubMedSearch in Google Scholar
• 12b Rössle M, Werner T, Baro A, Frey W, Christoffers J. Angew. Chem. Int. Ed. 2004; 43: 6547
  CrossrefPubMedSearch in Google Scholar
• 12c Che C, Qian Z, Wu M, Zhao Y, Zhu G. J. Org. Chem. 2018; 83: 5665
  CrossrefPubMedSearch in Google Scholar
• 13a Stetter H, Simons L. Chem. Ber. 1985; 118: 3172
  Search in Google Scholar
• 13b Palani N, Rajamannar T, Balasubramanian KK. Synlett 1997; 59
  Thieme Connect
• 13c Stepherson JR, Fronczek FR, Kartika R. Chem. Commun. 2016; 52: 2300
  CrossrefPubMedSearch in Google Scholar
• 14 2,5,6-Tri(het)aryl-4H-cyclopenta[b]thiophenes 8e–h; General Procedure The appropriate 5-(2-oxoethyl)cyclopentenone derivative 7 (0.2 mmol) was dissolved in dry toluene (3 mL), and Lawesson's reagent (0.089 g, 0.22 mmol) was added. The resulting mixture was refluxed for 0.5 h then poured into H₂O (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with H₂O (100 mL), dried (MgSO₄), and concentrated under vacuum. The residue was purified by column chromatography [silica gel, PE–EtOAc (15:1)].
• 15 CCDC 1904288 contains the supplementary crystallographic data for compound 9. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

• Supplementary Material