Copper-promoted cascade reaction of active methylenes with MBH-acetates of acetylenic aldehydes to functionalized cyclopentenes

Abstract

One-pot synthesis of substituted cyclopentenes was accomplished through a copper-mediated [4 + 1]-annulation of active methylene compounds with Morita–Baylis–Hillman (MBH) acetates of acetylenic aldehydes. The reaction sequence involves the cascade allylic substitution/5-exo-dig-carbocyclization, which was effective in providing methylene, alkylidene as well as arylidene cyclopentenes.

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Introduction

Cyclopentyl moiety is one of the important carbocyclic framework present in a number of bio-active natural products as well as pharmaceuticals and has attracted lot of attention for its synthesis.¹ Consequently, a range of methods have been developed for the synthesis of functionalized cyclopentyl derivatives. Among these methods, the classical thermal cyclization of an alkyne-bearing enolizable carbonyl group compounds, Conia-ene reaction, is a captivating method to obtain exocyclic-methylene cyclopentane products² and in few occasions the products are alkyl/arylidene cyclopentanes.³ To the best of our knowledge, there is a very limited number of methods known for the synthesis of functionalized cyclopentenes through alkyne-based cyclization reactions.⁴ This is particularly true for cyclopentenes with spirocyclic nature, which are common structural components in many bio-active natural products. For instance, jatamanin M, menellin A, trans-α-necrodol, (+)-oshalagrenol, sequosemperivirin-A, α-vetispirene are bio-active natural products having cyclopentene embedded in their structure (Fig. 1).⁵ Therefore, it is expedient to have an efficient method for the synthesis of functionalized cyclopentenes.

Fig. 1 Selected bio-active natural products having cyclopentene.

Very recently, we have reported an access to functionalized arylidene cyclopentenes under metal-free reaction conditions through the base-promoted [4 + 1]-annulation of Morita–Baylis–Hillman acetates of acetylenic aldehydes (C4-synthon) with active methylenes involving tandem allylic substitution followed by 5-exo-dig-carbocyclization.⁶ However, the inaccessibility of either methylene or alkylidene cyclopentenes was a constraint of the above method. To overcome this, further studies have been carried out with the objective of finding appropriate reaction conditions to obtain the alkylidene/methylene cyclopentenes, emphasizing on spirocyclic-cyclopentenes.

Morita–Baylis–Hillman (MBH) adducts and their derivatives have been proven to be one of the most flexible synthons in the rapid formation of useful heterocycles and carbocycles through various transformations.⁷ MBH-acetates/carbonates have also been utilized in the synthesis of substituted cyclopentenes via the phosphine-catalyzed annulation reaction.⁸ In continuation of our work on MBH-chemistry of acetylenic aldehydes,⁹ herein we wish to report the [4 + 1]-annulation of Morita–Baylis–Hillman acetates of acetylenic aldehydes with 1,1′-bisnucleophiles affording methylene and alkylidene as well as arylidene cyclopentenes under mild reaction conditions (Scheme 1).

Scheme 1 Synthesis of functionalized cyclopentenes.

Results and discussion

As our aim is to identify the suitable reaction conditions for MBH-acetate of acetylenic aldehyde bearing on alkyl group on alkyne functionality, the preliminary studies were performed by the reaction of MBH-acetate 1a with ethyl cyanoacetate (2a).

The reaction of 1a with 2a in the presence of K₂CO₃ provided the dialkylated product 4a in 72% yield at room temperature without giving any cyclized product (entry 1, Table 1). Change of base to Cs₂CO₃ resulted in no reaction even after 48 h at room temperature (entry 2, Table 1). From our earlier study, it was observed that the reaction of MBH-acetates of acetylenic aldehydes with active methylene derivatives proceeds through allylic substitution followed by conjugate addition in anti-fashion. This was supported by the faster reactivity of MBH-acetates having electron-deficient aromatics on alkyne functionality when compared to electron-rich aryl groups and no reactivity of MBH-acetates having alkyl group on alkyne.⁶ Therefore, we envisaged that the use of alkyne activators in the presence of base might promote the conjugate addition. Hence, I₂/NaHCO₃ system and the combination of Au–Ag catalysis/NaHCO₃ were tested and found that they were ineffective to promote even the alkylation neither at rt nor at 70 °C (entry 3 and 4, Table 1). Inspired by Balme et al. results,¹⁰ we were prompted to use a Cu-catalyst for activation of alkyne and gratified to see that the reaction proceeded to give the expected cyclopentene 3a (37%) in the presence of 10 mol%-CuI along with the monoalkylated compound 5a in 42% yield (entry 5, Table 1).¹¹ Subsequent optimization revealed that the use of 30 mol% CuI furnished 3a in 74% yield (entry 6, Table 1). Absence of base however did not show any progress in the reaction (entry 7, Table 1).

Table 1 Optimization of reaction conditions

Entry	Reagent system/T (°C)	Time (h)	Product/yield^a (%)
a Isolated yield.
1	K2CO3 (2.5 equiv.) DMF/80 °C	16	4a/72
2	Cs2CO3 (2 equiv.) DMF/80 °C	48	—
3	NaHCO3 (3 equiv.) I2 (3 equiv.)/CH3CN/rt – 70 °C	24	—
4	AuCl (PPh3) (0.1 equiv.) AgSbF6 (0.1 equiv.) NaHCO3 (12 equiv.)/EDC/rt	24	—
5	K2CO3 (2.5 equiv.)/CuI (0.1 equiv.) DMF/rt	36	3a/37 5a/42
6	K2CO3 (2 equiv.)/CuI (0.3 equiv.) DMF/rt	48	3a/74
7	CuI (0.3 equiv.) DMF/rt	48	—

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With the optimized conditions in hand, we next examined the scope of this [4 + 1]-annulation reaction with various active methylene derivatives as 1,1′-bis-nucleophiles and MBH-acetates of acetylenic aldehydes having different substitution on alkyne functionality and the results are summarized in Table 2. First, the reaction of MBH-acetate 1a and 1b having n-propyl and n-hexyl substitution on alkyne functionality, respectively, with other acyclic active methylene compounds, ethyl acetoacetate (2b) and ethyl picolinoylacetate (2c), was smoothly proceeded to give the corresponding alkylidene cyclopentenes, 3b to 3f, in good yields. To further expand the range of substrates, cyclic bis-nucleophiles were explored which are expected to offer the spiro-carbocycles, key structural frameworks in several bio-active natural products.¹

Table 2 Synthesis of alkylidene cyclopentenes

Nucleophile
	Product^a/reaction time/yield^b
a All the products are characterized by ^1H NMR, ^13C NMR, IR and MS spectra.b Isolated yield.c Isolated as E/Z mixture.
		R = n-C3H7 (3a)/48 h/74%
		R = n-C6H13 (3b)/48 h/72%
		R = n-C3H7 (3c)/48 h/62%
		R = n-C6H13 (3d)/48 h/65%
		R = n-C3H7 (3e)^c/36 h/57%
		R = n-C6H13 (3f)^c/36 h/52%
		R = n-C3H7 (3g)/16 h/80%
		R = n-C6H13 (3h)/16 h/83%
		R = n-C3H7 (3i)/24 h/63%
		R = n-C6H13 (3j)/24 h/59%
		R = n-C3H7 (3k)/24 h/86%
		R = n-C3H7 (3l)/24 h/85%

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Accordingly, MBH-acetate 1a was treated with 5,5-dimethyl-1,3-cyclohexanedione (2d) under CuI/K₂CO₃ conditions and the formation of spiro-carbocycle 3g in 80% yield was observed. Similarly, 1b was also reacted with 2d to give the spiro-cycle 3h in 83% yield. This success encouraged us to study the reactivity of additional cyclic bisnucleophiles such as 1,3-cyclopentanedione (2e) and 3,3-dimethyl barbutyric acid (2f), with MBH-acetates 1a and 1b. Interestingly, all these reactions afforded the corresponding spiro-cyclopentene derivatives, 3i to 3k, in good yields. Noteworthy to mention that, to the best of our knowledge there is only one example known in the literature using cyclic-1,3-diketone towards cyclopentane synthesis in Conia-ene reaction.¹² Therefore, the present method provides an easy access to spiro-cyclopentenes. Additionally, the reaction of phenyl sulphonylacetophenone (2g) with MBH-acetate 1a also afforded the corresponding cyclopentene 3l in 85% yield. The stereo chemical assignment of exocyclic trisubstituted olefin was studied on compound 3b using NOE experiments, which showed as Z-geometry (Fig. 2).

Fig. 2 Key NOE enhancement of compound 3b.

We continued to elucidate the scope of the present [4 + 1]-annulation with MBH-acetate 1c having terminal alkyne functionality. The reactions of 1c with different acyclic bisnucleophiles 2a and 2b as well as the cyclic bisnucleophile 2d progressed successfully to give the corresponding methylene-cyclopentenes 3m, 3n and 3o, respectively (Scheme 2).

Scheme 2 Reactions of MBH-acetate 1c.

Finally, the reactions of MBH-acetates bearing aryl groups on the alkyne with cyclic active methylene 2d were also investigated fruitfully to obtain the corresponding arylidene spiro-cyclopentenes 3p and 3q in 85% and 81% yield, respectively. It is important to disclose that these reactions furnished the inseparable mixture of compounds in the absence of CuI (Scheme 3).

Scheme 3 Reactions of MBH-acetates 1d and 1e.

A possible reaction mechanism is shown in Scheme 4. In the first step, MBH-acetate 1a reacts with 2a in the presence of base to provide mono-alkylated compound 5a.¹³ Then, it is anticipated that CuI promotes the K₂CO₃-mediated 5-exo-dig-carbocyclization through I and II involving anti-addition on alkyne to give the cyclopentene 3a.^10a,b The intermediate compound 5a was isolated and fully characterized (entry 5, Table 1). Further, 5a was also independently treated with 30 mol%-CuI/K₂CO₃ in DMF and the successful formation of 3a was observed. This method is a new variation of Conia-ene type reaction, providing cyclopentenes having Z-geometry on exocyclic olefin, while in the Conia-ene reaction the products are cyclopentanes with E-geometry as it proceeds through a concerted transition state leading to syn-addition to the alkyne.

Scheme 4 Proposed mechanism.

Conclusions

In summary, we have developed an approach to the construction of functionalized cyclopentenes using copper-mediated tandem cyclization reactions of MBH-acetates of acetylenic aldehydes and active methylene compounds. This approach allows one to make the methylidene, alkylidene as well as arylidene cyclopentenes in a single step with a wide substrate scope. The synthesis of various spiro cyclic-cyclopentenes is a salient feature of the method. We believe that the present protocol is a complementary approach to the existing methods, which can find applications in the synthesis of cyclopentenes.

Experimental

General

All the reactions were performed under nitrogen in oven-dried glassware. Commercially available reagents were used, unless otherwise indicated. Solvents ethyl acetate and petroleum ether were distilled prior to use for column chromatography. Column chromatography was carried out with silica gel (60–120 mesh). ¹H and ¹³C NMR spectra were recorded in CDCl₃ with 300 MHz and 500 MHz instruments at ambient temperature. Chemical shifts were measured in ppm scale with TMS as internal reference and coupling constants were expressed in Hertz (Hz). The shifts were measured relative to the TMS (0 ppm) and CDCl₃ (77.0 ppm). All ¹³C NMR spectra were proton decoupled. Infrared (IR) spectra were recorded on a Perkin-Elmer 400 FTIR spectrophotometer as KBr matrix. High resolution mass spectra (HRMS) were recorded on Agilent Technologies 6510 Q-TOF spectrometer.

General experimental procedure. To a stirred solution of MBH-acetate 1 (1.0 mmol) and active methylene compound 2 (1.1 mmol) in DMF (5.0 mL) at 0 °C, CuI (0.3 mmol) and K₂CO₃ (2.0 mmol) were added under N₂ atmosphere. Then the resulting heterogeneous mixture was slowly (∼20 min) brought to rt and continued stirring at rt for the specified time. After completion of the reaction (monitored by TLC), it was diluted with ethyl acetate (50 mL) and washed with cold water (2 × 20 mL) and brine (15 mL). The ethyl acetate layer was dried over Na₂SO₄ and concentrated under reduced pressure to obtain the crude material. Then, it was purified by column chromatography over silica gel to get the corresponding cyclopentene 3.

(Z)-1-Ethyl-3-methyl-5-butylidene-1-cyanocyclopent-3-ene-1,3-dicarboxylate (3a). Yield 74%; colorless liquid; ¹H NMR (CDCl₃, 300 MHz): δ 6.91 (br s, 1H), 6.01 (t, J = 7.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.41 (s, 2H), 2.50–2.34 (m, 1H), 2.29–2.13 (m, 1H), 1.57–1.39 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). 0.96 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 167.4, 164.2, 141.3, 141.0, 136.2, 133.4, 117.9, 63.3, 51.8, 46.8, 44.0, 31.1, 22.0, 13.9, 13.6; IR (KBr): [small nu, Greek, tilde]_max 2961, 2873, 2245, 1743, 1717, 1610, 1252, 1110, 1051, 746 cm⁻¹; MS (ESI): m/z 300 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₅H₂₀NO₄ (M + H)⁺: 278.1387, found: 278.1398.

(Z)-1-Ethyl-3-methyl-1-cyano-5-heptylidenecyclopent-3-ene-1,3-dicarboxylate (3b). Yield 72%; brown liquid, ¹H NMR (CDCl₃, 300 MHz): δ 6.91 (s, 1H), 6.01 (t, J = 7.5 Hz, 1H), 4.29 (q, J = 7.5 Hz, 2H), 3.78 (s, 3H), 3.41 (s, 2H), 2.50–2.35 (m, 1H), 2.30–2.13 (m, 1H), 1.53–1.21 (m, 11H), 0.88 (t, J = 6.8 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 167.3, 164.1, 141.2, 140.8, 136.4, 133.4, 117.9, 63.2, 51.8, 46.8, 43.9, 31.5, 29.3, 28.9, 22.4, 28.6, 13.9, 13.8; IR (KBr): [small nu, Greek, tilde]_max 3452, 2928, 2857, 2245, 1740, 1717, 1611, 1251, 1094, 747 cm⁻¹; MS (ESI): m/z 342 (M + H)⁺; HRMS (ESI): m/z calcd for C₁₉H₁₉O₅NNa (M + Na)⁺: 364.1155, found: 364.1171.

(Z)-1-Ethyl-3-methyl-1-acetyl-5-butylidenecyclopent-3-ene-1,3-dicarboxylate (3c). Yield 62%; brown liquid; ¹H NMR (CDCl₃, 300 MHz): δ 6.91 (s, 1H), 6.02 (t, J = 7.5 Hz, 1H), 4.30–4.08 (m, 2H), 3.77 (s, 3H), 3.49 (d, J = 18.1 Hz, 1H), 3.08 (d, J = 18.1 Hz, 1H), 2.43–1.92 (m, 5H), 1.52–1.35 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 202.0, 170.3, 164.9, 143.9, 141.4, 137.2, 132.8, 67.9, 61.8, 51.7, 40.6, 32.1, 25.7, 22.2, 13.8, 13.9; IR (KBr): [small nu, Greek, tilde]_max 3450, 2960, 1714, 1610, 1251, 1102, 751, 622 cm⁻¹ MS (ESI): m/z 312 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₆H₂₃O₅ (M + H)⁺ 295.1540, found 295.1556.

(Z)-1-Ethyl-3-methyl-1-acetyl-5-heptylidenecyclopent-3-ene-1,3-dicarboxylate (3d). Yield 65%; brown liquid; ¹H NMR (CDCl₃, 300 MHz): δ 6.91 (s, 1H), 6.02 (t, J = 7.5 Hz, 1H), 4.29–4.16 (m, 2H), 3.77 (s, 3H), 3.49 (d, J = 18.1 Hz, 1H), 3.09 (d, J = 18.1 Hz, 1H), 2.37–1.94 (m, 5H), 1.43–1.21 (m, 11H), 0.88 (t, J = 7.5 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): 202.2, 170.3, 165.5, 143.3, 141.3, 137.4, 135.1, 61.8, 61.3, 51.7, 50.1, 40.7, 31.6, 30.2, 29.1, 29.0, 25.8, 22.5, 14.0; IR (KBr): [small nu, Greek, tilde]_max 2928, 1716, 1610, 1251, 1437, 772, 623 cm⁻¹; MS (ESI): m/z 359 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₉H₂₉O₅ (M + H)⁺: 337.2010, found: 337.2021.

(E/Z)-1-Ethyl-3-methyl-5-butylidene-1-picolinoylcyclopent-3-ene-1,3-dicarboxylate (3e). Yield 57%; (28 : 72 E : Z). Brown liquid; ¹H NMR (CDCl₃, 300 MHz): δ 8.71–8.56 (m, 1H), 8.12–8.04 (m, 1H), 7.90–7.79 (m, 1H), 7.55–7.37 (m, 1H), 6.92 (s, 1H), 6.10 (t, J = 7.9 Hz, 1H), 4.27–3.90 (m, 3H), 3.73 (s, 3H), 2.92 (d, J = 18.9 Hz, 1H), 2.46–2.10 (m, 2H), 1.54–1.18 (m, 2H), 1.06 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 193.8, 170.6, 165.2, 151.3, 148.1, 144.1, 141.0, 137.5, 136.8, 134.9, 126.8, 123.3, 61.2, 51.4, 43.3, 40.7, 31.9, 22.3, 13.8, 13.6; IR (KBr): [small nu, Greek, tilde]_max 3450, 2959, 1708, 1613, 1244, 1186, 770 cm⁻¹; MS (ESI): m/z 379 (M + Na)⁺ HRMS (ESI): m/z calcd for C₂₀H₂₄O₅N (M + H)⁺: 358.1649, found 358.1642.

(E/Z)-1-Ethyl-3-methyl-5-heptylidene-1-picolinoylcyclopent-3-ene-1,3-dicarboxylate (3f). Yield 52%; (20 : 80 E : Z); brown liquid; ¹H NMR (CDCl₃, 300 MHz): δ 8.60 (d, J = 3.7 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.85 (dt, J = 7.5, 1.5 Hz, 1H), 7.43 (dt, J = 7.5, 1.5 Hz, 1H), 6.92 (s, 1H), 6.10 (t, J = 7.5 Hz, 1H), 4.25–4.05 (m, 2H), 3.99 (d, J = 18.8 Hz, 1H), 3.72 (s, 3H), 2.92 (d, J = 18.8 Hz, 1H), 2.19 (q, J = 7.5 Hz, 2H), 1.39–1.23 (m, 8H), 1.06 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 193.8, 170.6, 165.3, 151.5, 148.1, 144.1, 141.0, 137.7, 136.8, 132.9, 126.7, 123.3, 64.1, 61.2, 51.4, 43.4, 31.7, 30.0, 29.2, 29.0, 22.5, 14.0, 13.7; IR (KBr): [small nu, Greek, tilde]_max 3450, 2926, 2855, 1709, 1611, 1436, 1244, 1097, 747 cm⁻¹; MS (ESI): m/z 400 (M + H)⁺; HRMS (ESI): m/z calcd for C₂₃H₂₉O₅NNa (M + Na)⁺: 422.1937, found 422.1950.

(Z)-Methyl-4-butylidene-8, 8-dimethyl-6,10-dioxospiro[4.5]dec-2-ene-2-carboxylate (3g). Yield 80%; semi solid; ¹H NMR (CDCl₃, 300 MHz): δ 6.98 (br. s, 1H), 6.15 (t, J = 7.3 Hz, 1H), 3.72 (s, 3H), 3.09 (s, 2H), 2.90 (d, J = 14.5 Hz, 2H), 2.54 (d, J = 14.5 Hz, 2H), 1.79–1.52 (m, 3H), 1.51–1.35 (m, 1H), 1.22 (s, 3H), 1.03 (s, 3H), 0.87 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 203.7, 187.3, 145.5, 139.2, 136.7, 129.1, 72.8, 51.6, 51.3, 44.7, 33.8, 31.1, 30.3, 27.1, 21.7, 13.8; IR (KBr): [small nu, Greek, tilde]_max 2956, 2874, 1709, 1604, 1244, 1185, 1106, 1062, 747 cm⁻¹; MS (ESI): m/z 327 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₈H₂₄NaO₄ (M + Na)⁺ 327.1567, found 327.1568.

(Z)-Methyl-4-heptylidene-8,8-dimethyl-6,10-dioxospiro[4.5]dec-2-ene-2-carboxylate (3h). Yield 83%; pale yellow semi solid; ¹H NMR (CDCl₃, 300 MHz): δ 6.97 (s, 1H), 6.15 (t, J = 7.5 Hz, 1H), 3.72 (s, 3H), 3.09 (s, 2H), 2.89 (d, J = 14.3 Hz, 2H), 2.53 (d, J = 14.3 Hz, 2H), 1.43–1.09 (m, 11H), 0.96–0.81 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz): 205.4, 164.8, 143.4, 137.4, 134.8, 131.3, 72.3, 51.8, 37.9, 31.5, 30.0, 29.8, 29.6, 29.4, 29.5, 28.7, 27.8, 22.4, 13.98; IR (KBr): [small nu, Greek, tilde]_max 3409, 2955, 2858, 1704, 1608, 1437, 1250, 1093, 74–8 cm⁻¹; MS (ESI): m/z 369 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₁H₃₁O₄ (M + H)⁺: 347.2217, found: 347.2213.

(Z)-Methyl-4-butylidene-6,9-dioxospiro[4.4]non-2-ene-2 carboxylate (3i). Yield 63%; colorless oil; ¹H NMR (CDCl₃, 500 MHz): δ 6.99 (t, J = 1.6 Hz, 1H), 5.86 (t, J = 7.6 Hz, 1H), 3.74 (s, 3H), 3.06–2.98 (m, 2H), 2.93 (s, 2H), 2.92–2.84 (m, 2H), 1.76–1.52 (m, 2H), 1.63 (quintet, J = 7.4 Hz, 1H), 1.38 (sextet, J = 7.4 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 212.1, 164.4, 143.7, 132.9, 132.3, 126.3, 64.0, 51.7, 43.2, 35.5, 34.0, 21.9, 13.7; IR (KBr): [small nu, Greek, tilde]_max 2959, 2872, 1722, 1436, 1252, 1173, 1107, 747 cm⁻¹; MS (ESI): m/z 285 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₅H₁₈NaO₄ (M + Na)⁺: 285.1097, found: 285.1104.

(Z)-Methyl-4-heptylidene-6,9-dioxospiro[4.4]non-2-ene-2-carboxylate (3j). Yield 59%; brown liquid; ¹H NMR (CDCl₃, 300 MHz): δ 6.99 (s, 1H), 5.86 (t, J = 7.5 Hz, 1H), 3.74 (s, 3H), 3.27–3.10 (m, 6H), 1.76–1.52 (m, 2H), 1.37–1.17 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 212.0, 164.4, 143.7, 143.5, 132.8, 132.5, 64.0, 51.7, 43.1, 35.5, 32.1, 31.4, 28.8, 28.5, 22.3,13.9; IR (KBr): [small nu, Greek, tilde]_max 2929, 1725, 1437, 1254, 1108, 991, 772 cm⁻¹; MS (ESI): m/z 327 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₈H₂₅O₄ (M + H)⁺: 305.1747, found 305.1735.

(Z)-Methyl-4-butylidene-7,9-dimethyl-6,8,10-trioxo-7,9-diazaspiro[4.5]dec-2-ene-2-carboxylate (3k). Yield 86%; pale yellow solid, m. p = 126–128 °C; ¹H NMR (CDCl₃, 500 MHz): δ 7.02 (s, 1H), 5.91 (t, J = 7.7 Hz, 1H), 3.76 (s, 3H), 3.36 (s, 6H), 3.23 (s, 2H), 1.75 (t, J = 7.3 Hz, 2H), 1.37 (q, J = 7.3 Hz, 2H), 0.83 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 170.0, 164.3, 150.8, 145.6, 142.7, 133.8, 132.8, 56.4, 51.7, 46.8, 31.9, 28.8, 21.8, 13.7; IR (KBr): [small nu, Greek, tilde]_max 3420, 3084, 2961, 2925, 2853, 1679, 1749, 1609, 1440, 1376, 1284, 1108, 1052, 752 cm⁻¹; MS (ESI): m/z 343 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₆H₂₁O₅N₂ (M + H)⁺: 321.1445, found: 341.1444.

(Z)-Methyl-4-benzoyl-3-butylidene-4-(phenylsulfonyl)cyclopent-1-enecarboxylate (3l). Yield 85%; brown liquid; ¹H NMR (CDCl₃, 500 MHz): δ 8.08 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.58–7.46 (m, 4H), 7.39–7.33 (m, 2H), 6.91 (s, 1H), 6.10 (dd, J = 6.4, 9.1 Hz, 1H), 3.82 (d, J = 19.6 Hz, 1H), 3.76 (s, 3H), 3.45 (d, J = 19.6 Hz, 1H), 2.13–2.05 (m, 1H), 1.81–1.71 (m, 1H), 1.17–1.06 (m, 1H), 0.83–0.72 (m, 1H), 0.56 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 193.0, 164.2, 144.2, 141.3, 140.3, 136.7, 131.5, 133.8, 133.7, 133.1, 128.5, 128.2, 128.3, 82.6, 51.8, 40.9, 31.9, 21.6, 13.4; IR (KBr): [small nu, Greek, tilde]_max 2957, 2928, 2866, 1711, 1680, 1441, 1315, 1247, 1144, 1082, 765, 687, 603 cm⁻¹.

1-Ethyl-3-methyl-1-cyano-5-methylenecyclopent-3-ene-1,3-dicarboxylate (3m). Yield 64%; brown solid, m. p = 98–100 °C; ¹H NMR (CDCl₃, 300 MHz): δ 6.95 (s, 1H), 5.69 (s, 1H), 5.61 (s, 1H), 4.40–4.25 (m, 2H), 3.81 (s, 3H), 3.60 (d, J = 18.1 Hz, 1H), 3.30 (d, J = 18.1 Hz, 1H), 1.33 (t, J = 7.5 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): 166.2, 163.9, 149.1, 138.5, 138.2, 118.5, 116.2, 63.6, 52.6, 48.6, 41.5, 13.8; IR (KBr): [small nu, Greek, tilde]_max 3445, 2958, 2247, 1738, 1712, 1246, 1089, 938, 751, 622 cm⁻¹; elemental analysis: C 61.44, N 5.87, H 5.22.

1-Ethyl-3-methyl-1-acetyl-5-methylenecyclopent-3-ene-1,3-dicarboxylate (3n). Yield 57%; brown liquid; ¹H NMR (CDCl₃, 300 MHz): δ 6.93 (s, 1H), 5.64 (s, 1H), 5.53 (s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.49 (d, J = 18.1 Hz, 1H), 3.16 (d, J = 18.1 Hz, 1H), 2.22 (s, 3H), 1.29 (t, J = 6.8 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 200.6, 169.6, 164.6, 148.8, 140.9, 137.1, 117.4, 68.5, 62.0, 51.8, 38.8, 29.6, 13.9; IR (KBr): [small nu, Greek, tilde]_max 3456, 2958, 2957, 1736, 1253, 1102, 770 cm⁻¹; MS (ESI): m/z 291 (M + K).

Methyl-8,8-dimethyl-4-methylene-6,10-dioxospiro[4.5]dec-2-ene-2-carboxylate (3o). Yield 73%; white solid, m. p = 144–146 °C; ¹H NMR (CDCl₃, 300 MHz): δ 6.74 (s, 1H), 5.51 (s, 1H), 5.21 (s, 1H), 3.78 (s, 3H), 3.28 (s, 2H), 2.85 (d, J = 15.1 Hz, 2H), 2.63 (d, J = 15.1 Hz, 2H), 1.16 (s, 3H), 0.94 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 204.2, 164.5, 151.4, 139.6, 138.5, 113.9, 72.9, 51.5, 37.6, 29.84, 29.5, 27.6; IR (KBr): [small nu, Greek, tilde]_max 3401, 3077, 2957, 2861, 1715, 1612, 1250, 1090, 646 cm⁻¹; MS (ESI): m/z 285 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₅H₁₉O₄ (M + H)⁺: 263.1278, found 263.1264.

(Z)-Methyl-4-benzylidene-8,8-dimethyl-6,10-dioxospiro[4.5]dec-2-ene-2-carboxylate (3p). Yield 85%; white solid, m. p = 107–109 °C; ¹H NMR (CDCl₃, 300 MHz): δ 7.32–7.18 (m, 3H), 7.13 (d, J = 7.7 Hz, 2H), 7.05 (d, J = 7.7 Hz, 2H), 3.76 (s, 3H), 3.05 (s, 2H), 2.55 (d, J = 15.6 Hz, 2H), 2.09 (d, J = 15.6 Hz, 2H), 0.99 (s, 3H), 0.36 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 206.0, 164.3, 144.7, 136.7, 132.2, 133.1, 128.9, 127.9, 127.3, 70.5, 51.7, 51.2, 45.8, 29.9, 27.2, 29.4; IR (KBr): [small nu, Greek, tilde]_max 3392, 2948, 1707, 1604, 1433, 1360, 1259, 1241, 1094, 930, 749, 637 cm⁻¹; MS (ESI): m/z 361 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₁H₂₂NaO₄ (M + Na)⁺: 361.1410, found 361.1413.

(Z)-Methyl-4-(4-methoxybenzylidene)-8,8-dimethyl-6,10-dioxospiro[4.5]dec-2-ene-2-carboxylate (3q). Yield 81%; white solid, m. p = 127–129 °C; ¹H NMR (CDCl₃, 300 MHz): δ 7.13 (s, 1H), 7.06 (s, 1H), 6.97 (d, J = 8.6, 2H), 6.77 (d, J = 8.6 Hz, 2H), 3.76 (s, 6H), 3.06 (d, J = 1.5 Hz, 2H), 2.59 (d, J = 15.8 Hz, 2H), 2.16 (d, J = 15.8 Hz, 2H), 1.02 (s, 3H), 0.48 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 206.1, 164.5, 158.9, 145.1, 144.5, 132.5, 132.4, 130.3, 129.2, 113.4, 70.9, 55.2, 51.7, 51.3, 45.9, 30.2, 29.6, 27.5; IR (KBr): [small nu, Greek, tilde]_max 3397, 2957, 1703, 1604, 1509, 1246, 1178, 1.31, 830, 637 cm⁻¹; MS (ESI): m/z 391 (M + Na)⁺; HRMS (ESI): m/z calcd for C₂₂H₂₄O₅ (M + H)⁺: 369.1697, found 369.1697.

(E)-1-Ethyl-5-methyl-2-cyano-4-(hex-2-yn-1-ylidene) pentanedioate (5a). Yield 82%; colorless liquid; ¹H NMR (CDCl₃, 500 MHz): δ 6.87 (t, J = 2.2 Hz, 1H), 4.31–4.23 (m, 2H), 3.96 (dd, J = 7.1, 9.0 Hz, 1H), 3.79 (s, 3H), 3.21–3.09 (m, 2H), 2.43 (dt, J = 2.2, 7.0 Hz, 2H), 1.62 (dd, J = 7.1, 7.3 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz): δ 166.1, 165.4, 148.2, 134.8, 115.8, 107.2, 76.5, 62.8, 52.2, 39.8, 36.1, 29.4, 21.9, 13.8, 13.4; IR (KBr): [small nu, Greek, tilde]_max 2964, 2874, 2213, 1748, 1714, 1438, 1266, 1200, 1097, 1031, 758 cm⁻¹; MS (ESI): m/z 300 (M + Na)⁺; HRMS (ESI): m/z calcd for C₁₅H₂₀NaNO₄ (M + Na)⁺: 300.1206, found: 300.1221.

Acknowledgements

P. K thank the Council of Scientific and Industrial Research (CSIR), New Delhi, for research fellowship. C. R. R is grateful to DST, New Delhi for funding this project (SR/S1/OC-66/2011).

Notes and references

1. (a) J. A. Marshall and S. F. Brady, J. Org. Chem., 1970, 35, 4068; (b) R. Kaiser and P. Naegeh, Tetrahedron Lett., 1972, 13, 2009; (c) B. Diblas, E. Faitorusso, S. Magno, L. Mayoi, C. Pedone, C. Santacroci and D. Sica, Tetrahedron, 1976, 32, 473; (d) C. Pathirana, W. Fenical, E. Corcoran and J. Clardy, Tetrahedron Lett., 1993, 34, 3371; (e) P. W. Collins and S. W. Djuric, Chem. Rev., 1993, 93, 1533; (f) R. J. Clark, B. L. Stapleton and M. J. Garson, Tetrahedron, 2000, 56, 3071; (g) W. Oppolzer and F. Flachsmann, Helv. Chim. Acta, 2001, 84, 416; (h) R. H. Chen and M. A. Xiang, US2002/0111484 A1, USA, 2002; (i) S. Das, S. Chandrasekhar, J. S. Yadav and R. Gree, Chem. Rev., 2007, 107, 3286; (j) H. Zhi-You, L. Dong, L. Huan, L. Yan-Fei, N. Gang, Z. Qing-Jian, L. Li, S. Yi-Kang, S. Hua, C. Ruo-Yun and Y. De-Quan, J. Nat. Prod., 2012, 75, 1083; (k) C. D. Manoj, A. M. Nicholas and E. T. David, Successful Strategies for the Discovery of Antiviral Drugs, RSC Drug discovery, 2013, U. K.
2. For selected references, see: (a) J. M. Conia and P. L. Perchec, Synthesis, 1975, 1; (b) G. Mandville and J. M. Conia, Nouv. J. Chim., 1981, 5, 137; (c) N. Tsukada and Y. Yamamoto, Angew. Chem., Int. Ed. Engl., 1997, 36, 2477; (d) J. J. Kennedy-Smith, S. T. Staben and F. D. Toste, J. Am. Chem. Soc., 2004, 126, 4526; (e) S. Montel, D. Bouyssi and G. Balme, Adv. Synth. Catal., 2010, 352, 2315; (f) C. L. Chin, C. F. Liao, H. J. Liu, Y. C. Wong, M. T. Hsieh, P. K. Amancha, C. P. Chang and K. S. Shia, Org. Biomol. Chem., 2011, 9, 4778; (g) A. Matsuzawa, T. Mashiko, N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2011, 50, 7616.
3. (a) G. Fournet, G. Balme and J. Gore, Tetrahedron, 1991, 47, 6293; (b) H. Ito, Y. Makida, A. Ochida, H. Ohmiya and M. Sawamura, Org. Lett., 2008, 10, 5051; (c) D. Chen-Liang, S. Ren-Jie, L. Yi-Lin and L. Jin-Heng, Adv. Synth. Catal., 2009, 351, 3096; (d) L. Yan Chan, S. Kim, Y. Park and P. H. Lee, J. Org. Chem., 2012, 77, 5239.
4. (a) G. Fournet, G. Balme and J. Gore, Tetrahedron, 1991, 47, 6293; (b) H. Ito, Y. Makida, A. Ochida, H. Ohmiya and M. Sawamura, Org. Lett., 2008, 10, 5051; (c) D. Chen-Liang, S. Ren-Jie, L. Yi-Lin and L. Jin-Heng, Adv. Synth. Catal., 2009, 351, 3096; (d) L. Yan Chan, S. Kim, Y. Park and P. H. Lee, J. Org. Chem., 2012, 77, 5239.
5. (a) L. Sheng, L. Xiao-Hua, S. Yun-Heng, L. Hui-Liang, S. Lei, L. Run-Hui, X. Xi-Ke, Z. Wei-Dong, C. Tao and W. Hui, J. Nat. Prod., 2010, 73, 632; (b) N. Baldovini, S. Lavoine-Hanneguelle, G. Ferrando, G. Dusart and L. Lizzani-Cuvelier, Phytochemistry, 2005, 66, 1651; (c) N. H. Andersen, M. S. Falcone and D. D. Syrdal, Tetrahedron Lett., 1970, 11, 1759; (d) C. Xing-Yun, S. Jian-Fan, T. Li-Ying, Y. Xian-Wen, L. Yun-Qiu, H. Hui, Z. Xue-Feng, Y. Bin and L. Yonghong, Chem. Pharm. Bull., 2010, 58, 1391; (e) L. G. Cool, K. E. Vermillion, G. R. Takeoka and R. Y. Wong, Phytochemistry, 2010, 71, 1545; (f) Y.-M. Zhang, N.-H. Tan, M. He, Y. Lu, S.-Q. Shang and Q.-T. Zheng, Tetrahedron Lett., 2004, 45, 4319.
6. C. R. Reddy, P. Kumaraswamy and M. D. Reddy, Org. Biomol. Chem., 2012, 10, 9052.
7. For reviews on MBH-reaction, see: (a) K. Y. Lee, S. Gowrisankar and J. N. Kim, Bull. Korean Chem. Soc., 2005, 26, 1481; (b) V. Singh and S. Batra, Tetrahedron, 2008, 64, 4511; (c) V. Declerck, J. Martinez and F. Lamaty, Chem. Rev., 2009, 109, 1; (d) D. Basavaiah and D. V. Lenin, Eur. J. Org. Chem., 2010, 5650; (e) D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010, 110, 5447.
8. (a) F. Roth, P. Gygax and G. Frater, Tetrahedron Lett., 1992, 33, 1045; (b) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001, 34, 535; (c) Y. Du, X. Lu and C. Zhang, Angew. Chem., Int. Ed., 2003, 42, 1035; (d) Y. Du, J. Feng and X. Lu, Org. Lett., 2005, 7, 1987; (e) M. E. Krafft and T. F. N. Haxell, J. Am. Chem. Soc., 2005, 127, 10168; (f) J. Feng, X. Lu, A. Kong and X. Han, Tetrahedron, 2007, 63, 6035; (g) S. Zheng and X. Lu, Org. Lett., 2008, 10, 4481; (h) S. Zheng and X. Lu, Org. Lett., 2009, 11, 3978; (i) S. Zheng and X. Lu, Tetrahedron Lett., 2009, 50, 4532; (j) Q. Zhang, L. Yang and X. Tong, J. Am. Chem. Soc., 2010, 132, 2550; (k) M. Schuler, A. Voituriez and A. Marinetti, Tetrahedron: Asymmetry, 2010, 21, 1569; (l) H. P. Deng, Y. Wei and M. Shi, Org. Lett., 2011, 13, 3348; (m) R. Zhou, J. Wang, H. Song and Z. He, Org. Lett., 2011, 13, 580; (n) B. Tan, N. R. Candeias and C. F. Barbas, J. Am. Chem. Soc., 2011, 133, 4672; (o) F. Zhong, X. Han, Y. Wang and Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 7837; (p) H.-P. Deng, D. Wang, Y. Wei and M. Shi, Beilstein J. Org. Chem., 2012, 8, 1098.
9. (a) C. R. Reddy, M. D. Reddy, B. Srikanth and K. R. Prasad, Org. Biomol. Chem., 2011, 9, 6027; (b) C. R. Reddy, M. D. Reddy and B. Srikanth, Org. Biomol. Chem., 2012, 10, 4280; (c) C. R. Reddy, V. R. Rani and M. D. Reddy, J. Org. Chem., 2013, 78, 6495.
10. (a) D. Bouyssi, G. Balme and J. Gore, Tetrahedron Lett., 1991, 32, 6541; (b) D. Bouyssi, N. Monteiro and G. Balme, Tetrahedron Lett., 1999, 40, 1297; (c) N. Coia, D. Bouyssi and G. Balme, Eur. J. Org. Chem., 2007, 3158.
11. The prolonged reaction time (48 h) under K₂CO₃ (2.5 equiv.)/CuI (0.1 equiv.) resulted in the decomposition of intermediate 5a and the yield of the product 3a remained the same.
12. M. A. Boaventura, J. Drouin and J. M. Conia, Synthesis, 1983, 801.
13. (a) Y. J. Im, J. M. Kim and J. N. Kim, Bull. Korean Chem. Soc., 2002, 23, 1361; (b) A. Nakano, M. Ushiyama, Y. Iwabuchi and S. Hatakeyama, Adv. Synth. Catal., 2005, 347, 1790.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H NMR and ¹³C NMR spectra of all the new compounds. See DOI: 10.1039/c3ra46229c

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