Application of Flow Thermolysis in Organic Synthesis: Easy Access to α,ω-Bis Thienyl- and Bis Pyrrolyl- Alkanes from Methylene Derivatives of Meldrum's Acid

Abstract

Thermal decomposition of Meldrum's acid derivatives and rearrangement of (alkylsulfanyl) or (propargylamino)methylene ketene intermediates leads in one step to bis thienyl- or bis pyrrolyl-alkanes.

Introduction

The highly reactive hetero-substituted methyleneketene intermediates 2 can be easily generated by thermolysis of the corresponding Meldrum's acid derivatives 1 [1,2,3,4] and can undergo various thermal reactions depending on the nature of both the heteroatom X and the chain (CH₂)_nY. Alkoxymethyleneketenes 2 (X=O; Y=H; R=H,CH₃) are reasonably stable in solution at room temperature, and seem to be the most stable ones [3] .

A 1,4-hydrogen shift takes place during the thermolysis of methyleneketenes 2 bearing a tertiary alkylamino or allylamino substituent (X=NR'; Y=H, Me, CH=CH₂) [5,6] and the cyclisation of the ketenic ylides thus formed yields 1H-pyrrol-3(2H)-ones 3 (X=NR'), possibly accompanied by dihydroazepinones 4 (Scheme 1).

On the other hand, an intramolecular addition to the central double bond of the aminomethyleneketenes 2 ( X=NR' ) can also be observed when a nucleophilic group (Y= O, NMe) is present at the ω-position of the side chain (Scheme 2) .This cyclisation, which is performed under reduced pressures, constitutes an efficient access to the macrolactones and macrolactams 5 (n = 2-12 ) [7,8] .

We have also observed such an intramolecular nucleophilic addition with alkylsulfanyl methyleneketenes 2 (X = S) bearing on the sulfur atom an ω-hydroxy or ω−mercaptoethyl- or propyl substituent (Y= O, S; n=2,3) [9]. In order to extend this methodology to the synthesis of large sized sulfur heterocycles (n >3), we decided to examine the thermal behaviour of Meldrum's acid derivatives 1a (X = S; n=6; Y = S) and 1b ( X = S; n=6; Y = S(CH₂)₂O ) .

Results and discussion

The derivatives 1a,b were easily prepared from the methoxymethylene Meldrum's acid derivative 8 and 1,6-hexanedithiol 6a or 9-mercapto-3-thianonanol 6b (Scheme 3).

The thermolysis of 1a at 630°C ( 5x10^-2Torr) did not give the expected thiolactone 5a; instead a mixture of 3-hydroxythiophene 9a and its tautomer 9'a (Scheme 4) was isolated after flash chromatography on silica gel (9a/9'a = 9/1, 51% yield) .

The thermolysis of 1b, under the same conditions, gave a similar result: the lactone 5b was never detected and a mixture of thiophenes 9b and 9'b (Scheme 4) was obtained in 76% yield (9b/9'b = 9/1). Thus, whereas the ω−aminoalkyl or hydroxyalkyl aminomethyleneketenes (X= NR'; Y=NMe,O ; n=2-12) essentially led to enaminolactams or lactones 5 [7,8] the alkylsulfanyl methyleneketenes 2 bearing a large functionalised hydrocarbon chain (X=S; n >3) only provided hydroxythiophenes 9. The absence of large sized lactones or thiolactones 5a,b well illustrates the specific thermal behaviour of these alkylsulfanyl methyleneketenes 2a,b: the 1,4-hydrogen migration involving the rearrangement of 2a,b into planar dipolar species 7a,b [3,10] seems to be favored in that case; on the contrary, the intramolecular addition was favored in the case of alkylsulfanyl intermediates 2 with smaller ω−mercapto or ω-hydroxyalkyl chains (n=1-2) [9] .

The symmetrically substituted hexane 1c was prepared by treatment of 1,6-hexanedithiol 6a with two equivalents of enol ether 8 (Scheme 5) .The derivative 1c exhibited similar thermal behaviour and afforded at 610°C the 1,4-bis (2'-(3'-hydroxythienyl)) butane 9c, in equilibrium with its tautomeric keto form 9'c (80% yield).These compounds reacted with an excess of acetic anhydride to give exclusively the 1,4-bis(2'(3'-O-acetylated thienyl)) butane 10c (47%) . This method constitutes an easy access to the α-ω bis thienyl alkanes .

In order to compare the thermal behaviour of N-propargylamino methyleneketenes to that of Nallylamino methyleneketenes giving five and seven membered cyclic enaminones 3 and 4 (Scheme 1; X = NR'; n = 1; Y: CH=CH₂) [5], we have also examined the thermal decomposition of Meldrum's acid derivatives 1d,e (X = NR'; n=1; Y= C≡CH). N-propargyl aminomethylene Meldrum's acid derivative 1d was prepared from N-methylpropargylamine and enol ether 8 (70% yield). Flashvacuum pyrolysis of 1d was investigated in the temperature range 560-620°C (p=10^-5 Torr, pyrolysis products trapped in methanol matrix at -196° C) . An unexpected thermal rearrangement was observed during the pyrolysis of 1d: the aza-analogue of hydroxythiophene (2-ethynyl-3-hydroxypyrrole 3d) was never observed, but the unexpected 1,2-bis(2'-(N-methylpyrrolyl)) ethane 10d (Scheme 6) was the only product isolated from methanol matrix (42% after purification by liquid chromatography).

The ¹H-NMR spectrum (two doublets at 6.06 and 6.18 ppm, and only one signal at 6.65 ppm for aromatic protons), supported this structure and confirmed the link at the C₂ position of the two pyrrole moieties. In mass spectroscopy, the molecular ion M⁺ (188) was recorded in presence of the base peak at m/e 94 which indicates the symmetrical structure of 10d.¹³C-NMR data also confirmed this structural assignment (cf. Experimental Section: quaternary carbon at 132.8 ppm).

This methodology was extended to the preparation of bis pyrrolizinylethane (Scheme 7). The derivative 1e, easily obtained from N-propargylpyrrolidin-2-one [11], was submitted to thermolysis (T= 560-620°C; p = 10^-5 Torr) and afforded also the 1,2-bis(2,3-dihydro-1H-pyrrolizinyl)ethane 10e (34 %: significant formation of tar on the inner side of apparatus) .

In the ¹H-NMR spectrum only two aromatic protons were detected at 5.77 and 6.0 ppm for 10e, that indirectly corroborated the structure of 10d which in addition exhibited an aromatic proton at 6.65 ppm. Both of these results indicated that a new thermal rearrangement had taken place during the thermolysis of these N-propargylamino methyleneketenes. A priori, the derivatives 1d,e were expected to behave like the N-allyl analogues which after thermal decomposition lead to the enaminones 3 and 4 (Scheme 1) [5]. In reality, the corresponding ethynylenaminone 3d,e was never detected in the crude product. The bis-pyrrolyl ethanes 10d,e were necessarily formed by dimerisation of two molecules of the aminomethyleneketenes 2d,e and were formally obtained after elimination of two molecules of carbon monoxide and addition of two hydrogen atoms .

Conclusions

In summary, alkylsulfanylmethyleneketenes 2a,b bearing a large ω-hydroxy or mercaptoalkyl chain did not give access to lactone or thiolactone 5a,b but rather yielded the 3-hydroxythiophenes 9a,b. This reaction was extended to the synthesis of 1,4- bis-thienylbutane 9c. The N-propargylamino methyleneketenes 1d,e did not react like N-allyl analogues to yield enaminones 3 or 4 but the formation of 1,2-bis-pyrrolylethanes 10d,e was observed. Therefore the thermal decomposition of derivatives 1c-e provides a simple and new route for synthesis of α,ω−heterocyclic substituted alkanes and further investigations are planned to extend these reactions.

Experimental Section

General

NMR spectra (CDCl₃ solutions) were recorded on a Brucker 250 instrument operating at 250 and 62.5 MHZ or a Brucker 80 instument operating at 80 and 15.08 MHz respectively for ¹H and ¹³C-NMR spectra. Mass spectra were performed on a Nermag Riber R10 spectrometer operating at IE=70ev. IR spectra (reported in cm^-1) were recorded on Perkin Elmer 16PC FT-IR or Philips SP 2000 instruments.

Synthesis of Meldrum's acids 1a-e

6-Mercapto hexylsulfanyl methylene Meldrum's acid (1a) 

Enol ether 8 [3] (0.62 g, 33x10^-4 mol) and 1,6 hexanedithiol (0.5 g, 33x10^-4 mol) in acetonitrile (50mL) were placed in a two necked flask equipped with a reflux condenser. The solution was refluxed for 12-15 h and the solvent was then evaporated under vacuum. The crude product was purified by chromatography on silica gel (elution with 1:1 CH₂Cl₂/petroleum ether) to give 0.95 g (31x10^-4 mol, 94%) of a white solid. Mp = 160°C. ¹H-NMR: δ = 1.25 -1.50 (m, 5H); 1.55 (m, 2H); 1.65 (s, 6H); 1.75 (m, 2H); 2.45 (m, 2H); 2.95 (t, 2H, J =7.1Hz); 8.95 (s, 1H). MS m/z (%): 304 (M⁺., 3), 247 (8), 246 (31) , 203 (16), 202 (4), 150 (31), 148 (27), 126 (34), 117 (12), 116 (40), 87 (91), 69 (37), 67 (59), 60 (48), 57 (59), 55 (94), 443 (100). IR (KBr): 1716(ν_C=O), 1520(ν_C=C).

9-Hydroxy-7-thianonylsulfanyl methylene Meldrum's acid (1b) 

1b was prepared by a similar procedure from enol ether 8 (0.48 g, 26.10^-4 mol) and 9-mercapto-2-thianonanol (0.5 g, 26x10^-4 mol). The purification was performed by chromatography with acetone/ methanol: (10:1); 0.73 g of 1b was obtained (81%). ¹H-NMR: δ = 1.39 (m, 4H); 1.55 (m, 2H); 1.67 (s, 6 H); 1.72 (m, 2H); 2.2 (s, 1H); 2.47 (t, 2H, J =7.3Hz); 2.65 (m, 2H); 2.95 (t, 2H, J =7.3Hz); 3.66 (t, 2H, J = 6.0Hz); 8.94 (s, 1H). MS m/z (%): 348 (M⁺., 2), 246 (3), 161 (40), 86 (100), 84 (49), 61 (85), 55 (76), 43 (95), 41 (63). IR (KBr): 1712 (ν_C=O), 1520 (ν_C=C).

Hexamethylenedithio-bis-methylene Meldrum's acid (1c) 

1c was prepared by a similar procedure from enol ether 8 (2.48 g, 132x10^-4 mol) and hexanedithiol (1 g, 66x10^-4 mol). Purification was performed by chromatography using chloroform/acetone (2:1); 2.65 g of 1c was obtained (87%). Mp = 162°C. ¹H-NMR: δ = 1.5 (m, 4H); 1.73 (s, 12H); 1.8 (m, 4H); 3.02 (t, 4H, J =7.3Hz); 8.98 (s, 2H). MS m/z (%): 458 (M⁺., 2), 400 (5), 296 (22), 246 (49), 241 (29), 165 (20), 139 (36), 1321 (19), 43 (100). IR (KBr): 1716 (ν_C=O), 1518 (ν_C=C).

N-Methylpropargylaminomethylene Meldrum's acid (1d) 

1d was prepared by a similar procedure from enol ether 8 (6.7 g, 36x10^-3 mol) and N-methylpropargylamine (2.5 g, 36x10^-3 mol). Recrystallisation of the crude mixture from ethanol gave 5.6 g (25x10^-3 mol, 70%) of 1d. Mp = 123°C. ¹H-NMR showed two isomers: δ = 1.72 (s, 6H); 2.43 (t, 1H, J = 3.0Hz); 3.52 (s, 3H); 4.77 (d, 2H, J = 3.0Hz); 8.10 (s, 1H); and 1.73 (s, 6H); 2.65 (t, 1H, J = 3.0Hz); 3.42 (s, 3H); 4.31 (d, 2H, J = 3.0Hz), 8.32 (s, 1H). MS m/z (%): 223 (M⁺., 5), 208 (17), 166 (50), 165 (19), 122 (100), 121 (33), 93 (30), 82 (53), 68 (10), 67 (17), 66 (35), 65 (18). IR (CHCl₃): 3280 (ν _H-C+), 2100 (ν_C+C), 1680 (ν_C=O), 1590 (ν_C=C).

1-(Propargyl)-2-pyrrolidinylmethylene Meldrum's acid (1e) 

1e was prepared from N-propargylpyrrolidin-2-one following the procedure previously reported [6,11] ¹H-NMR: δ = 1.76 (s, 6H); 2.15 (qt, 2H, J =8.0Hz); 2.42 (t, 1H, J =3.0Hz); 3.53 (t, 2H, J = 8.0Hz); 3.97 (t, 2H, J = 8.0Hz); 4.45 (d, 2H, J = 3.0Hz). MS m/z (%): 249 (M⁺., 1) , 234 (12), 192 (20), 149(10), 148(95), 147(9), 119(38), 86(100). IR (CHCl₃): 3300 (ν _H-C≡), 2130 (ν_C≡C), 1710 (ν_C=O) , 1550 (ν_C=C).

Thermolysis of Meldrum's acids 1a-c

Thermolysis of derivatives 1a,c were carried out under flow conditions. Solutions of 1 were vaporised at the top of an electrical heated quartz column filled with quartz beads. The temperature was held constant during the thermolysis; the pressure was maintained at 5x10^-2 Torr. Products were condensed at -196°C and analysed after purification.

Thermolysis of 1a: T=630°C; 9a and 9'a were purified by chromatography on silica gel with CH₂Cl₂,/acetone (66/34). Yield: 68 mg (3.36x10^-4 mol, 51%) from 200 mg (6.58x10^-4 mol) of 1a. 1H-NMR of 9a: δ = 1.3 -1.6 (m, 9H); 2.65 (m, 3H); 6.56 (d, 1H, J = 5.4Hz); 6.85 (d, ¹H, J = 5.4Hz); ¹H-NMR of 9'a: δ = 1.3 -1.6 (m, 9H); 2.65 (m, 2H); 3.60 (m, 1H); 6.12 (d, 1H, J = 5.7Hz); 8.28 (d, 1H, J = 5.7Hz). MS m/z (%) : 202 (M⁺., 14), 139 (32), 113 (100), 87 (32), 55 (20).

Thermolysis of 1b: T=540°C; 9b and 9'b were purified by chromatography on silica gel with acetone. Yield: 107 mg (4.35x10^-4 mol, 76%) from 200 mg (5.74x10^-4 mol) of 1b.¹H-NMR of 9b: δ =1.36 (m, 4 H); 1.52 (m, 5H); 2.47 (t, 2H, J =6.0 Hz); 2.65 (m, 3H); 3.65 (t, 2H, J = 6.0Hz); 6.55 (d, 1H, J = 5.6Hz); 6.85 (d, 1H, J = 5.6Hz); ¹H-NMR of 9'b showed two specific signals for this tautomer: 6.13 (d, 1H, J = 5.7Hz); 8.3 (d, 1H, J = 5.7Hz). MS m/z (%): 246 (M⁺., 3), 159 (15), 55 (100), 45 (30), 43 (51).

Thermolysis of 1c: 610°C; 9c and 9'c purified by chromatography with CH₂Cl₂. Yield: 80%. ¹H-NMR of 9c (CDCl₃): δ = 1.6-1.7 (m, 6H); 2.65 (m, 4H); 6.55 (d, 2H, J = 5.4Hz); 6.86 (d, 2H, J = 5.4Hz); ¹H-NMR of 9'c: δ = 1.66 (m, 4H); 2.65 (m, 4H); 3.6 (m, 2H); 6.11 (d, 2H, J = 6.0Hz); 8.28 (d, 2H, J = 6.0Hz). 10c, purified by chromatography with CH₂Cl₂/acetone (90:10). Yield: 80 mg (2.36x10^-4 mol, 47%) from 230 mg (5x10^-4 mol) of 1c. ¹H-NMR: δ = 1.60 (m, 4H); 2.19 (s, 6H); 2.60 (m, 4H); 6.73 (d, 2H, J = 5.5Hz); 6.98 (d, 2H, J = 5.5Hz); ¹³C-NMR: δ = 20.8(q); 25.7(t); 30.1(t); 120.8(d); 121.9(d); 129.7(s); 142.9(s); 169.1(s). MS m/z (%): 340 (3), 338 (3), 336 (6), 294 (28), 293 (100), 292 (48), 140 (25), 139 (75), 136 (28), 43 (34).

Thermolysis of Meldrum's Acids 1d,e

Pyrolyses of 1d,e were carried out at low pressures (10^-4-10^-5 Torr) in a apparatus previously described [6,12] and the products were collected on a cold finger, cooled in liquid N₂ at the exit of the horizontal quartz tube heated by an electrical oven. An entrance port placed between the exit of the tube and the cold finger permits the coating of the cold finger with methanol.

Bis 2'-(N-methylpyrrolyl) -1,2 -ethane (10d). 

Purified by chromatography on silica gel with ether/petroleum ether/methanol (50:40:10). Yield of 10d: 146 mg (7.76x10^-4 mol, 42%) from 819 mg (36.7x10^-4 mol) of 1d. Mp = 97°C. ¹H-NMR: δ =2.96 (s, CΗ₂); 3.55 (s, CH₃); 6.06 (d, 1H, J = 3.5Hz); 6.18 (d, 1H, J = 3.5Hz); 6.65 (s, 1H); ¹³C-NMR: δ = 26.3 (t) ; 33.5 (q) ; 105.7 (d) ; 106.8 (d) ; 121.3 (d); 132.8 (s); MS m/z (%): 189 (M⁺¹, 17), 188 (M⁺., 98), 95 (67), 94 (100); IR (CHCl₃): ν = 3010, 2960, 2950, 1500, 1455, 1420, 1305, 1090; Anal. Found: C, 76.49; H, 8.71; N, 14.75. Calc. for C₁₂H₁₆N₂: C, 76.55; H, 8.56; N, 14.88%).

Bis 5'-(2,3-dihydro-1H-pyrrolizinyl) -1,2 -ethane (10e). 

Purified by chromatography on silica gel with petroleum ether/ether (60:40). Yield of 10e: 123 mg (5.12x10^-4 mol, 34%) from 760 mg (30.5x10^-4 mol) of 1e. ¹H-NMR: δ = 2.47 (qt, 2H, J = 7.1Hz); 2.85 (s, CH₂); 2.87 (t, 2H, J = 7.1Hz); 3.68 (t, 2H, J = 7.1Hz); 5,77 (sl, 1H); 6.0 (sl, 1H); ¹³C-NMR: δ = 24.5 (t); 27.6 (t); 28.1 (t); 44.3 (t); 98;2 (d); 108.5 (d); 127.4 (s); 135.5 (s); MS m/z (%) =240 (M⁺., 10); 121 (12); 120 (100)