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

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 (CH 2 ) n Y. Alkoxymethyleneketenes 2 (X=O; Y=H; R=H,CH 3 ) are reasonably stable in solution at room temperature, and seem to be the most stable ones [3] .
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(CH 2 ) 2 O ) .

Scheme 5
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=CH 2 ) [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 1 H-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 C 2 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. 13 C-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 1 H-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 (CDCl 3 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 1 H and 13 C-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.