Microwave-assisted synthesis of γ-thiolactams from ethyl isocyanoacetate

Thioamides and thiolactams are important intermediates in organic synthesis [1], [2], [3], in particular, for gaining access to heterocycles of natural products [4], [5], [6], [7]. Several procedures have been reported for the synthesis of thiolactams by conversion of the corresponding lactams; however, direct preparation of these compounds is not common [8], [9]. In this communication, we present an improved strategy for the synthesis of γ-thiolactams from simple isocyanoacetates [10] using microwaves (MWs)-assisted flash heating technology. In the early 1990s, Bachi reported n-Bu₃SnH mediated radical cyclization of alkenyl isothiocyanates to give thiolactams (Scheme 1) [8], [11]. The mechanism of this reaction involves addition of organotin radical to isothiocyanate 1 to generate a tin thioimidoyl radical 2 which undergoes 5-exo cyclization onto an alkenyl side chain to give a tin thioimidate 3, which is spontaneously hydrolyzed during chromatography to give thiolactam 4.

Scheme 1

Bachi’s synthesis of thiolactams from isothiocyanates.

Our interest in isocyanide radical chemistry and novel applications of MW technology to organic synthesis [12], [13], [14] led us to investigate the feasibility of using MW-assisted synthesis to Bachi’s approach to thiolactams. Our synthetic strategy first entailed the synthesis of alkenyl isothiocyanates that could be accessed by sequential reaction of an isocyanoacetic acid ester with alkenyl halides, followed by a reaction with tert-butyl mercaptan. A subsequent reaction with organotin reagents would give functionalized thiolactams (Scheme 2).

Scheme 2

Reagents and conditions: (i) cinnamyl bromide, BEMP, acetonitrile, MW 10 min at 110°C; (ii) t-BuSH (1.5 eq), azobisisobutyronitrile (AIBN) (0.2 eq), toluene, MW 6 min at 140°C; (iii) n-Bu₃SnH (1.15 eq), AIBN (0.2 eq), toluene, MW 6 min at 140°C.

We first synthesized alkenyl isocyanide 5 from commercially available ethyl isocyanoacetate and cinnamyl bromide using 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) as a base. The use of MWs afforded the desired compound in 10 min in 70% yield. Compound 5 was then allowed to react with tert-butyl thiol under MW irradiation to give the corresponding isothiocyanate 6 in 90% yield (Scheme 2). With isothiocyanate 6 in hand, it was then possible to perform the radical cyclization in the presence of tributyltin hydride which gave γ-thiolactams 7 and 8 in 78% isolated yield [1.6:1 mixture of diastereoisomers by proton nuclear magnetic resonance (¹H NMR)]. This reaction was also accomplished in 6 min at 140°C in the MW synthesizer. The high yield conversion of the isocyanide to isothiocyanate and the radical cyclization prompted us to perform a two-step one-pot conversion of alkenyl isocyanide 5 to the corresponding thiolactam without isolating the isothiocyanate. The reactions were performed in the same MW vessel and gave the desired thiolactams 7 and 8 in 76% overall yield (2:1 mixture of diastereoisomers by ¹H NMR). To further test this methodology, we then synthesized and reacted isocyanides 9 and 12 under the above conditions [11], [13]. Conversion of allyl isocyanide 9 directly to thiolactams 10 and 11 worked well and the desired products were obtained in high isolated yields (1:1 mixture of diastereoisomers by NMR). The reaction was completed in 12 min without isolation of the isothiocyanate (Scheme 3).

Scheme 3

Reagents and conditions: (i) t-BuSH (1.5 eq), AIBN (0.2 eq), toluene, MW 6 min at 140°C; (ii) n-Bu₃SnH (1.15 eq), AIBN (0.2 eq), toluene, MW 6 min at 140°C.

When bis-allylated isocyanide 12 was treated with tert-butyl thiol and n-Bu₃SnH under standard MW conditions, the corresponding thiolactams 13 and 14 were obtained in 90% yield as a 1:1 diastereomeric mixture (Scheme 4).

Scheme 4

Reagents and conditions: (i) t-BuSH (1.5 eq), AIBN (0.2 eq), toluene, MW 6 min at 140°C; (ii) n-Bu₃SnH (1.15 eq), AIBN (0.2 eq), toluene, MW 6 min at 140°C.

In conclusion, MW flash heating methodology was successfully employed to quickly and efficiently synthesize γ-thiolactams in a two-step one-pot procedure in good yields from alkenyl isocyanides that are accessible from commercially available ethyl isocyanoacetate. This methodology additionally provides quick access to isothiocyanates from isocyanides by MW-assisted radical reaction with tert-butyl thiol.