Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes

Abstract

Saturated 1,4-diazo heterocycles including piperazines, 1,4-diazepanes, and 1,4-diazocanes, are highly important for therapeutic development, but their syntheses are often tedious. We describe here an amphoteric diamination strategy to unite readily available 1,2-, 1,3- or 1,4-diamine derivatives with electron-deficient allenes via a formal [n + 2] (n = 4, 5, 6) cyclization mode to produce the corresponding 1,4-diazo heterocycles in just one step. This strategy features mild reaction conditions, high functional group tolerance, and scalability (gram scale). The reagents used are cheap and readily available and no transition metal catalysts are needed. More sophisticated products containing trifluoromethyl group or bicyclic ring systems can be accessed via a one-pot procedure as well. Our mechanistic studies support that formation of mono-iodinated or chlorinated diamine intermediates is important for the desired transformation and the commonly proposed chloride-iodide exchange process and a radical N-C bond formation is unlikely when the combination of NCS/KI is used.

Fig. 1

Amphoteric diamination cyclization. a A general design of an amphoteric diamination cyclization to an unsaturated π system. b Potential amphoteric diamination reagents and their syntheses. c This work: a transition-metal-free intermolecular amphoteric diamination of allenes to synthesize piperazines, 1,4-diazepanes, and 1,4-diazocanes

Fig. 2

Diversification of the vinylogous amide products. a Synthesis of α-CF₃-substituted piperazine 117 via a one-pot trap of the vinylogous amide intermediate 13 with TMSCF₃. b Synthesis of bicyclic piperazine products via an intramolecular Mannich-type reaction

Fig. 3

Removal of the tosyl and nosyl groups. a Deprotection of tosyl (Ts) group with MeSO₃H in a mixture of TFA and thioanisole at room temperature. b Deprotection of nosyl (4-Ns) group with PhSH and Cs₂CO₃ in DMF at 50 °C

Fig. 4

ESI-MS study of the reaction process. Both the NIS and NCS/KI procedures were monitored. The blue numbers are observed ion signals (m/z). MS analysis was performed by nanoelectrospray ionization-mass spectrometry (nanoESI-MS), using a 4000 QTRAP mass spectrometer, equipped with a home-built nanoESI source. NanoESI tips (~10 µm o.d.) were pulled from borosilicate glass capillary tips (1.5 mm o.d. and 0.86 mm i.d.) using a micropipette puller

Fig. 5

Proposed pathways for the first C−N bond formation. a A radical process for the C−N bond formation. b A concerted process for the C−N bond formation. c A stepwise ionic mechanism followed by I⁺ shift with iodoamine 11b. d A stepwise ionic mechanism with chloroamine 11a followed by ICl formation. e A stepwise ionic mechanism involving the formation of iodonium ion intermediate 134

Fig. 6

Probe reaction mechanism via 135 and 138. a Using vinyl cyclopropane-containing substrate 135 to probe the radical mechanism for the first C−N bond formation under the NIS conditions. b Synthesis of 137 from 135 without the NaBH₃CN reduction step and a crystal structure of 137. c Using 135 to probe the radical mechanism for the first C−N bond formation under the NCS/KI conditions. d Using 138 to probe the radical mechanism for the first C−N bond formation under the NCS/KI conditions

Fig. 7

Probe reaction mechanism with 140 and 12 with NIS and ICl. a Reaction of 140 and 12 under Cs₂CO₃ conditions without NIS. b Reaction of 140 and 12 under Cs₂CO₃ conditions followed by addition of NIS or ICl. c Reaction of 140 and 12 under ICl conditions instead of the NIS conditions. d Pre-treatment of 12 with NIS or ICl before the addition of 140. e Reaction of 12 with NIS or ICl in THF-d₈