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. 2017 Aug 1;8(8):5713-5720.
doi: 10.1039/c7sc00964j. Epub 2017 Jun 12.

Diversity-oriented synthesis of heterocycles and macrocycles by controlled reactions of oxetanes with α-iminocarbenes

Alejandro Guarnieri-Ibáñez  1 , Florian Medina  1 , Céline Besnard  2 , Sarah L Kidd  3 , David R Spring  3 , Jérôme Lacour  1
Affiliations

Diversity-oriented synthesis of heterocycles and macrocycles by controlled reactions of oxetanes with α-iminocarbenes

Alejandro Guarnieri-Ibáñez et al. Chem Sci. .

Abstract

Using N-sulfonyl triazoles as substrates, compounds as diverse as 2-imino tetrahydrofurans, 13- and 15-membered ring aza-macrocycles can be prepared selectively via formal [1 + 4], [5 + 4 + 4] and [3 + 4 + 4 + 4] condensations of α-imino carbenes and oxetanes under Rh(ii)-catalysis or thermal activation. Spirocyclic N-heterocycles are also accessible by means of Buchwald-Hartwig and Pictet-Spengler cyclizations. By reaction control, substrate selection or further derivatization, a large variety of chemical structures is thus achievable. Finally, using triazoles reacting under thermal activation, interesting mechanistic insight was obtained.

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Figures

Scheme 1
Scheme 1. Diversity-oriented synthesis of heterocycles and macrocycles by reaction of N-sulfonyl-1,2,3-triazoles, 1, with cyclic ethers, 3.
Scheme 2
Scheme 2. Reaction scope and isolated yields of 9. (a) Stick view of the crystal structure of 9aA; part of the tolyl group was removed for clarity. (b) Performed over 6 h. (c) Performed with 2 mol% of Rh2(S-TCPTTL)4 over 14 h. (d) Reduction with LiAlH4 at 0 °C over 30 min. (e) Metal-free at 60 °C over 6 h.
Scheme 3
Scheme 3. Reaction scope and yields of 5. (a) Stick view of the crystal structure of 5kA; part of the pBrC6H4 group was removed for clarity. (b) Performed with 2 mol% of Rh2(S-TCPTTL)4.
Scheme 4
Scheme 4. Observed products from the reaction of 1a and 3A. (a) NMR yield determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as a reference. (b) Isolated yields.
Scheme 5
Scheme 5. Reactivity of mesyl triazoles and 3,3-dimethyloxetane. Reagents and conditions: (a) stick view of the crystal structure of 6gA. (b) Performed with 2 mol% of Rh2(S-TCPTTL)4 over 7 h.
Scheme 6
Scheme 6. Reactivity of N-sulfonyl-4-phthalimido-1,2,3-triazoles 1p and 1q with 3,3-dimethyloxetane.
Scheme 7
Scheme 7. Rationale for the metal catalyzed pathway.
Scheme 8
Scheme 8. Formation of (Z)-5 and (E)-5. NX2 represents the phthalimido group.
Scheme 9
Scheme 9. Hydrogenation and tosyl group removal conditions.
Scheme 10
Scheme 10. Post-functionalization of 4 or 9. Reagents and conditions: (a) LiAlH4, 25 °C, 1 h. (b) Silica gel, 25 °C, 24 h. (c) HS(CH2)3SH, ClSiMe3, Zn(OTf)2, 25 °C, 1 h. (d) PhSH, K2CO3, CH3CN/DMSO (49 : 1), 50 °C, 2 h. (e) Pd(OAc)2, ±BINAP, K2CO3, toluene, 115 °C, 14 h. (f) (HCHO) n , TFAA, MsOH, 1,2-DCE, 0 °C, 25 min. (g) Stick view of the crystal structures of 7 and 8A; part of the tolyl groups has been removed for clarity.
Fig. 1
Fig. 1. Comparative PMI plot of fifty-three DOS library compounds (red dots), 40 top-selling brand-name drugs (blue triangles) and 60 diverse-natural products (green rhombi).
See this image and copyright information in PMC

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