Novel ynamide structural analogues and their synthetic transformations

Abstract

This Highlight accounts for a recent phenomenon in which a series of novel ynamide structural analogues have emerged and caught the attention of the synthetic community. Preparations and reactions of these de novo ynamide variants are delineated here to demonstrate their accessibility as well as their reactivity. This Highlight should help reveal that these unique N-containing alkynes can become highly versatile building blocks in organic syntheses.

1. Introduction: Ynamide Analogues

Ynamides 1 (Scheme 1), the electron-deficient alternatives of the important but labile ynamines,^1–14 represent one of the most significant and versatile N-containing building blocks in organic synthesis.^15–17 Particularly, in the past 15 years, interests in this versatile building block have raised dramatically.^18–21 This boom is closely related to the fact that rapid development of efficient synthesis methods^22–26 has rendered ynamides highly accessible. Very recently, preparations of structural analogues of ynamides have emerged as novel N-containing alkyne building blocks.^27–36 These preparations mainly are based on modified methods for ynamide synthesis^22–26 as described in Scheme 1. With the belief that these novel analogues will also become versatile synthons that will be tremendously useful to organic synthesis, especially in the arena of N-heterocycle constructions, we highlight herein syntheses and reactions of de novo ynamides analogues: diaminoacetylenes 2, ynimides 3, yne-imines 4, yne-hydrazides 5, amidinyl-ynamides 6, and yne-sulfoximines 7 (Scheme 1).

Scheme 1.

2. Discussions: Syntheses and Reactions

2.1 Diaminoacetylenes

Tamm²⁷ described a novel approach to access diaminoacetylenes 10 by Fristch-Buttenberg- Wiechell (FBW) rearrangement^37–39 of 1,1-dihalo-2,2-ethenediamines 8 via the LiBr-bound carbenoids 9 (Scheme 2). This preparation of diaminoacetylenes 10 led to their X-ray structures for the first time, thereby revealing a virtually perpendicular orientations for the two NC₃ planes (See P1 and P2 in box at right in Scheme 2).²⁷

Scheme 2.

With Brønsted acid or Lewis acid serving as catalysts, diaminoacetylene 10-a would undergo an intramolecular hydroarylation to afford indole 11. It is noteworthy that with polar solvent such as THF, 8-a is not subjected to FBW rearrangement. Instead, indole 13 was formed via an intramolecular 1,5 C-H insertion of the vinylidene intermediate 12.²⁷

The successful synthesis of 1,2-dipiperidinoacetylene 10-b enabled studies of coordination chemistry on diaminoacetylenes through preparations of a series of structurally interesting metal complexes such as monometallic complex 14, homobimetallic complex 15, and heterobimetallic complex 16 (Scheme 3). ⁴⁰

Scheme 3.

2.2 Ynimides

Sueda²⁸ reported an efficient synthesis of ynimides 19 via a copper catalyzed amidation of alkynyl(trialryl)bismuthonium salts 17. An application of these de novo N-ethynyl phthanlimides was demonstrated through a copper catalyzed [3 + 2] cycloaddition followed by hydrazinolysis, leading to 4-amino-1,2,3-triazole 22. This transformation represents as an alternative preparation of 22 to the existing [3 + 2] cycloaddition using the highly labile ethynamine.

In addition, with the aid of an Au(I) catalyst, which is a preferred π electrophilic Lewis acid, ynimides 19 reacted with methanol to afford β-ketoimides 23. On the other hand, with Ag(I) catalyst, oxazoles 24 were formed through an initial coordination of Ag(I) with the carbonyl oxygen (see 27). Similarly, 19-e could react with aniline, under Au(I)/Ag(I) or Ag(I) only catalysis, to afford phthalimide 29 and oxazolylbenzamide 30, respectively (Scheme 5).²⁹

Scheme 5.

Muñiz³⁰ later demonstrated a metal-free amination of aryl substituted terminal alkynes 31 using hypervalent iodine reagent 32 to synthesize ynimides 33. When treating the aniline derived acetylene 36 with 32, benzo-1,3-oxazine 37 was obtained likely through the ynimide intermediate 38 (Scheme 6).

Scheme 6.

2.3 Yne-Imines

Evano³¹ documented syntheses of yne-iminies 41 through copper catalyzed oxidative crosscouplings of terminal alkynes 39 with diaryl imines 40. By using Lindlar’s catalyst, these de novo yne-imines 41 could be reduced to afford Z-azadienes 42. On the other hand, the addition of MeLi induced dimerization of 41 led to the highly substituted azines 43 (Scheme 7).

Scheme 7.

2.4 Yne-Hydrazides

Batey³² reported a concise synthesis of yne-hydrazides 46 through a straightforward addition of lithiated acetylenes 44 to diazodicarboxylates 45 (Scheme 8). These novel yne-hydrazides were shown as useful building blocks in a series of interesting transformations. In addition to a Larock-type indole formation (Scheme 8),⁴¹ Batey showcased syntheses of structurally unique heterocycles such as 48, 50, and 52 through a sequence of [3 + 2] cycloaddition followed by condensation under acidic conditions (Scheme 9). It is noteworthy of the complete regioselectivity switch in the [3 + 2] cycloaddition step between using Cp*RuCl(COD) and Cu(OAc)₂ (see 47 versus 48),⁴² albeit the former used an internal yne-hydrazide, while the latter employed a terminal yne-hydrazide.

Scheme 8.

Scheme 9.

Recently, Batey³³ utilized yne-hydrazide 46-f to synthesize Z-ene-hydrazide 54, which represent an analogue of biologically active natural product hydrazidomycin A⁴³ (Scheme 10). The key Lindlar’s hydrogenation approach is similar to that of Hsung’s Z-enamides syntheses from ynamides.⁴⁴

Scheme 10.

2.5 Amidinyl-Ynamides

Neuville³⁴ reported syntheses of 1,2,4-trisubstituted imidazoles 58 from terminal alkynes 55 and amidines 56. Amidinly-ynamides 57 are believed to be the intermediates resulting from a copper catalyzed oxidative amination of 55 with 56 (Scheme 11).

Scheme 11.

2.6 Yne-Sulfoximines

Bolm³⁵ described the first preparations of yne-sulfoximines 61 through a copper catalyzed oxidative cross-coupling of sulfoximines 59 with terminal alkynes 60. These yne-sulfoximines 61 could be transformed to N-acyl sulfoximines 62 via simple hydrolysis upon silica gel column chromatography (Scheme 12).

Scheme 12.

Recognizing the excellent potential of yne-sulfoximines 61 as new synthetic building blocks, Bolm’s group also explored their usage in thermal [2 + 2] cycloaddition reactions.³⁶ They found that yne-sulfoximines 61 could react with ketenes 65 to form the sulfoximine derived cyclobutenones 63 via a [2 + 2] cycloaddition pathway. When using diphenyl ketene 65-e, allenyl amide 66 was also isolated in addition to the expected cyclobutenone 63-e. The formation of 66 is likely a result of pericyclic ring opening of the oxetene intermediate 67,^45–54 which could be envisioned through a hetero-[2 + 2] pathway (Scheme 13).

Scheme 13.

3. Conclusion

This Highlight presents a recent phenomenon in developing syntheses and reactions of novel structural analogues of ynamides. While their syntheses and reactivities are similar to those of ynamides in many aspects, their unique motifs have rendered them special merits in terms of reactivities. These N-containing alkynes should become new versatile building blocks in organic synthesis.

Scheme 4.