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Synlett 2023; 34(12): 1472-1476
DOI: 10.1055/a-2072-4537
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Special Issue Honoring Masahiro Murakami’s Contributions to Science

Regiodivergent Synthesis of Oxadiazocines via Dirhodium-Catalyzed Reactivity of Oxazolidines and α-Imino Carbenes

Olivier Viudes
a   Department of Organic Chemistry, University of Geneva, Quai E. Ansermet 30, 1211 Geneva 4, Switzerland
,
Alejandro Guarnieri-Ibáñez
a   Department of Organic Chemistry, University of Geneva, Quai E. Ansermet 30, 1211 Geneva 4, Switzerland
,
Céline Besnard
b   Laboratory of Crystallography, University of Geneva, Quai E. Ansermet 24, 1211 Geneva 4, Switzerland
,
Jérôme Lacour  ∗
a   Department of Organic Chemistry, University of Geneva, Quai E. Ansermet 30, 1211 Geneva 4, Switzerland
› Author Affiliations

We thank the Université de Genève and the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung for financial support (JL: 200020-184843 and 200020-207539).
› Further Information
 
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Dedicated to Prof. Masahiro Murakami on the occasion of his 65th birthday

Abstract

Using electron-rich or electron-poor N-substituted oxazolidines as substrates, selective formation of either ammonium or oxonium ylides is possible in the presence of α-imino carbenes. As such, treatment of 5-membered oxazolidine precursors with N-sulfonyl-1,2,3-triazoles under dirhodium catalysis (2 mol%) affords the regiodivergent synthesis of either 8-membered 1,3,6- or 1,4,6-oxadiazocines upon the initial N or O reactivity with the carbene.


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Key words

carbenes - diazaoxa heterocycles - 8-membered rings - regiodivergency - Rh(II) catalysis - triazoles - ylides

N-Sulfonyl-1,2,3-triazoles 1, made readily through Cu(I)-catalyzed azide alkyne cycloadditions (CuAACs),[1] are prime building blocks in biological, medicinal, and synthetic chemistry.[2] For the purpose of this study, under metal-catalyzed conditions, they decompose to afford α-imino carbenes.[3] [4] These electrophilic unsaturated intermediates have received much attention, as many synthetically useful and original processes can be afforded, from migrations to ylide-forming reactions and subsequent transformations.[5] Of importance for the current study, α-imino carbenes react equally well with oxygen[5n] and nitrogen[5ad] atoms to afford the corresponding oxonium or ammonium ylide intermediates. A large panel of reactions is then afforded by these processes occurring at single reactive sites. With substrates or functional groups containing both heteroatoms, competition between the two types of Lewis bases can then formally occur leading possibly to mixtures of products.[5a] Herein, in a new development, the intermolecular reactivity of N-sulfonyl-1,2,3-triazoles 1 with oxazolidines 2 is reported (Scheme [1]C). Under dirhodium catalysis (2 mol%), either 1,3,6-oxadiazocines 3 or 1,4,6-oxadiazocines 4 are afforded depending on the substitution of the nitrogen atom (yields up to 84%). Mechanistically, after the initial formation of α-imino carbenes, regiodivergent addition to oxazolidines of type 2 or 2′ occurs on either the N or O atoms to form the subsequent ammonium or oxonium ylide intermediates. Then, ring opening and trapping of the resulting iminium or oxycarbenium ions generates a fully divergent formation of 8-membered ring oxadiazocines 3 or 4 with regioisomeric ratios (r.r.) above 25:1.

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Scheme 1 Reactivity of the N-sulfonyl-1,2,3-triazoles 1 with activated 5-membered heterocycles

Previously, our group has shown that 5-membered dioxolanes and imidazolidines react readily with α-imino carbenes to yield the corresponding ylides and subsequent products (Schemes 1A and 1B). While reactions with dioxolanes generate 8-membered dioxazocines exclusively (Scheme [1]A),[5m] treatment of imidazolidines leads predominantly to [1,2]-Stevens and further Friedel–Crafts pathways to yield fused indolines piperazines (Scheme [1]B, left).[5al] Only with certain unsymmetrical imidazolidines, 8-membered ring formation of hexahydro-1,3,6-triazocines occurs nevertheless (Scheme [1]B, right). With these precedents in mind, we wondered what would happen with mixed oxazolidines and whether it would be possible to control the reactivity of α-imino carbene intermediates toward either Lewis basic (LB) oxygen or nitrogen atoms.

Preliminary experiments were performed with N-tosyl-1,2,3 triazole 1a (1.5 equiv) and N-tolyl oxazolidine 2A (0.1 mmol, 1.0 equiv) as reagent and substrate; the results are reported in Table [1] (entries 1–9). Using Rh2(Oct)4 as catalyst (3 mol%) in CH2Cl2 at 80 °C,[5al] clean formation of predominant product 3aA was observed (49% NMR yield, entry 1); the regiochemistry of the oxadiazocine being determined and discussed later (vide infra). Several dirhodium catalysts and different reaction conditions were then utilized (Figure [1] and Table S1 in the Supporting Information). The most effective were Rh2(R-DOSP)4 and Rh2(OPiv)4 affording 3aA in 76% and 81% yields respectively; the later catalyst was then selected. Decreasing temperature to 60 °C and catalyst loading to 2 mol% led to similar results and the milder/economical conditions were retained for the remainder of the study (entry 8).

Table 1 Preliminary Experiments with Oxazolidine 2A

Entry

Rh2L4

X (mol%)

Temp (°C)

Yield (%)a

1

Rh2(Oct)4

3

80

49

2

Rh2(TFA)4

3

80

 0

3

Rh2(S-PTTL)4

3

80

 0

4

Rh2(S-TCPTTL)4

3

80

56

5

Rh2(R-DOSP)4

3

80

76

6

Rh2(OPiv)4

3

80

81

7

Rh2(OPiv)4

2

80

81

8

Rh2(OPiv)4

2

60

80

9

Rh2(OPiv)4

2

40

 0

a NMR yields (1H, 400 MHz) calculated using 1,3,5-trimethoxybenzene as an internal standard.

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Figure 1 Dirhodium catalysts

Further temperature reduction to 40 °C led to a complete lack of reactivity (entry 9). Quantitative complexation between the Lewis acidic dirhodium complex and the LB oxazolidine 2 probably happens, rendering the catalyst ineffective. At 40 °C, the moderate temperature prohibits then the dissociation of the Lewis acid–base adduct, a step that is necessary for the decomposition of 1a.[6]

With the optimized conditions in hand, triazoles 1b to 1d were reacted with p-tolyl oxazolidine 2A to afford targeted products 3bA–dA in moderate to good isolated yields (68–79%), quite independent on the nature of the N-sulfonyl protecting group. With dimethylsulfamoyl 1e,[7] the decomposition was sluggish and compound 3eA was observed in the crude reaction mixture with a low yield (35% 1H NMR); clean isolation of 3eA could not be achieved unfortunately. While the phenyl group of 1a could be substituted by thiophene (1f) or methyl ester (1g) residues to afford the corresponding oxadiazocines 3fA and 3gA in the crude reaction mixtures (72% and 32% NMR yields), only compound 3fA could be isolated cleanly (66% yield). n-Propyl-substituted triazole 1h was also utilized,[8] a reagent providing often products with lower efficiency than aryl-substituted analogues; formation of the corresponding 3hA could not be evidenced in this case. With Davies’ N-sulfonyl-4-phthalimido triazole 1i,[9] product 3iA was formed under thermal activation, albeit in only 35% yield.

At this stage, care was taken to demonstrate the regioselectivity of the oxadiazocine formation. In fact, two outcome were possible as oxazolidine of type 2 can be viewed as bifunctional reagents possessing both O and N atoms susceptible to compete for electrophilic carbene intermediates. In our hands and others’, nitrogen atoms present often a higher nucleophilicity leading to a preferred formation of the ammonium ylides.[5a] [ag] Also, N-aryl-protected nitrogen atoms react readily with electrophilic carbenes to generate products of 1,2-Stevens rearrangement;[10] the aryl moiety being usually an electron-rich substituent. It was thus likely that an ammonium ylide formation would occur predominantly with substrate 2A and lead to 1,3,6-oxadiazocines 3 over its 1,4,6-regioisomer (vide infra, Scheme [2] and Scheme [3]). As mentioned earlier, this preferred regiochemistry could be established unambiguously by X-ray structural analysis of 3aA (Figure [2]).[11] 13C NMR spectroscopic analysis of compounds 3aA, 3bA, 3cA, 3dA, 3iA, and 3aB (CDCl3, 126 MHz) further indicated a well-conserved chemical shift value of δ +75.8 ± 0.4 ppm for methylene groups positioned between the N and O atoms (carbinolamine center). Of interest, compound 3aB (Figure [2]) made in 22% isolated yield from oxazolidine 2B carrying a p-nitrophenyl residue, presents also an analogous δ value (+75.7) for this CH2 group. This is an excellent indication that compound 3aB also presents a 1,3,6-oxadiazocine scaffold despite the presence of NO2 on the N-aryl group. Clearly, this substituent is sufficiently electron-withdrawing to reduce the nucleophilicity of the N atom,[12] but not enough to provoke a shift toward the formation of an oxonium ylide intermediate instead.

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Figure 2 Formation of 1,3,6 oxadiazocine regioisomers 3. a 1H NMR yield using 1,3,5-trimethoxybenzene as internal standard. b Isolated yields. c Reaction performed at 100 °C during 72 h. d Reaction performed without metal catalyst.

With the goal of achieving exclusive formation of the O-ylide, it was then clear that stronger electron-withdrawing groups (EWGs) were needed on the N atom to shield the nitrogen reactivity. Based on previous results with morpholines,[5ag] oxazolidine of type 2′ carrying either tosylate or carbamate (BOC) EWGs were selected and prepared. Validation of this approach was immediate in the reaction of N-tosyl oxazolidine 2C′ with triazoles 1a–d to afford 1,4,6-oxadiazocines 4aC′–dC′ in effective yields (87–99%, NMR, Scheme [2]). In the N-tosyl series, byproducts of triazole decomposition were found to co-elute on column or thin-layer chromatography with targeted derivatives 4. Clean isolation required then additional purification by either trituration or recrystallization reducing consequently the isolated yields (40–70%). This issue was not observed with N-Boc oxazolidine 2D′, which afforded 1,4,6-oxadiazocines 4aD′ and 4cD′ in good isolated yields (79–84%). Of note, for compounds 4 carrying a Boc protecting group, regiochemistry could be readily determined by HMBC (heteronuclear multiple bond correlation) NMR experiments. In fact, for 4aD′ and 4cD′, 3 J coupling can be observed between the protons of the aminal CH2 group and the carboxyl carbon of the carbamate (NC(O)Ot-Bu), which is only possible with a 1,4,6-oxadiazocine scaffold.

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Scheme 2 Formation of 1,4,6 oxadiazocine regioisomers 4. a 1H NMR yield using 1,3,5-trimethoxybenzene as internal standard. b Isolated yields. c After 6 h, 1.5 equiv of triazoles 1 were added. d Reaction performed at 100 °C during 72 h.
Zoom Image
Scheme 3 Mechanistic proposal

To rationalize the above divergence toward either 1,3,6- or 1,4,6-oxadiazocine products, a mechanistic rationale can be proposed; some of the steps being inspired from previous theoretical studies of the group (Scheme [3]).[5al] From complex A, C–N bond formation occurs between the carbene complex and oxazolidines 2 carrying aryl substituents, achieving the nitrogen ylide intermediate B (blue cycle). Most likely, the system rapidly evolves to B′ by switching the Rh catalyst from the C to the N atom of the former α-imino carbene. In this disposition, aminal opening occurs leading to the oxycarbenium intermediate C that ought to be quite stable compared to the initial reactants.[5al] At this stage, intermediate C evolves exclusively towards N-cyclizations and interesting mid-size 8-membered heterocycles of type 3; C-cyclization towards 1,4-morpholine adducts being totally absent in this study. When oxazolidines 2′ containing electron-withdrawing groups are used, C–O bond formation occurs with the carbene complex instead (red cycle) and leading to oxygen ylide intermediate D. Subsequent steps then follow an analogous pathway as detailed for the N series via isomerized D′, ring-opened iminium E and finally 1,4,6-oxadiazocine 4 upon N-cyclization.

With heterocycles 3aA and 4aC′ in hand, hydrogenation could be further achieved by addition of H2 (1 atm) under Pd(OH)2 over charcoal (Pearlman’s catalyst) to afford 8-membered ring derivatives 5 and 6 in 65% and 79% yields, respectively (Scheme [4]); the carbinolamine or aminal groups remaining intact during H2 addition. Not surprisingly, these saturated compounds presented a much higher shelf-life stability than the oxadiazocine precursors.

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Scheme 4 Hydrogenation of 1,3,6- and 1,4,6-oxadiazocines
Zoom Image
Figure 3 Potential applications

In summary, novel 1,3,6-oxadiazocine 3 and 1,4,6-oxadiazocine 4 were prepared in a single step from N-sulfonyl triazoles 1 and oxazolidines 2. Under dirhodium catalysis, α-imino carbenes were generated and led to the formation of either ammonium or oxonium ylide intermediates, depending upon the substituent on the N-atom. Then, after subsequent ring openings of the activated carbinolamine or aminal functional groups, intramolecular ring closures afforded 8-membered derivatives 3 and 4 exclusively.[13] Mechanistically, this regiodivergence could be engineered by the ‘simple’ choice of aryl groups or EWGs (Ts, Boc) on the nitrogen. Finally, with 3 and 4 in hand, saturated 1,3,6-oxadiazocane 5 and 1,4,6-oxadiazocane 6 were prepared efficiently upon hydrogenation. This methodology could open the door to the preparation of derivatives of type 7 and 8 that are potential antimicrobial agents or HIV integrase inhibitors (Figure [3]).[14]


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We also acknowledge the contributions of the Sciences Mass Spectrometry (SMS) platform at the Faculty of Sciences, University of Geneva.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2072-4537.
  • Supporting Information

Primary Data

    The dataset for this article can be found at the following DOI: 10.26037/yareta:3cndx4brorddfaq4rc3oq2ggke. It will be preserved for 10 years.
  • Primary Data

Corresponding Author

Jérôme Lacour
Department of Organic Chemistry, University of Geneva
Quai E. Ansermet 30, 1211 Geneva 4
Switzerland   

Publication History

Received: 24 February 2023

Accepted after revision: 12 April 2023

Accepted Manuscript online:
12 April 2023

Article published online:
31 May 2023

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Zoom Image
Scheme 1 Reactivity of the N-sulfonyl-1,2,3-triazoles 1 with activated 5-membered heterocycles
Zoom Image
Figure 1 Dirhodium catalysts
Zoom Image
Figure 2 Formation of 1,3,6 oxadiazocine regioisomers 3. a 1H NMR yield using 1,3,5-trimethoxybenzene as internal standard. b Isolated yields. c Reaction performed at 100 °C during 72 h. d Reaction performed without metal catalyst.
Zoom Image
Scheme 2 Formation of 1,4,6 oxadiazocine regioisomers 4. a 1H NMR yield using 1,3,5-trimethoxybenzene as internal standard. b Isolated yields. c After 6 h, 1.5 equiv of triazoles 1 were added. d Reaction performed at 100 °C during 72 h.
Zoom Image
Scheme 3 Mechanistic proposal
Zoom Image
Scheme 4 Hydrogenation of 1,3,6- and 1,4,6-oxadiazocines
Zoom Image
Figure 3 Potential applications