Annulation Reactions of In-Situ-Generated N

Nov 15, 2018 - This operationally simple synthetic process requires no use of malodorous isocyanides and can be conveniently conducted on a gram scale...
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Letter Cite This: Org. Lett. 2019, 21, 210−213

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Annulation Reactions of In-Situ-Generated N‑(Het)aroyldiazenes with Isothiocyanates Leading to 2‑Imino-1,3,4-oxadiazolines Qiongli Zhao, Linning Ren, Jiao Hou, Wenquan Yu,* and Junbiao Chang* College of Chemistry and Molecular Engineering; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China

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S Supporting Information *

ABSTRACT: A novel annulation reaction of N-(het)aroyldiazenes and isothiocyanates has been established. This transformation involves a sequential cyclization and desulfurization/intramolecular rearrangement to produce 2-imino-1,3,4oxadiazolines. The less-stable N-(het)aroyldiazenes can be conveniently generated in situ by I2-mediated oxidation of hydrazides, which allows a one-pot synthesis of the products directly from readily accessible hydrazide and isothiocyanate substrates. This operationally simple synthetic process requires no use of malodorous isocyanides and can be conveniently conducted on a gram scale.

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n recent years, N-acyldiazenes have attracted considerable attention as valuable participants in N-heterocyclic carbenes (NHC)-catalyzed annulation reactions including [2 + 3] cyclizations with α,β-unsaturated aldehydes,1 and [4 + 2] annulations with enamines,2 ketenes,3 or α-chloroaldehydes.4 The Smith group reported isothiourea-catalyzed asymmetric functionalization of carboxylic acid derivatives5 or α-aroyloxyaldehydes6 with N-aryl-N-aroyldiazenes. Subsequently, Meng and Wang achieved the DMAP-catalyzed cycloaddition of Nacyldiazenes with allenoates7 or isatin-derived Morita-BaylisHillman adducts.8 In 2017, Zhou and Liu developed an P(NMe2)3-mediated deoxygenative [4 + 1] cyclization of Nacyldiazenes and α-dicarbonyl compounds,9 and Koutentis and co-workers reported an aza-Wittig reaction of N-aryliminophosphoranes with N-aryl-N-aroyldiazenes.10 Recently, Mei and Shi disclosed catalytic asymmetric [3 + 2] cycloannulations of N-acyl azonaphthalenes with azlactones11 or 3-vinylindoles.12 To the best of our knowledge, annulation reactions of N-acyldiazenes with isothiocyanates have not been investigated. Herein, we report the construction of novel 2imino-1,3,4-oxadiazoline frameworks via this strategy in the absence of NHCs or other catalysts. N-Acyldiazenes are commonly prepared from the corresponding hydrazides using oxidizing reagents13 such as Pb(OAc)4, MnO2, CAN, NaNO2, NBS, or by transitionmetal-catalyzed aerobic oxidation.14 Nevertheless, simple and efficient protocols are still highly desirable, especially for the development of one-pot reactions, which makes isolation of the less-stable N-acyldiazene intermediates unnecessary. During our studies on I2-promoted reactions, we found that N-(het)aroyldiazenes could be conveniently generated by iodine oxidation of the corresponding hydrazides (Table S1 in the Supporting Information). Building on this, we developed a novel one-pot annulation reaction of hydrazides15 with isothiocyanates via N-(het)aroyldiazenes generated in situ for © 2018 American Chemical Society

the synthesis of 2-imino-1,3,4-oxadiazolines under transitionmetal-free conditions. In the presence of K2CO3 or K3PO4 as a base (Table S1), I2mediated oxidation of hydrazide 2a efficiently produced Nacyldiazene 4a in various solvents at room temperature. With 4a in hand, we investigated its annulation with isothiocyanate 3a for the synthesis of 2-imino-1,3,4-oxadiazoline 1a (Table 1). Solvent screening (Table 1, entries 1−7) indicated that MeCN is the best solvent for this transformation. Under basic conditions, the annulation of 3a and 4a at the reflux temperature gave product 1a in 72% yield (Table 1, entry 6). Using DMSO as the solvent led to a slightly decreased yield of 1a (Table 1, entry 7). The structure of compound 1a was confirmed by X-ray crystallography. Screening of a series of organic and inorganic bases (Table 1, entries 8−12) showed that K2CO3 is the best base (Table 1, entry 6). Encouraged by these results, we next probed the feasibility of a one-pot synthesis of 2-imino-1,3,4-oxadiazoline 1a directly from hydrazide 2a and isothiocyanate 3a. We found that I2-mediated one-pot annulation of 2a and 3a provided the desired product (1a). Consistent with the above results, the reaction in MeCN gave a higher yield than in DMSO (Table 1, entry 13 vs entry 14), and K2CO3 is better than K3PO4 for this one-pot synthesis (Table 1, entry 13 vs entry 15). Further optimization of the reaction conditions suggested that the complete consumption of substrate 3a requires 1.5 equiv of 2a and 1.5 equiv of I2, producing the highest yield of 1a (Table 1, entry 17). Increasing the amount of base failed to improve the yield of the product (Table 1, entry 18). Under the optimal reaction conditions, this reaction can be successfully performed on a gram scale (Table 1, entry 17). Received: November 15, 2018 Published: December 14, 2018 210

DOI: 10.1021/acs.orglett.8b03663 Org. Lett. 2019, 21, 210−213

Letter

Organic Letters Table 1. Optimization of Reaction Conditions for the Synthesis of 2-Imino-1,3,4-oxadiazoline 1aa

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

4a/2a (equiv) 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 2a 2a 2a 2a 2a 2a

(1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.0) (1.2) (1.5) (1.5)

I2 (equiv)

base (equiv)

solvent

temperature

time (h)

yield (%)b

− − − − − − − − − − − − 1.2 1.2 1.2 1.2 1.5 1.5

K2CO3 (2) K2CO3 (2) K2CO3 (2) K2CO3 (2) K2CO3 (2) K2CO3 (2) K2CO3 (2) K3PO4 (2) Na2CO3 (2) NaHCO3 (2) Et3N (2) DBU (2) K2CO3 (3) K2CO3 (3) K3PO4 (3) K2CO3 (3) K2CO3 (3) K2CO3 (4)

toluene CH2Cl2 DCE THF MeCN MeCN DMSO MeCN MeCN MeCN MeCN MeCN MeCN DMSO MeCN MeCN MeCN MeCN

reflux reflux reflux reflux 60 °C reflux 100 °C reflux reflux reflux reflux reflux reflux 100 °C reflux reflux reflux reflux

12 12 12 24 12 5 2 2 12 24 12 5 5 2 24 5 5 5

0 0 0 trace 40 72 53 67 62 trace 0 30 60 40 5 72 89 (84)c 87

a

BOld font indicates the optimal reaction conditions (entry 17): 2a (0.75 mmol), 3a (0.5 mmol), I2 (0.75 mmol), K2CO3 (3 mmol), MeCN (5 mL), reflux. bIsolated yields. cThe yield of gram-scale reaction (5 mmol) is given in parentheses.

corresponding isocyanide (5) was formed in either reaction. The reaction of isocyanide 5 with N-benzoyldiazene 4a under the optimal conditions resulted in only 1a, in 15% yield (Scheme 2B). These observations rule out an isocyanide-based [4 + 1] mechanism. In addition, no expected product (1a) was formed in the reactions of 6 (or 7) with 4a under the standard conditions (Scheme 2C). On the basis of the experimental results and the previous studies of annulation reactions involving N-acyldiazenes3,7 or isothiocyanates,18 a tentative mechanism was proposed for this one-pot annulation reaction (Scheme 3). Initially, iodinemediated oxidation of hydrazide 2 under basic conditions gives the N-(het)aroyldiazene 4. This in-situ-generated diazo compound then annulated with isothiocyanate 3 to form a 6membered intermediate D. The oxygen atom of the NR2 group then attacks the exocyclic imine, forming a plausible 5−3 bicycle intermediate E. Finally, the subsequent cleavage of the strained 3-membered ring affords the 2-imino-1,3,4-oxadiazoline framework (1) via S-extrusion.19 In summary, we have developed and reported a novel onepot annulation reaction of hydrazides with isothiocyanates for the synthesis of 2-imino-1,3,4-oxadiazoline under transitionmetal-free conditions. In this reaction, hydrazides are first oxidized by iodine to form N-(het)aroyldiazenes, which then undergo a sequential annulation with isothiocyanates, followed by desulfurization/intramolecular rearrangement to form the product. This synthetic approach is practically simple and requires no use of NHC or other organic catalysts. It can also avoid the need to isolate the less-stable N-(het)aroyldiazene intermediates and the use of malodorous isocyanides, and it provides a facile access to 2-imino-1,3,4-oxadiazoline derivatives in a scalable fashion. Further investigation and application of such reactions is currently ongoing in our laboratory.

Having estabished the optimal conditions for a one-pot reaction, we examined the substrate scope of hydrazides (2). As shown in Scheme 1, this reaction can tolerate both electrondonating groups (EDGs) and electron-withdrawing groups (EWGs) on the phenyl rings at the R1 (1b−1f) and R2 (1k− 1r) positions. Nevertheless, the presence of EWGs in the group at R2 affected the formation of the products (1l−1r). In particular, the presence of a halogen at the para- or orthoposition significantly decreased the yields (1l, 1m, and 1r). This one-pot protocol is also successful with β-naphthyl-, 2furanyl-, and 2-thiophenyl-substituted hydrazides (1g−1i) and tert-butyl-substituted products (1j and 1s) can be synthesized in moderate yields from the corresponding hydrazides. To further explore the reaction scope, a variety of isothiocyanates (3) were subjected to the above standard reaction conditions. These substrates were successfully converted to the expected 2-imino-1,3,4-oxadiazoline products by the reaction with the hydrazide 2a. This synthesis is compatible with phenyl isothiocyanates substituted with EDGs or EWGs (1t−1ab). Replacement of the aryl isothiocyanate with an aliphatic isothiocyanate significantly decreased the yield of the product (1ac). The relatively lower yields of the alkyl-substituted products (1j, 1s, and 1ac) could be due to the decreased stability of the corresponding diazenes and/or related intermediates (see Scheme 3, presented later in this work). The reaction of benzoyl isothiocyanate with 2a under the optimal annulation conditions produced the corresponding product (1ad). Control experiments were performed to investigate if isothiocyanates act as masked isocyanides15b in this reaction. Heating isothiocyanate 3a under basic conditions resulted in thiourea16 6 and urea17 7 (Scheme 2A) and a slow conversion was observed in the presence of iodine; however, none of the 211

DOI: 10.1021/acs.orglett.8b03663 Org. Lett. 2019, 21, 210−213

Letter

Organic Letters Scheme 1. Substrate Scopea

Scheme 2. Control Experiments

Scheme 3. Proposed Mechanism

bridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (W. Yu). *E-mail: [email protected] (J. Chang). ORCID

Wenquan Yu: 0000-0002-3711-0006 Junbiao Chang: 0000-0001-6236-1256 Notes

The authors declare no competing financial interest.

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a

Reaction conditions: 2 (0.75 mmol), 3 (0.5 mmol), I2 (0.75 mmol), K2CO3 (3 mmol), MeCN (5 mL), reflux (isolated yields are given).

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Nos. 81773570 and 81330075), the Outstanding Young Talent Research Fund of Zhengzhou University (No. 1521316004) for financial support.

ASSOCIATED CONTENT

* Supporting Information S

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03663. Experimental details, characterization data, and NMR spectra of isolated compounds (PDF)

REFERENCES

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Accession Codes

CCDC 1877670 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cam212

DOI: 10.1021/acs.orglett.8b03663 Org. Lett. 2019, 21, 210−213

Letter

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DOI: 10.1021/acs.orglett.8b03663 Org. Lett. 2019, 21, 210−213