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- Photochemically-generated intermediates in synthesis
Carlson, James H. Frederich, Mai Nguyen, Gordon C. Shore and Patrick G.
Read Photochemically Generated Intermediates In Synthesis
Tailored fragments of roseophilin selectively antagonize Mcl-1 in vitro. Tetrahedron Lett. Special issue in honor of Harry Wasserman , 56, Tristan E. Rose, Kenneth V. Lawson and Patrick G. Patrick G. Harran, Ryan A. Hollibaugh, Haixia Liu Filed September 17, Harran, James H. Frederich, Gordon Shore and Mai Nguyen MCL-1 Antagonists. Filed March 3, Kenneth V.
Lawson, Tristan E. Rose, Patrick G. USA , 40 , EE Harran Template-induced macrocycle diversity through large-ring forming alkylations of tryptophan. Tetrahedron Special issue in honor of P. Wender , 69 36 , James H. Frederich, Jennifer K. Matsui, Randy O. Chang and Patrick G. Substituted 2,2'-bipyrroles and pyrrolylfurans via intermediate isoxazolylpyrroles. Frederich and Patrick G. Harran , Xiaoguang Lei, Xiaodong Wang Nature Chemical Biology, 9, Total synthesis of ageliferin via acyl N-amidinyliminium ion rearrangement. Rachel M. Greer, Michael Peyton, Jill E.
Brekken, Xiaodong Wang, and John D. Cancer Research , 71, Rose, and Patrick G. Harran, Xiaodong Wang, Jef K. US Patent 7,, B2. The photolysis of 1a Scheme 1, interme- thesis of 2a through the heterocyclization of 2-nitrobenzoic acid diate A resulted in low yields of 2a because of the competitive [28,29] and X-ray structure analysis . The authors observed that the yields of both 2a and 3a in- In the past, research has been focused on the formation of creased with increasing amount of water as nucleophilic sol- 2-substituted 3H-azepines 3 as products of the photolysis or vent in the reaction mixture  and obtained a maximum yield thermolysis of aromatic azides [34,35].
It is currently believed that azepines are radicals .
These nitrenes form benzazirines  Scheme 1, intermediate B that rearrange into cyclic ketenimines — 1,2-didehydro- In the present research it is demonstrated that using ethanol as azepines Scheme 1, intermediate C . Thus, the optimization being the formation of B. Therefore, the direction of this reac- of the reaction conditions of the base-mediated photochemical tion solely depends on the conversion of A and formation of C. Dyall et al. As solvents, alco-  includes the benzofuroxan formation by photolysis of hols and aqueous organic solvent mixtures were tested and 2-azidonitrobenzene through the intermediate singlet nitrene A alkali metal hydroxides, carbonates or acetates were screened as Scheme 1 without the formation of other intermediates.
All reactions were carried out by irradiating the base suspended in the solution of 1a with a mercury low-pressure The formation of substituted 2,1-benzisoxazoles from aryl quartz lamp nm in a quartz reactor with intensive stirring. In another work , the tially increased in the presence of a base. No dependency on the photochemical formation of 3-aminonitro-2,1-benzisoxazole nature of the base could be observed and the yield did not starting from 2-azidonitrobenzamide was observed.
The improve further when more than 1 equivalent of the base was authors subsequently investigated the multiplicity of the used Table 1. Without irradiation, the reaction did not proceed involved nitrene by repeating the reaction in the presence of at all. The addition of isoprene change the yield of 2a. A chromatographic separation of the lead to a significantly increased yield of 3-aminonitro-2,1- reaction mixture obtained by photolysis of 1a in alcohols benzisoxazole and an insignificant decrease of the primary showed that 2a had formed as the sole product.
In this case, amine yield. Thus it was demonstrated that the formation of neither the formation of 3a nor the corresponding 2-ethoxy- or 3-aminonitro-2,1-benzisoxazole goes through an intermedi- 2-isopropoxy-substituted azepines could be detected. In our opinion, this effect of the solvent or base on the yield base donates an electron lone pair to the electron-deficient of 2a may be explained by the formation of 2a through a hetero- singlet nitrene fragment of A Lewis acid with formation of the cyclization of 2-azidobenzoate anions.
Therefore, the role of the N—O bond in 2 through a 1,5-electrocyclization reaction base in the reaction is the in situ generation of the 2-azidoben- [56,57]. Nonreacted singlet nitrenes A may undergo intersystem The best yield of 2a was obtained by photolysis of 1a in ethanol crossing ISC into the less reactive triplet state Scheme 1, in the presence of sodium acetate Table 1, entry Although a multiplicity change is a spin- forbidden transition, it can be partially allowed in some cases.
With the optimal conditions at hand, we next investigated the According to another report , the major products formed scope of the cyclization using differently substituted 2-azido- from triplet nitrenes are primary amines 4 through hydrogen- benzoic acids Table 2. Table 1: Optimization of conditions for the synthesis of substituted 2,1-benzisoxazole-3 1H -ones. Table 2: Substrate scope for the heterocyclization of 2-azidobenzoic The thermal stability of the products of 2 decreases in the acid.
Halogen-substituted com- pounds 2b—e decompose at room temperature within about 5—30 min and the products 2a,f are stable for a couple of hours. In these cases, the formation of aReaction conditions: 1 0. To further test the solvent effect on the outcome of the phenylmethyl group trityl group.
However, this possibility does not explain the formation of primary amines 4c,d. As is also shown in Table 3, the high photochemical sensitivity of both the C—I bond and the azide group present in 1e, unlike It should be noted that the photolysis of double ortho-substi- the others, complicates the synthesis of benzisoxazolone 2e. This confirms the suggestions of mation of several products in low yields. Therefore, the synthe- previous reports [61,62] about the impossibility of ring expan- sis towards benzisoxazolone 2e was reoptimized Table 4.
It sion of such aryl azides. We wondered if the yields of these compounds could be ysis of 1e Table 4, entry Under these conditions, in addi- improved to allow a preparative synthesis of 3a and 3c. For this tion to compound 2e, the formation of 2a together with some reason, the reaction conditions were optimized towards azepines other unidentified products was observed albeit in low yields.
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Thus, we attempted the Based on the results mentioned above and described in the preparative synthesis of 3a based on our technique described related reports Scheme 1 , a possible reaction mechanism for earlier . After irradiating a solution of azide 1a in aceto- the formation of 2 was proposed Scheme 2. Next, the salt was decomposed by irra- toring was observed. Following work-up and preparative diation and the singlet nitrene A Scheme 2, intermediate A column chromatography azepine 3a could be isolated in was formed. After this, the conversion of 1c according to I.
Thus, the first path of cyclization of 1 was realized. Table 4: Optimization of conditions for the synthesis of 5-iodo-2,1-benzisoxazole-3 1H -one 2e. Scheme 2: Proposed reaction mechanism of the base-mediated photochemical cyclization of 2-azidobenzoic acids. Meanwhile a molecular form of 1 produced azepine 3 path II Conclusion by irradiation. The detailed mechanism of the formation of 3 is In summary, we have developed an effective photochemical shown in Scheme 2.
The present work offers a method to Thus, in the photochemical reaction both ionic and molecular access 2,1-benzisoxazole-3 1H -ones in good yields by using forms of 1 can be used. To increase the yield of 2, it is neces- mild reaction conditions at room temperature. The proposed sary to shift the equilibrium towards the ionic form 1 in situ photochemical strategy permits the synthesis the high thermo- salt formation. Based on the results of the control experiments, it was Kraus, J.
Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis
Karimi, M. Chattopadhyaya, J. Quinoline, naphthalene and Supporting Information conformationally constrained quinoline or naphthalene derivates as anti-mycobacterial agents. Experimental procedures, characterization and spectral data Lyssikatos, J. Quinolinone for synthesized compounds. Massarotti, A. Drug Des.
Bamberger, E. Vladimir I. Faerman Lobachevsky State Univer- Wierenga, W. Chauhan, J. Tetrahedron Lett. References doi Pierce, A.
Kim, B. Parish, C. Diversity , 19, — Harris, G. Otley, K.
Photochemically-generated intermediates in synthesis
Tong, Y. Smith, P. Sowin, T. Stokes, B. Puetz, C. Analogs of nitrobenzylthioinosine. Anand, D. Patent 7,, B2, May 5, McClay, K. Antimicrobial compounds. Patent Kotov, A. The chemistry of Budruev, A.