Mitsunobu Type C-N Bond Formation with 4,7-Dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione(DHTD), a New Cyclic Azodicarboxamide

Tsunoda, Tetsuto; Kawamura, Yumi; Uemoto, Kaori; Itô, Shô

doi:10.3987/com-97-s(n)78

Cited by 11 publications

(2 citation statements)

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“…[20] Thus, 1,1'-(azodicarbonyl)dipiperidine (ADDP),[21] 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD),[22] and N,N,N',N'-tetramethylazodicarboxamide (TMAD)[23] have been developed as new reagents in combination with tributyl phosphine (TBP).…”

Section: Resultsmentioning

confidence: 99%

ADDP and PS-PPh₃: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

Humphries¹,

Quyen-Quyen²,

Wilhite³

2006

Beilstein J. Org. Chem.

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A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh 3 modified Mitsunobu protocol, which eliminated significant by-product formation. This method proved to be versatile, efficient and amenable to parallel synthesis.Page 1 of (page number not for citation purposes) FindingsPeroxisome proliferator-activated receptors (PPARs) are pharmaceutical targets of great importance. Their wide-ranging effects on key transcriptional pathways for lipid handling, insulin sensitivity, inflammation and other functions have led to marketed drugs and vast clinical and preclinical research efforts. [1][2][3][4][5][6][7][8][9][10][11] In 1991, a series of PPAR analogues were disclosed, which for the first time did not contain a thiazolidine-2,4-dione pharmacophore.[12] These were propanoic acid derivatives with α-substitution to collectively serve as a mimic for the thiazolidine-2,4-dione ring. Based on the above and a knowledge of PPAR ligands publicly disclosed, we wished to synthesize compounds represented by the general structure 1 (Figure 1). Aromatic ethers are structural motifs found in many naturally occurring molecules and compounds of medicinal interest.[13] We envisaged the pyridyl ether moiety of 1 to be efficiently formed via Our first attempt at the Mitsunobu reaction between pyridinol 2 and alcohol 3, utilizing a modification of the conditions originally reported by Mitsunobu, [18] afforded pyridyl ether 4 in 54% yield (Scheme 1). Interestingly, the reaction did not reach completion and pyridinol 2 was recovered, despite the fact that it was the limiting reagent. Upon closer examination, compound 5 was observed as a major by-product (46% based on 3).By-products analogous to 5 have been observed in the literature when diethyl azodicarboxylate (DEAD) is used in certain Mitsunobu reactions. [18,19] This by-product formation is believed to be dependent on the pK a of the acidic component (e. g. 2).[18]If the phenol has a pK a > 11, the yield is considerably lower; and with the phenol having pK a > 13, the desired reaction does not occur. The hydrazo anion 6, in these cases, attacks the alkoxyphosphonium directly to afford alkylated hydrazine derivative 7 as the by-product (side reaction in Figure 2), [19] since anion 6 is not efficient in deprotonating the weakly acidic phenol.One way to improve the above redox system is to enhance the basicity of anion 6 by the replacement of the alkoxy group OEt in DEAD with strong electron donating groups such as NR 2 .[16] Thus, 1,1'-(azodicarbonyl)dipiperidine (ADDP), [20] 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD), [21] and N,N,N',N'-tetramethylazodicarboxamide (TMAD) [22] have been developed as new reagents in combination with tributyl phosphine (TBP).We initially chose ADDP, due to its commercial availability and low cost. The original reference utilized ADDP and TBP in benzene, [20] but due to safety and ease of handling we chose to keep PS-PPh 3 and THF. Our first attempt was successful and no by-product 8 was obser...

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Section: Resultsmentioning

confidence: 99%

ADDP and PS-PPh₃: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

Humphries¹,

Quyen-Quyen²,

Wilhite³

2006

Beilstein J. Org. Chem.

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“…100 Tsunoda and et al studied reactions (Schemes 18-21) using ROH = butanol, benzyl alcohol, 2-butenol, and 2-octanol. [101][102][103][104][105][106] The mediators 36b, 38, 107 and 39b, incorporating PBu 3 were all more effective than 36a (PPh 3 -DEAD) in N-alkylations of 40 (pK a 11.7) (Scheme 18). In N-alkylation of 40 with 2-octanol, the yield of sulfonamide 41 obtained using 36b was only 40%, but 38, 39a, and 39b all gave high yields.…”

Section: Safetymentioning

confidence: 99%

Alkyl Phosphines as Reagents and Catalysts in Organic Synthesis

Valentine¹,

Hillhouse²

2003

Synthesis

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A literature review of the major stoichiometric uses of tertiary phosphines, with particular emphasis on the relative abilities of trialkylphosphines and triarylphosphines in Wittig, Staudinger, or Mitsunobu reactions, is presented. Pronounced differences in reaction rates and selectivity, product yields and ease of by-product removal are often observed when trialkylphosphines are compared with triarylphosphines as promoters in these types of reactions. Also presented here is a compilation of some useful physical properties for selected trialkylphosphines, their usual methods of preparation and typical uses in organic synthesis. 4Reactions Catalyzed by Trialkylphosphines 5Michael Reaction 6Conclusions

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N,N,N′,N′-Tetramethylazodicarbonxamide

Tsunoda

Kaku

2003

Encyclopedia of Reagents for Organic Synthesis

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Mitsunobu Type C-N Bond Formation with 4,7-Dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione(DHTD), a New Cyclic Azodicarboxamide

Cited by 11 publications

References 0 publications

ADDP and PS-PPh₃: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

ADDP and PS-PPh₃: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

Alkyl Phosphines as Reagents and Catalysts in Organic Synthesis

N,N,N′,N′-Tetramethylazodicarbonxamide

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Mitsunobu Type C-N Bond Formation with 4,7-Dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione(DHTD), a New Cyclic Azodicarboxamide

Cited by 11 publications

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ADDP and PS-PPh3: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

ADDP and PS-PPh3: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

Alkyl Phosphines as Reagents and Catalysts in Organic Synthesis

N,N,N′,N′-Tetramethylazodicarbonxamide

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ADDP and PS-PPh₃: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists

ADDP and PS-PPh₃: an efficient Mitsunobu protocol for the preparation of pyridine ether PPAR agonists