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Diethylaminosulfur Trifluoride (DAST)

DAST has proven itself to be an extremely popular reagent for nucleophilic fluorination, due to its ease of handling and versatility. It has regularly been employed in a myriad selective fluorinations of alcohols, alkenols, carbohydrates, ketones, sulfides, epoxides, thioethers, and cyanohydrins. In addition some novel organic cyclizations are possible when DAST is employed as a reagent.1

Fluorodeoxygenation was achieved using DAST in a preparatively simple synthesis of 5,5-difluoropipecolic acid from glutamic acid (Scheme 5).2

Scheme 5

Scheme 5

1,2,2-Trifluorostyrenes can be synthesized using a sequential reaction on the parent a-(trifluoromethyl)phenylethanol with DAST, followed by dehydrohalogenation with lithium bis(trimethylsilyl)amide (LHMDS). This method achieves the trifluorostyrene without requirement of palladium coupling (Scheme 6).3

Scheme 6

Scheme 6

DAST was recently used to obtain fluorinated analogues of 3,6-dibromocarbazole piperazine derivatives of 2-propanol (Scheme 7). A series of these analogues are described as the first small and potent modulators of the cytochrome c release triggered by Bid-induced Bax activation in a mitochondrial assay.4

Scheme 7

Scheme 7

The synthesis of a,a-difluoroamides via direct fluorination was recently reported using DAST as the fluorinating reagent in a one-pot reaction (Scheme 8). Decreasing the molar ratio of DAST to substrate resulted in the formation of the respective a-ketoamide.5

Scheme 8

Scheme 8

a-Fluorosulfides and secondary alcohols were coupled by Yb(OTf)3 to generate O,S-acetals, which are key intermediates in the assembly of ciguatoxins. In their synthesis, hydrogen was directly converted to fluorine using DAST and a catalytic amount of SbCl3 to make the a-fluorosulfide (Scheme 9).6

Scheme 9

Scheme 9

References

1.
Shreeve JM, Singh RP. 2002. Recent Advances in Nucleophilic Fluorination Reactions of Organic Compounds­ Using Deoxofluor and DAST. Synthesis.(17):2561-2578. http://dx.doi.org/10.1055/s-2002-35626
2.
Golubev AS, Schedel H, Radics G, Fioroni M, Thust S, Burger K. 2004. Hexafluoroacetone as a protecting and activating reagent: 5,5-difluoro- and trans -5-fluoropipecolic acids from glutamic acid. Tetrahedron Letters. 45(7):1445-1447. http://dx.doi.org/10.1016/j.tetlet.2003.12.038
3.
Anilkumar R, Burton DJ. 2003. A highly efficient room temperature non-organometallic route for the synthesis of ?,?,?-trifluorostyrenes by dehydrohalogenation. Tetrahedron Letters. 44(35):6661-6664. http://dx.doi.org/10.1016/s0040-4039(03)01628-9
4.
Bombrun A, Gerber P, Casi G, Terradillos O, Antonsson B, Halazy S. 2003. 3,6-Dibromocarbazole Piperazine Derivatives of 2-Propanol as First Inhibitors of CytochromecRelease via Bax Channel Modulation. J. Med. Chem.. 46(21):4365-4368. http://dx.doi.org/10.1021/jm034107j
5.
Singh RP, Shreeve JM. 2003. One-Pot Route to New ?,?-Difluoroamides and ?-Ketoamides. J. Org. Chem.. 68(15):6063-6065. http://dx.doi.org/10.1021/jo034487g
6.
Inoue M, Yamashita S, Hirama M. 2004. A new synthesis of key intermediates for the assembly of polycyclic ethers: Yb(OTf)3-promoted formation of O,S-acetals from ?-fluorosulfides and alcohols. Tetrahedron Letters. 45(10):2053-2056. http://dx.doi.org/10.1016/j.tetlet.2004.01.077