[Bis(2-m eth oxyeth yl)a m in o]su lfu r
Tr iflu or id e, th e Deoxo-F lu or Rea gen t:
Ap p lica tion tow a r d On e-F la sk Tr a n s-
for m a tion s of Ca r boxylic Acid s to Am id es
F IGURE 1. Structures of Deoxo-Fluro (1) and DAST (2).
J onathan M. White, Ashok Rao Tunoori,
Brandon J . Turunen, and Gunda I. Georg*
ditional transformations were explored as well, including
the conversion of carboxylic acids to acyl fluorides.7 Based
on these observations, we sought to take advantage of
the properties of acyl fluorides combined with this new
and facile protocol for their preparation. Our efforts have
led to a one-flask protocol for the conversion of carboxylic
acids to a variety of amides obtained through an inter-
mediate acyl fluoride. A full account of this work is
presented herein.9
Department of Medicinal Chemistry, University of Kansas,
1251 Wescoe Hall Drive, Lawrence, Kansas 60045-7582
georg@ku.edu
Received November 10, 2003
Abstr a ct: The use of the Deoxo-Fluor reagent is a versatile
method for acyl fluoride generation and subsequent one-flask
amide coupling. It provides mild conditions and facile
purification of the desired products in good to excellent
yields. We have explored the utility of this reagent for the
one-flask conversion of acids to amides and Weinreb amides
and as a peptide-coupling reagent.
Con ver sion of Ca r boxylic Acid s to Am id es. The
importance of amides cannot be overstated as they are
crucial in the architecture of biological systems and
prevalent in natural products and commercial medicines,
and their formation is widely utilized in the construction
of many molecules/materials. A special group of amides
which shows additional versatility are the N,O-dimeth-
ylhydroxylamides (Weinreb amides).10 These compounds
have become important and widely used building blocks
in organic synthesis.11-14 Accordingly, several methods
are available for their formation including the direct
conversion of carboxylic acids to amides. Some of these
procedures utilize peptide coupling reagents such as
BOP,15,16 DCC,17 or propylphosphonic anhydride/N-eth-
ylmorpholine.18,19 Einhorn et al. have developed a method
for the synthesis of Weinreb amides from carboxylic acids
using carbon tetrabromide and triphenylphosphine.20 Sibi
et al. have reported the synthesis of Weinreb amides from
carboxylic acids using 2-chloro-1-methylpyridinium iodide
(CMPI) or BMPI as the coupling agent.21 Drawbacks of
these methods include expensive coupling reagents and
difficult removal of excess reagent and reagent byprod-
ucts. Therefore, a continued interest exists in the devel-
opment of alternative methods for amide formation from
carboxylic acids that are operationally simple and allow
for easy removal of reagents and reagent byproducts.
In the course of our study, we found that carboxylic
acids could be readily converted to the corresponding
Acyl fluorides are versatile functional groups in organic
chemistry due to the unique nature of the carbonyl-
fluorine bond.1 Many useful chemical transformations are
elicited via this functionality since it possesses greater
stability than the corresponding acid chloride toward
neutral oxygen nucleophiles, yet is of high reactivity
toward anionic nucleophiles and amines.2 It has been
observed that acid fluorides react more like activated
esters than acid halides (Cl, Br, I).2 For example, Fmoc,3,4
Boc, and Cbz amino acid fluorides5 were found to be
stable, rapid-acting, acylating reagents for peptide bond
formation. It is also of note that no significant loss of
optical purity is observed during the conversion of acid
fluorides to amides.5,6 These properties make shelf-stable
acid fluorides possible and allow for their isolation
through organic extraction. It is these characteristics
which make them important for further synthetic study.1
A variety of techniques are available for the generation
of acyl fluorides.1,2 There are, however, disadvantages
associated with these methods, including poor yields,
dangerous or toxic chemicals, forcing reaction conditions,
and costly reagents. A recently developed alternative,
[bis(2-methoxyethyl)amino]sulfur trifluoride,the Deoxo-
Fluor reagent (1), which was first described by Lal et al.
as a thermally stable alternative to the DAST reagent
(2), overcomes several of these problems (Figure 1).7,8 The
initial investigation of this reagent showcased its utility
for the conversion of hydroxy alkanes to the correspond-
ing alkyl fluorides (deoxygenation-fluorination).8 Ad-
(9) Tunoori, A. R.; White, J . M.; Georg, G. I. Org. Lett. 2000, 2, 4091-
4093.
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(11) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15-40.
(12) Overhand, M.; Hecht, S. M. J . Org. Chem. 1994, 59, 4721-
4722.
* Corresponding author.
(1) Patai, S. The Chemistry of Acyl Halides; Interscience Publish-
ers: New York, 1972.
(2) Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M. Acc.
Chem. Res. 1996, 29, 268-274.
(3) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J .
Am. Chem. Soc. 1990, 112, 9651-9652.
(13) Lucet, D.; Le Gall, T.; Mioskowski, C.; Ploux, O.; Marquet, A.
Tetrahedron: Asymmetry 1996, 7, 985-988.
(14) Angelastro, M. R.; Mehdi, S.; Burkhart, J . P.; Peet, N. P.; Bey,
P. J . Med. Chem. 1990, 33, 11-13.
(15) Maugras, I.; Poncet, J .; J ouin, P. Tetrahedron 1990, 46, 2807-
2816.
(16) Shreder, K.; Zhang, L.; Goodman, M. Tetrahedron Lett. 1998,
39, 221-224.
(4) Kaduk, C.; Wenschuh, H.; Beyermann, M.; Forner, K.; Carpino,
L. A.; Bienert, M. Lett. Pept. Sci. 1996, 2, 285-288.
(5) Carpino, L. A.; Mansour, M. E.; Sadat-Aalaee, D. J . Org. Chem.
1991, 56, 2611-2614.
(17) Braun, M.; Waldmueller, D. Synthesis 1989, 856-858.
(18) Oppolzer, W.; Cunningham, A. F. Tetrahedron Lett. 1986, 27,
5467-5470.
(6) Bertho, J . N.; Loffet, A.; Pinel, C.; Reuther, F.; Sennyey, G.
Tetrahedron Lett. 1991, 32, 1303-1306.
(19) Dechantsreiter, M. A.; Burkhart, F.; Kessler, H. Tetrahedron
Lett. 1998, 39, 253-254.
(7) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M.; Cheng, H.
J . Org. Chem. 1999, 64, 7048-7054.
(20) Einhorn, J .; Einhorn, C.; Luche, J . L. Synth. Commun. 1990,
20, 1105-1112.
(8) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M. Chem.
Commun. 1999, 215-216.
(21) Sibi, M. P.; Stessman, C. C.; Schultz, J . A.; Christensen, J . W.;
Lu, J .; Marvin, M. Synth. Commun. 1995, 25, 1255-1264.
10.1021/jo035658k CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/04/2004
J . Org. Chem. 2004, 69, 2573-2576
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