A one-flask synthesis of weinreb amides from chiral and achiral carboxylic acids using the deoxo-fluor fluorinating reagent

Article abstract of DOI:10.1021/ol000318w

(Matrix presented) The reagent [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-Fluor reagent) converts carboxylic acids to the corresponding acid fluorides, which then react with N,N-dimethylhydroxylamine to give the corresponding Weinreb amides in high yields. The reaction proceeds without racemization when optically active acids are used as the starting material. This method is operationally simple and provides the products in high purity.

Full text of DOI:10.1021/ol000318w

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ORGANIC
LETTERS
2000
Vol. 2, No. 25
4091-4093
A One-Flask Synthesis of Weinreb
Amides from Chiral and Achiral
Carboxylic Acids Using the Deoxo-Fluor
Fluorinating Reagent
Ashok Rao Tunoori, Jonathan M. White, and Gunda I. Georg*
Department of Medicinal Chemistry and The Drug DiscoVery Program,
Higuchi Biosciences Center, UniVersity of Kansas, Lawrence, Kansas 66045
georg@ku.edu
Received October 18, 2000
ABSTRACT
The reagent [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-Fluor reagent) converts carboxylic acids to the corresponding acid fluorides,
which then react with N,N-dimethylhydroxylamine to give the corresponding Weinreb amides in high yields. The reaction proceeds without
racemization when optically active acids are used as the starting material. This method is operationally simple and provides the products in
high purity.
N-Methoxy-N-methyl amides (Weinreb amides)1 have be-
come important and widely used building blocks in organic
synthesis.2a-c,3a Several methods are available for the direct
conversion of carboxylic acids to the corresponding Weinreb
amides.2a,3 Some of these procedures utilize peptide coupling
reagents such as BOP,4,5 DCC,6 or propylphosphonic anhy-
dride/N-ethylmorpholine.7,8 Einhorn et al. have developed a
method for the synthesis of Weinreb amides from carboxylic
acids using carbon tetrabromide and triphenylphosphine.9
Recently Sibi et al. reported the synthesis of Weinreb amides
from carboxylic acids using 2-chloro-1-methylpyridinium
iodide (CMPI) or BMPI as the coupling agent.10 Drawbacks
of some of these methods are that some coupling reagents
are expensive and that removal of excess reagent and reagent
byproducts from the reaction product can be difficult.
Therefore, a continued interest exists in the development of
methods for Weinreb amide formation from carboxylic acids
that are operationally simple and allow easy removal of
reagents and reagent byproducts.
(1) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(2) (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15. (b) Overhand,
M.; Hecht, S. M. J. Org. Chem. 1994, 59, 4721. (c) Lucet, D.; Le Gall, T.;
Mioskowski, C.; Ploux, O.; Marquet, A. Tetrahedron: Asymmetry 1996,
7, 985.
(3) (a) Angelastrato, M. R.; Mehdi, S.; Burkhart, J. P.; Peet, N. P.; Bey,
P. J. Med. Chem. 1990, 33, 11. (b) Goel, O. P.; Krolls, U.; Stier, M.; Kesten,
S.; Ohira, S.; White, J. D. Org. Synth. 1989, 67, 68. (c) Angelastro, M. R.;
Burkhart, J. P.; Bey, P.; Peet, N. P. Tetrahedron Lett. 1992, 33, 3265. (d)
Reetz, M. T.; Drewes, M. W.; Lennick, K.; Schmitz, A.; Holdgru¨n, X.
Tetrahedron: Asymmetry 1990, 1, 375. (e) Kim, B. M.; Guare, J. P.; Hanifin,
C. M.; Arford-Bickerstaff, D. J.; Vacca, J. P.; Ball, R. G. Tetrahedron Lett.
1994, 35, 5153. (f) Poss, M. A.; Reid, J. A. Tetrahedron Lett. 1992, 33,
1411. (g) Brenner-Weiss, G.; Giannis, A.; Sandhoff, K. Tetrahedron 1992,
48, 5855. (h) Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 1992, 48,
7251.
We are now detailing a novel, convenient, high yielding
(73-92%), one-flask synthesis of Weinreb amides from
chiral and achiral carboxylic acids using the Deoxo-Fluor
reagent ([bis(2-methoxyethyl)amino]sulfur trifluoride).11,12 In
(7) Oppolzer, W.; Cunningham, A. F. Tetrahedron Lett. 1986, 27, 5467.
(8) Dechantsreiter, M. A.; Burkhart, F.; Kessler, H. Tetrahedron Lett.
1998, 39, 253.
(9) Einhorn, J.; Einhorn, C.; Luche, J.-L. Synth. Commun. 1990, 20, 1105.
(10) Sibi, M. P.; Stessman, C. C.; Schultz, J. A.; Christensen, J. W.; Lu,
J.; Marvin, M. Synth. Commun. 1995, 25, 1255.
(4) Maugras, I.; Poncet, J.; Jouin, P. Tetrahedron 1990, 46, 2807.
(5) Shreder, K.; Zhang, L.; Goodman, M. Tetrahedron Lett. 1998, 39,
221.
(6) Braun, M.; Waldmu¨ller, D. Synthesis 1989, 856.
10.1021/ol000318w CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/14/2000

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Table 1. Synthesis of Weinreb Amides from Carboxylic Acids20
this procedure, carboxylic acids are first converted into acid
fluorides by the Deoxo-Fluor reagent in the presence of N,N-
diisopropylethylamine. Weinreb amides are formed after
addition of N,O-dimethylhydroxylamine to the intermediate
acid fluorides (Scheme 1 and Table 1).
Acyl fluorides possess stability greater than that of the
corresponding acid chlorides toward neutral oxygen nucleo-
philes such as water and methanol yet are of high reactivity
toward anionic nucleophiles and amines.13 It has been
observed that acid fluorides react more like active esters than
acid halides (Cl, Br, I).13 For example, R-Fmoc,14 Boc, or Z
amino acid fluorides15 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.14,16 We
are now reporting that the Deoxo-Fluor reagent is a versatile,
easy to use reagent for the preparation of acid fluorides,
which can be converted to the corresponding Weinreb amides
(11) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem.
Commun. 1999, 215-216.
(12) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H.
J. Org. Chem. 1999, 64, 7048.
(14) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H. J.
Am. Chem. Soc. 1990, 112, 9651.
(15) Carpino, L. A.; Mansour, E.-S. M. E.; Sadat-Aalaee, D. J. Org.
Chem. 1991, 56, 2611.
(13) Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M. Acc.
Chem. Res. 1996, 29, 268.
(16) Bertho, J.-N.; Loffet, A.; Pinel, C.; Reuther, F.; Sennyey, G.
Tetrahedron Lett. 1991, 32, 1303.
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Org. Lett., Vol. 2, No. 25, 2000

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The crude products were purified by short path silica gel
column chromatography. The yields in Table 1 refer to
isolated yields, obtained after purification.18
Scheme 1
As shown in Table 1, a variety of N-methoxy-N-methyl
amides were prepared from commercially available carboxy-
lic acids. Saturated aliphatic and cyclic acids were cleanly
converted to the corresponding Weinreb amides (entries 1,
3, 4, and 12). We also prepared the Weinreb amide from
trans-crotonic acid in good yield (entry 2). Benzoic acids
with electron-withdrawing and electron-releasing groups
(entries 5 and 6) and 2-thiophenecarboxylic acid (entry 7)
provided good yields of the Weinreb amides. This methodol-
ogy is also applicable to the synthesis of Weinreb amides of
amino acids (entries 8-11). It is of further interst to note
that no racemization was seen at the chiral center of these
amino acids as determined by HPLC.18
In conclusion, we have developed a new and operationally
simple method for the synthesis of N-methoxy-N-methyl
amides from carboxylic acids and N,O-dimethylhydroxyl-
amine, using [bis(2-methoxyethyl)amino]sulfur trifluoride to
activate the acids toward amide formation. This method is
superior to some of the existing methods because excess
reagent and reagent byproduct impurities are easily remov-
able.19 The use of [bis(2-methoxyethyl)amino]sulfur trifluo-
ride for the formation of acid fluorides should also be of
advantage for amide synthesis in the preparation of solid-
and solution-phase combinatorial libraries.
in a one-flask procedure. To the best of our knowledge, no
reports have yet appeared on the conversion of acid fluorides
into Weinreb amides. The combination of effective fluorina-
tion properties, enhanced safety features compared to DAST,
and commercial availability will make this reagent a cost-
effective alternative for many uses.11,12
In a typical experiment (method A) the carboxylic acid
(1 equiv) was dissolved in CH2Cl2 under an argon atmo-
sphere, cooled to 0 °C, and then treated with diisopropyl-
ethylamine (1.5 equiv) and [bis(2-methoxyethyl)amino]sulfur
trifluoride (1.2 equiv). After stirring for 15 min (acid fluoride
formation), a solution of N,O-dimethylhydroxylamine (1.5
equiv) in CH2Cl2 was added.17 This mixture was stirred at 0
°C for an additional 15 min and then allowed to warm to
room temperature. Stirring was continued for 3-8 h (moni-
tored by TLC) at ambient temperature. After completion,
the reaction was diluted with additional CH2Cl2 and was then
extracted sequentially with aqueous NaHCO3, aqueous NH4-
Cl solution, and brine. The organic layer was then dried over
magnesium sulfate and concentrated under reduced pressure.
In cases where the substrate was insoluble in CH2Cl2, we
used DMF as the solvent (Method B). The same molar ratios
were used as in method A. The preparation of the N,O-
dimethylhyroxylamine was also carried out as previously
described, but with DMF as the solvent.17 Upon completion,
the reaction mixture was taken up in ether and sequentially
extracted with water, aqueous NaHCO3, aqueous NH4Cl, and
brine. The organic layer was dried with magnesium sulfate
and concentrated under reduced pressure.
Acknowledgment. We gratefully acknowledge financial
support from the National Institutes of Health (NCI) and a
NIH Predoctoral Training Grant (GM-08545 for J.M.W.).
We also thank Air Products for providing the Deoxo-Fluor
reagent as a gift.
OL000318W
(18) All Weinreb amides in the table were characterized by 1H NMR,
13C NMR, MS, and optical rotation (where appropriate). The spectroscopic
data were in agreement with the structures of the products. Compounds 2
and 8-12 are known compounds (see Table 1 for references). Optical
rotations for Weinreb amides 8-12: entry 8, found [R]D -28 (c ) 1.0,
MeOH), lit. [R]D -26 (c ) 1.0, MeOH);20 entry 9, found [R]D -24 (c )
1.0, MeOH), lit. [R]D -25.5 (c ) 1.00, MeOH);20 entry 10, found [R]D
-42 (c ) 1.0, MeOH), lit. [R]D -38 (c ) 1.0, MeOH);20 entry 11, found
[R]D +4.3 (c ) 1.0, MeOH); entry 12, found [R]D +57 (c ) 1.0, MeOH).
Further examination of entries 8-12 by HPLC showed that no racemization
of the chiral center had occurred. Both the R and S enantiomers were
prepared for comparison. HPLC analysis using the Chiralcel AD-RH
column: solvent, hexanes/2-propanol (95/5); flow rate, 1.00 mL/min;
detection 225 nm. Retention times (min): entry 8, (R) 8.2, (S) 6.6; entry 9,
(R) 7.9, (S) 8.7; entry 10, (R) 7.0, (S) 6.0; entry 12, (R) 5.6, (S) 6.4. Entry
11 could not be resolved under these conditions. Optical purity was >97%
for all compounds.
(17) Preparation of N,O-dimethylhydroxylamine solution in CH2Cl2. To
a stirred suspension of N,O-dimethylhydroxylamine hydrochloride in
methylene chloride at 0 °C (ice-water bath) was added dropwise N,N-
diisopropylethylamine (1.5 equiv). A clear, colorless solution was obtained
after 5 min. This solution was kept cold until use in the reaction.3b
(19) Reagent byproducts SO2 (gas) and HN(CH2CH2OMe)2 (liquid, bp
170-176 °C) are easily removed under reduced pressure.
(20) The Weinreb amides in entries 8-10 are commercially available
from Aldrich.
Org. Lett., Vol. 2, No. 25, 2000
4093