A convenient method for the conversion of hindered carboxylic acids to N-methoxy-N-methyl (Weinreb) amides

Article abstract of DOI:10.1021/jo048385h

The conversion of sterically hindered carboxylic acids to N-methoxy-N-methyl amides can be efficiently carried out with 1.1 equiv of methanesulfonyl chloride, 3 equiv of triethylamine, and 1.1 equiv of N-methoxy-N-methylamine. Yields for this process rang

Full text of DOI:10.1021/jo048385h

A Convenient Method for the Conversion of
Hindered Carboxylic Acids to
N-Methoxy-N-methyl (Weinreb) Amides
Jacqueline C. S. Woo, Erik Fenster, and
Gregory R. Dake*
Department of Chemistry, 2036 Main Mall, University of
British Columbia, Vancouver, B.C., Canada, V6T 1Z1
TABLE 1. Initial Attempts to Convert 2 or 3 to 1
starting
entry material
yield of
conditions
T (°C) t (h)
1 (%)a
21b
gdake@chem.ubc.ca
1
2
3
4
5
6
7
8
2
2
2
2
3
3
3
3
(MeO)MeNH, DCC,
HOBt, NEt3
0-rt
0-rt
14
14
14
0.5
2
Received September 13, 2004
(MeO)MeNH, EDC,
38b
HOBt, NEt3
(MeO)MeNH, PyBOP, rt
DIEA
(MeO)MeNH2Cl,
C5H5N, CBr4, PPh3
(MeO)MeNH‚HCl,
Al(CH3)3
(MeO)MeNH‚HCl,
Al(CH3)3
(MeO)MeNH‚HCl,
iPrMgCl
Abstract: The conversion of sterically hindered carboxylic
acids to N-methoxy-N-methyl amides can be efficiently
carried out with 1.1 equiv of methanesulfonyl chloride, 3
equiv of triethylamine, and 1.1 equiv of N-methoxy-N-
methylamine. Yields for this process range from 59% to 88%.
The major byproduct in these reactions, N-methoxy-N-
methylmethanesulfonamide, can be removed by placing the
product mixture under vacuum for 14-24 h.
21b
rt
30b
-15-rt
45
NR
15
2
complex
NR
-20
65
(MeO)MeNH‚HCl,
iPrMgCl
15
complex
Since their initial appearance in 1981, N-methoxy-N-
methyl (Weinreb) amides have proven to be important
acylating reagents in organic chemistry.1 The predictable
reactivity and effectiveness of Weinreb amides have
ensured their use as intermediates within many complex
total synthesis ventures.2 In the context of a total
synthesis project ongoing in our research laboratory,3 we
had a need to generate Weinreb amide 1 from carboxylic
acid 2 (or its corresponding methyl ester 3) (eq 1). Given
the relative simplicity of carboxylic acid 2, we were
surprised to discover that several literature procedures
for the construction of Weinreb amides gave disappoint-
ing results (eq 2 and Table 1).1a,4 This seemingly trivial
transformation to produce 1 was plagued with poor
isolated yields or low conversions.
a
NR ) no reaction; complex ) complex mixture. No desired
amide was observed in the product mixture by chromatography.
b Unreacted starting material was also obtained.
acyl mesylate).5 As this procedure appeared to be an
effective method for activating hindered carboxylic acids,
we subjected 2 (on a 50 mg scale) to the original
conditions of 5 equiv of distilled methanesulfonyl chloride
and 10 equiv of triethylamine followed by 10 equiv of
N,O-dimethylhydroxylamine (eq 3).6 To our delight, the
(3) Wilson, M. S.; Dake, G. R. Org. Lett. 2001, 3, 2041-2044.
(4) DCC coupling: (a) Gibson, C. L.; Handa, S. Tetrahedron:
Asymmetry 1996, 7, 1281-1284. PyBop coupling: (b) D’Aniello, F.;
i
Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 4870-4871. PrMgCl
and amine salt: (c) Williams, J. M.; Jobson, R. B.; Yasuda, N.;
Marchesini, G.; Dolling, U. H.; Grabowski, E. J. J. Tetrahedron Lett.
1995, 36, 5461-5464.
(5) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Choi, H. S.; Fong,
K. C.; He, Y.; Yoon, W. H. Org. Lett. 1999, 1, 883-886. (b) Nangia, A.;
Chandrasekaran, S. J. Chem. Res. S 1984, 100. (c) Jacobi, P. A.;
Sessions, E. H. Synth. Commun. 2003, 33, 2575-2579. (d) Chan-
drasekaran, S.; Turner, J. V. Synth. Commun. 1982, 12, 727-731. For
the use of p-TsCl and N-methylimidazole for simple esterification,
thioesterification, and amidation, see: (e) Wakasugi, K.; Iida, A.;
Misaki, T.; Nishii, Y.; Tanabe, Y. Adv. Synth. Catal. 2003, 345 (11),
1209-1214.
(6) For other recently disclosed methods for the formation of Weinreb
and related amides, see: (a) White, J. M.; Tunoori, A. R.; Turunen, B.
J.; Georg, G. I. J. Org. Chem. 2004, 69, 2573-2576 (deoxo-fluor
reagant). (b) Hioki, K.; Kobayashi, H.; Ohkihara, R.; Tani, S.; Kun-
ishima, M. Chem. Pharm. Bull. 2004, 52, 470-472 (DMT-MM). (c)
Katritzky A. R.; Kirichenko, N.; Rogovoy, B. V. Synthesis 2003, 2777-
2780 (acylbenzotriazole intermediate). (d) Kim, M.; Lee, H.; Han, K.
J.; Kay, K. Y. Synth. Commun. 2003, 33, 4013-4018 (trichlorometh-
ylchloroformate). (e) Sibi, M. P.; Hasegawa, H.; Ghorpade, S. R. Org.
Lett. 2002, 4, 3343-3346 (oxazolidinone with amine and lanthanide
triflate). (f) Banwell, M.; Smith, J. Synth. Commun. 2001, 31, 2011-
2019 (Mukaiyama amide coupling). (g) Huang, P. Q.; Zheng, X.; Deng,
X. M. Tetrahedron Lett. 2001, 42, 9039-9041 (DIBAL-H‚amine
complexes). (h) Bailen, M. A.; Chinchilla, R.; Dodsworth, D. J.; Najera,
C. Tetrahedron Lett. 2001, 42, 5013-5016 (thiouronium salts). (i) De
Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66, 2534-
2537 (CDMT and NMM). (j) Tunoori, A. R.; White, J. M.; Georg, G. I.
Org. Lett. 2000, 2, 4091-4093 (deoxo-fluor). (k) Raghuram, T.; Vijay-
saradhi, S.; Singh, I.; Singh, J. Synth. Commun. 1999, 29, 3215-3219
(pivaloyl chloride). (l) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron
Lett. 1997, 38, 2685-2688 (Me2AlCl‚amine complex).
We speculated that steric encumbrance around the
carboxyl group was the source of this problem. The
Nicolaou group had published a method for the formation
of hindered R-diazoketones that was presumed to proceed
through a mixed anhydride of methanesulfonic acid (an
(1) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. For reviews, see: (b) Khlestkin, V. K.; Mazhukin, D. G. Curr.
Org. Chem. 2003, 7, 967-993. (c) Singh, J.; Satyamurthi, N.; Aidhen,
I. S. J. Prakt. Chem. 2000, 342, 340-347. (d) Mentzel, M.; Hoffmann,
H. M. R. J. Prakt. Chem. 1997, 339, 517-524. (e) Sibi, M. P. Org. Prep.
Proc. Int. 1993, 25, 15-40.
(2) Some recent examples: (a) Perez, M.; del Pozo, C.; Reyes, F.;
Rodriguez, A.; Francesch, A.; Echavarren, A. M.; Cuevas, C. Angew.
Chem., Int. Ed. 2004, 43, 1724-1727. (b) Mulzer, J.; Berger, M. J. Org.
Chem. 2004, 69, 891-898. (c) Zanatta, S. D.; White, J. M.; Rizzacasa,
M. A. Org. Lett. 2004, 6, 1041-1044. (d) Davis, F. A.; Prasad, K. R.;
Nolt, M. B.; Wu, Y. Z. Org. Lett. 2003, 5, 925-927. (e) Evans, D. A.;
Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899-10905. (f)
Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J. Am.
Chem. Soc. 2003, 125, 5393-5407.
10.1021/jo048385h CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/09/2004
8984
J. Org. Chem. 2004, 69, 8984-8986

TABLE 2. Formation of Hindered Weinreb Amidesa
desired Weinreb amide 1 was formed in 80% isolated
yield. Unfortunately, the yield of 1 significantly dropped
to 55% due to byproduct formation (deprotection of the
p-methoxybenzyl group) when this reaction was scaled
to 1 g of 2 or larger. Subsequent modification of the
reaction parameters resulted in an optimized procedure
using 1.1 equiv of methanesulfonyl chloride, 3 equiv of
triethylamine, and 1.5 equiv of N,O-dimethylhydroxy-
lamine in THF at 0 °C to produce 1 in 80% yield on a 1
g scale. That this procedure succeeded where other
processes had failed was quite satisfying. Indeed, further
attempts to produce 1 with alternative conditions (SOCl2,
t
C5H5N, (MeO)MeNH or BuCO2Cl, Et3N, (MeO)MeNH‚
HCl) resulted in its formation in only 54% and 55%
yields, respectively.
A number of other hindered acids were subjected to
the optimized set of conditions to examine the effective-
ness of this procedure (eq 4 and Table 2).7 Simple,
unhindered carboxylic acids (e.g., butanoic acid) were not
examined because of the efficiency of previously estab-
lished procedures. As can be seen in the table, a number
of hindered acids are smoothly converted to their corre-
sponding Weinreb amides in reasonable yields (59-
88%).8,9 The reaction proceeds smoothly on aromatic
(entries 1 and 7) and aliphatic systems. Importantly, the
reaction conditions are mild enough such that epimer-
ization of stereogenic carbon centers adjacent to the
carbonyl carbon do not occur (eq 3 and Table 2, entries
11 and 12). The mildness of this procedure compared to
the reagent combination of trimethylaluminum and N,O-
dimethylhydroxylamine hydrochloride bodes well for its
use in “large scale” applications (multiples of grams) in
an academic setting.
Although the reaction proceeds smoothly, it can be
complicated by the formation of N-methoxy-N-methyl-
methanesulfonamide as a byproduct. The removal of this
contaminant with standard chromatography manipula-
tions can be tricky as it is difficult to visualize on thin-
layer chromatographs. The most successful approach to
removing this byproduct is gently warming the contami-
nated Weinreb amide under vacuum overnight. In most
cases this protocol can remove the majority of the
undesired byproduct, allowing for the isolation of the
desired amide in >98% purity by NMR spectroscopy.
In summary, a method useful for the formation of
N-methoxy-N-methylamides from sterically hindered car-
boxylic acids has been described. This procedure puta-
a Reactions were performed with 1.1 equiv of MsCl, 3 equiv of
NEt3, and 1.5 equiv of Me(MeO)NH. b Isolated yields.
tively involves the formation of a mixed anhydride of
methanesulfonic acid (an “acyl mesylate”). This procedure
was invaluable in solving our particular synthetic prob-
lem, and thus it may prove useful for other practitioners
of organic chemistry.
Experimental Section
(7) Carboxylic acids 4a-g,j,k are commercially available. Carboxylic
acids 4h and 4i can be prepared from 2,2-dimethyl-1,3-propanediol
with straightforward methods. Carboxylic acids 2 and 4l are products
resulting from an Ireland-Claisen rearrangement: Ireland, R. E.;
Wipf, P.; Armstrong, J. D. J. Org. Chem. 1981, 56, 650-657.
(8) Some of these amides have been previously prepared: 5a, 5c,
5d, 5k: see ref 6f. 5b: Rodriques, K. E. Tetrahedron Lett. 1991, 32,
1275-1278. All previously unreported amides have been fully char-
acterized (IR, 1H, 13C NMR). Please refer to the Supporting Informa-
tion.
Sample Experimental Procedure. N,O-Dimethylhydroxy-
lamine was prepared from its commercially available hydro-
chloride salt.10 A 250-mL round-bottom flask was charged with
24.3 g of N,O-dimethylhydroxylamine hydrochloride (250 mmol),
100 mL of ethylene glycol, and 41 mL of triethanolamine (310
mmol). A short-path distillation head was affixed to the flask
and the thick slurry heated to reflux to collect the free amine
(bp 47-50 °C).
(9) It was not rigorously established whether the reaction proceeds
through the intermediacy of an acyl mesylate, an acid chloride, or an
anhydride. Each is a conceivable intermediate.
(10) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem.
Soc. 1996, 118, 11054-11080.
J. Org. Chem, Vol. 69, No. 25, 2004 8985

To a solution of 7.33 g of acid 2 (23.92 mmol) in 240 mL of
THF at 0 °C was added 10.0 mL of triethylamine (71.77 mmol),
then 2.04 mL of freshly distilled methanesulfonyl chloride (26.31
mmol) was added dropwise. The reaction was stirred at 0 °C for
10 min, and salt formation was observed. To the suspension was
added 2.64 mL of N,O-dimethylhydroxylamine (35.88 mmol) and
the reaction was stirred at 0 °C for 1 h. The reaction was
quenched with 120 mL of H2O and diluted with 120 mL of Et2O.
The separated aqueous layer was extracted with 3 × 120 mL of
Et2O. The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, and concentrated in
vacuo to give a yellow oil. Purification by column chromatogra-
phy on silica gel (1/1 petroleum ether-ether) afforded 6.7 g (80%)
of a colorless oil.
Acknowledgment. The authors thank the Univer-
sity of British Columbia, the Natural Sciences and
Engineering Research Council (NSERC) of Canada, and
Merck-Frosst for the financial support of our programs.
Supporting Information Available: Experimental pro-
cedures and characterization data for previously unreported
N-methoxy-N-methylamides. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO048385H
8986 J. Org. Chem., Vol. 69, No. 25, 2004