Direct conversion of N-methoxy-N-methylamides (Weinreb amides) to ketones via a nonclassical Wittig reaction

Article abstract of DOI:10.1021/ol050337b

(Chemical Equation Presented) N-Methoxy-N-methylamides (Weinreb amides) are converted efficiently into ketones by reaction with alkylidenetriphenylphosphoranes and in situ hydrolysis of the product.

Full text of DOI:10.1021/ol050337b

ORGANIC
LETTERS
2
005
Vol. 7, No. 7
427-1429
Direct Conversion of
1
N-Methoxy-N-methylamides (Weinreb
Amides) to Ketones via a Nonclassical
Wittig Reaction
John A. Murphy,*,† Aur e´ lien G. J. Commeureuc, Thomas N. Snaddon,
†
†
†
†
†
‡
Thomas M. McGuire, Tanweer A. Khan, Kevin Hisler, Mark L. Dewis, and
§
Robert Carling
Department of Pure and Applied Chemistry, UniVersity of Strathclyde,
Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.,
International FlaVors and Fragrances (IFF-R & D), 1515 State Highway 36,
Union Beach, New Jersey 07735, and Merck, Sharp & Dohme Ltd., Neuroscience
Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
john.murphy@strath.ac.uk
Received February 17, 2005
ABSTRACT
N-Methoxy-N-methylamides (Weinreb amides) are converted efficiently into ketones by reaction with alkylidenetriphenylphosphoranes and in
situ hydrolysis of the product.
The efficient manipulation of the carbonyl functional group
is of pivotal importance in synthetic chemistry and crucial
for the successful and efficient preparation of synthetic targets
of varying complexity. An important and widely used
transformation has proven to be the direct conversion of
carbonyl compounds, at the carboxyl oxidation level, directly
to the corresponding aldehydes and ketones. The develop-
ment of N-methoxy-N-methylamides as carboxylate syn-
latent form, allowing a second transformation to be per-
formed chemoselectively in its presence.
(2) Recent representative examples include: (a) Kuethe, J. T.; Comins,
D. L. Org. Lett. 2000, 2, 855. (b) Davis, F. A.; Chao, B. Org. Lett. 2000,
2, 2623. (c) Lee, K.-Y.; Kim, Y.-H.; Oh, C.-Y.; Ham, W.-H. Org. Lett.
2000, 2, 4041. (d) Wallace, G. A.; Scott, R. W.; Heathcock, C. H. J. Org.
Chem. 2000, 65, 4145 (e) Smith, A. B., III; Beauchamp, T. J.; LaMarche,
M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K.
J. Am. Chem. Soc. 2000, 122, 8654. (f) Trost, B. M.; Gunzner, J. L. J. Am.
Chem. Soc. 2001, 123, 9449. (g) Ghosh, A. K.; Wang, Y.; Kim, J. T. J.
Org. Chem. 2001, 66, 8973. (h) Vanderwal, C. D.; Vosburg, D. A.; Sorensen,
E. J. Org. Lett. 2001, 3, 4307. (i) Crich, D.; Dudkin, V. J. Am. Chem. Soc.
1
thons has admirably fulfilled this role, allowing the direct
preparation of highly functionalized aldehydes and ketones
2002, 124, 2263. (j) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J.
2
upon reaction with appropriate organometallic nucleophiles.
Am. Chem. Soc. 2002, 124, 4552. (k) Crimmins, M. T.; Stanton, M. G.;
Allwein, S. P. J. Am. Chem. Soc. 2002, 124, 5958. (l) Trost, B. M.; Crawley,
M. L. J. Am. Chem. Soc. 2002, 124, 9328. (m) Cheung, A. K.; Snapper, M.
L. J. Am. Chem. Soc. 2002, 124, 11584. (n) Wipf, P.; Rector, S. R.;
Takahashi, H. J. Am. Chem. Soc. 2002, 124, 14848. (o) Denmark, S. E.;
Yang, S.-M. J. Am. Chem. Soc. 2002, 124, 15196. (p) Toda, N.; Ori, M.;
Takami, K.; Tago, K.; Kogen, H. Org. Lett. 2003, 5, 269. (q) Nicolaou, K.
C.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y.; Weyershausen, B.;
Mitchell, H. J.; Wei, H, -X.; Guntupalli, P.; Hepworth, D.; Sugita, K. J.
Am. Chem. Soc. 2003, 125, 15433. (r) Zanatta, S. D.; White, J. M.;
Rizzacasa, M. A. Org. Lett. 2004, 6, 1041. (s) Taillier, C.; Bellosta, V.;
Cossy, J. Org. Lett. 2004, 6, 2145. (t) Taillier, C.; Bellosta, V.; Meyer, C.;
Cossy, J. Org. Lett. 2004, 6, 2149. (u) Ghosh, A. K.; Gong, G. J. Am.
Chem. Soc. 2004, 126, 3704.
The efficiency of this process has been attributed to the
2
intermediacy of an exceptionally stable tetrahedral chelate,
which retards secondary addition of the nucleophile. The
stability of the chelate has itself found elegant application
3
in synthetic protocols, providing aldehydes and ketones in
†
University of Strathclyde.
International Flavors and Fragrances.
Merck, Sharp & Dohme Ltd.
‡
§
(1) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
1
0.1021/ol050337b CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/05/2005

Although the transformation is extremely useful, the
reactivity of the organometallic reagents that react with
Weinreb amides must be taken into account when planning
synthetic transformations. Reagents such as DIBAL-H,
Preliminary studies carried out on 1-chlorobenzyl-4-(N-
methoxy-N-methylamide) (1) under a variety of Wittig
conditions indicated that best yields of 4-chloroacetophenone
(2) were obtained when methylenetriphenylphosphorane (2.1
equiv), generated with n-BuLi, was allowed to react with 1
in THF.
To provide corroboratory evidence for such a pathway,
we worked up the product from reaction of Weinreb amide
2 2 4
5, with a D O and catalytic H SO quench, followed by
4
LiAlH , Grignard and organolithium reagents are incompat-
ible with a number of functional groups. It would be a
significant advance if less aggressive conditions could be
found for effecting the same transformations. Weinreb
amides have also found use in chemoselective preparation
4
,5
5
of â-ketoesters or [â-keto-Weinreb amides] where ester
enolates act as nucleophiles.
We now report a highly efficient conversion of N-
methoxy-N-methylamides to related ketones by a route that
avoids the highly reactive organometallic reagents; the
conversion is effected upon reaction with alkylidenetri-
phenylphosphoranes (Scheme 1). The reaction is particularly
Table 1. Reactions of Weinreb Amides with Phosphoranes
Scheme 1
surprising in view of the completely different reaction of
phosphonate anions with Weinreb amides. Thus, it is well-
2g,k
known that phosphonate anion reacts with Weinreb amides
to form â-ketophosphonates 4, a completely different
3
outcome from that seen in our reactions (Scheme 2).
Scheme 2
6
We propose a nonclassical Wittig reaction to account for
our observed product. Taking 1 as an example, reaction of
N-methoxy-N-methylamides would form oxaphosphetane A,
which upon cycloreversion extrudes triphenylphosphine
oxide affording putative enamine B. Mild hydrolysis of B
would then give rise to methyl ketone 2.
(3) For representative examples, see: (a) Kr u¨ ger, J.; Hoffmann, R. W. J.
Am. Chem. Soc. 1997, 119, 7499. (b) Evans, D. A.; Bender, S. L.; Morris,
J. J. Am. Chem. Soc. 1988, 110, 2506.
(
4) Turner, J. A.; Jacks, W. S. J. Org. Chem. 1989, 54, 4229.
(5) Sibi, M. P.; Christensen, J. W.; Kim, S.-G.; Eggen, M.; Stessman,
C.; Oien, L. Tetrahedron Lett. 1995, 36, 6209.
6) (a) Murphy, P. J.; Brennan, J. Chem. Soc. ReV. 1988, 17, 1. (b)
Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999, 3049.
(
1428
Org. Lett., Vol. 7, No. 7, 2005

normal workup procedures, affording a mixture of 8 and 7
in a 2.7:1 ratio (determined by H NMR) (Scheme 3). No
application of this reaction in an intramolecular fashion
affording 4,4-dimethylcyclohexanone (51%, entry 21) upon
treatment of the precursor phosphonium iodide with KHMDS
in THF.
1
7
Wittig reactions on amides are known; however, these
Scheme 3
systems are usually subject to severe perturbation, in a
conformational or electronic sense, limiting resonance con-
tribution from the nitrogen lone pair. We speculate that the
inductive effect from the oxygen of the N-OMe group locally
perturbs this system, thus permitting reactivity in the manner
described.
In conclusion, a new transformation of Weinreb amides
is announced that permits the efficient synthesis of related
ketones. The conditions of this reaction are much milder than
the conventional route using organometallic reagents. Its
chemoselectivity is particularly seen in the clean transforma-
tions of cyano- or halo-substituted substrates.
Acknowledgment. We thank EPSRC National Mass
Spectrometry Service Centre, Swansea, for high-resolution
mass spectra and EPSRC, Universities UK and University
of Strathclyde, for funding of T.A.K.
evidence of polydeuteration was observed that would arise
from exchange between 7 and D O under acidic conditions,
2
thus providing viable evidence for the existence of B.
The scope of the reaction was then tested (Table 1).
Entries 7 and 8 show that the reaction succeeds well with
R-branched Weinreb amides, although attempts to convert
the amide of pivalic acid (not shown) have not yet proved
successful. The reaction works well with aromatic Weinreb
amides (entries 1-4, 14-20), R,â-unsubstituted examples
Supporting Information Available: Typical experimen-
tal procedures for the reactions of Weinreb amides are
provided together with spectroscopic data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL050337B
(entry 9), and also with R-heterosubstitution (entry 8). Dual
transformation can be achieved with aldehyde-amide sub-
strates (entry 10). The reaction is also chemoselective, where
a nitrile group (entry 4) and aliphatic halides (chloride,
bromide) (entries 11-13) do not interfere with the reaction.
The reaction is not limited to methylenetriphenylphos-
phorane, with pentylenetriphenylphosphorane (entry 14),
butylenetriphenylphosphorane (entries 15-17), and 3-phe-
nylpropylenetriphenylphosphorane (entries 18-20) also giv-
ing excellent results. Also worthy of note is the successful
(
7) For intermolecular examples, see: (a) Bohlmann, R.; Strehlke, P.
Tetrahedron Lett. 1996, 37, 7249. (b) Kirby, A. J.; Komarov, I. V.; Wothers,
P. D.; Feeder, N. Angew. Chem., Int. Ed. 1998, 37, 785. (c) B e´ gu e´ , J.-P.;
Mesureur, D. Synthesis 1989, 309. (d) Prasitpan, N.; Patel, J. N.; De Croos,
P. Z.; Stockwell, B. L.; Manavalan, P.; Kar, L.; Johnson, M. E.; Currie, B.
L. J. Heterocycl. Chem. 1992, 29, 335. For intramolecular examples, see:
e) Le Corre, M.; Hercouet, A.; Le Stanc, Y.; Le Baron, H. Tetrahedron
985, 41, 5313. (f) Li, J. P.; Newlander, K. A.; Yellin, T. O. Synthesis
1988, 73. (g) Eitel, M.; Pindur, U. Synthesis 1989, 364. (h) Danieli, B.;
Lesma, G.; Palmisano, G.; Passarella, D.; Silvani, A. Tetrahedron 1994,
0, 6941. (i) Coulton, S.; Gilchrist, T. L.; Graham, K. J. Chem. Soc., Perkin
(
1
5
Trans. 1 1998, 1193.
Org. Lett., Vol. 7, No. 7, 2005
1429