Reactions of Weinreb amides: formation of aldehydes by Wittig reactions

Article abstract of DOI:10.1016/j.tetlet.2006.06.118

Aldehydes are prepared in excellent yield by Wittig reactions of phosphoranes on the Weinreb amide of formic acid followed by in situ hydrolysis.

Full text of DOI:10.1016/j.tetlet.2006.06.118

Tetrahedron Letters 47 (2006) 6293–6295
Reactions of Weinreb amides: formation
of aldehydes by Wittig reactions
Kevin Hisler, Regis Tripoli and John A. Murphy*
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building,
295 Cathedral Street, Glasgow, G1 1XL, United Kingdom
Received 16 May 2006; revised 16 June 2006; accepted 22 June 2006
Available online 18 July 2006
Abstract—Aldehydes are prepared in excellent yield by Wittig reactions of phosphoranes on the Weinreb amide of formic acid
followed by in situ hydrolysis.
Ó 2006 Elsevier Ltd. All rights reserved.
Weinreb amides (N-methoxy-N-methylamides) are very
O
O
O
R
(i) R'CH2MgX
or R'CH2Li
useful intermediates in synthetic organic chemistry1
allowing the direct preparation of highly functionalised
aldehydes and ketones upon reaction with appropriate
nucleophiles2 (see Scheme 1). The efficiency of this pro-
cess is attributed to the intermediacy of an exceptionally
stable tetrahedral intermediate,2 which does not break
down to the desired carbonyl product until work-up.
Accordingly, no secondary addition of the nucleophile
to this carbonyl product is seen. The stability of the
intermediate has itself found elegant application,3 pro-
viding aldehydes and ketones in masked form, allowing
a second transformation to be performed chemoselec-
tively in its presence. [Weinreb amides have also found
use in chemoselective preparation of b-ketoesters4,5 (or
b-keto-Weinreb amides5) where ester enolates act as
nucleophiles.]
OMe
(i) DIBAL-H
R
CH2R'
O
R
H
R
N
+
+
Me
(ii) H3O
(ii) H3O
2
1
CHR'
N
O
PPh3
+
OMe
OMe
CHR'
H3O
R
N
R
CH2R'
Me
1
Me
3
2
Scheme 1.
O
O
H
OMe
OMe
NaOMe, Et2O
N
+
H
OMe
H
N
− MeOH, NaOMe
Me
Me
6
4
5
Although the transformation is extremely useful, the
reactivity of the organometallic reagents that react with
Weinreb amides 1 must be taken into account when
planning synthetic transformations. Reagents such as
DIBAL-H, LiAlH4, Grignard and organolithium
reagents are incompatible with a number of functional
groups. Hence we have sought less aggressive conditions
for effecting the same transformations.
ONa
H
NaOMe, MeOH
MeOH
OMe
MeO
N
Me
7
Scheme 2.
Thus, we recently reported a highly efficient alternative
conversion of N-methoxy-N-methylamides 1 to related
(i) LDA [for cpd 11] or BuLi [all others]
+
RCH2CHO
RCH2PPh3
(ii) HCONMe(OMe)
(iii) H3O+
−
Br
*
Corresponding author. Tel.: +44 548 2389; fax: +44 548 4246; e-mail:
john.murphy@strath.ac.uk
Scheme 3.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.118

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K. Hisler et al. / Tetrahedron Letters 47 (2006) 6293–6295
Table 1. Aldehydes produced from Wittig reactions
Entry
Phosphonium salt
Aldehyde product
Yield (%)
−
+ Br
X
O(CH2)3CHO
X
O(CH2)3PPh3
1
2
3
4
8, X = H
9, X = Cl
10, X = OMe
11, X = CN
14, X = H
89
92
86
83
15, X = Cl
16, X = OMe
17, X = CN
−
Br
+
5
(CH2)3CHO
(CH2)3PPh3
12
18
88
95
+
−
6
C12H25CHO
C12H25PPh3
Br
13
19
ketones 2 by a route that avoids the highly reactive orga-
nometallic reagents; the conversion is effected upon
reaction with alkylidenetriphenylphosphoranes.6–8
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.118.
The preparation of ketones from Weinreb amides paral-
lels the attack of organometallics such as Grignard
and organolithium reagents, but we had no parallel
route to aldehydes. This letter reports a solution to
the task of producing aldehydes using these milder
methods.
References and notes
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hydes would be N-methoxy-N-methyl formamide9
6
(Scheme 2). Our attempts to prepare it initially foun-
dered. The procedure9 involves treating the free amine
N-methoxy-N-methylamine 4 with methyl formate 5 in
the presence of excess quantities of sodium methoxide.
Although the product 6 undoubtedly forms, as seen by
NMR, the vacuum distillation needed to purify it led
to essentially 0% yield. Our studies showed that the
product was converted to volatile compounds; the excess
base that was not removed during filtration was reform-
ing methyl formate 5, via 7, which was removed in
vacuo.
In fact, excess base should not be needed. If catalytic
base were to be used and remained at the start of the dis-
tillation, this might regenerate small quantities of amine
4 and methyl ester 5, but these would then disappear
from the distillation in vacuo. The amine 4 produced,
could not harm the remaining product. In practice, this
use of catalytic base led to reliable isolation of the
desired product 6.
This Weinreb amide was then reacted with a series of
phosphonium salts (Scheme 3) as shown in Table 1.
As seen, the reactions proceeded in excellent yield to
afford the corresponding aldehydes after work-up with
mild acid.10 This provides a simple route to aldehydes
using a Weinreb amide under mild conditions.
3. (a) Kruger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997,
¨
Acknowledgements
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4. Turner, J. A.; Jacks, W. S. J. Org. Chem. 1989, 54, 4229–
4231.
We thank the EPSRC national mass spectrometry
service centre, Swansea, for mass measurements.

K. Hisler et al. / Tetrahedron Letters 47 (2006) 6293–6295
6295
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8. For recent work on anomalous Wittig reactions, see:
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4888.
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7. Murphy, J. A.; Commeureuc, A. G. J.; Snaddon, T. N.;
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10. Reactions with secondary phosphonium salts have so far
not proved successful.