Rearrangement of unactivated N-alkyl-O-benzoyl hydroxamic acid derivatives with phosphazene bases

Article abstract of DOI:10.1016/S0040-4039(01)00062-4

The phosphazene super bases BTPP 5, P-2-^tBu 6, and P-4-^tBu 7 mediate the rearrangement of unactivated N-alkyl-O-benzoyl hydroxamic acid derivatives 8, 11a-f, 13 and 16 to give 2-benzoyloxy amides 9, 12a-f, 14 and 17. The rate of reac

Full text of DOI:10.1016/S0040-4039(01)00062-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2007–2009
Rearrangement of unactivated N-alkyl-O-benzoyl hydroxamic
acid derivatives with phosphazene bases
a,
a
a
b
Andrew J. Clark, * Yassair S. S. Al-Faiyz, Divya Patel and Michael J. Broadhurst
a
Chemistry Department, University of Warwick, Coventry CV4 7AL, UK
b
Roche Discovery Welwyn, Welwyn Garden City, Hertfordshire AL7 3AY, UK
Received 16 November 2000; revised 20 December 2000; accepted 10 January 2001
t
t
Abstract—The phosphazene super bases BTPP 5, P-2- Bu 6, and P-4- Bu 7 mediate the rearrangement of unactivated N-alkyl-O-
benzoyl hydroxamic acid derivatives 8, 11a–f, 13 and 16 to give 2-benzoyloxy amides 9, 12a–f, 14 and 17. The rate of reaction
was found to be dependant upon the steric nature of the N-alkyl substituent. © 2001 Elsevier Science Ltd. All rights reserved.
3
,5
We recently reported that N-alkyl-O-acyl hydroxamic
acid derivatives 1 containing suitably acidic a-protons
undergo smooth rearrangement to give 2-acyloxyamides
bases such as KHMDS or LDA were utilised. In fact
even the activated systems (e.g. 1) failed to react when
these inorganic bases were used suggesting that the
presence of a coordinating metal may switch the confor-
mation of the hydroxamic acid to an unreactive one. We
initially postulated that the rearrangement took place via
a [3,3]-sigmatropic rearrangement of the enolate or enol
form 4 and were interested to read the report of Hartley
2
upon heating with catalytic organic bases such as Et N
3
1–3
(
Scheme 1). After deprotection of the acyl protecting
group the reaction furnishes secondary 2-hydroxyamides
3,4
which are versatile synthetic intermediates. The reac-
tion failed however when no activating group (e.g. Ph)
able to stabilise a negative charge or enol form was
present in the substrate. Thus, it was not possible to
rearrange the substrate 3 even when strong inorganic
6
et al. that indicated that organic phosphazene super
bases 5–7 were useful alternatives to conventional inor-
ganic bases in [3,3]-sigmatropic Cope rearrangements.
7
Scheme 1.
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00062-4

2
008
A. J. Clark et al. / Tetrahedron Letters 42 (2001) 2007–2009
Scheme 2.
Initial studies concentrated on the effect of the various
yield in only 18 h. The rates of reaction with the
less sterically hindered s-Bu and i-Pr derivatives 11a–b
were much slower leading to lower 30% yields of 12a–b
(the rest of the mass balance being unreacted starting
material) after extended reaction times. Interestingly, it
was not possible to rearrange the primary substituted
precursor 11c with starting material being recovered
even after 3 days at 110°C (Table 2). The same trend
was found for the related series of precursors 11d–f
with the most efficient rearrangement being that of 11d
(Scheme 3).
bases 5–7 upon the reaction of the unactivated sub-
8
strate 8. Hence, heating 8 at 110°C in refluxing toluene
with 0.2 equivalents of phosphazene base 6 for 18 h
furnished the desired rearrangement compound 9 in
7
5% yield (Scheme 2). No reaction occurred under the
same conditions when Et N was used as base. Table 1
3
clearly indicates that the nature of the base is crucial
for successful rearrangement. Interestingly the most
basic phophazene compound 7 did not lead to any
reaction and only starting material was recovered. In
some reactions deprotection of the secondary hydroxyl
was observed, presumably due to hydrolysis in the
work-up stage.
The nature of the N-acyl substituent was briefly investi-
gated. Branching in the side chain 13 was tolerated
although the reaction was less efficient and significant
amounts of the deprotected 2-hydroxyamide 15 were
isolated. The presence of other functional groups (such
as an alkene 16) was also tolerated although the yield of
the reaction was low (30%).
Effect of the N-alkyl substituent
Having established that it was possible to mediate the
rearrangement of an unactivated precursor next we
briefly examined the scope of the reaction utilising the
t
most successful base, that being the P2- Bu base 6. It
In conclusion, we have shown that the use of strong
phosphazene bases can mediate the rearrangement of
N-alkyl-O-acyl hydroxamic acid derivatives to 2-acy-
loxy amides. The rate and yield of the reaction was
heavily dependant upon the steric nature of the N-alkyl
substituent.
became rapidly apparent that the efficiency of the rear-
rangement was heavily dependent upon the steric hin-
drance at the nitrogen substituent. The reaction of the
t-Bu derived precursor 8 was facile giving 9 in 75%
Table 1. Rearrangement of 8 with bases 5–7
Entry
Base
Equivalent
Yield 9 (%)
Yield 10 (%)
1
2
3
4
5
Et N
1
0.2
1
0.2
1
0
46
50
75
0
0
0
30
20
0
3
5
6
6
7
Scheme 3.

A. J. Clark et al. / Tetrahedron Letters 42 (2001) 2007–2009
Table 2. Effect of N-substituent upon yield
2009
Entry
Substrate
R1
R2
Time (h)
Yield 12 (%)
1
2
3
4
5
6
7
8
8
n-Bu
n-Bu
n-Bu
n-Bu
Me
Me
Me
Me
t-Bu
s-Bu
i-Pr
Me
t-Bu
s-Bu
i-Pr
Me
18
72
18
72
72
110
168
168
75
30
30
0
76
21
19
0
11a
11b
11c
11d
11e
11f
3
Acknowledgements
3. Clark, A. J.; Al-Faiyz, Y. S. S.; Broadhurst, M. J.; Patel,
D.; Peacock, J. L. J. Chem. Soc., Perkin Trans. 1 2000,
1117.
We wish to acknowledge the EPSRC and Roche Dis-
covery Welwyn for funding (CASE award for D.P.) and
the Saudi Arabian Government for funding (Y.S.S.A.-
F.).
4. Hoffmann, R. V.; Nayyar, N. K.; Chen, W. J. Org. Chem.
1992, 57, 5700.
5. Endo, Y.; Uchida, T.; Hizatate, S.; Shudo, K. Synthesis
1994, 1096.
6. Mamdani, H. T.; Hartley, R. C. Tetrahedron Lett. 2000,
41, 747.
References
7. For a review see: Seebach, D.; Beck, A. K.; Studer,
A. In Modern Synthetic Methods 1995; Ernst, B.;
Leumann, C., Eds.; Weinhein: VCH, 1995; Vol. 7, pp.
1–178.
1
. Clark, A. J.; Peacock, J. L. Tetrahedron Lett. 1998, 39,
265.
1
2
. Al-Faiyz, Y. S. S.; Clark, A. J.; Filik, R. P.; Peacock, J. L.;
Thomas, G. H. Tetrahedron Lett. 1998, 39, 1269.
8. All new compounds exhibited satisfactory spectroscopic
and analytical details.
.
.