Tetraallylstannane and Weinreb amides: A simple 'green' route to N-protected homoallylic alcohols and allyl ketones

Article abstract of DOI:10.1016/S0040-4039(00)01408-8

We have explored the addition of tetraallylstannane (7) to a variety of N-protected Weinreb amides (N-phthalimido and N-benzyl). Reactions were conducted in methanol and the ionic liquid, butylmethylimidazole tetrafluoroborate (bmim[BF₄]), yields of the corresponding N-protected allylketones were moderate to good. Allylation of the corresponding aminoaldehydes gave excellent yields of homoallylic alcohols (68-94%) and moderate to good diastereoselectivities (50-86%). (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01408-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8147–8151
Tetraallylstannane and Weinreb amides: a simple ‘green’
route to N-protected homoallylic alcohols and allyl ketones
Adam McCluskey,a,* James Garner,a David J. Youngb and Shirley Caballeroc
aMedicinal Chemistry Group, School of Biological and Chemical Sciences, The University of Newcastle, Callaghan,
NSW 2308, Australia
bFaculty of Science and Technology, Griffith University, Brisbane, Qld 4111, Australia
cDepartment of Chemistry, DeLa Salle University, Taft Avenue, Manila, Philippines
Received 21 August 2000
Abstract
We have explored the addition of tetraallylstannane (7) to a variety of N-protected Weinreb amides
(N-phthalimido and N-benzyl). Reactions were conducted in methanol and the ionic liquid, butyl-
methylimidazole tetrafluoroborate (bmim[BF4]), yields of the corresponding N-protected allylketones were
moderate to good. Allylation of the corresponding aminoaldehydes gave excellent yields of homoallylic
alcohols (68–94%) and moderate to good diastereoselectivities (50–86%). © 2000 Published by Elsevier
Science Ltd.
Keywords: Weinreb amides; tetraallylstannane; green chemistry; homoallylic alcohols; allyl ketones.
Over the past few years the allylation of a-amino aldehydes has been exploited as a key step
towards the stereoselective synthesis of statine and hydroxymethylene dipeptide isosteres.1 We
too have been involved in this area recently reporting the syn-diastereoselectivity in the
high-pressure addition of allyltrimethylstannane to N-protected a-aminoaldehydes.2
More recently we have been keen to develop organostannanes as reagents for green chem-
istry.3 Our main criteria for such reagents are:
“
Reactions should be conducted in environmentally benign solvents, or in the total absence of
solvent.
“
They should be high yielding reactions with high atom efficiency.
Our previous report of the high pressure addition of allyltrimethylstannane 2 is typical of an
organostannane based reaction, in that the reaction is moderately efficient and only a small
proportion of the atoms present on the reagent are found in the final product, Scheme 1.
* Corresponding author. Fax: +61 249 215472; e-mail: amcclusk@mail.newcastle.edu.au
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01408-8

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Scheme 1.
We have previously shown that allylations using 2 proceed under the influence of high pressure.2
More recently we have also demonstrated that similar allylations with 7 proceed rapidly in
methanol,4 water,3 and the ionic liquids bmim[BF4] and bmim[PF6],5 especially in the case of
aliphatic aldehydes. Ionic liquids are perhaps the ideal solvent, possessing no vapour pressure,
are tunable to the requirements of the reaction, have a wide range operating temperatures (−100
to +400°C with the correct choice of ionic liquid), and importantly are easily recycled. The most
commonly utilised ionic liquids are those based on 1-methyl imidazole,6 see Fig. 1. With
tetraallylstannane it is possible to obtain excellent yields in the case of ketones at methanol reflux.
However, we have been unable to successfully allylate esters. Herein, we wish to report our recent
development in the use of tetraallylstannane (7) as a reagent for green chemistry.
Figure 1.
Weinreb amides have been widely used as one of the key steps in the stereoselective synthesis
of statine and hydroxymethylene dipetide isosteres.1 It occurred to us that we may be able to
allylate the parent amide and by varying the amine protecting group, and in the case of the
corresponding aldehydes, influence the stereochemical outcome of the procedure. In conducting
these reactions we limited our choice of solvent to methanol and bmim[BF4].
Our initial studies on the parent Weinreb amides (Fig. 2) proved fruitless, no reaction was
observed either in methanol or bmim[BF4] after stirring at 30°C for 24 hours.
Fig. 2.
However, at methanol reflux after 2 hours we detected low yields of the corresponding
N-protected allylketones (8, 9), Scheme 2. Prolonged reflux, 5 days, afforded moderate to good
yields. Stirring in bmim[BF4] for 5 days at 50°C had a similar result, Table 1.
Scheme 2. Conditions: (i) Methanol reflux, 5-days; (ii) bmim[BF4], 50°C, 5-days

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Table 1
Yields of N-protected allyl ketones after treatment of N-protected Weinreb amides, 5 and 6, with 7
Amide
Allylketone yield (%)
Amide
Allylketone yield (%)
5a
5b
5c
33
39
55
6a
6b
6c
42
46
56
Scheme 3. Conditions: (i) Methanol 30°C, 24 h; (ii) bmim[BF4], 30°C, 24 h
In a typical procedure, the Weinreb amide (10 mmol) was dissolved in methanol (5 mL) and
to this was added 7 (0.705 g, 2.5 mmol) in methanol (5 mL) and the homogeneous mixture set
to reflux for 5 days. After this time the cloudy mixture was cooled, poured onto water (50 mL),
extracted with dichloromethane (3×25 mL), dried over Na2SO4, and the solvent removed to yield
the crude product. With bmim[BF4] the reaction is essentially identical, using 2 mL and adding
7 directly via a syringe, and the clear mixture warmed to 50°C for 5 days, followed by extraction
with diethylether (bmim[BF4] is miscible with dichloromethane).
A slight modification of the procedure was required in the case of the more reactive
N-protected aminoaldehydes. In these instances the reactions were conducted at 30°C for 24
hours and then worked up as before. In all instances the expected homoallylic alcohols, Scheme
3, were generated in good to excellent yields, see Tables 2 and 3.
Table 2
Observed diastereoselectivity after addition of 7 to N-phthalimido protected aminoaldehydes, 10a–ca
Entry
Compound
R
Ratio of syn-(12):anti-(13)7
Yield (%)
Yield (%)
MeOH
d.e. (%)b
Bmim[BF4]
1
2
3
10a
10b
10c
CH3
CH(CH3)2
PhCH2
75:25
89:11
91:9
82
56
45
94
68
80
50
78
82
a
L
-amino acids were used in the generation of the Weinreb amides, followed by LiAlH4 reduction.
b Determined by H and 13C NMR on a Varian AMX 300 MHz spectrometer.
1

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Table 3
Observed diastereoselectivity after addition of 7 to N-benzyl protected amino aldehydes, 11a–ca
Entry
Compound
R
Ratio of syn-(14):anti-(15)7
Yield (%)
Yield (%)
MeOH
d.e. (%)b
Bmim[BF4]
1
2
3
11a
11b
11c
CH3
CH(CH3)2
PhCH2
82:18
93:7
93:7
72
70
73
87
74
82
64
86
86
a
L
-amino acids were used in the generation of the Weinreb amides, followed by LiALH4 reduction.
b Determined by H and 13C NMR on a Varian AMX 300MHz spectrometer.
1
Disappointingly, we found no evidence of improved diastereoselectivity on using bmim[BF4]
as the solvent of choice, indeed using this system we achieved identical d.e.’s but with lower
chemical yields. We believe that the lower yields were a result of two factors. Firstly, product
extraction is slightly more difficult with the ionic liquid, and secondly the lower reaction
temperature. We are currently examining a wide-range of ionic liquids to determine the most
suitable system for this type of reaction, these results will be presented in due course.
We also conducted the equivalent transformations using the mono-N-benzyl-protected Wein-
reb amides (Scheme 4), these reactions proceeded exactly as the phthalimido series had, and the
results are shown in Table 3.
Scheme 4. Conditions: (i) Methanol 30°C, 24 h; (ii) bmim[BF4], 30°C, 24 h
Examination of Tables 2 and 3 suggest that the observed diastereoselectivity, is therefore a
function of both the amino acid, with Leu and Phe showing the best selectivity (Tables 2 and
3, entries 2 and 3, respectively), and the N-benzyl protecting group yielding the best d.e.=86%
.
(Table 3, entry 3).
These results show significant improvement upon, in a number of ways, our previous report
of Boc-protected amino aldehydes and reaction with allyltrimethylstannane. In those instances
the best d.e. observed was 76%. However, access to a high-pressure reactor was required. Thus,
in addition to increasing (albeit modestly) the diastereomeric excess of this type of reaction, it
is now considerably simpler, able to be conducted in any basic laboratory. Additionally we have
achieved a considerable increase in the atom efficiency of the process, only the Sn-atom of 7 is
not transferred to the product. Judicious choice of the solvent allows for a simple, environmen-
tally benign solvent being used, or in the case of the ionic liquid, a solvent that can be easily
recycled.

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Acknowledgements
This work received financial support from the University of Newcastle (RMCPG). We also
gratefully acknowledge the award of UNESCO visiting scholarship to S.C.
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