The synthesis and functionalisation of quinuclidine enamine N-oxide and borane complex

Article abstract of DOI:10.1016/S0040-4039(99)02033-X

The synthesis of quinuclidine enamine N-oxide and quinuclidine enamine borane complex is described. Selective deprotonation of the double bond allows the direct functionalisation at the α-position with a range of electrophiles.

Full text of DOI:10.1016/S0040-4039(99)02033-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 271–274
The synthesis and functionalisation of quinuclidine enamine
N-oxide and borane complex
Ian A. O’Neil,a,∗ Duncan Wynn a and Justine Y. Q. Lai b
aDepartment of Chemistry, University of Liverpool, Crown St, Liverpool L69 7ZD, UK
bRhône-Poulenc Rorer, Rainham Road South, Dagenham, Essex RM10 7XS, UK
Received 23 September 1999; accepted 26 October 1999
Abstract
The synthesis of quinuclidine enamine N-oxide and quinuclidine enamine borane complex is described. Selective
deprotonation of the double bond allows the direct functionalisation at the α-position with a range of electrophiles.
© 1999 Elsevier Science Ltd. All rights reserved.
Keywords: carbanions; N-oxides; enamines; boron; boron compounds.
The quinuclidine nucleus is the core component of the cinchona alkaloids, a family of natural products,
which not only exhibit antimalarial activity but have also found widespread use in numerous asymmetric
transformations.1
We recently reported the use of quinuclidine N-oxide as a potential replacement for hexamethyl-
phosphoric triamide (HMPA) in a number of synthetically important reactions.2 In order to increase
the scope of this reagent system we envisaged that the incorporation of additional metal binding sites
α to the nitrogen would increase the metal binding capability of these reagents. In addition, we were
intrigued by the possibility of linking two quinuclidine units together to yield a dimeric species such as
compound 2, which would almost certainly possess enhanced metal binding properties. One potential
building block for 2 was the enamine N-oxide 1 shown in Fig. 1. Examination of the literature showed
that this was an unknown compound, although the parent enamine has been prepared and studied by
Grob.3 We predicted that selective deprotonation of enamine N-oxide 1 at the unsaturated α carbon
should be possible, allowing for the functionalisation of this position. Subsequent dimerisation should
then be possible if appropriate functionality had been incorporated.
Fig. 1.
∗
Corresponding author. Tel: 0151 794 3485; fax: 0151 794 3588; e-mail: ion@liv.ac.uk (I. A. O’Neil)
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02033-X
tetl 15961

272
Enamine N-oxides have been prepared previously;4 however, they have been reported to undergo
fragmentation reactions on treatment with strong bases. In the example shown in Scheme 1, deprotonation
of 3 presumably occurs on one of the methyl groups, subsequent fragmentation to yield an iminium salt,
followed by hydrolysis to give cyclohexanone and formaldehyde.
Scheme 1.
In our approach to dimers such as 2 we have synthesised the enamine N-oxide 1 from commercially
available 3-hydroxyquinuclidine using the route outlined in Scheme 2.
Scheme 2.
Thus, tosylation of 3-hydroxyquinuclidine 4 followed by N-oxidation proceeded smoothly to give
the N-oxide 5. Treatment of the N-oxide 5 with 1 equiv. of KOtBu at −78°C, followed by warming
to room temperature, furnished the desired enamine N-oxide in good yield. N-Oxide 1 is a colourless,
1
hygroscopic solid. It is conveniently dried and stored over P2O5. The H NMR of 1 in CDCl3 showed
two characteristic vinyl protons at δ 6.71 and 6.48, the low chemical shift of these protons indicating the
powerful inductive effect of the nitrogen.5
We also found that the corresponding borane complex of the enamine could be prepared by an
analagous route (Scheme 3).
Scheme 3.
Having established a reliable protocol for the synthesis of 1 and 7 we next examined their
deprotonation.6,7 Treatment of 1 or 7 with 1 equiv. of tBuLi at −78°C in anhydrous THF gave the vinyl
carbanions 8 or 9. Quenching of these species with a suitable electrophile yielded the 2-functionalised
quinuclidine enamine derivatives (Scheme 4).
Scheme 4.
1
A range of electrophiles were examined. In each case the H NMR spectrum showed that the vinyl
signal at δ 6.71 due to the proton adjacent to the quinuclidine nitrogen had disappeared. The results are
summarised in Table 1. With non-enolisable ketones and aldehydes (entries 2, 4 and 5) the yields of the

273
Table 1
Reactions of 2-lithio quinuclidine enamine N-oxide and borane complex
addition products are good. These products are generally stable crystalline materials with the N-oxide
oxygen hydrogen bonded to the OH group. The lower yield with acetophenone is most likely due to
competing enolisation. The introduction of heteroatoms (entries 1, 3, 8 and 9) again went in good yield.
In summary, we have prepared the quinuclidine enamine N-oxide 1 and the quinuclidine enamine
borane complex 7 in good yield. Both of these species have been shown to undergo clean lithiation at
the vinylic position and the resulting carbanions can be trapped out with a range of electrophiles. We are
currently examining the coupling reactions of these functionalised quinuclidines in the construction of
dimeric species.

274
Acknowledgements
ION would like to thank Rhône-Poulenc Rorer for their generous support of this work.
References
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Plessner, T.; von Reisen, C. Synlett 1996, 690–692.
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NCH2CHH), 2.85 (1H, m, CH), 3.30 (2H, m, N–CHH), 3.56 (2H, m, N–CHH), 6.48 (1H, t, J=7 Hz), 6.71 (1H, d, J=7
Hz). δC (75 MHz, CDCl3) 29 (CH), 31 (N–(CH2)2–(CH2)2), 70 (N–(CH2)2), 134 (N–CH_CH), 151 (N–CH_CH). MS(CI)
[M+H]+ m/z: 126.09167; C7H12NO requires: 126.09189.
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Li, W. S.; Simpkins, N. S.; Fox. N. A. J. Chem. Soc., Perkin Trans. 1 1999, 2439–2447, and references cited therein.