Quimica

Tetrahedron 68 (2012) 1017e1028

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Tetrahedron
journal homepage: www.elsevier.com/locate/tet

An efficient synthesis of 3-alkyl-1,5,3-dioxazepanes and their use as electrophiles in double-Mannich reactions
Kevin Sparrow, David Barker, Margaret A. Brimble *
School of Chemical Sciences, University of Auckland, 23 Symonds St., Auckland, NewZealand

a r t i c l e i n f o
Article history: Received 15 September 2011 Received in revised form 12 November 2011 Accepted 28 November 2011 Available online 7 December 2011 Keywords: Methyllycaconitine Double-Mannich reactions Dioxazepanes Azabicyclo[3.3.1]nonanes Bis(aminol)ethers

a b s t r a c t
An efficient synthesis of 3-alkyl 1,5,3-dioxazepanes was developed for subsequent use indoubleMannich reactions with a variety of carbon-based nucleophiles. It was found that addition of methyltrichlorosilane to the dioxazepane led to a long-lasting reactive species that reacted rapidly with acidsensitive ketones and b-ketoesters to afford azabicyclo[3.3.1]nonanes in good yield. Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction The use of N-alkyl bis(aminol)ethers 1 indouble-Mannich reactions with b-ketoester 2 has allowed the rapid, high-yielding synthesis of bicyclic amines as AE ring analogues of methyllycaconitine 3 (Scheme 1).1 To date, the reported syntheses of bis(aminol)ethers have typically only proceeded in low to moderate yield,1 have required distillation to isolate the product from oligomeric impurities, and have exhibited low product stability. Theseproblems pose practical barriers for their use with expensive or high molecular weight amines.

2. Results and discussion In order to improve the overall efficiency of the reaction sequence, alternative bis(iminium) ion precursors were desired. 3Alkyl-1,5,3-dioxazepanes were first reported by Kapnang and coworkers2 and were later employed by that group as electrophiles in double-Grignard additions,forming differentially-substituted tertiary amines in good yields.3 More recently, a double-Mannich reaction of 3-benzyl-1,5,3-dioxazepane with cyclopentanone activated by iodotrimethylsilane was reported by Ooka et al.4 With these encouraging precedents, a range of 3-alkyl-1,5,3-

OMe RNH 2 i R N OEt OEt 1 EtO 2 O O EtO O ii R NE O N O O O O
A

O N
A E

OMe OH H OH OMeMethyllycaconitine 3

Scheme 1. Reagents and conditions: (i) paraformaldehyde, K2CO3, EtOH, 3 d, 11e47%; (ii) 1þ2, MeSiCl3, 18 h, 75e99%.

* Corresponding author. E-mail Brimble).

address: m.brimble@auckland.ac.nz

(M.A.

dioxazepanes 4aeg were synthesized by modification of Kapnang’s method2 via condensation of a primary amine, excess paraformaldehyde and ethylene glycol with azeotropic removal of water(Table 1).

0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.11.090

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K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028

Table 1 Reagents and conditions: (i) paraformaldehyde (1.5 equiv), ethylene glycol (1.1 equiv), amine (1 equiv), benzene or toluene, D, DeaneStark apparatus, 3e16 h

HO RNH 2 + 2 CH 2O HO

i

R
3

N

O51O 4a-g

Entry 1 2 3 4 5 6 7
a b

R Me Et n-Bu t-Bu Bn Ph(CH2)3 (R)-a-MeBn

Yield 54a 73b 97 70b Quant. 97 89

Compound 4a 4b 4c 4d 4e 4f 4g

Use of 1 equiv of SnCl4, BF3$OEt2, or 2 equiv of acetyl chloride failed to effect the desired reaction whilst use of 0.1 equiv of samarium(III) triflate (entry 5) gave 5e in moderate yield. Whilst thionyl chloride (entry 6) also gave 5e inmoderate yield it occurred in a rapid exothermic reaction and was thus not investigated further. Amongst the chlorosilane activators (entries 4, 7e9), methyltrichlorosilane5 proved to be the most efficient in terms of stoichiometry, reaction time and yield, consistent with related work published in our group.1 The use of titanium(IV) chloride (entries 10e12) as a Lewis acid activator initially appeared...