Synthesis of Azabicycles via Cascade Aza-Prins Reactions: Accessing the Indolizidine and Quinolizidine Cores

Article abstract of DOI:10.1021/acs.joc.5b01301

The first detailed studies of intramolecular aza-Prins and aza-silyl-Prins reactions, starting from acyclic materials, are reported. The methods allow rapid and flexible access toward an array of [6,5] and [6,6] aza-bicycles, which form the core skeletons of various alkaloids. On the basis of our findings on the aza-Prins and aza-silyl-Prins cyclizations, herein we present simple protocols for the intramolecular preparation of the azabicyclic cores of the indolizidines and quinolizidines using a one-pot cascade process of N-acyliminium ion formation followed by aza-Prins cyclization and either elimination or carbocation trapping. It is possible to introduce a range of different substituents into the heterocycles through a judicial choice of Lewis acid and solvent(s), with halo-, phenyl-, and amido-substituted azabicyclic products all being accessed through these highly diastereoselective processes.

Full text of DOI:10.1021/acs.joc.5b01301

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Article
Synthesis of azabicycles via cascade aza-Prins reactions:
accessing the indolizidine and quinolizidine cores
Freda K. I. Chio, Sebastien J. J. Guesne, Lorraine Hassall, Thomas McGuire, and Adrian P. Dobbs
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01301 • Publication Date (Web): 16 Sep 2015
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Synthesis of azabicycles via cascade aza-Prins reactions: accessing the
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indolizidine and quinolizidine cores
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Freda K.I. Chioa, Sébastien J.J. Guesnéb, Lorraine Hassallc, Thomas McGuirec and Adrian P. Dobbsa,b,d
aSchool of Biological & Chemical Sciences, QMUL, Mile End Road, London E1 4NS, UK
bDepartment of Chemistry, University of Exeter, Devon EX4 4QD, UK
cAstraZeneca, Alderley Park, Cheshire, SK10 4TG, UK
*
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dSchool of Science, University of Greenwich, Chatham Maritime, Kent ME4 4TB, UK
a.dobbs@gre.ac.uk
ABSTRACT
The first detailed study of intramolecular aza-Prins and aza-silyl-Prins reactions, starting from acyclic materials, are
reported. The methods allow rapid and flexible access towards an array of [6,5] and [6,6] aza-bicycles, which form
the core skeletons of various alkaloids. Based upon our findings on the aza-Prins and aza-silyl-Prins cyclisations,
herein we present simple protocols for the intramolecular preparation of the azabicyclic cores of the indolizidines and
quinolizidines using a one pot cascade process of N-acyliminium ion formation followed by aza-Prins cyclisation and
either elimination or carbocation trapping. It is possible to introduce a range of different substituents into the
heterocycles through a judicial choice of Lewis acid and solvent(s), with halo-, phenyl- and amido- substituted
azabicyclic products all being accessed through these highly diastereoselective processes.
INTRODUCTION
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Azabicyclic compounds are ubiquitous in nature, with the quinolizidine and indolizidine alkaloids being prime
examples, and which possess a wide range of biological activities. The polyhydroxylated indolizidine alkaloids, such as
(+)-castanospermine, have attracted particular attention as glycosidase inhibitors, as well as demonstrating anti-viral
(in particular anti-HIV), antitumour and immunomodulation activities. These properties continue to drive the search
for novel synthetic approaches towards their preparation. Herein we report a novel and highly efficient cascade
process for the rapid synthesis of azabicycles.
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Figure 1. Representative fused azabicycles
We have had a long standing interest in the Lewis acid-promoted Prins reaction1,2 and have, along with others, more
recently reported on the nitrogen equivalent of this reaction, the aza-Prins reaction,3-12 together with its silicon
modified counterpart the aza-silyl-Prins reaction.2,13-16 Both reactions involve the intermolecular reaction of a
carbonyl or related compound (aldehyde, ketone or epoxide) with a secondary homoallylic amine in order to form an
iminium ion, which then undergoes intramolecular Prins cyclisation to give either piperidines or tetrahydropyridines,
depending on the absence or presence of the silicon moiety on the alkene (Scheme 1). The aza-silyl-Prins reaction is
highly tolerant of a range of groups on the secondary amine, but is more limited to a sulfonamide in the aza-Prins
reaction.
Scheme 1. The aza-Prins6,17-19 and aza-silyl-Prins2,13,14 reactions
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It occurred to us that it may be possible to access the azabicyclic core of various alkaloids by a two-step one-pot
cascade process, first involving intramolecular iminium ion formation, followed by Prins cyclisation and either
carbocation trapping by a suitable nucleophile or elimination from the resultant carbocation (Scheme 2). Reddy20,
Saikia21,22, Overman23 and Waters24 have all prepared azabicyclic systems using a Prins or related cyclisation process,
but have either started from an intact or commercial mono-cyclic system,24 or have required the sequential formation
and purification of the mono-cyclic precursors, followed by a second cyclisation process.23 Thus the uniqueness and
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14 advantage of this approach in the one-pot double cyclisation, forming both rings in a single transformation.
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Scheme 2. Previous related work and proposed cascade process
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RESULTS AND DISCUSSION
In attempting to make the desired cyclisation precursors, we quickly established that the presence of both an
aldehyde and amine in the same precursor was problematic, and that they reacted together before the desired
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cascade sequence. Therefore an acetal was considered as a viable alternative. To test the feasibility of using an
acetal in an aza-silyl-Prins reaction, 1,1-dimethoxyhexane 2 was reacted with (Z)-N-benzyl-4-(trimethylsilyl)but-3-en-
1-amine 1 and gave the corresponding tetrahydropyridine 3 in good yield (Scheme 3).
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Scheme 3. Aza-silyl-Prins reaction using 1,1-dimethoxyhexane
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Therefore with the strategy of using an acetal in mind, both the required secondary amine and amide precursors
were prepared using related routes. It was envisaged that the cyclisation precursors could be obtained by two
possible routes, namely amine displacement of a suitably activated homoallylic alcohol or peptide coupling of a
homoallylic amine with a carboxylic acid.
The former method was examined first, with 5,5-dimethoxypentylamine 4 prepared in four steps and in 80%
overall yield from 5-aminopentanol (Scheme 4a). (Z)-4-(Trimethylsilyl)but-3-en-1-yl 4-toluenesulfonate 6 was
obtained from 3-butyn-1-ol via (Z)-4-(trimethylsilyl)but-3-en-1-ol 5. Unfortunately, all attempts at coupling these two
compounds failed to give the desired cyclisation precursor, with the product of amine dialkylation being the main
product obtained.
The latter amide coupling approach was then examined. The two prerequisite amines 7 and 8 were prepared from
the corresponding alcohols, namely 3-buten-1-ol and (Z)-4-(trimethylsilyl)but-3-en-1-ol 5, by tosylation, displacement
with azide and reduction with lithium aluminium hydride in 70% (5 steps from 3-butyn-1-ol) and 74% (from 3-buten-
1-ol) overall yields respectively (Scheme 4b). 8 could also be prepared quantitatively using Mitsunobu chemistry with
phthalimide followed by cleavage using hydrazine monohydrate.
4,4-Dimethoxybutanoic acid 9 was prepared in two steps from methyl 4-nitrobutanoate via a Nef reaction followed
by basic methanolysis, in 86% overall yield (Scheme 4c). 5,5-Dimethoxypenanoic acid 10 was also prepared in two
steps by ozonolysis of cyclopentene followed by methanolysis, in 47% overall yield (Scheme 4d).
Scheme 4. Synthesis of cyclisation precursors.
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Two methods were employed for the amide coupling reactions (Scheme 5). Acids 9 and 10 were activated with N-
hydroxysuccinimide prior to coupling the active esters with either amine 7 or 8 using N,N-dicyclohexylcarbodiimide.
Alternatively, the peptide coupling reagent n-propane phosphonic acid cyclic anhydride, T3P®,25 was also successfully
employed for the direct coupling of the acids and amides, albeit in slightly lower yields, but with the advantage that
purification was achieved by simple aqueous extraction. Finally, the secondary amines 15 and 16 were prepared by
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lithium aluminium hydride reduction of the amides 11 and 13. But-3-ynylamine was prepared from 3-butyn-1-ol by
tosylation, azide displacement and LiAlH4 reduction and the T3P® method again used to prepare the alkynyl
derivatives 17 and 18. Thus all the required linear cyclisation precursors could be obtained easily and in high overall
yields.
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Scheme 5. Synthesis of cyclisation precursors.
We have previously reported the use of indium trichloride in acetonitrile at reflux as being highly effective for
promoting the aza-silyl-Prins reaction with aldehydes2,3,13,14 and indeed this was successful in promoting an
intermolecular aza-silyl-Prins reaction with an acetal (Scheme 3). However, these conditions failed to give any of the
desired aza-bicycle when secondary amines 15 or 16 were employed, with starting material recovered. Changing the
solvent to toluene, and heating at reflux, gave traces of product but rapid decomposition of the starting material was
observed, at a rate considerably faster than the cyclisation. The addition of 4Å molecular sieves did not influence the
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outcome of the reaction. It is postulated that the Lewis acid may be complexing with the amine rather than
activating the acetal, preventing the first cyclisation occurring. Thus indium trichloride is seen as a promoter of the
intermolecular aza-Prins reaction with acetals, but a “poison” of an intramolecular variant.
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The same Lewis acid screening was then applied to the aza-silyl-Prins reaction amide precursors 13 and 14.
Gratifyingly, double cyclisation now took place relatively easily with a number of Lewis acids, with the [6,5] and [6,6]
bicycles being obtained in good yield, particularly when employing scandium triflate (Table 1 entries 2 & 5) and
14 indium triflate (Table 1 entries 1 & 4) as Lewis acids.
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Table 1. Iminium ion formation/Aza-Prins cyclisation cascades
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n
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Lewis Acida
In(OTf)3
Sc(OTf)3
InCl3
Product
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% Yieldb
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75
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In(OTf)3
Sc(OTf)3
InCl3
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traces
aAll reactions were performed at reflux temperature; bpurified, isolated yields.
Given that numerous indolizidine and quinolizidine alkaloids (Figure 1) are poly-hydroxylated, frequently at the
positions of the alkene produced in 19 and 20, attempts were made to perform an Upjohn OsO4/NMO
dihydroxylation reaction on the [6,5] product 19 (Table 1 entry 2). With no starting material or product isolated, the
reaction was repeated in d6-acetone/D2O (9:1) and monitored by NMR: the complete disappearance of the olefin
signals at δ = 5.77 and 5.67 was observed, and two new multiplet signals at δ = 3.71 and 3.85 appeared (for 2 x
CH(OH)), indicating the formation of two hydroxyl groups. Unfortunately, the diol was found to be very water soluble
and could not be extracted and purified after destruction of the osmate ester.26 Attempts to capture the diol as
either the acetate (using acetyl chloride) or 4-nitrobenzoate ester (from 4-nitrobenzoyl chloride) both failed. An
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identical outcome was observed when using 20: when the reaction was followed by 1H NMR, the two alkene peaks at
δ = 5.81 and 5.50 rapidly disappeared to be replaced by multiplets at δ = 3.74 and 4.01, but again the product was
completely water soluble.
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With a successful aza-silyl-Prins route into the indolizidine and quinolizidine cores to hand, attention turned to
utilizing the aza-Prins reaction to a similar end. As shown in Table 2, a number of Lewis acids were highly efficient at
promoting the double cyclisation: iron trichloride, indium trichloride and indium tribromide were all highly successful
promoters and provided a nucleophile for capture. Iron trichloride also gave the best diastereomeric ratios, ca. 9:1
(Table 2 entries 1 & 8). The yields of the [6,6] system with any particular Lewis acid were generally higher than the
equivalent [6,5] system with the same Lewis acid under identical conditions. Intriguingly, when using Lewis acid
triflates and boron trifluoride, a mixture of two inseparable unsaturated products 23a & 23b was isolated as the
major product, along with small amounts of the fluoride-trapped adduct. In all cases, diastereomeric ratios were
measured from the reaction mixture by comparing the integration of the signals for the C(5)H2 (6,5 adduct) or C(6)H2
(6,6), which were clearly separate in each diastereoisomer (Figure 2). NOE values consistently identified the major
adduct in both the (6,5) and (6,6) systems as the cis product.
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Figure 2. Diastereomeric ratio determination and NOE measurements for 21a (Table 2 entry 2), clearly showing
d.r.=4:1 from integration of peaks for H-C(5) at δ = 4.16:4.03 and 3.13:2.66
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Table 2. Iminium ion formation/Aza-Prins cyclisation cascades
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Solvent
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% Yieldb
(X=)
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% Yield
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(mixture)b
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FeCl3
InCl3
CH2Cl2
CH2Cl2
CH2Br2
CH2Br2
CH2Cl2
CH2Cl2
MeCN
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21b
21b
21c
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94 (Cl)
45 (Cl)
51 (Br)
16 (Br)
Traces (F)
6 (Cl)
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4:1
4:1
1:1
-
BBr3
InBr3
BF3.OEt2
In(OTf)3
In(OTf)3
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FeCl3
InCl3
CH2Cl2
CH2Cl2
CH2Br2
cHex
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64(Cl)
96 (Br)
25 (F)
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InBr3
-
BF3.OEt2
32d
aAll reactions were performed with 1 equiv. Lewis acid and at reflux temperature; purified, isolated yields. d.r.’s
were determined by NMR integration of the signal for C(5)H2 or C(6)H2. dAn additional third unsaturated product 23c
was also observed just in this particular reaction.
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When using 1 equiv. InBr3 (Table 2 entry 4), an intriguing product that is indicative of half-cyclisation, was also
isolated. This leads us to postulate on the mechanism of the double cyclisation process (Scheme 6). It is thought that
first, intramolecular Lewis acid-promoted acyl iminium ion (24) formation takes place. This process is followed by an
intramolecular aza-Prins cyclisation, to give the secondary cyclic carbocation (25). The ultimate reaction product is
then dependent upon the nature of the substituent on the alkene in the starting material. When this was a Z-
vinylsilane (terminal TMS group), the carbocation is presumably stabilised by the β-effect from silicon, and
elimination occurs to give the single alkene product (19 or 20), with no regioisomers. However, when the alkene was
un-substituted, there is no such stabilisation or favourable elimination reaction that can take place, so an external
nucleophile, normally from the Lewis acid, is trapped by the carbocation (21 or 22). An exception to this can be
found in Table 2 entry 4, where several additional products were observed in addition to the desired product: the
intramolecular acyliminium ion is trapped by the methoxide anion giving 26. It is highly likely that this remained as
part of a tight ion pair during the oxonium ion formation/cyclisation to acyliminium ion process, and thus trapping
52 was facile, although this product has not been observed in any other attempted double cyclisation. The addition of 1
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equiv. of InBr3 to the methoxy-intermediate provided bicycle 21b in quantitative yield (Scheme 6). This problem of
incomplete cyclisation could therefore be overcome by employing greater than 2 equiv. of Lewis acid in the reaction.
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Since all reactions in Table 2 were performed with 1 equiv. of Lewis acid, this suggests that some Lewis acids are able
to promote the first cyclisation but not the second. The best yields obtained in Table 2 for the ‘double cyclisation
approach’ are far superior to any two-step sequential cyclisation approach to the same targets.
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Scheme 6. Proposed mechanism and origin of stereochemical outcome for the aza-silyl-Prins and aza-Prins
cyclisations.
Thus overall, the examples presented in Tables 1 and 2 and Scheme 6 may be considered as N-acyliminium ion-type
cyclisations, given that the double cyclisation did not proceed when Y = 2xH (Scheme 2). Acyliminium ion cyclisations
have been comprehensively reviewed27,28 and these reviews cover many related examples of bicycle formation where
one ring is already in place, and the second is formed via an acyliminium cyclisation (Scheme 2). However, Hart has
reported the only related example of a double cyclisation, employing formic acid as the promotor of a double
cyclisation29 in the total synthesis of the Lythracaeae alkaloids Lythrancepine II and III.30,31
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Given Martín’s success in the Prins cyclisation of alkynes,4,32 we investigated the intramolecular cyclisation of
precursors 17 and 18. Neither gave products of double cyclisation. Cyclisation of 17 gave two products, 28 and 29,
derived from the initial cyclisation but no subsequent Prins reaction and 18 gave a complicated mixture from which
no compounds could be characterised.
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Scheme 7. Attempted alkyne aza-Prins reaction
The incorporation of alternative nucleophiles, in place of the anion from the Lewis acid, during a Prins cyclisation has
been reported and is an attractive feature of the reaction.17,33-35 This also adds a further layer of complexity to the
cascade process, making it now three sequential steps: following cyclisation/iminium ion formation and aza-Prins
cyclisation, the transformation may be terminated with Friedel-Crafts or Ritter reaction. In general, the trapping of
an external nucleophile occurs most readily when employing a Lewis acid poor in providing an anion for capture.
With this in mind, the double cyclisation was attempted using boron trifluoride, which had been shown to be poor
itself at supplying a nucleophilic anion, with the aim that the solvent may be incorporated favourably and rapidly
instead (Table 3).
Table 3. Capturing alternative nucleophiles during the double cyclisation.
n
1
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Solvent
PhH
sol =
Ph
Product
30a
% Yielda
20
Product
21c
% Yieldb
36
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2
MeCN
NHAc
30b
2 (NHAc)
21c
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30c
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MeCN
EtOAc
NHAc
OAc
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5 (OH)
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aisolated and purified yield of solvent-trapped adduct; bisolated and purified yield of F-containing product
Both Prins-Friedel-Crafts (entries 1 & 4) and Prins-Ritter (entries 2 & 5) reactions proceeded in modest yields, in both
[6,5] and [6,6] systems. Surprisingly, the O-acetyl group, from ethyl acetate, was also found to incorporate in modest
yield (entries 3 & 6). Pleasingly, the OAc trapped indolizidine (entry 3) was obtained as a single diastereoisomer in
crystalline form (Figure 3), confirming the proposed stereochemistry from the NMR data.
Figure 3. 3-oxooctahydroindolizin-7-yl acetate 30d. Displacement ellipsoids are drawn at the 50% probability level.
CONCLUSIONS
In conclusion, we have shown that both the aza-Prins and aza-silyl-Prins reactions may be utilised for the preparation
of azabicycles, the core structure for accessing indolizidine and quinolizidine alkaloids. The current approach offers a
number of advantages over existing methods for accessing the same architectures, namely good yields, starting from
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acyclic precursors and the ability to incorporate a range of nucleophiles in the bicyclic products. The Lewis acids FeCl3
(for n=1) and FeCl3, InCl3 and InBr3 (for n=2) were particularly efficient at promoting double cyclisations. The scope
and limitations of these reactions with respect to additional substituents and applications, will be reported in due
course.
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EXPERIMENTAL SECTION
GENERAL DETAILS
Commercially available reagents were used as supplied. All solvents were pre-dried prior to use. All reactions
19 were carried out under anhydrous conditions unless otherwise stated, and all glassware, syringes and needles
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were oven-dried and then allowed to cool prior to use in experiments. Infrared spectra were recorded in the
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range 4000-600 cm-1, obtained directly as either solids or neat liquids. Chemical shifts in H NMR spectra are
reported in δ (ppm) relative to residual solvent signals CDCl3 δH = 7.26 ppm; δC = 77.23 ppm or d6-DMSO δH =
2.50; δC = 39.51. Multiplicities of signals are reported using standard abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, b = broad. Coupling constants (J) are reported in hertz. Low resolution masses
were recorded in EI mode incorporating an SL Ion Trap. High resolution mass spectra were recorded using a LTQ
Orbitrap XL with resolution up to 100,000 (FWHM). Fourier Transform mass spectrometry was performed for
HRMS measurements.
General Procedure 1: Tosylation of alcohols (on 35 mmol scale)
To a cooled solution of homoallyl alcohol or penten-1-ol (1 equiv.) in CH2Cl2 (2 mL per mmol) were added DMAP
(0.6 equiv.) and p-TsCl (1.2 equiv.) at 0 °C. Et3N (1 equiv.) was then added dropwise and the solution was stirred
at 0 °C until TLC analysis showed complete consumption of the starting alcohol. The solution was diluted with
Et2O (2 mL per mmol) and stirred for another 30 min. Precipitated solid was removed by filtration and the
resulting solution washed with 10% aqueous copper sulfate solution (2 x 1.1 mL), followed by 15% aqueous
NaHCO3 solution (1.1 mL) and finally brine (0.9 mL per mmol). The organic phase was dried (MgSO4), filtered,
and volatile components were removed under reduced pressure and the residue purified by flash column
chromatography (PE:Et2O 1:1) to yield the tosylated alcohol.
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General procedure 2: Coupling reaction by T3P® (on 3 mmol scale)
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To a stirred solution of 4,4-dimethoxybutanoic acid 6 or 5,5-dimethoxypentanoic acid 7 (1 equiv.) and T3P® (1.15
equiv.) in dry EtOAc (8 mL per mmol) were added sequentially Et3N (2 equiv.) and (Z)-4-(trimethylsilyl)but-3-en-1-
amine 4 or 3-buten-1-amine 5 (1 equiv.). After complete consumption of the starting acid was detected by TLC
analysis, the mixture was acidified to pH 7 by the addition of 1.0 M aqueous HCl and the product was extracted into
EtOAc (10 mL per mmol). The organic layer was washed with water (2 x 10 mL per mmol) followed by brine (10 mL
14 per mmol), dried (MgSO4) and the volatiles removed under reduced pressure to yield the desired amide, which was
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used without further purification.
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General procedure 3: Azidation of tosylated alcohol (on 120 mmol scale)
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NaN3 (3 equiv.) was added portionwise to but-3-en-1-yl toluene-4-sulfonate or (Z)-4-(trimethylsilyl)but-3-en-1-yl
4-toluenesulfonate (1 equiv.) in DMF (2 mL per mmol). The resulting solution was heated and stirred to 60 °C for
2 h. After cooling to rt, the mixture was poured into a solution of Et2O:H2O (7 mL per mmol, 3:7, v/v). After
stirring for 30 min, the aqueous layer was separated, and the organic layer extracted with water (3 x 1 mL per
mmol). The aqueous layer was combined with the aqueous extracts and this was extracted with Et2O (3 x 1.3 mL
per mmol) and the combined organic extracts were washed with saturated aqueous LiCl (1.3 mL per mmol) and
37 brine (1.3 mL per mmol). The resulting organic solution was dried (MgSO4), filtered, the solution was
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concentrated under reduced pressure and the residue subjected to flash column chromatography (PE:Et2O 9:1)
to yield the pure azide.
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General procedure 4: Intramolecular aza-silyl-Prins reaction (on 0.70 mmol scale)
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To a Lewis acid (1 equiv.) suspension in MeCN (3.5 mL per mmol) heated to reflux was added a solution of (Z)-
4,4-dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-yl)butanamide 10 or (Z)-5,5-Dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-
yl)pentanamide 11 (1 equiv.) in MeCN (1.5 mL per mmol) dropwise over 1 min. The mixture was stirred at reflux
for 48 h or until GC-MS analysis showed complete disappearance of the amide peak. The solution was cooled to
rt, poured into a biphasic solution of CH2Cl2 (4 mL per mmol) and water (8 mL per mmol) and stirred for 30 min.
The organic layer was separated, the aqueous layer extracted with CH2Cl2 (3 x 2 mL per mmol). Combined
organic layers were washed with brine (4 mL per mmol), dried (MgSO4), filtered and volatiles were evaporated
under reduced pressure and purification by flash column chromatography yielded the unsaturated N-fused bicycle.
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General procedure 5: Intramolecular aza-Prins reaction (on 1 mmol scale)
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N-(But-3-en-1-yl)-4,4-dimethoxybutanamide 8 or N-(but-3-en-1-yl)-5,5-dimethoxypentanamide 9 (1 equiv.) was mixed
with the solvent (3.5 mL per mmol) for 5 min and the Lewis acid (1 equiv.) was added. The mixture was stirred for 48
h or until GCMS analysis showed complete disappearance of the amide. Water (5 mL per mmol) was added to quench
the reaction and the mixture was stirred for 30 min. The organic layer was separated, and the aqueous layer
14 extracted with solvent (3 x 4 mL per mmol). The combined organic solutions were washed with brine (4 mL), dried
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(MgSO4), filtered, and volatile components were evaporated under reduced pressure. Purification of the residue by
flash column chromatography yielded the bicyclic derivative.
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1. Precursor Syntheses
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(Z)-4-(Trimethylsilyl)but-3-en-1-ol (5)2
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To a cooled solution of DiBAL (1.0 M in hexane; 90 mL, 90 mmol, 3 equiv.) in Et2O (100 mL) at 0 °C was added 4-
(trimethylsilyl)but-3-yn-1-ol (4.27 g, 30 mmol, 1 equiv.) in Et2O (35 mL) dropwise over 15 min. The reaction was
heated at reflux overnight. After cooling to 0 °C, the reaction was quenched by the dropwise addition of aqueous
H2SO4 (2.0 M; 120 mL) over 30 min and stirred for 45 min, warming gradually to rt. The mixture was filtered
through celite®, diluted with Et2O (66 mL), the organic layer separated and the aqueous layer extracted 3 times
with Et2O (40 mL). The combined organic layers were washed with ice cold water (135 mL), dried (MgSO4),
filtered, and the solvent was removed under reduced pressure. Purification of residues by distillation under
reduced pressure (65 °C, 2 mmHg) yielded the title compound (3.94 g, 91 %) as a colourless oil. 1H NMR (400
MHz, CDCl3) δH = 6.16 (1H, dt, J 14.3, 7.4), 5.55 (1H, dt, J 14.3, 1.3), 3.54 (2H, d, J 6.5), 2.26 (2H, d, J 6.5), 1.50 (1H, bs),
0.00 (9H, s); m/z (EI+) 141 (1% [C8H17Si]), 83 (25% [C6H11]), 101 (30% [C4H9OSi]), 129 (60% [C6H13OSi]), 75 (100%
[(CH3)2HSi+]).
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(Z)-4-(Trimethylsilyl)but-3-en-1-yl 4-toluenesulfonate (6)
According to general procedure 1, to a cooled solution of (Z)-4-(trimethylsilyl)but-3-en-1-ol 5 (2.29 g, 15.9 mmol)
in CH2Cl2 (32 mL) were added DMAP (1.17 g, 9.54 mmol), p-TsCl (3.63 g, 19 mmol) and Et3N (2.20 mL, 15.9 mmol)
at 0 °C after 5 h TLC analysis showed the complete consumption of starting alcohol. Work up was carried out
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based on general procedure 1. Purification of the residue by flash column chromatography (PE:Et2O 1:1) yielded
the title compound (4.41 g, 93%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δH = 7.79 (2H, d, J 7.8), 7.34 (2H, d,
J 7.8), 6.12 (1H, dt, J 14.1, 7.1), 5.64 (1H, dt, J 14.1, 1.2), 4.03 (2H, t, J 6.9), 2.50-2.45 (2H, m), 2.45 (3H, s), 0.07
(9H, s); m/z (EI+) 165 (10% [C4H9SO3Si]+), 283 (20% [C13H20O3SSi]+), 91 (35% [C7H7]+), 229 (100% [(C4H8)SO3C7H8]).
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N-Benzyl-N-(Z)-(4-trimethylsilylbut-3-enyl)amine (1)2,36
Benzylamine (8.04 g, 75.00 mmol, 5 eq.) was warmed to 80 °C under nitrogen before adding a solution of (Z)-4-
(trimethylsilyl)but-3-en-1-yl 4-toluenesulfonate 6 (4.48 g, 15.00 mmol, 1 eq.) in dry ethanol (15 mL). The resulting
solution was stirred at 80 °C for 5 hours, when TLC showed complete consumption of starting material tosylate. The
ethanol was removed in vacuo and the excess of benzylamine carefully removed by distillation under reduced
pressure (Kugelrohr, 85 °C, 20 mmHg). The residue was partitioned between dichloromethane (60 mL) and 1.0 M
aqueous sodium hydroxide solution (40 mL). The organic layer was separated, the aqueous layer extracted with
dichloromethane (3 x 10 mL), the combined organic layers dried over magnesium sulfate, filtered and concentrated in
vacuo. The residue was purified by flash column chromatography (90% hexane 9% ethyl acetate 1% triethylamine) to
give the title compound 1 (2.28 g, 9.75 mmol, 65%) as a colourless oil. νmax(neat)/cm-1 3313, 1606;δH (300 MHz;
CDCl3) 7.36-7.21 (5H, m, H-Ar), 6.29 (1H, td, J 7.0, 14.1, H-C3), 5.58 (1H, td, J 1.2, 14.1, H-C4), 3.81 (2H, s, H-C5), 2.70
(2H, t, J 7.0, H-C1), 2.35 (2H, ddt, J 1.2, 7.0, 7.0; H-C2), 1.36 (1H, bs, H-NH), 0.12 (9H, s, H-CTMS); δC (75.5 MHz; CDCl3)
146.2 (C3), 140.5 (ArC), 131.2 (C4), 128.4 (ArCH), 128.1 (ArCH), 127.8 (ArCH), 54.0 (C5), 49.1 (C1), 34.1 (C2), 0.3
(CTMS).
(Z)-4-(Trimethylsilyl)but-3-en-1-amine (7)
NaN3 (2.93 g, 45 mmol) was added portionwise to a solution of (Z)-4-(trimethylsilyl)but-3-en-1-yl 4-
toluenesulfonate 6 (4.48 g, 15 mmol) in DMF (30 mL). The resulting solution was heated and stirred to 60 °C for
2 h. Work up was carried out based on general procedure 3. Purification of the residue by flash column
chromatography (PE:Et2O 9:1) yielded the )-(4-azidobut-1-en-1-yl)trimethylsilane (2.29 g, 90%) as a colourless
1
oil. H NMR (400 MHz, DMSO-d6) δH = 6.15 (1H, dt, J 14.2, 1.4), 5.50 (1H, dt, J 14.2, 7.3), 3.26 (2H, t, J 6.8), 2.26
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(2H, qd, J 6.8, 1.4), 0.00 (9H, s); m/z (EI+) 169 (1% [M]+), 126 (25% [C4H8N3Si]+), 100 (50% [C4H10NSi]+), 73 (100%
[C3H9Si]+).
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A solution of LiAlH4 (26.5 mL, 26.3 mmol; 1.0 M in THF) was diluted with THF (106 mL). After cooling to 0 °C, (Z)-
(4-azidobut-1-en-1-yl)trimethylsilane (4.24 g, 25 mmol) in THF (25 mL) was added dropwise over 2 h using a
syringe pump at a rate of 0.2 mmol per min. The mixture was stirred for 30 min at 0 °C and a solution of brine (4
mL per mmol) together with Et2O (2 mL per mmol) was added dropwise over 30 min. The mixture was allowed to
14 warm to rt over 30 min and any precipitate was removed by filtration through Celite®. The organic layer was
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separated and the aqueous layer extracted with Et2O (3 x 1.2 mL per mmol). The combined organic solution were
dried (MgSO4), filtered, and volatile components removed under reduced pressure to yield the pure title
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compound (3.29 g, 92%) as a clear oil and this was used without purification. H NMR (400 MHz, CDCl3) δH = 6.28
(1H, dt, J 14.2, 6.9), 5.61 (1H, d, J 14.2), 2.76 (2H, t, J 6.9), 2.27 (2H, qd, J 6.9, 6.9), 1.21 (2H, bs), -0.13 (9H, s);
m/z (EI+) 99 (40% [C5H11Si]+), 128 (50% [C7H16Si]+), 74 (100% [C3H10Si]+).
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3-Buten-1-amine hydrochloride (8)
To a solution of 3-buten-1-ol (0.50 g, 6.93 mmol, 1 equiv.) in THF (11 mL) was added Ph3P (1.99 g, 7.62 mmol, 1.1
equiv.) and phthalimide (1.12 g, 7.62 mmol, 1.1 equiv.) portionwise. This mixture was cooled to 0 °C and diisopropyl
azodicarboxylate (1.5 mL, 7.62 mmol, 1.1 equiv.) was added dropwise over 2 min. The reaction mixture was stirred
for 3 h at 0 °C before warming to rt overnight. n-Hexane (11 mL) was added and the suspension was filtered through
Celite®. The filtrate was washed sequentially with aqueous HCl (12 mL; 1.0 M) and saturated aqueous NaHCO3 (12
mL). The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. Purification of the
residue by flash column chromatography (PE:EtOAc 9:1) afforded N-(but-3-enyl)phthalimide37a white solid (1.39 g,
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100%). Mp 149-155 °C (lit mp 144 °C); νmax(neat)/cm-1 3021, 2927, 1708, 997, 956; H NMR (400 MHz, CDCl3) δH =
7.70-7.55 (4H, m), 5.66 (1H, ddt, J 17.2, 10.5, 7.0), 4.95-4.86 (2H, m), 3.63 (2H, t, J 6.8), 2.32 (2H, q, J 7.0); 13C NMR
+
(101 MHz, CDCl3) δC = 168.0, 134.4, 133.7, 132.0, 123.0, 117.3, 37.2, 32.7; m/z (EI+) 133 (15% [(CO)2C6H4 ]), 201 (45%
[M+]).
To a solution of N-(but-3-enyl)phthalimide (1 g, 4.97 mmol) in 98% ethanol (25 mL) was added dropwise 98%
hydrazine monohydrate (0.5 mL, 10 mmol) over 2 minutes. The mixture was heated to 50 °C and stirred under
nitrogen for 1 h. During this time a white suspension formed and slowly solidified. After cooling to rt, HCl (5 mL,
concentrated) was added dropwise over 3 minutes and the mixture was stirred for 10 minutes. The white
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precipitate was removed by filtration. After concentrating under reduced pressure, the residue was dissolved in
water and the residues removed by filtration. The solvent was removed under reduced pressure to give the title
compound 8 in quantitative yield as the HCl salt (0.53 g, 4.97 mmol). νmax(neat)/cm-1 3397, 2895, 1658, 998,
924; 1H NMR (270 MHz, D2O) δH = 5.82-5.67 (1H, m), 5.20-5.12 (2H, m), 3.04-2.99 (2H, t, J 6.7), 2.37 (2H, q, J 6.7);
13C NMR (270 MHz, D2O) δC = 133.3, 119.1, 38.7, 31.1. Treatment with dry triethylamine in dry dichloromethane
followed by an aqueous was provided the free amine.
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But-3-yn-1-amine38
21 To a cooled solution of 3-butyn-1-ol (5.40 mL, 71.34 mmol) in Et2O (72 mL) were added MsCl (8.15 mL, 105.13
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mmol) and Et3N (1.5 mL, 105.13 mmol) at 0 °C and the solution gradually warmed to rt overnight. Work up was
carried out based on general procedure 1. Purification of the residues by flash column chromatography (PE:EtOAc
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4:1) yielded but-3-yn-1-yl methanesulfonate38 (8.39 g, 89%) as a clear oil. νmax(CHCl3)/cm-1 3288 (C4), 2941 (CH), 1334
(S=O), 1169 (S=O); 1H NMR (400 MHz, CDCl3) δH = 4.26 (2H, t, J 6.9), 3.02 (3H, s), 2.64-2.60 (2H, m), 2.05 (1H, t, J 2.6);
13C NMR (101 MHz, CDCl3) δC = 78.9, 71.2, 67.5, 37.9, 20.1; m/z (EI+) 149 (1% [M]+), 109 (45% [C2H5O3S]+), 79 (100%
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[CH3O2S]+).
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NaN3 (7.80 g, 120 mmol) was added portionwise to a solution of but-3-yn-1-yl methanesulfonate (7.11 g, 47.97
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mmol) in DMF (50 mL). The resulting solution was heated and stirred to 60 °C for 2 h. Work up was carried out
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based on general procedure 3, and 4-azidobut-1-yne38 (4.11 g, 90%) was isolated as a clear oil and used without
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purification. νmax(CHCl3)/cm-1 3426, 2931, 2104; H NMR (400 MHz, CDCl3) δH = 3.37 (2H, t, J 7.0), 2.43 (2H, td, J 7.0,
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2.5), 2.02 (1H, t, J 2.5); 13C NMR (101 MHz, CDCl3) δC = 80.4, 70.6, 49.8, 19.5.
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To a cooled solution of LiAlH4 (1.0 M in THF; 37.1 mL, 37.1 mmol) in THF (106 mL) was added 4-azidobut-1-yne
(3.36 g, 35.33 mmol) in THF (35 mL) dropwise over 2 h at 0 °C. Work up was carried out based on general
procedure 5, and the title compound (0.49 g, 20%) was isolated as a clear oil and used without purification.
νmax(CHCl3)/cm-1 3410, 3293, 2924, 1556; 1H NMR (400 MHz, CDCl3) δH = 2.84 (2H, t, J 6.2), 2.32 (2H, td, J 6.2, 2.6), 2.00
(1H, t, J 2.6), 1.51 (2H, bs); 13C NMR (101 MHz, CDCl3) δC = 82.4, 69.7, 40.9, 23.4.
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2. Cyclisation Precursors
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N-(But-3-en-1-yl)-4,4-dimethoxybutanamide (11)
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According to General Procedure 2, to a stirred solution of 4,4-dimethoxybutanoic acid 9 (0.46 g, 3.10 mmol) and T3P®
(50% in EtOAc; 2.12 mL, 3.57 mmol) in EtOAc (23 mL) were added sequentially Et3N (0.86 mL, 6.20 mmol) and N-
homoallyl amine 5 (0.22 g, 3.10 mmol). After overnight stirring at rt, work up was carried out based on general
procedure 2, affording the title compound 11 (0.278 g, 65%) and this was used without any purification.
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νmax(neat)/cm-1 3011, 2937, 1688, 1457, 1173, 1080; H NMR (400 MHz, CDCl3) δH = 5.76 (1H, ddt, J 17.1, 10.5, 6.6),
5.59 (1H, bs), 5.12-5.07 (2H, m), 4.38 (1H, t, J 5.4), 3.36-3.30 (2H, m), 3.33 (6H, s), 2.28-2.20 (4H, m), 1.96-1.91 (2H,
m); 13C NMR (101 MHz, CDCl3) δC = 172.4, 135.3, 117.0, 103.9, 53.2, 38.5, 33.3, 31.4, 28.4; m/z (EI+) 131 (30%
[C6H11O3]+), 71 (100% [C4H8N]+); HRMS (NSI) Found (M+H+) 202.1437, C10H20 NO3 requires 202.1438.
N-(But-3-en-1-yl)-5,5-dimethoxypentanamide (12)
According to General Procedure 2, to a solution of 5,5-dimethoxypentanoic acid 10 (1.17 g, 7.21 mmol) and T3P®
(50% in EtOAc; 4.93 mL, 8.29 mmol) in EtOAc (54 mL) were added sequentially Et3N (2.01 mL, 14.42 mmol) and N-
homoallyl amine 5 (0.51 g, 7.21 mmol). After overnight stirring at rt, work up was carried out based on general
procedure 2, affording the title compound 12 (1.02 g, 66%) and this was used without any purification. νmax(neat)/cm-1
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3296, 2936, 2831, 1642, 1126, 1051; H NMR (400 MHz, CDCl3) δH = 5.75 (1H, ddt, J 17.1, 10.2, 6.9), 5.55 (1H, bs),
5.12-5.05 (2H, m), 4.35 (1H, t, J 5.4), 3.31 (2H, q, J 6.7), 3.31 (6H, s), 2.25 (2H, qt, J 6.8, 1.5), 2.18 (2H, t, J 7.3), 1.72-
1.59 (4H, m); 13C NMR (101 MHz, CDCl3) δC = 172.7, 135.5, 117.4, 104.7, 53.1, 38.5, 36.5, 34.0, 32.1, 21.0; m/z (EI+) 215
(1% [M]+), 184 (20% [C10H18NO2]+), 113 (35% [C6H10NO]+), 71 (100% [C4H8N]+); HRMS (NSI) Found (M+H+) 216.1595,
C11H22NO3 requires 216.1594.
(Z)-4,4-Dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-yl)butanamide (13)
According to General Procedure 2, to a solution of 4,4-dimethoxybutanoic acid 9 (0.20 mL, 1.33 mmol) and T3P® (50%
in EtOAc; 0.91 mL, 1.53 mmol) in EtOAc (10 mL) were added sequentially Et3N (0.37 mL, 2.66 mmol) and (Z)-4-
(trimethylsilyl)but-3-en-1-amine 7 (0.19 g, 1.33 mmol). After overnight stirring at rt, work up was carried out based
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on general procedure 2, affording the title compound 13 (0.15 g, 41%) and this was used without any purification.
νmax(CHCl3)/cm-1 3296, 2955, 1647, 1250, 1061; 1H NMR (400 MHz, CDCl3) δH = 6.22 (1H, dt, J 14.4, 7.3), 5.64 (1H, td,
J 14.4, 1.3), 5.59 (1H, bs), 4.38 (1H, t, J 5.6), 3.39-3.24 (2H, m), 3.32 (6H, s), 2.33 (2H, q, J 6.7), 2.23-2.19 (2H, m), 1.96-
1.91 (2H, m), 0.12 (9H, s); 13C NMR (101 MHz, CDCl3) δC = 172.6, 144.9, 132.8, 104.1, 53.5, 39.2, 33.5, 31.7, 28.6, 0.5;
m/z (EI+) 273 (1% [M]+), 128 (50% [C6H14NSi]+), 73 (65% [C3H9Si]+), 71 (100% [C4H8N]+); HRMS (APCI) Found (M+H+)
274.1832, C13H28NO3Si requires 274.1833.
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(Z)-5,5-Dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-yl)pentanamide (14)
21 According to General Procedure 2, to a solution of 5,5-dimethoxypentanoic acid 10 (0.43 g, 2.65 mmol) and T3P®
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(50% in EtOAc; 1.82 mL, 3.05 mmol) in EtOAc (15 mL) were added sequentially Et3N (0.74 mL, 5.30 mmol) and (Z)-4-
(trimethylsilyl)but-3-en-1-amine 7 (0.38 g, 2.65 mmol). After overnight stirring at rt, work up was carried out based
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on general procedure 2, affording the title compound 14 (0.39 g, 51%) and this was used without any purification. 1H
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NMR (400 MHz, CDCl3) δH = 6.23 (1H, dt, J 14.2, 7.3), 5.65 (1H, dt, J 14.2, 1.3), 5.50 (1H, bs), 4.36 (1H, t, J 5.4), 3.35-
3.30 (2H, m), 3.31 (6H, s), 2.33 (2H, qd, J 6.9, 1.3), 2.18 (2H, t, J 7.3), 1.73-1.60 (4H, m), 0.12 (9H, s); 13C NMR (101
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MHz, CDCl3) δC = 172.7, 145.0, 132.8, 104.7, 53.1, 39.1, 36.5, 33.6, 32.2, 21.0, 0.42; m/z (EI+) 287 (1% [M]+), 142 (35%
[C7H16NSi]+), 71 (100% [C4H8N]+).
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(Z)-5,5-Dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-yl)pentanamine (16).
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A solution of (Z)-5,5-dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-yl)pentanamide (14) (575 mg, 2.00 mmol, 1.00 eq.) in
tetrahydrofuran (4 mL) was added dropwise at room temperature to a stirred suspension of lithium aluminium
hydride (80 mg, 2.10 mmol, 1.05 eq.) in tetrahydrofuran (4.2 mL). The reaction was heated to 60 °C for 5 hours.
After this time the solution was cooled to room temperature and quenched with a saturated aqueous solution of
sodium chloride (10 mL) and diluted with diethyl ether (5 mL). Aluminum salts were then removed by filtration
through a pad of celite. The organic layer was separated and the aqueous layer extracted with diethyl ether (3 x 5
mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The pale
yellow residue was purified by a short flash column chromatography (100% ethyl acetate) to afford the title
compound 16 (493 mg , 1.80 mmol, 90%) as a colourless oil. νmax(neat)/cm-1 3318, 2950, 2828, 1606, 857; δH (400
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MHz; CDCl3) 6.26 (1H, td, J 7.2, 14.4, H-C3), 5.57 (1H, td, J 1.2, 14.4, H-C4), 4.35 (1H, t, J 5.6, H-C9), 3.30 (6H, s, H-C10),
2.66 (2H, t, J 7.2, H-C1), 2.61 (2H, t, J 7.2, H-C5), 2.33 (2H, ddt, J 1.2, 7.2, 7.2, H-C2), 1.74 (1H, bs, H-NH), 1.63 (2H, m,
H-C8), 1.55-1.48 (2H, m, H-C6), 1.40-1.33 (2H, m, H-C7), 0.11 (9H, s, H-CTMS); δC (100.6 MHz; CDCl3) 146.3 (C3), 131.2
(C4), 104.5 (C9), 52.8 (C10), 50.0 (C5), 49.8 (C1), 34.1 (C2), 32.5 (C8), 30.0 (C6), 22.5 (C7), 0.3 (CTMS); m/z (CI) 274
(MH+, 57), 242 (14), 86 (100); HRMS (CI) Found (M+H+) 274.2202, C14H32NO2Si requires 274.2202.
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N-(But-3-yn-1-yl)-4,4-dimethoxybutanamide (17)
To but-3-yn-1-amine (0.31 g, 4.48 mmol, 1 equiv.) in EtOAc (8 mL) was sequentially added 2,5-dioxopyrrolidin-1-yloxy
4,4-dimethoxybutanoate (1.10 g, 4.48 mmol, 1 equiv.) and N,Nʹ-dicyclohexylcarbodiimide (0.93 g, 4.48 mmol, 1
equiv.) portionwise. The mixture was stirred at rt overnight and the precipitate was filtered. The filtrate was washed
with saturated aqueous NaHCO3 (2 x 10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure.
Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:4) yielded the title compound 16 (0.52 g,
59%) as a clear oil. νmax(neat)/cm-1 3291, 3084, 2939, 1721, 1125, 1054; 1H NMR (400 MHz, CDCl3) δH = 6.12 (1H, bs),
4.35 (1H, t, J 5.3), 3.35 (2H, q, J 5.3), 3.29 (6H, bs), 2.37-2.34 (2H, m), 2.22 (2H, bt, J 7.3), 1.97 (1H, bt, J 2.5), 1.92-1.87
(2H, m); 13C NMR (101 MHz, CDCl3) δC = 172.7, 104.1, 81.8, 70.1, 53.5, 38.1, 31.4, 28.4, 19.5; m/z (EI+) 169 (20%
[C9H15NO2]+), 125 (50% [C7H11NO]+); HRMS (NSI) Found (M+Na+) 222.1099, C10H17NO3Na requires 222.1101.
N-(But-3-yn-1-yl)-5,5-dimethoxypentanamide (18)
To a solution of 5,5-dimethoxypentanoic acid 10 (0.070 g, 0.43 mmol) and T3P® (50% in EtOAc; 0.29 mL, 0.49 mmol)
in EtOAc (3.2 mL) were added sequentially Et3N (0.12 mL, 0.86 mmol) and but-3-yn-1-amine (0.030 g, 0.43 mmol).
After overnight stirring at rt, work up was carried out based on general procedure 2, affording the title compound 17
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(0.052 g, 57%) and this was used without any purification. νmax(neat)/cm-1 3308, 3011, 1666, 1257, 1166; H NMR
(400 MHz, CDCl3) δH = 5.89 (1H, bs), 4.35 (1H, t, J 5.4), 3.34 (2H, q, J 6.4), 3.31 (6H, s), 2.39 (2H, td, J 6.4, 2.6), 2.21 (2H,
t, J 7.2), 2.00 (1H, t, J 2.6), 1.74-1.60 (4H, m); 13C NMR (101 MHz, CDCl3) δC = 172.9, 104.6, 81.8, 70.1, 53.1, 38.1, 36.3,
32.0, 20.9, 19.7; m/z (EI+) 213 (1% [M]+); HRMS (NSI) Found (M+H+) 214.1438, C11H20NO3 requires 214.1438.
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3. Aza-Silyl-Prins Inter- and Intramolecular Cyclisations
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(±)-1-Benzyl-6-pentyl-1,2,3,6-tetrahydropyridine (3)2
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Following the general procedure 4, N-benzyl-N-Z-(4-trimethylsilylbut-3-enyl)amine 1 (234 mg, 1.00 mmol), in the
presence of 1,1-dimethoxyhexane (0.146 g, 172 μL, 1.00 mmol), disappeared on TLC after 12 hours of stirring at reflux
temperature. The work up gave a brown oil, which was purified by flash column chromatography (96% hexane 3%
ethyl acetate 1% triethylamine) to give the title compound 3 (182 mg, 75%) as a yellow oil. νmax(neat)/cm-1 3027,
2929, 2869, 1662; δH (400 MHz; CDCl3) 7.37-7.24 (5H, m), 5.81-5.77 (1H, m), 5.65-5.61 (1H, m), 3.94 (1H, d, J 13.6),
3.40 (1H, d, J 13.6), 2.93-2.86 (2H, m), 2.40-2.36 (1H, m), 1.05-2.98 (2H, m), 1.63-1.55 (2H, m), 1.34-1.22 (6H, m), 0.89
(3H, t, J 6.5); δC (100.6 MHz; CDCl3) 139.8, 130.2, 129.0, 128.2, 126.9, 125.1, 59.0, 58.2, 46.3, 33.4, 32.3, 25.1, 24.1,
22.8 , 14.2; m/z (CI) 244 (MH+, 100), 172 (70), 120 (15); HRMS (CI) Found (MH+) 244.2065, C17H26N requires 244.2063.
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Table 1 entry 2: 1,5,6,8a-Tetrahydroindolizin-3(2H)-one (19)36
33 According to General Procedure 4, a suspension of Sc(OTf)3 (0.08 g, 0.16 mmol) in MeCN (3.5 mL) was heated to
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reflux for 5 min. A solution of (Z)-4,4-dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-yl)butanamide 13 (0.05 g, 0.16
mmol) in MeCN (1.5 mL) was added dropwise over 1 min to the mixture. The suspension was stirred for 48 h.
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Work up was carried out based on general procedure 4. Purification of the residues by flash column
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chromatography (EtOAc:CH2Cl2 4:1) yielded the title compound 19 (0.0169 g, 75%) as a colourless oil.
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νmax(CHCl3)/cm-1 2927, 1665; H NMR (400 MHz, CDCl3) δH = 5.79-5.75 (1H, m), 5.68-5.65 (1H, dm, J 10.2), 4.19
(1H, dd, J 13.4, 6.8), 4.12 (1H, bs), 2.84 (1H, td, J 12.3, 5.0), 2.50-2.34 (2H, m), 2.27-2.19 (2H, m), 2.08-2.02 (1H,
dm, J 17.8), 1.63-1.53 (1H, m); 13C NMR (101 MHz, CDCl3) δC = 173.2, 128.5, 125.2, 55.1, 36.4, 31.9, 26.5, 24.7;
m/z (EI+) 137 (100% [M]+); HRMS (APCI) Found (M+H+) 138.0914, C8H12NO requires 138.0913.
Table 1 Entry 5: 2,3,6,7-Tetrahydro-1H-quinolizin-4(9aH)-one (20)36
According to General Procedure 4, a suspension of Sc(OTf)3 (0.34 g, 0.70 mmol) in MeCN (3.5 mL) was heated to
reflux for 5 min. A solution of (Z)-5,5-dimethoxy-N-(4-(trimethylsilyl)but-3-en-1-yl)pentanamide 14 (0.20 g, 0.70
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mmol) in MeCN (1.5 mL) was added dropwise over 1 min to the mixture. The suspension was stirred for 48 h.
Work up was carried out based on general procedure 4. Purification of the residues by flash column
chromatography (EtOAc:CH2Cl2 1:1) yielded the title compound 20 (0.068 g, 64%) as a colourless oil. 1H NMR
(400 MHz, CDCl3) δH = 5.84-5.79 (1H, m), 5.50 (1H, ddt, J 10.0, 2.8, 1.4), 4.81 (1H, ddt, J 12.5, 5.7, 1.1), 3.99-3.94
(1H, m), 2.58 (1H, td, J 12.5, 4.0), 2.50-2.43 (1H, m), 2.36-2.30 (1H, m), 2.28-2.18 (1H, m), 2.03-1.96 (2H, m),
1.87-1.80 (1H, m), 1.67 (1H, dddd, J 13.0, 5.6, 2.9, 1.1), 1.40 (1H, tdd, J 13.0, 11.4, 3.2); 13C NMR (101 MHz,
CDCl3) δC = 169.0, 129.1, 126.0, 55.3, 38.4, 32.6, 30.4, 25.3, 19.9; m/z (EI+) 151 (100% [M]+); HRMS (APCI) Found
(M+H+) 152.1069, C9H14NO requires 152.1070.
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Table 2 Entry 1: (7R*,8aR*)-7-Chlorohexahydroindolizin-3(2H)-one (21a)
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According to General Procedure 5, N-(but-3-en-1-yl)-4,4-dimethoxybutanamide 11 (0.11 g, 0.55 mmol) was mixed
with CH2Cl2 (5 mL) for 5 min and FeCl3 (0.09 g, 0.55 mmol) was added. The mixture was stirred for 48 h. Work up was
carried out based on general procedure 5. Purification of the residues by flash column chromatography
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(EtOAc:CH2Cl2 1:1) yielded the title compound 21a (0.08 g, 94%) as a clear oil. νmax(CHCl3)/cm-1 1673, 748; H NMR
(700 MHz, CDCl3) δH = 4.16 (1H, dd, J 13.6, 5.1), 3.93 (1H, tt, J 12.0, 3.8), 3.48 (1H, dtd, J 11.0, 7.2, 3.4), 2.66 (1H, td, J
13.3, 3.1), 2.40-2.32 (3H, m), 2.24-2.19 (1H, m), 2.17-2.15 (1H, dm, J 13.3), 1.67-1.60 (2H, m), 1.49 (1H, q, J 12.0); 13C
NMR (176 MHz, CDCl3) δC = 173.5, 56.5, 55.4, 43.9, 39.0, 35.3, 30.2, 24.6; m/z (EI+) 173 (25% [M]+), 138 (100%
[C8H12NO]+); HRMS (NSI) Found (M+H+) 174.0679, C8H1335ClNO requires 174.0680.
Table 2 Entry 3: (7R*,8aR*)-7-Bromohexahydroindolizin-3(2H)-one (21b)
According to General Procedure 5, N-(but-3-en-1-yl)-4,4-dimethoxybutanamide 11 (0.13 g, 0.63 mmol) was mixed
59 with CH2Br2 (5 mL) for 5 min and BBr3 (1.0 M in CH2Cl2; 0.63 g, 0.63 mmol) was added. The mixture was stirred for 48
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h. Work up was carried out based on general procedure 5. Purification of the residues by flash column
chromatography (EtOAc:CH2Cl2 1:1) yielded the title compound 21b (0.070 g, 51%) as a clear oil. νmax(CHCl3)/cm-1
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1673, 651; 1H NMR (400 MHz, CDCl3) δH = 4.05-4.00 (1H, m), 3.94 (1H, dtd, J 10.8, 7.4, 3.5), 3.12 (1H, td, J 12.8, 3.3),
2.41-2.36 (1H, m), 2.28-2.22 (2H, m), 2.02-1.99 (1H, m), 1.86-1.80 (1H, m), 1.67-1.56 (3H, m); 13C NMR (101 MHz,
CDCl3) δC = 173.8, 52.0, 49.8, 41.0, 35.6, 32.6, 29.1, 24.5; m/z (EI+) 217 (5% [M-H]+), 138 (100% [C8H12NO]+); HRMS (EI)
Found (M+) 217.0096, C8H1279BrNO requires 217.0097.
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N-(But-3-en-1-yl)-4,4-dimethoxybutanamide 11 (0.20 g, 0.99 mmol) was mixed with PhH (5 mL) for 5 min and
BF3.OEt2 (0.13 mL, 0.99 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on
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general procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded a
mixture of the title compounds (0.056 g, 36%) as a clear oil, in a mixture of diastereomers of ratio 1:1. νmax(CHCl3)/cm-
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1677, 1422; cis- isomer (7R*,8aR*)-7-Fluorohexahydroindolizin-3(2H)-one H NMR (400 MHz, CDCl3) δH = 5.02-
4.88 (1H, dm, JHF 47.0), 4.15 (1H, dddd, J 13.8, 5.7, 3.8, 1.5), 3.49-3.42 (1H, m), 2.62-2.55 (1H, tm, J 13.2), 2.37-
2.30 (1H, m), 2.23-2.15 (3H, m), 1.96 (1H, ddtd, J 16.5, 7.6, 3.8, 1.6), 1.67-1.57 (1H, m), 1.54-1.42 (1H, m), 1.38-
1.20 (1H, m); 13C NMR (101 MHz, CDCl3) δC = 173.8, 87.1 (d, JCF 169.6), 51.4, 38.1 (d, JCF 20.9), 36.8 (d, JCF 13.9),
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30.3), 29.4 (d, JCF 20.6), 25.1; trans- isomer (7R*,8aS*)-7-Fluorohexahydroindolizin-3(2H)-one H NMR (400 MHz,
CDCl3) δH = 4.58 (1H, dtt, JHF 47.8, 11.3, 4.4), 3.98 (1H, ddd, J 13.8, 6.1, 1.1), 3.75 (1H, dtd, J 11.5, 7.1, 3.7), 2.95
(1H, dt, J 13.3, 3.6), 2.37-2.30 (2H, m), 2.28-2.24 (1H, m), 2.11-2.03 (1H, m), 1.67-1.57 (1H, m), 1.54-1.42 (2H, m),
1.38-1.20 (1H, m); 13C NMR (101 MHz, CDCl3) δC = 173.6, 89.7 (d, JCF 175.8), 55.1 (d, JCF 12.5), 39.5 (d, JCF 18.1),
34.6 (d, JCF 2.1), 31.2 (d, JCF 19.5), 30.4, 24.7; 19F NMR (377 MHz, CDCl3), δF = −173.0 and −189.7; m/z (EI+) 157 (100%
[M]+); HRMS (APCI) Found (M+H+) 158.0973, C8H13FNO requires 158.0976.
Table 2 Entry 8: (8R*,9aR*)-8-Chlorohexahydro-1H-quinolizin-4(6H)-one (22a)
N-(But-3-en-1-yl)-5,5-dimethoxypentanamide 12 (0.21 g, 0.99 mmol) was mixed with CH2Cl2 (5 mL) for 5 min and
57 FeCl3 (0.16 g, 0.99 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on general
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procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded the title
compound 22a (0.16 g, 86%) as a clear oil. νmax(CHCl3)/cm-1 1626, 745; 1H NMR (600 MHz, CDCl3) δH = 4.80 (1H, ddd, J
13.7, 4.6, 2.5), 3.93 (1H, tt, J 11.8, 4.4), 3.27 (1H, dddd, J 11.3, 8.4, 5.6, 2.4), 2.42 (1H, td, J 13.7, 2.7), 2.40-2.34 (1H,
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dtm, J 17.1, 5.0), 2.29 (1H, ddd, J 17.4, 9.6, 5.6), 2.20-2.13 (2H, m), 1.99-1.95 (1H, m), 1.82-1.77 (1H, m), 1.68-1.57
(3H, m), 1.51 (1H, dddd, J 19.0, 11.1, 8.1, 3.2); 13C NMR (101 MHz, CDCl3) δC = 169.6, 56.1, 56.0, 44.3, 41.7, 36.2, 33.1,
30.2, 19.6; m/z (EI+) 187 (25% [M]+), 152 (100% [C9H14NO]+); HRMS (EI) Found (M+) 187.0759, C9H1435ClNO requires
187.0758.
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Table 2 Entry 10: (8R*,9aR*)-8-Bromohexahydro-1H-quinolizin-4(6H)-one (22b)
N-(But-3-en-1-yl)-5,5-dimethoxypentanamide 12 (0.21 g, 0.99 mmol) was mixed with CH2Br2 (5 mL) for 5 min and
InBr3 (0.55 g, 0.99 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on general
procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded the title
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compound 22b (0.22 g, 86%). νmax(CHCl3)/cm-1 1628, 647; H NMR (400 MHz, CDCl3) δH = 4.73 (1H, ddd, J 13.8, 4.7,
2.6), 4.03 (1H, tt, J 12.1, 4.4), 3.24 (1H, dddd, J 11.2, 8.3, 5.5, 2.4), 2.40 (1H, td, J 13.5, 2.7), 2.35-2.20 (4H, m, H-C3, H-
C7 and H-C9), 1.97-1.91 (1H, m), 1.81-1.74 (3H, m), 1.69-1.57 (1H, m), 1.53-1.42 (1H, m); 13C NMR (101 MHz, CDCl3) δC
= 169.4, 56.9, 46.7, 44.9, 42.6, 36.9, 32.9, 29.9, 19.3; m/z (EI+) 232 (5% [M]+), 152 (100% [C9H14NO]+); HRMS (APCI)
Found (M+H+) 232.0332, C9H1579BrNO requires 232.0332.
Table 2 Entry 11: Cis- and trans 8-Fluorohexahydro-1H-quinolizin-4(6H)-one (22c)
N-(But-3-en-1-yl)-5,5-dimethoxypentanamide 12 (0.21 g, 0.99 mmol) was mixed with PhH (5 mL) for 5 min and
BF3.OEt2 (0.13 mL, 0.99 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on
general procedure 5. Purification of the residues by flash column chromatography (EtOAc:CHCl3 2:3) yielded a mixture
of the title compounds and its isomer (0.056 g, 33%) as a colourless oil. νmax(CHCl3)/cm-1 1617, 1419, 1267; cis-
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isomer (8R*,9aR*)-8-fluorohexahydro-1H-quinolizin-4(6H)-one H NMR (400 MHz, CDCl3) δH = 4.65 (1H, ddd, J
13.5, 5.4, 1.7), 4.63 (1H, dtt, JHF 48.8, 11.0, 4.9), 3.31-3.24 (1H, m), 2.81 (1H, td, J 13.5, 2.8), 2.39-2.27 (2H, m),
2.18-2.06 (2H, m), 2.05-1.95 (2H, m), 1.87-1.76 (1H, m), 1.73-1.65 (1H, m), 1.61-1.55 (1H, m), 1.54-1.42 (1H, m);
13C NMR (101 MHz, CDCl3) δC = 169.6, 89.8 (d, JCF 176.3), 54.0 (d, JCF 12.7), 40.1 (d, JCF 16.3), 36.5, 33.0, 32.0 (d, JCF
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18.6), 30.3, 19.2; trans- isomer (8R*,9aS*)-8-fluorohexahydro-1H-quinolizin-4(6H)-one H NMR (400 MHz, CDCl3)
δH = 5.03-4.89 (1H, dm, JHF 47.9), 4.85 (1H, dtd, J 13.8, 4.8, 2.7), 3.69-3.62 (1H, m), 2.46-2.39 (1H, m), 2.39-2.27
(2H, m), 2.18-2.06 (1H, m), 2.05-1.95 (2H, m), 1.87-1.76 (2H, m), 1.61-1.55 (2H, m), 1.54-1.42 (1H, m); 13C NMR
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(101 MHz, CDCl3) δC = 169.6, 87.1 (d, JCF 168.8), 50.8, 39.5 (d, JCF 13.0), 38.6 (d, JCF 20.6), 33.1, 30.3 (d, JCF 20.8),
29.9, 19.6; 19F NMR (377 MHz, CDCl3), δF = −172.0 and −187.1; m/z (EI+) 151 (45% [C9H15FN]+), 171 (80% [M]+); HRMS
(APCI) Found (M+H+) 172.1131, C9H15FNO requires 172.1132.
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1-(But-3-yn-1-yl)-5-methoxypyrrolidin-2’-one (28)
N-(But-3-yn-1-yl)-4,4-dimethoxybutanamide 17 (0.07 g, 0.37 mmol) was mixed with CH2Cl2 (5 mL) for 5 min and FeCl3
(0.06 g, 0.37 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on general
procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded the title
compound 28 (0.015 g, 24%) as a clear oil. νmax(CHCl3)/cm-1 3289, 2942, 1660, 1283; H NMR (400 MHz, CDCl3) δH =
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5.08 (1H, dd, J 6.3, 1.3), 3.64 (1H, ddd, J 14.0, 7.6, 5.7), 3.32 (1H, dt, J 14.0, 7.6), 3.28 (3H, s), 2.58-2.46 (2H, m), 2.46-
2.38 (1H, m), 2.33 (1H, ddd, J 16.7, 10.0, 3.0), 2.21-2.11 (1H, m), 2.03-1.99 (1H, dm, J 9.7), 1.97 (1H, t, J 2.7); 13C NMR
(101 MHz, CDCl3) δC = 175.3, 90.9, 81.8, 69.9, 53.2, 39.7, 29.0, 24.1, 18.2; m/z (EI+) 167 (25% [M]+), 68 (100%
[C4H6N]+); HRMS (APCI) Found (M+H+) 168.1018, C9H14NO2 requires 168.1019.
1-(But-3-yn-1-yl)-5-methoxy-1H-pyrrol-2’(5H)-one (29)
N-(But-3-yn-1-yl)-4,4-dimethoxybutanamide 17 (0.074 g, 0.37 mmol) was mixed with CH2Cl2 (5 mL) for 5 min and
FeCl3 (0.060 g, 0.37 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on general
procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded the title
compound 29 (0.0024 g, 4%) as a clear oil. νmax(CHCl3)/cm-1 3286, 2932, 1697, 1093; H NMR (400 MHz, CDCl3) δH =
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6.90 (1H, dd, J 6.1, 1.6), 6.28 (1H, dd, J 6.1, 0.9), 5.64 (1H, bs), 3.75 (1H, ddd, J 13.6, 7.1, 5.9), 3.34 (1H, dt, J 13.6, 7.1),
3.12 (3H, s), 2.60-2.43 (2H, m), 1.98 (1H, t, J 2.7); 13C NMR (101 MHz, CDCl3) δC = 173.7, 144.0, 130.7, 88.7, 81.5, 70.2,
50.8, 38.3, 18.6; m/z (EI+) 150 (5% [C9H11NO]+), 96 (75% [C7H6NO]+); HRMS (APCI) Found (M+H+) 166.0860, C9H12NO2
requires 166.0863.
1-(But-3-en-1-yl)-5-methoxypyrrolidin-2’-one (26)
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The Journal of Organic Chemistry
N-(But-3-en-1-yl)-4,4-dimethoxybutanamide 15 (0.20 g, 0.99 mmol) was mixed with CH2Cl2 (5 mL) for 5 min and InCl3
(0.35 g, 0.99 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on general
procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded the title
compound 26 (0.025 g, 15%) as a clear oil. νmax(CHCl3)/cm-1 3009, 1696, 1079; 1H NMR (400 MHz, CDCl3) δH = 5.76 (1H,
ddt, J 17.1, 10.3, 6.8), 5.10-5.00 (2H, m), 4.94 (1H, dd, J 6.4, 1.4), 3.59 (1H, ddd, J 13.8, 8.0, 7.1), 3.25 (3H, s), 3.17-3.10
(1H, m), 2.49 (1H, dd, J 17.5, 8.8), 2.36-2.26 (3H, m), 2.10 (1H, ddd, J 10.0, 8.5, 6.4), 1.97 (1H, ddd, J 14.2, 3.2, 1.4); 13C
NMR (101 MHz, CDCl3) δC = 175.3, 135.5, 117.0, 90.3, 52.8, 40.0, 32.2, 29.2, 23.9; m/z (EI+) 169 (5% [M]+), 138 (25%
[C8H12NO]+), 68 (100% [C4H6N]+); HRMS (EI) Found (M+) 169.1096, C9H15NO2 requires 169.1097.
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1-(But-3-en-1-yl)-5-hydroxypyrrolidin-2’-one (27)
N-(But-3-en-1-yl)-4,4-dimethoxybutanamide 15 (0.20 g, 0.99 mmol) was mixed with CH2Cl2 (5 mL) for 5 min and InCl3
(0.35 g, 0.99 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on general
procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded the title
compound 27 (0.011 g, 7%) as a clear oil. νmax(CHCl3)/cm-1 3344, 2979, 1667, 1464; 1H NMR (600 MHz, CDCl3) δH = 5.77
(1H, ddt, J 17.1, 10.2, 7.0), 5.22-5.20 (1H, m), 5.08 (1H, dt, J 17.1, 1.6), 5.05-5.03 (1H, dm, J 10.2), 3.54 (1H, dt, J 13.8,
7.5), 3.28-3.23 (1H, dm, 13.8), 3.41 (1H, d, J 8.1), 2.58-2.51 (1H, m), 2.38-2.26 (4H, m), 1.91-1.87 (1H, m); 13C NMR
(101 MHz, CDCl3) δC = 175.0, 135.7, 117.2, 83.6, 39.6, 32.4, 29.1, 28.6; m/z (EI+) 68 (45% [C4H6N]+), 137 (25%
[C8H11NO]+), 96 (100% [C5H6NO]+); HRMS (EI) Found (M+-H2O) 137.0834, C8H11NO requires 137.0835.
Table 3 Entry 1: (7R*,8aR*)-7-Phenylhexahydroindolizin-3(2H)-one (30a)21
N-(But-3-en-1-yl)-4,4-dimethoxybutanamide 11 (0.20 g, 0.99 mmol) was mixed with PhH (5 mL) for 5 min and
BF3.OEt2 (0.13 mL, 0.99 mmol) was added. The mixture was stirred for 48 h. Work up was carried out based on
general procedure 5. Purification of the residues by flash column chromatography (EtOAc:CH2Cl2 1:1) yielded the title
compound 30a (0.043 g, 20%) as a clear oil. νmax(CHCl3)/cm-1 2936, 1672; 1H NMR (400 MHz, CDCl3) δH = 7.33-7.29 (2H,
m), 7.23-7.17 (3H, m), 4.25 (1H, ddd, J 13.4, 5.0, 1.8), 3.59 (1H, dtd, J 10.9, 7.3, 3.5), 2.79 (1H, td, J 13.0, 3.5), 2.72 (1H,
dt, J 12.4, 3.2), 2.43-2.38 (2H, m), 2.29-2.20 (1H, m), 2.09-2.04 (1H, dm, J 12.9), 1.90-1.85 (1H, dm, J 13.3), 1.69-1.61
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