On the steric acceleration of ene reactions

Article abstract of DOI:10.1039/b204778k

Steric buttressing, using the removable trityl group as a protecting group for substituted allylamines, is used to effect selective cycloadditions and uncatalysed ene reactions under remarkably mild conditions.

Full text of DOI:10.1039/b204778k

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On the steric acceleration of ene reactions
Nandeo Choony,a Nikolai Kuhnert,a Peter G. Sammes,*a Graham Smitha and Robert W. Wardb
a Department of Chemistry, School of Physics and Chemistry, UniS, Guildford, Surrey,
1
UK GU2 7XH
b GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex,
UK CM19 5AW
Received (in Cambridge, UK) 16th May 2002, Accepted 26th June 2002
First published as an Advance Article on the web 5th August 2002
Steric buttressing, using the removable trityl group as a protecting group for substituted allylamines, is used to effect
selective cycloadditions and uncatalysed ene reactions under remarkably mild conditions.
The ene reaction is a synthetically useful process that has been
exploited in a wide range of chemistry.1 Normally the ene
reaction requires the use of heating at temperatures greater
than 140 ЊC to proceed and, for systems where the enophile is
not activated by an electron-withdrawing group, much higher
temperatures are often required.2 For systems with electron-
deficient enophiles, the process may be catalysed with Lewis
acids, whereby the reaction has been observed to proceed
at ambient temperatures3 but such catalysis is not generally
effective for non-activated enophiles.
The stereochemistry of the ene process has also been exam-
ined and, under vigorous thermal conditions, stereocontrol is
often lost. Thus, heating the simple dimethylallylamino com-
pound 1 at 220 ЊC for 30 min effects an intramolecular ene
process and converts it into the mixture of cis- and trans-
pyrrolidines 2 and 34 (Scheme 1). The latter compounds are of
molecular ene process in order to maximise the selectivity for
producing either the cis- or trans-stereoisomers would therefore
be of great synthetic value.
We have previously used steric buttressing as an aid to assist-
ing cycloaddition reactions;6 herein we describe examples of use
of the trityl steric buttress that assists ene reactions to occur
under uncatalysed and relatively low temperature conditions. A
preliminary account of this work has been published.7
As an initial model system, the trityl-protected N-allyl-N-
dimethylallylamine 4, prepared by standard methods, was
heated in xylene, under argon at 140 ЊC, for 100 h, by which
time all the starting material had disappeared. The reaction
produced the ene product 6 in almost quantitative yield. The
product was isolated as predominantly one isomer (>95%),
1
assigned, from H NOE experiments, as the cis-isomer indi-
cated. The cis-isomer is known to be the preferred stereoisomer
in analogous carbocyclic ene reactions.2 That a buttressing
effect is operating was supported by the observation that no
sign of any cyclisation product was obtained upon heating the
parent amine 5 under these conditions for extended periods
(several weeks). The ease of the buttressed cyclisation, com-
pared with the harsh conditions normally reported for un-
activated ene reactions,2 led us to seek other examples of the
sterically assisted ene process. Thus the corresponding propar-
gylamine† derivative 7 was smoothly transformed into the
ene-product 8 by heating at 110 ЊC for 72 h.
In earlier work we had shown that, on heating, the protected
N-allylfurfurylamine 9 undergoes intramolecular cycloaddition
to form the adduct 10.8 At room temperature this cycloaddition
is slow (months) and the furan ring of the open form could be
made to react in a competitive manner by intermolecular
cycloaddition to a dienophile. Thus dimethyl butynedioate
reacted with compound 9 at room temperature to form the
adduct 11. On heating, this adduct underwent a retro-Diels–
Alder reaction to release the acetylenic ester and reform the
starting material 9, which then cyclised intramolecularly to
form 10 (Scheme 2).
Scheme 1 Conditions: i, 220 ЊC, 30 min; ii, 140 ЊC, 4 days.
interest as members of the kainic acid family of neuroactive
agents,5 the natural stereoisomer being the cis-isomer 3. Any
method for controlling the stereochemistry of the intra-
† The IUPAC name for propargyl is prop-2-ynyl.
DOI: 10.1039/b204778k
J. Chem. Soc., Perkin Trans. 1, 2002, 1999–2005
This journal is © The Royal Society of Chemistry 2002
1999

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The intramolecular cycloaddition reaction across the furan
group is sensitive to the presence of alkyl substituents on the
allylic group and the dimethylallyl derivative 19 undergoes
incomplete cyclisation on heating, the corresponding cyclo-
adduct 20 only forming in 80% yield, in equilibrium with
uncyclised amine9 (Scheme 4).
᎐
Scheme 2 Reagents and conditions: i, 120 ЊC, 24 h; ii, MeO2C–C᎐C–
᎐
CO2Me, rt; iii, 120 ЊC.
Incidentally, the behaviour of the trityl-protected furfuryl-
amine 13 with dimethyl butynedioate was also studied. This
also gave the expected cycloadduct 14 in good yield at room
1
temperature. In its H NMR spectrum, it showed loss of the
furan ring signals and a characteristic pattern for the ring pro-
tons of the oxa-bridged cyclohexadiene system. Deprotection
of the cycloadduct 14 with dilute hydrochloric acid in ethanol
gave the unstable amine 15 (Scheme 3). On heating this amine
Scheme 4 Reagents and conditions: i, Ph3CCl; ii, 140 ЊC, 7 days;
᎐
iii, MeO2C–C᎐C–CO2Me, rt, 5 days.
᎐
When the tritylated amine 19 was allowed to react with
dimethyl butynedioate at room temperature over five days, a
new product formed in high yield. However, the compound was
not the expected Diels–Alder product 21 but, instead, the ene
product 22, isolated as a crystalline solid, mp 164–166 ЊC.
᎐
Scheme 3 Reagents and conditions: i, Ph3CCl; ii, MeO2C–C᎐C–
᎐
CO2Me, rt; iii, aq. HCl in EtOH; iv, 110 ЊC.
1
In its H NMR spectrum compound 22 showed loss of the
rearranged to a new isomeric product, shown to be the thermo-
dynamic product 16 obtained from the reaction of furfuryl-
amine 12 with dimethyl butynedioate. The (Z)-configuration
about the olefinic bond was confirmed by the presence of the
intramolecular hydrogen bond between the amino group and
the adjacent ester group. This material was identical to one of
the two isomers produced by the direct reaction of dimethyl
butynedioate with furfurylamine 12, the other, kinetic, product
being the (E)-isomer 17, which, on heating, was converted into
the stable isomer 16. No cycloadducts across the furan ring
were obtained in these model studies with the parent furfuryl-
amine 12. Presumably the thermal rearrangement of the un-
stable amine 15 into the adduct 16 also involves a retro-
Diels–Alder process, the furfurylamine then reacting via
addition of the amino group to the triple bond of the released
butynedioate.
Since the maleic ester group in the intermediate 14
could behave as an enophile, the possibility of using this type
of structure in an intramolecular ene reaction was examined.
This required preparation of the dimethylallyl analogue 19,
which was obtained by tritylation of the secondary amine
18, itself prepared via alkylation of the trifluoroacetamide
of furfurylamine, followed by base-catalysed hydrolysis (see
Experimental section).
isopropylidene group and the furan ring protons and formation
of an isopropenyl group. The ring protons showed as a tightly
coupled system. An extensive NMR study allowed the assign-
ment of the relative stereochemistry of this product as indicated
in structure 22; assignments and coupling constants are given in
Tables 1 and 2. 1H–1H COSY experiments showed the expected
cross peaks. The small W-coupling 4J between H-2eq and H-4eq
of 2.1 Hz allows an unambiguous assignment of these protons.
The H-5 proton couples by a 3J to H-4ax in an axial–axial
manner, indicating that the isopropenyl substituent must adopt
an equatorial position on the azacyclohexane ring. The relative
stereochemistry at positions 6 and 7 is derived from two
spectroscopic arguments. First, NOE difference spectra show a
strong NOE effect between the two methoxy groups, indicating
that their syn arrangement is retained in the cycloaddition–ene
cascade reaction, as expected. Second, a weak NOE is observed
between the two methoxy groups and the olefinic protons,
H-9 and H-10. These observations indicate that the methoxy-
carbonyl groups must be in an endo-position with respect to the
double bond; some of these NOE results are summarised in
Fig. 1. Further support for this assignment and the relative
stereochemistry of C-7 and C-8 comes from comparison of
established values of coupling constants in structurally related
camphor systems.10 According to the Karplus relationship a
2000
J. Chem. Soc., Perkin Trans. 1, 2002, 1999–2005

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Table 1 Assignment of 1H NMR signals to compound 22, in CDCl3
Assignmenta
Chemical shift, δ (ppm)
Coupling constants, J/Hz
H-2 (ax)
H-2 (eq)
H-4 (ax)
H-4 (eq)
H-5 (ax)
H-7
2.52, d
3.59, dd
2.11, t
2J = 12.9
2J = 12.9, 4J = 2.1
2J = 3J = 11.8
2.97, dd
3.04, d
3.35, d
5.92, dd
6.74, dd
5.92, d
4.58, s
4.75, s
3.63, s
3.25, s
1.76, s
2J = 11.8, 4J = 2.1
3J = 11.8
3JH-7, H-8 = 4.2
H-8
H-9
3JH-7, H-8 = 4.2; 3JH-8, H-9 = 1.6
3JH-9, H-10 = 5.7, 3H-8, H-9 = 1.6
3J = 5.7
H-10
C᎐CH [pro-(E)]b
᎐
C᎐CH [pro-(Z)]b
᎐
COOMe (C-6)
COOMe (C-7)
᎐CMe
᎐
a All assignments from H–H-COSY and H–C-HMBC experiments. b Assignments from NOE difference spectra.
Table 2 Assignment of 13C NMR signals to compound 22, in CDCl3
Assignment
Chemical shift, δ (ppm)a
Assignment argument
C-1
C-2
C-4
C-5
C-6
C-7
90.1 (q)
48.0 (Ϫ)
49.9 (Ϫ)
56.9 (ϩ)
62.3 (q)
56.9 (ϩ)
DEPT-HMBC
HSQC-DEPT
HSQC-DEPT
HSQC-DEPT
DEPT-HMBC
HSQC
C-8
C-9
81.0 (ϩ)
139.1 (ϩ)
HSQC
HSQC
C-10
135.7 (ϩ)
HSQC
C-6 (COOMe)
C-7 (COOMe)
Isopropenyl
Trityl
52.1 (ϩ), 172.3 (q)
51.4 (ϩ), 171.1 (q)
113.5 (Ϫ), 145.2 (q), 23.5 (ϩ)
128.0 (ϩ), 127.9 (ϩ), 126.5 (ϩ), 135.1 (q)
HMBC, DEPT, HSQC
HMBC, DEPT, HSQC
HMBC, DEPT, HSQC
a (ϩ) refers to CH3 or CH, (Ϫ) to CH2 and (q) to quaternary carbons in the DEPT experiment.
Heating compound 23 at 140 ЊC in xylene for several days gave
no indication of the intramolecular cyclisation product 24.
Reaction of the sulfonamide 23 with dimethyl butynedioate
was allowed to proceed for two weeks at room temperature
before working up. A new compound slowly formed but this
was found to be the intermolecular cycloadduct 25 and not the
ene product corresponding to compound 22 (see Scheme 4), viz.
compound 26. We therefore deduce that the intramolecular ene
reaction, 21 to 22, is effected because of the tight buttressing of
the dimethylallyl group and the double bond of the cycloadduct
21, caused by the presence of the space-demanding trityl group.
Heating the intermolecular cycloadduct 25 in toluene at 110
ЊC caused an isomerisation and the furan derivative 27 was
formed. The formation of the latter could either occur by a
retro-Diels–Alder process, with extrusion of dimethyl butyne-
dioate, followed by an intermolecular ene reaction (Scheme 5,
path A), or, alternatively, involve the transient formation of the
ene product 26, followed by an intramolecular retro-Diels–
Alder process to give compound 27 (Scheme 5, path B). By
conducting the reaction at 70 ЊC over a period of several days,
transient formation of an intermediate corresponding to the
ene product 26 could be detected but this was never at a propor-
tion greater than 20% and decayed as the final isomer 27
formed.
Fig. 1 NOE correlations found for compound 22.
3J H-8–H-7exo coupling constant of 4–5 Hz would be expected,
as observed, whereas the corresponding H-8–H-7endo coupling
constant would be in the range 0–1 Hz.
The preferred transition state leading to the ene product 22 is
thus as indicated by structure 21a and involves reaction from
the least hindered exo-face of the oxabicycloheptadiene system.
It is noteworthy that the ene reaction involves a type 1 process
of a 1,7-diene system that would normally proceed in only
modest yields at very high temperatures.2,11
In order to prove that the intermediate 26 lay on the pathway
between compounds 25 and 27, an authentic sample was pre-
pared by deprotection of the tritylated ene product 22 at room
temperature, to give the amine 28, followed by tosylation. The
pure sample of compound 26 was reasonably stable at room
temperature but, on heating to 70 ЊC, slowly isomerised to
the furan derivative 27, proving it is the intermediate and that
the conversion of 25 to 27 follows path B (Scheme 5). Of note is
the observation that heating the tritylated cycloadduct 22 at
In order to ascertain whether or not the formation of this ene
product is principally due to the steric buttressing of the bulky
trityl group, a comparison with a model compound incorporat-
ing a ‘smaller’ buttress was made. This was the toluene-4-
sulfonamide derivative 23. The arylsulfonyl group can act as
a steric buttress but it is not as effective as the trityl group.6
J. Chem. Soc., Perkin Trans. 1, 2002, 1999–2005
2001

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᎐
Scheme 5 Reagents and conditions: i, 140 ЊC, xylene, 7 days; ii, MeO2C–C᎐C–CO2Me, rt, 22 days; iii, 100 ЊC, toluene, 20 h; iv, toluene-4-sulfonyl
᎐
chloride, pyridine, rt; v, 70 ЊC, 12 h.
temperatures up to 110 ЊC does not lead to the retro-Diels–
Alder process and that no tritylated compound corresponding
to the furan 27 is observed. Thus the trityl group not only acts
as a stimulus for the ene process (viz. 21 to 22) but also holds
the cyclic product together, preventing the retro-Diels–Alder
reaction from occurring.
This assumption is fully compatible with molecular model-
ling studies; Fig. 2 shows a view of the starting cycloadducts 21
and 25, adopting the conformation leading to the ene reaction
in their energy-minimised conformations.12 It is clear that the
steric crowding is much more evident in the presence of the
trityl buttress than when using the much smaller sulfonamide
group. Furthermore, in the trityl derivative 21, the ene reaction
centres (depicted in Fig. 2) between the transferred hydrogen
and the alkene bond terminus are held much more closely
together in space than they are in the corresponding sul-
fonamide derivative 25. In the former both the dimethylallyl
group and the bicyclic moiety have much less conformational
freedom (space in which to move) than in the latter.
Experimental
Melting points were determined on a Kofler hot-stage appar-
atus and are uncorrected. Mass spectra were obtained from the
EPSRC National Mass Spectrometry Service Centre, Swansea;
infrared spectra were obtained on a Perkin Elmer System 2000
FTIR spectrometer, as either liquid films or as Nujol mulls. 1H
NMR spectra were obtained on a Bruker AC300 at 300 MHz
using solutions in CDCl3 with tetramethylsilane as internal ref-
erence; chemical shifts are quoted in ppm and coupling con-
stants in Hz. The detailed stereochemical studies on structure
22 were carried out on a Bruker DRX500 Avance instrument
using CDCl3 as solvent. Microanalytical determinations were
carried out by MEDAC Ltd, Englefield Green, Surrey. Thin
layer chromatography was carried out using 0.25 mm GF60A
silica plates and column chromatography utilised Sorbisil silica,
particle size 50–200 µm (70–290 mesh). Solvent ratios are in
volumes prior to mixing. Dichloromethane solvent was dried
over calcium hydride and then distilled. THF was obtained dry
by distillation in the presence of benzophenone–sodium. Other
solvents were purified and dried according to literature
methods.13 Petroleum ether refers to the fraction of boiling
range 40–60 ЊC. Organic extracts were dried using anhydrous
sodium sulfate as drying agent. Extraction solvents were mainly
removed using a rotary evaporator, followed by evacuation on a
high vacuum rotary pump.
Fig. 2 a) Reactive conformation leading from 21 to 22; energy
minimised using the MM3 geometry optimisation algorithm in
Alchemy 2000.12 b) Reactive conformation leading from 25 to 26.
Preparation of secondary amines
Method a, direct alkylation. To a stirred solution of the
amine, such as furfurylamine (0.25 mol), in dichloromethane
containing triethylamine (0.25 mol) cooled in an ice-bath was
added, dropwise over 1 h, the allyl halide, such as allyl bromide
2002
J. Chem. Soc., Perkin Trans. 1, 2002, 1999–2005

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(0.25 mol). After addition the solution was stirred for a further
1 h and then washed with water (2 × 150 cm3), the organic layer
dried, the mixture filtered and the organic solvent removed to
produce a mobile yellow liquid. This was chromatographed
through silica gel, using dichloromethane as eluant, the tertiary
amine eluting first, followed by the required secondary amine,
obtained in yields in the range 15–45%.
N-(Triphenylmethyl)-3-isopropenyl-4-methylenepyrrolidine
8. The tritylated amine 7 (0.51 g, 14 mmol) was dissolved in dry
toluene (20 cm3) and the solution heated to reflux under
nitrogen for 72 h. The solvent was then removed and the light
brown residue dissolved in the minimum of dichloromethane
and then chromatographed through silica gel, eluting with
dichloromethane–ether, to afford the title pyrrolidine as an off-
white powder (0.45 g, 88%), which was recrystallised from
methanol to show, mp 143–145 ЊC; νmax (film) 3475, 3031, 3059,
2977, 1644, 1596, 1490, 1448, 1032, 892 cmϪ1; δH 1.56 (3 H, s,
Me), 2.19 (1 H, t, J 7, CH ), 2.81 (2 H, m, NCH2), 3.28 (2 H, m,
Method b, via trifluoroacetamide. Trifluoroacetamide was
alkylated with the first component and the product then re-
alkylated with the second substituent, using sodium hydride
in dimethylformamide as the base, as described in the method
reported by Hodge et al.14 The product N,N-dialkylated tri-
fluoroacetamide could be hydrolysed under mild basic condi-
tions to release the required secondary amine, which was then
converted to the tritylated product or toluene-4-sulfonamide, as
required, in overall yields of 50–80%.
NCH ), 4.75 (1 H, br s, HC᎐C), 4.80 (1 H, br s, HC᎐C), 4.83
᎐
᎐
2
(1 H, br s, HC᎐C), 4.91 (1 H, br s, HC᎐C), 7.0–7.6 (15 H, m,
᎐
᎐
Ar); m/z (CI) 366 (MHϩ), 243 (trityl cation). Found: C, 88.5; H,
7.45; N, 3.8; C27H27N requires C, 88.7; H, 7.4; N, 3.8%.
Preparation of compound 11
Using these methods the following compounds were
prepared.
N-Allyl-3-methylbut-2-enylamine 5. As an oil which showed
The tritylated furfurylamine 97 (0.52 g, 1.4 mmol) in dry
dichloromethane (10 cm3) was stirred with dimethyl butyne-
dioate (0.97 g, 6.8 mmol) at room temperature for 5 days. The
mixture was evaporated to dryness and the residue chromato-
graphed through silica gel, using dichloromethane as eluant, to
afford the Diels–Alder adduct 11 (0.15 g, 21%) as a viscous, pale
yellow oil; δH 3.15 (1 H, dd, J 9.9, 16.0, NCH ), 3.43 (1 H, dd,
J 6.9, 16.0, NCH ), 3.14 and 3.55 (2 H, AB q, J 14.6, NCH2),
3.57 (3 H, s, CO2Me), 3.75 (3 H, s, CO2Me), 4.75–4.80 (2 H, m,
HC᎐C), 5.10–5.25 (1 H, m, HC᎐C), 5.66 (1 H, d J 1.8), 7.03–
δH 1.64 (3 H, s, Me), 1.72 (3 H, s, Me), 3.19 (2 H, d, J 9.5,
NCH ), 3.23 (2 H, d, J 6.1, NCH ), 5.09 (1 H, d, J 11.9, CH᎐C),
᎐
2
2
5.20 (1 H, d, J 15.6, CH᎐C), 5.27 (1 H, t, J 6.1, CH᎐C), 5.86–
᎐
᎐
5.95 (1 H, m, CH᎐C), NH peak not observed as a sharp signal;
᎐
νmax (film) 3420, 2975, 644, 995, 942 cmϪ1; characterised as its
trityl derivative, 4.
N-Prop-2-ynyl-3-methylbut-2-enylamine. νmax (film) 3305,
2971, 2918, 2106, 1093, 650 cmϪ1; δH 1.41 (1 H, br s, NH ), 1.68
᎐
᎐
7.53 (17 H, m, Ar and vinylic H); m/z 522 (MHϩ; C33H31-
NO5ؒHϩ requires 522.
᎐
(3 H, s, Me), 1.73 (3 H, s, Me), 2.22 (1 H, t, J 2.4, HC᎐C), 3.31
᎐
(2 H, d, J 7.0, NCH2), 3.41 (2 H, d, J 2.4, NCH2), 5.23 (1 H, t,
Heating the adduct 11 (0.10 g) in toluene (5 cm3) at 110 ЊC
under nitrogen for 3 days caused elimination of the acetylenic
ester and formation of the known cycloadduct7 10 in almost
quantitative yield (70 mg), with identical TLC behaviour.
J 7, HC᎐C); characterised as its trityl derivative 7.
᎐
N-(Triphenylmethyl)-N-allyl-3-methylbut-2-enylamine 4. To
a solution of the amine (1.13 g, 8.8 mmol) in dry dichloro-
methane (25 cm3) were added dry triethylamine (1.25 g,
12.5 mmol) and then freshly prepared triphenylmethyl chloride
(2.93 g, 10.5 mmol). The yellow solution was warmed to reflux
under dry nitrogen for 48 h, the mixture cooled and then
washed with saturated aqueous sodium hydrogen carbonate
solution (3 × 30 cm3) before drying, filtering and evaporating to
dryness. The orange oil obtained was immediately passed
through silica gel, eluting with dichloromethane, to give, as a
viscous yellow oil, the title amine (2.4 g, 75%); δH 1.32 (3 H, s,
Me), 1.62 (3 H, s, Me), 2.92 (2 H, d, J 6.9, NCH2), 2.95 (2 H, d,
Reaction of N-tritylfurfurylamine 13 with dimethyl butynedioate
2-Furfurylamine (0.88 cm3, 10 mmol) and triethylamine (1.09
cm3, 15 mmol) were added to a solution of triphenylmethyl
chloride (2.8 g, 10 mmol) in dichloromethane (10 cm3) under
nitrogen and the solution stirred for 1 h at room temperature.
The solution was then washed with 2 M sodium hydroxide solu-
tion (50 cm3) and water (2 × 50 cm3), dried, filtered and the
solution evaporated to dryness to afford a yellow gum, which
crystallised on trituration with hot ethanol and cooling to pro-
duce N-tritylfurfurylamine 13 as a white solid (2.3 g, 68%), mp
101–102 ЊC; δH 2.00 (1 H, br s, NH ), 3.30 (2 H, s, NCH2), 6.22
(1 H, d, J 3.2, 3-furyl H ), 6.32 (1 H, dd, J 1.9, 3.2, 4-furyl H ),
7.17–7.55 (16 H, m, Ar and 5-furyl H ). Found: C, 85.1; H, 6.2;
N, 4.0; C24H21NO requires C, 85.0; H, 6.2; N, 4.1%.
The tritylated amine 13 (2.7 g, 8 mmol) and dimethyl butyne-
dioate (4.55 g, 32 mmol) were stirred in dry dichloromethane
(10 cm3) at room temperature for 20 h. The solvent was then
removed under reduced pressure and the product mixture
chromatographed through silica gel, using dichloromethane as
eluant to afford, as a major fraction, the cycloadduct 14 which
was recrystallised from ethanol (2.7 g, 72%), mp 118–120 ЊC,
δH 2.17 (1 H, dd, J 4.3, 10.9, exch. with D2O, NH ), 2.76 (1 H,
dd, J 4.3, 12.6, NCH ), 3.18 (1 H, dd, J 10.9, 12.6, NCH ), 3.80
(3 H, s, CO2Me), 3.85 (3 H, s, CO2Me), 5.66 (1 H, d, J 1.8,
J 6.5, NCH ), 4.83 (1 H, dd, J 10.4, 1.4, HC᎐C), 4.87 (1 H, dd,
᎐
2
J 18.0, 1.4, HC᎐C), 5.36 (1 H, t, J 6.5, HC᎐C), 5.98 (1 H, m,
᎐
᎐
HC᎐C), 7.10–7.54 (15 H, m, Ar). Found: C, 88.2; H, 8.0; N, 3.7;
᎐
C27H29N requires C, 88.2; H, 8.0; N. 3.8%.
N-(Triphenylmethyl)-N-prop-2-ynyl-3-methylbut-2-enylamine
7. Prepared in a similar manner to the tritylated amine 4, this
compound was obtained in high yield (>80%) as a waxy solid,
which was recrystallised from methanol to give the title amine
as a white solid (33% yield), mp 92–93 ЊC; δH 1.49 (3 H, s,
᎐
Me), 1.72 (3 H, s, Me), 1.90 (1 H, t, J 2.4, HC᎐C), 3.13 (2 H, d,
᎐
J 6.1, NCH2), 3.32 (2 H, d, J 2.4, NCH2), 5.51 (1 H, t, J 6.1,
HC᎐C), 7.12–7.54 (15 H, m, aryl H); ν
(Nujol) 3288, 2360,
᎐
max
1595, 1080, 1032, 746, 708 cmϪ1. Found: C, 88.4; H, 7.5; N, 3.7;
C27H27N requires C, 88.7; H, 7.45; N, 3.8%.
cis-N-(Triphenylmethyl)-3-isopropenyl-4-methylpyrrolidine
6. The tritylated amine 4 (0.16 g) in xylene (2 cm3) was heated
under argon for 4 days at 140 ЊC, before removal of the
solvent under reduced pressure to leave an orange oil. The
product was dissolved in dichloromethane and chromato-
graphed through silica to give the title pyrrolidine as a viscous
pale yellow oil (0.14 g, 87%), δH 0.57 (3 H, d, J 7, Me), 1.61
(3 H, s, Me), 2.05–2.18 (2 H, m, 2 × CH ), 2.51–2.42 (2 H, m,
2 × NCH ), 2.70–2.95 (2 H, m, 2 × NCH ), 4.51 (1 H, br s,
HCO), 6.93 (1 H, d, J 5.3, HC᎐C), 7.15 (1 H, dd, J 1.8, 5.3, HC᎐
᎐
᎐
C), 7.18–7.52 (15 H, m, Ar). Found: C, 75.0; H, 5.8; N, 2.8;
C30H27NO5 requires C, 74.8; H, 5.65; N, 2.9%.
Preparation of dimethyl 2-[N-(2-furfuryl)amino]fumarate 16 and
dimethyl 2-[N-(2-furfuryl)amino]maleate 17
HC᎐C), 4.73 (1 H, br s, HC᎐C), 7.1–7.5 (15 H, m, Ar);
To a solution of 2-furfurylamine (1.94 g, 20 mmol) in dichloro-
methane (10 cm3) at room temperature was added, dropwise,
dimethyl butynedioate (2.84 g, 20 mmol) over 15 min and the
solution then stirred for a further 4 h. The solvent was removed
᎐
᎐
νmax (film) 3418, 3084, 3058, 3029, 2965, 2927, 2871, 1646, 1597,
1493, 1448, 1032, 898 cmϪ1. Found: m/z 367.2287; C27H29N
requires 367.2300.
J. Chem. Soc., Perkin Trans. 1, 2002, 1999–2005
2003

View Article Online
under reduced pressure and the residue was chromatographed
through silica gel, using dichloromethane as eluant, to afford,
initially, the fumarate ester 16 (1.90 g, 40%) as a viscous oil,
δH 3.68 (3 H, s, CO2Me), 3.83 (3 H, s, CO2Me), 4.57 (2 H, d, J
stirred at room temperature under nitrogen for 5 days. After
this time monitoring by TLC indicated the formation of one
major new compound. The reaction mixture was worked up
by chromatography through silica gel, eluting with dichloro-
methane, in order to remove the excess of the dienophile. One
major new fraction was obtained as a crystallising oil (0.48 g).
This was recrystallised from methanol to afford (1SR,5SR,
6RS,7RS,8SR)-3-(triphenylmethyl)-5-isopropenyl-6,7-bis-
(methoxycarbonyl)-11-oxa-3-azatricyclo[6.2.1.01,6]undec-9-ene
22 (0.12 g, 16%), mp 153–155 ЊC; NMR details as reported in
Tables 1 and 2. Found: C: 76.3; H, 6.45; N, 2.5; C35H35NO5
requires C, 76.5; H, 6.4; N, 2.6%.
6.2, NCH ), 5.24 (1 H, s, HC᎐C), 6.18 (1 H, d, J 3.1, 3-furyl H ),
᎐
2
6.29 (1 H, dd, J 1.5, 3.1, 4-furyl H ), 7.35 (1 H, d, J 1.5, 5-furyl
H ), 8.30 (1 H, br s, slowly exch. with D2O, NH ). Found: C,
55.0; H, 5.5; N, 5.8; C11H13NO5 requires C, 55.2; H, 5.5; N,
5.9%.
The second fraction was the maleate isomer 17 (1.85 g, 39%)
but on standing this isomerised to the more stable fumarate
1
isomer. The H NMR spectrum of the impure product isomer
showed peaks at δH 1.68 (1 H, br s, exch. with D2O), 3.66 (3 H,
s), 3.88 (3 H, s), 4.18 (2 H, d, J 5.1), 4.86 (1 H, s), 6.34 (1 H, d,
J 3.3), 6.47 (1 H, dd, J 1.5, 3.3), 7.38 (1 H, d, J 1.5).
Preparation of N-(3-methylbut-2-enyl)-N-(4-tolylsulfonyl)-2-
furfurylamine 23
To a solution of furfurylamine (10 g, 103 mmol) in dry pyridine
(60 cm3) at 0 ЊC was added toluene-4-sulfonyl chloride (23.6 g,
124 mmol) and the solution stirred under nitrogen at 0 ЊC for
4 h before pouring the mixture into ice–water and collecting the
solid formed by filtration, washing well with cold water before
recrystallisation from ethanol to afford the N-(4-tolylsulfonyl)-
2-furfurylamine (21.5 g, 88%), mp 111–112 ЊC.
The tosylated furfurylamine (10 g, 42 mmol) was added to
dry dimethylformamide (50 cm3) and the solution stirred under
nitrogen at room temperature before adding sodium hydride
(1.11 g, 46 mmol) and the mixture stirred for 1 h before adding
1-bromo-3-methylbut-2-ene (8.16 g, 55 mmol) and the mixture
then stirred at room temperature for a further 20 h. The mix-
ture was poured into ice–water (600 cm3) and extracted with
dichloromethane (3 × 100 cm3), dried, filtered and the extract
evaporated to dryness under reduced pressure. The residual
liquid was dissolved in ether (50 cm3) and washed with water
(3 × 50 cm3) and then dried, filtered and the solvent removed
under reduced pressure to afford an orange solid. The product
was recrystallised from petroleum ether to give the title sul-
fonamide as a white solid (6.35 g, 50%), mp 48–50 ЊC; δH 1.56
(3 H, s, Me), 1.66 (3 H, s, Me), 2.39 (3 H, s, ArMe), 3.76 (2 H, d,
Deprotection of the cycloadduct 14
The cycloadduct (3.09 g. 6.2 mmol) was dissolved in warm
ethanol (15 cm3) and dilute sulfuric acid (2 M, 5 cm3) added
dropwise. The mixture was stirred for a further 10 min and then
filtered to remove the white precipitate that had formed. The
filtrate was neutralised with aqueous sodium hydroxide (2 M)
and the solution extracted with dichloromethane, washing the
organic extract with water (25 cm3), and then dried, filtered and
the solvent removed under reduced pressure to afford the amino
cycloadduct 15 as an unstable, hygroscopic solid (1.2 g, 80%).
On heating a sample of this material (0.4 g) in toluene (5 cm3)
for several hours, a rearrangement occurred and TLC monitor-
ing indicated the formation of the fumarate 16 as the major
product. The solvent was removed under reduced pressure and
the residue was purified by filtration through a short column of
silica gel, using dichloromethane as eluant, to afford 16 (0.25 g,
1
62%), which showed an identical H NMR spectrum to the
fumarate 16.
N-(Triphenylmethyl)-N-(3-methylbut-2-enyl)-2-furfurylamine 19
N-(3-Methylbut-2-enyl)-2-furfurylamine 18 was prepared either
by the direct alkylation of furfurylamine with 1-bromo-3-
methylbut-2-ene under standard conditions7 or by use of the
trifluoroacetamide route (see above) using N-trifluoroacetyl-
furfurylamine as starting material. The amine, obtained as a
pale yellow oil, showed δH 1.63 (3 H, s, Me), 1.73 (3 H, s, Me),
1.92 (1 H, br s, NH ), 3.27 (2 H, d, J 7.0, NCH2), 3.83 (2 H, s,
J 7.1, NCH ), 4.36 (2 H, s, NCH ), 5.01 (1 H, t, J 7.1, HC᎐C),
᎐
2
2
6.12 (1 H, d, J 2.0, 3-furyl H ), 6.24 (1 H, dd, J 2.0, 4.2, 4-furyl
H ), 7.23 (1 H, d, J 4.2, 5-furyl H ), 7.24 (2H, d, J 8.3, Ar), 7.65
(2 H, d, J 8.3, Ar). Found: C, 63.9; H, 6.7; N 4.3; C17H21NO3S
requires C, 63.9; H, 6.6; N, 4.4%.
Reaction of the tosylated amine 23 with dimethyl butynedioate
NCH ), 5.25 (1 H, t, J 7.0, HC᎐C), 6.27 (1 H, d, J 3.0, 3-furyl
᎐
2
H ), 6.33 (1 H, dd, J 1.9, 3.0, 4-furyl H ), 7.38 (1 H, d, J 1.9,
5-furyl H ).
The tosylamide (4.85 g, 15 mmol) and dimethyl butynedioate
(6.82 g, 48 mmol) in dichloromethane (25 cm3) containing
hydroquinone (5 mg) were stirred at room temperature for
22 days. The solvent was then removed and the residue chroma-
tographed through silica gel, using 1 : 9 methanol–dichloro-
methane as eluant, to give the cycloadduct 25 (3.86 g, 54%), mp
(ethanol) 108–109 ЊC; δH 1.54 (6 H, s, 2 × Me), 2.43 (3 H, s,
ArMe), 3.79 (3 H, s, CO2Me), 3.87 (3 H, s, CO2Me), 3.96 (2 H,
d, J 3.8, NCH2), 3.83 and 4.23 (2 H, ABq, J 15.5, NCH2), 4.71
The amine 18 (5.05 g, 30 mmol) was tritylated with triphenyl-
methyl chloride (10.14 g, 36 mmol) in dry dichloromethane
(25 cm3) in the presence of triethylamine (4.29 g, 42 mmol) and
the solution heated at reflux under nitrogen for 24 h, after which
the solution was cooled to room temperature and stirred for a
further 48 h at room temperature. The solution was then
washed with saturated aqueous sodium hydrogen carbonate
solution (3 × 50 cm3) and then water (50 cm3), dried, filtered
and the solvent removed under reduced pressure to afford a
gummy solid. This was triturated with warm methanol to afford
a white solid, which was recrystallised from hot methanol to
afford the title tritylated amine (6.47 g, 52.5%), mp 134–135 ЊC;
δH 1.23 (3 H, s, Me), 1.41 (3 H, s, Me), 2.92 (2 H, d, J 6.0,
(1 H, t, J 3.8, HC᎐C), 5.64 (1 H, d, J 1.8, HCO), 7.18 (1 H, dd,
᎐
J 1.8, 5.2, HC᎐C), 7.22 (1 H, d J 5.2, HC᎐C), 7.28 (2 H, d J 8.1,
᎐
᎐
Ar), 7.70 (2 H, d, J 8.1, Ar); νmax (Nujol) 2927, 1722, 1706, 1277
and 1166 cmϪ1; m/z (CI) 479.3 (M ϩ NH4ϩ).
Thermal rearrangement of the cycloadduct 25
NCH ), 3.4 (2 H, s, NCH ), 4.85 (1 H, t, J 6.0, HC᎐C), 6.03
᎐
2
2
The cycloadduct 25 (0.38 g, 0.8 mmol) was dissolved in dry
toluene (5 cm3) and the yellow solution heated at 100 ЊC for 20 h
under nitrogen. The solvent was then removed under reduced
pressure and the brown residue dissolved in the minimum of
dichloromethane before chromatographing through silica gel,
eluting with dichloromethane, to afford the furan derivative 27,
obtained as a viscous, pale yellow gum (0.32 g, 83%); δH 1.67
(3 H, s, Me), 2.41 (3 H, s, ArMe), 3.42–3.47 (3 H, m, NCH2 and
CH ), 3.74 (3 H, s, CO2Me), 3.77 (3 H, s, CO2Me), 4.45 and
(1 H, d, J 3.1, 3-furyl H ), 6.23 (1 H, dd, J 1.6, 3.1, 4-furyl H ),
7.10–7.69 (16 H, m, Ar and 5-furyl H ). Found: C, 85.4; H, 7.1;
N, 3.3; C29H29NO requires C, 85.5; H, 7.2; N, 3.4%.
Reaction of the tritylated amine 19 with dimethyl butynedioate
The amine (1.02 g, 2.5 mmol) and dimethyl butynedioate (1.77
g, 12.5 mmol) were dissolved in dichloromethane (5 cm3) con-
taining a few crystals of hydroquinone and the solution was
2004
J. Chem. Soc., Perkin Trans. 1, 2002, 1999–2005

View Article Online
4.47 (2 H, ABq, J 12, NCH ), 4.80 (1 H, s, HC᎐C), 4.97 (1 H, s,
product 27 was observed and, after a further 7 h, none of the
᎐
2
HC᎐C), 5.99 (1 H, s, HC᎐C), 6.08 (1 H, d, J 1.9, 3-furyl H ),
starting cycloadduct 26 remained and no sign of the starting
material 25 could be detected.
᎐
᎐
6.21 (1 H, dd, J 1.9, 2.4, 4-furyl H ), 7.17 (1 H, d, J 2.4, 5-furyl
H ), 7.22 (2 H, d, J 8.1, Ar), 7.60 (2 H, d, J 8.1, Ar); m/z (CI)
479.2 (M ϩ NH4ϩ). Found: C: 59.8; H, 6.05; N, 3.0;
C23H27NO7S requires: C, 59.85; H, 5.9; N, 3.0%.
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for a CASE award
(G.S.) and MEDAC Ltd for its support (N.C.).
Preparation and reactions of the intermediate 26
To a solution of a sample of the tritylated ene product 22
(0.187 g, 0.34 mmol) in warm ethanol (5 cm3) was added aque-
ous hydrochloric acid (0.5 cm3, 3 M) and the solution stirred for
1 h at room temperature. The solvent was then removed under
reduced pressure and the residual crude amine 28 was dissolved
in pyridine (5 cm3) at room temperature before adding toluene-
4-sulfonyl chloride (0.10 g, 0.53 mmol) and stirring the solution
under nitrogen for 12 h. The reaction mixture was quenched
over ice–water (50 cm3) and then extracted with ether (3 ×
30 cm3) and dichloromethane (2 × 30 cm3), washing the organic
extracts with water (3 × 25 cm3), before drying, filtering and
evaporating to dryness. The product was isolated by preparative
TLC (silica gel, using 1 : 1 dichloromethane–ethyl acetate as
eluant). The major product was the tosylated ene product 26 (84
mg, 54%) isolated as a pale yellow gum; δH 1.80 (3 H, s, Me),
2.39 (1 H, d, J 12.2, CH ), 2.43 (3 H, s, ArMe), 2.68 (1 H, dd,
J 3.6, 12.2, NCH ), 3.05 (1 H, t, J 12.2, NCH ), 3.17 (1 H, d,
J 4.1, CH ), 3.48 (3 H, s, CO2Me), 3.63 (3 H, s, CO2Me), 3.65
(1 H, dd, J 3.6, 13.3, NCH ), 4.19 (1 H, d, J 13.3, NCH ), 4.65
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(1 H, s, HC᎐C), 4.90 (1 H, s, HC᎐C), 5.03 (1 H, dd, J 1.0,
᎐
᎐
4.1, HCO), 6.02 (1 H, d, J 5.7, HC᎐C), 6.81 (1 H, dd, J 1.0, 5.7,
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᎐
476.
HC᎐C), 7.32 (2 H, d, J 7.9, Ar), 7.69 (2 H, d, J 7.9, Ar). Found:
᎐
(FAB MS) 462.1592; C23H27NO7SؒHϩ requires 462.1598.
A sample of the ene product 26 (25 mg) in deuterated
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1
benzene was heated in a sealed NMR tube and the H NMR
spectrum monitored with time. After 5 h almost complete con-
version of the starting material into the retro-Diels–Alder
J. Chem. Soc., Perkin Trans. 1, 2002, 1999–2005
2005