Recognition-mediated regiocontrol of a dipolar cycloaddition reaction

Article abstract of DOI:10.1016/S0040-4020(01)00402-1

The rational design of a recognition-based system that is capable of accelerating and controlling the regiochemical outcome of a dipolar cycloaddition reaction between an azide and an alkyne is presented. The origins of the acceleration and control of the cycloaddition reactions are rationalized - using molecular mechanics calculations - in terms of the formation of a complex between the reagents which organizes and orients them prior to reaction.

Full text of DOI:10.1016/S0040-4020(01)00402-1

TETRAHEDRON
Pergamon
Tetrahedron 57 12001) 4945±4954
Recognition-mediated regiocontrol of a dipolar
cycloaddition reaction
Sarah J. Howell,a Neil Spencerb and Douglas Philpa,p
aCentre for Biomolecular Sciences, School of Chemistry, University of St Andrews, North Haugh, St Andrews,
Fife KY169ST, UK
bSchool of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received 25 January 2001;revised 12 March 2001;accepted 30 March 2001
AbstractÐThe rational design of a recognition-based system that is capable of accelerating and controlling the regiochemical outcome of a
dipolar cycloaddition reaction between an azide and an alkyne is presented. The origins of the acceleration and control of the cycloaddition
reactions are rationalizedÐusing molecular mechanics calculationsÐin terms of the formation of a complex between the reagents which
organizes and orients them prior to reaction. q 2001 Elsevier Science Ltd. All rights reserved.
The acceleration of chemical reactions, and the control of
their regio- and/or stereochemical outcome through the
intervention of recognition processes in solution, is a key
component of enzymatic systems and has prompted
synthetic chemists to design a variety1 of unnatural systems
which are capable of performing similar tasks. In principle,
the location of complementary recognition sites on the
reagents 1A and B, Fig. 1) in a chemical reaction permits
the association of these reagents through their mutually
compatible recognition sites to form a complex [AzB]
prior to reaction 1Fig. 1). The formation of this reactive
[AzB] complex renders the chemical reaction between the
reagents pseudointramolecular. Thus, we might expect such
reactive complexes to effect signi®cant rate acceleration2,3
of chemical reactions. In addition, the use of speci®c recog-
nition to preassociate the reactive partners should permit the
control of the stereo- and/or regiochemical outcome of the
reaction through the orientation of the reagents prior to
reaction. Hence, a reaction which exploits the formation
of a reactive [AzB] complex might be engineered to afford
a different product 1P0) to that obtained when the reaction
between A and B proceeds bimolecularly 1P). These recog-
nition-mediated effects on reactivity will manifest them-
selves when the reaction in question is under kinetic
control, and the selective stabilisation of one transition
state with respect to another serves to accelerate4 the forma-
tion of one product. Recently, we have been exploring5 the
acceleration and control in solution phase reaction processes
through the use of recognition-mediated processes, such as
the formation of reactive [AzB] complexes.
Dipolar cycloaddition reactions are synthetically useful6 as
a result of the wide variety of 1,3-dipoles7 available to
participate in cycloaddition reactions of this type, and the
potential use8 of the resulting ®ve-membered heterocyclic
rings in natural product syntheses. Seminal work9 by
Huisgen and co-workers in the early 1960's led to the
elucidation of the mechanisms, patterns of reactivity and
selectivity10 in 1,3-dipolar cycloaddition reactions. The
relative reactivities of cycloaddition reactions were
rationalised by Sustmann11 who demonstrated that the inter-
action between the HOMO and LUMO with the smallest
energy difference predominates. The extent to which each
type of molecular orbital predominates can be manipulated
electronically via the attachment of electron de®cient or
electron rich groups favouring LUMO-dipolarophile and
HOMO-dipole control respectively. The reaction between
Figure 1. A bimolecular reaction between A and B affords a product P.
Association of A and B through their complementary recognition sites
affords a reactive complex [AzB]. Within this complex A and B are oriented
such that reaction between them gives a product P0 with different regio- or
stereochemistry from the bimolecular pathway.
an alkyne 1dipolarophile) and azide 1dipole) affords12
a
1,2,3-triazole 1Scheme 1). The regioselectivities of these
cycloaddition reactions are generally low, and thus, if the
Keywords: azides;cycloaddition;kinetics;molecular recognition.
Corresponding author. Tel.: 11334-467264;fax: 11334-463808;
e-mail: d.philp@st-andrews.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020101)00402-1

4946
S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
N
cation. The mutual recognition between the ammonium
R1
N
N
N
R1
R1
cation and the crown ether should permit the formation of
the [1z2] complex 1Fig. 2). Within this complex, molecular
modeling suggested 1Fig. 2) that the azide and the alkyne
should adopt coconformations in which the azide and alkyne
are disposed in the correct orientation for reaction. Thus, we
might expect the rate of the cycloaddition reaction between
1 and 2 would be accelerated by the formation of the [1z2]
complex through the mechanism discussed above. Addition-
ally, the regiochemistry of the cycloadduct should also be
controlled. Molecular mechanics calculations14 suggested
1Fig. 3) that the 1,4-substituted triazole15 product 3 is the
only cycloadduct which is feasible from a reaction which
occurs within the [1z2] complex. We therefore expected that
N
N
N
N
N
∆
+
R3
R2
R2
R3
R3
R2
Scheme 1.
alkyne is unsymmetrical, two regioisomers will be formed
in an approximately 1:1 ratio 1Scheme 1). This lack of regio-
selectivity is a direct result of the low-lying unoccupied
molecular orbitals of the C±C triple bond and, hence,
leads13 to the reaction being controlled by both dipole-
HOMO and dipole-LUMO interactions simultaneously.
The improvement of the poor regioselectivity of dipolar
cycloadditions involving alkynes is an attractive target for
our recognition-based methodology. Accordingly, we
designed 1Fig. 2) the azide 1 which bears a benzo-15-
crown-5 ring and alkyne 2, which bears an ammonium
Figure 3. The regioisomeric products obtained from the reaction between 1
and 2 are 3 and 4. Regioisomer 3 is the only plausible product from reaction
between 1 and 2 in the [1z2] complex. The CPK representations of the
molecular structures of 3 and 4 are derived from conformational searching.
C atoms are dark grey, N atoms are light grey, O atoms are speckled and H
atoms are white.
Figure 2. Azide 1 and alkyne 2 associate through their complementary
recognition sites to give a reactive complex [1z2]. The CPK representations
of the molecular structures of 1, 2 and [1z2] are derived from conforma-
tional searching. C atoms are dark grey, N atoms are light grey, O atoms are
speckled and H atoms are white.

S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
4947
O
O
O
58%
O
O
O
LiAlH4
O
O
OCH3
OH
O
THF
rt / 4 h
O
O
5
6
SOCl2 / Et3N CH2Cl2 / rt / 5h
72%
O
O
42%
O
O
O
O
O
O
NaN3
O
O
N
Cl
N
(CH3)2CO
N
1
7
∆ / 16 h
Scheme 2.
86%
94%
MeO
MeO
MeO
MeO
MeO
MeO
SOCl2
NaN3
N3
OH
Cl
CHCl3
rt / 5 h
(CH3)2CO
∆ / 16 h
10
8
9
Scheme 3.
the recognition-mediated reaction should be highly selec-
tive for cycloadduct 3 1the 1,4 regioisomer) over 4 1the 1,5
regioisomer).
coupled with alkyne 15 using a procedure originally
reported by Bumagin and co-workers18 to afford the desired
alkyne 16. It should be noted that the dropwise addition of
the alkyne is crucial in this step in order to minimise the
oxidative dimerisation of the alkyne as a competitive reac-
tion. Simple deprotection of the BOC protecting group was
achieved using 5% tri¯uoroacetic acid, in the presence of
anisole, to give the desired dipolarophile 2 in 41% yield.
The preparation of the target azide dipole 1 was achieved
in six steps 1Scheme 2) starting from the commercially
available 3,4-dihydroxybenzoic acid. 40-Carboxy methyl-
benzo-15-crown-5 5 was prepared16 according to literature
procedures and was then reduced17 using lithium aluminium
hydride to afford 40-hydroxymethylbenzo-15-crown-5 6 in
58% yield. Alcohol 6 was converted to the corresponding
chloride 7 using thionyl chloride, the product being obtained
in 72% yield after trituration at 2788C with petroleum ether
and diethyl ether. The target compound, 40-azidomethyl-
benzo-15-crown-5 1 was prepared by the reaction of
40-chloromethylbenzo-15-crown-5 7 with sodium azide in
re¯uxing acetone, affording the desired compound in 42%
yield.
In order to correctly assign the regiochemistry of the
isolated triazoles in future reactions it was necesssary to
11
13
Br
OH
NH2.HCl
K2CO3 / 18C6
CH3CN
(Boc)2O
iPr2NEt
CHCl3
rt / 16 h
TsO
14
15
∆ / 48 h
In order to make effective comparisons between the recog-
nition-mediated reaction and the intermolecular reaction
channel, it was necessary to identify a control compound,
which did not possess any recognition sites, to assess the
bimolecular reactivity of the azide 1. Accordingly, we
selected azide 10 as the control compound and this material
was synthesised readily 1Scheme 3) starting from 3,4-
dimethoxybenzylalcohol 8.
92%
O
Br
94%
NHBoc
12
Pd(PPh3)4
CuI / PPh3
Et3N / ∆ / 24 h
42%
Preparation of the target alkyne dipolarophile 2 was readily
achieved in three steps starting from the commercially
available bromide 11 1Scheme 4). The amine hydrochloride
11 was ®rst protected as its carbamate by the addition of
N,N-diisopropylethylamine to generate the free amine in
situ, followed by the slow addition of di-tert-butyldicarbo-
nate affording 12 in 92% yield. Prop-3-yn-1-140-tert-butyl-
phenyl)ether 15 was prepared by treatment of 4-tert-butyl
phenol 13 with propargyl toluenesulfonate 14 under basic
conditions at re¯ux for 2 days. Bromide 12 was then
O
NHBoc
16
CF3CO2H
Anisole
rt / 2 h
41%
O
NH3 CF3CO2
2
Scheme 4.

4948
S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
1
MeO
MeO
close to that of the CH2NH3 group would be a suitable
mimic of the dipolarophile 2, and that we could assign the
regiochemistry of our ®nal products by comparison with
these model compounds.
N
N
N
8
The regiochemistry of each model product was con®dently
assigned using nOe experiments 1Scheme 5). For example,
in the case of 19, irradiation of the resonance arising from
CF3
O
17
0
HA/HA 1centred on d 5.15) resulted in the observation of a
0
strong nOe in the resonance arising from HB/HB 1centred on
d 5.60). The observation of this nOe suggests that this the
1,5-substituted product 19. In support of this, irradiation of
PhMe / 100 °C
48 h
0
the resonance from HA/HA 1centred on d 5.01) in the 1,4-
substituted regioisomer 18 did not give an observable nOe
OMe
MeO
H
18
0
to HB/HB 1centred on d 5.46). These assignments were
further con®rmed by COSY, {1H±13C} Heteronuclear
Multiple Bond Correlation 1HMBC) and {1H±13C} C±H
Correlation 1HMQC) experiments. The assignment of the
regiochemistry by nOe studies allowed the isomer ratios
to be calculated using 1H NMR spectroscopy through
deconvolution of the CH2-N resonances for the 1,4-substi-
tuted product versus the analogous CH2-N resonances for
the 1,5-substituted product in the recognition-mediated and
control reaction. The progress of the recognition-mediated
and control reactions could be assessed, in terms of per-
centage completion, by deconvolution of the CH2-N
resonances for the 1,4- and the 1,5- regioisomers against
the CH2-N resonance for the starting azide centred on d
4.23.
H
N
H
N
HB
HB'
N
H
O
HA
H
HA'
H
F3C
OMe
MeO
H
19
H
N
HB
HB
N
N
H
Following the successful syntheses of all of the required
compounds, namely 1, 2, 10, a series of test experiments
were performed in order to ®nd the optimum reaction condi-
tions for the cycloaddition. It was found that the reactions
are very sensitive to the polarity of the solvent. In polar
solvents such as acetonitrile no reaction occurred even
after 70 hours at 908C. As the percentage of a non-polar
solvent such as 1,1,2,2-tetrachloroethane 1TCE) was
increased the percentage completion of the reaction also
increased 1Table 1). This effect is presumably a result
of stabilisation of the 1,3-dipole by the polar solvent.
Unfortunately, as a result of the relative insolubility of the
dipolarophile 2 in TCE, it was found that it was not possible
to dissolve the dipolarophile 2 at high concentrations in
solvent mixtures containing less than 25% acetonitrile.20
From these results it was concluded that the optimum con-
ditions to analyse this recognition-mediated 1,3-dipolar
H
O
H
HA
H
HA
CF3
Scheme 5.
prepare pure samples of each regioisomer. Therefore, 3-14-
tri¯uoromethylphenyl)prop-2-yn-1-140-tert-butylphenyl)-
ether 17 was reacted with 3,4-dimethoxybenzyl azide 10 at
1008C in toluene solution for 2 days 1Scheme 5). After this
period two products were observed by TLC, corresponding
to the 1,4-substituted 18 and the 1,5-substituted 19 triazole
regioisomers. Fortunately, these two products could be
separated by column chromatography. We considered that
the para-CF3 group in 17, which has a Hammett s value19
Table 1. Outcomes of 1,3-dipolar cycloaddition reactions between 1 and 2 and 2 and 10 in different solvents.
Solvent
Reactiona
d2-TCE%b
CD3CN%c
Isomer ratiod 1,4:1,5
% Completione
112
75
75
87.5
87.5
25
25
12.5
12.5
90:10
60:40
97:3
10
2
30
12
2110 1Control)
112
2110 1Control)
57:43
a
All reactions were carried out in a thermostatted heating block. In each case, the starting concentration of each reactant was 50 mM and the reactions were
carried out for 67 hours at 908C.
b
c
d
e
D2-1,1,2,2-tetrachloroethane 199.8% atom D).
D-acetonitrile 199.8% atom D).
Determined by deconvolution of the respective product CH2N resonances in the 400 MHz 1H NMR spectrum.
Determined by deconvolution of the respective product CH2N resonances in the 400 MHz H NMR spectrum with respect to the CH2N resonance of the
starting azide.
1

S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
4949
25
20
15
10
5
O
NHBoc
16
3M HCl
EtOH
–10 °C / 1 h
O
NH3 Cl
20
KPF6
MeOH
rt / 16 h
0
65%
NH3 PF6
Recognition-
Mediated
Control
O
21
Reaction
Figure 4. Product concentrations determined for the reactions between 1
and 2 1Recognition-mediated) and 2 and 10 1Control). In both cases, the
starting concentration of each reactant was 50 mM and the reactions were
carried out in a mixture of D2-1,1,2,2-tetrachloroethane and D-acetonitrile
17:1) for 67 hours at 908C. The product concentrations were determined by
deconvolution of the respective product CH2N resonances in the 400 MHz
1H NMR spectrum with respect to the CH2N resonance of the starting azide.
Dark bars represent the 1,4-substituted regioisomer and light bars represent
the 1,5-substituted regioisomer.
CF3CO2H
MeOH
rt / 2 h
100%
NH3 PF6
CF3CO2
O
22
Scheme 6.
cycloaddition reaction were a concentration of 50 mM with
respect to both the dipole and the dipolarophile, at a
temperature of 908C for 70 hours in a solvent mixture
with the composition 87.5% D2-TCE and 12.5% CD3CN.
hydrochloride salt 20. Counterion exchange of 20 using
potassium hexa¯uorophosphate in methanol gave the target
hexa¯uorophosphate salt 21 in good yield.
Unfortunately, dipolarophile 21 is relatively insoluble in the
solvent mixture used previously. However, dipolarophile
22, containing a mixture of the tri¯uoroacetate and hexa-
¯uorophosphate counterions 11:1, estimated by negative ion
MALDI-tof mass spectrometry), which could be prepared
readily by a simple ion-exchange extraction, was suf®-
ciently soluble to permit some assessment of the effect of
the counterion. When the reactions between 1 and 22 and 10
and 22 were performed under identical conditions to those
employed previously, signi®cantly more product 1Fig. 5)
was observed. However, although the recognition-mediated
reaction was still signi®cantly more selective than the
control reaction, the rate enhancement with respect to the
control reaction 12.4-fold) was similar to that observed with
dipolarophile 2 12.5-fold). We therefore concluded that,
while the counterion has a signi®cant effect on the reactivity
of the alkyne dipolarophile, it has little effect on the
ef®ciency of the [AzB] complex pathway.
Using these optimum reaction conditions, the product ratios
shown in Fig. 4 were measured for the recognition-mediated
reaction between 1 and 2 and the control reaction between 2
and 10. It is apparent from the results shown in Fig. 4 that
the recognition process between the ammonium cation and
the crown ether ring successfully controls the regio-
selectivity of this cycloaddition reaction. The ratio of the
1,4 to the 1,5 regioisomer is 97:3, compared with an
approximate 1:1 ratio of regioisomers in the control
reaction. Unfortunately, as a result of the high reaction
temperature required, it was not possible to monitor the
course of the reaction via 1H NMR spectroscopy, and,
hence, rate constants for the two reactions could not be
determined.
Disappointingly, this system gave only modest rate
enhancement 12.5-fold)Ðgiving 30% yield of products
after 67 hours for the recognition-mediated reaction,
compared with 12% yield of products for the control reac-
tion. We considered that this poor acceleration could be a
result of strong ion pair association between the tri¯uoro-
acetate ion and the ammonium cation inhibiting the
reaction. It was thought that this problem could be addressed
In conclusion, we have demonstrated that [AzB] complex
methodology can be applied in a logical manner to the
control of the regiochemistry in a 1,3-dipolar cycloaddition
reaction. The recognition-mediated reaction shows a high
level of regio control, at best better than 30:1, in favour of
the regioisomer predicted by molecular modelling studies.
The rate acceleration achieved by the recognition-mediated
process is, however, very modest. It is clear that, with
relatively unreactive dipoles and dipolarophiles, such as
those discussed here, the advantage gained by rendering
the cycloaddition reaction pseudointramolecular through
the formation of a reactive [AzB] complex is offset by the
2
by the use of an alternative counterion such as PF6 that
does not possess any hydrogen bonding sites. Hence the
dipolarophile 21 was synthesised as shown in Scheme 6.
N-Boc-4-aminobenzylprop-2-yn-1-140-tert-butylphenyl)-
ether 16 was added to a solution of 1 M HCl in ethanol and
left to stir for one hour at 2108C and then for a further 30
minutes at room temperature affording the corresponding

4950
S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
25
20
15
10
5
sequence, with deuterated solvent as the lock and residual
solvent as internal reference. The values of all coupling
constants 1J) are reported in Hz.
1.2. Kinetic procedures
All solutions for kinetic studies were made up at room
temperature 1218C) using volumetric ¯asks 12 ml^
0.02 ml). The experimental samples were prepared by dilu-
tion of the stock solutions with the appropriate deuterated
solvent, using either Hamilton 1 ml, 500 ml or 250 ml gas
tight syringes. Samples were analysed immediately by
1
either 300 MHz, 400 MHz or 500 MHz H NMR spectro-
scopy. Errors derived from the concentration of product,
either by deconvolution or integration, are estimated to be
^ 3%.
0
Recognition-
Mediated
Control
Reaction
1.3. Cycloaddition AB system ,50 mM)
Figure 5. Product concentrations determined for the reactions between 1
and 22 1Recognition-mediated) and 10 and 22 1Control). In both cases, the
starting concentration of each reactant was 50 mM and the reactions were
carried out in a mixture of D2-1,1,2,2-tetrachloroethane and D-acetonitrile
17:1) for 67 hours at 908C. The product concentrations were determined by
deconvolution of the respective product CH2N resonances in the 400 MHz
1H NMR spectrum with respect to the CH2N resonance of the starting azide.
Dark bars represent the 1,4-substituted regioisomer and light bars represent
the 1,5-substituted regioisomer.
A stock solution 1100 mM) of 3-14-benzylammonium)prop-
2-yn-1-140-tert-butylphenyl)ether
tri¯uoroacetate
was
made up in 75% deuterated tetrachoroethane 199.8 atom%
D);25% deuterated acetonitrile 199.8 atom% D). Stock
solutions 1100 mM) 4-azidobenzo-15-C-5 and 3,4-
dimethoxybenzyl azide were made up in deuterated tetra-
chloroethane 199.8 atom% D). All solutions were stored at
2128C in a sample tube with a PTFE lined cap and sealed
with para®lm. Deuterated solvents were stored in a
dessicator. For the kinetic runs, 0.35 ml of azide stock solu-
tion was added to a vial containing 0.35 ml of propargyl
ether stock solution and the resultant solution homogenised
via shaking or soni®cation as necessary. The reaction
mixtures were then heated to 908C in a heating block before
high reaction temperatures required. These high temperatures
entropically disfavour the formation of the reactive [AzB]
complex. We are currently seeking methods of overcoming
this limitation of our methodology.
1
being transferred to a dry NMR tube for analysis via H
400 MHz NMR 1Bruker AMX400).
1. Experimental
1.1. General procedures
1.4. Synthetic procedures
Chemicals were purchased from Aldrich or Lancaster and
used as received. Solvents were purchased from Fisher
Scienti®c and used as received unless speci®ed. Tetrahydro-
furan was distilled under nitrogen from sodium and benzo-
phenone ketyl. Dichloromethane and acetonitrile were
distilled under nitrogen from calcium hydride. Thin layer
chromatography 1TLC) was carried out on aluminium
sheets coated with Kieselgel 60 F254 1Merck 5554). Flash
Chromatography was carried out using Kieselgel 60
10.040±0.063 mm mesh, Merck 9385). Developed plates
were air dried, and visualised under a UV lamp 1254 nm)
or using potassium permanganate 11% solution in water).
Melting points were determined using an Electrothermal
9200 melting point apparatus and are uncorrected. Electron
impact mass spectrometry 1EIMS), chemical Ionisation
1CIMS), fast atom bombardment mass spectrometry
1FABMS), using a m-nitrobenzyl alcohol matrix, were
carried out on either VG Prospec or VG Zabspec instru-
1.4.1. 4-Hydroxymethylbenzo-15-crown-5 6. 4-Carboxy-
methyl benzo-15-crown-5 5 15.00 g, 1.62 mmol) in anhy-
drous THF 115 ml) was added dropwise to a slurry of
lithium aluminium hydride 11.22 g, 31.15 mmol) in anhy-
drous THF 150 ml), whilst stirring vigorously under a dry
nitrogen atmosphere. After the addition was complete, ethyl
acetate 1100 ml), H2O 1100 ml) and aqueous 1 M HCl were
added slowly. The aqueous phase was then extracted with
ethyl acetate 12£100 ml) and the combined organic layers
dried 1MgSO4). The solvent was removed in vacuo affording
the crude product as a yellow oil, which was puri®ed by
column chromatography 1SiO2, 1:1 v/v hexane:CH2Cl2)
affording 4-hydroxymethylbenzo-15-crown-5 6 as a colour-
less solid 12.58 g, 58%) mp 46±478C 1lit.21 45±478C); dH
1300 MHz, CDCl3) 6.90±6.80 13H, m, Ar), 4.59 12H, s,
CH2), 4.14±4.11 14H, m), 3.91±3.88 14H, m), 3.75 18H,
s); dC 175 MHz, CDCl3) 149.8 1C, quat, Ar), 149.4 1C,
quat, Ar), 134.3 1C, quat, Ar), 119.2 1CH, Ar), 113.8 1CH,
Ar), 112.9 1CH, Ar), 71.0 12£CH2), 70.5 12£CH2), 69.6
12£CH2), 69.1 1CH2), 68.8 1CH2), 65.2 1CH2-OH); m/z
1EI) 298 1M1, 50%), 166 156), 137 153), 55 155), 43
1100). 1HRMS) 298.1416 1M1 C15H22O6 requires
298.1422).
1
ments. H Nuclear Magnetic Resonance 1NMR) spectra
were recorded on either a Bruker AC300 1300 MHz), a
Bruker AMX400 1400 MHz) or
1500 MHz) spectrometer using the deuterated solvent as
a Bruker DRX500
the lock and residual solvents as an internal reference. 13C
NMR spectra were recorded on a Bruker AC300
175.5 MHz) spectrometer using the PENDANT pulse
1.4.2. 4-Chloromethylbenzo-15-crown-5 7. Triethylamine

S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
4951
11.28 ml, 9.23 mmol) was added to 4-hydroxymethyl benzo-
15-crown-5 6 12.50 g, 8.39 mmol) in CH2Cl2 140 ml) and
the resulting mixture was cooled to 258C 1ice/acetone
bath). Thionyl chloride 10.92 ml, 12.58 mmol) in anhydrous
CH2Cl2 115 ml) was added dropwise whilst under a dry
nitrogen atmosphere and the resulting reaction mixture
was kept at 258C for a further 45 mins before stirring at
room temperature for 3 hours. The reaction mixture was
washed with H2O 1100 ml), saturated aqueous NaHCO3
1100 ml), aqueous 2 M HCl 1100 ml) and H2O 12£100 ml)
and dried 1MgSO4). The solvent was removed in vacuo
affording the crude product as a colourless oil which was
puri®ed via crystallisation 1petroleum ether/diethyl ether
50:5 v/v) at 2158C to give 4-chloromethylbenzo-15-
crown-5 7 as a colourless solid 11.70 g, 72%) mp 62±
648C 1lit.22 60±618C); dH 1300 MHz, CDCl3) 6.91±6.79
13H, m, Ar), 4.53 12H, s, CH2), 4.16±4.10 14H, m), 3.92±
3.88 14H, m), 3.75 18H, s); dC 175 MHz, CDCl3) 149.4 1C,
quat, Ar), 149.2 1C, quat, Ar), 130.5 1C, quat, Ar), 121.7
1CH, Ar), 114.4 1CH, Ar), 113.7 1CH, Ar), 71.5 12£CH2),
70.4 12£CH2), 69.5 12£CH2), 69.1 1CH2), 68.7 1CH2)
46.6 1CH2-Cl); m/z 1EI) 316 1M1, 28%), 149 1100);
1HRMS) 339.0975 [1M1 Na)1];C 15H21O5NaCl requires
339.0986).
518C); dH 1300MHz, CDCl3) 6.94±6.90 12H, m, Ar), 6.83±
6.80 11H, m, Ar), 4.56 12H, s, CH2), 3.89 13H, s, CH3), 3.87
13H, s, CH3); dC 175MHz, CDCl3) 149.2 1C, quat, Ar),
149.1 1C, quat, Ar), 130.0 1C, quat, Ar), 121.2 1CH, Ar),
111.7 1CH, Ar), 111.1 1CH, Ar), 56.0 1CH3), 55.9 1CH3),
46.8 1CH2-Cl); m/z 1EI) 186 1M1, 21%), 151 1100), 107
1
112);1HRMS) 186.0443 1M
186.0448).
C9H11O2Cl requires
1.4.5. 3,4-Dimethoxybenzyl azide 10. Sodium azide
12.79 g, 42.90 mmol) was added to a stirred solution of
3,4-dimethoxybenzyl chloride 9 14.86 g, 26.10 mmol) in
acetone 160 ml) and the resulting reaction mixture was
heated to re¯ux for 16 hrs under an inert nitrogen
atmosphere. The product was extracted with dichloro-
methane 13£100 ml) and the organic phases combined and
washed with water 150 ml) before drying 1MgSO4). The
solvent was removed in vacuo without heating, affording
the crude product as a yellow oil which was puri®ed by
column chromatography 1SiO2;2:1 v/v CH Cl2: hexane) to
2
afford 3,4-dimethoxybenzyl azide 10 as a pale yellow liquid
14.74 g, 94%). 1Found;C, 55.85;H, 5.86;N, 21.75.
C9H11N3O2 requires C, 55.96;H, 5.70;N, 21.76); nmax
/
cm21 2098s 1N3), 1606 and 1592 1Ar, CvC) 1516
1COOMe); dH 1300MHz, CDCl3) 6.85±6.82 13H, m, Ar),
4.26 12H, s, CH2), 3.81 13H, s, CH3), 3.80 13H, s, CH3); dC
175 MHz, CDCl3) 149.2 1C, quat, Ar), 149.0 1C, quat, Ar)
127.8 1C, quat, Ar), 120.8 1CH, Ar), 111.3 1CH, Ar), 111.1
1.4.3. 4-Azidomethylbenzo-15-crown-5 1. Sodium azide
10.24 g, 3.73 mmol) was added to a stirred solution of
4-chloromethylbenzo-15-crown-5 5 10.74 g, 2.33 mmol)
dissolved in acetone 140 ml). The resulting reaction mixture
was heated to re¯ux for 20 hours under a dry nitrogen
atmosphere. The organic phase was washed with H2O
12£50 ml), 2 M HCl 125 ml) and dried 1MgSO4). The
solvent was removed in vacuo affording 4-azidomethyl-
benzo-15-crown-5 1 as a cream coloured solid 10.51 g,
42%) mp 56±57.58C;1Found;C, 55.63, H, 6.49, N, 12.99,
C9H11N3O2 requires C, 55.73;H, 6.50;N, 13.00); nmax/cm21
2104s 1N3), 1605 and 1590 1Ar, CvC); dH 1300 MHz,
CDCl3) 6.84±6.82 13H, m, Ar), 4.24 12H, s, CH2), 4.16±
4.11 14H, m), 3.92±3.89 14H, m), 3.77±3.75 18H, m);
dC 175 MHz, CDCl3) 149.3 1C, 2£quat, Ar), 128.4 1C,
quat, Ar), 121.5 1CH, Ar), 114.1 1CH, Ar), 113.9 1CH,
Ar), 71.2 12£CH2), 70.83 12£CH2), 70.6 12£CH2), 69.6
1CH2), 69.1 1CH2), 54.8 1CH2-N3); m/z 1EI) 323 1M1,
50%), 149 1100).
1CH, Ar), 55.9 1CH3), 55.9 1CH3), 54.8 1CH2-N3); m/z 1EI)
C9H11N3O2 requires
1
193 1M1);1HRMS) 193.0851 1M
193.0840).
1.4.6. N-Boc-4-bromobenzylamine 12. N,N-Diisopropyl-
ethylamine 13.91 ml, 24.72 mmol) was added to a suspen-
sion of 4-bromobenzylamine hydrochloride 11 15.00 g,
22.47 mmol) in CHCl3 1100 ml) and stirred for 10 minutes
under a dry nitrogen atmosphere. Di-tert-butyldicarbonate
14.90 g, 22.47 mmol) in c CHCl3 125 ml) was added drop-
wise, and the resulting reaction mixture was stirred at room
temperature for 18 hrs. After this time the solvent was
removed in vacuo and the crude product was puri®ed by
column chromatography 1SiO2, CHCl3) to afford N-boc-4-
bromobenzylamine 12 as a white solid 15.92 g, 92%) mp
83±848C 1lit.24 84±858C);1Found;C, 50.52, H, 5.67, N,
4.94, C9H11N3O2 requires C, 50.35;H, 5.59;N, 4.96);
1.4.4. 3,4-Dimethoxybenzyl chloride 9. 3,4-Dimethoxy-
benzyl alcohol 6 18.25 g, 50 mmol) and triethylamine
17.7 ml, 55 mmol) were dissolved in dichloromethane
1100 ml) before freshly distilled thionyl chloride 15.45 ml,
75 mmol) was added dropwise via syringe under a dry nitro-
gen atmosphere. The reaction temperature was maintained
between 258C and 08C throughout the addition 1ice/acetone
bath). The reaction mixture was then left to stir for 30
minutes at 08C, and then for a further 3 hours at room
temperature, after this time, it was washed with water
150 ml), 2 M HCl 150 ml), saturated aqueous NaHCO3
150 ml) and again with water 125 ml) before drying
1MgSO4). The solvent was removed in vacuo, affording
the crude product as a brown oil which was triturated with
petroleum ether 1bp 80±1008C) and diethyl ether at 2788C.
The resulting colourless precipitate was ®ltered and washed
with n-pentane, affording 3,4-dimethoxybenzyl chloride 9
as a colourless powder 19.33 g, 86%). mp 49±518C 1lit.23
n
max/cm21 3325 and 3300 1CONH), 1682 1CvO), 1538
1CvC), 798s 1C±Br); dH 1300 MHz, CDCl3) 7.45±7.42
3
12H, m, Ar), 7.16±7.13 12H, d, JHH 8.5, Ar), 4.87 11H, b
t
s, NH), 4.26±4.24 12H, m, CH2), 1.45 19H, s, Bu);
dC 175 MHz, CDCl3) 155.8 1C, quat, CvO), 138.1 1C,
quat, Ar), 131.6 12£CH, Ar), 129.3 12£CH, Ar), 121.2 1C,
t
quat, Ar), 44.0 1CH2), 28.4 13£CH3, Bu), 27.3 1C, quat,
tBu); m/z 1EI) 286 1M1, 3%), 247 129), 186 161), 106
1100), 58 131).
1.4.7. Prop-3-yn-1-yl,4-tert-butylphenyl) ether 15. Potas-
sium carbonate 15.28 g, 38.22 mmol) and benzo-18-crown-
6 10.34 g, 1.27 mmol) were added to a solution of propargyl
toluenesulfonate 14 15.0 g, 25.48 mmol) and 4-tert-butyl
phenol 13 13.80 g, 25.48 mmol) in acetonitrile 170 ml).
The resulting reaction mixture was heated to re¯ux for 2
days after which time the organic phase was cooled, washed
with water 150 ml) and extracted with CH2Cl2 13£50 ml).

4952
S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
The combined organic phases were then dried 1MgSO4) and
the solvent removed in vacuo to afford the crude product as
a pale yellow oil. Prop-3-yn-1-yl14-tert-butylphenyl) ether
15 was puri®ed by ¯ash column chromatography 1SiO2,
4:1 v/v hexane:CH2Cl2) affording a clear viscous oil
15.06 g, 94%). 1Found;C, 76.32, H, 8.15. C 13H16O requires
C, 76.56;H, 8.57); dH 1300 MHz, CDCl3) 7.35±7.32 12H, d,
3JHH 8.8, Ar), 6.95±6.92 12H, d, 3JHH 8.8, Ar), 4.68 12H, m,
oil. The product was puri®ed via crystallisation at 2158C
12:1 v/v ether:hexane) affording the product as a cream solid
10.34 g, 41%) mp 131.5±1348C. 1Found;C, 64.69;H, 5.82;
N, 3.36, C22H24NO3F3 requires C, 64.86;H, 5.90;N, 3.44);
n
max/cm21 3492b 1NH31), 121w 1alkyne), 1608,1582 and
1514 1Ar, CvC), 1695 1COO2); dH 1300 MHz, CDCl3)
8.13 13H, b, s, NH31), 7.43±7.35 14H, m, Ar), 7.38±7.35
12H, m, Ar), 6.97±6.94 12H, m, Ar), 4.92 12H, s, CH2), 4.07
12H, s, CH2), 1.28 19H, s, tBu); dC 175 MHz, CDCl3) 156.5
1C, quat, Ar), 145.2 1C, quat, Ar), 135.0 12£quat, Ar), 131.1
12£CH, Ar), 130.4 12£CH, Ar), 127.4 12£CH, Ar), 123.6
1C, quat, Ar), 115.4 12£CH, Ar), 86.7 1C, quat, CuC), 86.5
1C, quat, CuC), 57.19 1CH2), 43.8 1CH2), 34.8 1C, quat,
t
CH2), 2.58±2.56 11H, m, CuC±H)1.32 19H, s, Bu); dC
175 MHz, CDCl3) 155.8 1C, quat, Ar), 144.3 1C, quat, Ar),
126.3 12£CH, Ar), 114.4 12£CH, Ar), 78.9 1C, terminal,
CuC), 75.4 1C, quat, CuC), 55.9 1CH2), 34.2 1C, quat,
t
tBu), 31.5 13£CH3, Bu); m/z 1EI) 188 1M1, 29%), 173
t
1100), 91 127), 39 132).
tBu), 31.8 13£CH3, Bu); m/z 1FAB) 294 1M1 - CF3COO2,
89%), 277 124), 221 1100); m/z 1MALDI) 112 1CF3COO2,
82%), 97 1CF3CO2, 100), 69 1CF32, 31);1HRMS) 294.1858
1M1 C20H24NO requires 294.1855).
1.4.8. N-Boc-4-Aminobenzylprop-2-yn-1-,40-tert-butyl-
phenyl)ether 16. 4-Bromo-N-Boc-benzylamine 12
12.00 g, 6.99 mmol) dissolved in DMF 125 ml) and Et3N
14.2 ml) was degassed for 20 mins by passing a constant
stream of nitrogen through the reaction solvents. Tetrakis-
1triphenylphosphine) palladium10) 10.40 g, 0.35 mmol),
copper iodide 10.20 g, 1.05 mmol, 0.15 equiv.) and PPh3
10.09 g, 0.35 mmol) were added to the constantly stirred
solution whilst under a positive nitrogen atmosphere. The
resulting reaction mixture was left to stir for 30 min before
prop-3-yn-1-14-tert-butylphenyl) ether 15 was added drop-
wise via syringe over 1 hour. The mixture was then heated to
re¯ux for 50 hours after which time it was allowed to cool to
room temperature before ®ltering through a short pad of
Celite to remove metal salts. The reaction was then
quenched with H2O 1100 ml) and washed with aqueous
2 M HCl 1125 ml) before extracting the aqueous phase
with CH2Cl2 12£100 ml). The combined organic layers
were then washed with H2O 12£100 ml) and dried
1MgSO4) and the solvent was removed in vacuo affording
the crude product as a brown oil. This residual oil was
puri®ed via column chromatography 1SiO2, 11:1 v/v hexa-
ne:ethyl acetate) affording N-Boc-4-aminobenzylprop-2-yn-
1-140-tert-butylphenyl)ether 16 as a pale yellow solid
11.11 g, 42%) mp 104±106.58C;1Found;C, 76.6;H, 7.77;
N, 3.49. C25H31NO3 requires C, 76.4;H, 7.95;N, 3.58);
1.4.10. 3-,4-Tri¯uoromethyl)phenylprop-2-yn-1-,4-tert-
butylphenyl) ether 17. 4-Iodobenzotri¯uoride 12.72 g
10.00 mmol) was dissolved in freshly distilled diisopropyl-
amine 180 ml) and degassed by bubbling dry nitrogen gas
through the solution for 20 minutes. Palladium 1II) bis-
triphenylphosphine dichloride 10.42 g, 0.60 mmol), copper
1II) acetate 10.11 g, 0.60 mmol) and triphenylphosphine
10.16 g, 0.60 mmol) were added successively to the
constantly stirred solution under a positive nitrogen
atmosphere and the mixture stirred for 2 minutes. Prop-2-
yn-1-14-tert-butylphenyl) ether 15 13.65 g, 24.00 mmol,
1.2 equiv.) was added dropwise via syringe over 20 minutes
and the resulting reaction mixture was heated to re¯ux, with
stirring, for 14 hours. The mixture was cooled and ®ltered to
remove waste solids. The solid residue was washed with
dichloromethane and the ®ltrate collected and solvent
removed in vacuo. The residue was redissolved in CH2Cl2
140 ml), washed with water 115 ml) and dried 1MgSO4). The
solvent was removed in vacuo and the crude product
puri®ed via ¯ash column chromatography 1SiO2, 8:1 v/v
hexane:CH2Cl2) affording 3-14-tri¯uoromethyl)phenyl-
prop-2-yn-1-14-tertbutylphenyl) ether 17 as a colourless
solid 11.23 g, 37%) mp 88±908C; dH 1300MHz, CDCl3)
7.61±7.50 14H, m), 7.49±7.30 12H, m), 7.02±6.93 12H,
n
max/cm21 3334 and 3328 1CONH), 1578, 1549 and 1515
t
1Ar, CvC); dH 1300 MHz, CDCl3) 7.42±7.39 12H, m, Ar),
7.35±7.31 12H, m, Ar), 7.23±7.20 12H, m, Ar), 6.99±6.94
12H, m, Ar), 4.88 12H, s, CH2), 4.83 11H, m, NH), 4.31±4.29
m), 4.90 12H, s), 1.41 19H, s, Bu); dC 175 MHz, CDCl3)
155.5 1C, quat, Ar) 144.4 1C, quat, Ar), 132.1 12£CH,
Ar), 126.4 12£CH, Ar), 125.3 12£CH, Ar), 125.2±125.1
1CF3), 114.5 12£CH, Ar), 86.8 1C, quat, CuC), 85.6 1C,
quat, CuC), 56.6 1CH2), 34.2 1C, quat, tBu), 31.5
t
t
12H, m, CH2), 1.45 19H, s, Bu), 1.30 19H, s, Bu); dC
175 MHz, CDCl3) 155.6 1C, quat, CvO), 144.2 1C, quat,
Ar), 138.1 1C, quat, Ar), 137.5 1C, quat, Ar), 132.1 12£CH,
Ar), 127.3 12£CH, Ar), 126.3 12£CH, Ar), 121.3 1C, quat,
Ar), 114.4 12£CH, Ar), 86.7 1C, quat, CuC), 84.2 1C, quat,
CuC), 56.7 1CH2), 56.6 1CH2), 44.4 1C, quat, tBu), 34.1 1C,
t
13£CH3, Bu); m/z 1EI) 332 1M1, 9%), 263 175), 253
1
1100);1HRMS) 332.3589 1M
332.3595).
C20H19F3O requires
t
t
quat, Bu), 31.5 13£CH3, Bu), 28.4 13£CH3, tBu); m/z 1CI)
411 1M11NH4, 88%), 355 163), 263 1100), 207 150), 146
134).
1.4.11. 1-,4-Benzyl-15-crown-5)-4-[methyl,40-tert-butyl-
phenyl)ether]-5-,benzylammoniumtri¯uoroacetate) 1,2,3-
triazole 18 and 1-,4-benzyl-15-crown-5)-5-[methyl,40-
tert-butyl-phenyl)ether]-4-,benzylammoniumtri¯uoro-
acetate) 1,2,3-triazole 19. 4-Tri¯ouromethylbenzylprop-2-
yn-1-140-tert-butylphenyl)ether 17 10.16 g, 0.48 mmol) and
3,4-dimethoxy azide 10 10.08 g, 0.48 mmol) were dissolved
in toluene 12.00 ml) and heated to re¯ux for 2 days under an
atmosphere of dry nitrogen after which time the solvent
was removed in vacuo and the two regioisomers formed
separated via column chromatography 1SiO2, 3:1 v/v
hexane:ethyl acetate) affording the pure 1,4 18 and 1,5 19
1.4.9. 3-,4-Benzylammonium)prop-2-yn-1-,40-tert-butyl-
phenyl)ether tri¯uoroacetate 2. N-Boc-4-aminobenzyl-
prop-2-yn-1-140-tert-butylphenyl)ether 16 10.80 g, 2.04
mmol) in anisole 10.22 ml, 2.04 mmol) was dissolved in a
mixture of CH2Cl2/tri¯uoroacetic acid 130 ml: 0.52 ml / 5 %
w/v) and stirred at room temperature for 17 hours under a
dry nitrogen atmosphere. The solvent was removed in vacuo
1without heating) affording the crude product as a yellow

S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
4953
products as colourless solids 174 mg, 28% and 36 mg, 14%
respectively).
phenyl)ether chloride 20. N-Boc-4-aminobenzylprop-2-
yn-1-140-tert-butylphenyl)ether 16 10.25 g, 0.64 mmol)
was added to a solution of 3 M HCl in ethanol and
left to stir for 1 hour at 2108C. The resulting reaction
mixture was then allowed to warm to room temperature
and left to stir for a further 30 minutes, after which
time the solvent was removed in vacuo yielding 3-14-
1.4.12. 1-,4-Benzyl-15-crown-5)-4-[methyl,40-tert-butyl-
phenyl)ether]-5-,benzylammoniumtri¯uoroacetate) 1,2,3-
triazole 18.
benzylamine
hydrochloride)prop-2-yn-1-140-tert-butyl-
phenyl)ether 20 as a colourless solid which was used
without further puri®cation. m/z 1FAB) 294 1[M1 - Cl],
49%), 221 1100), 128 167).
1.4.15. 3-,4-Benzylammonium)prop-2-yn-1-,40-tert-butyl-
phenyl)ether hexa¯ourophosphate 21. Potassium hexa-
¯ourophosphate 10.41 g, 2.25 mmol) was added to a
solution of 3-14-benzylammonium)prop-2-yn-1-140-tert-
butylphenyl)ether chloride 20 10.18 g, 56.78 mmol) in
methanol 130 ml) and the resulting reaction mixture left to
stir overnight under an atmosphere of dry nitrogen. The
solvent was removed in vacuo after which the residue was
redissolved in water and nitromethane 1v/v 10:10 ml) and
left to stir for a further 30 minutes. The organic phase was
isolated and washed with water before being dried over
MgSO4. The solvent was removed in vacuo affording
the crude product as a pale yellow solid. 3-14-benzyl-
ammonium)prop-2-yn-1-140-tert-butylphenyl)ether hexa-
¯ourophoshate 21 was obtained after recrystallisation
from CH2Cl2:hexane as a white solid 10.16 g, 65%) mp
decomposes .2208C. 1Found;C, 54.76;H, 5.40;N;3.12.
3
dH 1300 MHz, CDCN3/TCE) 7.77±7.74 12H, d, JHH 8.1,
3
H7), 7.52±7.49 12H, d, JHH 8.1, H6), 7.29±7.26 12H, m,
3
H5), 6.84±6.81 12H, m, H4), 6.79±6.76 11H, d, JHH 8.1,
3
2
H1), 6.55±6.52 11H, dd, JHH 8.1, JHH 2.0, H2), 5.46
1CH2-N), 5.01 1CH2-O), 3.73 1CH3), 3.59 1CH3), 1.25
13£CH3, tBu); dC 1125 MHz, CDCN3/TCE) 156.9 1C,
quat, F), 150.2 1C, quat, A or B), 150.1 1C, quat, A or B),
145.0 1C, quat, G), 142.9 1C, quat, E), 136.7 1C, quat, D),
131.9 1C, quat, H), 131.6 12£CH, C6), 128.8 1C, quat, C),
1
127.2 12£CH, C5), 126.2 12£CH, C7), 125.4 1CF3, JCF
270.1), 121.1 1CH, C2), 115.6 12£CH, C4), 112.8 1CH,
C1), 112.3 1CH, C3), 62.2 1CH2-O), 56.4 1CH3), 56.2
1CH3), 53.0 1CH2-N), 34.7 1C, quat, tBu), 31.7 13£CH3,
tBu); m/z 1ES) 548 1[M1Na]1, 100%);1HRMS) 548.2119
1M1 C29H30N3O3F3Na requires 548.2137).
C20H24NOPF6 requires C, 54.72;H, 5.51;N, 3.20);
dH
1300 MHz, CDCl3) 7.51±7.48 16H, m, Ar), 6.98±6.94
12H, m, Ar), 4.93 12H, s, CH2), 4.11 12H, s, CH2),
t
2.88 13H, bs, NH31), 1.29 19H, s, Bu); dC 175 MHz,
1.4.13. 1-,4-Benzyl-15-crown-5)-5-[methyl,40-tert-butyl-
phenyl)ether]-4-,benzylammoniumtri¯uoroacetate) 1,2,3-
triazole 19.
CDCl3) 156.4 1C, quat, Ar), 145.0 1C, quat, Ar), 142.2
1C, quat, Ar), 132.6 12£CH, Ar), 128.2 1CH, Ar), 127.4
12£CH, Ar), 121.5 1C, quat, Ar), 115.3 12£CH, Ar),
87.1 1C, quat, CuC), 85.3 1C, quat, CuC), 57.2
1CH2-O), 44.4 1CH2- NH31), 34.7 1C, quat, Bu), 28.5
t
13£CH3, Bu); m/z 1FAB) 294 1M1 - PF62, 19%), 277
t
116), 221 1100), 144 143), 128 159); m/z 1MALDI) 144
C20H24NO
2
1
1PF6
requires 294.1855).
,
49%);1HRMS) 294.1858 1M
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council 1Quota award to S. J. H.), the University of
Birmingham and the University of St Andrews for ®nancial
support. We acknowledge the assistance of Dr Deirdre
Hickey and the ®nancial support of SmithKline Beecham
at an early stage in this project.
3
dH 1300 MHz, CDCN3/TCE) 7.89±7.86 12H, d, JHH 8.3,
3
H6), 7.75±7.72 12H, d, JHH 8.3, H7), 7.35±7.30 12H, m,
H5), 6.83±6.80 15H, m, H4, H1, H2, H3), 5.60 1CH2-N),
5.15 1CH2-O), 3.74 1CH3), 3.56 1CH3), 1.27 13£CH3, tBu);
dC 175 MHz, CDCN3/TCE) 156.5 1C, quat, F), 150.3 12£C,
quat, A/B), 146.4 1C, quat, E), 145.7 1C, quat, G), 135.9 1C,
quat, H), 130.8 1C, quat, D), 130.4 1C, quat, 3JCF 32.1), 129.0
12£CH, C6), 128.5 1C, quat, C), 127.4 12£CH, C5), 126.8
References
1
1CH, C7), 126.7 1CH, C7), 125.5 1CF3, JCF 269.6), 121.4
1CH, C2), 115.5 12£CH, C4), 112.9 1CH, C1), 112.8 1CH,
1. For general reviews, see: 1a) Kirby, A. J. Angew. Chem. Int.
Ed. Engl. 1996, 35, 707±724. For some ef®cient examples,
see: 1b) Hosseini, M. W.;Lehn, J. M.;Jones, K. C.;Plute,
K. E.;Mertes, K. B.;Mertes, M. P. J. Am. Chem. Soc. 1989,
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34.8 1C, quat, tBu), 31.7 13£CH3, tBu); m/z 1ES) 548
1
1[M1Na]1,
C29H30N3O3F3Na requires 548.2137).
100%);1HRMS)
548.2146
1M
1.4.14. 3-,4-Benzylammonium)prop-2-yn-1-,40-tert-butyl-

4954
S. J. Howell et al. / Tetrahedron 57 +2001) 4945±4954
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13. Fleming, I. In Frontier Molecular Orbitals and Organic Chemi-
cal Reactions, Wiley & Sons: Chichester, 1976;pp 155±156.
14. All molecular mechanics calculations were carried out using
the AMBER* force®eld as implemented in Macromodel
1Version 5.0: Mohamadi, F.;Richards, N. G. J.;Guida, W.
C.;Hendrickson, T.;Still, W. C. J. Comput. Chem. 1990, 11,
440) together with the GB/SA solvation model for CHCl3. All
calculations were performed on a Silicon Graphics Indigo2
computer. Conformational searching was carried out using
10000 step Monte Carlo simulations, and all conformations
located within 50 kJ of the global minimum were minimized.
15. Throughout this work, we use the descriptors 1,4 and 1,5 to
describe the regioisomers formed in the cycloaddition reac-
tions. We de®ne the 1,4 regioisomer as that which bears the
CH2OAr substituent on position 4 relative to the substituent on
N at position 1. We de®ne the 1,5 regioisomer as that which
bears the CH2OAr substituent on position 5 relative to the
substituent on N at position 1.
3. For general examples of accelerated cycloaddition reactions
see: 1a) Kang, J.;Hilmersson, G.;Santamaria, J.;Rebek, Jr., J.
J. Am. Chem. Soc. 1998, 120, 7389±7390. 1b) Kang, J.;
Hilmersson, G.;Santamaria, J.;Rebek, Jr., J. J. Am. Chem.
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Chem.
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16. 1a) Ouchi, M.;Inoue, Y.;Kanzaki, T.;Hakushi, T.
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Camps, F.;Coll, J.;Ricart, S. J. Heterocyclic. Chem. 1983, 20,
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4. In order to distinguish between transition state effects and
ground state effects, we will use the description accelerated
when the rate of a reaction is enhanced by the lowering of the
energy of the transition state by a recognition event and the
description facilitated when the extent of reaction is enhanced
by the lowering of the energy of the product by a recognition
event.
17. Hyde, E. M.;Shaw, B. L.;Shepherd, I. J. Chem. Soc. Dalton
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18. Bumagin, N. A.;Ponomaryov, A. B.;Beletskaya, I. P. Synth-
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acceleration and control of cycloaddition reactions, see:
1a) Philp, D.;Robertson, A. Chem. Commun. 1998, 879±
880. 1b) Booth, C. A.;Philp, D. Tetrahedron Lett. 1998, 39,
6987±6990.
19. There is a wide variation in the measurement of the ammoni-
um Hammett substituent ranging from dpˆ0.6 to 1.7, giving an
average for the benzylammonium group as 0.53. 1a) Hine, J.
J. Am. Chem. Soc. 1960, 82, 4877±4880. 1b) Hansch, C.;Taft,
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20. Reaction solutions of the appropriate concentration with
solvent compositions of 87.5% D2-TCE and 12.5% CD3CN
can be prepared readily by mixing equal volumes of a stock
solution of dipolarophile 2 in D2-TCE / CD3CN 175:25) and a
stock solution of dipole 1 in neat D2-TCE.
8. Nicolaou, E.;Sorensen, E. Classics in Total Synthesis, VCH:
Weinheim, 1996.
9. 1a) Huisgen, R. Angew. Chem. Int. Ed. Engl. 1963, 2, 565±
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