Preparation of functionalised aryl alkynes as precursors to extended cyclophanes

Article abstract of DOI:10.1016/S0040-4020(99)01002-9

The preparation of 2,6-substituted arylhalides and triflates is described. These compounds are suitable precursors for cyclophane formation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01002-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 407–415
Preparation of Functionalised Aryl Alkynes as Precursors to
Extended Cyclophanes
*
Geoffrey T. Crisp and Peter D. Turner
Department of Chemistry, University of Adelaide, Adelaide, 5005, South Australia, Australia
Received 8 September 1999; revised 14 October 1999; accepted 4 November 1999
Abstract—The preparation of 2,6-substituted arylhalides and triflates is described. These compounds are suitable precursors for cyclophane
formation. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
rings in close proximity and their optoelectronic
properties. The report herein presents methodologies
for the preparation of 2,6-bis(hydroxymethyl)aryl and
2,6-bis(halomethyl)aryl compounds as precursors for
cyclophane formation. The palladium-catalysed coupling
of 2,6-bis(substituted)aryl compounds with arylalkynes is
described, along with subsequent functional group transfor-
mations of the aryl side chains.
Structures based on cyclophanes continue to arouse interest
because of their unique physical properties, and their ability
to act as model compounds for the study of intramolecular
processes1,2 and host–guest chemistry.3 Cyclophanes
containing extended p-conjugation have been investigated
as mimics for solid-state interactions involving photoexci-
tation4 and for electron transfer processes involving
extended orthogonal p-systems.5 The classical, and still
often used, methodology for the preparation of cyclophanes
relies on the formation of a benzyl halide precursor.2 Two
basic methodologies exist for the preparation of functional-
ised or p-extended cyclophanes. The first involves
functionalisation of the benzyl halide precursor with cyclo-
phane formation as the final step.6 The second involves the
functionalisation of the cyclophane itself, and often suffers
from the disadvantage of the close proximity of the two aryl
rings which alters the outcome of functional group manip-
ulation.7 We required a series of p-conjugated cyclophanes
in order to investigate the relationship between aromatic
Results and Discussion
The direct route to aryl alkynes containing side-arms suitable
for cyclophane formation would be the bis-hydroxymethyl-
ation of p-bromo- 28 and p-iodophenol 3. Whilst p-bromo-
phenol could be readily bis-hydroxymethylated to give the
desired compound 10 in a low yield of 14%, the reaction
involving p-iodophenol produced no isolable material
(Scheme 1). Both halophenols appeared to undergo exten-
sive polymerisation and, for p-iodophenol, the aryl iodide
bond appeared to be reduced.
Scheme 1. Conditions: (a) CH2O, NaOH; (b) CH2O, morpholine; (c) CH2O, morpholine, AcOH; (d) Ac2O, AcOH; (e) base hydrolysis.
Keywords: arylhalides; cyclophanes; triflates.
* Corresponding author. Tel.: ϩ61-8-83035497; fax: ϩ61-8-83034358; e-mail: geoffrey.crisp@adelaide.edu.au
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01002-9

408
G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
Scheme 2. Conditions: (a) NaI, Chloramine-T, DMSO; (b) NaH, PhNTf2, THF; (c) guanidine, CH3OH; (d) K2CO3, PhNTf2, THF.
An indirect route was therefore sought for the introduction
of the 2,6-functionality and the formation of bis(morpho-
linomethyl) compounds via a Mannich reaction9 was
investigated. The literature conditions for the Mannich reac-
tion of p-bromophenol10 with morpholine and formaldehyde
met with little success in our hands. When acetic acid was
used as both solvent and activator the desired material 5 was
isolated in 82% yield (Scheme 1). Unfortunately, appli-
cation of this procedure to p-iodophenol gave compound 6
in only 2% yield. Extensive decomposition of the starting
materials and formation of molecular iodine took place
during the reaction. Formation of the parent compound,
2,6-bis(morpholinomethyl)phenol 4, could also be achieved
using this procedure without acetic acid, yielding the
2,6-bis(morpholinomethyl)phenol 4 in 20–30% yield.
Although the yield was low, it was reproducible on a
large scale (ϳ60 g).
deacetylation (Scheme 2). To gain access to the iodinated
analogue of 12, direct iodination of 4 with NaI/Chloramine-
T in dimethylsulphoxide15 was investigated and gave 2,6-
bis(morpholinomethyl)-4-iodophenol
(Scheme 2).
6 in 68% yield
Phenol 12 could be readily converted to triflate 13 using
N-phenyltriflimide and potassium carbonate, whereas
phenol 6 required NaH and N-phenyltriflimide for conversion
to triflate 14.16 When the unprotected phenol 10 was treated
with NaH and N-phenyltriflimide the anilinomethyl triflate
15 was formed in 57% yield (Scheme 2). The formation of
15 could have resulted from either direct triflation of the
hydroxymethyl group or by an intramolecular transfer of a
triflate group from the phenoxy position. The use of milder
bases such as potassium carbonate or triethylamine gave no
triflation and starting material was recovered.
Morpholinomethylphenol 4 was converted to the triacetate 7
in 57% yield by heating 4 in acetic anhydride.11 The
analogous bromophenol 5 was also readily converted to
the corresponding triacetate 8 in 64% yield using a modifi-
cation to this procedure in which both acetic anhydride and
acetic acid were necessary.
The isophthalate compound 1617 proved to be an efficient
entry into a variety of functionalised aryl alkynes. The direct
iodination of diester 16 could not be achieved with either
chloramine-T/NaI15 in DMF, or tBuOCl/NaI in acetoni-
trile.18 However, BTMA·ICl2 iodinated 16 readily and
19
17 was isolated in 71%. Triflation of 17 was performed
using N-phenyltriflimide and triethylamine in acetonitrile
and gave 18 in a quantitative yield (Scheme 3).
The iodination of triacetate 7 under a variety of conditions
met with little success with starting material being
recovered in each case.12 Attempts to selectively deacetylate
only the phenolic acetate of 7 to the corresponding phenol
with either guanidine in methanol,13 sodium hydroxide in
ethanol, potassium carbonate in methanol or zinc in
methanol14 gave either decomposition or complete hydro-
lysis of all the acetate protecting groups. However, tri-
acetate 8 could be selectively deacetylated using a
methanolic solution of guanidine at Ϫ10 to Ϫ20ЊC, whereas
at higher temperatures there was no selectivity for the
On a small scale (0.020 g) the reduction of 17 with lithium
aluminium hydride in THF at 0ЊC gave reasonable yields
(20–30%) of the desired alcohol 11, provided the suspen-
sion was allowed to warm gradually to room temperature
over 3 h after the addition of hydride. By NMR, integration
of the benzyl peaks gave the ratio of 11:9 as 11:1. However,
on a larger scale (0.30 g), under the same conditions, the
ratio was reversed and increased to a disappointing 1:29 for
11:9. A more successful approach to the formation of 11
Scheme 3. Conditions: (a) BTMA·ICl2, NaHCO3, MeOH; (b) PhNTf2, Et3N, CH3CN; (c) LiAlH4, THF, 0ЊC to rt.

G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
409
same reagent at room temperature converted trihydroxy
compound 10 into 20 in 64% yield.
The preparation of p-conjugated aryl alkynes was then
investigated with the coupling of diester 2122 to phenyl-
acetylene using Pd(PPh3)4, NaI, ZnCl2 and piperidine in
DMF23 at 60ЊC to give 22 in 70% yield. The reduction of
the ester groups of 22 proceeded selectively at room
temperature giving the desired bis-hydroxymethyl
compound 23 in 84% yield (Scheme 5).
Scheme 4.
was to perform an initial hydride reduction on the parent
diester 16 to form 9 in 94%, followed by iodination to give
the aryl–iodide 11 in 89% yield. Of interest with the phenol
9 was a reversible enantiotropic polymorphism which was
observed as two distinct melting points.20
Conversion of the hydroxyl groups of 23 to the correspond-
ing iodides could not be achieved with trimethylsilyl iodide
as decomposition of the starting materials occurred. The
conversion of the hydroxyl groups to bromides was then
investigated and PPh3/CBr4 in ether24 proved efficacious
with the desired material 24 being isolated in 65% yield
(Scheme 5).
The conversion of the acetoxy or hydroxy groups into good
leaving groups for cyclophane formation was then investi-
gated. Trimethylsilyl iodide, generated in situ, from
trimethylsilyl chloride and sodium iodide,21 could convert
triacetoxy 8 to 19 in 62% yield (Scheme 4). The phenolic
acetoxy group remains unchanged during this reaction. The
Palladium-catalysed coupling of phenylacetylene with 6
gave 25 in 94% yield. Treatment of 25 with acetic anhydride
and acetic acid at reflux successfully produced the
Scheme 5. Conditions: (a) Pd(PPh3)4, NaI, ZnCl2, piperidine, DMF; (b) LiAlH4, THF; (c) PPh3, CBr4, ether.
Scheme 6. Conditions: (a) PhCxCH, Pd(PPh3)4, CuI, piperidine; (b) Ac2O, AcOH; (c) 5M H2SO4, THF.
Scheme 7. Conditions: (a) i. Me3SiCxCH, Pd(PPh3)4, Et3N, CuI, DMF; (b) PhNTf2, Et3N, CH3CN; (c) K2CO3, MeOH; (d) Pd(PPh3)4, CuI, Et3N; (e) i. LiAlH4,
THF; ii. Bu4NF, CH2Cl2; (f) i. DIBAL-H, THF; ii. Bu4NF, CH2Cl2.

410
G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
tri-acetate 26 in 75% yield (Scheme 6). Treatment of 25
under a range of basic conditions, including guanidine in
methanol, sodium methoxide in methanol and potassium
hydroxide in methanol gave only partial hydrolysis. Even
with extensive heating of the reaction mixture only one, or
at most two, of the acetates could be cleaved and no trihy-
droxy 27 could be isolated. Hydrolysis of 27 under acidic
conditions, THF with 5M H2SO4 at reflux for 17 h, gave the
desired bis-hydroxymethyl compound 27 in 48% yield.
These last two steps confirmed the fact that the acetylenic
functionality would remain intact under strongly acidic
conditions whilst the linker-arm precursor was manipulated.
A more convenient methodology for the preparation of 27
was the palladium catalysed coupling of 11 with phenyla-
cetylene and this gave 27 in 46% yield.
mass spectrometer. Liquid secondary ionisation mass
spectrometry (LSIMS) and accurate mass spectra were
performed by the University of Tasmania mass spectro-
metric service. Infrared spectra were recorded on an ATI
Mattison Genesis FTIR as nujol mulls between sodium
chloride plates. Elemental analyses were performed at the
University of Otago, New Zealand. Solvents were purified
and dried using standard laboratory procedures and all
organic extracts were dried over anhydrous magnesium
sulphate. All solvents for palladium catalysed coupling
reactions were degassed by the freeze–pump–thaw method
and kept under an atmosphere of nitrogen.
A typical extractive workup for the palladium catalysed
coupling reactions involved addition of the reaction mixture
to saturated NH4Cl and extraction with two portions of
organic solvent. The organic layers were then combined,
washed with water, dried and the solvent removed under
vacuum.
Attention was then directed to the synthesis of extended aryl
alkynes containing side arms suitable for cyclophane for-
mation. Triflate 30 was prepared from methyl 4-iodosalicyl-
ate 2815 via the phenol 29,26 using a palladium catalysed
coupling reaction followed by mild triflation with N-phenyl-
triflimide. Arylalkyne 33 was a known compound,25
however, it was prepared from methyl 3-iodobenzoate
3127 via the protected alkyne 3225 using an alternative
method to that described in the literature. Coupling of
triflate 30 to arylalkyne 33 using Pd(PPh3)4 and CuI resulted
in a 94% isolated yield of 34 (Scheme 7). Conversion of the
diester 34 to the bis-hydroxymethyl compound 34 was
attempted using lithium aluminium hydride at 0ЊC, followed
by deprotection with Bu4NF. The isolated product was the
trans vinyl derivative 35 resulting from the reduction of the
triple bond in addition to the ester groups. This reaction
was reminiscent of the reduction of propargyl alcohols
to allylic alcohols via the anti-addition of hydride.
Evidence to support the assignment of the double bond as
trans has been obtained by a homonuclear decoupling
experiment.
The following compounds were prepared according to
published procedures: 1-acetoxy-2,6-bis(acetoxymethyl)-
benzene 7,11 2,6-bis(hydroxymethyl) phenol 9,20 2,6-bis-
(hydroxymethyl)-4-bromophenol 10,8 dimethyl 2-hydroxyi-
sophthalate 16,17 dimethyl 5-bromoisophthalate 21,22 and
methyl 4-iodosalicylate 2815.
2,6-Bis(morpholinomethyl)phenol 4. To a 38% formalde-
hyde solution (35.2 mL, 450 mmol) was added phenol
(20.0 g, 210 mmol) followed by morpholine (38.6 mL,
440 mmol). The resulting suspension was stirred vigorously
and heated at 50ЊC for 15 h. Water (100 mL) and ethyl ace-
tate (20 mL) were then added with cooling to 0ЊC. Over
0.5 h a white precipitate formed which was collected by
vacuum filtration and washed with a solution of water/
ethyl acetate (10:1) (100 mL). The solid was recrystallised
from hexane to give the title compound as colourless plates
(12.0 g, 20%); mp 123.5–124.5ЊC; Anal. Calcd for
C16H24N2O3: C, 65.73; H, 8.27, Found: C, 66.02; H, 8.07;
dH (300 MHz) 2.51 (8H, t, Jˆ4.6 Hz), 3.61 (4H, s,
ArCH2R), 3.71 (8H, t, Jˆ4.6 Hz), 6.74 (1H, t, Jˆ7.5 Hz,
ArH), 7.04 (2H, d, Jˆ7.5 Hz, ArH); dC (75.47 MHz) 53.1,
59.2, 66.7 (ArCH2R), 118.5, 122.0 (ArCH2R), 129.0, 155.9
(ArOH); m/z (EI) 292 (Mϩ, 75%), 205 (100);); nmax
The problem of over-reduction was solved by the use
DIBAL-H at Ϫ20ЊC in THF. Reduction under these con-
ditions, followed by deprotection with Bu4NF gave the
desired bis-hydroxymethyl compound 36 in a quantitative
yield from the ester 34.
In summary, we have prepared a series of aryl alkynes
containing hydroxymethyl and bromomethyl side chains.
We will report in the near future how these precursors
have been converted into orthogonal p-conjugated aryl
alkynes and subsequently into cyclophanes.
3430 cmϪ1
.
2,6-Bis(morpholinomethyl)-4-bromophenol 5. To a solu-
tion of p-bromophenol (8.65 g, 50 mmol) in acetic acid
(10 mL) was added morpholine (9.60 mL, 110 mmol) and
38% formaldehyde solution (11 mL, 110 mmol). The result-
ing solution was then heated at 80ЊC for 6 h. The reaction
mixture was then taken up into dichloromethane (200 mL)
and washed with water (100 mL), saturated NaHCO3
(100 mL) and finally water (100 mL). The solution was
dried and passed through a short squat column of Silica
gel 60. The solvent was removed in vacuo, to yield a yellow
solid (16.45 g, 82%); mp 115.0–115.5ЊC; Anal. Calcd for
C16H23N2O3Br: C, 51.76; H, 6.24; N, 7.54, Found: C, 52.03;
H, 6.23; N, 7.42; dH (300 MHz) 2.53 (8H, t, Jˆ4.6 Hz), 3.59
(4H, s, ArCH2R), 3.74 (8H, t, Jˆ4.6 Hz), 7.20 (2H, s, ArH);
dC (75.47 MHz) 52.7, 58.2, 66.3, 110.1 (ArBr), 124.0,
130.8, 154.7 (ArOH); m/z (EI) 372 (Mϩ, 81Br, 40%), 370
Experimental
1H NMR spectra were recorded at 300 MHz on a Varian
Gemini NMR (75.47 MHz for 13C) or at 200 MHz on a
Varian Gemini spectrometer (50.28 MHz for 13C) using a
dual 5 mm 13C/1H probe. All spectra were recorded as dilute
solutions in deuteriochloroform using tetramethylsilane as
an internal standard. Melting points were determined on a
Kofler hot-stage micro-melting point apparatus equipped
with a Reichart microscope and are uncorrected. Electron
impact (EI) and fast atom bombardment (FAB) mass spectra
were recorded at 70 eV on a Vacuum Generators ZAB 2HF
(Mϩ, 79Br, 41%), 285 (100), 283 (84); nmax 3400 cmϪ1
.

G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
411
2,6-Bis(morpholinomethyl)-4-iodophenol 6. To a solution
of phenol 4 (2.00 g, 6.85 mmol) in dimethylsulphoxide
(10 mL) was added NaI (1.23 g, 8.22 mmol) and chlora-
mine-T trihydrate (2.32 g, 8.22 mmol) with stirring. The
resulting suspension was heated at 50ЊC for 45 min after
which time the reaction mixture was taken up into dichloro-
methane (50 mL) and washed with water (50 mL). The
aqueous layer was re-extracted with dichloromethane
(50 mL), the organic layers combined and washed with satu-
rated Na2S2O3 ꢀ2×50 mL† and water (50 mL). The solvent
was dried and removed in vacuo to give a yellow oil. The
product was purified by flash chromatography on silica gel
[ethyl acetate, Rf 0.36] to give a colourless oil which was
taken up into hot hexane and upon cooling gave off-white
prisms (1.95 g, 68%); mp 108.0–109.0ЊC; Exact Mass
Calcd for C16H23IN2O3: 418.0755. Found: 418.0763; dH
(300 MHz) 2.52 (8H, t, Jˆ4.6 Hz), 3.59 (4H, s, ArCH2R),
3.74 (8H, t, Jˆ4.6 Hz), 7.34 (2H, s, ArH); dC (75.47 MHz)
53.1, 58.5, 66.7, 113.1 (ArI), 125.0, 137.3, 156.1 (ArOH);
79 mmol) to sodium methoxide (1.78 g, 77.4 mmol, in
800 mL of dry methanol). A solution of bromobenzene 8
(600 mg, 1.67 mmol) in methanol (8 mL) and dichloro-
methane (8 mL) was cooled to Ϫ25ЊC before 0.5 M guani-
dine in methanol (3.34 mL, 1.67 mmol) was added over
0.5 h. During this time the reaction temperature was kept
between Ϫ20 and Ϫ25ЊC and stirred for a further 3 h. Acetic
acid (0.2 mL) was then added to quench the reaction. The
mixture was taken up into dichloromethane (75 mL) and
washed with 5% NH4Cl (40 mL) and water (40 mL). The
solvent was dried and removed in vacuo to yield an off-
white solid which was recrystallised from hexane to give
the title compound as a colourless powder (353 mg, 67%);
mp 82.0–83.0ЊC; Exact Mass Calcd for C12H13O5Br:
315.9947, Found: 315.9948; dH (300 MHz) 2.13 (6H, s,
ArCH2OCOCH3), 5.10 (4H, s, ArCH2OAc), 7.41 (2H, s,
ArH); dC (75.47 MHz) 20.8 (CH3CO2CH2Ar), 61.8 (ArCH2-
OAc), 119.9 (ArBr), 125.4, 134.1, 152.9 (ArOH), 172.5
(CyO); m/z (EI) 318 (Mϩ, 81Br, 8%), 316 (Mϩ, 79Br, 8%),
216 (30), 214 (32); nmax 3380, 1745, 1734, 1712,
m/z (EI) 418 (Mϩ, 44%), 331 (98); nmax 3410 cmϪ1
.
1693 cmϪ1
.
1-Acetoxy-2,6-bis(acetoxymethyl)-4-bromobenzene 8. A
solution of bromophenol 5 (5.00 g, 13.5 mmol) in acetic
anhydride (30 mL) and acetic acid (2 mL) was refluxed
for 24 h. The reaction mixture was concentrated by rotary
evaporation and the resulting red/brown oil taken up into
dichloromethane (150 mL), washed with saturated NaHCO3
ꢀ3×75 mL† and water (75 mL). The solvent was dried and
removed in vacuo to give a red oil. This oil was then shaken
with a solution of 3% methanol in hexane (10 mL) for 5 min
before being placed in the fridge to crystallise overnight.
The crude product was collected and recrystallised from
hexane to give colourless needles (3.08 g, 64%); mp
81.0–82.0ЊC; Anal. Calcd for C14H15O6: C, 46.82; H,
4.21, Found: C, 46.73; H, 4.02; dH (300 MHz) 2.10
(6H, s, ArCH2OCOCH3), 2.35 (3H, s, ArOCOCH3),
5.00 (4H, s, ArCH2R), 7.57 (2H, s, ArH); dC
(75.47 MHz) 20.4, 20.7, 60.5, 119.4 (ArBr), 131.1
(ArCH2OAc), 132.8, 146.3 (ArOAc), 168.7 (CyO), 170.3
(CyO); m/z (FAB) 361 ((MϩH)ϩ, 81Br, 60%), 359
((MϩH)ϩ, 79Br, 61%), 301 (13), 209 (13), 259 (16), 257
Phenyl-2,6-bis(acetoxymethyl)-4-bromotrifluoromethyl-
sulphonate 13. Bromophenol 12 (100 mg, 3:16×10Ϫ4 mol†;
potassium carbonate (52 mg, 3:78×10Ϫ4 mol† and
N-phenyltriflimide (136 mg, 3:78×10Ϫ4 mol† in THF
(6 mL) were stirred together at room temperature for 16 h.
The reaction mixture was taken up into dichloromethane
(40 mL) and washed with 5% NH4Cl ꢀ2×25 mL† and
water (25 mL). The solvent was dried and removed in
vacuo to give a colourless oil. The crude product was puri-
fied by flash chromatography [dichloromethane, Rf 0.49] to
give the title compound as colourless oil that crystallised
upon addition of pentane as colourless prisms (118 mg,
84%); mp 59.5ЊC; Anal. Calcd for C13H12BrF3O7S: C,
34.76; H, 2.69, Found: C, 34.67; H, 2.46; dH (300 MHz)
2.15 (6H, s, ArCH2OCOCH3), 5.20 (4H, s, ArCH2OAc),
7.63 (2H, s, ArH); dC (75.47 MHz) 20.6 (CH3CO2CH2Ar),
60.0 (ArCH2OAc), 118.4 (q, Jˆ319 Hz, CF3SO2Ar), 122.6
(ArBr), 132.6, 133.3, 142.3 (ArOTf), 170.2 (CyO); m/z
(FAB) 451 ((MϩH)ϩ, 81Br, 4%), 449 ((MϩH)ϩ, 79Br,
4%), 391 (18), 289 (18), 301 (20), 299 (20); nmax 1746,
(17); nmax 1734, 1768 cmϪ1
.
1210 cmϪ1
.
2,6-Bis(hydroxymethyl)-4-iodophenol 11. To a solution of
phenol 9 (1.22 g, 7.92 mmol) in methanol (40 mL) was
added NaHCO3 (3.32 g, 39.61 mmol) and benzyltrimethyl-
ammonium dichloroiodate (2.90 g, 8.32 mmol). The result-
ing suspension was stirred at room temperature for 2 h. The
reaction mixture was concentrated in vacuo and then
purified by squat column chromatography [dichloro-
methane/ethyl acetate 1:1 (v/v), Rf 0.50] to give the title
compound as a fawn solid (1.98 g, 89%). A small sample
was recrystallised from a methanol/water mixture as orange
needles; mp 155.0–156.5ЊC; Exact Mass Calcd for
C8H9IO3: 279.9598, Found 279.9608; dH (200 MHz,
d6-acetone) 4.72 (4H, s, ArCH2OH), 7.46 (2H, s,
ArH); dC (50.28 MHz) 61.2, 81.5 (ArI), 131.0, 135.4,
154.4 (ArOH); m/z (EI) 280 (Mϩ, 37%), 262
Phenyl-2,6-bis(morpholinomethyl)-4-bromotrifluoro-
methylsulphonate 14. Bromophenol 5 (500 mg, 1.35 mmol)
in dry THF (5 mL) was added dropwise via syringe to a
suspension of NaH (50 mg, 2.08 mmol) in dry THF
(10 mL) at 0ЊC under a nitrogen atmosphere. N-phenyl-
triflimide (530 mg, 1.48 mmol) in dry THF (5 mL) was
added via syringe and the suspension refluxed for 3 h. The
reaction mixture was quenched by dropwise addition of
water before being taken up into dichloromethane (50 mL)
and washed with water (50 mL). The aqueous layer was
re-extracted with dichloromethane (50 mL), the organic
layers combined and dried. The solvent was removed in
vacuo and the resulting golden oil purified by flash chroma-
tography on silica gel [dichloromethane/ethyl acetate 4:1
(v/v), Rf 0.50] to give the title compound as a colourless oil
(374 mg, 55%); Exact Mass Calcd for C17H22BrF3N2O5S:
505.0444, Found: 505.0464; dH (300 MHz) 2.45 (4H,
t, Jˆ4.3 Hz), 3.58 (4H, s, ArCH2R), 3.71 (8H, t, Jˆ4.6 Hz),
7.72 (2H, s, ArH); dC (75.47 MHz) 53.2, 56.4, 66.5, 118.3 (q,
(100);(nmax 3330 cmϪ1
.
2,6-Bis(acetoxymethyl)-4-bromophenol 12. A stock solu-
tion of 0.5 M guanidine in methanol was prepared by the
addition of guanidine hydrogencarbonate (14.20 g,

412
G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
Jˆ321 Hz, CF3SO2R), 122.1 (ArBr), 132.6, 134.1, 144.4
(ArOTf); m/z 505 ((MϩH)ϩ, 81Br, 65%), 503 ((MϩH)ϩ
[79Br] and (MϪH)ϩ [81Br], 89%), 501 ((MϪH)ϩ, 79Br,
25%); nmax 1210 cmϪ1.
1-Acetoxy-2,6-bis(iodomethyl)-4-bromobenzene 19. To a
solution of triacetoxybromobenzene 8 (1.00 g, 2.78 mmol)
in acetonitrile (20 mL) was added trimethylsilylchloride
(2.5 mL, 19.63 mmol) and NaI (2.51 g, 16.71 mmol). The
resulting suspension was heated at 50ЊC for 20 h. The
reaction mixture was quenched by addition to Na2CO3
(50 mL) and extracted with dichloromethane ꢀ2×50 mL†:
The organic layers were combined and washed with 5%
Na2S2O3 (50 mL) and finally water (50 mL). The solvent
was dried and removed to give a tan solid which was
recrystallised from methanol/water to give off-white needles
(0.85 g, 62%); mp 190.5–192.0ЊC; Anal. Calcd for
C10H9BrI2O2: C, 24.27; H, 1.83, Found: C, 24.42; H, 1.90;
dH (300 MHz) 2.48 (3H, s, ArOCOCH3), 4.21 (4H, s,
ArCH2OAc), 7.46 (2H, s, ArH); dC (75.47 MHz) Ϫ3.9
(ArCH2I), 20.6 (ArOCOCH3), 119.4 (ArBr), 133.4, 134.8,
146.2, 167.7 (CyO); m/z (EI) 496 (Mϩ, 81Br, 17%), 494
(Mϩ, 79Br, 17%), 454 (81Br, 65%), 452 (79Br, 65%), 369
(81Br, 89%), 367 (79Br, 90%), 327 (81Br, 79%), 325 (79Br,
2-(Anilinomethyl)-4-bromo-6-(hydroxymethyl)phenyl-
trifluoromethanesulphonate 15. Bromophenol 10 (220 mg,
0.77 mmol) in dry THF (10 mL) was added dropwise via
syringe to a suspension of NaH (17 mg, 0.77 mmol) in dry
THF (5 mL) at 0ЊC under a nitrogen atmosphere. N-phenyl-
triflimide (285 mg, 0.80 mmol) was then added and the
suspension refluxed for 3 h. The reaction mixture was
quenched by dropwise addition of ‘wet’ ether until no
further effervescence was observed. The solvent was
removed in vacuo and the resulting oil purified by flash
chromatography on silica gel [dichloromethane, Rf 0.22]
to give the title compound as a colourless oil which slowly
solidified on standing (100 mg, 57); mp 85.0–88.0ЊC; Exact
Mass Calcd for C15H13BrF3NO4S: 438.9718, Found:
438.9718; dH (200 MHz): 4.69 (2H, s, ArCH2R), 4.96
(2H, s, ArCH2R), 7.01 (1H, d, Jˆ2.4 Hz, ArH), 7.20–7.33
(6H, m, ArH); dC (75.47 MHz) 50.8, 63.9, 111.5, 120.5
(q, Jˆ324.4 Hz, ArOSO2CF3), 123.6, 126.7, 129.1, 129.2,
129.3, 130.6, 132.6, 136.4, 153.6; m/z (EI) 441 (Mϩ, 81Br,
49%), 439 (Mϩ, 79Br, 60%), 424 (81Br, 31%), 422 (79Br,
25%), 290 (81Br, 40%), 288 (79Br, 41%); nmax 1230, 1200,
81%), 199 (81Br, 56%), 197 (79Br, 54%); nmax 1749 cmϪ1
.
2,6-Bis(iodomethyl)-4-bromophenol 20. To a solution of
trihydroxybromophenol 10 (100 mg, 4:29×10Ϫ4 mol† in dry
acetonitrile
(3 mL)
was
added
NaI
(322 mg,
2:14×10Ϫ3 mol† and trimethylsilylchloride (0.24 mL,
1:88×10Ϫ3 mol†: The resulting suspension was stirred at
room temperature for 1.5 h. The reaction mixture was
added to ether (20 mL), washed with water (20 mL) and
the aqueous layer re-extracted with ether (20 mL). The
organic layers were combined and washed with saturated
Na2S2O3 (20 mL). The organic layer was dried and the
solvent removed. Purification by sublimation at 120ЊC/
0.01 mmHg gave the title compound as a fawn solid
(124 mg, 64%); mp 155.5–157.0ЊC; Exact Mass Calcd for
C8H779BrI2O: 451.7774, Found: 451.7745; dH (200 MHz)
4.36 (4H, s, ArCH2I), 7.35 (2H, s, ArH); dC (50.28 MHz)
Ϫ0.7 (ArCH2I), 111.7, 128.8, 132.4, 151.5; m/z (EI) 454
(Mϩ, 81Br, 32%), 452 (Mϩ, 79Br, 32%), 200 (81Br, 61%),
1180 cmϪ1
.
Dimethyl 2-hydroxy-5-iodoisophthalate 17. To a solution
of dimethyl 2-hydroxyisophthalate (1.00 g, 4.76 mmol) in
methanol (50 mL) was added NaHCO3 (2.00 g,
10.48 mmol) and benzyltrimethylammonium dichloro-
iodate (1.74 g, 5.00 mmol). The resulting suspension was
stirred at rt for 3 h, and then filtered and the solvent
removed. The crude product was then taken up into chloro-
form (150 mL), washed with saturated Na2S2O3 (100 mL)
and brine (100 mL). The solvent was dried and removed to
give the title compound as an off-white solid (1.13 g, 71%).
A small sample was purified for analysis by sublimation at
85ЊC/0.03 mmHg; mp 135.0–138.0ЊC with rapid heating;
Anal. Calcd for C10H9O5I: C, 35.74; H, 2.70, Found: C,
35.98; H, 2.44; dH (300 MHz) 3.96 (6H, s, ArCO2CH3),
8.32 (6H, s, ArH); dC (75.47 MHz) 52.7 (ArCO2CH3),
78.9 (ArI), 118.6, 114.6, 161.2, 166.8 (CyO); m/z (EI)
336 (Mϩ, 100%), 304 (62), 273 (41), 246 (66); nmax 3390,
198 (79Br, 61%)%); nmax 3380 cmϪ1
.
Dimethyl 5-(2-phenyl-1-ethynyl)isophthalate 22. To a
solution of dimethyl 5-bromoisophthalate (200 mg,
0.0733 mmol) in degassed DMF (3 mL) was added
Pd(PPh3)4 (42 mg, 0.0366 mmol), phenylacetylene
(0.09 mL, 0.0821 mmol), DBU (0.20 mL, 0.134 mmol),
undried ZnCl2 (20 mg, 0.0147 mmol) and NaI (22 mg,
0.01.47 mmol). The resulting suspension was then stirred
at 60ЊC for 3 h. An extractive workup with dichloromethane
(20 mL) gave a tan solid. Purification by flash chromato-
graphy [dichloromethane/hexane 2:1 (v/v), Rf 0.37] and
then recrystallisation from hexane gave the title compound
as colourless needles (150 mg, 70%); mp 115.0–116.0ЊC;
Anal. Calcd for C18H14O4: C, 73.46; H, 4.80, Found: C,
73.59; H, 4.57; dH (300 MHz) 3.93 (6H, s, ArCO2CH3),
7.32–7.35 (3H, m, ArH), 7.50–7.53 (2H, m, ArH), 8.31
(2H, d, Jˆ1.5 Hz, ArH), 8.58 (1H, t, Jˆ1.5 Hz, ArH); dC
(75.47 MHz) 52.4, 87.3 (CxC), 91.2 (CxC), 122.5, 124.4,
128.5, 128.9, 130.0, 130.9, 131.8, 136.5, 165.7 (CyO); m/z
(EI) 294 (Mϩ, 100%), 263 (47), 235 (10), 220 (13); nmax
1733, 1681 cmϪ1
.
Dimethyl 5-iodo-2-{[(trifluoromethyl)sulphonyl]oxy}isoph-
thalate 18. Iodoisophthalate 17 (200 mg, 5:95×10Ϫ4 mol†;
triethylamine (0.10 mL, 1:39×10Ϫ3 mol† and N-phenyl-
triflimide (276 mg, 7:74×10Ϫ4 mol† in dry CH3CN (5 mL)
were stirred together for 16 h at room temperature under
nitrogen. The reaction mixture was then concentrated in
vacuo and then purified by flash chromatography [hexane/
ethyl acetate 6:1 (v/v), Rf 0.36] to give the title compound as
a colourless oil which crystallised upon addition of pentane
as colourless needles (278 mg, 100%); mp 96.0–98.0ЊC;
Anal. Calcd for C11H8F3ISO7: C, 28.22; H, 1.72, Found:
C, 28.43; H, 1.72; dH (300 MHz) 3.96 (6H, s, ArCO2CH3),
8.46 (2H, s, ArH); dC (75.47 MHz) 53.2 (ArCO2CH3), 92.1
(ArI), 118.5 (q, Jˆ321 Hz, CF3SO2Ar), 127.5, 144.7, 146.2,
162.9 (CyO); m/z (EI) 468 (Mϩ, 100%), 437 (36), 404 (14),
2214, 1722 cmϪ1
.
1,3-Bis(hydroxymethyl)-5-(2-phenyl-1-ethynyl)benzene 23.
To a suspension of LiAlH4 (69 mg, 2.04 mmol) in dry THF
373 (49); nmax 1739, 1726, 1220 cmϪ1
.

G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
413
(15 mL) was added the diester 22 (300 mg, 1.02 mmol) in
dry THF (15 mL) dropwise with stirring at room tempera-
ture. The suspension was stirred for further 1 h. The reaction
mixture was quenched with ‘wet’ ether and then added to
5% HCl (30 mL). The organic layer was separated, and the
aqueous layer extracted with ether ꢀ2×30 mL†: The organic
layers were combined, dried and the solvent removed to
give a tan solid. Recrystallisation from a chloroform/hexane
mixture gave the title compound as colourless needles
(204 mg, 84%); mp 100.0–102.0ЊC; Exact Mass Calcd for
C16H14O2: 238.0994, Found: 238.0988; dH (300 MHz) 4.70
(4H, s, ArCH2OH), 7.33–7.36 (4H, m, ArH), 7.45–7.46
(2H, m, ArH), 7.51–7.54 (2H, m, ArH); dC (75.47 MHz)
63.9 (ArCH2OH), 88.9 (CxC), 89.1 (CxC), 122.9, 123.0,
125.0, 128.1, 128.2, 128.5, 131.3, 141.7; m/z (EI) 238
380.1260, Found: 380.1260; dH (300 MHz): 2.07 (6H,
s, ArCH2OCOCH3), 2.32 (3H, s, ArOCOCH3), 5.02 (4H,
s, ArCH2OAc), 7.33 (3H, m, ArH), 7.50 (2H, m, ArH),
7.58 (2H, s, ArH); dC (75.47 MHz): 20.2 (CH3COR),
20.5 (CH3COR), 60.9 (ArCH2OAc), 87.9 (CxC), 90.2
(CxC), 121.9, 123.0, 128.4, 128.6, 129.8, 131.7,
133.4, 147.5 (ArOAc), 168.8 (CyO), 170.5 (CyO);
m/z (EI) 380 (Mϩ, 16%), 338 (34), 278 (100), 236
(79); nmax 1761, 1741 cmϪ1
.
2,6-Bis(hydroxymethyl)-4-(2-phenyl-1-ethynyl)phenol
27. Method A: a solution containing iodophenol 11 (140 mg,
4:16×10Ϫ4 mol†; Pd(PPh3)4 (48 mg, 4:16×10Ϫ5 mol†;
phenylacetylene (0.09 mL, 8:33×10Ϫ4 mol† and CuI
(16 mg, 8:33×10Ϫ4 mol† in degassed piperidine (3 mL)
was stirred at room temperature for 1.5 h. An extractive
workup with dichloromethane (40 mL) gave an orange oil.
Purification by flash chromatography [dichloromethane/
ethyl acetate 1:1 (v/v), Rf 0.48] gave the title compound
as a colourless solid (59 mg, 46%).
(Mϩ,100); nmax 3326, 2200 cmϪ1
.
1,3-Bis(bromomethyl)-5-(2-phenyl-1-ethynyl)benzene
24. To a solution of the diol 23 (20 mg, 0.0040 mmol) in dry
ether (4 mL) was added CBr4 (61 mg, 0.0185 mmol) and
PPh3 (48 mg, 0.0185 mmol). The resulting solution was
refluxed for 16 h. The solvent was removed in vacuo and
the residue purified by flash chromatography [hexane/
dichloromethane 8:1 (v/v), Rf 0.30] to give the title
compound as a colourless oil which solidified on standing
(20 mg, 65%). A small sample was sublimed at 100ЊC/
0.05 mmHg to give a colourless powder; mp 111.0–
114.0ЊC; Anal. Calcd for C16H12Br2: C, 52.78; H, 3.32,
Found: C, 52.75; H, 3.11; dH (300 MHz) 4.46 (4H, s,
ArCH2Br), 7.34–7.38 (4H, m, ArH), 7.49–7.54 (4H, m,
ArH); dC (75.47 MHz) 32.0 (ArCH2Br), 88.1 (CxC), 90.4
(CxC), 122.7, 124.5, 128.4, 128.6, 129.3, 131.6, 131.9,
138.6; m/z (EI) 366 (Mϩ, 81Br81Br, 27%), 364 (Mϩ,
81Br79Br, 54%), 362 (Mϩ, 79Br79Br, 27%), 285 (81Br,
Method B: 5M sulphuric acid (2 mL) was added to a
solution of 26 (50 mg, 1:31×10Ϫ4 mol† in THF (7 mL).
The resulting solution was refluxed for 17 h. The reaction
mixture was concentrated by rotary evaporation, taken up
into dichloromethane (30 mL) and washed with water
(30 mL). The solvent was dried and removed to give a
colourless oil that crystallised upon addition of chloroform.
The solid was recrystallised from chloroform/hexane to give
the title compound as colourless needles (13 mg, 48%); mp
125.0–126.0ЊC; Exact Mass Calcd for C16H14O2: 238.0994.
Found: 238.0988; dH (300 MHz) 4.75 (4H, s, ArCH2OH),
7.33 (5H, m, ArH), 7.48 (2H, m, ArH); dC (75.47 MHz) 61.7
(ArCH2OH), 88.3 (CxC), 90.7 (CxC), 115.4, 125.3, 128.9,
129.1, 129.6, 131.4, 132.4, 155.4 (ArOH); m/z (LSIMS) 238
98%), 283 (79Br, 97%); nmax 2208 cmϪ1
.
(Mϩ, 100%), 207 (14), 191 (28); nmax 3451, 3275 cmϪ1
.
2,6-Bis(morpholinomethyl)-4-(2-phenyl-1-ethynyl)phenol
25. A solution of iodophenol 6 (1.00 g, 2.03 mmol),
Pd(PPh3)4 (0.23 g, 0.20 mmol), phenyl acetylene
(0.45 mL, 4.06 mmol) and CuI (38 mg, 0.20 mmol) in
degassed piperidine (15 mL) was stirred at room tempera-
ture for 1 h. An extractive workup with dichloromethane
(60 mL) gave an orange/red oil. Purification by flash
chromatography on silica gel [ethyl acetate, Rf 0.40] gave
the title compound as a golden oil (0.83 g, 94%); Exact
Mass Calcd for C24H28N2O3: 392.2100, Found: 392.2103;
dH (300 MHz) 2.72 (8H, t, Jˆ4.4 Hz), 3.80 (4H s, ArCH2R),
3.92 (8H, t, Jˆ4.4 Hz), 7.51 (5H, m, ArH), 7.69 (2H, m,
ArH); dC (50.28 MHz) 53.1, 58.6, 66.6 (ArCH2R), 113.2,
122.5, 123.6, 127.7, 128.2, 131.3, 132.3, 156.6 (ArOH); m/z
Methyl 2-hydroxy-5-(trimethylsilylethynyl)salicylate 29.
A solution of methyl 5-iodosalicylate (4.00 g, 14.39 mmol),
Pd(PPh3)4 (0.16 g, 0.14 mmol), trimethylsilylacetylene
(2.54 mL, 17.99 mmol) and CuI (27 mg, 0.14 mmol) in a
degassed solvent system of triethylamine (5 mL)/DMF
(10 mL) was stirred at 40ЊC for 2 h. An extractive workup
with ether (100 mL) gave a fawn solid. Purification by squat
column chromatography [hexane/dichloromethane 2:1
(v/v), Rf 0.56] yielded the title compound as a colourless
oil which solidified on standing (3.30 g, 93%). A small
sample was recrystallised from a methanol/water mixture
as pale yellow needles; mp 70.0–71.5ЊC (no lit. mp)26; dH
(200 MHz) 0.24 (9H, s, RSi(CH3)3), 3.94 (3H,
s, ArCO2CH3), 6.88 (1H, d, Jˆ8.6 Hz, ArH), 7.50 (1H,
dd, Jˆ2.2 and 8.6 Hz, ArH), 7.94 (1H, d, Jˆ2.2 Hz,
ArH); dC (50.28 MHz) Ϫ0.2 (RSi(CH3)3), 52.3
(ArCO2CH3), 92.8 (CxC), 103.9 (CxC), 112.3, 114.2,
117.8, 133.8, 138.9, 161.6 (ArOH), 169.9 (CyO); m/z (EI)
248 (Mϩ, 84%), 233 (76), 216 (49), 201 (100); nmax (neat)
(EI) 392 (Mϩ, 23%), 305 (100); nmax 3380, 2208 cmϪ1
.
1-Acetoxy-2,6-bis(acetoxymethyl)-4-(2-phenyl-1-ethynyl)-
benzene 26. A solution of phenol 25 (883 mg, 2.25 mmol)
in acetic anhydride (25 mL) and acetic acid (1 mL) was
refluxed for 14 h. The reaction mixture was concentrated
by rotary evaporation and the resulting oil taken up
into dichloromethane (100 mL), then washed with sat
Na2CO3 ꢀ3×50 mL† and water (50 mL). The solvent
was dried and removed in vacuo to give an off-white
solid which was recrystallised from hexane to give the
title compound as fine colourless needles (644 mg,
75%); mp 80.0ЊC; Exact Mass Calcd for C22H20O6:
2158, 1681 cmϪ1
.
Methyl 5-(trimethylsilylethynyl)-2-{[(trifluoromethyl)-
sulphonyl]oxy}benzoate 30. The procedure was analogous
to that for 21 using the phenol 29 and purification was
performed using flash chromatography [hexane/dichloro-
methane 2:1 (v/v), Rf 0.40] to give the title compound as a

414
G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
colourless oil (88%); Exact Mass Calcd for C14H16O5F3SSi:
381.0458, Found: 381.0421; dH (200 MHz) 0.26 (9H,
s, RSi(CH3)3), 3.96 (3H, s, ArCO2CH3), 7.23 (1H,
d, Jˆ8.6 Hz, ArH), 7.66 (1H, dd, Jˆ8.6 and 2.2 Hz, ArH),
8.15 (1H, d, Jˆ2.2 Hz, ArH); dC (50.28 MHz) Ϫ0.4
(RSi(CH3)3), 52.7 (ArCO2CH3), 98.1 (CxC), 101.7
(CxC), 118.7 (q, Jˆ321 Hz, CF3SO2Ar), 122.9, 124.2,
124.6, 136.2, 137.1, 147.6, 163.6 (CyO); m/z (LSIMS)
381 ((MϩH)ϩ, 100%), 248 (46); nmax (neat) 2164,
ArH), 8.09 (1H, br s, ArH), 8.24 (1H, t, Jˆ1.5 Hz, ArH); dC
(75.47 MHz) Ϫ0.2 (Si(CH3)3), 52.2 (ArCO2CH3), 52.3
(ArCO2CH3), 88.5 (CxC), 95.0 (CxC), 97.6 (CxC), 103.4
(CxC), 123.1, 123.3, 123.6, 128.5, 129.6, 130.6, 131.9,
132.8, 133.9,134.1, 134.6, 135.8, 165.7 (CyO), 166.3
(CyO); m/z (EI) 390 (Mϩ, 16%), 375 (18); nmax 2156,
1718, 1704 cmϪ1
.
4-{[E)-2-[3-(hydroxymethyl)phenyl]-1-ethenyl}-3-(hydroxy-
methyl)ethynylbenzene 35. A suspension of LiAlH4 (10 mg,
0.263 mmol) in dry THF (3 mL) was cooled to 0ЊC under
nitrogen, and then diester 34 (50 mg, 0.128 mmol) in dry
THF (3 mL) was added with stirring. The resulting suspen-
sion was allowed to warm to room temperature over 5 h.
The reaction mixture was quenched with ‘wet’ ether and
then added to 1% HCl (10 mL), followed by extraction
with ether ꢀ2×10 mL†: The organic layers were combined,
dried and the solvent removed to give a tan solid. The solid
was taken up into dichloromethane (5 mL), Bu4NF (60 mg,
0.192 mmol) was added and the resulting solution stirred for
2 h at rt. The reaction mixture was concentrated in vacuo
and purification of the residue by flash chromatography
[dichloromethane/ethyl acetate 1:1 (v/v), Rf 0.39] yielded
an off-white solid. Recrystallisation from a benzene/hexane
mixture gave the title compound as fine off-white needles
(30 mg, 91%); mp 138.0–139.0ЊC; Exact Mass Calcd for
C18H16O2: 264.1150, Found: 264.1153; dH (300 MHz,
CD3CN) 3.43 (1H, s, ArCxCH), 4.58 (2H, d, Jˆ3.9 Hz,
ArCH2OH), 4.71 (2H, d, Jˆ3.9 Hz, ArCH2OH), 7.17 (1H,
d, Jˆ16.2 Hz, HCyCH), 7.13–7.48 (7H, m), 7.43 (1H, d,
Jˆ16.2 Hz), 7.68 (1H, d, Jˆ8.1 Hz, ArH); dC (50.28 MHz,
CDCl3/CD3CN) 62.4, 64.6, 79.1 (CxC), 84.3 (CxC), 121.6,
125.4, 125.8, 126.3, 126.4, 127.3, 129.5, 131.8, 132.3,
132.4, 137.3, 138.1, 140.0, 143.4; m/z (LSIMS) 264 (Mϩ,
1738 cmϪ1
.
Methyl 3-(trimethylsilylethynyl)benzoate 32. A solution
of methyl 3-iodobenzoate 3127 (10.00 g, 38.16 mmol),
Pd(PPh3)4 (0.44 g, 0.14 mmol), trimethylsilylacetylene
(6.46 mL,
45.81 mmol),
triethylamine
(10.62 mL,
76.34 mmol) and CuI (73 mg, 0.38 mmol) in degassed
DMF (20 mL) was stirred at 40ЊC for 16 h. An extractive
workup with ether (200 mL) gave a fawn solid. Purification
by squat column chromatography [hexane/dichloromethane
2:1 (v/v), Rf 0.43] gave the title compound as a colourless
solid (8.69 g, 98%). A small sample was recrystallised from
a methanol/water mixture as fawn needles; mp 52.0ЊC (no
lit. mp)25; dH (200 MHz) 0.29 (9H, s, RSi(CH3)3), 3.95 (3H,
s, ArCO2CH3), 7.41 (1H, t, Jˆ7.8 Hz, ArH), 7.67 (1H, dt,
Jˆ7.8 and 1.6 Hz, ArH), 8.00 (1H, dt, Jˆ7.8 and 1.6 Hz,
ArH), 8.18 (1H, t, Jˆ1.6 Hz, ArH); dC (50.28 MHz) Ϫ0.3
(RSi(CH3)3), 52.1 (ArCO2CH3), 95.3 (CxC), 103.9 (CxC),
123.6, 128.3, 129.4, 130.3, 133.1, 135.9, 166.3 (CyO); m/z
(EI) 232 (Mϩ, 43%), 217 (100), 201 (62); nmax 2157,
1732 cmϪ1
.
Methyl 3-ethynylbenzoate 33. A solution of 32 (500 mg,
2.15 mmol) in methanol (20 mL) was stirred with potassium
carbonate (30 mg, 0.22 mmol) at room temperature for 2 h.
The solvent was removed in vacuo and the resulting tan solid
was sublimed at 45ЊC/0.03 mmHg to give the title compound
as a colourless solid (76 mg, 76%); mp 54.0–55.0ЊC with
rapid heating (lit.25 48–50ЊC); dH (200 MHz) 3.13 (1H,
s, ArCxCH), 3.93 (3H, s, ArCO2CH3), 7.41 (1H,
t, Jˆ7.8 Hz, ArH), 7.66 (1H, dt, Jˆ7.8 and 1.4 Hz, ArH),
8.01 (1H, dt, Jˆ7.8 and 1.4 Hz, ArH), 8.17 (1H, t, Jˆ1.4 Hz,
ArH); dC (50.28 MHz) 52.2 (ArCO2CH3), 78.1 (CxC), 82.5
(CxC), 122.6, 128.5, 129.8, 130.5, 133.3, 136.3, 166.3
(CyO); m/z (EI) 160 (Mϩ, 60%), 159 (21), 129 (100), 101
(63); nmax 3311, 2106, 1732 cmϪ1.
100%), 247 (78); nmax 3330, 3275 cmϪ1
.
4-{2-[3-(Hydroxymethyl)phenyl]-1-ethynyl}-3-(hydroxy-
methyl)ethynylbenzene 36. A solution of diester 34
(19 mg, 0.0487 mmol) in dry THF (3 mL) was cooled to
Ϫ20ЊC and 1.5M DIBAL-H in toluene (0.20 mL,
0.300 mmol) was added with stirring. The resulting solution
was allowed to warm to 0ЊC over 0.5 h. The reaction
mixture was quenched with ‘wet’ ether and then added to
1% HCl (10 mL), followed by extraction with ether
ꢀ2×10 mL†: The organic layers were combined, dried and
the solvent removed to give a fawn solid. The solid was
taken up into dichloromethane (3 mL) and Bu4NF
(0.0570 mmol) added. The resulting solution was stirred
for 15 min at rt, followed by concentration in vacuo and
purification by flash column chromatography [ethyl ace-
tate/dichloromethane 1:1 (v/v), Rf 0.50] to give the title
compound as a fawn solid (13 mg, 100%). A sample was
recrystallised from a benzene/hexane mixture to give fine
pale yellow needles; mp 87.0–88.5ЊC; Exact Mass Calcd for
C18H14O2: 262.0994, Found: 262.0998; dH (300 MHz) 3.20
(1H, s, ArCxCH), 4.68 (2H, d, Jˆ5.1 Hz, ArCH2OH), 4.87
(2H, d, Jˆ5.7 Hz, ArCH2OH), 7.34–7.47 (5H, m, ArH),
7.53 (1H, s, ArH), 7.63 (1H, d, Jˆ0.9 Hz, ArH); dC
(75.47 MHz) 62.0 (ArCH2OH), 63.5 (ArCH2OH), 78.5
(CxC), 82.9 (CxC), 85.7 (CxC), 95.5 (CxC), 120.9,
121.7, 122.3, 126.8, 128.1, 129.4, 129.8, 129.9, 130.1,
131.4, 141.6, 143.0; m/z (LSIMS) 262 (Mϩ, 100%), 245
(94); nmax 3340, 3321 cmϪ1; UV–Vis (nm) 230 (8000),
Methyl 2-{2-[3-(methoxycarbonyl)phenyl]-1-ethynyl}-5-
(trimethylsilylethynyl)-benzoate 34. A solution containing
triflate 30 (1.22 g, 3.21 mmol), Pd(PPh3)4 (185 mg,
0.16 mmol), methyl 3-ethynylbenzoate 33 (539 mg,
3.37 mmol) and CuI (31 mg, 0.16 mmol) in a degassed
solvent system of triethylamine (4 mL)/DMF (8 mL) was
stirred at 50ЊC for 2 h. An extractive workup with ether
(100 mL) gave a tan solid. Purification by flash chroma-
tography [hexane/ethylacetate 5:1 (v/v), Rf 0.46] yielded
the title compound as a colourless solid (1.18 g, 94%). A
small sample was sublimed at 100ЊC/0.05 mmHg to give a
colourless powder; mp 106.0–107.5ЊC; Anal. Calcd for
C23H22O4Si: C, 70.74; H, 5.68, Found: C, 70.64; H, 5.65;
dH (300 MHz) 0.26 (9H, s, Si(CH3)3), 3.94 (3H,
s, ArCO2CH3), 3.97 (3H, s, ArCO2CH3), 7.46 (1H,
t, Jˆ7.5 Hz, ArH), 7.57 (2H, br s, ArH), 7.45 (1H, dt,
Jˆ7.5 and 1.5 Hz, ArH), 8.02 (1H, dt, Jˆ7.5 and 1.5 Hz,

G. T. Crisp, P. D. Turner / Tetrahedron 56 (2000) 407–415
415
14. Gonzalez, A. G.; Jorge, Z. D.; Lopez Dorta, H. L. Tetrahedron
Lett. 1981, 22, 335–338.
283 (27 000), 291 (30 000), 300 (38 000), 309 (31 000),
320 (35 000); Fluorescence (nm) 332.
15. Kometani, T.; Watt, D. S.; Ji, T. Tetrahedron Lett. 1985, 26,
2043–2046.
16. Hendrickson, J. B.; Bair, K. W.; Bergeron, R.; Giga, A.;
Skipper, P. L.; Sternbach, D. D.; Wareing, J. A. Org. Prep. Proced.
Int. 1977, 9, 173.
17. (a) Todd, D.; Martell, A. E. Org. Synth., Coll. Vol. 5, 617. (b)
Moshfegh, A.; Fallab, S.; Erlenmeyer, H. Helv. Chim. Acta 1957,
40, 1157–1166.
18. Kometani, T.; Watt, D. S.; Ji, T.; Fitz, T. J. Org. Chem. 1985,
50, 5384–5387.
19. Kajigaeshi, S.; Kakinami, T.; Fujisaki, S.; Kondo, M.;
Okamoto, T. Chem. Lett. 1987, 2109–2112.
20. (a) Freeman, J. H. J. Am. Chem. Soc. 1952, 74, 6257–6260. (b)
Jelley, E. E. In Techniques of Organic Chemistry, 2nd ed.;
Weissberger, A., Ed.; Interscience: New York, 1949; Vol. 1,
pp 886–889.
21. Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra, R.
J. Org. Chem. 1979, 44, 1247–1251.
22. Sherrod, S. A.; da Costa, R. L.; Barnes, R. A.; Boekelheide, V.
J. Am. Chem. Soc. 1974, 96, 1565–1577.
References
1. Diederich, F. Cyclophanes; The Royal Society of Chemistry:
Cambridge, 1991.
2. Konig, B. Top. Curr. Chem. 1998, 196, 91–136.
3. Seel, C.; Vogtle, F. Angew. Chem., Int. Ed. Engl. 1992, 31,
528–549.
4. Bazan, G. C.; Oldham Jr., W. J.; Lachicotte, R. J.; Tretiak, S.;
Chernyak, V.; Mukamel, S. J. Am. Chem. Soc. 1998, 120,
9188–9204.
5. Reiser, O.; Konig, B.; Meerholz, K.; Heinze, J.; Wellauer, T.;
Gerson, F.; Frim, R.; Rabinovitz, M.; de Meijere, A. J. Am. Chem.
Soc. 1993, 115, 3511–3518.
6. Bodwell, G. J.; Houghton, T. J.; Koury, H. E.; Yarlagadda, B.
Synlett 1995, 751–752.
7. Yamato, T.; Matsumoto, J.; Tokuhisa, K.; Shigekuni, M.;
Suehiro, K.; Tashiro, M. J. Org. Chem. 1992, 57, 395–396.
8. Moshfegh, A. A.; Mazandarani, B.; Nahid, A.; Hakimelahi,
G. H. Helv. Chim. Acta 1982, 65, 1229–1232.
9. Heaney, H. In Comprehensive Organic Synthesis, Trost, B. M.,
Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 953–973.
10. Albrecht, M. Synthesis 1996, 230–236.
11. Lemon, P. H. R. B.; King, J. G.; Murray, G.; Leoni, H.; Gerber,
A. H. Chem. Abstr. 113, P213239y; 114, P67342d.
12. (a) Orito, K.; Hatakeyama, T.; Takeo, M.; Suginome, H.
Synthesis 1995, 1273–1277. (b) Kajigeshi, S.; Kakinami, T.;
Yamasaki, H.; Fujisaki, S.; Kondo, M.; Okamoto, T. Chem. Lett.
1987, 2109–2112. (c) Baird, W. C.; Surridge, J. H. J. Org. Chem.
1970, 35, 3436–3442.
23. Crisp, G. T.; Turner, P. D.; Stephens, K. A. J. Organomet.
Chem. 1998, 570, 219–224.
24. Lan, A. J. Y.; Heuckeroth, R. O.; Mariano, P. S. J. Am. Chem.
Soc. 1987, 109, 2738–2745.
25. Austin, W. B.; Billow, N.; Kelleghan, W. J.; Lau, K. S. Y. J.
Org. Chem. 1981, 46, 2280–2286.
26. Takalo, H.; Kankare, J.; Hanninen, E. Acta Chem. Scand.
Ser. B 1988, B42, 448–454.
27. Barluenga, J.; Gonzalez, J. M.; Garcia-Martin, M. A.; Campos,
P. J.; Asensio, G. J. Chem. Soc., Chem. Commun. 1992,
1016–1017.
13. Kunesh, N.; Miet, C.; Poisson, J. Tetrahedron Lett. 1987, 28,
3569–3572.