The palladium-catalysed copper-free Sonogashira coupling of isoindoline nitroxides: A convenient route to robust profluorescent carbon-carbon frameworks

Article abstract of DOI:10.1039/b806963h

A series of novel acetylene-substituted isoindoline nitroxides were synthesised via palladium-catalysed copper-free Sonogashira coupling. These results demonstrate that the Sonogashira reaction is suitable for the generation of a wide range of aryl nitrox

Full text of DOI:10.1039/b806963h

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The palladium-catalysed copper-free Sonogashira coupling of isoindoline
nitroxides: a convenient route to robust profluorescent carbon–carbon
frameworks†
Daniel J. Keddie, Kathryn E. Fairfull-Smith and Steven E. Bottle*
Received 24th April 2008, Accepted 4th June 2008
First published as an Advance Article on the web 3rd July 2008
DOI: 10.1039/b806963h
A series of novel acetylene-substituted isoindoline nitroxides were synthesised via palladium-catalysed
copper-free Sonogashira coupling. These results demonstrate that the Sonogashira reaction is suitable
for the generation of a wide range of aryl nitroxides of expanded structural variety. The novel
aryl-iodide containing nitroxide, 5-iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl, 3, was a key
intermediate for this coupling, giving acetylene-substituted isoindoline nitroxides in high yield.
Subsequent reaction of the deprotected ethynyl nitroxide 12 with iodinated polyaromatics furnished
novel aromatic nitroxides with extended-conjugation. Such nitroxides have been described as
profluorescent, as their quantum yields are significantly lower than those of the corresponding
diamagnetic derivatives. The quantum yields of the naphthyl- and phenanthryl-acetylene isoindoline
nitroxides (13 and 14) were found to be ∼200-fold and ∼65-fold less than the non-radical
methoxyamine derivatives (23 and 24). Ethyne- and butadiyne-linked nitroxide dimers could also be
synthesised by this cross coupling methodology.
and a base.16 Cyclic amines are most commonly employed, as
they often lead to enhanced yields in comparison to simple
alkylamines.17
Introduction
Aryl-acetylenes are common precursors in the synthesis of natural
products, pharmaceuticals and organic molecular materials.1 Since
the initial investigations in 1975 by Cassar,2 Heck and Dieck,3 and
Sonogashira et al.,4 the Pd-catalysed alkynylation reaction (now
often referred to as the Sonogashira reaction) has proven to be a
convenient and frequently utilised method for the synthesis of aryl-
acetylenes.5 Whilst aryl-acetylenes are accessible via several Pd-
catalysed cross coupling methodologies such as Stille (Sn), Suzuki
(B) and Negishi (Zn) couplings,1 the Sonogashira reaction remains
attractive because the generation of alkynyl-organometallics is not
required prior to the coupling reaction. Rather, with respect to
the traditional Sonogashira reaction, a Cu-acetylide is formed
in situ from a Cu(I) co-catalyst. The use of alkylamines, such as
triethylamine, as the solvent is commonplace since these also serve
as a base to remove the hydrogen halide (HX) generated from
the reaction.5 The Cu(I) salts commonly used in Sonogashira
couplings are also known to catalyse the homocoupling of
terminal alkynes in the presence of Pd catalysts.6–9 These are
often observed as unwanted side reactions when coupling to less
activated aryl-halides,10 and copper-free Sonogashira coupling has
been employed to address this.6,10–15 The nature of the amine is
critical, as it performs multiple roles in the coupling reaction,
including accelerating oxidative insertion and acting as a ligand
Although Sonogashira couplings to t-butylphenyl,18,19
nitronyl19–21 and pyrroline22 nitroxides have been described, these
reactions are often performed on somewhat activated starting
materials. To date, little has been reported on Sonogashira
reactions using more deactivated aromatic halogenated nitroxides,
such as the isoindolines, as coupling partners.
Despite possessing some advantages over commercially avail-
able nitroxides, including structural rigidity, superior EPR
linewidths23–26 and enhanced thermal and chemical stability,27 ap-
plications of the isoindoline class of nitroxides have been limited, in
part, by a lack of structural variation. Expansion of the structural
diversity of the isoindoline nitroxides is particularly important
with regards to the generation of extended conjugated systems
that possess substantial (masked) fluorescence. These compounds
possess interesting fluorescence properties as quenching of the
fluorophore excited state, via enhanced intersystem crossing, by
the unpaired electron of the nitroxide makes these nitroxide–
fluorophore hybrids profluorescent.28,29 Such profluorescent ni-
troxides are able to detect reactive species by radical scavenging
or by redox activity as indicated by an increase in fluorescence
generated by the diamagnetic derivatives, such as the alkoxyamine
or hydroxylamine.30–33
Herein we report the first Sonogashira couplings performed
on the isoindoline class of nitroxides. The syntheses of two
novel profluorescent acetylene-linked nitroxides incorporating
naphthalene and phenanthrene fluorophores are detailed and their
fluorescent properties reported. Furthermore, the synthesis of two
novel acetylene-linked dinitroxides arising from coupling of the
terminal acetylene nitroxide is described.
ARC Centre of Excellence for Free Radical Chemistry and Biotechnology,
Queensland University of Technology, Brisbane 4001, Australia. E-mail:
s.bottle@qut.edu.au
† Electronic supplementary information (ESI) available: Scheme and
full details of experimental conditions attempted for the Sonogashira
couplings of halogenated isoindoline nitroxides 1–3 and alkynes 8–10.
See DOI: 10.1039/b806963h
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3135–3143 | 3135
©

View Article Online
Scheme 1 Sonogashira coupling of isoindoline nitroxides.
The coupling reactions between (trimethylsilyl)acetylene 8 and
the bromo nitroxide 1 or the nitro-bromo nitroxide 2, utilis-
ing the aerobic copper-free conditions of Li et al.6 (2 mol%
Pd(OAc)2, 3 equiv. DABCO, MeCN, air, 50 ◦C) gave trace
amounts of both the (trimethylsilyl)acetylene nitroxide 4 and the
nitro-(trimethylsilyl)acetylene nitroxide 5, which were observed
by GCMS of the crude reaction mixture. When performed at
80 ◦C in air, the yields did not increase markedly, whilst under
an argon atmosphere at 80 ◦C the yields could be increased
to 5% and 9% for 4 and 5 respectively (see entries 5 and
6, Table 1). Attempts to couple 2-methyl-3-butyn-2-ol 9 and
phenylacetylene 10 under the same conditions gave only trace
amounts of the desired compounds. Further attempts to optimise
the bromo coupling, including increasing the catalyst loadings
and using Heck-type conditions did not improve the yield of
the reaction. Additional equivalents of (trimethylsilyl)acetylene
8 only improved the reaction slightly (entry 7), whilst an increased
reaction temperature, in MeCN or DMF, did not increase the yield
of the desired product, with the DMF reactions failing to produce
any of the desired product.
Results and discussion
Synthesis of novel nitroxides via Pd-catalysed Sonogashira
coupling
Recently, we have shown that the Pd-catalysed Heck coupling can
be successfully performed on brominated isoindoline nitroxides,34
although more vigorous conditions than commonly employed are
required to obtain acceptable yields. With this result in hand, we
first attempted Sonogashira couplings with the bromo nitroxide
1 (Scheme 1), using the typical conditions of Pd(PPh3)2Cl2–CuI
as the catalyst and triethylamine as the solvent/base.35 None of
the targeted products were obtained using these conditions when
attempting to couple (trimethylsilyl)acetylene 8 or phenylacetylene
10 to the bromo nitroxide 1 at either room temperature or in
refluxing triethylamine (see entries 1–4, Table 1). Instead only
starting material 1 and the homocoupled alkynes (butadiynes)
could be isolated from the reaction mixture. The presence of
CuI is known to disfavour the Sonogashira cross coupling of less
active aryl halides,6 promoting the homocoupling of the acetylene
compounds. Nitration of the bromo nitroxide 1, with HNO3–
Due to the low reactivity of the brominated isoindoline ni-
troxides towards palladium-catalysed reactions, a limitation we
previously encountered whilst investigating Heck couplings,34 we
investigated the use of the iodo nitroxide30 3 to improve the viability
of the reaction. Aryl-iodides are known to undergo oxidative
24
H2SO4 in AcOH gave the nitro-bromo nitroxide 2 in excellent
yield (95%). The attempted coupling of (trimethylsilyl)acetylene
8 with the nitro-bromo compound 2, with presumably reduced
electron density, still only yielded the homocoupled acetylenes.
Table 1 Sonogashira couplings of halogenated isoindoline nitroxides and alkynes
Entry
Nitroxide
Alkyne
Catalyst system and solvent
Conditions
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
1
3
3
3
8 (1.2 equiv.)
10 (2 equiv.)
8 (1.2 equiv.)
10 (2 equiv.)
8 (5 equiv.)
8 (5 equiv.)
8 (20 equiv.)
8 (5 equiv.)
9 (5 equiv.)
10 (5 equiv.)
Pd(PPh3)2Cl2 (2 mol%), CuI (0.5 mol%), Et3N
Pd(PPh3)2Cl2 (2 mol%), CuI (10 mol%), Et3N
Pd(PPh3)2Cl2 (2 mol%), CuI (0.5 mol%), Et3N
Pd(PPh3)2Cl2 (2 mol%), CuI (10 mol%), Et3N
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
rt, Ar, 72 h
rt, Ar, 96 h
4
7
4
7
4
5
4
4
6
7
0
0
0
0
5
90 ◦C, Ar, 72 h
90 ◦C, Ar, 96 h
80 ◦C, Ar, 72 h
80 ◦C, Ar, 72 h
80 ◦C, Ar, 72 h
80 ◦C, Ar, 24 h
80 ◦C, Ar, 24 h
80 ◦C, Ar, 24 h
9
8a
92
78
96
10
a Yield determined by HPLC, product not isolated.
3136 | Org. Biomol. Chem., 2008, 6, 3135–3143
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
addition more readily in Pd-catalysed couplings.36 Indeed, in this
case, the coupling of (trimethylsilyl)acetylene 8 with iodo nitroxide
3 (2 mol% Pd(OAc)2, 3 equiv. DABCO, MeCN, argon, 80 ◦C,
24 h), gave the (trimethylsilyl)acetylene nitroxide 4 in an excellent
yield (92%) (see entry 8, Table 1), although the product was
difficult to separate from the starting material 3 using standard
chromatography. By comparison the bromo nitroxide 1 gave a poor
yield of 4 (5%) using the same reaction conditions. Reaction of the
iodo nitroxide 3 with 2-methyl-3-butyn-2-ol 9 and phenylacetylene
10 gave the desired acetylene nitroxides 6 and 7, with yields of
78% and 96% respectively (see entries 9 and 10, Table 1). The
reduced yield of the dimethyl propargyl alcohol nitroxide 6 can
be attributed to a competing cyclotrimerisation reaction,37 which
gives a substituted 3-benzylidene-2,3-dihydrofurane nitroxide 11
as an undesired side product (detected by GCMS of the reaction
mixture).
Scheme 2 Synthesis of acetylene nitroxide 12. Reagents and conditions:
(a) 4, 0.5 M KOH, MeOH, rt, 1 h (90 %) ; (b) 6, KOH (8 equiv.), toluene,
110 ◦C, 1 h (88 %).
The Sonogashira coupling of the acetylene nitroxide 12 with
1-iodonaphthalene 17 (2 mol% Pd(OAc)2, 3 equiv. DABCO,
MeCN, Ar, 80 ◦C, 4 h) gave the naphthylacetylene nitroxide
13 (Scheme 3) in high yield (78%) (see entry 1, Table 2). Due
to the electron deficiency of 1-iodonaphthalene 17, the reaction
rate was significantly increased (complete conversion within 4 h)
compared with the coupling reactions performed on the iodo
nitroxide 3 (cf . 24 h). Similar results were obtained using 9-
iodophenanthrene 18 as the aryl-halide coupling partner, giving
the phenanthrylacetylene nitroxide 14 in 90% yield within 4 h
(entry 2, Table 2). Although the homocoupled side product, a
butadiyne-linked nitroxide dimer 16, can be detected by TLC of
the reaction mixture, the high reactivity of both aryl halides 17
and 18, ensured that 16 was only formed in trace amounts and
could be readily separated from the desired products.
Coupling of the iodo nitroxide 3 and the acetylene nitroxide
12 gave the targeted acetylene-linked dinitroxide 15, albeit in a
moderate yield of 36% (see entry 3, Table 2). The butadiyne-
linked nitroxide dimer 16 was again a side product of the reaction,
although due to the decrease in reactivity of the aryl-halide 3
(complete conversion 24 h), it was formed in larger amounts
(40%). The formation of the homocoupled product 16, and the
resulting decrease in the concentration of alkyne 12, may explain
the diminished yield of this reaction compared to those using aryl
halides 17 and 18.
Treatment of the (trimethylsilyl)acetylene nitroxide 4 with
aqueous KOH in MeOH gave the desired terminal alkyne nitroxide
12 in 90% yield (see Scheme 2a). Although this method resulted in
a high product yield, separation of the desired product 12 from the
starting material 4 proved troublesome on a preparative scale due
to the loss of band resolution when using greater loadings on the
silica gel columns. Thus, an alternative alkyne protecting group
was employed for the synthesis of the alkyne nitroxide 12.
Treatment of the dimethyl propargyl alcohol nitroxide 6 with
KOH in refluxing toluene gave the acetylene nitroxide 12 in
high yield (88%) (see Scheme 2b). The presence of the polar
OH group facilitated the separation of traces of the protected
alkyne 6 from the product 12, which allowed 12 to be isolated in
larger quantities and in higher purity than when prepared from
the (trimethylsilyl)acetylene nitroxide 4. Therefore, this was the
synthetic route of choice for the synthesis of 12 for use in the
subsequent coupling reactions.
Scheme 3 Sonogashira and Eglinton couplings with alkyne nitroxide 12.
The Royal Society of Chemistry 2008 Org. Biomol. Chem., 2008, 6, 3135–3143 | 3137
This journal is
©

View Article Online
Table 2 Sonogashira and Eglinton couplings of alkyne nitroxide 12
Entry
Aryl halide
Reagents
Conditions
Product
Isolated yield (%)
1
2
3
4
17
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Pd(OAc)2 (2.5 mol%), DABCO (3 equiv.), MeCN
Cu(OAc)2 (1.5 equiv.), MeOH, pyridine
80 ◦C, Ar, 4 h
80 ◦C, Ar, 4 h
80 ◦C, Ar, 24 h
reflux, air, 1 h
13
14
15
16
78
90
36
91
18
3
N/A
The butadiyne nitroxide dimer 16, obtained as a side product
in the Sonogashira reaction, could be selectively synthesised via
Eglinton oxidative coupling. Refluxing the alkyne nitroxide 12 in
pyridine–methanol with Cu(OAc)2 (1.5 equiv.) gave the butadiyne-
linked nitroxide dimer 16 in excellent yield (91%).
nitroxide 14 and its methoxyamine analogue 24 (Fig. 2) reveals
a substantial differential in fluorescence intensity. A measure of
the fluorescence suppression of the naphthyl and phenanthryl
nitroxides 13 and 14 respectively can be attained by comparison
of the quantum yields.
Synthesis of methoxyamines via radical trapping
Methoxyamine analogues 19–26 of the acetylene substituted
nitroxides 4, 6, 7 and 12–16 were prepared following the previously
published literature procedure.34 Reaction of the nitroxides 4, 6, 7
and 12–16 with methyl radicals (formed using Fenton chemistry
by reaction of FeSO4·7H2O with H2O2 in DMSO) gave the desired
methoxyamine adducts in moderate to high yields (31–82%) (see
Scheme 4 and Table 3). Unlike the nitroxide precursors, the
methoxyamines 19–26 can be analysed by NMR spectroscopy as
the paramagnetic centre is no longer present.
Fig. 1 Fluorescence spectra of 13 (---) and 23 ( ) excited at 320 nm in
cyclohexane normalised to 1 lM.
Quantum yields of the nitroxides (13 and 14) and the
methoxyamines (23 and 24) were calculated using anthrancene
(UF = 0.36, in cyclohexane) as a standard. As expected, the
quantum yields of the naphthyl 23 (UF = 0.83) and phenanthryl
24 (UF = 0.26) methoxyamines were significantly larger than
Scheme 3 Synthesis of methoxyamines 19–26. Reagents and Conditions:
(a) FeSO4·7H2O, H2O2, DMSO, rt, 1 h (31–82%).
the analogous nitroxides 13 (UF = 4.0 × 10−3) and 14 (UF
=
Fluorescence
4.0 × 10−3). The nitroxides 13 and 14 and the phenanthryl
methoxyamine 24 have quantum yields similar to related nitroxides
and methoxyamines that have been previously reported.32 Notably,
A comparison of the fluorescence spectra of naphthyl nitroxide
13 and its methoxyamine derivative 23 (Fig. 1) and phenanthryl
Table 3 Isolated yields of methoxyamine derivatives of the nitroxides synthesised
Entry
R =
Nitroxide starting material
Methoxyamine product
Isolated yield (%)
1
2
3
4
5
6
7
Me3Si-
(CH3)2HOC-
Ph-
4
19
20
21
22
23
24
25
79
55
62
76
64
82
75
6
7
H-
12
13
14
15
Naphthyl-
Phenanthryl-
8
16
26
31
3138 | Org. Biomol. Chem., 2008, 6, 3135–3143
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
formation of the methoxyamines. This Sonogashira cross coupling
methodology is currently being investigated for the synthesis
of other acetylene extended isoindoline nitroxide systems for a
variety of applications. These results will be reported in due
course.
Experimental
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
400 spectrometer in CDCl3. Coupling constants are given in Hz. IR
spectra were recorded on a Nicolet 870 Nexus Fourier transform
infrared spectrometer equipped with a DTGS TEC detector and
an ATR objective. High accuracy mass spectra were recorded
using a Micromass autospec double focusing magnetic sector mass
spectrometer (EI+ spectra). Formulations were calculated in the
elemental analysis programs of Mass Lynx 4.0 or Micromass
Opus 3.6. Spectrofluorimetry was performed on a Varian Cary
Eclipse fluorescence spectrophotometer equipped with a standard
multicell Peltier thermostatted sample holder. All fluorescence
measurements were performed in cyclohexane and quantum yields
were calculated using anthracene (UF = 0.36) as the standard.
Reversed-phase preparatory HPLC was performed on an Agilent
1200 Series prep-HPLC using an Agilent Semi-Prep-C18 (21.2 ×
150 mm, 10 lm) column. Melting points were measured on
a Gallenkamp variable temperature apparatus by the capillary
method. Microanalyses were performed by the Microanalytical
Service, Department of Chemistry, University of Queensland.
5-Bromo-1,1,3,3-tetramethylisoindolin-2-yloxyl38 1 and 5-iodo-
1,1,3,3-tetramethylisoindolin-2-yloxyl30 3 were synthesised by the
literature procedures.
Fig. 2 Fluorescence spectra of 14 (---) and 24 ( ) excited at 320 nm in
cyclohexane normalised to 1 lM.
the presence of the heterocyclic ring does not impact significantly
on the fluorescence quantum yield. To test this we prepared the
unsubstituted parent compound 1-(phenylethynyl)naphthalene14
27 and recorded its quantum yield. After preparation by coupling
1-iodonaphthalene and phenylacetylene, the quantum yield (UF)
of 1-(phenylethynyl)naphthalene 27 in cyclohexane was found to
be quite similar (0.80) to the naphthylacetylene methoxyamine 23
(0.83).
5-Nitro-6-bromo-1,1,3,3-tetramethylisoindolin-2-yloxyl (2)
Conclusion
To an ice–water cooled solution of 5-bromo-1,1,3,3-tetra-
methylisoindolin-2-yloxyl 1 (200 mg, 0.74 mmol) in glacial acetic
acid (0.6 mL) was added conc. H2SO4 (1.15 mL), followed by
conc. HNO3 (0.3 mL). The resultant solution was heated at
40 ◦C for 4 h, after which the reaction was quenched by the
slow addition of NaOH (5 M, 10 mL) and extracted with CHCl3
(3 × 30 mL). The combined organics were washed with water
(30 mL), dried (Na2SO4) and the solvent removed under reduced
pressure. Recrystallisation from MeCN gave orange needles of 5-
nitro-6-bromo-1,1,3,3-tetramethylisoindolin-2-yloxyl 2 (220 mg,
The first examples of palladium-catalysed Sonogashira cross cou-
pling reactions performed on isoindoline nitroxides are reported.
Attempts to couple the electron rich bromo nitroxide 1 with
substituted alkynes under copper or copper-free Sonogashira
conditions were unsuccessful due to the low reactivity of the
brominated isoindoline nitroxide 1. The more reactive iodo
nitroxide 3 underwent palladium-catalysed Sonogashira couplings
with substituted alkynes under copper-free conditions, to give
acetylene nitroxides (4, 6 and 7) in good yield (78–96%). The
terminal alkyne nitroxide 12 could be prepared preparatively
by cleavage of the 2-methylpropan-2-ol group of 6 with base.
Subsequent reaction of the ethynyl nitroxide 12 with iodinated
polyaromatics under copper-free Sonogashira conditions gave
nitroxides (13 and 14) possessing extended conjugation in high
yield (78–90%). Notably, the electron deficient nature of the
iodinated polyaromatics significantly increased the rate of the
reaction compared with use of the iodo nitroxide 3. Ethyne- and
butadiyne-linked dinitroxides (15 and 16) could also be formed in
moderate yield (36–40%) using this cross coupling approach, but
could be raised to 91% using Eglinton conditions. Examination
of the fluorescent properties of the profluorescent nitroxides (13
and 14) and their corresponding diamagnetic derivatives (23
and 24) revealed a significant suppression of fluorescence for
the nitroxide containing compounds, which was restored upon
◦
0.70 mmol, 95%); mp 246–248 C (decomp.); mmax (ATR-FTIR):
3032 (aryl CH), 2979 and 2931 (alkyl CH), 1577 and 1530 (NO2),
1473 and 1463 (aryl C–C), 1430 (NO•) cm−1; +EI MS found M+
•
313.0187 (0.3 ppm from calc. mass of C12H14BrN2O3 ): m/z 313
(M+, 63%), 298 (47), 283 (69), 268 (100), 143 (87), 128 (62).
Sonogashira reactions performed using halogenated isoindoline
nitroxides (1–3)
The general procedure for the synthesis of substituted acetylene
nitroxides 4–7 is given below. The synthesis of the (trimethylsi-
lyl)acetylene nitroxide 4 from the bromo nitroxide 1 is used as
a representative example. Alterations of the procedure for the
synthesis of 4 using iodo nitroxide 3 as starting material and
acetylene nitroxides 5–7 are also given below.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3135–3143 | 3139
©

View Article Online
•
5-[2-(Trimethylsilyl)ethynyl]-1,1,3,3-
tetramethylisoindolin-2-yloxyl (4)
2.93 mmol, 78%); (found: C, 74.3; H, 8.3; N, 5.0; C17H22NO2
requires C, 75.0; H, 8.1; N, 5.1%); mmax (ATR-FTIR): 3387 (OH),
≡
2976 and 2930 (alkyl CH), 2165 (C C), 1490 and 1453 (aryl
5-Iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl
3
(59
mg,
C–C), 1431 (NO•) cm−1; +EI MS found M+ 272.1654 (1.3 ppm
0.186 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (62.5 mg,
0.557 mmol, 3 equiv.) and Pd(OAc)2 (1 mg, 2.5 mol%) were
dissolved in dry MeCN (1 mL). (Trimethylsilyl)acetylene 8
(131 lL, 91 mg, 0.927 mmol, 5 equiv.) was added and the
mixture heated at 80 ◦C under argon in a sealed Schlenk vessel
for 24 h. The solvent was removed under reduced pressure and
the residue taken up in CHCl3 (∼1 mL). Purification of the
resulting solution by column chromatography (SiO2, eluant: 10%
EtOAc, 90% n-hexane) gave 5-[2-(trimethylsilyl)ethynyl]-1,1,3,3-
tetramethylisoindolin-2-yloxyl 4 as a yellow–orange gum (49 mg,
0.171 mmol, 92%); (found: C, 70.7; H, 8.5; N, 4.7; C17H24SiNO•
requires C, 71.3; H, 8.4; N, 4.9%); mmax (ATR-FTIR): 2972 and
•
from calc. mass of C17H22NO2 ): m/z 272 (M+, 100%), 257 (95),
242 (92), 227 (87).
5-[2-(Phenyl)ethynyl]-1,1,3,3-tetramethylisoindolin-2-yloxyl (7)
5-Iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl
3
(59
mg,
0.186 mmol), DABCO (62.5 mg, 0.557 mmol, 3 equiv.),
Pd(OAc)2 (1 mg, 2.5 mol%), phenylacetylene 10 (102 lL,
95 mg, 0.930 mmol, 5 equiv.) and MeCN (1 mL) were treated
as described above. Column chromatography (SiO2, eluant:
10% EtOAc, 90% n-hexane) gave 5-[2-(phenyl)ethynyl]-1,1,3,3-
tetramethylisoindolin-2-yloxyl 7 as a yellow–orange solid (52 mg,
0.179 mmol, 96%); mp 108–112 ◦C; (found: C, 82.0; H, 6.9; N, 4.7;
C20H20NO• requires C, 82.7; H, 6.9; N, 4.8%); mmax (ATR-FTIR):
≡
2928 (alkyl CH), 2154 (C C), 1487 and 1465 (aryl C–C), 1431
(NO•) cm−1; +EI MS found M+ 286.16265 (0.25 ppm from calc.
mass of C17H24SiNO•): m/z 286 (M+, 12%), 271 (21), 256 (100),
241 (79), 225 (32).
≡
3047 (aryl CH) 2977 and 2928 (alkyl CH), 2214 (C C), 1487 and
1465 (aryl C–C), 1431 (NO•) cm−1; +EI MS found M+ 290.1542
(1.0 ppm from calc. mass of C20H20NO•): m/z 290 (M+, 90%), 275
(75), 260 (100), 245 (50), 215 (40).
Alternate synthesis of 5-[2-(trimethylsilyl)ethynyl]-1,1,3,3-
tetramethylisoindolin-2-yloxyl (4)
5-Bromo-1,1,3,3-tetramethylisoindolin-2-yloxyl
1
(50 mg,
0.186 mmol), DABCO (62.5 mg, 0.557 mmol, 3 equiv.), Pd(OAc)2
(1 mg, 2.5 mol%), (trimethylsilyl)acetylene 8 (131 lL, 91 mg,
0.927 mmol, 5 equiv.) and MeCN (1 mL) were treated as
described above. Column chromatography (SiO2, eluant: 10%
EtOAc, 90% n-hexane) gave 5-[2-(trimethylsilyl)ethynyl]-1,1,3,3-
tetramethylisoindolin-2-yloxyl 4 (3 mg, 0.010 mmol, 5%). GCMS
analysis showed that the product was identical to that reported
above.
5-Ethynyl-1,1,3,3-tetramethylisoindolin-2-yloxyl (12)
5-(3-Hydroxy-3-methyl)butynyl-1,1,3,3-tetramethylisoindolin-2-
yloxyl 6 (478 mg, 1.76 mmol) was dissolved in dry toluene
(320 mL). Solid KOH was added (0.8 g, 14.3 mmol, 8 equiv.)
and the mixture refluxed for 1 h. The dark brown suspension
was washed with water (3 × 200 mL) and brine (200 mL), dried
(Na2SO4) and the solvent removed under reduced pressure. The
residue was taken up in CHCl3 (∼5 mL) and purified by column
chromatography (SiO2, eluant: 30% EtOAc, 70% n-hexane) to
give 5-ethynyl-1,1,3,3-tetramethylisoindolin-2-yloxyl 12 as a pale
yellow crystalline solid (331 mg, 1.54 mmol, 88%); mp 126–128 ◦C;
5-[2-(Trimethylsilyl)ethynyl]-6-nitro-1,1,3,3-
tetramethylisoindolin-2-yloxyl (5)
5-Nitro-6-bromo-1,1,3,3-tetramethylisoindolin-2-yloxyl 2 (58 mg,
0.186 mmol), DABCO (62.5 mg, 0.557 mmol, 3 equiv.), Pd(OAc)2
(1 mg, 2.5 mol%), (trimethylsilyl)acetylene 8 (131 lL, 91 mg,
0.927 mmol, 5 equiv.) and MeCN (1 mL) were treated as
described above. Column chromatography (SiO2, eluant: 10%
EtOAc, 90% n-hexane) gave 5-[2-(trimethylsilyl)ethynyl]-6-nitro-
1,1,3,3-tetramethylisoindolin-2-yloxyl 5 as a yellow–orange solid
(5 mg, 0.016 mmol, 9%); mp 144–147 ◦C; mmax (ATR-FTIR): 3045
≡
mmax (ATR-FTIR): 3196 ( CH), 2978 and 2929 (alkyl CH), 2097
•
−1
≡
(C C), 1487 and 1464 (aryl C–C), 1428 (NO ) cm ; +EI MS
found M+ 214.1235 (1.5 ppm from calc. mass of C14H16NO•): m/z
214 (M+, 86%), 199 (90), 184 (100), 169 (84), 152 (53).
Alternate synthesis of 5-ethynyl-1,1,3,3-
tetramethylisoindolin-2-yloxyl (12)
≡
(aryl CH), 2972 and 2927 (alkyl CH), 2150 (C C), 1573 and
1523 (NO2), 1480 and 1467 (aryl C–C), 1431 (NO•) cm−1; +EI MS
A solution of 5-[2-(trimethylsilyl)ethynyl]-1,1,3,3-tetramethyl-
isoindolin-2-yloxyl 4 (113 mg, 0.39 mmol) was dissolved in
degassed MeOH (2.1 mL). Aqueous KOH was added (50 lL,
0.5 M) and the solution was stirred at room temperature for 1 h.
The reaction mixture was treated with water (50 mL), extracted
with Et2O (2 × 50 mL), dried (Na2SO4) and the solvent was
removed under reduced pressure to give the 5-ethynyl-1,1,3,3-
tetramethylisoindolin-2-yloxyl 12 and a trace amount of unreacted
starting material 4, which were inseparable by SiO2 column
chromatography. Reversed-phase prep-HPLC (50% THF, 50%
H2O) gave 5-ethynyl-1,1,3,3-tetramethylisoindolin-2-yloxyl 12 as a
yellow crystalline solid (78 mg, 0.37 mmol, 90%). GCMS analysis
and mp comparison showed that the product was identical to that
reported above.
•
found M+ 331.14808 (0.85 ppm from calc. mass of C17H23SiN2O3 ):
m/z 331 (M+, 100%), 316 (43), 301 (52), 286 (22).
5-(3-Hydroxy-3-methyl)butynyl-1,1,3,3-tetramethylisoindolin-
2-yloxyl (6)
5-Iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl
3
(1.18
g,
3.73 mmol), DABCO (1.25 g, 11.14 mmol, 3 equiv.), Pd(OAc)2
(20 mg, 2.5 mol%), 2-methyl-3-butyn-2-ol 9 (1.82 mL, 1.60 g,
19 mmol, 5 equiv.) and MeCN (20 mL) were treated as described
above. Column chromatography (SiO2, eluant: 50% EtOAc,
50% n-hexane) gave 5-(3-hydroxy-3-methyl)butynyl-1,1,3,3-
tetramethylisoindolin-2-yloxyl 6 as a brown–orange oil (797 mg,
3140 | Org. Biomol. Chem., 2008, 6, 3135–3143
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
••
Sonogashira reactions performed using ethynyl nitroxide (12)
mass of C26H30N2O2 ): m/z 402 (M+, 95%), 387 (40), 372 (50),
357 (100), 342 (83).
The procedure for the synthesis of substituted acetylene nitroxides
13–15 is detailed below. The synthesis of the naphthyl-acetylene
nitroxide 13 is used as an example. Alterations of the procedure for
the synthesis of acetylene nitroxides 14 and 15 are also described
below.
1,4-Bis-[5,5ꢀ-(1,1,3,3-tetramethylisoindolin-2-yloxylyl)]-1,3-
butadiyne (16)
5-Ethynyl-1,1,3,3-tetramethylisoindolin-2-yloxyl 12 (50 mg,
0.233 mmol) and Cu(OAc)2 (65 mg, 0.358 mmol, 1.5 equiv.),
were dissolved in MeOH (0.5 mL) and pyridine (0.5 mL) and
the resultant mixture was refluxed for 1 h. H2SO4 (conc.) was
added to the resultant mixture until a suspension formed, which
was subsequently extracted with DCM (3 × 20 mL), washed with
H2O (20 mL), dried (Na2SO4) and the solvent removed under re-
duced pressure to give 1,4-bis-[5,5ꢀ-(1,1,3,3-tetramethylisoindolin-
2-yloxylyl)]-1,3-butadiyne 16 as an orange crystalline solid (45 mg,
0.105 mmol, 91%); mp 183–185 ◦C (decomp.); mmax (ATR-FTIR):
5-[2-(1-Naphthyl)ethynyl]-1,1,3,3-tetramethylisoindolin-2-yloxyl
(13)
1-Iodonaphthalene 17 (28.3 lL, 49 mg, 0.193 mmol), DABCO
(62.5 mg, 0.557 mmol,
3 equiv.) and Pd(OAc)2 (1 mg,
2.5 mol%) were dissolved in dry MeCN (1 mL). 5-Ethynyl-
1,1,3,3-tetramethylisoindolin-2-yloxyl 12 (50 mg, 0.233 mmol,
1.2 equiv.) was added and the mixture heated at 80 ◦C under
argon for 4 h. The solvent was removed under reduced pressure
and the residue taken up in CHCl3 (∼1 mL). Purification of the
resulting solution by column chromatography (SiO2, eluant: 10%
EtOAc, 90% n-hexane) gave 5-[2-(1-naphthyl)ethynyl]-1,1,3,3-
tetramethylisoindolin-2-yloxyl 13 as an orange solid (51 mg,
0.151 mmol, 78%); mp 145–148 ◦C; mmax (ATR-FTIR): 3055 (aryl
≡
3046 (aryl CH), 2975 and 2928 (alkyl CH), 2150 (C C), 1487 and
1463 (aryl C–C), 1430 (NO•) cm−1; +EI MS found M+ 426.2307
••
(0.1 ppm from calc. mass of C28H30N2O2 ): m/z 426 (M+, 40%),
411 (28), 396 (35), 381 (100), 366 (33).
Synthesis of methoxyamines (19–24)
≡
CH), 2972 and 2924 (alkyl CH), 2211 (C C), 1488 and 1460 (aryl
C–C), 1430 (NO•) cm−1; +EI MS found M+ 340.1701 (0.1 ppm
from calc. mass of C24H22NO•): m/z 340 (M+, 84%), 325 (60), 310
(100), 295 (32), 265 (35).
A general procedure for the synthesis of methoxyamines 19–24 is
shown below. For the synthesis of dimethoxyamines 25 and 26 the
amounts of all reagents were doubled.
General procedure
5-[2-(9-Phenanthryl)ethynyl]-1,1,3,3-tetramethylisoindolin-2-
yloxyl (14)
To a solution of acetylene-substituted nitroxide (0.077 mmol) and
FeSO4·7H2O (0.154 mmol, 2 equiv.) in DMSO (2.6 mL) was added
H2O2 (30%, 18 lL). The reaction mixture was stirred under argon
at room temperature for 1.5 h. NaOH (1 M) was added and the
resulting solution extracted with Et2O. The organic phase was
washed with H2O and dried (Na2SO4). Removal of the solvent
under reduced pressure gave the crude methoxyamine. Subsequent
purification was achieved by column chromatography (see below
for specific conditions).
9-Iodophenanthrene 18 (59 mg, 0.194 mmol), DABCO (62.5 mg,
0.557 mmol, 3 equiv.), Pd(OAc)2 (1 mg, 2.5 mol%), 5-ethynyl-
1,1,3,3-tetramethylisoindolin-2-yloxyl 12 (50 mg, 0.233 mmol,
1.2 equiv.) and MeCN (1 mL) were treated as described above. Col-
umn chromatography (SiO2, eluant: 10% EtOAc, 90% n-hexane)
gave 5-[2-(9-phenanthryl)ethynyl]-1,1,3,3-tetramethylisoindolin-
2-yloxyl 14 as an orange solid (52 mg, 0.179 mmol, 90%);
mp 175–178 ◦C; mmax (ATR-FTIR): 3070 (aryl CH), 2971 and
≡
2924 (alkyl CH), 2214 (C C), 1490 and 1451 (aryl C–C), 1430
5-[2-(Trimethylsilyl)ethynyl]-2-methoxy-1,1,3,3-
tetramethylisoindoline (19)
(NO•) cm−1; +EI MS found M+ 390.1857 (0.2 ppm from calc.
mass of C28H24NO•): m/z 390 (M+, 72%), 375 (45), 360 (100), 345
(25).
Yield: 18 mg, 0.061 mmol, 79%; chromatography: SiO2, 10%
EtOAc, 90% n-hexane; dH: 0.27 (9H, s, SiCH3) 1.43 (12H, br s,
CH3), 3.79 (3H, s, NOCH3), 7.04 (1H, dd, J 0.5 and 7.8 Hz, 7-H),
7.22 (1H, dd, J 0.5 and 1.4 Hz, 4-H), 7.36 (1H, dd, J 1.4 and
7.8 Hz, 6-H); dC: 0.0 (SiCH3) 30.3 (CH3), 65.5 (OCH3), 67.0 (alkyl
1,2-Bis-[5,5ꢀ-(1,1,3,3-tetramethylisoindolin-2-yloxylyl)]ethyne (15)
5-Iodo-1,1,3,3-tetramethylisoindolin-2-yloxyl
3
(61
mg,
0.193 mmol), DABCO (62.5 mg, 0.557 mmol, 3 equiv.), Pd(OAc)2
(1 mg, 2.5 mol%), 5-ethynyl-1,1,3,3-tetramethylisoindolin-2-
yloxyl 12 (50 mg, 0.233 mmol, 1.2 equiv.) and MeCN (1 mL) were
treated as described above and heated at 80 ◦C for 24 h. Column
chromatography (SiO2, eluant: 10% EtOAc, 90% n-hexane)
gave the desired 1,2-bis-[5,5ꢀ-(1,1,3,3-tetramethylisoindolin-2-
yloxylyl)]ethyne 15 and the homocoupled acetylene 1,4-bis-
[5,5ꢀ-(1,1,3,3-tetramethylisoindolin-2-yloxylyl)]-1,3-butadiyne 16.
Reversed-phase prep-HPLC (45% THF, 55% H2O) gave 1,2-
bis-[5,5ꢀ-(1,1,3,3-tetramethylisoindolin-2-yloxylyl)]ethyne 15 as a
yellow crystalline solid (28 mg, 0.070 mmol, 36%); mp 214–216 ◦C
(decomp.); mmax (ATR-FTIR): 3045 (aryl CH), 2972 and 2928
≡
≡
C*), 67.1 (alkyl C*), 93.3 (C C), 105.4 (C C), 121.5 (C-7), 121.8
(C-5), 125.2 (C-6), 131.2 (C-4), 145.3 (C-3a), 145.9 (C-7a).
5-(3-Hydroxy-3-methyl)butynyl-2-methoxy-1,1,3,3-
tetramethylisoindoline (20)
Yield: 12 mg, 0.042 mmol, 55%; chromatography: SiO2, 30%
EtOAc, 70% n-hexane; dH: 1.43 (12H, br s, CH3), 1.64 (6H, s,
CCCH3), 2.06 (1H br s, OH), 3.79 (3H, s, NOCH3), 7.04 (1H, dd,
J 0.6 and 7.8 Hz, 7-H), 7.18 (1H, dd, J 0.6 and 1.5 Hz, 4-H), 7.30
(1H, dd, J 1.5 and 7.8 Hz, 6-H); dC: 29.7 (CH3), 31.5 ( CCCH3),
65.5 ( CC*) 65.7 (OCH3), 67.0 (alkyl C*), 67.1 (alkyl C*), 82.4
(C C), 93.1 (C C), 121.4 (C-5), 121.5 (C-7), 124.9 (C-6), 130.8
(C-4), 145.4 (C-3a), 145.6 (C-7a).
≡
≡
≡
≡
≡
≡
(alkyl CH), 2207 (C C), 1496 and 1466 (aryl C–C), 1433
(NO•) cm−1; +EI MS found M+ 402.2306 (0.3 ppm from calc.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3135–3143 | 3141
©

View Article Online
ꢀ
ꢀ
≡
5-[2-(Phenyl)ethynyl]-2-methoxy-1,1,3,3-tetramethylisoindoline
(21)
(C C), 121.6 (C-5 and C-5 ), 122.1 (C-7 and C-7 ), 124.8 (C-6 and
C-6ꢀ), 130.8 (C-4 and C-4ꢀ), 145.4 (C-3a and C-3aꢀ), 145.5 (C-7a
and C-7aꢀ).
Yield: 15 mg, 0.048 mmol, 62%; chromatography: SiO2, 10%
EtOAc, 90% n-hexane; dH: 1.46 (12H, br s, CH3), 3.81 (3H, s,
NOCH3), 7.10 (1H, d, J 7.8 Hz, 7-H), 7.30 (1H, d, J 1.5 Hz,
4-H), 7.36 (3H, m, ArH), 7.43 (1H, dd, J 1.5 and 7.8 Hz, 6-H),
7.55 (2H, m, ArH); dC: 30.3 (CH3), 65.5 (OCH3), 67.1 (alkyl C*),
1,4-Bis-[5,5ꢀ-(2-methoxy-1,1,3,3-tetramethylisoindoline)]-1,3-
butadiyne (26)
≡
≡
67.2 (alkyl C*), 88.7 (C C), 89.7 (C C), 121.6 (C-7), 122.0 (C-
Yield: 11 mg, 0.024 mmol, 31%; chromatography: SiO2, 10%
EtOAc, 90% n-hexane; dH: 1.45 (24H, br s, CH3), 3.79 (6H, s,
NOCH3), 7.08 (2H, dd, J 0.5 and 7.8 Hz, 7-H), 7.28 (2H, dd, J
0.5 and 1.5 Hz, 4-H), 7.41 (2H, dd, J 1.5 and 7.8 Hz, 6-H); dC:
30.3 (CH3), 65.5 (OCH3), 67.0 (alkyl C*), 67.2 (alkyl C*), 73.4
≡
5), 123.4 (ArC-C ), 124.8 (C-6), 128.2 (ArC), 128.4 (ArC), 130.8
(C-4), 131.6 (ArC), 145.5 (C-3a), 145.6 (C-7a).
5-Ethynyl-2-methoxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (22)
ꢀ
ꢀ
≡
≡
(C C), 81.8 (C C), 120.6 (C-5 and C-5 ), 121.8 (C-7 and C-7 ),
125.8 (C-6 and C-6ꢀ), 131.7 (C-4 and C-4ꢀ), 145.6 (C-3a and C-3aꢀ),
146.7 (C-7a and C-7aꢀ).
Yield: 14 mg, 0.059 mmol, 76%; chromatography: SiO2, 10%
EtOAc, 90% n-hexane; dH: 1.45 (12H, br s, CH3), 3.07 (1H, s,
≡CH), 3.80 (3H, s, NOCH3), 7.08 (1H, dd, J 0.5 and 7.8 Hz,
7-H), 7.27 (1H, dd, J 0.5 and 1.4 Hz, 4-H), 7.40 (1H, dd, J 1.4
and 7.8 Hz, 6-H); dC: 30.3 (CH3), 65.4 (OCH3), 66.9 (alkyl C*),
1-(Phenylethynyl)naphthalene (27)14
≡
≡
67.1 (alkyl C*), 76.5 (C C), 83.9 (C C), 120.8 (C-5), 121.5 (C-7),
125.3 (C-6), 131.3 (C-4), 145.5 (C-3a), 146.2 (C-7a).
1-Iodonaphthalene 17 (57.6 lL, 100 mg, 0.393 mmol), DABCO
(130 mg, 1.200 mmol, 3 equiv.) and Pd(OAc)2 (2 mg, 2.5 mol%)
was dissolved in dry MeCN (1 mL). Phenylacetylene 10 (51.6 lL,
48 mg, 0.470 mmol, 1.2 equiv.) was added and the mixture heated at
80 ◦C under argon for 4 h. The solvent was removed under reduced
pressure and the residue taken up in CHCl3 (∼1 mL). Purification
of the resulting solution by column chromatography (SiO2, eluant:
10% EtOAc, 90% n-hexane) gave 1-(phenylethynyl)naphthalene 27
as a colourless oil (85 mg, 0.373 mmol, 95%); dH: 7.40–7.73 (8H,
m ArH), 7.80–7.92 (3H, m, ArH), 8.49–8.53 (1H, m, ArH); dC:
5-[2-(1-Naphthyl)ethynyl]-2-methoxy-1,1,3,3-
tetramethylisoindoline (23)
Yield: 17 mg, 0.049 mmol, 64%; chromatography: SiO2, 10%
EtOAc, 90% n-hexane; dH: 1.49 (12H, br s, CH3), 3.82 (3H, s,
NOCH3), 7.15 (1H, dd, J 0.5 and 7.8 Hz, 7-H), 7.40 (1H, dd, J
0.5 and 1.5 Hz, 4-H), 7.48 (1H, m, ArH), 7.56 (2H, m, ArH), 7.63
(1H, m, ArH), 7.78 (1H, dd, J 1.5 and 7.8 Hz, 6-H), 7.86 (1H,
m, ArH), 7.89 (1H, m, ArH), 8.46 (1H, m ArH); dC: 30.3 (CH3),
≡
65.5 (OCH3), 67.2 (alkyl C*), 67.3 (alkyl C*), 86.9 (C C), 94.6
≡
≡
87.6 (C C), 94.4 (C C), 121.0 (ArC), 123.5 (ArC), 125.4 (ArC),
126.3 (ArC), 126.5 (ArC), 126.9 (ArC), 128.4 (ArC), 128.5 (ArC),
128.5 (ArC), 128.9 (ArC), 130.5 (ArC), 131.8 (ArC), 133.3 (ArC),
133.3 (ArC). The NMR data was in agreement with that previously
reported.14
≡
≡
(C C), 121.0 (C-5), 121.7 (C-7), 122.2 (ArC-C ), 124.8 (C-6),
125.3 (ArC), 126.3 (ArC), 126.4 (ArC), 126.8 (ArC), 128.3 (ArC),
128.7 (ArC), 130.3 (ArC), 130.9 (C-4), 133.2 (ArC), 133.3 (ArC),
145.6 (C-3a), 145.8 (C-7a).
5-[2-(9-Phenanthryl)ethynyl]-2-methoxy-1,1,3,3-
tetramethylisoindoline (24)
Fluorescence quantum yield calculations
Yield: 26 mg, 0.063 mmol, 82%; chromatography: SiO2, 10%
EtOAc, 90% n-hexane; dH: 1.51 (12H, br s, CH3), 3.83 (3H, s,
NOCH3), 7.17 (1H, dd, J 0.6 and 7.8 Hz, 7-H), 7.44 (1H, dd, J 0.6
and 1.5 Hz, 4-H), 7.59 (1H, dd, J 1.5 and 7.8 Hz, ArH), 7.63 (1H,
m, ArH), 7.70 (1H, m, ArH), 7.74 (2H, m, ArH), 7.90 (1H, dd, J
1.5 and 7.8 Hz, 6-H), 8.11 (1H, s, ArH), 8.58 (1H, m, ArH), 8.70
(1H, m, ArH), 8.74 (1H, m, ArH); dC: 30.3 (CH3), 65.5 (OCH3),
Fluorescence quantum yield measurements were calculated using
cyclohexane as the solvent and anthracene (UF = 0.36) as the
standard. Stock solutions of naphthyl and phenanthryl com-
pounds 13, 14, 23, 24 and 27 (approximately 1 mg 100 mL−1,
measured accurately, exact concentrations listed below) were
diluted using analytical glassware to give four solutions of
decreasing concentration, ensuring that the UV–vis absorbance of
the highest concentration did not exceed 0.1 absorbance units at
the fluorescence excitation wavelength (320 nm). The fluorescence
detector voltage was set at 480 V for naphthalenes 13, 23 and 27
and 600 V for the phenanthrenes 14 and 24. The total fluorescence
emission was plotted against UV–vis absorbance to give a straight
line with gradient (m), which was ratioed against the anthracene
standard, giving the quantum yield (UF).
≡
≡
67.1 (alkyl C*), 67.2 (alkyl C*), 87.1 (C C), 94.3 (C C), 119.7
≡
(C-5), 121.8 (C-7), 122.1 (ArC-C ), 122.7 (ArC), 122.8 (ArC),
124.9 (C-6), 125.6 (ArC), 127.0 (ArC), 127.1 (ArC), 127.4 (ArC),
128.6 (ArC), 130.1 (ArC), 130.3 (ArC), 131.0 (C-4), 131.2 (ArC),
131.3 (ArC), 131.8 (ArC), 135.8 (ArC), 145.6 (C-3a), 145.9 (C-7a).
1,2-Bis-[5,5ꢀ-(2-methoxy-1,1,3,3-tetramethylisoindoline)]ethyne
(25)
Yield: 25 mg, 0.058 mmol, 75%; chromatography: SiO2, 10%
EtOAc, 90% n-hexane; dH: 1.46 (24H, br s, CH3), 3.80 (6H, s,
NOCH3), 7.09 (2H, dd, J 0.6 and 7.8 Hz, 7-H), 7.29 (2H, dd, J
0.6 and 1.5 Hz, 4-H), 7.42 (2H, dd, J 1.5 and 7.8 Hz, 6-H); dC:
30.3 (CH3), 65.5 (OCH3), 67.1 (alkyl C*), 67.2 (alkyl C*), 89.0
Anthracene (28)
Stock solution 28 (1.07 mg, 0.00600 mmol, 0.0600 mM). Diluted to
give solutions of 12.000, 9.600, 7.200 and 4.800 lM; m = 157765.
3142 | Org. Biomol. Chem., 2008, 6, 3135–3143
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
5-[2-(1-Naphthyl)ethynyl]-1,1,3,3-tetramethylisoindolin-2-yloxyl
(13)
6 J.-H. Li, Y. Liang and Y.-X. Xie, J. Org. Chem., 2005, 70, 4393–4396.
7 Q. Liu and D. J. Burton, Tetrahedron Lett., 1997, 38, 4371–4374.
8 Y. Nishihara, K. Ikegashira, K. Hirabayashi, J.-i. Ando, A. Mori and
T. Hiyama, J. Org. Chem., 2000, 65, 1780–1787.
Stock solution 13 (1.07 mg, 0.00314 mmol, 0.0314 mM). Diluted
to give solutions of 5.024, 3.768, 2.512 and 1.256 lM; m = 1896;
UF = 0.36 (1896/157765) = 0.004.
9 R. Rossi, A. Carpita and C. Bigelli, Tetrahedron Lett., 1985, 26, 523–
526.
10 N. E. Leadbeater and B. J. Tominack, Tetrahedron Lett., 2003, 44,
8653–8656.
11 C. Yi and R. Hua, J. Org. Chem., 2006, 71, 2535–2537.
12 T. Ljungdahl, K. Pettersson, B. Albinsson and J. Maartensson, J. Org.
Chem., 2006, 71, 1677–1687.
5-[2-(9-Phenanthryl)ethynyl]-1,1,3,3-tetramethylisoindolin-2-
yloxyl (14)
13 J.-H. Li, X.-D. Zhang and Y.-X. Xie, Synthesis, 2005, 804–808.
14 J. Cheng, Y. Sun, F. Wang, M. Guo, J.-H. Xu, Y. Pan and Z. Zhang,
J. Org. Chem., 2004, 69, 5428–5432.
15 S. Urgaonkar and J. G. Verkade, J. Org. Chem., 2004, 69, 5752–5755.
16 A. Tougerti, S. Negri and A. Jutand, Chem.–Eur. J., 2007, 13, 666–
676.
Stock solution 14 (0.99 mg, 0.00254 mmol, 0.0254 mM). Diluted
to give solutions of 3.048, 2.540, 2.032 and 1.016 lM; m = 5514;
UF = 0.36 (5514/1338220) = 0.004.
5-[2-(1-Naphthyl)ethynyl]-2-methoxy-1,1,3,3-
tetramethylisoindoline (23)
17 M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron Lett., 1993, 34,
6403–6406.
18 Y. Miura and Y. Ushitani, Macromolecules, 1993, 26, 7079–7082.
19 Y. Miura, T. Issiki, Y. Ushitani, Y. Teki and K. Itoh, J. Mater. Chem.,
1996, 6, 1745–1750.
Stock solution 23 (1.07 mg, 0.00301 mmol, 0.0301 mM). Diluted
to give solutions of 4.816, 3.612, 2.408 and 1.204 lM; m = 361630;
UF = 0.36 (361630/157765) = 0.825.
20 C. Stroh, M. Mayor and C. von Haenisch, Tetrahedron Lett., 2004, 45,
9623–9626.
21 F. M. Romero and R. Ziessel, Tetrahedron Lett., 1999, 40, 1895–1898.
22 T. Kalai, M. Balog, J. Jeko, W. L. Hubbell and K. Hideg, Synthesis,
2002, 2365–2372.
5-[2-(9-Phenanthryl)ethynyl]-2-methoxy-1,1,3,3-
tetramethylisoindoline (24)
23 D. G. Gillies, L. H. Sutcliffe and M. R. Symms, J. Chem. Soc., Faraday
Trans., 1994, 90, 2671–2675.
Stock solution 24 (1.17 mg, 0.00289 mmol, 0.0289 mM). Diluted
to give solutions of 4.624, 3.468, 2.312 and 1.156 lM; m = 40375;
UF = 0.36 (343353/1338220) = 0.257.
24 R. Bolton, D. G. Gillies, L. H. Sutcliffe and X. Wu, J. Chem. Soc.,
Perkin Trans., 1993, 2, 2049–2052.
25 S. E. Bottle, D. G. Gillies, D. L. Hughes, A. S. Micallef, A. I. Smirnov
and L. H. Sutcliffe, J. Chem. Soc., Perkin Trans. 2, 2000, 2, 1285–1291.
26 S. E. Bottle, D. G. Gillies, A. S. Micallef, D. A. Reid and L. H. Sutcliffe,
Magn. Reson. Chem., 1999, 37, 730–734.
1-(Phenylethynyl)naphthalene (27)14
27 S. E. Bottle, U. Chand and A. S. Micallef, Chem. Lett., 1997, 857–858.
28 N. V. Blough and D. J. Simpson, J. Am. Chem. Soc., 1988, 110, 1915–
1917.
29 G. L. Gerlock, P. J. Zacmanidis, D. R. Bauer, D. J. Simpson, N. V.
Blough and I. T. Salmeen, Free Radical Res. Commun., 1990, 10, 119–
121.
30 K. E. Fairfull-Smith, J. P. Blinco, D. J. Keddie, G. A. George and S. E.
Bottle, Macromolecules, 2008, 41, 1577–1580.
31 A. S. Micallef, J. P. Blinco, G. A. George, D. A. Reid, E. Rizzardo, S. H.
Thang and S. E. Bottle, Polym. Degrad. Stab., 2005, 89, 427–435.
32 J. P. Blinco, J. C. McMurtrie and S. E. Bottle, Eur. J. Org. Chem., 2007,
4638–4641.
Stock solution 27 (1.08 mg, 0.00473 mmol, 0.0473 mM). Diluted
to give solutions of 3.784, 2.838, 1.892 and 0.946 lM; m = 348354;
UF = 0.36 (348354/157765) = 0.795.
Acknowledgements
This work was produced with the support of the Australian
Research Council under the ARC Centres of Excellence program,
CE0561607.
33 C. Coenjarts, O. Garcia, L. Llauger, J. Palfreyman, A. L. Vinette and
J. C. Scaiano, J. Am. Chem. Soc., 2003, 125, 620–621.
34 D. J. Keddie, T. E. Johnson, D. P. Arnold and S. E. Bottle, Org. Biomol.
Chem., 2005, 3, 2593–2598.
35 E.-i. Negishi and L. Anastasia, Chem. Rev., 2003, 103, 1979–2017.
36 J. Tsuji, Palladium Reagents and Catalysts: Innovations in Organic
Synthesis, John Wiley & Sons, New York, 1995.
37 S. Oi, Hideki, Orihara, H. Kawai and Y. Inoue, Heterocycles, 2005, 66,
621–625.
38 A. S. Micallef, R. C. Bott, S. E. Bottle, G. Smith, J. M. White, K.
Matsuda and H. Iwamura, J. Chem. Soc., Perkin Trans. 2, 1999, 2,
65–71.
References
1 K. Sonogashira, in Handbook of Organopalladium Chemistry for
Organic Synthesis, ed. E.-i. Negishi, John Wiley & Sons, Inc., Hoboken,
N. J., 2002, vol. 1, pp. 493–529.
2 L. Cassar, J. Organomet. Chem., 1975, 93, 253–257.
3 H. A. Dieck and F. R. Heck, J. Organomet. Chem., 1975, 93, 259–263.
4 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975,
16, 4467–4470.
5 L. Brandsma, S. F. Vasilevsky and H. D. Verkruijsse, Application of
Transition Metal Catalysts in Organic Synthesis, Springer, Berlin, 1997.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3135–3143 | 3143
©