Highly regioselective synthesis of substituted isoindolinones via ruthenium-catalyzed alkyne cyclotrimerizations

Article abstract of DOI:10.1002/adsc.201300055

(Cyclooctadiene)(pentamethylcyclopentadiene) ruthenium chloride [Cp*RuCl (cod)] has been used to catalyze the regioselective cyclization of amide-tethered diynes with monosubstituted alkynes to give polysubstituted isoindolinones. Notably, the presence of a trimethylsilyl group on the diyne generally led to complete control over the regioselectivity of the alkyne cyclotrimerization. The cyclization reaction worked well in a sustainable non-chlorinated solvent and was tolerant of moisture. The optimized conditions were effective with a diverse range of alkynes and diynes. The 7-silylisoindolinone products could be halogenated, protodesilylated or ring opened to access a range of usefully functionalized products.

Full text of DOI:10.1002/adsc.201300055

FULL PAPERS
DOI: 10.1002/adsc.201300055
Highly Regioselective Synthesis of Substituted Isoindolinones via
Ruthenium-Catalyzed Alkyne Cyclotrimerizations
a
b
a
a,
Robert W. Foster, Christopher J. Tame, Helen C. Hailes, and Tom D. Sheppard *
a
Department of Chemistry, University College London, Christopher Ingold Laboratories, London, WC1H 0AJ, U.K.
Fax : (+44)-(0)20-7679-7463; phone: (+44)-(0)20-7679-2467; e-mail: tom.sheppard@ucl.ac.uk
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG12NY, U.K.
b
Received: January 21, 2013; Revised: May 23, 2013; Published online: August 12, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300055.
ꢀ
2013 The authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under
the terms of the Creative Commons Attribution Licence, which permits use, distribution and reproduction in
any medium provided the original work is properly cited.
Abstract: (Cyclooctadiene)(pentamethylcyclopenta- ed solvent and was tolerant of moisture. The opti-
diene)ruthenium chloride [Cp*RuCl ACHUTNRGNENUG( cod)] has been mized conditions were effective with a diverse range
used to catalyze the regioselective cyclization of of alkynes and diynes. The 7-silylisoindolinone prod-
amide-tethered diynes with monosubstituted alkynes ucts could be halogenated, protodesilylated or ring
to give polysubstituted isoindolinones. Notably, the opened to access a range of usefully functionalized
presence of a trimethylsilyl group on the diyne gen- products.
erally led to complete control over the regioselectivi-
ty of the alkyne cyclotrimerization. The cyclization Keywords: alkynes; amide tether; cyclotrimerization;
reaction worked well in a sustainable non-chlorinat- isoindolinones; ruthenium; trimethylsilyl group
Introduction
the regioselective synthesis of compounds that would
be extremely difficult to make via traditional aromatic
Substituted isoindolinones have recently generated chemistry. The regioselectivity of a cyclotrimerization
considerable interest because of their diverse biologi- is normally controlled by tethering two or three of
cal activities, including the inhibition of angiogene- the alkyne components together, so this strategy is
[
1]
[2]
sis, tumour necrosis factor production, MDM2-p53 best suited to the synthesis of bicyclic and tricyclic
[
3]
protein-protein
interactions,
hypoxia-inducible ring systems. This allows for the assembly of substitut-
[4]
[5]
factor-1a and histone deacetylase. The majority of ed multiple-ring aromatic compounds from alkyne
existing protocols for isoindolinone synthesis require precursors in a single step.
the construction of a g-lactam adjacent to a pre-
formed aromatic core. Recent examples include the nized the potential of alkyne cyclotrimerizations for
one-pot transformation of 2-halobenzaldimines into the synthesis of isoindolinones bearing substituents on
Yamamoto and co-workers have previously recog-
[
6]
[
10]
chiral 3-substituted isoindolinones and the Ni-mediat- the aromatic ring. They reported the cyclization of
ed cyclization of N-benzoyl aminals in the presence of amide-tethered diynes 1 with monoynes 2 using
[
7,8]
a stoichiometric Lewis acid.
However, the inevita- Cp*RuCl ACHTUNGTERNNNU(G cod) 3 as the catalyst to give regioisomeric
ble limitation of these approaches is the accessibility isoindolinones 4 and 5 (Scheme 1). In general the re-
of the arene starting material itself. The synthesis of gioselectivity of the cyclotrimerization was poor to
polysubstituted arenes is often non-trivial, frequently moderate, with the exception of a single example
1
requiring numerous steps, the use of protecting group bearing a methyl group at R . In addition, a significant
strategies and/or functional group interconversions.
limitation of this method is the use of 1,2-dichloro-
The transition metal-catalyzed [2+2+2]cyclotrime- ethane (DCE) as solvent, a substance which is poten-
rization of alkynes is emerging as an elegant, atom ef- tially detrimental to human health and is generally
[
11]
ficient and convergent approach to the synthesis of avoided within industry.
highly substituted arenes. The strategy allows for
[
9]
Adv. Synth. Catal. 2013, 355, 2353 – 2360
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Robert W. Foster et al.
FULL PAPERS
Results and Discussion
Diyne Synthesis
Initially several amide-tethered diynes 6 were pre-
pared by the coupling of propargylic amines 7 with 3-
(
trimethylsilyl)propiolic acid 8, via the corresponding
[13]
acid chloride (Scheme 2). Where necessary the cor-
responding amines were prepared using literature
procedures.
[
14–15]
Scheme 1. Isoindolinone synthesis as reported by Yamamoto
[10]
and co-workers.
Optimization
The aim of this study was to explore the regioselec-
tive synthesis of polysubstituted isoindolinones using Various conditions were screened for the cyclotrimeri-
more industrially viable reaction conditions, to estab- zation of diyne 6a with 1-hexyne 9a to form isoindoli-
lish the general applicability of the reaction, and to none 10a, and the results are summarized in Table 1.
develop the synthetic potential of the cyclized prod- All reactions were conducted for 16 h at which point
ucts. On the basis of previously reported cyclizations
we envisaged that the introduction of a trimethylsilyl
1
group at R in diyne 1 would direct the regioselectivi-
ty of the cyclisation reaction effectively with a broad
[
10,12]
range of monoynes.
The arylsilane unit present in
the isoindolinone product could then be transformed
using standard chemical techniques to access a variety
of 7-substituted derivatives.
Scheme 2. Synthesis of diynes 6a–e.
Table 1. Optimization of the cyclotrimerization of 6a and 9a.
[a,b]
[a]
Entry Solvent
Equivalents of 9a Catalyst
Catalyst loading [mol%] Conversion
[%] Ratio 10a:11
[
c]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
PhMe[
4
4
4
4
4
4
4
4
2
4
2
1.1
2
2
RhCl
A
H
U
G
R
N
U
G
5
10
5
<5
<5
5
5
50
100
100
60
100
100
100
100
100
90
–
–
3
3
c]
PhMe
Co (CO)
2
[
2
c]
CH Cl
Grubbs I
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
Cp*RuCl
n.d.
n.d.
3:2
3:1
5:1
4:1
2:1
8:1
9:1
5:2
5:1
5:1
3:1
3:1
2
[
c]
DCE
neat[
[
d]
d]
neat
CPME
CPME
CPME
CPME
CPME
CPME
MTBE
2-MeTHF
CPME/10% water 2
water
[
[
[
[
[
[
e]
e]
e]
e]
e]
e]
0
1
2
3
4
5
6
70
30
4
[
[
[
[
[
a]
1
Determined by analysis of the crude H NMR spectrum.
b]
1
Conversion of 6a into 10a and 11 (determined by crude H NMR without the use of an internal standard).
Solvent dried over activated 4 ꢁ molecular sieves and degassed.
ACHTUNGTRENNUNG( cod) 3 was added to the reaction mixture at 08C, which was then allowed to reach room temperature.
Diyne 6a in CPME was added dropwise over 3 h to a stirring solution of 9a and 3 in CPME.
c]
d]
e]
Cp*RuCl
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Adv. Synth. Catal. 2013, 355, 2353 – 2360

Highly Regioselective Synthesis of Substituted Isoindolinones
conversion and selectivity were determined by analy- The cyclization of 6a and 9a was also effective when
1
sis of the crude H NMR spectrum.
2-MeTHF or MTBE were used as solvents, but in
The cyclotrimerization of diyne 6a and alkyne 9a both cases a greater degree of homo-coupling of 6a
was examined using four different literature proce- was observed than with CPME (entries 13 and 14).
dures. Neither RhCl ACHTUNGRTENN(NUG PPh ) nor Co (CO) were effec- The reaction proved to be relatively water tolerant,
3 3 2 8
tive in catalyzing the alkyne cyclotrimerization, with with a significant conversion and a reasonable selec-
no measurable conversion of diyne 6a (entries 1 and tivity observed when the reaction was conducted in
[16]
2).
Treating diyne 6a with 5 mol% Grubbsꢂ first the presence of 10% water (entry 15). Cyclization was
generation catalyst and 4 equivalents of 1-hexyne 9a even observed when the reaction was conducted in
in dried, degassed CH Cl resulted in formation of the water as solvent (entry 16). This is important as it
2
2
target isoindolinone 10a with only 5% conversion could enable the extension of the reaction to aqueous
[17]
(
entry 3). Treating diyne 6a with 1-hexyne 9a and conditions for reactions of water-soluble substrates.
mol% Cp*RuCl(cod) in dried, degassed DCE also Following the optimization study the conditions de-
gave isoindolinone 10a, again with 5% conversion of scribed in entry 11 were taken as the “optimized” cy-
1
ACHTUNGTRENNUNG
[10]
6
a (entry 4). Given that the latter procedure gave
ACHTUNGTRENNUcGN lization conditions as they required a reduced excess
a similar conversion with a lower catalyst loading, of monoyne and minimized the formation of dimer
Cp*RuCl
tion.
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(cod) was selected for subsequent optimiza- 11. Crucially this protocol did not require the CPME
solvent to be either degassed or dried. This, together
Interestingly, treating diyne 6a with 1-hexyne 9a with the environmental benefits of CPME, makes this
and 1 mol% Cp*RuCl(cod) with no solvent (neat) at reaction a very practical method for the synthesis of
8C gave isoindolinone 10a with a 50% conversion isoindolinones. Dimer 11 could be readily separated
entry 5). This suggests that using DCE as a solvent from the desired product by flash column chromatog-
AHCTUNGTRENNUNG
0
(
for this reaction is actually detrimental. In addition to raphy, and the optimized conditions described in
the desired isoindolinone 10a, dimer 11 was also entry 11 gave the target isoindolinone 10a in 81% iso-
[
12]
formed as a significant by-product.
lated yield (Table 2, entry 1). This reaction was also
Crucially, regioisomeric cyclotrimerization product scaled up to a 500-mg scale and isoindolinone 10a was
2 was not observed at all in the crude H NMR spec- isolated in 66% yield (428 mg product).
1
1
trum. The reaction under neat conditions reached
completion within 16 h when 3 mol% of catalyst 3
was used, and with a significant reduction in the pro- Monoyne Scope
portion of homo-coupled product 11 produced
(
entry 6).
The cyclization of 6a was then examined with a variety
We were interested in using cyclopentyl methyl of monoynes using the optimized conditions described
ether (CPME) as a solvent for this cyclization as it above to determine how robust the reaction was for
has been recently established as a safer and more en- a range of different substrates. Diyne 6a cyclized with
vironmentally benign alternative to many traditional a wide range of monynes 9 as detailed in Table 2.
[18]
organic solvents. As shown in entry 7, when the re- Crucially, no evidence for the formation of regioiso-
action was conducted in CPME with 3 mol% of cata- meric isoindolinones was observed in any of the cycli-
lyst 3, diyne 6a was completely consumed within 16 h zation reactions. Alkyl monoynes 9a–e cyclized effi-
and an improved selectivity for the cross-coupled ciently with 6a to give the corresponding isoindoli-
product 10a was observed. By comparison, the same nones 10a–e in good isolated yield (entries 1–5, 66–
reaction using only 1 mol% catalyst resulted in a com- 83%). Little formation of the undesired dimer 11 was
parable level of selectivity, but a lower conversion observed, except in the reaction of tert-butylacetylene
(
entry 8). Reducing the number of equivalents of 1- 9b, presumably due to high steric crowding about the
hexyne 9a to two resulted in the complete consump- monoalkyne. Carbamate 9f cyclized with 6a to give
tion of diyne 6a but also a significantly increased level 10f in reasonable yield and with modest levels of
of homo-coupling.
homo-coupling (entry 6).
In an attempt to minimise the formation of dimer
Ether 9g and acetal 9h both underwent cyclotrime-
1
1, diyne 6a was added dropwise over 3 h to a stirring rization with 6a, but with the formation of significant
[19]
solution of monoyne 9a and catalyst 3,
and this quantities of dimer 11. Propargylic alcohol 9i and me-
proved to be highly effective (entry 10). When using thoxyacetylene 9j both failed to cyclize with diyne 6a,
the 3-hour dropwise addition it was possible to reduce with only starting material being recovered in both
the number of equivalents of 1-hexyne 9a from four cases. In addition to aliphatic monoynes, diyne 6a cy-
to two with no increase in homo-coupling (entry 11). clized effectively with a broad range of aromatic mon-
A further reduction to 1.1 equivalents of 1-hexyne 9a oynes. Electron-rich (entries 12, 13, 17 and 18), elec-
did result in increased homo-coupling, but target iso- tron-poor (entry 16) and sterically hindered substrates
indolinone 10a was still the major product (entry 12). (entries 12 and 14) could all be tolerated and products
Adv. Synth. Catal. 2013, 355, 2353 – 2360
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Robert W. Foster et al.
FULL PAPERS
[a]
Table 2. Reaction of diyne 6a with a selection of monoynes 9.
[b]
[c]
Entry
Alkyne 9
3 [mol%]
Time [h]
Product 10
Yield of 10 [%]
Ratio 10:11
1
2
3
3
16
16
10a
10b
81
66
9:1
2:1
3
3
16
10c
81
9:1
4
3
16
10d
81
6:1
5
6
3
5
16
24
10e
10f
83
63
8:1
2:1
7
8
9
3
3
3
16
24
16
10g
10h
–
56
43
0
3:2
4:5
–
1
1
0
1
3
4
16
24
–
10k
0
83
–
6:1
1
2
3
3
4
16
24
10l
93
83
>10:1
1
10m
6:1
14
3
16
10n
80
8:1
1
1
1
1
1
2
5
6
7
8
9
0
3
24
24
24
24
16
24
10o
10p
10q
10r
–
83
79
79
79
0
5:1
5:1
6:1
7:1
-
3
5
10
3
20
10t
50
2:1
2
2
1
2
3
5
16
24
10u
10v
0
-
55
3:1
[
a]
Reaction conditions: A solution of 6a in CPME was added dropwise to a stirring solution of 9 and 3 in CPME over 3 h at
room temperature.
Isolated yield.
Determined by the analysis of crude H NMR spectra.
[
[
b]
c]
1
were isolated in good yields (79–93%) with low levels higher catalyst loadings, were required to drive the re-
of diyne homo-coupling. For most of these examples action to completion. However the reactions with
longer reaction times (up to 24 h), and in some cases ortho-substituted arylacetylenes 9l and 9n reached
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Adv. Synth. Catal. 2013, 355, 2353 – 2360

Highly Regioselective Synthesis of Substituted Isoindolinones
[a]
Table 3. Cyclizations involving diynes with different N-substituents.
1
2
[b]
[c]
Entry
R
R
3 [mol%]
Time [h]
Product 13
Yield of 13 [%]
Ratio of 13:14
1
2
3
4
5
t-Bu 6b
t-Bu 6b
t-Bu 6b
H 6c
n-Bu 9a
Ph 9k
o-tolyl 9l
n-Bu 9a
o-tolyl 9l
3
4
3
10
10
16
24
16
24
24
13a
13b
13c
13d
13e
84
89
94
10:1
>10:1
>10:1
2:1
[d]
51 (90% )
[d]
H 6c
62 (90% )
7:1
[
a]
Reaction conditions: a solution of 6 in CPME was added dropwise to a stirring solution of 9 and 3 in CPME over 3 h at
room temperature.
Isolated yield.
[
[
[
b]
c]
d]
1
Determined by the analysis of crude H NMR spectra.
Conversion of diyne 6 to 13/14 (determined by crude H NMR without the use of an internal standard).
1
completion within 16 h with only 3 mol% of catalyst 3 increased loading of catalyst 3, and also occurred with
entries 12 and 14). Monoyne 9l also cyclized with ex- very little formation of dimer 14a (entry 3).
ceptionally high selectivity for the cross-coupled prod- The N-H diyne 6c proved less effective for the syn-
uct 10l over dimer 11, whereas ortho-bromo alkyne thesis of isoindolinones, with the cyclization of 6c and
n gave a slightly lower selectivity. Although Yama- 1-hexyne 9a requiring 10 mol% Cp*RuCl(cod) 3 and
(
9
ACHTUNGTRENNUNG
moto et al. have reported the [2+2+2]cycloaddition 24 h to achieve a 90% conversion of diyne 6c
of an electron-deficient nitrile and an amide-tethered (entry 4). Isoindolinone 13d was only formed in
[
20]
diyne to give a pyridine, in our reaction nitrile 9s modest yield (51%) and significant formation of
failed to cyclize with 6a to form any product via reac- dimer 14b was observed. Under the same conditions
tion of either the alkyne or the nitrile (entry 19). the cyclization of 2-tolylacetylene 9l and N-H diyne
Only a limited quantity of 11 (~10%) was formed in 6c gave the desired isoindolinone 13e in a slightly
this reaction suggesting that 9s may inhibit the cata- higher yield with 90% conversion. Again, the reaction
lyst. Heterocycle-containing alkyne 9t cyclized effec- with 2-ethynyltoluene 9l proved to be unusually selec-
tively with 6a to give the corresponding 2-pyridyl de- tive, with 13e and 14b formed in the ratio 7:1
rivative 10t in a moderate 50% yield (entry 20). In (entry 5). The lack of a sterically bulky N-substituent
contrast N-methylimidazole 9u failed to cyclize with is presumably responsible for both the reduced reac-
6
(
a, with unreacted starting material being recovered tivity of N-H diyne 6c with monoynes and the high
entry 21). Alkyne 9v cyclized with 6a to give bora- level of diyne homo-coupling observed in these reac-
[
21]
mide 10v in reasonable yield (entry 22).
tions.
The cyclization of amide-tethered diynes bearing
different alkyne substituents was also explored
(Table 4). With doubly substituted diynes 6d and 6e,
no homo-coupling of the diyne was observed and
Diyne Scope
The cyclization of amide-tethered diynes bearing dif- dropwise addition of the diyne to the reaction
ferent N-substituents was examined and the results was unnecessary (entries 1–3). With 10 mol% of
are summarized in Table 3. N-t-Bu diyne 6b proved to Cp*RuCl ACHUTNGRNENUG( cod), methyl-substituted diyne 6d cyclized
be an excellent substrate for the synthesis of 5,7-sub- with 1-hexyne 9a to form a 9:1 mixture of regioiso-
stituted isoindolinones. Treatment of 6b with 1- meric isoindolinones 15a and 16a (entry 1).
hexyne 9a under the optimized reaction conditions
Ethyl-substituted diyne 6e reacted with 1-hexyne
gave isoindolinone 13a in 84% yield with little forma- 11a with lower regioselectivity, giving a 2:1 mixture of
tion of the dimer 14a (entry 1). The cyclization of 6b isoindolinones 15b and 16b (entry 2). However, diyne
with 9k required 4 mol% 3 and 24 h to reach comple- 6e cyclized with 2-ethynyltoluene 9l, to give a 5:1 mix-
tion, giving isoindolinone 13b in 89% yield (entry 2). ture of isoindolinones 15c and 16c (entry 3). Interest-
The reaction of 6b with 2-ethynyltoluene 9l proceeded ingly, the presence of diastereotopic benzylic protons
1
in 94% yield without an elevated reaction time or an in the H NMR spectrum suggests that isoindolinone
Adv. Synth. Catal. 2013, 355, 2353 – 2360
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Robert W. Foster et al.
FULL PAPERS
[a]
Table 4. Cyclizations involving diynes with different alkyne substitutents.
1
2
3
[b]
[c]
Entry Diyne 6
R
R
R
3 [mol%] Time [h] Isolated products Yield of (15+16) [%]
Ratio of 15:16
1
2
3
4
5
6d
6e
6e
6f
6f
SiMe3 Me n-Bu 9a 10
SiMe3 Et n-Bu 9a 10
SiMe3 Et o-tolyl 9l 10
24
24
24
16
16
15a/16a
15b/16b
15c/16c
15d
15e
69
57
73
85
94
9:1
2:1
5:1
>20:1
>20:1
[
[
d]
d]
[e]
Me
H
n-Bu 9a
3
Me
H
o-tolyl 9l
3
[
a]
Reaction conditions: A solution of 6 in CPME was added to a stirring solution of 9 and 3 in CPME over 1 min at room
temperature.
Isolated yield.
[
[
[
[
b]
c]
d]
e]
1
Determined by the analysis of crude H NMR spectra.
Diyne 6f in CPME was added dropwise over 3 h to a solution of 9 and 3 in CPME.
Evidence of limited homo-coupling of 6f was observed in the crude H NMR spectrum.
1
1
5c is a chiral molecule, presumably due to restricted
rotation about the hindered biaryl unit.
The dependence of the cyclotrimerization on an
SiMe3 regiodirecting group was also investigated.
Diyne 6f with a terminal methyl substituent reacted
with 1-hexyne 9a under the optimized cyclization con-
ditions to give isoindolinone 15d in 85% yield
(
entry 4). Crucially, there was no trace of the regioiso-
1
meric isoindolinone 16d by crude H NMR. Similarly,
diyne 6f cyclized with 2-ethynyl toluene 9l to give iso-
indolinone 15e in 94% yield, with no evidence for the
formation of regioisomer 16e (entry 5).
Functional Group Manipulation of Cyclized Products
Scheme 3. Synthesis of usefully functionalized isoindoli-
nones.
Conversion of the cyclized isoindolinone products
into a number of synthetically interesting motifs was
examined. Isoindolinone 10a was converted to aryl
halides 17 and 18, in 79% and 90% yields, respective-
ly, via an ipso substitution of the silyl group
[22]
(
Scheme 3).
Treatment of N-t-butylisoindolinone
1
3a with triflic acid resulted in a simultaneous depro-
tection of the lactam and protodesilylation within
[
23]
30 min to give N-H isoindolinone 20 in good yield.
Alternatively, treatment of 13a with iodine mono-
chloride followed by deprotection with triflic acid
gave 7-iodoisoindolinone 19 in 83% yield. Thus, an N-
t-Bu diyne can be used as an indirect method for the Scheme 4. Synthesis of a tetrasubstituted benzene ring.
synthesis of N-H isoindolinones via this acid-mediated
deprotection.
19 with di-tert-butyl dicarbonate gave N-Boc isoindo-
It was also possible to access a tetrasubstituted linone 21, which could be reduced with lithium boro-
monocyclic benzene. Treatment of N-H isoindolinone hydride to form N-Boc protected amino alcohol 22,
2358
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Adv. Synth. Catal. 2013, 355, 2353 – 2360

Highly Regioselective Synthesis of Substituted Isoindolinones
together with cyclic aminol 23, in a combined yield of ery. We would also like to acknowledge Simon Peace (GSK)
for helpful discussions.
78% (Scheme 4). The preparation of mono-cyclic sub-
stituted arenes via tethered alkyne cyclotrimerizations
has little precedent and such systems are somewhat
difficult to access via traditional aromatic substitution
References
[
24]
reactions, highlighting the value of this strategy.
[
1] F. A. Luzzio, A. V. Mayorov, S. S. W. Ng, E. A. Kruger,
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Conclusions
In summary, we have demonstrated the regioselective
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Cp*RuCl ACHTUNGTRENNUNG( cod)-catalyzed cyclotrimerization of amide-
[
tethered diynes and monoynes. This cyclization is ef-
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a Monoyne
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3
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solvent was removed under vacuum to give the crude prod-
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.21 (7H, m, ArH), 4.68 (2H, s, CH N), 4.24 (2H, s, CH N),
2
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Acknowledgements
This work was supported by the Engineering and Physical
Sciences Research Council (Advanced Research Fellowship
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