Diastereoselective intermolecular ene reactions: Synthesis of 4,5,6,7-tetrahydro-1H-benzo[d]imidazoles

Article abstract of DOI:10.1039/c2ob26009c

The Diels-Alder cycloadducts of 4-vinylimidazoles and N-phenylmaleimide are shown to undergo facile intermolecular ene reactions. Overall the reaction of three simple molecules (a diene, a dienophile and an enophile) in a two-step process gives 4,5,6,7-te

Full text of DOI:10.1039/c2ob26009c

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PAPER
Diastereoselective intermolecular ene reactions: synthesis of
4,5,6,7-tetrahydro-1H-benzo[d]imidazoles†
Lynsey J. Watson, Ross W. Harrington, William Clegg and Michael J. Hall*
Received 23rd May 2012, Accepted 5th July 2012
DOI: 10.1039/c2ob26009c
The Diels–Alder cycloadducts of 4-vinylimidazoles and N-phenylmaleimide are shown to undergo facile
intermolecular ene reactions. Overall the reaction of three simple molecules (a diene, a dienophile and an
enophile) in a two-step process gives 4,5,6,7-tetrahydro-1H-benzo[d]imidazoles with high yields, high
atom economy and diastereocontrol of up to 5 new stereocentres.
Introduction
1H-Benzo[d]imidazoles are a core structure of many biologically
active molecules, including drugs such as mebendazole and
albendazole. However, despite the success of many aromatic
compounds of this type, medicinal chemistry is moving from
stereochemistry as “a source of problems” to stereochemistry as
a vital tool for improving selectivity and efficacy.1,2 Thus, there
is an increasing interest in unsaturated, chiral 1H-benzo[d]imid-
azole analogues as medicinal leads.3
Recently we disclosed our investigations into the Diels–Alder
Scheme 1 Observed by-products arising from postulated IMDA/IME
reactions of vinyl-heteroaromatics.
(D–A) reactions of N-trityl-4-vinylimidazoles and N-phenyl-
maleimide. This resulted in the observation of novel domino
reaction processes including D–A, [1,3]-H shift, [1,3]-trityl
migrations and D–A, [1,3]-H shift, [1,3]-trityl migration,
Michael reactions.4
Intermolecular pericyclic reactions are powerful tools in syn-
thetic organic chemistry due to their ability to generate multiple
covalent bonds and stereocentres in a single step.7 Thus use of
an intermolecular Diels–Alder and an intermolecular ene reac-
tion would allow, in two steps and from three simple starting
materials, rapid access to complex unsaturated 1H-benzo[d]-
imidazole analogues with 100% atom economy and high
diastereomeric control in the formation of the multiple C–C and
C–X bonds.7,8
These results prompted us to examine the reactivity of the
D–A cycloadducts of 4-vinylimidazoles and maleimides in more
detail.5 During the study of D–A reactions of various vinyl-
heteroaromatics with reactive dienophiles, a handful of research
groups have reported the observation of an intriguing, if low-
yielding, by-product formed from one molecule of vinyl-hetero-
aromatic and two molecules of the dienophile. It has been
postulated that this occurs via an intermolecular Diels–Alder/
intermolecular ene (IMDA/IME) reaction sequence, the products
of which are shown (Scheme 1).6 There are, however, no
examples of this reaction sequence being carried out with the
separation of the ene reaction from the other steps, allowing vari-
ation of the enophile.
Through the introduction of different enophiles this reaction
sequence would provide
a hitherto unexplored synthetic
approach for the diastereoselective generation of complex
unsaturated 1H-benzo[d]imidazoles. Herein we discuss our investi-
gations into the ability of the D–A cycloadducts of 4-vinyl-
imidazoles and N-phenylmaleimide to undergo diastereoselective
ene reactions with a broad range of enophiles (Scheme 2).9
Examination of the X-ray crystal structures of molecules such
as 5 shows that the twix C–H σ-bond is coplanar with the elec-
tron-rich cyclohexenyl CvC π-bond.10 In addition an ene reac-
tion involving the twix C–H results in the rearomatisation of the
imidazole ring providing highly favourable thermodynamics.11
Thus we envisaged that ene reactions with molecules such as 5
would be both regio- and diastereoselective.
School of Chemistry, Bedson Building, Newcastle University, Newcastle
upon Tyne, NE1 7RU, UK. E-mail: michael.hall@ncl.ac.uk;
Fax: +44 (0) 191 222 6929; Tel: +44 (0) 191 222 7321
†Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra for all compounds, X-ray structures and .cif files for 6b,
7c, 7d, 8a. CCDC 860567–860571. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob26009c
This journal is © The Royal Society of Chemistry 2012
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Table 1 Ene reactions of 5aa
Scheme 2 Planned IMDA/IME reaction sequence of vinylimidazoles.
Enophile
Reaction conditions
Product
Yieldc
95%
r.t., 1 h
Results and discussion
The desired cycloadducts (5a–b) were prepared through the D–A
reaction of N-phenylmaleimide (NPM) and the requisite vinyl-
imidazole precursors (4a–b). 1-Benzyl-4-vinyl-1H-imidazole
(4a) was synthesised via a thermal decarboxylation of urocanic
acid followed by a benzyl protection of the sterically most acces-
sible nitrogen atom. (E)-1-Benzyl-4-(3-((tert-butyldimethylsilyl)-
oxy)prop-1-en-1-yl)-1H-imidazole (4b) was also synthesised
starting from urocanic acid via an esterification, N-benzyl protec-
tion, DIBAL reduction and finally O-TBS protection. Vinyl-
imidazoles (4a–b) were then reacted with NPM to give (5a–b)
respectively (Scheme 3).4,6b
r.t., 2 h
68%
87%
r.t., 1 h
Reaction of 5a was successful with a range of reactive eno-
philes including arylnitroso compounds (6a–c),12 benzyne (6d,
generated from trimethylsilylphenyl triflate and TBAF in situ),13
PTAD (6e), and diethyl 2-oxomalonate (6f). These reactions
gave good to excellent yields of the ene products as single dia-
stereomers (Table 1). The ene reactions proved to be remarkably
facile, requiring a few hours at moderate to low temperatures
without the requirement of a Lewis acid catalyst. Relative stereo-
chemistry of the ene products was determined through compari-
son with the results of single-crystal X-ray analysis of 6b (see
ESI†).14
TBAF, 40 °C, 2 h
68%
74%
d
−78 °C, 1 h
Interestingly, in the case of less reactive enophiles (N-phenyl-
or N-methylmaleimide, maleic anhydride, etc.) even extended
reaction times resulted in no observed ene products but only
rearomatisation of the imidazole, and in some cases concurrent
oxidation (potentially air oxidation) of the imidazolyl
methylene.
r.t., 16 h
83%
We then subjected 5b to our previous ene reaction conditions.
For 5b ene reactions with arylnitroso compounds were not suc-
cessful, but reactions with PTAD and diethyl 2-oxomalonate
gave moderate yields of 6(g–h) as single diastereomers, resulting
in the generation, over two steps, of four contiguous stereo-
centres and three C–C/X bonds via the IMDA/IME three-
component reaction sequence (Table 2).
a All compounds shown were isolated as single diastereomers.
b Structure confirmed by single-crystal X-ray analysis. c Isolated yield of
the ene reaction. d Benzyne precursor.
Both 5a and 5b were then reacted with the prochiral eno-
philes, ethyl 2-oxoacetate and ethyl 3,3,3-trifluoro-2-oxo-
propanoate, in order to introduce an additional exocyclic
stereocentre, generating overall a total of five contiguous stereo-
centres (Table 3). In all cases reasonable yields were obtained
with the endo-ene product as the major diastereomer.
Scheme 3 Synthesis of reactive cycloadducts 5a and 5b.
6650 | Org. Biomol. Chem., 2012, 10, 6649–6655
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Table 2 Ene reactions of 5ba
Table 3 Carbonyl ene reactions of 7(a–b)a
Enophile
Reaction conditions
r.t., 1 h
Product
Yieldb
61%
Substrate,
conditions and
yieldsb
Major
diastereomer
(endo-)
Minor
diastereomer
(exo-)
Enophile
R = H (7a/8a); r.t.,
30 h, 72%
R = CH2OTBS
(7b/8b); r.t., 16 h,
59%
r.t., 2 h
65%
R = H (7c/8c); r.t.,
16 h, 53%
R = CH2OTBS
(7d/8d); r.t., 72 h,
53%
a All compounds shown were isolated as single diastereomers. b Isolated
yield of the ene reaction.
a All compounds shown were isolated as single diastereomers. b Isolated
yields. c Structures confirmed by single-crystal X-ray analysis. d 8b not
observed. e 8c not observed.
Relative stereochemistry of the products was determined through
comparison with the results of single-crystal X-ray analysis of
7c,15 7d and 8a (see ESI†).14
(diethyl ether–methanol, 98 : 2) to yield the product as a white
solid, 313 mg (80%).
Conclusions
Rf 0.13 (UV active, diethyl ether–methanol, 98 : 2); mp:
In summary, we have successfully demonstrated that the D–A
cycloadducts of 4-vinylimidazoles are viable substrates for high-
yielding and highly diastereoselective ene reactions with a wide
range of enophiles. Our exemplified 2-step IMDA/IME process
allows for the overall combination of three simple components
(a vinylimidazole, a dienophile and an enophile) to generate,
with 100% atom economy, complex 4,5,6,7-tetrahydro-1H-
benzo[d]imidazoles containing up to 5 new stereocentres through
the generation of C–C/X bonds. Current investigations are aimed
towards enantioselective variants, extension to other vinyl-aro-
matic systems, and reaction telescoping.
1
193–195 °C (lit.6b 195–196 °C); H NMR (300 MHz, CDCl3):
δH 7.45–7.28 (9H, m), 7.16–7.13 (2H, m), 5.62 (1H, ddd,
J = 7.9, 3.8, 3.8 Hz), 4.90 (1H, d, J = 15.1 Hz), 4.77 (1H, d, J =
15.1 Hz), 4.02 (1H, ddd, J = 7.7, 3.8, 3.8 Hz), 3.64 (1H, dd,
J = 8.9, 7.7 Hz), 3.12 (1H, ddd, J = 8.9, 6.7, 1.8 Hz), 3.11 (1H,
ddd, J = 15.4, 7.9, 1.8 Hz), 1.95 (1H, dddd, J = 15.4, 6.7, 3.8,
3.8 Hz); 13C NMR (101 MHz, CDCl3): δC 177.8, 173.9, 159.4,
154.6, 135.3, 131.6, 129.1, 129.2, 128.8, 128.3, 128.1, 126.5,
102.4, 56.9, 49.9, 41.1, 36.8, 25.5; IR (neat): νmax/cm−1 3067,
3029, 2964, 2829, 1771, 1699, 1542, 1496, 758, 694; HRMS
(ES-ToF): calcd for C22H19N3O2 (M + H)+: 358.1550, found
358.1554.
Experimental section
1,3-Dibromo-2-nitrosobenzene12
(5aS*,8aS*)-1-Benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a)
To 2,6-dibromoaniline (0.52 g, 2.05 mmol) in trifluoroacetic
acid (3.5 mL) was added H2O2 (35% solution in water,
0.15 mol, 4.67 mL), and the mixture stirred at r.t. for 16 h. The
mixture was then poured into ice-water (20 mL) and the orange/
brown precipitate was filtered and recrystallised from n-hexane
to give the title compound as a beige solid, 339 mg (62%).
Rf 0.60 (UV active, diethyl ether–petroleum ether 40–60,
50 : 50); mp: 112–114 °C; 1H NMR (300 MHz, CDCl3): δH 7.77
To 1-benzyl-4-vinyl-1H-imidazole (200 mg, 1.09 mmol) in
dichloromethane (5 mL) was added N-phenylmaleimide
(470 mg, 6.93 mmol) and the reaction mixture was stirred at
50 °C for 6 h. The solution was concentrated to a low volume
then cooled and filtered to give a white solid. The filtrate was
concentrated and purified by chromatography with silica gel
This journal is © The Royal Society of Chemistry 2012
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(2H, d, J = 7.7 Hz), 7.28 (1H, t, J = 7.7 Hz); 13C NMR
(101 MHz, CDCl3): δC 172.5, 138.6, 134.5, 116.7; IR (neat):
νmax/cm−1 3069, 1563, 1437, 1279, 777, 733; HRMS (ES-ToF):
calcd for C6H3NOBr2 (M + H)+: 265.8633, found 265.8625.
in dichloromethane (5 mL) was added 1,3-dibromo-2-nitroso-
benzene (163 mg, 0.62 mmol), and the solution stirred at r.t. for
72 h. The solvent was removed and the crude residue was chro-
matographed on silica gel (diethyl ether–petrol, 80 : 20) to yield
the title compound as an oil, 256 mg (73%).
Rf 0.22 (UV active, diethyl ether–petrol, 80 : 20); 1H NMR
(400 MHz, CDCl3): δH 7.49–7.23 (11H, m), 6.98 (2H, d, J =
6.3 Hz), 6.90 (1H, t, J = 8.0 Hz), 6.62 (1H, br s, OH), 5.82 (1H,
d, J = 15.8 Hz), 5.34 (1H, t, J = 3.2, 2.9 Hz), 5.18 (1H, d, J =
15.8 Hz), 4.03–3.97 (1H, m), 3.78 (1H, d, J = 7.9 Hz),
3.03–2.97 (1H, m), 1.91–1.84 (1H, m); 13C NMR (101 MHz,
CDCl3): 178.0, 174.2, 144.3, 139.2, 136.2, 135.8, 131.6, 129.5,
129.4, 129.0, 128.1, 127.3, 126.4, 122.3, 56.2, 50.0, 39.4, 38.4,
30.6; IR (neat): νmax/cm−1 2980, 2907, 2850, 1781, 1713, 1598,
1497, 1377, 748, 717, 691, 615; HRMS (ES-ToF): calcd for
(4S*,5aS*,8aS*)-1-Benzyl-4-(hydroxy(phenyl)amino)-7-phenyl-
5,5a,7,8a-tetrahydroimidazo[4,5-e]isoindole-6,8(1H,4H)-dione (6a)
To (5aS*,8aS*)-1-benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a) (200 mg, 0.56 mmol)
in dichloromethane (15 mL) was added nitrosobenzene (60 mg,
0.56 mmol) and the solution stirred at r.t. for 1 h. The reaction
was concentrated and purified by chromatography with silica gel
(ethyl acetate–petroleum ether 40–60, 50 : 50) to yield the
product as an off-white solid, 248 mg (95%).
Rf 0.33 (UV active, ethyl acetate–petroleum ether 40–60,
50 : 50); mp: 189–190 °C; 1H NMR (400 MHz, CDCl3): δH 7.61
(1H, s), 7.47–7.44 (2H, m), 7.40–7.34 (4H, m), 7.28–7.18 (8H,
m), 6.96 (1H, t, J = 7.2 Hz, N-phenyl C–H), 5.67 (1H, d, J =
15.3 Hz), 5.34 (1H, d, J = 15.3 Hz), 4.75 (1H, dd, J = 7.8, 4.9
Hz), 3.94 (1H, d, J = 8.1 Hz), 3.55 (1H, dd, J = 13.1, 5.5 Hz),
2.38–2.32 (1H, m), 2.25–2.18 (1H, m); 13C NMR (101 MHz,
CDCl3): δC 177.0, 174.7, 150.8, 139.4, 138.7, 135.7, 131.5,
129.3, 129.2, 128.9, 128.8, 128.4, 127.6, 126.4, 122.0, 121.4,
117.2, 57.5, 49.9, 39.4, 38.7, 23.4; IR (neat): νmax/cm−1 2980,
2884, 1773, 1715, 1597, 1496, 1377, 734, 690; HRMS (ES-ToF):
calcd for C28H23N4O3 (M + H)+: 465.1921, found 465.1916.
C28H22Br2N4O3 (M +
H)+: 621.0131, found 621.0130;
EA: calcd C: 54.04%, H: 3.56%, N: 9.00%, found C: 53.92%,
H: 3.45%, N: 8.95%.
(4R*,5aS*,8aS*)-1-Benzyl-4,7-diphenyl-5,5a,7,8a-tetrahydro-
imidazo[4,5-e]isoindole-6,8(1H,4H)-dione (6d)
To (5aS*,8aS*)-1-benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a) (200 mg, 0.56 mmol)
and trimethylsilylphenyl triflate (250 mg, 0.84 mmol, 204 μL) in
dichloromethane (10 mL) was added tetra-butylammonium
fluoride (1 M in THF, 219 mg, 0.84 mmol, 840 μL) and the solu-
tion heated at 40 °C for 2 h. The solvent was removed and the
crude residue was chromatographed on silica gel (diethyl ether–
petroleum ether 40–60, 50 : 50 → diethyl ether) to yield the title
compound as a white solid, 165 mg (68%).
(4S*,5aS*,8aS*)-1-Benzyl-4-(hydroxy(o-tolyl)amino)-7-phenyl-
5,5a,7,8a-tetrahydroimidazo[4,5-e]isoindole-6,8(1H,4H)-dione (6b)
To (5aS*,8aS*)-1-benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a) (200 mg, 0.56 mmol)
in dichloromethane (5 mL) was added 2-nitrosotoluene (81 mg,
0.67 mmol) and the solution stirred at r.t. for 2 h. The solvent
was removed and the crude residue was chromatographed on
silica gel (diethyl ether) to yield the title compound as an off-
white solid, 181 mg (68%).
1
Rf 0.13 (UV active, diethyl ether); mp: 228–229 °C; H NMR
(400 MHz, CDCl3): δH 7.55 (1H, s), 7.47–7.45 (2H, m),
7.40–7.30 (6H, m), 7.29–7.19 (5H, m), 7.14–7.12 (2H, m), 5.77
(1H, d, J = 15.6 Hz), 5.32 (1H, d, J = 15.6 Hz), 4.08 (1H, dd,
J = 8.1, 4.9 Hz), 3.94 (1H, d, J = 8.2 Hz), 3.38–3.33 (1H, m),
2.65–2.59 (1H, m), 2.17–2.10 (1H, m); 13C NMR (101 MHz,
CDCl3): δC 177.1, 174.8, 142.1, 141.7, 139.4, 136.2, 131.6,
129.3, 129.2, 128.9, 128.7, 128.4, 128.2, 127.4, 127.0, 126.4,
119.9, 49.8, 39.5, 38.9, 38.8, 32.9; IR (neat): νmax/cm−1 3034,
2916, 2866, 1775, 1703, 1598, 1496, 734, 693; HRMS
(ES-ToF): calcd for C28H23N3O2 (M + H)+: 434.1863, found
434.1862.
1
Rf 0.12 (UV active, diethyl ether); mp: 202–204 °C; H NMR
(400 MHz, CDCl3): δH 7.60 (1H, d, J = 7.3 Hz), 7.49 (1H, s),
7.46–7.42 (2H, m), 7.39–7.33 (4H, m), 7.25–7.14 (5H, m),
7.12–7.10 (1H, m), 7.06–7.03 (1H, m), 6.82 (1H, br s),
5.70 (1H, d, J = 15.6 Hz), 5.30 (1H, d, J = 15.6 Hz), 4.29 (1H,
dd, J = 7.3, 5.0 Hz), 3.90 (1H, d, J = 7.8 Hz), 3.64–3.59 (1H,
m), 2.39–2.32 (1H, m), 2.26 (3H, s), 2.16–2.10 (1H, m);
13C NMR (101 MHz, CDCl3): δC 176.9, 174.6, 149.0, 139.2,
135.7, 131.5, 131.3, 130.8, 129.3, 129.2, 128.9, 128.4, 127.6,
126.4, 126.3, 125.2, 121.8, 121.1, 57.9, 49.9, 39.5, 38.7, 24.8,
18.1; IR (neat): νmax/cm−1 3068, 3030, 2879, 1781, 1703, 1597,
1498, 1377, 730, 691; HRMS (ES-ToF): calcd for C29H28N4O3
(M + H)+: 479.2078, found 479.2065; HRMS (ES-ToF): calcd
for C29H26N4O3 ([M − H2O] + H)+: 461.1972, found 461.1967.
(4S*,5aS*,8aS*)-1-Benzyl-4-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-
1-yl)-7-phenyl-5,5a,7,8a-tetrahydroimidazo[4,5-e]isoindole-6,8-
(1H,4H)-dione (6e)
To (5aS*,8aS*)-1-benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a) (200 mg, 0.56 mmol)
in dichloromethane (7 mL) at −78 °C was added 4-phenyl-1,2,4-
triazoline-3,5-dione (98 mg, 0.56 mmol) in dichloromethane
(3 mL) dropwise, and the solution stirred for 1 h. The solvent
was removed and the crude residue was chromatographed on
silica gel (ethyl acetate 100%) to yield the title compound as a
white solid, 220 mg (74%).
(4S*,5aS*,8aS*)-1-Benzyl-4-((2,6-dibromophenyl)(hydroxy)amino)-
7-phenyl-5,5a,7,8a-tetrahydroimidazo[4,5-e]isoindole-6,8(1H,4H)-
dione (6c)
To (5aS*,8aS*)-1-benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a) (200 mg, 0.56 mmol)
Rf 0.31 (UV active, ethyl acetate, 100%); mp: 173–174 °C; 1H
NMR (400 MHz, CDCl3): δH 7.44–7.26 (12H, m), 7.16 (2H, d,
6652 | Org. Biomol. Chem., 2012, 10, 6649–6655
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J = 7.4 Hz), 7.07–7.05 (2H, m), 5.46 (1H, d, J = 15.4 Hz), 5.28
(1H, dd, J = 8.1, 5.4 Hz), 5.17 (1H, d, J = 15.4 Hz), 3.92 (1H, d,
J = 8.2 Hz), 3.51–3.46 (1H, m), 2.63–2.57 (1H, m), 2.18–2.11
(1H, m); 13C NMR (101 MHz, CDCl3): δC 176.1, 174.1, 154.7,
153.6, 139.8, 135.4, 135.1, 131.4, 129.3, 129.3, 129.2, 129.0,
128.6, 128.3, 127.7, 126.5, 126.0, 122.2, 49.9, 49.6, 38.8, 38.3,
26.0; IR (neat): νmax/cm−1 3067, 1770, 1705, 1598, 1499, 862,
739, 692; HRMS (ES-ToF): calcd for C30H24N6O4 (M + H)+:
533.1932, found 533.1923; EA: calcd C: 67.66%, H: 4.54%, N:
15.78%, found C: 67.73%, H: 4.58%, N: 15.59%.
837, 777, 692; HRMS (ES-ToF): calcd for C29H35N3O3Si
(M + H)+: 502.2520, found 502.2517.
(4S*,5R*,5aS*,8aS*)-1-Benzyl-5-(((tert-butyldimethylsilyl)oxy)-
methyl)-4-(3,5-dioxo-4-phenyl-1,2,4-triazolidin-1-yl)-7-phenyl-
5,5a,7,8a-tetrahydroimidazo[4,5-e]isoindole-6,8(1H,4H)-dione (6g)
To (5S*,5aS*,8aS*)-1-benzyl-5-(((tert-butyldimethylsilyl)oxy)-
methyl)-7-phenyl-1,5,5a,8b-tetrahydroimidazo[4,5-e]isoindole-6,8-
(7H,8aH)-dione (5b) (250 mg, 0.50 mmol) in dichloromethane
(5 mL) at −78 °C was added dropwise 1,2,4-phenyltriazoline-
3,5-dione (87 mg, 0.50 mmol) in dichloromethane (5 mL), and
the solution stirred for 1 h. The solvent was removed and the
crude residue was chromatographed on silica gel (eluting with
diethyl ether–methanol, 98 : 2) to yield the major diastereo-
isomer as an orange solid, 206 mg (61%).
Diethyl 2-((4S*,5aS*,8aS*)-1-benzyl-6,8-dioxo-7-phenyl-1,4,5,5a,
6,7,8,8a-octahydroimidazo[4,5-e]isoindol-4-yl)-2-hydroxymalonate
(6f)
To (5aS*,8aS*)-1-benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a) (230 mg, 0.64 mmol)
in dichloromethane (6 mL) was added diethyl ketomalonate
(134 mg, 0.77 mmol, 118 μL) and the solution stirred at r.t. for
16 h. The solvent was removed and the crude residue was chro-
matographed on silica gel (diethyl ether) to yield the title com-
pound as a white solid, 283 mg (83%).
Rf 0.37 (UV active, diethyl ether–methanol, 95 : 5); mp:
1
147–148 °C; H NMR (300 MHz, CDCl3): δH 7.57–7.37 (12H,
m), 7.22–7.18 (3H, m), 5.63 (1H, d, J = 15.4 Hz), 5.35–5.32
(1H, m), 5.29 (1H, d, J = 15.4 Hz), 4.37 (1H, dd, J = 10.5,
6.2 Hz), 4.12 (1H, dd, J = 10.5, 6.2 Hz), 3.99 (1H, d, J = 8.1
Hz), 3.83 (1H, dd, J = 8.1, 4.5 Hz), 2.52–2.45 (1H, m);
13C NMR (101 MHz, CDCl3): 175.1, 174.0, 154.8, 154.0,
140.2, 136.0, 135.5, 131.6, 131.5, 129.4, 129.4 129.3, 129.1,
128.7, 128.5, 127.8, 126.5, 126.2, 122.5, 62.7, 52.9, 50.1, 42.4,
40.7, 39.5, 26.2, 18.6, −5.2, −5.3; IR: νmax/cm−1 3067, 2930,
2857, 1771, 1712, 1600, 1500, 1380, 836, 778, 705, 690;
HRMS (ES-ToF): calcd for C37H40N6O5Si (M + H)+: 677.2902,
found 677.2899.
1
Rf 0.16 (UV active, diethyl ether); mp: 147–149 °C; H NMR
(400 MHz, CDCl3): δH 7.47–7.28 (7H, m), 7.24–7.23 (2H, m),
7.15–7.13 (2H, m), 5.61 (1H, d, J = 15.5 Hz), 5.28 (1H, d, J =
15.5 Hz), 4.46–4.22 (4H, m), 4.13 (1H, s, OH), 3.92 (1H, dd,
J = 8.4, 1.3 Hz), 3.85 (1H, dd, J = 9.9, 4.5 Hz), 3.56–3.52 (1H,
m), 2.39 (1H, dt, J = 13.4, 4.6 Hz), 2.08–2.00 (1H, m),
1.34–1.31 (6H, m); 13C NMR (101 MHz, CDCl3): δC 177.1,
175.1, 170.3, 169.6, 138.9, 137.9, 136.0, 131.8, 129.5, 129.4,
129.1, 128.5, 127.8, 126.6, 120.8, 80.8, 63.2, 63.1, 49.9, 40.1,
38.7, 37.4, 24.3, 14.4, 14.3; IR (neat): νmax/cm−1 3481, 2982,
2967, 1783, 1711, 1734, 1597, 1499, 1380, 1249, 1029, 1185,
737, 690; HRMS (ES-ToF): calcd for C29H29N3O7 (M + H)+:
532.2078, found 532.2071.
(4S*,5R*,5aS*,8aS*)-Diethyl 2-(1-benzyl-5-(((tert-butyldimethylsilyl)-
oxy)methyl)-6,8-dioxo-7-phenyl-1,4,5,5a,6,7,8,8a-octahydroimidazo-
[4,5-e]isoindol-4-yl)-2-hydroxymalonate (6h)
To (5S*,5aS*,8aS*)-1-benzyl-5-(((tert-butyldimethylsilyl)oxy)-
methyl)-7-phenyl-1,5,5a,8b-tetrahydroimidazo[4,5-e]isoindole-6,8-
(7H,8aH)-dione (7b) (250 mg, 0.50 mmol) in dichloromethane
(18 mL) was added diethyl ketomalonate (87 mg, 76 μL,
0.50 mmol) and the solution stirred at r.t. for 16 h. The solvent
was removed and the crude residue was chromatographed on
silica gel (diethyl ether–petroleum ether 40–60, 60 : 40) to yield
the title compound as a white solid, 175 mg (65%).
(5S*,5aS*,8aS*)-1-Benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl)-
7-phenyl-1,5,5a,8b-tetrahydroimidazo[4,5-e]isoindole-6,8(7H,8aH)-
dione (5b)
To (E)-1-benzyl-4-(3-(tert-butyldimethylsilyloxy)prop-1-enyl)-
1H-imidazole (772 mg, 2.35 mmol) in dichloromethane
(23.5 mL) was added N-phenylmaleimide (1.02 g, 5.87 mmol)
and the solution stirred at 50 °C for 16 h. The solvent was
removed and the crude residue was chromatographed on silica
gel (petroleum ether 40–60–ethyl acetate, 25 : 75) to yield the
title compound as a white solid, 802 mg (68%).
Rf 0.32 (UV active, petroleum ether 40–60–ethyl acetate,
25 : 75); mp: 199–201 °C (lit.6b mp: 203–204 °C); 1H NMR
(400 MHz, CDCl3) δH 7.46–7.33 (7H, m), 7.31–7.29 (2H, m),
7.12–7.10 (2H, m), 5.44 (1H, dd, J = 4.1, 4.1 Hz), 4.91 (1H, d,
J = 15.2 Hz), 4.80 (1H, d, J = 15.2 Hz), 4.35 (1H, dd, J = 9.6,
8.9 Hz), 4.06–4.01 (2H, m), 3.62 (1H, t, J = 8.4 Hz), 3.35 (1H,
dd, J = 8.5, 4.9 Hz), 2.24–2.15 (1H, m), 0.89 (9H, s), 0.09 (6H,
s); 13C NMR (101 MHz, CDCl3): δC 175.8, 173.9, 159.9, 154.4,
135.5, 134.4, 131.8, 129.4, 129.0, 128.6, 128.3, 126.9, 105.1,
63.1, 57.8, 50.3, 41.9, 41.8, 38.2, 26.2, 18.6, −5.0, −5.1; IR
(neat): νmax/cm−1 2951, 2927, 2855, 1772, 1703, 1541, 1498,
Rf 0.22 (UV active, diethyl ether–petroleum ether, 25 : 75);
1
mp: 112–114 °C; H NMR (400 MHz, CDCl3): δH 7.45–7.25
(9H, m), 7.06–7.04 (2H, m), 5.70 (1H, d, J = 15.6 Hz), 5.32
(1H, d, J = 15.6 Hz), 4.43–4.36 (2H, m), 4.29 (2H, q, J =
7.2 Hz), 4.03 (1H, s), 3.97 (1H, dd, J = 8.6, 6.5 Hz), 3.84 (1H,
br s), 3.77–3.71 (3H, m), 2.75–2.71 (1H, m), 1.36 (3H, t, J =
7.2 Hz), 1.31 (3H, t, J = 7.2 Hz), 0.72 (9H, s), −0.10 (3H, s),
−0.18 (3H, s); 13C NMR (101 MHz, CDCl3): 176.9, 174.9,
170.6, 169.5, 138.6, 136.4, 135.7, 132.2, 129.4, 129.3, 128.9,
128.4, 127.5, 126.7, 122.2, 82.6, 66.2, 64.9, 63.6, 62.8, 50.1,
41.9, 41.7, 39.9, 38.6, 26.1, 18.6, 15.6, 14.4, 14.3, −5.4; IR
(neat): νmax/cm−1 3474, 2988, 2941, 1711, 1597, 1498, 1381,
1284, 1225, 1248, 1029, 1185, 740, 691; HRMS (ES-ToF):
calcd for C36H45N3O8Si (M + H)+: 676.3049, found 676.3042;
EA: calcd C: 63.98%, H: 6.71%, N: 6.22%, found C: 63.99%,
H: 6.65%, N: 6.12%.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6649–6655 | 6653

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(R*)-Ethyl 2-((4S*,5aS*,8aS*)-1-benzyl-6,8-dioxo-7-phenyl-1,4,5,5a,
6,7,8,8a-octahydroimidazo[4,5-e]isoindol-4-yl)-2-hydroxyacetate
(7a) and (S*)-ethyl 2-((4S*,5aS*,8aS*)-1-benzyl-6,8-dioxo-7-
phenyl-1,4,5,5a,6,7,8,8a-octahydroimidazo[4,5-e]isoindol-4-yl)-2-
hydroxyacetate (8a)
ethyl glyoxalate (50% in toluene, 0.48 mmol, 98 μL) and the
solution stirred at r.t. for 16 h. The solvent was removed and the
crude residue was chromatographed on silica gel (diethyl ether)
to yield the title compound as a white solid, 142 mg (59%).
NB: only one diastereomer was observed.
1
Rf 0.23 (UV active, diethyl ether); mp: 76–78 °C; H NMR
To (5aS*,8aS*)-1-benzyl-7-phenyl-1,5,5a,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (5a) (200 mg, 0.56 mmol)
in dichloromethane (5 mL) was added ethyl glyoxalate (50% in
toluene, 0.14 mmol, 0.67 mL) and the solution stirred at r.t. for
30 h. The solvent was removed and the crude residue was chro-
matographed on silica gel (ethyl acetate–methanol, 95 : 5) to
yield the major diastereomer 7a as a white solid, 154 mg (60%),
and the minor diastereomer 8a as a white solid, 32 mg (12%).
(400 MHz, CDCl3): δH 7.48–7.44 (3H, m), 7.40–7.29 (4H, m),
7.24–7.22 (2H, m), 7.13–7.11 (2H, m), 5.64 (1H, d, J =
15.5 Hz), 5.27 (1H, d, J = 15.5 Hz), 4.45 (1H, dd, J = 6.4, 2.5
Hz), 4.40 (1H, dq, J = 10.7, 7.1 Hz), 4.33 (1H, dq, J = 10.7,
7.1 Hz), 4.13 (1H, dd, J = 9.8, 7.3 Hz), 3.96–3.91 (2H, m), 3.85
(1H, d, J = 8.2 Hz), 3.51–3.49 (1H, m), 2.98 (1H, d, J =
6.4 Hz), 2.58–2.52 (1H, m), 1.34 (3H, t, J = 7.1 Hz), 0.84 (9H,
s), 0.02 (3H, s), 0.00 (3H, s); 13C NMR (101 MHz, CDCl3): δC
176.2, 174.9, 174.1, 139.3, 136.3, 134.0, 131.9, 129.6, 129.4,
129.1, 128.5, 127.3, 126.6, 122.5, 64.6, 62.6, 50.3, 41.5, 39.0,
38.9, 38.1, 26.0, 18.5, 14.2, −5.3, −5.4; IR (neat): νmax/cm−1
2953, 2929, 2857, 1782, 1714, 1498, 1377, 1252, 1191, 1099,
836, 778, 691; HRMS (ES-ToF): calcd for C33H41N3O6Si
(M + H)+: 604.2837, found 604.2822.
Major diastereomer
(S*)-Ethyl
2-((4S*,5aS*,8aS*)-1-benzyl-6,8-dioxo-7-phenyl-
1,4,5,5a,6,7,8,8a-octahydroimidazo[4,5-e]isoindol-4-yl)-2-hydro-
xyacetate (7a). Rf 0.18 (UV active, ethyl acetate–methanol,
95 : 5); mp: 80–82 °C; 1H NMR (400 MHz, CDCl3): δH
7.47–7.43 (3H, m), 7.40–7.32 (4H, m), 7.25–7.21 (2H, m),
7.16–7.14 (2H, m), 5.64 (1H, d, J = 15.5 Hz), 5.28 (1H, d, J =
15.5 Hz), 4.38 (1H, dq, J = 10.7, 7.1 Hz), 4.33–4.24 (2H, m),
4.08 (1H, br s), 3.92 (1H, dd, J = 8.4, 1.0 Hz), 3.56–3.52 (1H,
m), 3.29–3.24 (1H, m), 2.53 (1H, dt, J = 13.6, 4.6 Hz), 1.97
(1H, ddd, J = 13.7, 10.4, 5.6 Hz), 1.32 (3H, t, J = 7.2 Hz);
13C NMR (101 MHz, CDCl3): δC 177.1, 175.1, 173.3, 139.1,
139.0, 136.0, 131.8, 129.5, 129.5, 129.2, 128.7, 127.8, 126.7,
120.6, 73.6, 62.1, 50.0, 40.2, 38.8, 35.6, 26.3, 14.6; IR:
νmax/cm−1 2935, 1709, 1597, 1497, 1383, 1187, 724, 693;
HRMS (ES-ToF): calcd for C26H24N3O5 (M + H)+: 460.1867,
found 460.1862.
(S*)-Ethyl 2-((4S*,5aS*,8aS*)-1-benzyl-6,8-dioxo-7-phenyl-1,4,5,
5a,6,7,8,8a-octahydroimidazo[4,5-e]isoindol-4-yl)-3,3,3-trifluoro-
2-hydroxypropanoate (7c). To (5aS*,8aS*)-1-benzyl-7-phenyl-
1,5,5a,8b-tetrahydroimidazo[4,5-e]isoindole-6,8(7H,8aH)-dione
(5a) (90 mg, 0.25 mmol) in dichloromethane (2 mL) was added
ethyl trifluoropyruvate (64 mg, 0.38 mmol, 50 μL) and the solu-
tion stirred at r.t. for 16 h. The solvent was removed and the
crude residue was chromatographed on silica gel (diethyl ether–
petroleum ether 40–60, 60 : 40) to yield the title compound as a
white solid, 70 mg (53%). NB: only one diastereomer was
observed.
Rf 0.77 (UV active, ethyl acetate–petroleum ether 40–60,
2 : 1); mp: 174–175 °C; 1H NMR (400 MHz, CDCl3): δH
7.47–7.43 (2H, m), 7.40–7.31 (5H, m), 7.25–7.23 (2H, m),
7.12–7.11 (2H, m), 5.65 (1H, d, J = 15.5 Hz), 5.28 (1H, d,
J = 15.5 Hz), 4.52 (1H, dqd, J = 10.6, 7.1, 1.4 Hz), 4.37 (1H,
dqd, J = 10.6, 7.1, 1.4 Hz), 4.02 (1H, d, J = 1.0 Hz), 3.90 (1H,
d, J = 8.2 Hz), 3.67 (1H, dd, J = 9.2, 5.0 Hz), 3.62–3.57 (1H,
m), 2.61–2.55 (1H, m), 2.23–2.16 (1H, m), 1.36 (3H, dt, J = 7.1,
1.4 Hz); 13C NMR (101 MHz, CDCl3): δC 176.9, 174.9, 169.9,
138.9, 136.6, 136.0, 131.8, 129.5, 129.5, 129.1, 128.6, 127.8,
126.6, 125.0 (q, J = 287.8 Hz), 121.5, 78.7 (q, J = 28.1 Hz),
64.3, 50.0, 39.9, 38.7, 35.4, 23.9, 14.2; 19F NMR (376 MHz,
CDCl3): δF −73.37; IR (neat): νmax/cm−1 3651, 2982, 1705,
1596, 1497, 1375, 1172, 739, 694; HRMS (ES-ToF): calcd for
C27H24F3N3O5 (M + H)+: 528.1741, found 528.1731; EA: calcd
C: 61.48%, H: 4.59%, N: 7.97%, found C: 61.59%, H: 4.52%,
N: 7.90%.
Minor diastereomer
(R*)-Ethyl
2-((4S*,5aS*,8aS*)-1-benzyl-6,8-dioxo-7-phenyl-
1,4,5,5a,6,7,8,8a-octahydroimidazo[4,5-e]isoindol-4-yl)-2-hydro-
xyacetate (8a). Rf 0.10 (UV active, ethyl acetate–methanol,
95 : 5); mp: 198–199 °C; H NMR (400 MHz, CDCl3): δH 7.52
1
(1H, s), 7.47–7.43 (2H, m), 7.40–7.32 (4H, m), 7.21–7.16 (4H,
m), 5.62 (1H, d, J = 15.4 Hz), 5.31 (1H, d, J = 15.4 Hz), 5.02
(1H, br s), 4.33 (1H, dq, J = 10.6, 7.1 Hz), 4.22 (1H, dq, J =
10.6, 7.1 Hz), 3.95 (1H, d, J = 8.4 Hz), 3.68 (1H, br s),
3.54–3.49 (1H, m), 3.28–3.25 (1H, m), 2.28 (1H, dt, J = 13.5,
4.2 Hz), 1.98 (1H, ddd, J = 13.5, 10.6, 5.5 Hz), 1.30 (3H, t, J =
7.1 Hz); 13C NMR (101 MHz, CDCl3): δC 177.1, 175.1, 174.0,
139.4, 139.2, 136.0, 131.8, 129.6, 129.4, 129.2, 128.6, 127.9,
126.7, 120.5, 70.9, 62.1, 50.0, 40.2, 38.9, 35.8, 22.6, 14.6; IR
(neat): νmax/cm−1 2933, 1743, 1712, 1597, 1495, 1383, 1190,
726, 691; HRMS (ES-ToF): calcd for C26H26N3O5 (M + H)+:
460.1867, found 460.1865.
(S*)-Ethyl 2-((4S*,5S*,5aS*,8aS*)-1-benzyl-5-(((tert-butyl-
dimethylsilyl)oxy)methyl)-6,8-dioxo-7-phenyl-1,4,5,5a,6,7,8,8a-octa-
hydroimidazo[4,5-e]isoindol-4-yl)-3,3,3-trifluoro-2-hydroxypropanoate
(7d) and (2R*)-ethyl 2-((5aS*,8aS*)-1-benzyl-5-(((tert-butyldi-
methylsilyl)oxy)methyl)-6,8-dioxo-7-phenyl-1,4,5,5a,6,7,8,8a-octa-
hydroimidazo[4,5-e]isoindol-4-yl)-3,3,3-trifluoro-2-hydroxy-
Ethyl 2-((5S*,5aS*,8aS*)-1-benzyl-5-(((tert-butyldimethylsilyl)-
oxy)methyl)-6,8-dioxo-7-phenyl-1,4,5,5a,6,7,8,8a-octahydroimidazo-
[4,5-e]isoindol-4-yl)-2-hydroxyacetate (7b). To (5S*,5aS*,8aS*)-1-
benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl)-7-phenyl-1,5,5a,
propanoate
(8d). To
(5S*,5aS*,8aS*)-1-benzyl-5-(((tert-
8b-tetrahydroimidazo[4,5-e]isoindole-6,8(7H,8aH)-dione
(5b)
butyldimethylsilyl)oxy)methyl)-7-phenyl-1,5,5a,8b-tetrahydro-
(200 mg, 0.40 mmol) in dichloromethane (6 mL) was added
imidazo[4,5-e]isoindole-6,8(7H,8aH)-dione (5b) (400 mg,
6654 | Org. Biomol. Chem., 2012, 10, 6649–6655
This journal is © The Royal Society of Chemistry 2012

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0.80 mmol) in dichloromethane (6 mL) was added ethyl trifluoro-
pyruvate (162 mg, 0.12 mL, 0.96 mmol) and the solution stirred
at r.t. for 72 h. The solvent was removed and the crude residue
was chromatographed on silica gel (diethyl ether–petrol, 40 : 60)
to yield the major diastereoisomer 7d as pale yellow crystals,
196 mg (36%), and the minor diastereoisomer 8d as a white
solid, 92 mg (17%).
EPSRC for X-ray crystallography facilities at Newcastle (EP/
F03637X/1), the EPSRC National Mass Spectrometry Service
(University of Swansea), Diamond Light Source for access to
beamline I19 and Dr David Allan for assistance with data collec-
tion, Prof. William McFarlane and Dr Corinne Wills (Newcastle)
for NMR studies, and Dr Tom Sheppard (University College
London) for advice on the synthesis of 2,6-dibromo-1-
nitrosobenzene.
Major diastereomer
(S*)-Ethyl 2-((4S*,5S*,5aS*,8aS*)-1-benzyl-5-(((tert-butyldi-
methylsilyl)oxy)methyl)-6,8-dioxo-7-phenyl-1,4,5,5a,6,7,8,8a-
octahydroimidazo[4,5-e]isoindol-4-yl)-3,3,3-trifluoro-2-hydroxy-
propanoate (7d). Rf 0.30 (UV active, diethyl ether–petrol,
50 : 50); mp: 176–178 °C; 1H NMR (400 MHz, CDCl3): δH
7.49–7.31 (7H, m), 7.25–7.23 (2H, m), 7.03–7.01 (2H, m), 5.80
(1H, d, J = 15.7 Hz), 5.33 (1H, d, J = 15.7 Hz), 4.55–4.43 (2H,
m), 4.04 (1H, s), 3.96 (1H, dd, J = 8.6, 6.1 Hz), 3.78 (1H, br s),
3.71 (1H, d, J = 8.6 Hz), 3.61 (1H, dd, J = 10.1, 4.5 Hz), 3.44
(1H, dd, J = 10.1, 8.4 Hz), 3.10–3.06 (1H, m), 1.45 (3H, t, J =
7.2 Hz), 0.80 (9H, s), −0.09 (3H, s), −0.10 (3H, s); 13C NMR
(101 MHz, CDCl3): δC 176.2, 174.9, 169.9, 139.3, 136.3, 134.0,
131.9, 129.6, 129.4, 129.1, 128.5, 127.3, 126.6, 122.5, 64.6,
62.6, 50.3, 41.5, 39.0, 38.9, 38.1, 26.0, 18.5, 14.2, −5.3, −5.4;
19F NMR (376 MHz, CDCl3): δF −72.62; IR (neat): νmax/cm−1
3435, 2949, 2935, 2865, 1749, 1781, 1712, 1598, 1498, 1374,
1244, 1027, 1158, 1149, 1098, 836, 775, 689; HRMS (ES-ToF):
Notes and references
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calcd for C34H40F3N3O6Si (M
672.2705.
+
H)+: 672.2711, found
Minor diastereomer
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14 The crystallographic data for 6b, 7c, 7d, 8a, and rearomatised 5a have
been deposited with the Cambridge Crystallographic Data Centre, depo-
sition nos. CCDC 860567–860571, respectively.
(R*)-Ethyl 2-((4S*,5S*,5aS*,8aS*)-1-benzyl-5-(((tert-butyldi-
methylsilyl)oxy)methyl)-6,8-dioxo-7-phenyl-1,4,5,5a,6,7,8,8a-
octahydroimidazo[4,5-e]isoindol-4-yl)-3,3,3-trifluoro-2-hydroxy-
propanoate (8d). Rf 0.15 (UV active, diethyl ether–petrol,
50 : 50); mp: 113–114 °C; 1H NMR (400 MHz, CDCl3): δH 7.57
(1H, s), 7.48–7.30 (6H, m), 7.23–7.21 (2H, m), 7.05–7.04 (2H,
m), 5.85 (1H, d, J = 15.8 Hz), 5.36 (1H, d, J = 15.8 Hz), 4.69
(1H, s), 4.37 (1H, dq, J = 10.7, 7.2 Hz), 4.29 (dq, J = 10.7, 7.2
Hz), 3.92 (1H, s), 3.88 (1H, dd, J = 8.7, 6.4 Hz), 3.75 (1H, d,
J = 8.7 Hz), 3.58 (1H, dd, J = 10.2, 4.2 Hz), 3.48 (1H, dd, J =
10.2, 7.5 Hz), 2.63–2.58 (1H, m), 1.32 (3H, t, J = 7.2 Hz), 0.76
(9H, s), −0.10 (3H, s), −0.14 (3H, s); 13C NMR (101 MHz,
CDCl3): δC 176.0, 174.5, 169.7, 139.3, 136.3, 133.8, 131.8,
129.5, 129.4, 129.1, 128.4, 127.2, 126.5, 123.1 (q, J = 287.4
Hz), 121.7, 80.9 (q, J = 28.7 Hz), 64.1, 63.1, 50.4, 41.5, 39.9,
38.4, 38.2, 26.0, 18.5, 14.2, −5.4, −5.5; 19F NMR (376 MHz,
CDCl3): δF −73.26; IR (neat): νmax/cm−1 3476, 3067, 2954,
2858, 1378, 1250, 1027, 1161, 1143, 836, 745, 692.
Acknowledgements
15 Crystallographic data for 7c are of low quality due to weak scattering and
suspected but unresolved twinning; however, they are sufficient for the
determination of the relative stereochemistry of the compound.
The authors thank Newcastle University for PhD funding
(L.J.W.), EPSRC for a “First Grant” to M.J.H. (EP/I033959/1),
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6649–6655 | 6655