Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl groups

Article abstract of DOI:10.1039/c2ob26057c

Sulfamates are important functional groups in certain areas of current medicinal chemistry and drug development. Alcohols and phenols are generally converted into the corresponding primary sulfamates (ROSO₂NH ₂ and ArOSO₂NH₂, respectively) by reaction with sulfamoyl chloride (H₂NSO₂Cl). The lability of the O-sulfamate group, especially to basic conditions, usually restricts this method to a later stage of a synthesis. To enable a more flexible approach to the synthesis of phenolic O-sulfamates, a protecting group strategy for sulfamates has been developed. Both sulfamate NH protons were replaced with either 4-methoxybenzyl or 2,4-dimethoxybenzyl. These N-protected sulfamates were stable to oxidising and reducing agents, as well as bases and nucleophiles, thus rendering such masked sulfamates suitable for multi-step synthesis. The protected sulfamates were synthesised by microwave heating of 1,1′-sulfonylbis(2-methyl-1H-imidazole) with a substituted phenol to give an aryl 2-methyl-1H-imidazole-1-sulfonate. This imidazole-sulfonate was N-methylated by reaction with trimethyloxonium tetrafluoroborate, which enabled subsequent displacement of 1,2-dimethylimidazole by a dibenzylamine (e.g. bis-2,4-dimethoxybenzylamine). The resulting N-diprotected, ring-substituted phenol O-sulfamates were further manipulated through reactions at the aryl substituent and finally deprotected with trifluoroacetic acid to afford a phenol O-sulfamate. The use of 2,4-dimethoxybenzyl was particularly attractive because deprotection occurred quantitatively within 2 h at room temperature with 10% trifluoroacetic acid in dichloromethane. The four key steps in the protocol described [reaction of 1,1′-sulfonylbis(2-methyl-1H-imidazole) with a phenol, methylation, displacement with a dibenzylamine and deprotection] all proceeded in very high yields.

Full text of DOI:10.1039/c2ob26057c

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PAPER
Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl
groups†
Tristan Reuillon, Annalisa Bertoli, Roger J. Griffin, Duncan C. Miller and Bernard T. Golding*
Received 1st June 2012, Accepted 31st July 2012
DOI: 10.1039/c2ob26057c
Sulfamates are important functional groups in certain areas of current medicinal chemistry and drug
development. Alcohols and phenols are generally converted into the corresponding primary sulfamates
(ROSO2NH2 and ArOSO2NH2, respectively) by reaction with sulfamoyl chloride (H2NSO2Cl). The
lability of the O-sulfamate group, especially to basic conditions, usually restricts this method to a later
stage of a synthesis. To enable a more flexible approach to the synthesis of phenolic O-sulfamates, a
protecting group strategy for sulfamates has been developed. Both sulfamate NH protons were replaced
with either 4-methoxybenzyl or 2,4-dimethoxybenzyl. These N-protected sulfamates were stable to
oxidising and reducing agents, as well as bases and nucleophiles, thus rendering such masked sulfamates
suitable for multi-step synthesis. The protected sulfamates were synthesised by microwave heating of
1,1′-sulfonylbis(2-methyl-1H-imidazole) with a substituted phenol to give an aryl 2-methyl-1H-
imidazole-1-sulfonate. This imidazole-sulfonate was N-methylated by reaction with trimethyloxonium
tetrafluoroborate, which enabled subsequent displacement of 1,2-dimethylimidazole by a dibenzylamine
(e.g. bis-2,4-dimethoxybenzylamine). The resulting N-diprotected, ring-substituted phenol O-sulfamates
were further manipulated through reactions at the aryl substituent and finally deprotected with
trifluoroacetic acid to afford a phenol O-sulfamate. The use of 2,4-dimethoxybenzyl was particularly
attractive because deprotection occurred quantitatively within 2 h at room temperature with 10%
trifluoroacetic acid in dichloromethane. The four key steps in the protocol described [reaction of
1,1′-sulfonylbis(2-methyl-1H-imidazole) with a phenol, methylation, displacement with a dibenzylamine
and deprotection] all proceeded in very high yields.
sulfamate groups (–OSO2NH2) can compromise their passage
through several steps of a synthesis. In a drug discovery program
Introduction
The success of the O-sulfamate topiramate as a treatment for
epilepsy and migraine1 and the discovery of O-sulfamates that
inhibit steroid sulfatase2 and carbonic anhydrase,3 has encour-
aged the search for new therapeutically useful derivatives of
sulfamic acid (NH2SO3H). The conversion of alcohols (ROH) and
phenols (ArOH) into the corresponding sulfamates (ROSO2NH2
and ArOSO2NH2, respectively) is generally performed by direct
reaction with sulfamoyl chloride (H2NSO2Cl), which is prepared
from chlorosulfonyl isocyanate and formic acid.4 This method is
best implemented at a late stage of a synthesis owing to the
inherent lability of O-sulfamates, particularly under basic con-
ditions, which facilitates decomposition by an E1Cb mechanism.
Furthermore, in common with O-sulfates the polarity of
for which phenol O-sulfamates were targets we needed a strategy
for the protection of the amido (NH2) group of such sulfamates.
The aim was to render these sulfamates stable to bases and
nucleophiles, thus able to survive a multi-step synthesis before
release of the free phenol O-sulfamate at the final stage.
Results and discussion
The sensitivity of primary sulfamates to basic conditions was
apparent when attempts to perform Suzuki cross-couplings on
phenol O-sulfamates without protection of the amido group led
to low product yields, giving predominantly a mixture of
desulfamoylated product and starting material (Scheme 1). A
variety of conditions was explored in which the base component
was varied. The best results were obtained with weak bases such
as sodium carbonate with 1,1′-bis(diphenylphosphino)ferrocene–
palladium(II)dichloride [Pd(dppf)Cl2] as catalyst. However,
despite extensive optimisation efforts, the highest product yield
was around 20%. The instability of primary phenol O-sulfamates
Newcastle Cancer Centre, Northern Institute for Cancer Research,
School of Chemistry, Bedson Building, Newcastle University, Newcastle
upon Tyne, NE1 7RU, UK. E-mail: bernard.golding@newcastle.ac.uk;
Fax: +44 (0)191 2226929; Tel: +44 (0)191 2226647
†Electronic supplementary information (ESI) available: Experimental
procedures and analytical data. See DOI: 10.1039/c2ob26057c
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Scheme 1 Synthesis of 3-hydroxybiphenyl O-sulfamate [Reagents and
conditions: i, H2NSO2Cl, DMA/toluene, 0 °C to room temp., 24 h,
87%; ii, PhB(OH)2, 2 M aq. Na2CO3, Pd(dppf)Cl2, DME, microwave
heating (80 °C, 20 min), 22%].
Scheme 3 Synthesis of 4-bromophenyl 2-methyl-1H-imidazole-1-sul-
fonate (5a) [Reagents and conditions: substituted phenol, Cs2CO3, THF,
microwave heating (80 °C, 30 min), 92%; for 5b–5m, see Table 2].
Attempted reaction of the imidazole-sulfate 5a with dibenzyl-
amine under various conditions failed to displace the imidazole
moiety. Activation of imidazole-sulfonates to nucleophilic attack
by methylation has been utilised for the synthesis of protected
sulfates of phenolic steroids (e.g. oestrone).14 In the first step, an
alkoxysulfonyl chloride was reacted with imidazole or 2-methyl-
imidazole to give an alkyl imidazole-1-sulfonate. Following
methylation with methyl trifluoromethanesulfonate (methyl
triflate), the resulting sulfamoyl imidazolium salt acted as an
electrophilic sulfonyl donor: addition of oestrone gave the corre-
sponding protected sulfate. Owing to the extremely hazardous
nature of methyl triflate, Meerwein’s salt (trimethyloxonium tet-
rafluoroborate) was used in the present work to effect the methyl-
ation of aryl 2-methyl-1H-imidazole-1-sulfonates (e.g. 5a) in
high yield to give intermediate 6 [Scheme 4; n.b. attempts to
methylate sulfonyl-diimidazole 4 using Meerwein’s salt were
unsuccessful].15,16 Reactions of 6 with dibenzylamine or a
methoxy-substituted dibenzylamine at room temperature now
proceeded in high yields to give fully protected sulfamates (e.g.
7, 8a, 9a and 10) (Scheme 4). These compounds were subjected
to Suzuki cross-coupling conditions in the presence of potassium
carbonate, to afford the desired biphenyls (e.g. 11, 12, 13 and
14), with no desulfamoylation being observed.
Deprotection of bis-benzylsulfonamides is precedented
under strongly acidic conditions.17,18 However, subjecting the
bis-benzylsulfamate (11) to trifluoroacetic acid (48 h at room
temperature) or conc. sulfuric acid (24 h at room temperature)
resulted in exclusive recovery of starting material. As expected,
incorporation of the methoxy functionality at the 4-, 2,4- and
3,4-positions of the benzyl groups facilitated deprotection to
4-hydroxydiphenyl O-sulfamate 15a (Scheme 4, Table 1), result-
ing in high yields of the desired primary sulfamates under mild
to moderate acidic conditions. As the conditions required for
removing 3,4-dimethoxybenzyl were similar to those employed
for 4-methoxybenzyl, but the reaction proceeded in much poorer
yield, 3,4-dimethoxybenzyl protection was not studied further. It
should be noted that 4-methoxybenzyl-protected sulfamates are
stable to the acidic conditions that will remove an N-t-butyloxy-
carbonyl (BOC) group (see below).
Scheme 2 Synthesis of methoxy-substituted dibenzylamines [Reagents
and conditions: i, EtOH, heat at reflux, 4 h; ii, NaBH4, room temp.,
16 h].
under basic conditions is due to an E1Cb mechanism in which
deprotonation of one of the sulfamate NH2 protons precedes
elimination of the phenol.5
Reported protecting groups for sulfamates include N-alkyloxy-
carbonyl (alkyl = t-butyl-,6 benzyl-7 or methyl-8) and the N-t-
butyl group.9 However, these groups all retain one proton on the
sulfamate nitrogen and the sulfamate is still vulnerable to E1Cb
degradation. Hence, a protecting group that masks both NH2
protons may confer improved base stability on the sulfamate.
Although the NH2 group of sulfonamides has been protected
with benzyl groups, these can be difficult to remove from nitro-
gen atoms.10 The addition of electron-releasing groups to the
benzyl ring enables deprotection under mild acidic conditions.
Thus, benzyl (reference standard), 4-methoxybenzyl, 2,4-
dimethoxybenzyl and 3,4-dimethoxybenzyl were selected for
investigation as potential dual protecting groups for sulfamates.
This strategy required methoxy-substituted dibenzylamines
(1–3), which were readily prepared (Scheme 2).
Initially, the reaction of dibenzylamine with sulfuryl chloride
in the presence of pyridine or triethylamine was investigated, but
gave N,N-bis-benzylsulfamoyl chloride in poor yield. The sub-
sequent reaction of this chloride with phenols also proceeded in
disappointing yield.
1,1′-Sulfonylbis(2-methyl-1H-imidazole) (4) has been used as
a sulfonyl transfer reagent for the preparation of phenyl
2-methyl-1H-imidazole-1-sulfonates and for the synthesis of cyclic
sulfamates.11,12 The preparation of phenyl 2-methyl-1H-imida-
zole-1-sulfonates entailed the reaction of 4 with a phenoxide in
THF at room temperature. These conditions were reported to be
unsuitable for poorly nucleophilic phenols such as 4-nitrophenol
or 4-hydroxyacetophenone.13 We applied this method to the
preparation of 4-bromophenyl 2-methyl-1H-imidazole-1-sulfo-
nate. Thus, microwave irradiation of 4-bromophenol with 1,1′-
sulfonylbis(2-methyl-1H-imidazole) in the presence of caesium
carbonate afforded the corresponding 4-bromophenyl 2-methyl-
1H-imidazole-1-sulfonate (5a) in high yield (Scheme 3).
To investigate the scope and limitations of this methodology, a
range of phenols with diverse steric and electronic properties
was progressed through the synthetic sequence. For the reaction
of phenols with 1,1′-sulfonylbis(2-methyl-1H-imidazole), the
time required for completion of the reaction for phenols with no
ortho-substituent was found to correlate with the pKa of the
phenol: those with an electron-withdrawing substituent required
extended reaction times. Sterically hindered phenols such as
2,6-dimethylphenol also required prolonged reaction times.
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Table 2 Optimised conditions for microwave heating of substituted
phenols with 4
Phenol
substituent(s) pKa Product (isolated yield/%) (isolated yield/%)
Conditionsa
Conditionsb
4-MeO
4-Br
4-Cl
3-Cl
2-Cl
2,6-Me2
2,6-Cl2
4-NO2
3-NO2
2-NO2
4-CN
2-CN
4-CF3
10.4 5b
9.7 5a
9.5 5c
9.3 5d
7.7 5e
10.2 5f
7.1 5g
6.8 5h
9.3 5i
6.9 5j
7.7 5k
7.0 5l
8.5 5m
97
93
93
83
90
92
0
0
72
0
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
84
82
n.d.
70
59
0
80
80
72
n.d.
a 15 min, 120 °C, 1,1′-sulfonylbis(2-methyl-1H-imidazole (2 equiv.).
b 15 min, 180 °C, 1,1′-sulfonylbis(2-methyl-1H-imidazole (10 equiv.).
n.d. = not determined.
Scheme 4 Synthesis of 4-hydroxydiphenyl O-sulfamate 15a [Reagents
and conditions: i, Me3O·BF4, DCM, 0 °C to room temp., 8 h, 90%; ii,
Dibenzylamine (or 1, 2 or 3), MeCN, room temp., 16 h; iii, PhB(OH)2,
K2CO3, MeCN, microwave heating (120 °C, 20 min); iv, TFA, DCM,
for time and temp. see Table 1].
Table 3 Isolated yields for methylation/substitution with bis-4-
methoxybenzylamine or bis-2,4-dimethoxybenzylamine of aryl 2-
methyl-1H-imidazole-1-sulfamates followed by deprotection
Table 1 Reaction conditions for deprotection of N-protected
4-hydroxydiphenyl O-sulfamates and yields for 15a
Phenol
substituent
(s)
Protected phenol
O-sulfamate (8b–
8f, 9b–9m)
Phenol O-
Yield/ sulfamate
Yield/
%
%
(15b–15m)
Compound % TFA in DCM T/°C
Time/h Yield of 15a/%
4-MeO
4-Cl
3-Cl
8b (X = H)
8c (X = H)
8d (X = H)
8e (X = H)
80
81
72
78
62
65
63
61
68
61
63
62
57
61
63
60
66
15b
15c
15d
15e
15f
15b
15c
15d
15e
15f
15g
15h
15i
15j
15k
15l
93
90
86
92
92
90
84
90
81
90
89
80
87
40
92
86
90
12
12
14
14
13
13
13
100
50
80
100
50
10
5
50
42
42
50
12
24
30
24
85
90
63
50
95
95
90
2-Cl
2,6-Me2
4-MeO
4-Cl
3-Cl
2-Cl
2,6-Me2
2,6-Cl2
4-NO2
3-NO2
2-NO2
4-CN
2-CN
4-CF3
8f (X = H)
Room temp. 0.2
Room temp.
Room temp.
9b (X = OMe)
9c (X = OMe)
9d (X = OMe)
9e (X = OMe)
9f (X = OMe)
9g (X = OMe)
9h (X = OMe)
9i (X = OMe)
9j (X = OMe)
9k (X = OMe)
9l (X = OMe)
9m (X = OMe)
2
7
However, very electron poor (4-nitrophenol) and/or sterically
hindered phenols (2,6-dichlorophenol), failed to yield any
product.
To determine conditions of general applicability for diverse
phenols, the two least reactive phenols (4-nitrophenol and 2,6-
dichlorophenol) were selected for further optimisation. Four
parameters were investigated: time, temperature (microwave
heating), solvent and the stoichiometry of 4. Employing THF as
solvent and increasing the temperature of the reaction to 150 °C
did not significantly improve conversion for these phenols. For
4-nitrophenol, the use of either DMF or acetonitrile instead of
THF greatly enhanced the rate of the reaction, and after 10 min
at 150 °C no starting material remained. However, a major by-
product was 4,4′-oxybis(nitrobenzene), presumably resulting
from SNAr attack of the unreacted phenol on the product, with
subsequent elimination of sulfamate (NH2SO3−). The conversion
was also improved for 2,6-dichlorophenol in these solvents,
although unreacted 2,6-dichlorophenol was the major component
after heating for 10 min.
15m
O-sulfamates. For phenols with pKa > 7.1 and the sterically
demanding phenol 2,6-dimethylphenol, high conversions could
routinely be achieved under relatively mild conditions (15 min,
microwave heating at 120 °C, 2 equiv. of 4, MeCN) (Table 2).
One-pot methylation followed by substitution with 2 pro-
ceeded in similar yield for all phenols studied and deprotection
was also clean and high yielding for all examples (see Table 3
and Scheme 5). The optimised conditions were also applied to
the protection of a defined set of phenol O-sulfamates, N-pro-
tected by 4-methoxybenzyl. In all cases deprotection with 50%
TFA in dichloromethane proceeded in high yield to the corre-
sponding phenol O-sulfamate (Table 3 and Scheme 5).
Raising the reaction temperature to 180 °C did not improve
conversion to the product. However, increasing the molar
equivalents of 4 led to reduced formation of 4,4′-oxybis(nitro-
benzene) and gave excellent yields of the protected phenol
To assess the broad chemical stability of 2,4-dimethoxybenzyl
for N-protection of sulfamates, a suitable set of compounds was
prepared (see ESI† for synthetic routes) to determine the
robustness of N-2,4-dimethoxybenzyl to some common
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Scheme 5 Synthesis of substituted phenol O-sulfamates [Reagents and
conditions: i, Me3O·BF4, DCM, 8 h, 0 °C to room temp.; ii, 1 or 2,
DCM/MeCN, 42 °C, 24 h; iii, TFA, DCM, (24 h, 42 °C for 8b–8f; 2 h,
room temp. for 9b–9m); substituents for 8b–8f, 9b–9m and 15b–15m
correspond to those for 5b–5m: see Scheme 3; for X see Table 3].
Scheme 7 Deprotection of BOC-anilines (R
(pmb) or 2,4-dimethoxybenzyl) [Reagents and conditions: 10% TFA in
=
4-methoxybenzyl
DCM, room temp., 2 h].
Scheme 8 Synthesis of secondary sulfamates [Reagents and con-
ditions: i, R′R′′NH, MeCN, room temp., 16 h; ii, Pd(PPh3)4, PhB(OH)2,
K2CO3, MeCN, microwave heating (120 °C, 20 min); iii, 10% TFA/
DCM, room temp., 2 h (R′ = 2,4-dimethoxybenzyl) or 50% TFA/DCM,
42 °C, 24 h (R′ = 4-methoxylbenzyl)].
Table 4 Isolated yields for steps i–iii in Scheme 8
R′
R′′
i
ii
iii
4-Methoxybenzyl
Me
Me
Bn
95%
96%
89%
85%
87%
90%
87%
85%
96%
95%
96%
93%
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
2,4-Dimethoxybenzyl
iBu
Scheme 6 Reactions demonstrating the stability of 2,4-dimethoxy-
benzyl-protected phenol O-sulfamates (16a–16g) towards some common
reagents [Reagents and conditions: i, H2, Pd/C, 60 °C, 24 h; ii, LiOH,
aq. THF, 60 °C, 18 h; iii, LiAlH4, THF, 0 °C, 2 h; iv, MnO2, DCM,
room temp., 16 h; v, PhMgBr, THF, 0 °C, 3 h, (all yields > 84%)].
but is readily removed by dilute trifluoroacetic acid in dichloro-
methane. This enables the application of a variety of reaction
types (e.g. Suzuki coupling) to functional groups on the phenol
O-sulfamates. Furthermore, masking of the polar sulfamate
group is convenient in multistep synthesis. The strategy com-
prises reaction of a phenol with 1,1′-sulfonylbis(2-methyl-1H-
imidazole) to give an aryl 2-methyl-1H-imidazole-1-sulfonate,
which is activated by reaction with trimethyloxonium tetrafluoro-
borate, before further reaction with a methoxy-substituted diben-
zylamine. With either 4-methoxy- or 2,4-dimethoxybenzyl,
deprotection of the nitrogen and release of the phenol O-sulfa-
mate could easily be accomplished by treatment with dilute trifl-
uoroacetic acid. Each step proceeds in excellent yield (16 diverse
examples of phenols). The sulfamate protecting groups are stable
to common reaction conditions, providing useful orthogonality
with other protecting groups. The developed mode of protection
is also amenable to secondary sulfamates. It is anticipated that
the methodology described will become standard for sulfamate
protection.
transformations. Importantly, sulfamates bis-N-protected with
2,4-dimethoxybenzyl were stable to hydrogen/palladium catalyst,
aqueous lithium hydroxide, lithium aluminium hydride, manga-
nese dioxide and phenylmagnesium bromide (Scheme 6, dmb =
2,4-dimethoxybenzyl).
Deprotection of the N-t-butyloxycarbonyl (BOC)-aniline 17a
occurred with simultaneous removal of bis-N-2,4-dimethoxyben-
zyl from the sulfamate group to afford 3-aminophenyl O-sulfa-
mate (18a). However, when 4-methoxybenzyl was used to
protect the sulfamate (17b), the BOC group was removed with
retention of the sulfamate protecting group (18b, Scheme 7). A
further extension of the methodology is the synthesis of second-
ary sulfamates (21a–21c) from 6, via 19a–19d and 20a–20d
(Scheme 8 and Table 4).
Conclusions
Experimental
A reliable procedure for the protection and deprotection of sulfa-
mates derived from phenols has been presented. Especially
attractive is the use of 2,4-dimethoxybenzyl as a bis-N-protecting
group that is stable to bases, nucleophiles, and other reagents,
For details of the preparation of compounds 5b–5m, 8c–8f,
9b–9m, 15b–15m, 16a–16g, 17a, 17b, 18a, 18b, 19a–19d,
20a–20d, 21a–21c and S1–S12 (compounds not explicitly
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mentioned in the above text) and corresponding schemes see
ESI.†
EtOAc (3 × 25 mL). The pooled organic extracts were washed
with water (30 mL) and brine (30 mL), dried over MgSO4 and
concentrated in vacuo. The crude product was purified by
column chromatography.
Materials and methods
General procedure F. The appropriate 2,4-dimethoxybenzyl
protected sulfamate (1 mol equiv.) was solubilised in 10% TFA/
DCM mixture (10 mL mmol−1 of sulfamate). The resulting sol-
ution was stirred at room temperature for 2 h. Upon completion,
the solvent was removed in vacuo. The crude residue was dis-
solved in EtOAc (20 mL), washed with 10% aq. NaHCO3
(20 mL) and extracted with EtOAc (3 × 25 mL). The pooled
organic extracts were washed with water (30 mL) and brine
(30 mL), dried over MgSO4 and concentrated in vacuo. The
crude product was purified by column chromatography.
Chemicals and solvents were obtained from reputable suppliers.
Solvents were either dried by standard techniques or purchased
as anhydrous. Petrol was reagent grade (bp range 40–60 °C). All
reactions that required inert or dry atmosphere were carried out
under dry nitrogen. Glassware was dried in an oven prior to use.
Reactions needing microwave irradiation were carried out in an
Initiator™ Sixty Biotage apparatus. Concerning chromatographic
and spectroscopic methods see the ESI.†
General procedure A. To the appropriate amine (1 mol
equiv.) in ethanol (0.5 mL mmol−1 of benzylamine) was added
the appropriate benzaldehyde (1 mol equiv.) and MgSO4
(400 mg). The mixture was stirred at 78 °C for 4 h. After cooling
to room temperature, sodium borohydride (1.1 mol equiv.) was
carefully added to the reaction mixture. The resulting mixture
was stirred overnight at room temperature. The solvent was
removed in vacuo. The residue was dissolved in EtOAc (60 mL),
washed with sat. aq. NH4Cl, water and brine (30 mL each), dried
over MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography.
General procedure G. The appropriate 4-methoxybenzyl pro-
tected sulfamate (1 mol equiv.) was solubilised in a 50% TFA/
DCM mixture (10 mL mmol−1 of sulfamate). The resulting sol-
ution was heated at 42 °C for 24 h. Upon completion, the
solvent was removed in vacuo. The crude residue was dissolved
in EtOAc (20 mL), washed with 10% aq. NaHCO3 (20 mL) and
extracted with EtOAc (3 × 25 mL). The pooled organic extracts
were washed with water (30 mL) and brine (30 mL), dried over
MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography.
General procedure B. To 1,1′-sulfonylbis(2-methyl-1H-imida-
zole) (4) (2 mol equiv.) and caesium carbonate (1.1 mol equiv.)
in acetonitrile was added the appropriate phenol (1 mol equiv.).
The mixture was heated at 120 °C for 15 min under microwave
irradiation. After cooling, the mixture was concentrated in vacuo.
The residue was dissolved in sat. aq. NH4Cl (15 mL) and the
mixture was extracted with EtOAc (3 × 15 mL). The pooled
organic extracts were washed with water (20 mL) and brine
(20 mL), dried over MgSO4 and concentrated in vacuo. The
crude product was purified by column chromatography.
General procedure H. To the appropriate phenyl 2-methyl-
1H-imidazole-1-sulfonate (1 mol equiv.) in DCM (10 mL
mmol−1 of sulfonate), cooled at 0 °C, was added trimethyloxo-
nium tetrafluoroborate (1 mol equiv.). The resulting solution was
stirred at 0 °C for 1 h and allowed to warm to room temperature.
After 8 h, the reaction was diluted with acetonitrile (5 mL
mmol−1 of sulfonate) and the appropriate benzylamine (1 mol
equiv.) was added. The resulting reaction mixture was heated at
42 °C for 24 h. Upon completion, the solvent was removed
in vacuo to yield a crude product. The crude product was
purified by column chromatography.
General procedure C. To 1,1′-sulfonylbis(2-methyl-1H-imida-
zole) (4) (10 mol equiv.) and caesium carbonate (1.1 mol equiv.)
in acetonitrile was added the appropriate phenol (1 mol equiv.).
The mixture was heated at 180 °C for 15 min under microwave
irradiation and worked up as in General procedure B.
bis(4-Methoxybenzyl)amine, (1). Compound
1 was syn-
thesised according to general procedure A, using the following
reagents: 4-methoxybenzylamine (3.22 mL, 3.38 g, 24.6 mmol),
4-methoxybenzaldehyde (3.0 mL, 3.36 g, 24.6 mmol), sodium
borohydride (1.03 g, 27.1 mmol) and ethanol (12.3 mL). The
crude product was purified by column chromatography (DCM :
MeOH – 1 : 0 → 94 : 6) to yield the title compound as an orange
oil (4.81 g, 75%): Rf 0.28 (DCM : MeOH – 94 : 6); δH
(500 MHz, CDCl3) 3.73 (s, 4H, 2 × ArCH2), 3.81 (s, 6H, 2 ×
OCH3), 6.87 (d, J = 8.7 Hz, 4H, H-3, 5), 7.25 (d, J = 8.7 Hz,
General procedure D. To 1-((4-bromophenoxy)sulfonyl)-2,3-
dimethyl-1H-imidazol-3-ium tetrafluoroborate (6) (1 mol equiv.)
in acetonitrile (8 mL mmol−1 of tetrafluoroborate) was added the
appropriate dibenzylamine (1 mol equiv.). The mixture was
stirred for 8 h, after which the solvent was removed in vacuo to
yield a crude product that was used in the next step without
further purification.
1
4H, H-2, 6); LRMS (ESI+) m/z 258.4 [M + H]+; H NMR and
LRMS data were identical to literature data.19
General procedure E. A solution of the appropriate 4-bromo-
phenyl protected sulfamate (1 mol equiv.) in acetonitrile (20 mL
mmol−1 of 4-bromophenyl sulfamate) was sparged with nitrogen
for 15 min. To this solution potassium carbonate (3 mol equiv.),
phenylboronic acid (1.5 mol equiv.) and tetrakis(triphenylphos-
phine)palladium(0) (0.1 mol equiv.) were added. The mixture
was heated at 120 °C for 20 min under microwave irradiation.
The solvent was removed in vacuo and the residue was distribu-
ted between EtOAc (20 mL) and water (20 mL). The EtOAc
phase was separated and the aqueous phase was extracted with
bis(2,4-Dimethoxybenzyl)amine, (2). Compound 2 was syn-
thesised according to general procedure A, using the following
reagents: 2,4-dimethoxybenzylamine (2.72 mL, 3.03 g,
18.0 mmol), 2,4-dimethoxybenzaldehyde (3.0 g, 18.0 mmol),
sodium borohydride (0.75 g, 19.9 mmol) and ethanol (9 mL).
The crude product was purified by column chromatography
(DCM : MeOH – 1 : 0 → 9 : 1) to yield the title compound as a
pale yellow oil (4.91 g, 85%): Rf 0.34 (DCM : MeOH – 9 : 1); δH
(500 MHz, CDCl3) 3.73 (s, 4H, 2 × ArCH2), 3.79 (s, 6H,
7614 | Org. Biomol. Chem., 2012, 10, 7610–7617
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2 × OCH3), 3.79 (s, 6H, 2 × OCH3), 6.46–6.41 (m, 4H, H-3, 5),
7.17 (d, J = 8.6 Hz, 2H, H-6); LRMS (ESI+) m/z 318.4
[M + H]+; 1H NMR data were identical to literature data.20,21
(petrol : EtOAc – 8 : 2); λmax (EtOH)/nm 271.0, 278.0; IR (film)
νmax/cm−1 1573, 1556, 1429, 1201, 1177, 1044; δH (500 MHz,
CDCl3) 2.68 (s, 3H, CH3), 6.92 (d, J = 1.8 Hz, 1H, Himidazole),
7.19 (d, J = 1.9 Hz, 1H, Himidazole), 7.26–7.20 (m, 1H, H-4),
7.39 (d, J = 8.1 Hz, 2H, H-3, 5); δC (126 MHz, CDCl3) 15.33,
120.25, 128.15, 129.19, 129.72, 129.80, 143.09, 146.81; HRMS
(ESI) calcd for C10H9Cl2N2O3S [M + H]+: 306.9705; found
306.9709.
bis(3,4-Dimethoxybenzyl)amine, (3). Compound 3 was syn-
thesised according to general procedure A, using the following
reagents: 3,4-dimethoxybenzylamine (2.72 mL, 3.02 g,
18.0 mmol), 3,4-dimethoxybenzaldehyde (3.0 g, 18.0 mmol),
sodium borohydride (0.75 g, 19.9 mmol) and ethanol (9 mL).
The crude product was purified by column chromatography
(DCM : MeOH – 1 : 0 → 9 : 1) to yield the title compound as a
yellow solid (3.91 g, 68%): Rf 0.33 (DCM : MeOH – 9 : 1); mp:
68.5–70.5 °C; δH (500 MHz, CDCl3) 3.74 (s, 4H, 2 × ArCH2),
3.87 (s, 6H, 2 × OCH3), 3.89 (s, 6H, 2 × OCH3), 6.82 (d, J =
8.2 Hz, 2H, H-5), 6.86 (dd, J = 8.2, 1.8 Hz, 2H, H-6), 6.90
(d, J = 1.8 Hz, 2H, H-2); LRMS (ESI+) m/z 318.4 [M + H]+;
1H NMR and LRMS data were identical to literature data.22
1-((4-Bromophenoxy)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium
tetrafluoroborate, (6). To 4-bromophenyl 2-methyl-1H-imida-
zole-1-sulfonate (5a) (4.18 g, 13.2 mmol) in DCM (60 mL),
cooled to 0 °C, was added trimethyloxonium tetrafluoroborate
(1.96 g, 13.2 mmol). The resulting solution was stirred at 0 °C
for 1 h and allowed to warm up to room temperature. After 8 h,
the reaction was cooled in an ice-bath, and petrol (120 mL) was
added to the mixture. The white precipitate was filtered off,
washed with cold petrol (60 mL) and dried under high vacuum.
The white fluffy solid (4.97 g, 90%) was used in the next step
without further purification: mp: 131.0–133.0 °C; λmax (EtOH)/
nm 223.0; IR (film) νmax/cm−1 3139, 1605, 1479, 1449, 1235,
1212 1149, 1023; δH (500 MHz, MeOD) 2.90 (s, 3H, CH3), 3.96
(s, 3H, NCH3), 7.26 (d, J = 9.1 Hz, 2H, H-2, 6), 7.68 (d, J = 9.1
Hz, 2H, H-3, 5), 7.70 (d, J = 2.4 Hz, 1H, Himidazole), 7.83 (d, J =
2.4 Hz, 1H, Himidazole); δC (126 MHz, MeOD) 11.87, 36.87,
122.37, 124.16, 124.60, 125.12, 135.19, 149.62, 150.19; HRMS
(ESI) calcd for C11H12BrN2O3S [M − BF4]+: 330.9747; found
330.9749.
1,1′-Sulfonylbis(2-methyl-1H-imidazole), (4). To 2-methyl-
imidazole (20.3 g, 247 mmol) in DCM (100 mL), cooled to
0 °C, was added dropwise over 30 min sulfuryl chloride (5 mL,
8.32 g, 61.7 mmol) in DCM (40 mL). The resulting solution was
stirred at 0 °C for 1 h and allowed to warm up to room tempera-
ture. After 24 h, the reaction was quenched by cautious addition
of water (100 mL) and extracted with DCM (2 × 50 mL). The
pooled organic extracts were washed with brine (100 mL), dried
over MgSO4 and concentrated in vacuo. The crude yellow solid
was purified by column chromatography (DCM : MeOH – 1 : 0
→ 93 : 7) to yield the title compound as an off-white solid
4-Bromophenyl dibenzylsulfamate, (7). Compound 7 was syn-
thesized following two different procedures.
(10.2 g, 73%): Rf 0.32 (DCM : MeOH
– 93 : 7); mp:
86.0–88.0 °C; λmax (EtOH)/nm 220.0; δH (500 MHz, CDCl3)
2.52 (s, 6H, CH3), 6.95 (d, J = 1.7 Hz, 2H), 7.37 (d, J = 1.8 Hz,
2H); δC (126 MHz, CDCl3) 15.11, 120.18, 128.64, 146.15;
LRMS (ESI+) m/z 227.2 [M + H]+; 1H NMR data were identical
to literature data.23
1st procedure: To 4-bromophenol (29 mg, 0.17 mmol) and
caesium carbonate (60 mg, 0.18) in anhydrous THF was added
dibenzylsulfamoyl chloride (S1). The resulting mixture was
heated at 67 °C for 16 h. After cooling, the mixture was concen-
trated in vacuo. The resulting residue was dissolved in sat. aq.
NH4Cl (10 mL) and the mixture was extracted with EtOAc (3 ×
10 mL). The pooled organic extracts were washed with water
(20 mL) and brine (20 mL), dried over MgSO4 and concentrated
in vacuo. The crude product was purified by column chromato-
graphy (petrol : EtOAc – 1 : 0 → 97 : 3) to yield the title com-
pound as a white solid (29 mg, 40%).
2nd procedure: Compound 7 was synthesised according to
general procedure D, using the following reagents: 1-((4-bromo-
phenoxy)sulfonyl)-2,3-dimethyl-1H-imidazol-3-ium tetrafluoro-
borate (6) (400 mg, 0.96 mmol), dibenzylamine (184 μL,
189 mg, 0.96 mmol) and acetonitrile (7.7 mL). The crude
product was purified by column chromatography (petrol : EtOAc
– 1 : 0 → 97 : 3) to yield the title compound as a white solid
(320 mg, 77%): Rf 0.34 (petrol : EtOAc – 96 : 4); mp:
86.5–88.5 °C; λmax (EtOH)/nm 258.0; IR (film) νmax/cm−1 1481,
1452, 1369, 1154, 1061; δH (500 MHz, CDCl3) 4.39 (s, 4H, 2 ×
ArCH2), 6.99 (d, J = 8.8 Hz, 2H, H-2, 6), 7.31–7.27 (m, 4H, 4 ×
ArH), 7.39–7.32 (m, 6H, 6 × ArH), 7.44 (d, J = 8.9 Hz, 2H,
H-3, 5); δC (126 MHz, CDCl3) 51.28, 120.19, 123.78, 128.46,
128.88, 129.16, 132.92, 134.71, 149.42; HRMS (ESI) calcd for
C20H19BrNO3S [M + H]+: 432.0264; found 432.0272.
4-Bromophenyl 2-methyl-1H-imidazole-1-sulfonate, (5a).
Compound 5a was synthesised according to general procedure
B, using the following reagents: 1,1′-sulfonylbis(2-methyl-1H-
imidazole) (4) (262 mg, 1.16 mmol), caesium carbonate
(207 mg, 0.64 mmol), 4-bromophenol (100 mg, 0.58 mmol) and
acetonitrile (5 mL). The crude yellow oil was purified by column
chromatography (petrol : EtOAc – 1 : 0 → 8 : 2) to yield the title
compound as a clear oil (169 mg, 93%): Rf 0.35 (petrol : EtOAc
– 8 : 2); λmax (EtOH)/nm 220.5; IR (film) νmax/cm−1 1553, 1480,
1422, 1207, 1147, 1043, 1012; δH (500 MHz, CDCl3) 2.50 (s,
3H, CH3), 6.81 (d, J = 8.9 Hz, 2H, H-2, 6), 6.89 (d, J = 1.7 Hz,
1H, Himidazole), 7.12 (d, J = 1.8 Hz, 1H, Himidazole), 7.49 (d, J =
9.0 Hz, 2H, H-3, 5); δC (126 MHz, CDCl3) 15.09, 120.52,
122.37, 123.44, 128.25, 133.56, 146.85, 148.00; HRMS (ESI)
calcd for C10H10BrN2O3S [M + H]+: 316.9590; found 316.9598.
2,6-Dichlorophenyl 2-methyl-1H-imidazole-1-sulfonate, (5g).
Compound 5g was synthesised according to general procedure
C, using the following reagents: 1,1′-sulfonylbis(2-methyl-1H-
imidazole) (4) (3.47 g, 15.3 mmol), caesium carbonate (550 mg,
1.69 mmol), 2,6-dichlorophenol (250 mg, 1.53 mmol) and
acetonitrile (20 mL). The crude yellow oil was purified by
column chromatography (petrol : EtOAc – 1 : 0 → 85 : 15) to
yield the title compound as a clear oil (396 mg, 84%): Rf 0.34
4-Bromophenyl bis(4-methoxybenzyl)sulfamate, (8a). Com-
pound 8a was synthesised according to general procedure D,
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using the following reagents: 1-((4-bromophenoxy)sulfonyl)-
2,3-dimethyl-1H-imidazol-3-ium tetrafluoroborate (6) (600 mg,
1.43 mmol), bis(4-methoxybenzyl)amine (1) (370 mg,
1.43 mmol) and acetonitrile (11.5 mL). The crude product was
purified by column chromatography (petrol : EtOAc – 1 : 0 →
95 : 5) to yield the title compound as a pale orange solid
(595 mg, 84%): Rf 0.34 (petrol : EtOAc – 95 : 5); mp:
61.5–63.5 °C; λmax (EtOH)/nm 274.5; IR (film) νmax/cm−1 1614,
1513, 1479, 1456, 1361, 1249, 1169, 1033; δH (500 MHz,
CDCl3) 3.82 (s, 6H, 2 × OCH3), 4.30 (s, 4H, 2 × ArCH2), 6.88
(d, J = 8.7 Hz, 4H, H-3′, 5′), 7.00 (d, J = 8.9 Hz, 2H, H-2, 6),
7.20 (d, J = 8.7 Hz, 4H, H-2′, 6′), 7.45 (d, J = 8.9 Hz, 2H, H-3,
5); δC (126 MHz, CDCl3) 50.39, 55.47, 114.21, 120.10, 123.86,
126.77, 130.54, 132.89, 149.48, 159.74; HRMS (ESI) calcd for
C22H26BrN2O5S [M + NH4]+: 509.0740; found 509.0740.
purified by column chromatography (petrol : EtOAc – 1 : 0 →
65 : 35) to yield the title compound as a white solid (675 mg,
85%): Rf 0.32 (petrol : EtOAc – 65 : 35); mp: 99.5–101.5 °C;
λmax (EtOH)/nm 278.0; IR (film) νmax/cm−1 1595, 1518, 1464,
1358, 1259, 1238, 1141, 1024; δH (500 MHz, CDCl3) 3.82 (s,
6H, 2 × OCH3), 3.89 (s, 6H, 2 × OCH3), 4.33 (s, 4H, 2 ×
ArCH2), 6.77 (dd, J = 8.1, 1.9 Hz, 1H, H-6′), 6.82 (d, J =
8.2 Hz, 2H, H-5′), 6.84 (d, J = 1.9 Hz, 2H, H-2′), 7.05 (d, J =
8.9 Hz, 2H, H-2, 6), 7.47 (d, J = 8.9 Hz, 2H, H-3, 5); δC
(126 MHz, CDCl3) 51.14, 56.04, 56.10, 111.04, 112.17, 120.21,
121.69, 123.69, 127.23, 132.99, 149.26, 149.40, 149.52; HRMS
(ESI) calcd for C24H30BrN2O7S [M + NH4]+: 569.0952; found
569.0947.
[1,1′-Biphenyl]-4-yl dibenzylsulfamate, (11). Compound 11
was synthesised according to general procedure E, using the fol-
lowing reagents: 4-bromophenyl dibenzylsulfamate (7) (250 mg,
0.58 mmol), potassium carbonate (240 mg, 1.73 mmol), phenyl
boronic acid (106 mg, 0.87 mmol), tetrakis(triphenylphosphine)
palladium(0) (67 mg, 0.06 mmol) and acetonitrile (11.5 mL).
The crude product was purified by column chromatography
(petrol : EtOAc – 1 : 0 → 97 : 3) to yield the title compound as a
white solid (320 mg, 72%): Rf 0.42 (petrol : EtOAc – 96 : 4);
4-Methoxyphenyl bis(4-methoxybenzyl)sulfamate, (8b). Com-
pound 8b was synthesised according to general procedure H,
using the following reagents: 4-methoxyphenyl 2-methyl-1H-
imidazole-1-sulfonate (4) (300 mg, 1.12 mmol), trimethyloxo-
nium tetrafluoroborate (165 mg, 1.12 mmol), DCM (11.2 mL),
acetonitrile (5.6 mL) and bis(4-methoxybenzyl)amine (1)
(288 mg, 1.12 mmol). The crude product was purified by
column chromatography (petrol : EtOAc – 1 : 0 → 85 : 15) to
yield the title compound as a clear oil (398 mg, 80%): Rf 0.30
(petrol : EtOAc – 85 : 15); λmax (EtOH)/nm 274.5; IR (film)
νmax/cm−1 1612, 1502, 1367, 1247, 1165, 1031; δH (500 MHz,
CDCl3) 3.80 (s, 3H, OCH3), 3.82 (s, 6H, 2 × OCH3), 4.29 (s,
4H, 2 × ArCH2), 6.83 (d, J = 9.1 Hz, 2H, H-3, 5), 6.86 (d, J =
8.7 Hz, 4H, H-3′, 5′), 7.05 (d, J = 9.1 Hz, 2H, H-2, 6), 7.20 (d,
J = 8.6 Hz, 4H, H-2′, 6′); δC (126 MHz, CDCl3) 50.36, 55.43,
55.74, 114.10, 114.70, 123.16, 127.03, 130.53, 143.86, 158.12,
159.59; HRMS (ESI) calcd for C25H30NO8S [M + H]+:
504.1687; found 504.1677.
mp: 131.5–133.5 °C; λmax (EtOH)/nm 251.0; IR (film) νmax
/
cm−1 1483, 1455, 1363, 1187, 1149, 1051; δH (500 MHz,
CDCl3) 4.43 (s, 4H, 2 × ArCH2), 7.21 (d, J = 8.7 Hz, 2H, H-3,
5), 7.39–7.27 (m, 11H, 11 × ArH), 7.45 (t, J = 7.6 Hz, 2H,
H-4′), 7.58–7.52 (m, 4H, 4 × ArH); δC (126 MHz, CDCl3)
51.30, 122.26, 127.26, 127.72, 128.37, 128.55, 128.83, 129.01,
129.20, 134.88, 140.04, 140.16, 149.85; HRMS (ESI) calcd for
C26H24NO3S [M + H]+: 430.1471; found 430.1478.
[1,1′-Biphenyl]-4-yl bis(4-methoxybenzyl)sulfamate, (12).
Compound 12 was synthesised according to general procedure
E, using the following reagents: 4-bromophenyl bis(4-methoxy-
benzyl)sulfamate (8a) (400 mg, 0.81 mmol), potassium carbon-
ate (337 mg, 2.44 mmol), phenyl boronic acid (149 mg,
1.22 mmol), tetrakis(triphenylphosphine)palladium(0) (94 mg,
0.08 mmol) and acetonitrile (16 mL). The crude product was
purified by column chromatography (petrol : EtOAc – 1 : 0 →
95 : 5) to yield the title compound as a pale yellow oil (330 mg,
83%): Rf 0.38 (petrol : EtOAc – 95 : 5); λmax (EtOH)/nm 251.0;
IR (film) νmax/cm−1 1610, 1511, 1484, 1379, 1248, 1178, 1153,
1052, 1031; δH (500 MHz, CDCl3) 3.81 (s, 6H, 2 × OCH3),
4.34 (s, 4H, 2 × ArCH2), 6.87 (d, J = 8.7 Hz, 4H, H-3′′, 5′′),
7.24–7.19 (m, 6H, 6 × ArH), 7.39–7.34 (m, 1H, H-4′), 7.45 (dd,
J = 7.6, 7.6 Hz, 2H, H-3′, 5′), 7.58–7.52 (m, 4H, H-2, 6 & H-2′,
6′); δC (126 MHz, CDCl3) 50.41, 55.45, 114.17, 122.32, 126.95,
127.25, 127.72, 128.51, 129.01, 130.57, 139.97, 140.17, 149.88,
159.67; HRMS (ESI) calcd for C28H31N2O5S [M + NH4]+:
507.1948; found 507.1945.
4-Bromophenyl bis(2,4-dimethoxybenzyl)sulfamate, (9a).
Compound 9a was synthesised according to general procedure
D, using the following reagents: 1-((4-bromophenoxy)sulfonyl)-
2,3-dimethyl-1H-imidazol-3-ium tetrafluoroborate (6) (600 mg,
1.43 mmol), bis(2,4-dimethoxybenzyl)amine (2) (456 mg,
1.43 mmol) and acetonitrile (11.5 mL). The crude product was
purified by column chromatography (petrol : EtOAc – 1 : 0 →
85 : 15) to yield the title compound as a clear oil (680 mg, 86%):
Rf 0.30 (petrol : EtOAc – 85 : 15); λmax (EtOH)/nm 277.0; IR
(film) νmax/cm−1 1613, 1588, 1507, 1481, 1370, 1208, 1156,
1035; δH (500 MHz, CDCl3) 3.73 (s, 6H, 2 × OCH3), 3.80 (s,
6H, 2 × OCH3), 4.44 (s, 4H, 2 × ArCH2), 6.39 (d, J = 2.4 Hz,
2H, H-3′), 6.43 (dd, J = 8.4, 2.4 Hz, 2H, H-5′), 6.92 (d, J =
8.9 Hz, 2H, H-2, 6), 7.24 (d, J = 8.4 Hz, 2H, H-6′), 7.39 (d, J =
8.9 Hz, 2H, H-3, 5); δC (126 MHz, CDCl3) 47.10, 55.25, 55.54,
98.33, 104.15, 116.62, 119.72, 123.85, 131.14, 132.62, 149.54,
158.62, 160.84; HRMS (ESI) calcd for C24H27BrNO7S
[M + H]+: 552.0686; found 552.0676.
[1,1′-Biphenyl]-4-yl bis(2,4-dimethoxybenzyl)sulfamate, (13).
Compound 13 was synthesised according to general procedure
E, using the following reagents: 4-bromophenyl bis(2,4-
dimethoxybenzyl)sulfamate (9a) (450 mg, 0.81 mmol), potass-
ium carbonate (337 mg, 2.44 mmol), phenyl boronic acid
(149 mg, 1.22 mmol), tetrakis(triphenylphosphine)palladium(0)
(94 mg, 0.08 mmol) and acetonitrile (16 mL). The crude product
was purified by column chromatography (petrol : EtOAc – 1 : 0
4-Bromophenyl bis(3,4-dimethoxybenzyl)sulfamate, (10).
Compound 10 was synthesised according to general procedure
D, using the following reagents: 1-((4-bromophenoxy)sulfonyl)-
2,3-dimethyl-1H-imidazol-3-ium tetrafluoroborate (6) (600 mg,
1.43 mmol), bis(3,4-dimethoxybenzyl)amine (3) (456 mg,
1.43 mmol) and acetonitrile (11.5 mL). The crude product was
7616 | Org. Biomol. Chem., 2012, 10, 7610–7617
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→ 85 : 15) to yield the title compound as a yellow oil (375 mg,
83%): Rf 0.32 (petrol : EtOAc – 85 : 15); λmax (EtOH)/nm 250.5;
IR (film) νmax/cm−1 1612, 1590, 1507, 1469, 1369, 1206, 1154,
1042, 1034; δH (500 MHz, CDCl3) 3.73 (s, 6H, 2 × OCH3),
3.78 (s, 6H, 2 × OCH3), 4.48 (s, 4H, 2 × ArCH2), 6.39 (d, J =
2.4 Hz, 2H, H-3′′), 6.43 (dd, J = 8.4, 2.4 Hz, 2H, H-5′′), 7.15
(d, J = 8.7 Hz, 2H, H-3, 5), 7.27 (d, J = 8.4 Hz, 2H, H-6′′),
7.38–7.33 (m, 1H, H-4′), 7.44 (dd, J = 7.6, 7.6 Hz, 2H, H-3′, 5′),
7.51 (d, J = 8.7 Hz, 2H, H-2, 6), 7.55 (dd, J = 8.3, 1.2 Hz, 2H,
H-2′, 6′); δC (126 MHz, CDCl3) 47.04, 55.25, 55.52, 98.30,
104.14, 116.80, 122.32, 127.23, 127.60, 128.29, 128.96, 131.12,
139.56, 140.31, 149.97, 158.61, 160.75; HRMS (ESI) calcd for
C30H32NO7S [M + H]+: 550.1894; found 550.1887.
7.75 (d, J = 8.7 Hz, 2H, H-2, 6), 8.04 (s, 2H, NH2); LRMS
1
(ESI−) m/z 248.2 [M − H]−; H NMR data were identical to
literature data.24
Acknowledgements
The authors thank: Cancer Research UK for financial support,
the EPSRC National Mass Spectrometry Service at the Univer-
sity of Wales (Swansea) for mass spectrometric determinations,
Dr C. Cano and Dr I. R. Hardcastle for helpful discussions.
Notes and references
[1,1′-Biphenyl]-4-yl bis(3,4-dimethoxybenzyl)sulfamate, (14).
Compound 14 was synthesised according to general procedure
E, using the following reagents: 4-bromophenyl bis(3,4-
dimethoxybenzyl)sulfamate (10) (450 mg, 0.81 mmol), potass-
ium carbonate (337 mg, 2.44 mmol), phenyl boronic acid
(149 mg, 1.22 mmol), tetrakis(triphenylphosphine)palladium(0)
(94 mg, 0.08 mmol) and acetonitrile (16 mL). The crude product
was purified by column chromatography (petrol : EtOAc – 1 : 0
→ 65 : 35) to yield the title compound as a yellow solid
(385 mg, 86%): Rf 0.35 (petrol : EtOAc – 65 : 35); mp:
120.5–122.5 °C; λmax (EtOH)/nm 237.5; IR (film) νmax/cm−1
1593, 1518, 1450, 1370, 1261, 1237, 1140, 1019; δH (500 MHz,
CDCl3) 3.82 (s, 6H, 2 × OCH3), 3.87 (s, 6H, 2 × OCH3), 4.36
(s, 4H, 2 × CH2), 6.78 (dd, J = 8.2, 1.8 Hz, 2H, H-6′′), 6.81 (d,
J = 8.2 Hz, 2H, H-5′′), 6.87 (d, J = 1.8 Hz, 2H, H-2′′), 7.25 (d,
J = 8.6 Hz, 2H, H-3, 5), 7.39–7.32 (m, 1H, H-4′), 7.44 (dd, J =
7.6, 7.6 Hz, 2H, H-3′, 5′), 7.59–7.51 (m, 4H, H-2, 6 & H-2′, 6′);
δC (126 MHz, CDCl3) 51.15, 56.03, 56.08, 111.01, 112.20,
121.69, 122.15, 127.22, 127.43, 127.76, 128.57, 129.01, 140.05,
149.17, 149.36, 149.90; HRMS (ESI) calcd for C30H35N2O7S
[M + NH4]+: 567.2159; found 567.2155.
1 B. E. Maryanoff, J. Med. Chem., 2009, 52, 3431.
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1st procedure: Compound 15a was synthesised according to
general procedure F, using the following reagents: [1,1′-biphe-
nyl]-4-yl bis(2,4-dimethoxybenzyl)sulfamate (13) (180 mg,
0.33 mmol), DCM (3.0 mL) and TFA (0.33 mL). The crude
product was purified by column chromatography (petrol : EtOAc
– 1 : 0 → 7 : 3) to yield the title compound as an off-white solid
(77 mg, 95%).
2nd procedure: Compound 15a was synthesised according to
general procedure G, using the following reagents: [1,1′-biphe-
nyl]-4-yl bis(4-methoxybenzyl)sulfamate (12) (100 mg,
0.20 mmol), DCM (1.0 mL) and TFA (1.0 mL). The crude
product was purified by column chromatography (petrol : DCM
– 1 : 0 → 0 : 1) to yield the title compound as an off-white solid
(45 mg, 90%): Rf 0.34 (petrol : EtOAc – 7 : 3); δH (500 MHz,
DMSO) 7.42–7.34 (m, 3H, H-3, 5 & H-4′), 7.48 (dd, J = 7.7,
7.7 Hz, 2H, H-3′, 5′), 7.66 (dd, J = 8.3, 1.1 Hz, 2H, H-2′, 6′),
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Org. Biomol. Chem., 2012, 10, 7610–7617 | 7617