Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2- trifluoroethoxysulfonates

Article abstract of DOI:10.1039/b922717b

The attenuated S_N2 reactivity of the 2,2,2-trifluoroethyl group has been exploited for the synthesis of a series of 6-cyclohexylmethoxy-2- arylaminopurines in which a sulfonamide moiety was attached to the aryl ring via a methylene group. These were required as potential inhibitors of serine-threonine kinases of interest for the treatment of cancer. 3-Nitrophenylmethanesulfonyl chloride was converted into the corresponding 2,2,2-trifluoroethoxysulfonyl ester by reaction with 2,2,2-trifluoroethanol in the presence of triethylamine/4-dimethylaminopyridine. Catalytic hydrogenation of the nitro group employing 2,2,2-trifluoroethanol as solvent gave 2,2,2-trifluoroethyl 3-aminophenylmethanesulfonate, which was reacted with 6-cyclohexylmethoxy-2-fluoropurine in 2,2,2-trifluoroethanol/trifluoroacetic acid to afford 2,2,2-trifluoroethyl 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino) phenylmethanesulfonate. 3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino) phenylmethanesulfonamides were synthesised by microwave heating of the trifluoroethoxysulfonate with an amine and 1,8-diazabicycloundec-7-ene in tetrahydrofuran. The mechanism of this process was shown to involve an intermediate sulfene by a deuterium-labelling experiment. 3-(6- Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide derivatives were assayed as inhibitors of human cyclin-dependent kinase 2. Previous structure-activity studies demonstrated that relocating the sulfonamide group of O⁶-cyclohexylmethoxy-2-(4′-sulfamoylanilino)purine from the 4- to the 3-position on the 2-arylamino ring resulted in a 40-fold reduction in potency against CDK2. In the present study, no further loss of activity was observed on introducing a methylene group between the sulfonamide and the aryl ring, 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide proving equipotent with O⁶-cyclohexylmethoxy-2-(3′-sulfamoylanilino) purine (IC₅₀ = 0.21 μM). N-Alkylation of the sulfonamide reduced CDK-2 inhibitory activity, while a substituted benzyl or 3-phenylpropyl group on the sulfonamide resulted in a loss of potency compared with 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide. The dimethylaminopropyl derivative, 1-[3-(6-cyclohexylmethoxy-9H-purin-2-ylamino) phenyl]-N-(3-dimethylaminopropyl)methanesulfonamide was only 2-fold less potent than 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide, suggesting an interaction between the basic dimethylamino group and the kinase. The presence of alicyclic groups on the pendant sulfonamide showed IC ₅₀ values in the 0.5-1.5 μM range. N-(4-tert-Butylphenyl)-1-[3-(6- cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methanesulfonamide was markedly less active (IC₅₀ = 34 μM), suggesting a steric effect within the ATP-binding domain.

Full text of DOI:10.1039/b922717b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting
the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates
Christopher Wong,a Roger J. Griffin,a Ian R. Hardcastle,a Julian S. Northen,c Lan-Zhen Wangb and
Bernard T. Golding*a
Received 30th October 2009, Accepted 22nd February 2010
First published as an Advance Article on the web 24th March 2010
DOI: 10.1039/b922717b
The attenuated SN2 reactivity of the 2,2,2-trifluoroethyl group has been exploited for the synthesis of a
series of 6-cyclohexylmethoxy-2-arylaminopurines in which a sulfonamide moiety was attached to the
aryl ring via a methylene group. These were required as potential inhibitors of serine-threonine kinases
of interest for the treatment of cancer. 3-Nitrophenylmethanesulfonyl chloride was converted into the
corresponding 2,2,2-trifluoroethoxysulfonyl ester by reaction with 2,2,2-trifluoroethanol in the presence
of triethylamine/4-dimethylaminopyridine. Catalytic hydrogenation of the nitro group employing
2,2,2-trifluoroethanol as solvent gave 2,2,2-trifluoroethyl 3-aminophenylmethanesulfonate, which was
reacted with 6-cyclohexylmethoxy-2-fluoropurine in 2,2,2-trifluoroethanol/trifluoroacetic acid to
afford 2,2,2-trifluoroethyl 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonate.
3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamides were synthesised by
microwave heating of the trifluoroethoxysulfonate with an amine and 1,8-diazabicycloundec-7-ene in
tetrahydrofuran. The mechanism of this process was shown to involve an intermediate sulfene by a
deuterium-labelling experiment. 3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesul-
fonamide derivatives were assayed as inhibitors of human cyclin-dependent kinase 2. Previous
structure–activity studies demonstrated that relocating the sulfonamide group of O6-cyclohexyl-
methoxy-2-(4¢-sulfamoylanilino)purine from the 4- to the 3-position on the 2-arylamino ring resulted in
a 40-fold reduction in potency against CDK2. In the present study, no further loss of activity was
observed on introducing a methylene group between the sulfonamide and the aryl ring,
3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide proving equipotent with
O6-cyclohexylmethoxy-2-(3¢-sulfamoylanilino)purine (IC50 = 0.21 mM). N-Alkylation of the
sulfonamide reduced CDK-2 inhibitory activity, while a substituted benzyl or 3-phenylpropyl group on
the sulfonamide resulted in a loss of potency compared with 3-(6-cyclohexylmethoxy-9H-purin-2-
ylamino)phenylmethanesulfonamide. The dimethylaminopropyl derivative, 1-[3-(6-cyclohexylmethoxy-
9H-purin-2-ylamino)phenyl]-N-(3-dimethylaminopropyl)methanesulfonamide was only 2-fold less
potent than 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide, suggesting an
interaction between the basic dimethylamino group and the kinase. The presence of alicyclic groups on
the pendant sulfonamide showed IC50 values in the 0.5–1.5 mM range. N-(4-tert-Butylphenyl)-1-[3-(6-
cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methanesulfonamide was markedly less active (IC50
34 mM), suggesting a steric effect within the ATP-binding domain.
=
SN2 reaction with potassium iodide in acetone than 4,4,4-
trifluorobutan-1-ol O-p-toluenesulfonate. This behaviour was as-
cribed to repulsive interactions in the transition state between
the electronegative fluorine atoms and the entering and leaving
groups.2,3 An alternative explanation derives from the prefer-
ence of an electron-withdrawing trifluoromethyl group to be
attached to a carbon atom donating an orbital of relatively
high p character and hence minimal s character. This raises
the energy of the pentacoordinated transition state for SN2
displacement because the methylene carbon donates an sp2
hybrid orbital to the CF3 group.2 {A. Eschenmoser, personal
communication}
Introduction
Hine and Ghirardelli1 showed that progressive substitution of
fluorine atoms at C-2 of iodoethane had a remarkable effect
on the rate of SN2 reaction with sodium thiophenoxide in
methanol. 2,2,2-Trifluoro-1-iodoethane was shown to react some
2 ¥ 104 times slower than iodoethane at 20 ◦C. Subsequently,
Bordwell and Brannen2 demonstrated that 2,2,2-trifluoroethanol
O-p-toluenesulfonate is much less reactive (ca. 104-fold) in a
aNorthern Institute for Cancer Research, School of Chemistry, Bedson
Building, Newcastle University, Newcastle upon Tyne, UK NE1 7RU
bNorthern Institute for Cancer Research, Paul O’Gorman Building, Medical
School, Framlington Place, Newcastle University, Newcastle upon Tyne, UK
NE2 4HH
We have exploited this unique, attenuated SN2 reactivity for the
synthesis of a series of purine derivatives (1a–1l) bearing benzylic
sulfonamides from the 2,2,2-trifluoroethoxysulfonate 7 in which
trifluoroethoxy acts solely as a leaving group (Scheme 1) and
cOnyx Scientific Ltd, Silverbriar Enterprise Park East, Sunderland, UK SR5
2TQ
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Scheme 1 Synthesis of 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamides.
is not subject to perceptible SN2 attack. 6-Cyclohexylmethoxy-
2-arylaminopurines (1a–1l) substituted with sulfonamide groups
were required as potential inhibitors of serine-threonine kinases
of interest as therapeutic targets for the treatment of cancer.
Ordered progression of the cell cycle4,5 is mediated by the CDKs,
the abnormal functioning of which is implicated in the molecular
pathology of cancer.6 As a consequence, there is evidence to sug-
gest that inhibition of CDKs may be therapeutically advantageous
by inducing the apoptosis of tumour cells.5,7 Although a large
number of small molecule ATP-competitive CDK inhibitors have
been reported to date, kinase selectivity remains a challenge.8–10
or abolish CDK2 inhibitory activity, with a view to revealing
other kinase targets for this chemotype. We have now found
a synthetic strategy suitable for a multiple-parallel format that
enables the generation of a library of novel kinase inhibitors
containing the desired structural motif. As reported in this paper,
we synthesised the 2,2,2-trifluoroethoxysulfonate 7 and studied its
reactions with amines. In this way the sulfonamide derivatives 1a–
1l were obtained and shown to exhibit only modest inhibition of
CDK2 compared with the parent purine 7 (see Table 1).
Results and discussion
Synthesis
Commercially available 3-nitrophenylmethanesulfonyl chloride
(4) was converted into the 2,2,2-trifluoroethyl ester 5 by reaction
with neat 2,2,2-trifluoroethanol in the presence of triethylamine
and 4-dimethylaminopyridine. Reduction of the nitro group of 5 to
the corresponding aniline 6 was achieved by hydrogenation using
palladium on carbon, employing 2,2,2-trifluoroethanol (TFE) as
solvent. In agreement with Bailey et al. we have found TFE
to be a useful alternative solvent to methanol and ethanol for
catalytic hydrogenations.14 The ability of the trifluoroethyl group
to withstand conditions of catalytic hydrogenation contrasts with
the trichloroethyl group. The latter was recently recommended as
a protecting group for sulfonic acids with the trichloroethylsul-
fonates being deprotected by catalytic hydrogenation.15
We have previously described O6-cyclohexylmethoxy-2-(4¢-
sulfamoylanilino)purine (NU6102, 3) and related compounds as
potent inhibitors of cyclin-dependent kinase 2 (CDK2).11,12 This
and related compounds were readily prepared by reaction of 6-
cyclohexylmethoxy-2-fluoropurine 2 with the appropriate aniline
(e.g. sulfanilamide leading to 3) in trifluoroacetic acid-2,2,2-
trifluoroethanol.13 As part of our continuing interest in purine-
based kinase inhibitors derived from 3, it was of interest to explore
the effect, upon kinase-inhibitory activity, of inserting a methylene
group between the sulfonamide and benzenoid moiety attached
to the purine. To explore further the impact of the sulfonamide
group on kinase inhibition we also wished to synthesise analogues
of 3 in which the sulfonamide group was moved to the meta-
position of the benzenoid ring, separated from this ring by a single
methylene group and N-substituted with a range of functionalities.
In addition to further delineating structure–activity relationships
for CDK inhibition, an objective of these studies was to reduce
Reaction of the aniline
6 with 6-cyclohexylmethoxy-2-
fluoropurine 2 in a 2,2,2-trifluoroethanol/trifluoroacetic acid mix-
ture afforded the 2,2,2-trifluoroethoxysulfonate 7. Sulfonamides
1a–1l (Table) were synthesised by heating 7 with an excess of
the required amine and 1,8-diazabicycloundec-7-ene (DBU) in
tetrahydrofuran (THF) under microwave conditions at 160 ◦C for
15 min. In most cases the yield of sulfonamide exceeded 70%. The
transformations described are summarised in Scheme 1. Cleavage
of the p-methoxybenzyl (PMB) group of 1d in neat TFA proceeded
smoothly to give 8 (Scheme 2).
During the course of the study described herein,
Caddick and coworkers reported an excellent method for
synthesising alkylsulfonamides by treatment of the corresponding
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Table 1 Structures, synthetic yields and activities for inhibitors of the kinase CDK2
Compound number
R1 and R2
Yield (%)
CDK2 Inhibition (IC50 mM)a
3 (NU6102)
—
—
—
—
85
70
92
93
89
72
71
91
75
75
72
57
47
0.005
0.21b
0.24
1.1
0.53
1.6
3.0
36
64
1.1
10 (NU6176)
8
R1 = R2 = H
1a
1b
1c
1d
1e
1f
1g
1h
1i
R1 = CH(CH3)2, R2 = H
R1 = CH2CH2CH2N(CH3)2, R2 = H
R1 = CH2CH2N(CH2CH2)2O, R2 = H
R1 = CH2-p-C6H4OCH3, R2 = H
R1 = CH2-p-C6H4CH3, R2 = H
R1 = CH2CH2CH2Ph, R2 = H
R1, R2 = (CH2)4
R1, R2 = (CH2)5
1.6
R1, R2 = (CH2)4NH
0.45
0.82
2.4
1j
1k
l1
R1, R2 = (CH2)4O
R1 = p-C6H4OCH3, R2 = H
R1 = p-C6H4CH(CH3)3, R2 = H
34
a Concentration of inhibitor required to reduce kinase activity by 50% of control. Values are the mean of at least three determinations. b Reference 12.
Scheme 2 Synthesis of [3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methane-sulfonamide.
pentafluorophenylsulfonate with an amine.16,17 For example,
heating pentafluorophenyl 3-methylbutylsulfonate with 4-
methylbenzylamine gave the required N-(4-methylbenzyl)-3-
methylbutylsulfonamide in excellent yield. When the reaction
between pentafluorophenyl 3-methylbutylsulfonate and 4-
methylbenzylamine was carried out in a mixture of THF and D2O
the product contained one atom of deuterium in the methylene
group attached to sulfonamide nitrogen.17 This led to the proposal
starting materials with DBU was subjected to microwave heating
to give 1m labelled with deuterium. Mass spectrometric, H and
1
13C NMR analysis showed the dominant species in the methylene
group adjacent to the sulfonamide to be CHD. In particular, the
13C NMR showed a triplet (13C-D 19 Hz) at d 59.32 for CHD
alongside a singlet for residual CH2 at d 59.60 in a ratio ca. 2 : 1.
This was in agreement with the ratio of CHD to CH2 of ca. 2 : 1
observed in the 1H NMR spectrum. The results of this experiment
are consistent with the intermediacy of sulfene 9 and hence a
similar mechanism (Scheme 3) to that demonstrated by Caddick
et al. in their studies (see above).17 If it is assumed that during
the experiment described for 7 that the proton abstracted from
the benzylic methylene group exchanges with the deuterons (N-D)
introduced into 7, then the theoretical deuterium content of 1m
should be ca. 87% (note that 2.5 mol equiv. of 3-phenylpropan-1-
amine was used), which compares with ca. 65–70% observed.
18–20
=
of a sulfene intermediate (Me2CHCH2CH SO2).
Caddick
and his group reported similar preparations of sulfonamides from
amines and 2,4,6-trichlorophenylsulfonates using microwave and
conventional heating.21
To explore the mechanism of the synthesis of sulfonamides from
7, the amino group of 3-phenylpropan-1-amine and NH groups of
sulfonate ester 7 were initially deuterated by exchange in deuter-
ated methanol (CD3OD). The resulting mixture of deuterated
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Scheme 3 Mechanism for incorporation of deuterium into 1-[3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(3-phenylpropyl)[2H1]methane-
sulfonamide via a sulfene intermediate.
Activity of sulfonamides against CDK2
characteristics (see e.g. ref. 23), numerous methods have been
reported for the synthesis of sulfonamides beyond the classical
reaction of sulfonyl chlorides with amines.24 Recent reports include
the activation of sulfonic acids using either 2,4,6-trichloro-[1,3,5]-
triazine25 or triphenylphosphine ditriflate26 followed by addition of
an amine, and the reaction of sulfonic acids with an isocyanide.27
In addition, methyl sulfinates have been reacted with a lithium
amide, followed by oxidation to the corresponding sulfonamide
using m-chloroperbenzoic acid.28 Oxidation of sulfenamides to
sulfonamides using either m-chloroperbenzoic acid, or a mixture
of KMnO4 and CuSO4 have been reported in modest yields.29,30
The method described in this paper starts with the relatively
stable trifluoroethoxysulfonate 7, avoids noxious or hazardous
reagents and affords good yields of the target sulfonamides. The
exploitation of trifluoroethyl as a leaving group because of its
abrogated SN2 reactivity is, to the best of our knowledge, a novelty.
The evaluation of compounds 1a–1l against kinase targets other
than CDK2 is being pursued and will be reported elsewhere.
Compounds 1a–1l were assayed for the inhibition of human
cyclin-dependent kinase 2, as described22 and the results are
summarised in Table 1. Previous structure–activity studies with
this class of CDK inhibitor, demonstrated that relocating the
sulfonamide group of NU6102 (3) from the 4- to the 3-position
on the 2-arylamino ring (10) resulted in a 40-fold reduction
in potency against CDK2.12 In the present study, no further
loss of activity was observed on introducing a methylene group
between the sulfonamide and the aryl ring, the homosulfonamide
8 proving equipotent with 10. N-Alkylation of the sulfonamide
generally reduced CDK-2 inhibitory activity as observed for 1a
and 1c, while a substituted benzyl (1d, 1e) or 3-phenylpropyl
(1f) group on the sulfonamide resulted in a marked loss of
potency compared with the parent compound (8). Interestingly,
the dimethylaminopropyl derivative (1b) was only some two-fold
less potent than 8, perhaps suggesting an interaction between the
basic dimethylamino group and the kinase. 6-Cyclohexylmethoxy-
2-arylaminopurines bearing alicyclic amines on the pendant
sulfonamide (1g, 1h, 1i, 1j) showed a less dramatic reduction in
potency, with IC50 values inthe 0.5–1.5 mMrange, and although the
N-4-methoxyphenylsulfonamide (1k) exhibited low micromolar
activity against CDK2, the corresponding 4-t-butylphenyl deriva-
tive (1l) was markedly less active (IC50 = 34 mM), suggesting a
steric effect within the ATP-binding domain.
Experimental section
General procedures
Chemicals and solvents were obtained from reputable suppliers.
THF was freshly distilled from sodium/benzophenone. Other
dry solvents were obtained from commercial sources and used
directly. Triethylamine was dried by distillation from calcium
hydride and stored over potassium hydroxide, under nitrogen.
Microwave irradiation was conducted in an Initiator(tm) Sixty
Biotage reactor. Chromatography, spectroscopy and combustion
analyses were performed as previously described.31–34
Conclusion
Given the special importance of the sulfonamide group in
medicinal chemistry, on account of its unique hydrogen bonding
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General procedure A
292 nm (EtOH); nmax(film)/cm-1 3436, 3112, 2924, 2848, 1591,
1537, 1494, 1435, 1392, 1338, 1287, 1151, 1028, 950, 812; dH
(300 MHz, DMSO-d6) 1.0–1.9 (11H, m, cyclohexyl), 4.35 (2H,
d, J 6.2 Hz, OCH2), 4.84 (2H, s, ArCH2), 4.94 (2H, q, J 8.6 Hz,
CH2CF3), 6.99 (2H, d, J 7.6 Hz, 2 ¥ ArH overlap), 7.31 (1H, t,
J 7.8, 8.1 Hz, ArH), 7.86–7.88 (2H, m, 2 ¥ ArH), 8.03 (1H, s,
H8), 9.44 (1H, s, ArNHAr), 12.86 (1H, br, N9H). LCMS (MeOH)
(ESI+) m/z 500 (M + H)+.
For the synthesis of the 2-arylaminopurine derivatives 1a–1m,
[3-(6-cyclohexylmethoxy-9H-purin-2-ylanilino]methane(2,2,2-
trifluoroethyl)sulfonate ester 7, 1,8-diazabicyclo[5.4.0]undec-7-
ene, and the appropriate amine (quantities of reagents are given
below for individual compounds) were heated under microwave
conditions in anhydrous tetrahydrofuran (2 mL) for 15 min
at 160 ◦C. After removal of the solvent, the white solid was
extracted with ethyl acetate or THF and washed with aq. sodium
bicarbonate and brine. The organic phase was concentrated to give
a residue that was purified by medium pressure chromatography
or by normal phase chromatography with a Biotage SP4 machine.
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-iso-
propylmethanesulfonamide
(1a). Following
the
general
procedure A, the reaction of 2,2,2-trifluoroethyl-3-(6-cyclohexyl-
methoxy-9H-purin-2-ylamino)phenylmethanesulfonate (75 mg,
0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (68 ml,
0.45 mmol), and isopropylamine (32 ml, 0.38 mmol) was
purified by medium pressure chromatography on Biotage KP-
NH silica using 95% ethyl acetate–methanol to give the title
compound as a white solid (48 mg, 70%). Rf 0.37 (9 : 1 v/v
EtOAc–MeOH, KP-NH), mp 230–231 ◦C; UV lmax 272 nm
(EtOH); nmax(film)/cm-1 3435, 3254, 3088, 2928, 2851, 1734, 1598,
1530, 1487, 1447, 1393, 1348, 1300, 1241, 1115, 1026, 974, 938,
905, 858, 790, 691; dH (300 MHz, DMSO-d6) 1.00–1.90 (11H,
m, cyclohexyl), 1.08 (6H, d, J 6.4 Hz, (CH3)2CH), 3.35 (1H, m,
overlap with H2O, CHMe2), 4.21 (2H, s, ArCH2), 4.34 (2H, d, J
6.0 Hz, OCH2), 6.92 (1H, d, J 7.3 Hz, ArH), 7.00 (1H, d, J 7.3 Hz,
ArH), 7.25 (1H, dd, J 7.8, 7.9 Hz, ArH), 7.83 (1H, s, ArH),
7.84 (1H, s, H8), 7.98 (1H, br, SO2NH), 9.38 (1H, s, ArNHAr),
12.77 (1H, s br, N9H); LCMS (MeOH) (ESI+) m/z 459.42 (M +
H)+. HRMS (ESI+) C22H30N6O3S + H requires 459.2173, found
459.2172. HPLC purity (as area %):98.
2,2,2-Trifluoroethyl 3-nitrophenylmethanesulfonate (5). To a
stirred solution of DMAP (155 mg, 1.27 mmol) and Et3N
(5.37 mL, 38 mmol) in 2,2,2-trifluoroethanol (30 cm3) was added
3-nitromethanesulfonyl chloride (3 g, 12.7 mmol). After stirring
at room temperature for 3 h the solvent was removed. The brown
residue was extracted into dichloromethane (250 mL) was washed
with 0.05 M HCl soln. (1 ¥ 250 mL) and water (1 ¥ 250 mL).
The organic layer was dried through a phase separator (Biotage
ISOLUTE) and concentrated to give a colourless oil that was
sonicated in water (50 mL) to give the title compound as a white
crystalline solid that was collected by suction filtration (3.66 g,
96%). Rf 0.52 (6 : 4 v/v EtOAc-petrol), mp 84–85 ◦C; (Found: C,
36.2; H, 2.6; N, 4.5%. C9H8F3NO5S requires C, 36.1; H, 2.7; N,
4.7%); dH (300 MHz, DMSO-d6) 5.00 (2H, q, J 8.6 Hz, OCH2CF3),
5.18 (2H, s, ArCH2), 7.76 (1H, dd, J 7.8, 8.0 Hz, ArH), 7.91 (1H,
d, J 7.8 Hz, ArH), 8.29 (1H, d, J 8.2 Hz, ArH), 8.37 (1H, s, ArH).
2
dC (125 MHz, DMSO) 53.86, 64.86 (q, JC–F 36 Hz), 122.50 (q,
1JC–F 276 Hz), 123.80, 125.52, 130.02, 130.25, 137.39, 147.76.
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(3-
dimethylaminopropyl)methanesulfonamide (1b). Following the
general procedure A, the reaction of 2,2,2-trifluoroethyl-
3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesul-
fonate (60 mg, 0.12 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene
(55 ml, 0.36 mmol), and N,N-dimethylpropane-1,3-diamine (38 ml,
0.30 mmol) was purified by medium pressure chromatography on
KP-NH silica using 85% ethyl acetate–methanol to give the title
compound as a white solid (55 m◦g, 92%). Rf 0.13 (9 : 1 v/v EtOAc–
MeOH, KP-NH), mp 167–168 C; (Found: C, 57.8; H, 7.15; N,
19.7%. C24H35N7O3S requires C, 57.5; H, 7.0; N, 19.55%); UV
lmax 272, 293 nm (EtOH); nmax(film)/cm-1 2924, 2850, 1589, 1541,
1489, 1441, 1390, 1356, 1308, 1243, 1214, 1146, 1121, 973, 887,
789, 693; dH (300 MHz, DMSO-d6) 1.00–1.90 (13H, m, cyclohexyl
and NCH2CH2CH2NH), 2.07 (6H, s, 2 ¥ CH3), 2.19 (2H, t, J
6.9 Hz, Me2NCH2), 2.95 (2H, t, J 6.7 Hz, CH2CH2NH), 4.23
(2H, s, ArCH2), 4.35 (2H, d, J 5.8 Hz, OCH2), 6.92 (1H, d,
J 5.8 Hz, ArH), 7.26 (1H, dd, J 7.8, 7.8 Hz, ArH), 7.83 (1H,
d, J 7.7 Hz, ArH), 7.84 (1H, s, ArH), 8.00 (1H, s, H8), 9.35
(1H, s, ArNHAr). LCMS (MeOH) (ESI+) m/z 502.36 (M +
H)+. HRMS (ESI+) C24H35N7O3S + H requires 502.2595, found
502.2600. HPLC purity (as area %):99.
2,2,2-Trifluoroethyl 3-aminophenylmethanesulfonate (6). To 5
(3.5 g, 11.7 mmol) in 2,2,2-trifluoroethanol (35 mL) was added
10% palladium on carbon (1.05 g) and the reaction mixture
was stirred under H2 for 18 h. The resulting mixture was
filtered through Celite and concentrated in vacuo to give the title
compound 6 as a pale yellow solid (2.92 g, 93%). Rf 0.81 (6 : 4 v/v
EtOAc-petrol), mp 77–78 ◦C; (Found: C, 40.2; H, 3.7; N, 5.15%.
C9H10F3NO3S requires C, 40.15; H, 3.7; N, 5.2%); dH (300 MHz,
DMSO-d6) 4.71 (2H, s, ArNH2), 4.89 (2H, q, J 8.6 Hz, OCH2CF3),
5.22 (2H, s, ArCH2), 6.52–6.62 (3H, m, 3 ¥ ArH), 7.03 (1H, dd, J
7.6, 7.8 Hz, ArH).
2,2,2-Trifluoroethyl-3-(6-cyclohexylmethoxy-9H -purin-2-yl-
amino)phenylmethanesulfonate (7). To 6 (2.8 g, 10.4 mmol) and
6-cyclohexylmethoxy-2-fluoropurine12 (1.24 g, 5.0 mmol) in 2,2,2-
trifluoroethanol (25 mL), was added trifluoroacetic acid (1.84 mL,
24.8 mmol). The mixture was boiled at reflux for 24 h and allowed
to cool to room temperature. The solvent and TFA were removed
in vacuo and the residue was extracted into EtOAc (100 mL). The
resulting solution was washed with saturated aqueous NaHCO3
solution (100 mL) and dried (Na2SO4). The solvents were removed
to furnish the crude product, which was dry loaded onto silica
(~50 mL) and purified by medium pressure chromatography using
60% ethyl acetate-petrol as eluent to give a viscous oil that was
triturated with dichloromethane (~35 mL), giving the product 7 as
a pale yellow powder (1.83 g, 74%). Rf 0.22 (6 : 4 v/v EtOAc-
petrol), mp 199–200 ◦C; (Found: C, 50.8; H, 4.6; N, 13.9%.
C21H24F3N5O4S requires C, 50.5; H, 4.8; N, 14.0%); UV lmax 272,
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(2-
morpholin-4-ylethyl)methanesulfonamide (1c). Following the
general procedure A, the reaction of 2,2,2-trifluoroethyl-
3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesul-
fonate (60 mg, 0.12 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene
(55 ml, 0.36 mmol), and 2-morpholinoethanamine (39 ml,
This journal is
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Org. Biomol. Chem., 2010, 8, 2457–2464 | 2461
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0.30 mmol) was purified by medium pressure chromatography on
KP-NH silica using 85% ethyl acetate–methanol to give the title
compound as a colourless solid (59 mg, 93%). Rf 0.23 (9 : 1 v/v
EtOAc–MeOH, KP-NH), mp 136–137 ◦C; UV lmax 272, 293 nm
(EtOH); nmax(film)/cm-1 2924, 2852, 2158, 2021, 1973, 1588, 1542,
1491, 1443, 1393, 1356, 1304, 1243, 1214, 1115, 973, 787, 692;
dH (300 MHz, DMSO-d6) 1.00–1.86 (11H, m, cyclohexyl), 2.34
(6H, br m, 2 ¥ NCH2CH2O and CH2CH2SO2NH), 3.03 (2H, t,
J 6.6 Hz, CH2NH), 3.52 (4H, t, J 4.6 Hz, 2 ¥ NCH2CH2O),
4.31 (2H, s, ArCH2), 4.34 (2H, d, J 6.0 Hz, OCH2), 6.93 (1H,
d, J 7.4 Hz, ArH), 7.26 (1H, dd, J 7.6, 7.7 Hz, ArH), 7.81
(1H, s, ArH), 7.83 (1H, d, J 7.7 Hz, ArH), 8.00 (1H, s, H8),
9.34 (1H, s, ArNHAr). LCMS (MeOH) (ESI+) m/z 530.43 (M +
H)+. HRMS (ESI+) C25H35N7O4S + H requires 530.2544, found
530.2549. HPLC purity (as area %):95.
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(3-
phenylpropyl)methanesulfonamide
(1f). Following
the
general procedure A, the reaction of 2,2,2-trifluoroethyl-
3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesul-
fonate (75 mg, 0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene
(68 ml, 0.45 mmol), and 3-phenylpropan-1-amine (53 mg,
0.38 mmol) was purified by medium pressure chromatography on
silica using 90% ethyl acetate-petrol to give the title compound
as a white solid (57 mg, 71%). Rf 0.41 (EtOAc), mp 138–139 ◦C;
UV lmax 272 nm (EtOH); nmax(film)/cm-1 3277, 2923, 2850, 2444,
2361, 1586, 1551, 1510, 1447, 1395, 1352, 1310, 1126, 976, 951,
882, 787, 741, 695; dH (300 MHz, DMSO-d6) 1.00–1.90 (11H, m,
cyclohexyl), 1.70 (2H, m, CH2CH2CH2NH), 2.56 (2H, t, J 7.7 Hz,
PhCH2), 2.92 (2H, m, CH2CH2NH), 4.24 (2H, s, ArCH2), 4.35
(2H, d, J 6.0 Hz, OCH2), 6.91 (1H, d, J 7.5 Hz, ArH), 7.10–7.28
(7H, m, 7 ¥ ArH), 7.80–7.85 (2H, m, ArH and SO2NH), 8.01
(1H, s, H8), 9.36 (1H, s, ArNHAr), 12.69 (1H, s br, N9H); dC
(500 MHz, CD3OD) 25.59, 26.25, 29.58, 31.98, 32.49, 37.45,
42.82, 58.29, 71.81, 118.62, 120.87, 123.57, 124.81, 125.47, 127.97,
128.03, 128.39, 137.84, 141.18, 141.48, 156.31; LCMS (MeOH)
(ESI+) m/z 535.45 (M + H)+. HRMS (ESI-) C28H34N6O3S - H
requires 533.2340, found 533.2350. HPLC purity (as area %):95.
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(4-
methoxybenzyl)methanesulfonamide
(1d). Following
the
general procedure A, the reaction of 2,2,2-trifluoroethyl-
3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesul-
fonate (150 mg, 0.3 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene
(136 ml, 0.9 mmol), and 4-methoxybenzylamine (97 ml, 0.75 mmol)
was purified by medium pressure chromatography on silica using
90% ethyl acetate-petrol to give the title compound as a white
1-(3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmeth-
anesulfonyl)pyrrolidine (1g). Following the general procedure A,
the reaction of 2,2,2-trifluoroethyl-3-(6-cyclohexylmethoxy-9H-
purin-2-ylamino)phenylmethanesulfonate (75 mg, 0.15 mmol),
1,8-diazabicyclo[5.4.0]undec-7-ene (68 ml, 0.45 mmol), and pyrro-
lidine (32 ml, 0.38 mmol), was purified by medium pressure
chromatography on silica using 80% ethyl acetate-petrol to give the
title compound as a white solid (53 mg, 75%). Rf 0.74 (EtOAc),
mp 120–121 ◦C; UV lmax 272, 292 nm (EtOH); nmax(film)/cm-1
2926, 2852, 2159, 2031, 1590, 1540, 1492, 1445, 1394, 1317, 1122,
789; dH (300 MHz, DMSO-d6) 1.0–1.9 (15H, m, cyclohexyl and
2 ¥ pyrrolidine CH2), 3.15 (4H, t, J 6.5 Hz, 2 ¥ pyrrolidine CH2),
4.35 (4H, s and d, J 5.8 Hz, OCH2 and ArCH2), 6.96 (1H, d, J
7.5 Hz, ArH), 7.26 (1H, dd, J 7.8, 7.9 Hz, ArH), 7.81 (1H, d,
J 8.4 Hz, ArH), 7.89 (1H, s, ArH) 7.98 (1H, s, H8), 9.41 (1H, s,
ArNHAr), 12.78 (1H, br, N9H); LCMS (MeOH) (ESI+) m/z 471
(M + H)+. HRMS (ESI+) C23H30N6O3S + H requires 471.2173,
found 471.2172. HPLC purity (as area %):100.
◦
solid (143 mg, 89%). Rf 0.37 (EtOAc), mp 118–119 C; UV lmax
272 nm (EtOH); nmax(film)/cm-1 2922, 2850, 2361, 2338, 2026,
1589, 1541, 1506, 1444, 1395, 1354, 1303, 1244, 1121, 1030,
947, 887, 787, 730, 692; dH (300 MHz, DMSO-d6) 1.00–1.90
(11H, m, cyclohexyl), 3.70 (3H, s, OCH3), 4.05 (2H, d, J 9.0 Hz,
ArCH2NH), 4.22 (2H, s, ArCH2SO2NH), 4.35 (2H, d, J 6.1 Hz,
OCH2), 6.86–6.90 (3H, m, 3 ¥ ArH), 7.23 (2H, d, J 7.0 Hz,
ArH), 7.26 (1H, dd, J 7.6, 7.9 Hz, ArH), 7.57 (1H, t, J 6.0 Hz,
SO2NH), 7.81–7.85 (2H, m, 2 ¥ ArH), 7.99 (1H, s, H8), 9.37
(1H, s, ArNHAr), 12.77 (1H, s br, N9H); LCMS (MeOH) (ESI+)
m/z 537.40 (M + H)+. HRMS (ESI-) C27H32N6O4S - H requires
535.2133, found 535.2143. HPLC purity (as area %):95.
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(4-
methylbenzyl)methanesulfonamide
(1e). Following
the
general procedure A, the reaction of 2,2,2-trifluoroethyl-
3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesul-
fonate (75 mg, 0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene
(68 ml, 0.45 mmol), and p-tolylmethanamine (48 ml, 0.38 mmol)
was purified by medium pressure chromatography on silica
using 75% ethyl acetate-petrol to give the title compound as a
colourless solid (56 mg, 72%). Rf 0.46 (8 : 2 v/v EtOAc-Petrol),
mp 147–148 ◦C; (Found: C, 62.2; H, 6.2; N, 16.0%. C27H32N6O3S
requires C, 62.3; H, 6.2; N, 16.15%); UV lmax 272 nm (EtOH);
1-(3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmeth-
anesulfonyl)piperidine
(1h). Following
the
general
procedure A, the reaction of 2,2,2-trifluoroethyl-3-(6-cyclo-
hexylmethoxy - 9H - purin - 2 - ylamino ) phenylmethanesulfonate
(75 mg, 0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (68 ml,
0.45 mmol), and piperidine (37 ml, 0.38 mmol) was purified
by medium pressure chromatography on silica using 95% ethyl
acetate–methanol to give the title compound as a white solid
(54 mg, 75%). Rf 0.26 (EtOAc), mp 217–218 ◦C; (Found: C,
59.2; H, 6.6; N, 17.2%. C24H32N6O3S requires C, 59.5; H, 6.7; N,
17.3%); UV lmax 272, 293 nm (EtOH); nmax(film)/cm-1 2922, 2853,
2362, 2338, 1589, 1541, 1437, 1396, 1350, 1310, 1242, 1152, 1121,
1067, 1045, 949, 888, 789, 694; dH (300 MHz, DMSO-d6) 1.0–1.8
(11H, m, cyclohexyl), 1.47 (6H, m, piperidyl CH), 3.12 (4H, br m,
2 ¥ piperidyl CH2), 4.28 (2H, s, ArCH2), 4.35 (2H, d, J 6.2 Hz,
OCH2), 6.94 (1H, d, J 7.5 Hz, ArH), 7.25 (1H, dd, J 7.9, 8.0 Hz,
ArH), 7.81 (1H, d, J 8.5 Hz, ArH), 7.88 (1H, s, ArH), 8.02 (1H, s,
n
max(film)/cm-1 2922, 2850, 2361, 2338, 1589, 1540, 1491, 1443,
1393, 1352, 1306, 1121, 1059, 974, 945, 887, 837, 787, 691; dH
(300 MHz, DMSO-d6) 1.00–1.86 (11H, m, cyclohexyl), 2.26 (3H, s,
ArCH3), 4.07 (2H, s, ArCH2NH), 4.23 (2H, s, ArCH2SO2NH),
4.35 (2H, d, J 6.1 Hz, OCH2), 6.90 (1H, d, J 7.5 Hz, ArH), 7.12
(2H, d, J 7.8 Hz, 2 ¥ ArH), 7.20 (2H, d, J 7.9 Hz, 2 ¥ ArH),
7.26 (1H, dd, J 7.8, 7.8 Hz, ArH), 7.81–7.85 (2H, m, 2 ¥ ArH),
8.01 (1H, s, H8), 9.35 (1H, s, ArNHAr), 12.79 (1H, s br, N9H);
LCMS (MeOH) (ESI+) m/z 521.39 (M + H)+. HRMS (ESI+)
C27H32N6O3S + H requires 521.2329, found 521.2328. HPLC
purity (as area %):97.
2462 | Org. Biomol. Chem., 2010, 8, 2457–2464
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H8), 9.42 (1H, s, ArNHAr), 12.76 (1H, br, N9H); LCMS (MeOH)
(ESI+) m/z 485.18 (M + H)+.
H)+. HRMS (ESI+) C26H30N6O4S + H requires 523.2122, found
523.2122. HPLC purity (as area %):97.
1-(3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmeth-
N-(4-tert-Butylphenyl)-C-[3-(6-cyclohexylmethoxy-9H-purin-
2-ylamino)phenyl]methanesulfonamide (1l). Following the gen-
eral procedure A, the reaction of 2,2,2-trifluoroethyl-3-(6-cyclo-
hexylmethoxy - 9H - purin - 2 - ylamino ) phenylmethanesulfonate
(75 mg, 0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (68 ml,
0.45 mmol), and 4-t-butylaniline (60 ml, 0.38 mmol) was purified
by medium pressure chromatography on silica using 75% ethyl
acetate-petrol to give the title compound as a colourless ◦powder
(39 mg, 47%). Rf 0.54 (8 : 2 EtOAc-Petrol), mp 132–133 C; UV
anesulfonyl)piperazine
(1i). Following
the
general
procedure A, the reaction of 2,2,2-trifluoroethyl-3-(6-cyclo-
hexylmethoxy - 9H - purin - 2 - ylamino ) phenylmethanesulfonate
(75 mg, 0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (68 ml,
0.45 mmol), and piperazine (45 mg, 0.53 mmol) was purified
using the Biotage SP4 with KP-NH silica and 95% ethyl acetate–
methanol to give the title compound as a colourless solid (66 mg,
91%). Rf 0.73 (8 : 2 v/v EtOAc–MeOH, KP-NH), mp 127–128 ◦C;
UV lmax 272, 293 nm (EtOH); nmax(film)/cm-1 2922, 2853, 2362,
2338, 1589, 1541, 1437, 1396, 1350, 1310, 1242, 1152, 1121, 1067,
1045, 949, 888, 789, 694; dH (300 MHz, DMSO-d6) 1.0–1.9 (11H,
m, cyclohexyl), 3.11 (4H, br, 2 ¥ piperazinyl CH2), 3.16 (4H, br,
2 ¥ piperazinyl CH2), 4.33 (2H, s, ArCH2), 4.35 (2H, d, J 6.7 Hz,
OCH2), 6.95 (1H, d, J 7.5 Hz, ArH), 7.26 (1H, dd, J 7.8, 7.9 Hz,
ArH), 7.62 (1H, d, J 8.0 Hz, ArH), 7.91 (1H, s, ArH), 7.97 (1H, s,
H8), 9.34 (1H, s, ArNHAr), 12.77 (1H, br, N9H); LCMS (MeOH)
(ESI+) m/z 486 (M + H)+. HRMS (ESI+) C23H31N7O3S + H
requires 484.2136, found 484.2145. HPLC purity (as area %):95.
l
max 273 nm (EtOH); nmax(film)/cm-1 3356, 2923, 2851, 2361, 2338,
1707, 1591, 1499, 1442, 1398, 1356, 1300, 1147, 1125, 934, 835, 785,
691; dH (300 MHz, DMSO-d6) 1.00–1.83 (11H, m, cyclohexyl),
1.25 (9H, br s, C(CH3)3), 4.29 (2H, d, J 6.2 Hz, OCH2), 4.31
(2H, s, ArCH2SO2NH), 6.79 (1H, d, J 7.1 Hz, ArH), 7.14 (2H, d,
J 8.6 Hz, 2 ¥ ArH), 7.24 (1H, dd, J 7.7, 8.0 Hz, ArH), 7.32 (2H,
d, J 8.5 Hz, 2 ¥ ArH), 7.76 (1H, s, ArH), 7.81 (1H, d, J 7.9 Hz,
ArH), 8.00 (1H, s, H8), 9.37 (1H, s, ArNHAr), 12.79 (1H, s br,
N9H); LCMS (MeOH) (ESI+) m/z 549.49 (M + H)+. HRMS
(ESI+) C29H36N6O3S + H requires 549.2642, found 549.2647.
HPLC purity (as area %):95.
4-(3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmeth-
anesulfonyl)morpholine
(1j). Following
the
general
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(3-
procedure A, the reaction of 2,2,2-trifluoroethyl-3-(6-cyclo-
hexylmethoxy - 9H - purin - 2 - ylamino ) phenylmethanesulfonate
(46 mg, 0.09 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (42 ml,
0.18 mmol), and morpholine (16 ml, 0.18 mmol), was purified
by medium pressure chromatography on silica using 80% ethyl
acetate-petrol as eluent to give the title compound as a white solid
(32 mg, 72%). Rf 0.64 (EtOAc), mp 140–141 ◦C; UV lmax 216, 272,
292 nm (EtOH); nmax(film)/cm-1 3302, 2924, 2854, 1587, 1552,
1494, 1396, 1307, 1242, 1141, 943, 788; dH (300 MHz, DMSO-d6)
1.0–1.9 (11H, m, cyclohexyl), 3.11 (4H, t, J 4.5 Hz, NCH2CH2O),
3.57 (4H, t, J 4.5 Hz, NCH2CH2O), 4.34 (2H, d, J 7.3 Hz, OCH2),
4.35 (2H, s, ArCH2), 6.96 (1H, d, J 7.6 Hz, ArH), 7.27 (1H, dd,
J 7.8, 8.1 Hz, ArH), 7.83–7.85 (2H, m, 2 ¥ ArH), 7.98 (1H, s,
H8), 9.43 (1H, s, ArNHAr), 12.77 (1H, br, N9H); LCMS (MeOH)
(ESI+) m/z 487 (M + H)+. HRMS (ESI+) C23H30N6O4S + H
requires 487.2122, found 487.2116. HPLC purity (as area %):100.
phenylpropyl)[2H1]methanesulfonamide
(1m). 2,2,2-Trifluoro-
ethyl-3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylme-
thanesulfonate (75 mg, 0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-
7-ene (68 ml, 0.45 mmol) and 3-phenylpropan-1-amine (54 ml,
0.38 mmol) were dissolved in ethyl acetate (5 mL) and concentrated
to a residue that was co-evaporated with CD3OD (2 ¥ 2 mL,
after an initial incubation for 2 h each time) in vacuo followed
by anhydrous THF (2 mL). The residual material was subjected
to general procedure A (8 min microwave heating) and the crude
product was purified by medium pressure chromatography on
silica using 90% ethyl acetate-petrol as eluent to give the title
compound as a white solid (48 mg, 60%). Rf 0.41 (EtOAc), mp
139–140 ◦C; UV lmax 272, 294 nm (EtOH); nmax(film)/cm-1 3279,
2923, 2851, 2361, 2337, 1725, 1589, 1549, 1489, 1447, 1381,
1350, 1310, 1287, 1130, 1083, 974, 945, 889, 787, 743, 692; dH
(300 MHz, DMSO-d6) 1.00–1.87 (11H, m, cyclohexyl), 1.69 (2H,
m, CH2CH2CH2NH), 2.56 (2H, t, J 7.6 Hz, PhCH2), 2.92 (2H,
m, CH2CH2NH), 4.22 (ca. 0.6H, br s, ArCHDSO2NH), 4.24
(ca. 0.3H, br s, ArCH2SO2NH), 4.35 (2H, d, J 6.1 Hz, OCH2),
6.91 (1H, d, J 7.3 Hz, ArH), 7.12–7.28 (7H, m, 7 ¥ ArH),
7.81–7.86 (2H, m, ArH and SO2NH), 8.01 (1H, s, H8), 9.38
(1H, s, ArNHAr), 12.79 (1H, s br, N9H); dC (125 MHz, CD3OD)
59.32 (t, JC-D 19 Hz), 59.60 (s) and other peaks as observed in the
spectrum of 1f; LCMS (MeOH) (ESI+) m/z 536.40 (M + H)+.
HRMS (ESI+) C28H33DN6O3S + H requires 536.2540, found
536.2532. HPLC purity (as area %):95.
1-[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]-N-(4-
methoxyphenyl)methanesulfonamide (1k). Following the gen-
eral procedure A, the reaction of 2,2,2-trifluoroethyl-3-(6-cyclo-
hexylmethoxy - 9H - purin - 2 - ylamino ) phenylmethanesulfonate
(75 mg, 0.15 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (68 ml,
0.45 mmol), and 4-aminoanisole (45 mg, 0.38 mmol) was purified
by medium pressure chromatography on silica using 80% ethyl
acetate-petrol to give the title compound as a white solid (45 mg,
57%). Rf 0.43 (8 : 2 EtOAc-Petrol), mp 220–221 ◦C; UV lmax
273 nm (EtOH); nmax(film)/cm-1 3341, 2924, 2850, 2361, 2337,
1632, 1608, 1579, 1553, 1499, 1438, 1404, 1362, 1331, 1296, 1220,
1150, 1120, 1030, 934, 824, 791, 693; dH (300 MHz, DMSO-d6)
1.00–1.83 (11H, m, cyclohexyl), 3.73 (3H, s, ArOCH3), 4.24 (2H, s,
ArCH2SO2NH), 4.27 (2H, d, J 6.2 Hz, OCH2), 6.80 (1H, d, J
7.5 Hz, ArH), 6.89 (2H, d, J 8.9 Hz, 2 ¥ ArH), 7.16 (2H, d,
J 8.9 Hz, 2 ¥ ArH), 7.25 (1H, dd, J 7.9, 7.9 Hz, ArH), 7.75–
7.82 (2H, m, 2 ¥ ArH), 8.01 (1H, s, H8), 9.39 (1H, s, ArNHAr),
12.79 (1H, s br, N9H); LCMS (MeOH) (ESI+) m/z 523.40 (M +
[3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methane-
sulfonamide
(8). [3-(6-Cyclohexylmethoxy-9H-purin-2-yl-
(1d,
amino)phenyl]-N-(4-methoxybenzyl)methanesulfonamide
80 mg, 0.15 mmol) was stirred in neat TFA (2 mL) for 6 h.
Upon completion of the reaction, the TFA was removed in vacuo
and the residual solid was extracted into EtOAc (50 mL). The
organic layer was washed with aqueous sodium bicarbonate
(50 mL), dried (Na2SO4) and concentrated to give a white solid.
This journal is
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Org. Biomol. Chem., 2010, 8, 2457–2464 | 2463
©

View Article Online
Purification by medium pressure chromatography on silica using
ethyl acetate as eluent gave the title compound as a white powder
(53 mg, 85%). Rf 0.50 (EtOAc), mp 134–135 ◦C; UV lmax 272,
292 nm (EtOH); nmax(film)/cm-1 3344, 2924, 2852, 2361, 2338,
1719, 1599, 1542, 1488, 1449, 1393, 1336, 1256, 1156, 1123, 1046,
966, 951, 890, 856, 834, 789, 692; dH (300 MHz, DMSO-d6)
1.0–1.9 (11H, m, cyclohexyl), 4.20 (2H, s, ArCH2SO2NH2), 4.34
(2H, d, J 6.0 Hz, OCH2), 6.85 (2H, s br, SO2NH2), 6.93 (1H, d,
J 7.3 Hz, ArH), 7.26 (1H, dd, J 7.8, 7.9 Hz, ArH), 7.75 (1H, s,
ArH), 7.85 (1H, d, J 8.3 Hz, ArH), 7.97 (1H, s, H8), 9.37 (1H, s,
ArNH), 12.77 (1H, br, N9H); LCMS (MeOH) (ESI+) m/z 417
(M + H)+. HRMS (ESI+) C19H24N6O3S + H requires 417.1703,
found 417.1702. HPLC purity (as area %):96.
14 P. D. Bailey, M. A. Beard, H. P. T. Dang, T. R. Phillips, R. A. Price and
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