Tandem free-radical addition/substitution chemistry and its application to the preparation of novel AT1 receptor antagonists

Article abstract of DOI:10.1039/c0ob00573h

Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT₁ receptor antagonist properties. While the sulfur-containing systems were prepared following

Full text of DOI:10.1039/c0ob00573h

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PAPER
Tandem free-radical addition/substitution chemistry and its application to the
preparation of novel AT1 receptor antagonists†‡
Maree K. Staples,a,b Rebecca L. Grange,a,b James A. Angus,a,c James Ziogas,a,c Nichole P. H. Tan,a,b
Michelle K. Taylora,b,d and Carl H. Schiesser*a,b
Received 13th August 2010, Accepted 21st September 2010
DOI: 10.1039/c0ob00573h
Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives
milfasartan and eprosartan were prepared and tested for AT1 receptor antagonist properties. While the
sulfur-containing systems were prepared following existing methodology, the selenium-containing
analogues required the development of novel, tandem free-radical chemistry involving addition of aryl
radicals to alkynes, followed by intramolecular homolytic substitution at the higher heteroatom. All
four compounds prepared proved to be excellent AT1 receptor antagonists, with pKB estimates of
7.2–9.5.
Introduction
Persistently high blood pressure (hypertension) is a major risk
factor for many serious illnesses including stroke, myocardial
infarction, heart failure and renal failure.1 Hypertension is now
considered to be the world’s third leading cause of death.1 As
such, there is some urgency in gaining a further understanding of
the causes of, and chemical mechanisms involved in hypertension,
as well as the development of new and improved treatments.
Current therapeutic intervention for the treatment of hyper-
tension mostly involves drugs that interact with the Renin–
Angiotensin Cascade. Sartans, for example, are a family of drugs
that selectively act on the Angiotensin II, subtype 1 (AT1) receptor
thereby reducing blood pressure.2
Milfasartan3 (1; Y = S) and eprosartan4–7 (2; Y = S) are
thiophene-containing sartans; milfasartan reached Phase I clinical
trials, while eprosartan is on the market in many countries.4,8,9
We recently reported that the selenium-containing analogues
of these compounds (1, 2; Y = Se), as well as selenofonsartan
analogues, are at least as potent as the parent in their ability to
bind to the AT1 receptor in Chinese Hamster Ovary (CHO) cell
assays.10,11 Given the outcome of our previous work, and as part of
an ongoing study, were were curious about the effect that size of the
chalcogen-containing heterocyclic unit may have on milfasartan
and eprosartan potency.
We now report the preparation and preliminary pharmacolog-
ical testing of benzothiophene and benzoselenophene analogues
(3, 4) of milfasartan and eprosartan.
aARC Centre of Excellence for Free Radical Chemistry and Biotechnology,
Bio21 Molecular Science and Biotechnology Institute, The University of
Melbourne, The University of Melbourne, Victoria, 3010, Australia
bSchool of Chemistry, Bio21 Molecular Science and Biotechnology Institute,
The University of Melbourne, Victoria, 3010, Australia. E-mail: carlhs@
unimelb.edu.au; Fax: +61 3 9347 8189; Tel: +61 3 8344 2432
Results and discussion
cDepartment of Pharmacology, The University of Melbourne, Victoria, 3010,
Australia
The milfasartan analogues were prepared by adapting the general
protocol decribed by Salimbeni,3 while the eprosartan analogues
were prepared by adapting the general protocol of Keenan.7 To
that end, the sulfur-containing sartans (3, 4; Y = S) required the
preparation of the known benzothiophenes (5, 6; Y = S),12,13 while
the selenium-containing sartans required the preparation of the
novel benzoselenophenes (5, 6; Y = Se).
dCurrent address: Division of Chemistry, School of Science and Technology,
The University of New England, Armidale, NSW, 2351, Australia
† Dedicated to Professor Athel Beckwith and in recognition of his many
contributions to free radical chemistry; he was an exceptional scientist, a
gentleman and a scholar. The world has lost a scientific treasure.
‡ Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 3 (Y = Se), 4 (Y = S), 4 (Y = Se), 5 (Y = Se), 9, 10,
12 (Y = Se), 13 (Y = Se). See DOI: 10.1039/c0ob00573h
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While our previous work made extensive use of the benzylseleno
group for radical ring-closure at selenium, we rapidly discovered
that we were unable to prepare 2-(benzylseleno)phenyldiazonium
tetrafluoroborate (8a) under standard (aqueous) conditions due to
solubility problems. We eventually prepared 8a under anhydrous
conditions from 2-(benzylseleno)aniline20 using in situ generated
nitrosyl fluoride as described by Doyle and Bryker (Scheme 3),21
however this tetrafluoroborate salt, when isolated, proved to be
unstable, decomposing to a bright red liquid within 5 min at 0 ◦C.
Attempted immediate use of 8a in any reactions of interest resulted
in a red solution and a complex mixture of products as evidenced
by TLC.
Malonate (5; Y = S) was prepared from benzo[b]thiophene-
2-carboxaldehyde14 in 54% yield by condensation with diethyl
malonate with subsequent reduction with sodium borohydride
(Scheme 1),7 while 2-(bromomethyl)benzo[b]thiophene (6; Y =
S, X = Br) was prepared in 91% yield by NBS bromination of
commercially-available 2-methylbenzo[b]thiophene.
Scheme 3 Reagents and conditions: (a) Me2Se2, NaBH4, EtOH, r.t., 90%;
(b) Na2S2O3, EtOH/H2O, reflux, 31%; (c) NaNO2; (d) HBF4, 10% H2SO4,
0
◦C, quantitative; (e) t-BuONO, BF3·OEt2, -15 to 5 ◦C (unstable); (f)
Scheme 1 Reagents and conditions: (a) Diethyl malonate, piperidine,
benzoic acid, cyclohexane, reflux; (b) NaBH4, EtOH, r.t., 54% over two
steps.
3,3¢-dipicolyl diselenide, NaBH4, EtOH, r.t., 72%; (g) Na2S2O4, EtOH,
reflux, 40%.
In order to improve solubility, we also attempted to prepared
a pyridyl-substituted salt, however, diazotization of 2-(pyridin-
3-ylmethylseleno)aniline 9 under standard conditions did not
provide the required diazonium salt as a precipitate, presumably
because the salt is too soluble under the acidic reaction conditions.
Given that the key homolytic substitution step (Scheme 2)
involves a reactive vinyl radical, we reasoned that while not ideal,
the required reaction should proceed even with a methyl radical
as leaving group because of the required disparity of reactivities
between attacking and leaving radicals in the SHi step. To that
end, 8b was prepared by the reaction of 2-fluoronitrobenzene
with sodium methylselenoate (formed by the reaction of
dimethyl diselenide with sodium borohydride in ethanol) fol-
lowed by reduction and diazotisation under standard conditions
(Scheme 3).
The analogous selenium-containing starting materials (5, 6;
Y = Se) required the development of a novel approach for the
construction of the core heterocyclic unit and we recognised
that ethyl benzo[b]selenophene-2-carboxylate (7; R = CO2Et)
would be a key intermediate for the construction of both
compounds. Ester (7; R = CO2Et) and related compounds have
been prepared previously,15 but the methodology reported is
somewhat tedious and was therefore not appealing to us. With
our background in free-radical chemistry, especially involving
the construction of selenium-containing rings,16 including tandem
addition/substitution sequences,17,18 we began to explore the
tandem addition of aryl radicals to alkynes as synthetically viable
methodology for the construction of the required heterocyclic ring
system (7) (Scheme 2).
With diazonium salt 8b in hand, reactions with alkynes
of varying electronic demand were attempted. To our de-
light, alkynes bearing electron-withdrawing groups provided
benzo[b]selenophenes (7, 10) in 19–50% conversion (Scheme
4). In the absence of electron-withdrawing substituents on the
alkyne, only poor yields were obtained (entries 3, 4), while the
more sterically demanding TMS group resulted in an absence
of reaction (entry 5). The “one-pot” tandem sequence described
herein represents a significant improvement over previous methods
for the preparation of benzo[b]selenophenes bearing electron-
withdrawing groups at positions 2 and 3, especially for the
preparation of the required ester (7; R = CO2Et).
Scheme 2
Developing the tandem chemistry
Inspired by the work of Zanardi and coworkers,19 our attention
turned to the use of aryldiazonium tetrafluoroborates such as
8 for the generation of aryl radicals catalysed by iron(II) salts.
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Scheme 6 Reagents and conditions: (a) 6, NaH, LiBr, DMF, 0 ◦C r.t.,
57–72%; (b) MeOH, reflux, 89–96%.
Scheme 4 Reagents and conditions: FeSO4, DMSO/H2O, 15 min., r.t.
It should be noted that in our hands yields were not improved
through the use of additional FeSO4 or copper powder in acetone,19
and increasing the amount of diazonium salt led to more complex
reaction mixtures.
With convenient access to selenophene (7; R = CO2Et), it was
then reduced by the action of DiBALH and the resultant alcohol
converted to the corresponding chloride (6; X = Cl, Y = Se) by
reaction with thionyl chloride (Scheme 5). Subsequent treatment
with diethyl malonate as described by Kaiser afforded 5 (Y = Se)
in 32% yield.12
Scheme 7 Reagents and conditions: (a) KOH, EtOH, r.t. 65–88%; (b) 14,
piperidine, benzoic acid, cyclohexane/toluene, reflux; (c) NaOH, EtOH,
H2O, r.t. 29–51% (2 steps).
Scheme 5 Reagents and conditions: (a) DiBALH, Et2O, -78 ◦C, 75%; (b)
SOCl2, dioxane, reflux, 68%; (c) Diethyl malonate, NaH, DMF, 32%.
Synthesis of the novel sartan analogues
With key materials (5, 6) in hand, the route to the milfasartan ana-
logues (3) involved coupling of 6 to the common trityl-protected
biphenyl “scaffold” (11) following the procedure of Salimbeni;3
subsequent deprotection afforded sartans 3 in acceptable yield
(Scheme 6).
The eprosartan analogues were prepared by conversion of the
diesters (5) to the corresponding half-acids (13). Condensation
with the formylimidazole (14)6 followed by saponification afforded
the target compounds (4) in 29–51% yield (Scheme 7).
Fig. 1 Inhibition of angiotensin II-evoked increases in intracellular
calcium in CHO cells stably expressing the AT1a receptor by milfasasrtan
derivation (Se) against the parent milfasartan 1 (S).
Similar data were obtained for the other sartans in this study and
the pKB estimates are summarized in Table 1.
Inspection of Table 1 reveals that in each series of sartans,
increasing the size of the heterocyclic unit serves to lower the
ability of the compound to bind to the AT1 receptor (entries
1 versus 2 and 4 versus 5). However, in moving from sulfur to
selenium (entries 3 and 6), binding affinity appears to be somewhat
restored. While the origins of this phenomenon are not clear
at this point, it would appear that, at least for benzothiophene
and benzoselenophene analogues of milfasartan and eprosartan,
incorporation of selenium into the heterocyclic unit appears to
engender an increased receptor binding affinity over the sulfur–
containing analogue.
Preliminary pharmacology
Chinese hamster ovary cells stably expressing the rat AT1a receptor
were used to assess the receptor antagonist properties of the sartan
analogues prepared in this study.22 In initial experiments, the
ability of 30 nM of compounds 3 and 4 to inhibit angiotensin
II mediated increases in intracellular calcium was compared to
the parent sartans 1, 2 (Y = S). Fig. 1 shows the right-ward shift
of the angiotensin concentration response curve for milfasartan
derivative 3 (Se) from a which a pKB estimate of 9.5 was obtained.
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Table 1 pKB Estimates of the sartans (3, 4) prepared in this study as
compared with the parent compounds milfasartan and eprosartan
(100) 65.1 (33); (Found: C, 49.1; H, 3.5. C12H10N2O2Se requires C,
49.2; H, 3.4%).
Entry
Sartan
pKB estimatea
2-(Pyridin-3-ylmethylseleno)aniline (9)
1
2
3
4
5
6
Milfasartan (1, Y = S)
3 (Y = S)
9.5
7.9
9.5
8.4
7.2
8.1
2-(Pyridin-3-ylmethylseleno)nitrobenzene (0.1 g, 0.36 mmol) was
dissolved in ethanol (5 mL) and water (2 mL). Sodium dithionite
(0.37 g, 2.15 mmol) was added and the mixture heated at reflux
for 3 h. The solution was made basic with ammonia solution
and the product extracted into chloroform (3 ¥ 50 mL) and
the solvent removed in vacuo. The product was purified by flash
chromatography (2% methanol–dichloromethane) to give the title
aniline (36 mg, 40%). 1H NMR (500 MHz, CDCl3) d 8.39 (dd, J =
1.6, 4.8, 1H), 8.30 (d, J = 2.1, 1H), 7.33 – 7.28 (m, 1H), 7.24 (dd,
J = 8.4, 10.0, 1H), 7.11 (m, 2H), 6.71 (dd, J = 6.7, 1.3, 1H), 6.56
(td, J = 6.0, 1.3, 1H), 4.25 (s, 2H), 3.89 (s, 2H); 13C NMR (126
MHz, CDCl3) d 149.8, 148.8, 147.9, 138.5, 136.0, 135.1, 130.8,
123.0, 118.6, 114.6, 112.8, 27.6; 77Se NMR (95.4 MHz, CDCl3)
d 289.8; HRMS calcd for C12H13N2Se [M+H]+ 265.02385, found
265.02387.
3 (Y = Se)
Eprosartan (2, Y = S)
4 (Y = S)
4 (Y = Se)
a See text.
Conclusions
Benzothiophene and benzoselenophene derivatives (3, 4) of mil-
fasartan and eprosartan were prepared and assessed for their
AT1 receptor antagonist properties. The selenium–containing
analogues required the development of novel, tandem, homolytic
addition/substitution chemistry for construction of the benzose-
lenophene moiety and this was achieved through the use of
diazonium salt chemistry. All sartan derivatives prepared proved
to be excellent AT1 receptor antagonists, with pKB estimates of
7.2–9.5. While the benzothiophene analogues showed reduced
sartan activity when compared with the parent compounds,
incorporation of selenium into these molecules appears to restore
AT1 receptor binding ability.
General procedure for the reaction of 2-(methylseleno)-
phenyldiazonium tetrafluoroborate (8b) with alkynes
DMSO (1.1 mL) was degassed with argon for 10 min. Iron(II)
sulfate heptahydrate (0.22 g, 1.35 mmol, 1.5 eq) and water
(0.2 mL) and the alkyne (2.6 eq) were added and the solution
degassed for a further 20 min. 2-(Methylseleno)phenyldiazonium
tetrafluoroborate (8b) (5.21 mmol) was added and the reaction
stirred for 15 min. Significant evolution of gas was observed in
the initial stages of the reaction. The reaction was diluted with
water (25 mL) and extracted into diethyl ether (3 ¥ 20 mL). The
combined organic extracts were dried (MgSO4) and the solvent
removed. The product was purified and characterized as detailed
below.
Experimental‡
2-(Methylseleno)phenyldiazonium tetrafluoroborate (8b)
2-(Methylseleno)aniline was dissolved in 10% sulfuric acid
(0.73 mmol of aniline per mL) and the solution chilled to 0 ◦C. A
chilled solution of sodium nitrite (1.05 equivalents) in water (20%
of the volume of the acid) was added dropwise to the aniline solu-
tion followed by stirring for 30 min. at 0 ◦C. Cold tetrafluoroboric
acid (43% solution in water, 2.4 equivalents) was added dropwise
to form a precipitate, which was filtered through a chilled sintered
glass funnel and washed with cold water (2 ¥ 3 mL), cold ether (3
¥ 5 mL) and dried under vacuum at 0 ◦C. The diazonium salt was
used immediately and without further purification.
2-Phenylbenzo[b]selenophene (7, R = Ph)24. was purified by
flash chromatography (2% ethyl acetate/petroleum spirits) to◦give
the product as a redsolid (30%). Mp154–156 ◦C (Lit.24 mp160 C);
1H NMR (500 MHz, CDCl3) d 7.87 (dd, J = 1.1, 8.0, 1H), 7.77
(d, J = 8.0, 1H), 7.71 (s, 1H), 7.67 – 7.62 (m, 2H), 7.45 – 7.38
(m, 2H), 7.37 – 7.31 (m, 2H), 7.28 – 7.22 (m, 1H); 13C NMR (126
MHz, CDCl3) d 147.69, 143.26, 140.94, 136.20, 128.94, 128.25,
126.87, 125.40, 125.37, 124.84, 124.50, 123.04; 77Se NMR (95.4
MHz, CDCl3) d 515.57; MS (EI) m/z (relative intensity) 258.1
(100), 178.1 (58).
2-(Pyridin-3-ylmethylseleno)nitrobenzene
3,3¢-Dipicolyl diselenide23 (0.22 g, 0.64 mmol) was dissolved
in ethanol (20 mL) and excess sodium borohydride (48 mg,
0.13 mmol) added until the solution became a pale orange
colour. 2-Fluoronitrobenzene was added and the reaction stirred
overnight. The ethanol was removed in vacuo and the product ex-
tracted into diethyl ether (70 mL), washed with water (2 ¥ 70 mL),
dried (MgSO4) and the solvent removed. The product was purified
by flash chromatography (2% methanol–dichloromethane) to give
the title compound (0.26 g, 72%). Mp 90–91 C; H NMR (500
MHz, CDCl3) d 8.66 (s, 1H), 8.52 (d, J = 3.3, 1H), 8.31 (dd, J = 1.0,
8.3, 1H), 7.75 (d, J = 7.9, 1H), 7.61 – 7.50 (m, 2H), 7.36 (ddd, J =
1.7, 6.8, 8.3, 1H), 7.27 (q, J = 4.6, 1H), 4.16 (s, 2H); 13C NMR (500
MHz, CDCl3) d 150.2, 148.8, 146.4, 136.7, 133.9, 133.5, 131.8,
129.1, 126.5, 126.0, 123.6, 27.7; 77Se NMR (95.4 MHz, CDCl3)
d 400.0; MS (EI) m/z (relative intensity) 294.1 (10) 186 (31) 92.1
Ethyl benzo[b]selenophene-2-carboxylate (7, R = CO2Et)15. was
purified by flash chromatography (10% ethyl acetate/petroleum
1
spirits) to give the product as a yellow oil (29%). H NMR (500
MHz, CDCl3) d 8.27 (s, 1H), 7.88 (dd, J = 6.7, 1.9, 2H), 7.38 (dq,
J = 5.6, 1.6, 2H), 4.37 (q, J = 7.1, 2H), 1.39 (t, J = 7.1, 3H); 13C
NMR (126 MHz, CDCl3) d 164.0, 144.1, 141.3, 136.5, 134.3, 127.5,
126.9, 125.9, 125.1, 61.7, 14.4; 77Se NMR (95.4 MHz, CDCl3) d
540.1; IR (neat): 1699 cm-1; MS (EI) m/z (relative intensity) 254
(68), 226 (26), 209 (100), 181 (28), 89.1 (42).
◦
1
Diethyl benzo[b]selenophene-2,3-dicarboxylate (10, R1 = R2 =
CO2Et). was purified by flash chromatography (5% ethyl ac-
etate/petroleum spirits) to give the product (15%). 1H NMR (500
MHz, CDCl3) d 7.92 – 7.83 (m, 2H), 7.49 – 7.39 (m, 2H), 4.50
476 | Org. Biomol. Chem., 2011, 9, 473–479
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(q, J = 7.1, 2H), 4.38 (q, J = 7.1, 2H), 1.47 – 1.36 (m, 6H); 13C
NMR (126 MHz, CDCl3) d 165.97, 163.04, 142.85, 139.37, 137.82,
135.83, 127.58, 126.48, 125.86, 125.82, 62.35, 62.28, 14.41, 14.38;
77Se NMR (95.4 MHz, CDCl3) d 551.0; IR (neat): 1718 cm-1; MS
(EI) m/z (relative intensity) 326.1 (52), 281 (15), 253 (100), 209
(14), 169 (18), 89.1 (20); HRMS calcd. for C14H15O4Se [M+H]+
327.01301, found 327.01297.
124.2, 124.6, 124.8, 125.4, 126.5, 141.4, 142.1, 144.9, 168.4; 77Se
NMR (95.4 MHz, CDCl3) d 534.83; HRMS calcd. for C16H19O4Se
[M+H]+ 355.0443, found 355.0444.
2-(Bromomethyl)benzo[b]thiophene (6, X = Br, Y = S).13
N-Bromosuccinimide (107 mg, 0.600 mmol) and AIBN
(9 mg, 0.054 mmol) were added to
a solution of 2-
methylbenzo[b]thiophene (95 mg, 0.63 mmol) in a,a,a-
trifluorotoluene (5 mL). The mixture was refluxed for 1.5 h,
cooled and filtered to remove solids. The filtrate was concentrated
in vacuo to afford the crude product, which was used without
further purification (125 mg, 91%); 1H NMR (500 MHz, CDCl3)
d 4.83 (s, 2H), 7.32–7.36 (m, 3H), 7.72–7.30 (m, 1H), 7.78–7.80
(m, 1H); 13C NMR (126 MHz, CDCl3) d 27.2, 122.5, 123.8, 124.5,
124.6, 125.0, 139.2, 140.6, 141.1. mp 46.5 - 47.1 ◦C. MS (ESI) m/z
226, ([M(79Br)]+), 228 ([M(81Br)]+).
Diethyl ((benzo[b]thiophen-2-yl)methyl)malonate (5, Y = S).12
Piperidine (92 mL, 0.87 mmol) and benzoic acid (28.9 mg,
0.237 mmol) were added to a solution of 2-benzo[b]thiophene-
2-carboxaldehyde14 (1.10 g, 6.81 mmol) and diethyl malonate
(1.0 mL, 6.59 mmol) in cyclohexane (36 mL) and the mixture was
refluxed overnight with azeotropic removal of water. The solvent
was removed in vacuo and the residue was dissolved in diethyl
ether. The solution was washed with 10% aqueous hydrochloric
acid (3¥), sat. sodium bicarbonate (3¥) and brine (1¥). Drying
(magnesium sulfate) followed by concentration in vacuo afforded a
crude mixture of diethyl 2-benzo[b]thiophenylidenemalonate and
diethyl malonate which was used without further purification.
Sodium borohydride (19.2 mg, 51 mmol) was added to a solution
of the crude diethyl 2-benzo[b]thiophenylidenemalonate (260 mg)
in dry EtOH (2.5 mL) at 0 ◦C and the mixture was stirred at 0 ◦C
for 30 min. The pH was adjusted to 6 with 5% aqueous acetic
acid and the solids were removed by filtration. The ethanol was
removed in vacuo and the product was extracted into diethyl ether.
The organic layer was washed with water (2¥) and brine. Drying
(sodium sulfate) followed by concentration in vacuo provided the
crude product and flash chromatography (hexane: ethyl acetate
80 : 20) furnished the title compound as a yellow oil (170 mg,
2-(Hydroxymethyl)benzo[b]selenophene (6, X = OH, Y = Se).25
Ethyl benzo[b]selenophene-2-carboxylate (7, R = CO2Et) (88 mg,
0.35 mmol) was dissolved in dry diethyl ether (6 mL) and chilled
◦
to -78 C. DiBALH (1 M in hexane, 0.87 mL, 0.87 mmol) was
added dropwise and the reaction stirred for 17 h, returning to
room temperature. Water (35 mL), 15% aqueous sodium hydroxide
◦
(35 mL) and water (87 mL) were added sequentially at 0 C and
the resultant solution stirred for a further 20 min. Magnesium
sulfate was added and the mixture was filtered through celite, solids
were washed with diethyl ether and the filtrate was dried in vacuo
to afford the desired product, which was used without further
purification (55 mg, 75%). Mp 104–105 ◦C. 1H NMR (500 MHz,
CDCl3) d 7.89 (d, J = 8.0, 1H), 7.74 (d, J = 7.9, 1H), 7.41 – 7.33 (m,
2H), 7.29 – 7.24 (m, 1H), 4.96 (dd, J = 1.0, 6.0, 2H), 2.06 (t, J = 6.1,
1H); 13C NMR (500 MHz, CDCl3) d 149.2, 141.8, 141.2, 125.6,
125.2, 124.6, 124.3, 124.3, 62.8; 77Se NMR (CDCl3) d 520.64; IR:
3260, 1454, 1437 cm-1; MS (EI) m/z 212 ([M+H]+); HRMS calcd.
for C9H8OSe ([M+Ag]+) 318.87858, found 318.87867.
1
54%). H NMR (CDCl3) d 1.24 (t, J = 7.0 Hz, 6H), 3.51 (d, J =
7.5 Hz, 2H), 3.76 (t, J = 7.5 Hz, 1H), 4.20 (q, J = 7.0 Hz, 4H),
7.08 (s, 1H), 7.26 – 7.33 (m, 2H), 7.67 (d, J = 7.4 Hz, 1H), 7.75
(d, J = 7.9 Hz, 1H); 13C NMR (CDCl3) d 13.9, 30.0, 53.5, 61.7,
122.0, 122.5, 123.0, 123.8, 124.1, 139.5, 139.7, 141.0, 168.3; Mass
spectrum (ESI) 329 ([M + H]+).
2-(Chloromethyl)benzo[b]selenophene (6, X = Cl, Y = Se).26
Diethyl ((benzo[b]selenophen-2-yl)methyl)malonate (5, Y = Se)
2-(Hydroxymethyl)benzo[b]selenophene (53 mg, 0.25 mmol) and
thionyl chloride (0.29 mL, 4 mmol) were refluxed for 2 h in
anhydrous dioxane (4 mL). The solvent was removed in vacuo
and the crude residue purified by flash column chromatography
(petroleum spirits) to give the product as a white solid (55 mg,
68%); mp 67 ◦C (sharp). 1H NMR (500 MHz, CDCl3) d 7.85 (dd,
J = 0.8, 7.8, 1H), 7.73 (d, J = 7.7, 1H), 7.36 (ddd, J = 1.1, 7.2,
8.2, 1H), 7.27 (ddd, J = 1.3, 4.6, 7.2, 2H), 4.92 – 4.87 (m, 2H);
13C NMR (500 MHz, CDCl3) d 144.7, 142.1, 141.4, 127.5, 125.6,
125.6, 125.1, 124.9, 43.6; 77Se NMR (CDCl3) d 533.02; IR: 1454,
1255 cm-1; MS (EI) m/z 230 ([M+H]+).
Sodium hydride (60% dispersion in mineral oil) (37.0 mg,
0.925 mmol) was added to anhydrous DMF (5 mL) and was
stirred vigorously for 30 min under argon at room tempera-
ture. Diethyl malonate (140 mL, 0.922 mmol) was added to
the suspension and the mixture was stirred for 30 min. 2-
(Chloromethyl)benzo[b]selenophene (6, X = Cl, Y = Se) (205 mg,
0.892 mmol) was added, after which the mixture was stirred at
r.t. for 3 h and for another 4 h at 60 ◦C. After cooling, the
reaction mixture was poured into a water–ice mixture and the
product was extracted into ethyl acetate. Drying (sodium sulfate),
followed by concentration in vacuo provided a crude product.
Excess diethyl malonate was removed using Ku¨gelrohr distillation.
Further purification by flash chromatography (Petroleum spirit:
dichloromethane 1 : 1) furnished the title compound as pale yellow
Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2¢-[1-(triphenylmethyl)-1H-
tetrazol-5-yl][1,1¢-biphenyl]-4-yl]methyl]-1(6H)pyrimidinyl]-
methyl]-3-benzo[b]selenophene (12, Y = Se)
1
oil (100 mg, 32%). H NMR (500 MHz, CDCl3) d 1.26 (t, J = 7
Hz, 3H), 3.56 (dd, J = 7.5, 1.0 Hz, 2H), 3.74 (t, J = 7.5 Hz, 1H),
4.22 (m, 4H), 7.21 (dd, J = 7.2, 1.2 Hz, 1H), 7.27 (s, 1H), 7.32 (dd,
J = 7.5, 1.2 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.81 (dd, J = 8.0,
1.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 14.0, 32.3, 54.0, 61.8,
Following the procedure of Salimbeni,3 a solution of 6-butyl - 2 -
methyl - 5 - [[2¢ - [1 - (triphenylmethyl) - 1H - tetrazol - 5 - yl][1,1¢-
biphenyl]-4-yl]methyl]pyrimidin-4(1H)-one (140 mg, 0.218 mmol)
(10) in DMF (1 mL) was added to a suspension of NaH (60%
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dispersion in mineral oil, 14 mg, 0.35 mmol)) in anhydrous DMF
(0.5 mL) at 0 ◦C. The mixture was stirred at 0 ◦C for 10 mins,
followed by addition of lithium bromide (57 mg, 0.65 mmol) in
DMF (1 mL). After stirring for a further 10 min. at 0 ◦C a solution
of 2-(chloromethyl)benzo[b]selenophene (6, X = Cl, Y = Se) (55
mg, 0.24 mmol) in DMF (0.5 mL) was added. The mixture was
allowed to warm to ambient temperature. After stirring for 2 h
the solution was poured carefully into ice water (30 mL) and
acidified to pH 5 with 10% aqueous acetic acid. The resulting
precipitate was collected via filtration, washed with water and
dried under vacuum. Purification by flash column chromatography
(gradient elution: 15 : 85 to 30 : 70 ethyl acetate : petroleum spirit)
afforded the title compound as a white solid (104 mg, 57%.) Mp
sodium bicarbonate and the solution was washed with diethyl
ether. The aqueous layer was acidified to pH 0 with 5% aqueous
sulfuric acid and the product was extracted into diethyl ether
(2¥). The combined organic layers were dried (sodium sulfate)
and concentrated in vacuo to provide the title compound as an
orange oil (0.130 g, 88%). 1H NMR (CDCl3) d 1.25 (t, J = 7.2 Hz,
3H), 3.54 (t, J = 7.5 Hz, 2H), 3.82 (t, J = 7.5 Hz, 1H), 4.23 (q, J =
7.0 Hz, 2H), 7.09 (s, 1H), 7.26 – 7.33 (m, 2H), 7.67 (d, J = 7.6 Hz,
1H), 7.75 (d, J = 7.6 Hz, 1H); 13C NMR (CDCl3) d 13.8, 29.6, 53.2,
62.1, 122,0, 122.6, 123.0, 123.9, 124.2, 139.5, 139.7, 140.5, 168.1,
173.7; IR: 1732, 1713 cm-1; Mass spectrum (EI) 278 (M+., 35), 234
(31), 147 (100). (Found: C, 60.5; H, 5.0. C14H14O4S requires C,
60.4; H, 5.1%).
◦
1
92–96 C (dec.). H NMR (500 MHz, CDCl3) d 7.89 – 7.83 (m,
1H), 7.79 (d, J = 7.5, 1H), 7.69 (d, J = 8.0, 1H), 7.43 (ddd, J =
1.6, 6.0, 12.5, 3H), 7.37 – 7.20 (m, 12H), 7.05 (q (apparent), J =
8.2, 4H), 6.95 – 6.88 (m, 6H), 5.40 (s, 2H), 3.87 (s, 2H), 2.61
(s, 3H), 2.49 – 2.40 (m, 2H), 1.48 (m, 2H), 1.29 (dd, J = 10.7,
18.3, 2H), 0.85 (t, J = 7.3, 3H); 13C NMR (500 MHz, CDCl3) d
164.1, 163.0, 162.9, 155.5, 142.3, 142.3, 142.0, 141.3, 141.0, 138.8,
138.5, 130.8, 130.3, 130.2, 129.8, 129.3, 128.2, 127.9, 127.6, 127.3,
127.2, 126.4, 125.5, 125.2, 124.9, 124.7, 120.9, 46.4, 34.6, 31.1,
30.5, 29.7, 22.8, 22.7, 14.0; 77Se NMR (CDCl3) d 545.8; IR: 1649
cm-1; HRMS calcd. for C51H44N6OSe [M+Ag] 943.17873, found
943.17878.
2-Carboethoxy-3-(benzo[b]selenophen-2-yl)propanoic acid (13,
Y = Se). was prepared in analogous fashion to 13 (Y = S)
using potassium hydroxide (12.7 mg, 0.226 mmol) and diethyl
((benzo[b]selenophen-2-yl)methyl)malonate (5, X = Se) (80.0 mg,
0.226 mmol) and isolated as a red oil (36 mg, 65% brsm). 1H NMR
(500 MHz, CDCl3) d 1.26 (t, J = 7 Hz), 3.57 (m, 2H), 3.80 (t, J = 7
Hz, 1H), 4.23 (q, J = 7 Hz, 2H), 7.22 (m, 1H), 7.28 (s, 1H), 7.32 (td,
J = 7.5, 1 Hz 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.80 (dd, J = 0.5, 8 Hz,
1H); 13C NMR (126 MHz, CDCl3) d 14.0, 32.2, 53.7, 62.2,124.3,
124.6, 124.9, 125.4, 126.7, 141.4, 142.0, 144.1, 168.2; 77Se NMR
(95.4 MHz, CDCl3) d 534.85; HRMS calcd. for C14H14O4Se [M -
H]- 324.9985, found 324.9980.
Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2¢-[1-(triphenylmethyl)-
1H -tetrazol-5-yl][1,1¢-biphenyl]-4-yl]methyl]-1(6H)pyrimidinyl]-
methyl]-3-benzo[b]thiophene (12, Y = S). was prepared in
analogous fashion to 12 (Y = Se) from 2-(bromomethyl)-
benzo[b]thiophene (6, X = Br, Y = S) (65 mg, 0.28 mmol), 6-butyl
- 2 - methyl - 5 - [[2¢ - [1 - (triphenylmethyl) - 1H - tetrazol - 5 - yl][1,
1¢-biphenyl]-4-yl]methyl]pyrimidin-4(1H)-one (10) (122 mg,
0.19 mmol), sodium hydride (15 mg, 0.38 mmol) and lithium
bromide (57 mg, 0.65 mmol). Purification by flash column
chromatography (2 : 1.5 petroleum spirit : ethyl acetate) yielded
the title compound as a white solid (107 mg, 72%). Mp 79–83 ◦C
Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2¢-(1H-tetrazol-5-yl)-
[1,1¢-biphenyl]-4-yl]methyl]-1(6H)pyrimidinyl]methyl-2-
benzo[b]thiophene (3, Y = S)
The trityl protected sartan (12, Y = S) (107 mg, 0.136 mmol)
was refluxed in methanol (10 mL) for 17 h. Cooling, followed by
concentration in vacuo afforded the crude product. Purification
by flash column chromatography (Gradient elution: 0 – 5%
methanol–dichloromethane) afforded t◦he title compound as a
1
white solid (71 mg, 96%). Mp 106–108 C (dec.). H NMR (500
1
MHz, CDCl3) d 8.17–8.19 (m, 1H), 7.81–7.83 (m, 1H), 7.71–7.73
(m, 1H), 7.51–7.57 (m, 2H), 7.41 (dd, 1H), 7.31–7.37 (m, 2H),
7.25–7.28 (m), 7.12–7.13 (m, 2H), 5.46 (s, 2H), 3.97 (s, 2H), 2.69
(s, 3H), 2.62 (t, 2H), 1.59–1.63 (m, 2H), 1.36–1.41 (m, 2H), 0.90–
0.93 (t, 3H). 13C NMR (126 MHz, CDCl3) d 163.6, 162.9, 156.4,
155.0, 141.2, 140.1, 139.9, 139.0, 138.2, 137.2, 130.9, 130.8, 129.3,
128.8, 128.1, 124.9, 124.7, 123.8, 123.6, 122.8, 122.6, 120.2, 44.1,
34.6, 31.5, 30.7, 22.9, 22.6, 14.0. IR: 1651, 1542 cm-1; HRMS calcd.
for C32H30N6OS ([M+H]+) 547.2281, found 547.2283. (Found: C,
70.2; H, 5.5; N, 15.2. C32H30N6OS requires C, 70.3; H, 5.5; N,
15.4%).
(dec.). H NMR (500 MHz, CDCl3) d 7.88 (ddd, J = 0.5, 1.5,
7.5 Hz, 1H), 7.75 – 7.75 (m, 1H), 7.71 – 7.69 (m, 1H), 7.47 (ddd,
J = 1.5, 7.5, 7.5, 1H), 7.42 (ddd, J = 1.5, 7.5, 7.5, 1H), 7.37 –
7.23 (m, 13H), 7.08 (d, J = 8.5 Hz, 2H), 7.05(d, J = 8.5 Hz, 2H),
6.95 – 6.92 (m, 6H), 5.42 (s, 2H), 3.87 (s, 2H), 2.61 (s, 3H), 2.49
– 2.47 (m, 2H), 1.54 – 1.48 (m, 2H), 1.36 – 1.27 (sextet, J = 7.5
Hz, 2H), 0.88 (t, J = 7.5, 3H); 13C NMR (500 MHz, CDCl3)
d 164.1, 162.9, 155.5, 149.6, 142.2, 141.3, 140.0, 139.1, 138.8,
138.5, 130.8, 130.3, 130.2, 129.8, 129.3, 128.2, 127.9, 127.6, 127.2,
126.4, 124.7, 124.5, 123.5, 123.4, 122.3, 120.8, 82.8, 43.8, 34.7,
31.2, 30.5, 22.8, 17.6, 14.0; IR: 1651 cm-1. HRMS calcd. for
C51H44N6OS [M+H]+ 789.33701, found 789.33744. (Found: C,
77.6; H, 5.5; N, 10.6. C51H44N6OS requires C, 77.6; H, 5.6; N,
10.7%).
Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2¢-(1H-tetrazol-5-yl)[1,
1¢ - biphenyl] - 4 - yl]methyl] - 1(6H)pyrimidinyl]methyl - 2 - benzo[b]-
selenophene (3, Y = Se). was prepared in identic◦al fashion to
1
3 (Y = S) and isolated in 89% yield. Mp 124–130 C (dec.). H
2-Carboethoxy-3-(benzo[b]thiophen-2-yl)propanoic acid
(13, Y = S)
NMR (500 MHz, CDCl3) d 8.07 (d, J = 7.7, 1H), 7.91 (d, J = 8.0,
1H), 7.70 (d, J = 8.0, 1H), 7.58 – 7.51 (m, 1H), 7.51 – 7.45 (m,
1H), 7.44 – 7.38 (m, 2H), 7.34 (t, J = 7.5, 1H), 7.29 – 7.23 (m,
1H), 7.17 (d, J = 8.1, 2H), 7.09 (d, J = 8.2, 2H), 5.39 (s, 2H), 3.91
(s, 2H), 2.59 (s, 3H), 2.55 – 2.48 (m, 2H), 1.60 – 1.49 (m, 2H), 1.33
(dd, J = 7.4, 14.9, 2H), 0.88 (t, J = 7.3, 3H); 13C NMR (126 MHz,
CDCl3) d 163.9, 163.1, 156.2, 154.8, 142.4, 141.6, 141.1, 141.0,
Potassium hydroxide (29.6 mg, 0.527 mmol) in ethanol (0.5
mL) was added to a solution of diethyl ((benzo[b]thiophen-2-
yl)methyl)malonate (5, Y = S) (0.162 g, 0.530 mmol) in ethanol
(84 mL). The mixture was stirred for 48 h at r.t. after which the
solvent was removed in vacuo. The residue was taken up in sat.
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140.2, 137.3, 131.4, 130.9, 130.9, 129.2, 129.0, 128.2, 127.7, 125.9,
125.3, 125.2, 124.9, 122.6, 120.1, 46.6, 34.7, 31.5, 30.8, 22.9, 22.7,
14.0; 77Se NMR (95.4 MHz, CDCl3) d 544.42; IR (neat): 2957,
2927, 1649, 1544 cm-1; HRMS calcd. for C32H31N6OSe [M+H]+
595.17191, found 595.17193.
Acknowledgements
This work would not have been possible without the generous
support of the Australian Research Council through the Centres
of Excellence Scheme. We thank Mark Ross-Smith, Department
of Pharmacology, University of Melbourne, for conducting the
CHO cell assays.
2-Butyl-1-(4-carboxybenzyl)-5-[2-carboxy-3-(benzo[b]thiophen-2-
yl)prop-1-enyl]-1H-imidazole (4, Y = S)
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10% Aqueous sodium hydroxide (1.0 mL, 2.6 mmol) was added
to a solution of the freshly prepared diester in ethanol (2.6 mL)
and the mixture was stirred at r.t. for 4 h. 10% Aqueous acetic
acid (3 mL) was added and the ethanol was removed in vacuo.
The reaction mixture was extracted with chloroform: iso-propanol
9 : 1 (4¥). The combined organic layers were dried (sodium sulfate)
and concentrated in vacuo. The resulting solid was triturated with
hexane (2¥) and chloroform (2¥) to give the title compound as a
1
pale solid (45 mg, 29% over two steps). H NMR (DMSO-d6) d
0.86 (t, J = 7.5 Hz, 3H), 1.30 (sextet, J = 7.5 Hz, 2H), 1.62 (quintet,
J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 4.16 (s, 2H), 5.27 (s, 2H),
7.00 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.22 – 7.30 (m, 2H), 7.34 (s,
1H), 7.39 (s, 1H), 7.56 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.73 (d,
J = 7.6 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H); 13C NMR (DMSO-d6) d
13.4, 22.2, 26.7, 29.5, 46.5, 120.7, 121.9, 122.7, 123.5, 123.9, 125.6,
125.9, 127.1, 128.3, 130.3, 130.5, 131.0, 139.3, 139.8, 140.5, 142.0,
151.6, 168.1, 169.2; IR: 2963, 1702 cm-1; Mass spectrum (ESI) 473
([M + H]+); HRMS calcd. for C23H24N2O4Se [M + H]+ 475.1691,
found 475.1684.
2-Butyl-1-(4-carboxybenzyl)-5-[2-carboxy-3-(benzo[b]seleno-
phen-1-yl)prop-1-enyl]-1H-imidazole (4,
Y = Se). was pre-
pared in identical fashion to 4 (Y = S) from 2-butyl-1-[4(4-
carbomethoxyphenyl)methyl]-1H -imidazole-5-carboxaldehyde
(16.5 mg, 0.055 mmol) and 2-carboethoxy-3-(benzo[b]selenophen-
2-yl)propionic acid (13, Y = Se) (36 mg, 0.110 mmol) and isolated
as as colourless solid (14 mg, 51%, 2 steps). 1H NMR (500 MHz,
1 : 1 CDCl3: CD3OD) d 0.85 (t, J = 7.5 Hz, 3H), 1.32 (m, 2H),
1.60 (m, 2H), 2.66 (t, J 7.5 Hz, 2H), 4.19 (s, 2H), 5.21 (s, 2H),
7.05 (d, J = 8 Hz, 2H), 7.16 (m, 2H), 7.27 (td, J = 7.5, 1 Hz, 1H),
7.38 (s, 1H), 7.55 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.77 (d, J =
8 Hz, 1H), 7.99 (d, J = 7.5 Hz, 2H); 13C NMR (126 MHz, 1 : 1
CDCl3: CD3OD) d 13.2, 22.2, 26.7, 29.6, 31.9, 46.6, 123.8, 124.3,
124.4, 124.5, 125.1, 125.7, 127.4, 129.3, 130.5, 130.7, 130.8, 140.7,
140.9, 142.3, 145.9, 151.6, 168.3, 169.3; 77Se NMR (95.4 MHz,
1 : 1 CDCl3: CD3OD) d 534.59; HRMS calcd. for C27H26N2O4Se
[M+H]+ 523.1131, found 523.1130.
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Org. Biomol. Chem., 2011, 9, 473–479 | 479
©