Synthesis of 3-(carboxyarylalkyl)imidazo[2,1-f][1,2,4]triazines as potential inhibitors of AMP deaminase

Article abstract of DOI:10.1039/b810850a

C-Ribosyl 1,2,4-triazolo[1,2,4]triazines which are able to undergo covalent hydration are of interest as potential inhibitors of AMP deaminase. In a search for compounds with improved bioavailability we have synthesized compounds in which the sugar has been replaced by carboxyarylalkyl based ribose phosphate mimics. The target carboxyarylalkyl imidazotriazines 11 and 12 were synthesized using a linear seven step sequence starting from simple benzoate derivatives. Alternatively, the hydroxyethyl imidazotriazine 39 is available in five steps and this synthon was used to prepare the imidazotriazines 34 and 48 in a short convergent manner.

Full text of DOI:10.1039/b810850a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of 3-(carboxyarylalkyl)imidazo[2,1-f ][1,2,4]triazines as potential
inhibitors of AMP deaminase†
Joseph K. Kirkman,a Stephen D. Lindell,*b Simon Maechling,b Alexandra M. Z. Slawinc and
Christopher J. Moody*a,d
Received 25th June 2008, Accepted 9th September 2008
First published as an Advance Article on the web 22nd October 2008
DOI: 10.1039/b810850a
C-Ribosyl 1,2,4-triazolo[1,2,4]triazines which are able to undergo covalent hydration are of interest as
potential inhibitors of AMP deaminase. In a search for compounds with improved bioavailability we
have synthesized compounds in which the sugar has been replaced by carboxyarylalkyl based ribose
phosphate mimics. The target carboxyarylalkyl imidazotriazines 11 and 12 were synthesized using a
linear seven step sequence starting from simple benzoate derivatives. Alternatively, the hydroxyethyl
imidazotriazine 39 is available in five steps and this synthon was used to prepare the imidazotriazines 34
and 48 in a short convergent manner.
interested in replacing the polar acids and salts in structures 7–10
with more lipophilic methyl esters.
Introduction
The enzyme AMP deaminase (AMPDA, EC 3.5.4.6) is a potential
target for novel herbicides1,2 and antiischemic drugs.3 For example,
the herbicidally active natural product carbocyclic coformycin (1)4
has been shown to undergo in planta 5¢-phosphorylation to give
the nucleotide 2, which is a potent inhibitor of AMPDA (IC50
=
20 nM).1 Modified C-nucleosides are also of interest as potential
AMPDA inhibitors, as exemplified by the ribosides 32,5 and 4.6
In order to inhibit AMPDA, these compounds must undergo 5¢-
phosphorylation and a covalent hydration of the aglycone ring to
give the nucleotide derivatives 5 and 6.7 Kasibhatla and co-workers
have described simplified inhibitors, as exemplified by structures
7–9 (Ki = 0.5–32 mM),8 in which the entire sugar phosphate moiety
of inhibitor 2 has been replaced by a benzoic acid attached to the
aglycone by a 2- or 3-atom tether. Of special note is the inhibitor 10
(Ki = 15 nM),3,8 containing a more lipophilic tetrahydronaphthoic
acid side chain as the ribose phosphate mimic, which has a similar
AMPDA inhibition potency to the nucleotide 2. Inhibitors 7–
10 are important because, compared to polar nucleotide based
inhibitors such as compound 2, they are expected to show
improved bioavailability and hence, biological activity.3 However,
the diazepinol aglycone present in these structures is comparatively
difficult to synthesize and rather unstable.9 Therefore, it is of
interest to try and replace the diazepinol with a more stable and
easily accessible aglycone, such as the imidazotriazine present in
structure 4.6 In addition, because esters have often been shown to
be effective prodrugs with enhanced delivery properties,10 we were
aDepartment of Chemistry, School of Biological and Chemical Sciences,
University of Exeter, Stocker Road, Exeter, EX4 4QD, U.K.
bBayer CropScience AG, Werk Ho¨chst, G836, D-65926, Frankfurt am Main,
Germany. E-mail: stephen.lindell@bayercropscience.com
cSchool of Chemistry, University of St. Andrews, Fife, Scotland, KY16 9ST,
U.K.
dSchool of Chemistry, University of Nottingham, University Park, Notting-
ham, NG7 2RD, U.K. E-mail: c.j.moody@nottingham.ac.uk
† Electronic supplementary information (ESI) available: Experimental
details for compounds 18–21, 24–26, 30–32, and 35–37. CCDC reference
number 694838. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b810850a
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This paper describes new synthetic routes leading to the
potential AMPDA hybrid-inhibitors 11–14, in which an imi-
dazotriazine aglycone is attached to a carboxyarylalkyl ribose
phosphate mimic. Disconnection of the C3-N4 bond in 11–
14, with introduction of a second methylsulfanyl group, leads
to the imines 15 which should be obtainable by condensation
of the known aminotriazine 166,11 and the bromoaldehydes 17
(Scheme 1).
Scheme 3 Reagents, conditions and yields: (i) 5% Pd/C, H2, EtOAc (91%);
(ii) (COCl)2, DMSO, Et3N, CH2Cl2 to give 26 (79%); (iii) Amberlyst A-26
(Br3 form), CHCl3 to give 27; (iv) 16, CHCl3, 4 A mol. sieve, reflux (50%
Scheme 1
-
˚
over two steps); (v) N2H4, MeOH (54%); (vi) HgO, CHCl3 (37%).
Results and discussion
to give the alkynols 18 and 24, respectively. Hydrogenation over
palladium on charcoal yielded the homologous alcohols 19 and
25 which were oxidized to the corresponding aldehydes 20 and 26
using Swern13 conditions. Bromination to give the bromoaldehydes
21 and 27 was achieved using polymer supported tribromide
according to the method described by Bongini et al.14 Subsequent
condensation of 6-aminotriazine 166 with the bromoaldehydes 21
and 27 in refluxing chloroform yielded the bis-sulfides 22 and 28.
Finally, the 8-methylmercapto group was removed in a two step
sequence involving initial displacement with hydrazine hydrate to
give the hydrazines 23 and 29, followed by oxidation with yellow
mercuric oxide to yield the target imidazotriazines 11 and 12.
We next turned our attention to the synthesis of imidazotri-
azine 13 in which the benzoate is attached to the rest of the
molecule via an ether linkage. In this case the key intermediate
30 was synthesized via a Mitsunobu15 coupling reaction of 4-
benzyloxy-1-butanol and methyl 3-hydroxybenzoate (Scheme 4).
Hydrogenolysis to remove the benzyl protecting group, followed
by oxidation and bromination as previously described, yielded
the bromoaldehyde 33. This reactive intermediate was allowed to
react without purification with the 6-aminotriazine 166 to give the
imidazotriazine 34. Although the synthetic routes to compounds
11, 12 and 34 are straightforward and work well, a more convergent
route would enable new analogues to be more efficiently prepared.
Therefore, it was decided to refocus our synthetic efforts in this
direction and the alcohol 39 was identified as an interesting
intermediate from which a variety of target molecules, including
13 and 14, should be accessible.
The first two target molecules 11 and 12 were synthesized following
a common route as detailed in Schemes 2 and 3. The syntheses
began with a Sonogashira12 coupling reaction of 3-butynol and 4-
pentynol with methyl 3-iodobenzoate and methyl 2-iodobenzoate
The synthesis of the imidazotriazine 39 was achieved in
five steps and 23% overall yield, starting from 1,4-butanediol
which was monoprotected to give the t-butyldiphenylsilyl (TB-
DPS) ether derivative 35 according to the method described by
Scheme 2 Reagents, conditions and yields: (i) 5% Pd/C, H2, EtOAc (65%);
(ii) (COCl)2, DMSO, Et3N, CH2Cl2 to give 20 (80%); (iii) Amberlyst A-26
(Br3 form), CHCl3 to give 21 (62%); (iv) 16, CHCl3, 4 A mol. sieve, reflux
-
˚
(58%); (v) N2H4, MeOH (72%); (vi) HgO, CHCl3 (33%).
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Fig. 1 X-Ray crystal structure of imidazotriazine 38.
precursor 38. The 8-methylmercapto group was removed as
before in a two step sequence involving initial displacement with
hydrazine hydrate to give the hydrazine 40, followed by oxidation
with yellow mercuric oxide to yield the target imidazotriazine 41
(Scheme 6). It was also possible to remove the 6-methylsulfanyl
using a two step oxidation-reduction procedure.6 In our previous
studies, a selective oxidation of the 6-methylsulfanyl group in re-
lated systems had been achieved using either m-chloroperbenzoic
acid (MCPBA) or acidic potassium permanganate.6 In the case of
the imidazotriazine 38, only a modest conversion to the sulfone 42
was achieved using MCPBA and no product at all was obtained
using permanganate, possibly due to the acid lability of the silicon
protecting group. However, good results were obtained using
ruthenium tetroxide which gave a near quantitative yield of the
desired sulfone 42. Treatment of the sulfone with sodium boro-
hydride removed the 6-substituent to yield the 6-unsubstituted
imidazotriazine 43 (Scheme 6). In addition to the bis-sulfide 38,
the monosulfides 41 and 43 are also potential precursors for use
in more convergent inhibitor synthesis strategies.
Scheme 4 Reagents, conditions and yields: (i) 5% Pd/C, H2, EtOAc (98%);
(ii) (COCl)2, DMSO, Et3N, CH2Cl2 to give 32 (62%); (iii) Amberlyst A-26
-
˚
(Br3 form), CHCl3 to give 33; (iv) 16, CHCl3, 4 A mol. sieve, reflux (42%
over two steps).
Brimble and co-workers.16 Sequential oxidation, bromination and
condensation with the 6-aminotriazine 166 yielded the TBDPS
protected imidazotriazine 38 (Scheme 5). The structure of this
key intermediate was confirmed by single-crystal X-ray diffraction
(Fig. 1).17 Removal of the silyl ether using tetrabutylammonium
fluoride (TBAF) yielded the deprotected alcohol 39 ready for
further derivatisation.
Scheme 5 Reagents, conditions and yields: (i) (COCl)2, DMSO, Et3N,
-
CH2Cl2 to give 36 (85%); (ii) Amberlyst A-26 (Br3 form), CHCl3 to give
+
-
˚
37 (90%); (iii) 16, CHCl3, 4 A mol. sieve, reflux (62%); (iv) n-Bu4N F ,
THF (72%). TBDPS = t-butyldiphenylsilyl.
Scheme 6 Reagents, conditions and yields: (i) N2H4, EtOH; (ii) HgO,
EtOH (51% over two steps); (iii) RuCl3, NaIO4, H2O, CH3CN, EtOAc
(96%); (iv) NaBH4, MeOH, CHCl3 (67%). TBDPS = t-butyldiphenylsilyl.
Before continuing with inhibitor synthesis it was decided to
first investigate the removal of the methylsulfanyl groups in the
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Having confirmed the feasibility of accessing 8- and 6-
unsubstituted imidazotriazines, we turned our attention back to
the synthesis of new inhibitors starting from the key synthon 39.
Our first target was a resynthesis of compound 34, which was
efficiently achieved in a single step using a Mitsunobu15 coupling
between the alcohol 39 and methyl 3-hydroxybenzoate (Scheme 7).
In order to attach the tetrahydronaphthoate side chain required
for target inhibitor 14 we envisaged using a cross-metathesis
reaction.18 To this end, the alcohol 39 was first converted to the
mesylate derivative 44 and then treated with DBU to give the
olefin 45 (Scheme 7). The cross-metathesis partner, styrene 47, was
obtained in a single step from the previously described bromide 463
upon treatment with DBU. Although cross metathesis reactions on
sulfur-containing compounds are known,19 the presence of sulfur
in a substrate can be problematic due to catalyst sequestration.
Therefore, it was especially pleasing that the cross metathesis
reaction between the olefins 45 and 47 proceeded smoothly in
the presence of the Hoveyda-Grubbs second generation catalyst20
to give the desired product 48, albeit in a modest 38% yield.
In the next step, however, in which we tried to hydrogenate the
alkene, none of the conditions we tried (eg. H2, Pd/C or Pt/C;
TFA/Et3SiH) showed any trace of the desired hydrogenation
product, possibly due to interference by the methylsulfanyl groups.
Biological testing results showed that compounds 11 and 12
did not exhibit any significant herbicidal activity. This may be
because inhibitors bearing simple benzoic acid side chains are
insufficiently potent to achieve an in vivo effect8 and for this reason
the desulfurisation of the sulfide 34 to give the target compound 13
has not been pursued. However, significantly better inhibition is
expected for compounds bearing the tetrahydronaphthoate side
chain3,8 and we hope that the methodology developed for the
synthesis of imidazotriazines 11, 12 and 41 can be applied to the
synthesis of target inhibitor 14 in the future.
In summary, the synthesis of the first examples of potential
AMPDA inhibitors combining an imidazotriazine ring with a
carboxyalkylaryl ribose mimic, compounds 11 and 12, have been
successfully synthesized. In addition, the imidazotriazinyl alcohol
39 has been prepared and shown to be an interesting synthon
which can be used in more convergent synthetic strategies towards
other new inhibitors.
Experimental
Commercially available reagents were used without further pu-
rification and solvents were dried using standard procedures as
required. Analytical thin layer chromatography was carried out
using aluminium-backed plates coated with Merck Kieselgel 60
GF254. Plates were visualized under UV light (254, 360 nm)
or stained with KMnO4 solution. Flash chromatography was
carried out using Merck Kieselgel 60 H silica or Matrix silica
60. IR spectra were recorded using a Nicolet Magna FT-550
spectrometer. 1H and 13C NMR spectra were recorded using
Bruker 300, 400 or 500 MHz instruments (1H frequencies; the
corresponding 13C frequencies were 75, 100 or 125 MHz) and
J values are quoted in Hz. In the 13C NMR spectra, signals
corresponding to CH, CH2, or CH3 groups are assigned from
DEPT. Mass spectra were recorded on a Micromass GCT time of
flight high resolution mass spectrometer, on a Finnigan MAT 95
SQ spectrometer or on a Bruker-Daltonics esquire 2000 under
electron impact (EI), chemical ionisation (CI) or electrospray
(ES) conditions. Elemental analysis was carried out on a Perkin
Elmer 2400 CHN analyser. Melting points were determined on a
Reichert-Ko¨fler hot stage apparatus and are uncorrected.
Experimental details for compounds 18–21, 24–26, 30–32, and
35–37 are given in the Electronic supplementary information
(ESI).
Scheme 7 Reagents, conditions and yields: (i) methyl 3-hydroxybenzoate, (NCO2i-Pr)2, PPh3, THF (54%); (ii) MeSO2Cl, Et3N, CH2Cl2; (iii) DBU, THF
(58% over two steps); (iv) 47, Hoveyda-Grubbs second generation catalyst, PhCH3, 80 ◦C (38%); (v) DBU, THF (53%).
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6,8-Bis(methylsulfanyl)-3-[2-(3-methoxycarbonylphenyl)ethyl]-
imidazo[2,1-f ][1,2,4]triazine 22
CDCl3) 8.87 (1 H, s), 7.84–7.81 (2 H, m), 7.50 (1 H, s), 7.29–7.27
(2 H, m), 3.85 (3 H, s), 3.26 (2 H, m), 3.07 (2 H, m), 2.55 (3 H, s);
dC (75 MHz; CDCl3) 167.11 (C), 163.13 (C), 148.95 (CH), 140.81
(C), 134.22 (CH), 134.22 (C), 133.05 (CH), 130.57 (C), 129.64 (C),
129.54 (CH), 128.76 (CH), 127.88 (CH), 52.30 (CH3), 33.14 (CH2),
25.04 (CH2), 14.38 (CH3); m/z (EI) 328 (M+, 72%), 297 (5), 180
(10), 179 (100).
A solution of 6-amino-3,5-di(methylsulfanyl)[1,2,4]triazine 16
(0.30 g, 1,60 mmol) and 3-(3-bromo-4-oxobutyl)benzoic acid
methyl ester 21 (0.45 g, 1.58 mmol) in CHCl3 containing activated
˚
4 A molecular sieves (0.9 g) was heated at reflux for 48 h. The
molecular sieves were filtered off over a short pad of Celite, and the
reaction mixture washed with water and brine, dried over MgSO4
and evaporated in vacuo. Purification by column chromatography
(30–50% ethyl acetate in heptane) yielded the title compound 22 as
a colourless solid (0.34 g, 0.91 mmol, 58%); mp 122–124 ◦C (ethyl
acetate); (Found: C, 54.5; H, 4.9; N, 15.0. C17H18N4O2S2 requires C,
54.5; H, 4.9; N, 14.8%); (Found: MH+, 375.0955. C17H19N4O2S2
requires 375.0949); nmax (CHCl3)/cm-1 3689, 3600, 3054, 2956,
2932, 1720, 1575, 1508, 1441, 1356, 1280, 1204, 1150, 1107; dH
(300 MHz; CDCl3) 7.84 (1 H, s), 7.82 (1 H, m), 7.29 (3 H, m), 3.85
(3 H, s), 3.19 (2 H, t, J = 7.5), 3.04 (2 H, t, J = 7.5), 2.60 (3 H, s),
2.54 (3 H, s); dC (75 MHz; CDCl3) 167.44 (C), 163.36 (C), 161.38
(C), 141.33 (C), 133.40 (CH), 133.02 (C), 131.46 (CH), 130.79 (C),
129.87 (CH), 129.52 (C), 128.99 (CH), 128.07 (CH), 52.56 (CH3),
33.73 (CH2), 25.49 (CH2), 14.63 (CH3), 12.17 (CH3); m/z (CI) 375
(MH+, 100%), 329 (10), 225 (12), 127 (17), 101 (15), 75 (11).
6,8-Bis(methylsulfanyl)-3-[3-(2-methoxycarbonylphenyl)-
propyl]imidazo[2,1-f ][1,2,4]triazine 28
3-(5-Oxopentyl)benzoic acid methyl ester 26 (600 mg, 2.73 mmol)
was converted to 3-(3-bromo-5-oxopentyl)benzoic acid methyl
ester 27 as described above for compound 21. The crude bromide
27 was then converted, as described above for compound 22, to the
title compound 28 which was isolated after purification as a colour-
less solid (536 mg, 1.38 mmol, 50%); mp 99–102 ◦C (MeOH);
(Found: M+, 388.1008. C18H20N4O2S2 requires 388.1028); nmax
(CH2Cl2)/cm-1 3408, 3145, 3064, 3049, 2987, 2955, 2938, 2866,
1749, 1716, 1602, 1575, 1510, 1488, 1432, 1363, 1320, 1212, 1186,
1149, 1136, 1089, 1026; dH (300 MHz; CDCl3) 7.82 (1 H, m), 7.38
(1 H, m), 7.21–7.15 (3 H, m), 3.87 (3 H, s), 3.02–2.90 (4 H, m)
2.59 (3 H, s), 2.50 (3 H, s), 2.00 (2 H, quint, J = 7.4); dC (75 MHz;
CDCl3) 168.25 (C), 163.16 (C), 161.14 (C), 144.01 (C), 132.45
(CH), 131.41 (CH), 131.36 (CH), 131.26 (CH), 130.65 (C), 129.70
(C), 126.52 (CH), 115.40 (C), 52.35 (CH3), 34.48 (CH2), 29.46
(CH2), 23.61 (CH2), 14.58 (CH3), 12.15 (CH3); m/z (EI) 388 (M+,
100%), 193 (50), 180 (29), 133 (10), 69 (15).
8-Hydrazino-6-methylsulfanyl-3-[2-(3-methoxycarbonylphenyl)-
ethyl]imidazo[2,1-f ][1,2,4]-triazine 23
Hydrazine monohydrate (0.18 mL, 3.7 mmol) was added
to a solution of the 6,8-bis(methylsulfanyl)-3-[2-(3-methoxy-
carbonylphenyl)ethyl]imidazo[2,1-f ][1,2,4]triazine 22 (138 mg,
0.37 mmol) in MeOH (3 mL) and the reaction was stirred at
ambient temperature for 20 h. After this time the precipitated
product was removed by filtration and recrystallized from CHCl3
to give the title compound 23 as a colourless solid (95 mg,
8-Hydrazino-6-methylsulfanyl-3-[3-(2-methoxycarbonylphenyl)-
propyl]imidazo[2,1-f ][1,2,4]-triazine 29
The reaction and purification were performed as described above
for compound 23. Starting from 6,8-bis(methylsulfanyl)-3-[3-
(2-methoxycarbonylphenyl)propyl]imidazo[2,1-f ][1,2,4]triazine
28 (122 mg, 0.31 mmol), the title product 29 was isolated as a
colourless solid (65 mg, 0.17 mmol, 54%); mp 82–85 ◦C (CH2Cl2);
(Found: MH+, 373.1429. C17H21N6O2S requires 373.1447); nmax
(CHCl3)/cm-1 3691, 3426, 3364, 2953, 2931, 1718, 1601, 1558,
1525, 1471, 1436, 1406, 1378, 1332, 1316, 1293, 1267, 1191, 1135,
1110, 1084; dH (300 MHz; CDCl3) 9.04 (1 H, s), 7.89 (1 H, d, J =
5.7), 7.45–7.38 (2 H, m), 7.28–7.23 (2 H, m), 4.22 (2 H, s) 3.86
(3 H, s), 3.07 (2 H, m), 2.97 (2 H, m), 2.58 (3 H, s), 2.08 (2 H, m);
dC (75 MHz; CDCl3) 167.61 (C), 162.31 (C), 151.92 (C), 142.35
(C), 133.52 (CH), 130.61 (C), 130.26 (CH), 129.95 (C), 129.11 (C),
128.84 (CH), 127.67 (CH), 126.34 (CH), 52.54 (CH3), 35.54 (CH2),
29.40 (CH2), 23.16 (CH2), 14.43 (CH3); m/z (CI) 373 (MH+, 43%),
356 (100), 342 (6), 326 (4).
◦
0.27 mmol, 72%); mp 172–174 C (CHCl3); (Found: MH+,
359.1283. C16H19N6O2S requires 359.1290); nmax (CHCl3)/cm-1
3427, 3335, 3060, 2972, 2954, 2932, 1719, 1630, 1600, 1556, 1523,
1443, 1406, 1341, 1289, 1264, 1178, 1109, 1084; dH (300 MHz;
CDCl3) 8.53 (1 H, s), 7.85–7.81 (2 H, m), 7.29 (2 H, m), 7.17
(1 H, s), 4.14 (2 H, s), 3.85 (3 H, s), 3.15 (2 H, m), 3.04 (2 H, m),
2.53 (3 H, s); dC (75 MHz; CDCl3) 167.52 (C), 162.47 (C), 152.01
(C), 141.60 (C), 133.44 (CH), 130.78 (C), 129.93 (CH), 129.69 (C),
129.21 (CH), 128.96 (CH), 128.47 (C), 128.01 (CH), 52.57 (CH3),
33.98 (CH2), 30.13 (CH2), 14.50 (CH3); m/z (CI) 359 (MH+, 13%),
358 (M+, 7), 205 (17), 204 (100).
6-Methylsulfanyl-3-[2-(3-methoxycarbonylphenyl)-
ethyl]imidazo[2,1-f ][1,2,4]triazine 11
Yellow mercuric oxide (4 eq.) was added to a solution of the
8-hydrazino-6-methylsulfanyl-3-[2-(3-methoxycarbonylphenyl)-
ethyl]imidazo[2,1-f ][1,2,4]triazine 23 (79 mg, 0.22 mmol) in CHCl3
(1 mL) at ambient temperature. The mixture was stirred at ambient
temperature for 18 h and then filtered through a short pad
of Celite to remove residual mercury. Purification by column
chromatography (50% ethyl acetate in heptane) yielded the title
compound 11 as a pale yellow oil (24 mg, 0.073 mmol, 33%);
(Found: M+, 328.0999. C16H16N4O2S requires 328.0994); nmax
(CHCl3)/cm-1 2973, 2955, 2929, 2856, 1720, 1592, 1522, 1468,
1436, 1422, 1344, 1309, 1290, 1269, 1114, 1086, 1070; dH (300 MHz;
6-Methylsulfanyl-3-[3-(2-methoxycarbonylphenyl)propyl]-
imidazo[2,1-f ][1,2,4]triazine 12
The reaction and purification were performed as described above
for compound 11. Starting from 8-hydrazino-6-methylsulfanyl-
3-[3-(2-methoxycarbonylphenyl)propyl]imidazo[2,1-f ][1,2,4]tria-
zine 29 (35 mg, 0.094 mmol), the title compound 12 was isolated
◦
as a colourless solid (12 mg, 0.035 mmol, 37%); mp 126–129 C
(CHCl3); (Found: M+, 342.1146. C17H18N4O2S requires 342.1150);
n
max (CHCl3)/cm-1 3442, 2954, 2929, 2856, 1718, 1592, 1520, 1488,
1436, 1423, 1346, 1291, 1205, 1187, 1164, 1135, 1112, 1087; dH
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(300 MHz; CDCl3) 8.93 (1 H, s), 7.90 (1 H, dd, J = 1.3, 8.2), 7.69
(1 H, s), 7.43 (1 H, dt, J = 1.3, 8.2), 7.29–7.23 (2 H, m), 3.86 (3 H,
s) 3.11–3.04 (4 H, m), 2.58 (3 H, s), 2.13 (2 H, quint, J = 7.5); dC
(75 MHz; CDCl3) 168.50 (C), 162.67 (C), 149.03 (CH), 143.93 (C),
139.23 (C), 138.93 (C), 134.51 (CH), 132.51 (CH), 131.41 (CH),
131.33 (CH), 129.62 (C), 126.61 (CH), 52.35 (CH3), 34.50 (CH2),
29.16 (CH2), 23.49 (CH2), 14.62 (CH3); m/z (EI) 342 (M+, 27%),
295 (16), 283 (100), 179 (10), 76 (34).
3-(2-Hydroxyethyl)-6,8-bis(methylsulfanyl)imidazo[2,1-
f ][1,2,4]triazine 39
A solution of tetra-n-butylammonium fluoride (TBAF) in THF
(1 M; 0.4 mL, 0.4 mmol) was added to a solution of the
methylsulfanyl imidazotriazine 38 (99 mg, 0.2 mmol) in THF
(6 mL) at ambient temperature. The mixture was heated at reflux
for 20 min and then concentrated under reduced pressure. The
crude product was purified by column chromatography (30–50%
ethyl acetate in heptane) to yield the title compound 39 as a
pale yellow oil (37 mg, 0.14 mmol, 72%); (Found: M+, 256.0449.
C9H12N4OS2 requires 256.0453); nmax (CHCl3)/cm-1 3623, 3392,
3019, 3006, 2961, 2932, 2857, 1717, 1575, 1511, 1441, 1357, 1317,
1259, 1152, 1113, 1044; dH (300 MHz; CDCl3) 7.49 (1 H, s), 4.01
(2 H, t, J 6.1), 3.23 (2 H, t, J 6.1), 2.67 (3 H, s), 2.60 (3 H, s); dC
(75 MHz; CDCl3) 163.29 (C), 161.57 (C), 132.28 (C), 132.28 (CH),
128.07 (C), 60.66 (CH2), 21.48 (CH2), 14.60 (CH3), 12.24 (CH3);
m/z (EI) 256 (M+, 100%), 225 (47), 209 (10), 179 (53), 69 (20).
6-Bis(methylsulfanyl)-3-[2-(3-methoxycarbonylphenoxy)ethyl]-
imidazo[2,1-f ][1,2,4]triazine 34
Method A. 3-(4-Oxobutoxy) benzoic acid methyl ester 32
(132 mg, 0.59 mmol) was converted to methyl 3-(3-bromo-
4-oxobutoxy)benzoate 33 (Found: M+, 300.0003. C12H1379BrO4
requires 299.9997) as described above for compound 21. The
crude bromide 33 was then converted, as described above for
compound 22, to the title compound 34 which was isolated after
purification as a colourless solid (96 mg, 0.25 mmol, 42%); mp 93–
3-[2-(tert-Butyldiphenylsilanyloxy)ethyl]-8-hydrazino-6-
methylsulfanylimidazo[2,1-f ][1,2,4]-triazine 40
◦
96 C (MeOH); (Found: MH+, 391.0895. C17H19N4O3S2 requires
391.0893); nmax (CHCl3)/cm-1 2954, 2848, 2257, 1721, 1588, 1489,
1448, 1290, 1233, 1192, 1104, 1081, 1053; dH (300 MHz; CDCl3)
7.60 (1 H, d, J = 8.2), 7.51 (1 H, m), 7.30 (2 H, m), 7.06 (1 H, m),
4.36 (2 H, t, J = 6.3), 3.90 (3 H, s), 3.44 (2 H, t, J = 6.3), 2.66 (3 H,
s), 2.58 (3 H, s); dC (75 MHz; CDCl3) 202.08 (CH), 167.29 (C),
165.77 (C), 162.85 (C), 161.14 (C), 159.03 (C), 157.26 (C), 131.82
(C), 129.84 (CH), 122.52 (CH), 120.20 (CH), 114.99 (CH), 67.26
(CH2), 52.59 (CH3), 40.96 (CH2), 14.52 (CH3), 12.33 (CH3); m/z
(CI) 391 (MH+, 7%), 390 (M+, 42), 374 (20), 240 (16), 239 (47),
238 (15), 226 (13), 225 (100), 192 (11), 120 (37), 106 (16), 91 (22),
86 (33), 84 (48), 49 (47), 47 (28).
The reaction and purification were performed as described
above for compound 23. Starting from 3-[2-(tert-butyldiphenyl-
silyloxy)ethyl]-6,8-bis(methylsulfanyl)imidazo-[2,1-f ][1,2,4]tria-
zine 38 (2.65 g, 5.4 mmol), the title product 40 was isolated as a
colourless solid (1.0 g, 2.1 mmol, 39%); mp 59–62 ◦C (CHCl3);
(Found: M+, 478.1968. C24H30N6OSiS requires 478.1971); nmax
(CHCl3)/cm-1 3668, 3364, 3070, 2995, 2961, 2932, 2860, 1959,
1900, 1827, 1601, 1560, 1527, 1473, 1440, 1381, 1333, 1189, 1110,
1029; dH (300 MHz, CDCl3) 9.58 (1 H, s), 7.56 (4 H, m), 7.49 (1 H,
s), 7.43–7.26 (6 H, m) 4.22 (2 H, s), 4.01 (2 H, t, J = 7.4), 3.47 (2 H,
t, J = 7.4), 2.43 (3 H, s), 1.01 (9 H, s); dC (75 MHz, CDCl3) 162.61
(C), 156.84 (C), 151.18 (C), 135.27 (CH), 133.20 (C), 129.93 (CH),
129.51 (CH), 127.76 (C), 127.43 (CH), 60.94 (CH2), 26.79 (CH2),
26.65 (CH3), 18.73 (C), 14.06 (CH3); m/z (CI) 478 (M+, 100%),
447 (36), 421 (27), 344 (31), 324 (40), 297 (76), 223 (21), 208 (12).
Method B. The Mitsunobu reaction and purification were
performed as described for compound 30. Starting from 3-(2-
hydroxyethyl)-6,8-bis(methylsulfanyl)imidazo[2,1-f ][1,2,4]tri-
azine 39 (24 mg, 0.094 mmol), the the title compound 34 was
obtained as a colourless solid (20 mg, 0.051 mmol, 54%); physical
data identical to those given above.
3-[2-(tert-Butyldiphenylsilanyloxy)ethyl]-6-
methylsulfanylimidazo[2,1-f ][1,2,4]triazine 41
Hydrazine hydrate (25 mL, 0.52 mmol) was added under argon
to a stirring solution of 3-[2-(tert-butyldiphenylsilyloxy)ethyl]-
6,8-bis(methylsulfanyl)imidazo-[2,1-f ][1,2,4]triazine 38 (26 mg,
0.052 mmol) in absolute ethanol (2 ml) and the solution was heated
at reflux for 1 h to give the hydrazine 40 as judged by t.l.c. The
reaction mixture was cooled to rt and yellow mercury(II) oxide
(113 mg, 0.52 mmol) was added, causing the reaction mixture to
turn black. The mixture was heated at 80 ◦C for 1 h and then
a second portion of mercury(II) oxide (56 mg, 0.26 mmol) was
added. After heating at 80 ◦C for a further 1 h, a third portion
of mercury(II) oxide (56 mg, 0.26 mmol) was added. The reaction
mixture was heated for 1 h, cooled to rt and filtered through a
column of Celite. Concentration under reduced pressure gave the
title compound 41 as a pale yellow solid (12 mg, 0.027 mmol,
51%); (Found: MH+, 449.1845. C24H29N4OSiS requires 449.1831);
dH (300 MHz; CDCl3) 8.87 (1 H, s), 7.73 (1 H, s), 7.51 (4 H, m),
7.41–7.29 (6 H, m), 4.03 (2 H, t, J = 5), 3.21 (2H, t, J = 5), 2.43
(3 H, s), 0.99 (9 H, s); dC (100 MHz, CDCl3) 162.65 (C), 148.62
(CH), 135.38 (CH), 134.79 (C), 134.08 (CH), 133.17 (C), 129.63
3-[2-(tert-Butyldiphenylsilyloxy)ethyl]-6,8-
bis(methylsulfanyl)imidazo[2,1-f ][1,2,4]triazine 38
The reaction and purification were performed as described above
for compound 22. Starting from 4-tert Butyldiphenylsilyloxy-2-
bromobutanal 37, the title compound 38 (3.55 g, 8.76 mmol) was
obtained as a colourless solid (2.69 g, 5.44 mmol, 62%); (Found:
C, 61.0; H, 6.2; N, 11.3. C25H30ON4SiS2 requires C, 60.7; H,
6.1; N, 11.3%); (Found: MH+, 495.1703. C25H31ON4SiS2 requires
495.1703); nmax (liquid film)/cm-1 3072, 3049, 2960, 2932, 2859,
1963, 1830, 1576, 1513, 1472, 1439, 1356, 1317, 1150, 1112; dH
(300 MHz; CDCl3) 7.53–7.49 (5 H, m), 7.40–7.28 (6 H, m), 4.01
(2 H, t, J = 6.0), 3.15 (2 H, t, J = 6.0) 2.67 (3 H, s), 2.43 (3 H, s),
1.00 (9 H, s); dC (75 MHz; CDCl3) 163.08 (C), 161.61 (C), 135.82
(CH), 133.67 (C), 132.87 (C), 132.69 (CH), 130.01 (CH), 127.94
(CH), 127.80 (C), 61.15 (CH2), 27.34 (CH2), 27.23 (CH3), 19.49
(C), 14.49 (CH3), 12.14 (CH3); m/z (CI) 495 (MH+, 100%), 449
(11), 437 (8), 274 (20), 196 (16), 114 (13), 112 (22), 111 (30), 98
(33), 83 (36), 72 (55).
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(CH), 127.97 (C), 127.60 (CH), 60.50 (CH2), 26.77 (CH3), 26.54
(C) 19.06 (CH2), 14.09 (CH3).
127.95 (CH), 61.30 (CH2), 40.22 (CH2), 27.22 (CH3), 19.47 (C),
12.13 (CH3); m/z (CI) 449 (MH+, 100%), 392 (31), 371 (40), 345
(78), 314 (54), 193 (16).
3-[2-(tert-Butyldiphenylsilyloxy)ethyl]-6-methylsulfonyl-8-
methylsulfanylimidazo[2,1-f ][1,2,4]-triazine 42
4-[(E)-2-(2,4-Bis-methylsulfanyl-imidazo[2,1-f ][1,2,4]triazin-7-yl)-
vinyl]-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl
ester 48
Method A. A mixture of 3-[2-(tert-butyldiphenylsilyloxy)-
ethyl]-6,8-bis(methylsulfanyl)imidazo-[2,1-f ][1,2,4]triazine
38
(192 mg, 0.39 mmol) in CH2Cl2 (1 mL) and 3-chloroperoxybenzoic
acid (202 mg, 1.17 mmol) was stirred at ambient temperature for
24 h. The reaction was diluted with ethyl acetate, washed with
water, dried over MgSO4 and the solvent removed under reduced
pressure. The residue was purified by column chromatography
(30–100% ethyl acetate in heptane) to afford the title compound
42 as a colourless solid (47 mg, 0.089 mmol, 23%); mp 131–134 ◦C
(diethyl ether); (Found: MH+, 527.1600. C25H31N4O3S2Si requires
527.1601); nmax (CHCl3)/cm-1 3110, 3061, 3034, 2934, 2892, 1621,
1501, 1462, 1421, 1396, 1375, 1124, 1076, 1042; dH (300 MHz;
CDCl3) 7.77 (1 H, s), 7.51–7.46 (4 H, m), 7.42–7.27 (6 H, m), 4.04
(2 H, t, J = 5.8), 3.26 (3 H, s) 3.22 (2 H, t, J = 5.8), 2.81 (3 H, s),
1.00 (9 H, s); dC (75 MHz; CDCl3) 166.88 (C), 156.02 (C), 135.94
(C), 135.77 (CH), 133.40 (C), 130.09 (CH), 129.98 (C), 128.17
(CH), 128.01 (CH), 60.86 (CH2), 40.22 (CH3), 29.66 (CH2), 27.24
(CH3), 19.47 (C), 12.87 (CH3); m/z (CI) 527 (MH+, 100%), 454
(36), 451 (42), 434 (53), 423 (72), 419 (76), 406 (52), 399 (58), 391
(66).
(a) Methanesulfonyl chloride (64 mL, 0.84 mmol) followed by
diisopropylethylamine (DIEA) (289 mL, 1.68 mmol) were added to
a solution of 3-(2-hydroxyethyl)-6,8-bis(methylsulfanyl)imidazo-
[2,1-f ]-1,2,4-triazine 39 (144 mg, 0.56 mmol) in CH2Cl2 (20 mL).
The reaction mixture was stirred for 90 minutes at room temper-
ature, then hydrochloric acid (1 M; 10 ml) was added and the
mixture was extracted with CH2Cl2 (3 ¥ 30 ml). The combined or-
ganic phases were washed with saturated aqueous NaHCO3, dried
(MgSO4) and concentrated under vacuum to afford the mesylate
44 (Rf = 0.5, 100% EtOAc) which was immediately redissolved
in THF (5 ml). 1,3-Diazabicyclo[5.4.0]undecane (DBU) (416 mL,
3.36 mmol) was added in one portion to the stirring mixture under
argon. After stirring for 3 h at room temperature, EtOAc was
added to the reaction mixture and the organic phase was washed
with hydrochloric acid (1 M; 10 ml), dried and concentrated
in vacuo. The residue was purified by column chromatography
(10–50% ethyl acetate in heptane) to afford 2,4-bis-methylsulfanyl-
7-vinyl-imidazo[2,1-f ][1,2,4]triazine 45 as a yellow solid (78 mg,
0.33 mmol, 58%); (Rf = 0.67, 50% EtOAc); dH (400 MHz; CDCl3)
7.70 (1 H, s), 7.92 (1 H, m), 6.24 (1 H, m), 5.52 (1 H, m), 2.68 (3 H,
s), 2.60 (3 H, s); dC (100 MHz; CDCl3) 164.48 (C), 161.01 (C),
133.22 (C), 131.82 (CH), 128.42 (C), 121.65 (CH), 117.56 (CH2),
14.46 (CH3), 12.03 (CH3). This material was used without further
purification directly in the next step.
(b) 1,3-Diazabicyclo[5.4.0]undecane (DBU) (44 mL, 294 mmol)
was added to a solution of the bromide 46 (44.6 g, 150 mmol,
prepared according to reference 3) in THF (300 mL) and the
mixture was heated to reflux for one hour and then stirred at
room temperature for 2 h. Hydrochloric acid (1 M; 150 ml)
was added to the reaction mixture and the aqueous phase was
extracted with t-BuOMe (3 ¥ 150 ml). The combined organic
extracts were dried (MgSO4), concentrated and purified by column
chromatography (1–8% ethyl acetate in heptane) to afford 4-vinyl-
5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester 47
as a pale yellow oil (17.3 g, 80 mmol, 53%); dH (400 MHz; CDCl3)
7.92 (1 H, s), 7.68 (1 H, s) 6.95–6.88 (1 H, m) 5.67 (1 H, m), 5.33
(1 H, m), 3.90 (3 H, s), 2.87–2.73 (4 H, m), 1.89–1.73 (4 H, m); dC
(100 MHz; CDCl3) 167.62 (C), 140.00 (C), 137.78 (C), 137.66 (C),
134.36 (CH), 129.89 (CH), 127.43 (C), 124.41 (CH), 116.77 (CH2),
52.18 (CH3), 30.24 (CH2), 27.19 (CH2), 23.21 (CH2), 22.69 (CH2).
This material was used without further purification directly in the
next step.
Method B. A solution of 3-[2-(tert-butyldiphenylsilyloxy)-
ethyl]-6,8-bis(methylsulfanyl)imidazo-[2,1-f ][1,2,4]triazine
38
(46 mg, 0.093 mmol) in MeCN/EtOAc (1.2 mL/1.2 mL) was
added to a vigorously stirred solution of sodium periodate (44 mg,
0.21 mmol) dissolved in water (400 mL). Ruthenium trichloride
(2 mg, 0.013 mmol) was then added and vigorous stirring was
continued for 1 h. After this time EtOAc (50 mL) was added,
followed by brine (50 mL) and the aqueous phase was extracted
with EtOAc (2 ¥ 50 mL). The combined organic phases was
dried and evaporated in vacuo to give the title sulfone 42 (47 mg,
0.13 mmol, 96% theory); physical data identical to those described
above.
3-[2-(tert-Butyldiphenylsilyloxy)ethyl]-8-
methylsulfanylimidazo[2,1-f ][1,2,4]triazine 43
Sodium borohydride (5.5 mg, 0.14 mmol) was added to a solution
of 3-[2-(tert- butyldiphenylsilyloxy)ethyl]-6-methylsulfonyl-8-me-
thylsulfanylimidazo[2,1-f ][1,2,4]triazine 42 (37 mg, 0.070 mmol)
in methanol (0.2 mL) and CHCl3 (0.2 mL) and the mixture
was stirred at ambient temperature for 5 min. The mixture was
quenched with water, extracted with CHCl3 and washed with
water. The organic phase was dried over MgSO4 and evaporated
under reduced pressure. The residue was purified by column
chromatography (50% ethyl acetate in heptane) to afford the title
compound 43 as a pale orange oil (21 mg, 0.047 mmol, 67%);
(Found: MH+, 449.1833. C24H29N4OSiS requires 449.1831); nmax
(CHCl3)/cm-1 3924, 3606, 3149, 3084, 2950, 2902, 2854, 1648,
1595, 1523, 1409, 1356, 1204, 1126, 1014; dH (300 MHz; CDCl3)
8.24 (1 H, s), 7.54 (1 H, s), 7.44 (4 H, m), 7.32–7.19 (6 H, m), 3.94
(2 H, t, J = 6.2) 3.12 (2 H, t, J = 6.2), 2.63 (3 H, s), 0.93 (9 H,
s); dC (75 MHz; CDCl3) 166.88 (C), 146.73 (CH), 135.83 (CH),
133.66 (C), 133.40 (CH), 133.19 (C), 130.08 (C), 129.98 (CH),
(c) A solution of 2,4-bis-methylsulfanyl-7-vinyl-imidazo[2,1-
f ][1,2,4]triazine 45 (67 mg, 0.28 mmol) and 4-vinyl-5,6,7,8-
tetrahydro-naphthalene-2-carboxylic acid methyl ester 47 (70 mg,
0.32 mmol) in toluene (2.8 ml) was heated to 80 ◦C under an
atmosphere of argon. When the temperature had stabilized after
ca. 20 min., Hoveyda-Grubbs 2nd Generation catalyst {[1,3-
bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[[2-(1-
methylethoxy)phenyl]methylene]-ruthenium} (8 mg, 0.014 mmol)
was added. After 24 h at 80 ◦C a second portion of catalyst (8 mg)
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was added and the reaction mixture was heated for a further
24 h. The resulting dark brown reaction mixture was concentrated
in vacuo and the residue was purified by column chromatography
(10–50% ethyl acetate in heptane) to afford the title compound 48
as a yellow oil (45 mg, 0.11 mmol, 38%); (Found: MH+, 427.1255.
C21H23N4O2S2 requires 427.1262); nmax (dry film)/cm-1 2938, 2862,
1725, 1662, 1580, 1430, 1354, 1310, 1215, 1160; dH (400 MHz;
CDCl3) 8.11 (1 H, s), 7.95 (1 H, d, J = 16.0), 7.79 (1 H, s), 7.71
(1 H, s), 7.22 (1 H, d, J = 16.0), 3.89 (3 H, s), 2.92–2.82 (4H,
m) 2.72 (3 H, s), 2.68 (3 H, s), 2.94–2.78 (4 H, m); dC (100 MHz;
CDCl3) 167.32 (C), 163.20 (C), 161.87 (C), 140.23 (C), 138.11 (C),
136.51 (C), 133.5 (C), 132.76 (CH), 130.16 (CH), 128.52 (CH),
128.22 (C), 127.53 (C), 123.88 (CH), 115.35 (CH), 52.14 (CH3),
30.10 (CH2), 27.36 (CH2), 23.02 (CH2), 22.46 (CH2), 14.44(CH3),
11.91 (CH3); m/z (ES) 427 (MH+, 100%).
6 P. J. Dudfield, V.-D. Le, S. D. Lindell and C. W. Rees, J. Chem. Soc.
Perkin Trans., 1999, 1, 2929–2936.
7 S. Maechling and S. D. Lindell, Targets in Heterocyclic Systems, 2006,
10, 66–90.
8 S. R. Kasibhatla, B. C. Bookser, G. Probst, J. R. Appleman and M. D.
Erion, J. Med. Chem., 2000, 43, 1508–1518; S. R. Kasibhatla, B. C.
Bookser, W. Xiao and M. D. Erion, J. Med. Chem., 2001, 44, 613–618.
9 E. Chan, S. R. Putt, H. D. H. Showalter and D. C. Baker, J. Org. Chem.,
1982, 47, 3457–3464.
10 See for example F. Firooznia, C. Gude, K. Chan, C. A. Fink, Y. Qiao,
Y. Satoh, N. Marcopoulos, P. Savage, M. E. Beil, C. W. Brusco, A. J.
Trapani and A. Y. Jeng, Bioorg. Med. Chem. Lett., 2001, 11, 375–378;
S. Mathur, F. Picard, U. Dossou, C. Barassin, S. B. Seidel, M.-J. Kang
and R. W. Hartmann, J. Enzyme Inhib. Med. Chem., 2004, 19, 425–429;
M. Streiber, F. Picard, C. Scherer, S. B. Seidel and R. W. Hartmann,
J. Pharm. Sci., 2005, 94, 473–480.
11 C.-C. Tzeng, N. C. Motola and R. P. Panzica, J. Org. Chem., 1983, 48,
1271–1275.
12 K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975,
16, 4467–4470.
13 K. Omura and D. Swern, Tetrahedron, 1978, 34, 1651–1660.
14 A. Bongini, G. Cainelli, M. Contento and F. Manescalchi, Synthesis,
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Acknowledgements
We thank Bayer CropScience AG for a research studentship
(to J. K. K.) and for a postdoctoral fellowship (to S. M.).
15 O. Mitsunobu and M. Yamada, Bull. Chem. Soc. Jpn., 1967, 40, 2380–
2382.
16 V. Caprio, M. A. Brimble and D. P. Furkert, Tetrahedron, 2001, 57,
4023–4034.
17 CCDC-694838 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB21EZ,
UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk).CCDC.
18 A. K. Chatterjee, T. L. Choi, D. P. Sanders and R. H. Grubbs, J. Am.
Chem. Soc., 2003, 125, 11360–11370; S. J. Connon and S. Blechert,
Angew. Chem. Int. Ed., 2003, 42, 1900–1923.
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