Synthesis of 1,3-dithiol-2-ones as proligands related to molybdopterin

Article abstract of DOI:10.1039/b209217d

The reaction of suitably disubstituted alkynes with diisopropyl xanthogen disulfide gives differentially substituted 4,5-disubstituted-1,3-dithiol-2-ones as proligands for metal complexes related to the molybdenum cofactor.

Full text of DOI:10.1039/b209217d

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Synthesis of 1,3-dithiol-2-ones as proligands related to
molybdopterin
Ben Bradshaw,a David Collison,a C. David Garnerb and John A. Joule*a
a Chemistry Department, The University of Manchester, Manchester, UK M13 9PL
b School of Chemistry, University of Nottingham, University Park, Nottingham, UK NG7 2RD
Received 20th September 2002, Accepted 16th October 2002
First published as an Advance Article on the web 27th November 2002
The reaction of suitably disubstituted alkynes with diisopropyl xanthogen disulfide gives differentially substituted
4,5-disubstituted-1,3-dithiol-2-ones as proligands for metal complexes related to the molybdenum cofactor.
Introduction
We have described linear1–4 and convergent5,6 routes to differen-
tially 4,5-disubstituted 1,3-dithiol-2-ones 1 (and -2-thione
analogues) and shown how these can be used to form metal com-
plexes7–12 via hydrolytic release of the masked ene-1,2-dithiolate
ligand from 1,3-dithiol-2-one. We have also demonstrated how
appropriately substituted 1,3-dithiol-2-ones 1 can serve as key
intermediates for the construction of tricyclic pyrano-quinoxal-
ines, and complexes therefrom, which mimic13,14 the structure
of molybdopterin 2, and we have constructed molybdopterin
itself, in protected form and with the ene-dithiolate masked in
this way, 3.15
Scheme 1
Based on Gareau’s observations, there seemed to be two
reasons why the process might not be suitable for our purposes:
(1) the considerable size of alkyne substituents that would be
required to generate relevant proligands, and (2) the presence of
the imine unit of the quinoxaline/pteridine substituent that
might act like a conjugated carbonyl group, and discourage
reaction. Nevertheless, we have now examined five relevantly
disubstituted alkynes, finding in each case a very useful, in some
cases, high yielding, synthesis of 4,5-differentially disubsti-
tuted-1,3-dithiol-2-ones.
Taylor and co-workers were the first to describe the synthesis
of 2-alkynylquinoxalines and 6-alkynylpteridines related to
molybdopterin,19 such as would be required for the application
of the Gareau method for the assembly of proligands for
molybdopterin and its analogues. In our previous studies we
have also described the synthesis of various 2-alkynylquinoxal-
ines13,14,20,21 and 6-alkynylpteridines.22,23
In the context of the synthesis of 1,3-dithiol-2-ones, key
intermediates in our strategy for the construction of molyb-
dopterin and its analogues, we were attracted to reports by
Gareau16,17 that the reaction of alkynes with diisopropyl xan-
thogen disulfide† 4 (and the corresponding dithiodiisopropyl
xanthogen disulfide), in the presence of a radical initiator, leads
directly to these five-membered heterocycles. Gareau proposed
that homolytic cleavage of the S–S bond produces a radical 5
that adds to the alkyne, generating 6, which cyclises with loss of
an isopropyl radical (Scheme 1). At the time it seemed signifi-
cant that all of the examples (12) given in the two papers
involved terminal alkynes and thus led to mono-substituted
1,3-dithiol-2-ones 7. Accordingly, we did not immediately
investigate the method in the context of our molybdopterin
research.
Results and discussion
Synthesis of alkynes
The alkynes chosen for study were 8–10,11b,12b. Full details
of the synthesis of 8 by palladium()-catalysed coupling of
2-chloroquinoxaline with racemic but-3-yn-2-ol have been
published.14 We have previously described4 a synthesis of the
alkynyl-acetal 9 from 2-(-arabino-tetrahydroxybutyl)quinoxal-
ine, but for the present work, it was made by coupling of
2-chloroquinoxaline with (4R)-4-ethynyl-2,2-dimethyl-1,3-
dioxolane;24 the analogous protected pteridine 10 was made in
this way too, coupling to 6-chloro-2-(dimethylaminomethylene-
amino)-3-(2,2-dimethylpropanoyloxymethyl)pteridin-4-one.15
Later, Gareau reported18 the successful application of his
route to 1,3-dithiol-2-ones using disubstituted alkynes, though
yields were poorer, especially where the alkynes had carbonyl
conjugation and/or bulky substituents.
† The IUPAC name for diisopropyl xanthogen disulfide is bis(isopropy-
loxythiocarbonyl) disulfide.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 2 9 – 1 3 3
129

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From other, previously unpublished work on an alternative
route to such substances, the alkyne-diols 11b and 12b were
available to us. Quinoxaline 11b was made by coupling 2-chlo-
roquinoxaline with 4-tert-butyldiphenylsiloxy-3-hydroxybut-1-
yne, giving 11a, followed by fluoride deprotection. Diol 12b was
prepared by coupling 6-chloro-2-(dimethylaminomethylene-
amino-3-(2,2-dimethylpropanoyloxymethyl)pteridin-4-one15
with 3,4-bis(tert-butyldiphenylsiloxy)but-1-yne, giving 12a,
followed by fluoride deprotection; in this much more polar
pteridine series, the use of the doubly O-silylated C4-alkyne-diol
facilitated handling and isolation.
Scheme 2
We found that the best route for the synthesis of the alkyne
coupling partners started from commercially available (Z)-1,4-
dihydroxybut-2-ene which was mono-protected by reaction
with tert-butyldiphenylsilyl chloride giving 13, the alkene was
then epoxidised using m-chloroperbenzoic acid generating 14,
and then this was transformed25 into the alkyne 15a by treat-
ment with n-butyllithium. Finally, the doubly silyl-protected
alkyne 15b was prepared by exposure again to tert-butyl-
diphenylsilyl chloride (Scheme 2).
Given the relative efficiency of the alkyne coupling procedure
and the directness of this approach (e.g. the synthesis of a
6-iodopterin, as was previously required,15 is not necessary),
this route now proves to be the strategy of choice to the key
1,3-dithiol-2-one intermediates 17 and 18 in our route to
molybdopterin and pteridine and quinoxaline analogues
thereof.
We shall be reporting on the use of this method for the
synthesis of suitably modified analogues which will be designed
to cast light on the mode of action of the cofactor of the
oxomolybdoenzymes.
Synthesis of 1,3-dithiol-2-ones
Notwithstanding the reservations mentioned above, reaction
of each of the alkynes 8–10, 11b, and 12b with diisopropyl
xanthogen disulfide 4, initiated using AIBN, gave rise to 1,3-
dithiol-2-ones, 16–20 respectively. The acetal protected sub-
strates reacted in better yields (17 (77%); 18 (61%)) than the
alcohol 8 (41%) or the diols 11b (30%) and 12b (20%). We have
previously shown14,15 that it is easy to remove the acetal protec-
tion from 17 and 18, revealing diols, 19 and 20, and thus clearly
the method of choice for the synthesis of these substances
involves the formation of 17 and 18, then acetal hydrolysis.
Experimental
General
Organic solutions were dried over anhydrous MgSO4. Solid
products were dried under reduced pressure using P4O10 as a
desiccant. Proton nuclear magnetic resonance (1H NMR)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 2 9 – 1 3 3
130

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spectra were recorded on Inova-300 Athos (300 MHz) and
Unity 500 (500 MHz) spectrometers. Carbon nuclear magnetic
resonance (13C NMR) spectra were recorded on an Inova-300
Athos spectrometer running at 75 MHz. All chemical shifts (δ)
are quoted in parts per million (ppm) downfield from tetra-
methylsilane (TMS). Signal splittings are reported as singlet (s),
doublet (d), double doublet (dd), triplet (t), quartet (q), multi-
plet (m), and broad (br); J values are given in Hertz (Hz). UV
spectra were recorded on a Hewlett Packard 8452A diode array
spectrophotometer and are given in nm. IR spectra were
recorded on an Ati Mattson Genesis Series FTIR spectrometer;
only absorptions of importance to structure determination are
listed. Mass spectra were recorded on a Fisons VG Trio 2000
(EI/CI{NH3}/ES) (abundance relative to the base peak is
given in parentheses as a percentage; only fragment ions of
intensity >10% of the base peak are cited), and a Concept IS
(MM/FAB) spectrometer for accurate mass determinations.
Melting points were recorded on a Reichart heated stage
microscope and are uncorrected. Flash column chromato-
graphy was carried out using Merck 9385 silica gel 60 (230–400
mesh). Acetonitrile, dichloromethane, and triethylamine were
distilled from calcium hydride. Petroleum ether was the fraction
bp 40–60 ЊC.
On cooling, the mixture was concentrated and the residue
partitioned between water (50 ml) and CH2Cl2 (150 ml). The
mixture was filtered through Celite to break the emulsion, the
layers separated and the aqueous layer re-extracted with
CH2Cl2 (2 × 100 ml). The combined organic extracts were
dried (MgSO4) and concentrated. Purification by flash
chromatography (silica, 1 2% MeOH in CH2Cl2) provided
10 (1.76 g, 65%) as a yellow solid, mp 186 ЊC (dec.); νmax(film)/
cmϪ1 2983, 2934, 2875, 1731, 1705, 1634, 1527, 1448, 1423,
1393, 1368, 1330, 1144, 1115, 1061; 1H NMR (300 MHz,
CDCl3) δ 8.95 (1H, s, H-7Ј), 8.78 (1H, s, CHNMe2), 6.38 (2H, s,
NCH2OCOt-Bu), 4.98 (1H, t, J = 6.3 Hz, CHO), 4.25 (1H,
dd, J = 6.6, 8.1, one of CH2O), 4.08 (1H, dd, J = 6.3, 8.1, one
of CH2O), 3.25 (3H, s, NCH3), 3.08 (3H, s, NCH3), 1.55 (3H, s,
CH3), 1.41 (3H, s, CH3), 1.08 (9H, s, t-Bu); 13C NMR (75 MHz,
CDCl3) δ 177.7, 161.2, 159.7, 157.8, 153.8, 153.1, 135.0, 130.2,
111.0, 90.8, 82.5, 69.9, 66.1, 66.0, 42.0, 39.0, 36.0, 27.2,
26.4, 26.1; m/z (CI) 457 (MHϩ, 100%), 391 (40), 279 (20);
found C, 57.65; H, 6.01, N, 18.54%; M ϩ Hϩ 456.2121.
C22H28N6O5 requires C, 57.88; H, 6.18, N, 18.41%, M (ϩ H)
456.2121.
(Z)-4-tert-Butyldiphenylsiloxy-1-hydroxybut-2-ene 13
To a stirred solution of (Z)-1,4-dihydroxybut-2-ene (192 g, 2.18
mol), DMAP (1.33 g, 0.012 mol) and Et3N (30 ml) in dry
CH2Cl2 (300 ml) at 25 ЊC, was added tert-butyldiphenylsilyl
chloride (30 g, 0.11 mol) over 30 min. After 6 h water (200 ml)
was added and the organic layer separated, the aqueous layer
was then extracted with CH2Cl2 (2 × 100 ml). The combined
organic extracts were washed with 12% citric acid solution (100
ml), brine (100 ml), dried (MgSO4) and the solvent was evapor-
ated. Purification by flash chromatography (silica, 5 10%
EtOAc in petroleum ether) provided 13 (35.6 g, 99%) as a
colourless oil; λmax(CHCl3)/nm 226, 266; νmax(film)/cmϪ1 3331,
3070, 3049, 3024, 2957, 2931, 2891, 2857, 1690, 1589, 1471,
(R)-(؉)-4-Ethynyl-2,2-dimethyl-1,3-dioxolane24
To a stirred solution of freshly prepared (ϩ)-2,3-O-isopropyli-
dene--glyceraldehyde26 (5.0 g, 38.4 mmol) and the Bestmann–
Ohira reagent (7.38 g, 38.4 mmol, prepared according to the
modified method of Callant et al.27 using p-acetamidobenze-
nesulfonyl azide28 as the diazo transfer reagent) in methanol
(250 ml) at 0 ЊC was added K2CO3 (7.1 g, 51.2 mmol) portion-
wise over 30 min. The resulting mixture was stirred for a further
18 h then a solution of saturated aqueous NH4Cl (250 ml)
was added and the aqueous layer was extracted with pentane
(3 × 750 ml). The combined organic layers were dried
(MgSO4) and the solvent concentrated very carefully at reduced
pressure (care!—product is quite volatile). Purification by flash
chromatography (silica, 5 10% Et2O in pentane) provided the
alkyne (2.66 g, 55%) as a colourless oil with spectroscopic data
consistent with the published data.24
1
1428, 1390, 1361, 1188, 1109, 1079, 823; H NMR (300 MHz,
CDCl3) δ 7.76 (4H, m, ArH ), 7.46 (6H, m, ArH ), 5.75 (2H, m,
H-2 and H-3), 4.35 (2H, d, J = 5.5 Hz, H-4), 4.08 (2H, d, J = 6.9
Hz, H-1), 2.25 (1H, br s, OH ), 1.15 (9H, s, t-Bu); 13C NMR (75
MHz, CDCl3) δ 135.6, 134.9, 133.4, 130.7, 130.0, 129.8, 127.9,
127.7, 60.2, 58.5, 26.8, 19.1; m/z (CI) 327 (MHϩ, 100%) 196
(40); found MHϩ, 327.1784. C20H26O2Si requires M (ϩ H)
327.1780. The spectroscopic data were exactly comparable with
those reported for this compound prepared previously from the
diol using n-butyllithium in THF at Ϫ78 ЊC29 or subsequently
using sodium hydride in ether at room temperature.30
1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(quinoxalin-2-yl)ethyne 9
To a degassed solution of 2-chloroquinoxaline (2.27 g, 13.7
mmol), (R)-(ϩ)-4-ethynyl-2,2-dimethyl-1,3-dioxolane (1.81 g,
14.4 mmol) and Et3N (15 ml) in MeCN (35 ml), was added
Pd(OAc)2 (155 mg, 0.69 mmol), Ph3P (362 mg, 1.38 mmol) and
CuI (263 mg, 1.38 mmol) and the resulting mixture stirred for
18 h then refluxed for 2 h. On cooling, the mixture was concen-
trated and the residue partitioned between water (50 ml) and
CH2Cl2 (100 ml). The mixture was filtered through Celite to
break the emulsion, the layers separated and the aqueous layer
re-extracted with CH2Cl2 (2 × 50 ml). The combined organic
extracts were dried (MgSO4) and concentrated. Purification by
flash chromatography (silica, 10 20% EtOAc in petroleum
ether) provided 9 (2.61 g, 75%) as a yellow oil, with physical and
spectroscopic data identical to those reported previously.14
3-Hydroxymethyl-2-tert-butyldiphenylsilyloxymethyloxirane 14
To a stirred solution of m-chloroperbenzoic acid (52.5 g, 0.15
mol) in CH2Cl2 (250 ml) was added a solution of alkene 13
(35 g, 0.11 mol) in CH2Cl2 (100 ml) over 0.5 h. After 36 h the
solution was cooled to 0 ЊC, precipitating m-chlorobenzoic acid,
which was removed by filtration. Water was added, the organic
layer separated and washed with aqueous Na2SO3 (2 × 350 ml),
aqueous NaHCO3 (3 × 350 ml), brine (300 ml), dried (MgSO4)
and the solvent evaporated. Purification by flash chromato-
graphy (silica, 10% EtOAc in petroleum ether) provided
epoxide 14 (36.72 g, 100%) as a colourless oil; λmax(CHCl3)/nm
214, 226, 266; νmax(film)/cmϪ1 3426, 3070, 3048, 3012, 2996,
2954, 2933, 2892, 2859, 1589, 1471, 1428, 1391, 1361, 1260,
1188, 1109, 1091, 1046, 975, 937; 1H NMR (300 MHz, CDCl3)
δ 7.72 (4H, m, ArH ), 7.45 (6H, m, ArH ), 4.0–3.75 (4H, m,
H-2,3 and CH2OH), 3.28 (2H, m, CH2OSi), 1.92 (1H, br s,
OH ), 1.1 (9H, s, t-Bu); 13C NMR (75 MHz, CDCl3) δ 135.5,
135.4, 132.9, 132.7, 129.9, 127.8, 62.2, 60.7, 56.3, 56.1, 26.7,
19.1; m/z (CI) 360 (MNHϩ, 100%) 343 (MHϩ, 50%); found
MNH4ϩ 360.1991. C20H26O3Si ϩ NH4ϩ requires 360.1995. The
spectroscopic data were exactly comparable with those reported
1-[2-(Dimethylaminomethyleneamino)-3-(2,2-dimethyl-
propanoyloxymethyl)-4-oxopteridin-6-yl]-2-[(4R)-2,2-di-
methyl-1,3-dioxolan-4-yl]ethyne 10
To
a
degassed solution of 6-chloro-2-(dimethylamino-
methyleneamino)-3-(2,2-dimethylpropanoyloxymethyl)-
pteridin-4-one15 (2.17 g, 5.92 mmol), (4R)-(ϩ)-4-ethynyl-2,2-
dimethyl-1,3-dioxolane (1.12 g, 8.88 mmol) and Et3N (15 ml)
in MeCN (50 ml), was added Pd(OAc)2 (60 mg, 0.30 mmol),
Ph3P (155 mg, 0.59 mmol) and CuI (113 mg, 0.59 mmol) and
the resulting mixture stirred at rt for 18 h then refluxed for 2 h.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 2 9 – 1 3 3
131

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previously29 for this compound prepared in homochiral form
using Sharpless’ method.
m, ArH ), 4.90 (1H, t, J = 5.4 Hz, H-3), 4.22 (1H, br s, OH ),
4.05 (2H, m, H-4) 1.14 (9H, s, t-Bu); 13C NMR (75 MHz,
CDCl3) δ 146.9, 141.9, 140.8, 138.7, 135.6, 135.5, 132.8, 130.7,
130.6, 129.9, 129.0, 127.8, 92.9, 82.7, 77.6, 77.2, 76.8, 67.3, 63.6,
26.8, 19.3; m/z (CI) 453 (MHϩ, 70%); found Mϩ 452.1919.
C28H28N2O2Si requires M 452.1919.
3-Hydroxy-4-tert-butyldiphenylsiloxybut-1-yne 15a
To a stirred solution of 14 (12 g, 0.033 mol) in THF (150 ml) at
Ϫ78 ЊC was added a solution of n-BuLi (62.5 ml, 0.10 mol) over
0.5 h. After 1 h the solution was warmed to room temperature
and a solution of sat. aq. NH4Cl (150 ml) was added. The
organic layer was separated and the aqueous layer re-extracted
with Et2O (2 × 100 ml). The combined organic extracts were
washed with brine (100 ml), dried (MgSO4) and the solvent
evaporated. Purification by flash chromatography (silica,
1-(Quinoxalin-2-yl)-3,4-dihydroxybut-1-yne 11b
To a stirred solution of quinoxaline 11a (0.5 g, 1.11 mmol) in
THF (10 ml) at 0 ЊC was added HF–pyridine (7 : 3, 3 ml). The
mixture was then allowed to warm to room temperature. After
2 h the solution was diluted with water (20 ml) and the resulting
mixture neutralised by the addition of solid NaHCO3. CH2Cl2
(50 ml) was added, the layers separated, and the aqueous layer
re-extracted with CH2Cl2 (2 × 50 ml), the organic layer was
washed with brine (30 ml), dried and concentrated. Purification
5
10% EtOAc in petroleum ether) provided alkyne 15a
(8.13 g, 76%) as a colourless oil; λmax(CH2Cl2)/nm 266; νmax(film)/
cmϪ1 3560, 3422, 3291, 3071, 3050, 2957, 2931, 2890, 2859,
1472, 1428, 1132, 1020, 938, 823; 1H NMR (300 MHz, CDCl3)
δ 7.62 (4H, m, ArH ), 7.34 (6H, m, ArH ), 4.4 (1H, m, H-3),
3.7 (2H, m, CH2OSi), 2.58 (1H, d, J = 5.6 Hz, OH ), 2.35 (1H, d,
J = 2.19 Hz, H-1), 1.1 (9H, s, t-Bu); 13C NMR (75 MHz, CDCl3)
δ 135.7, 135.6, 135.5, 132.8, 132.7, 129.9, 127.8, 82.1 73.6, 67.3,
62.9, 26.9, 26.8, 19.3; m/z (CI) 342 (MNH4ϩ, 100%), 325 (MHϩ,
by flash chromatography (silica, 0
2
5
8% MeOH in
EtOAc) provided 11b (152 mg, 64%) as a white solid, mp >230
ЊC; 1H NMR (300 MHz, CD3OD) δ 8.95 (1H, s, H-3Ј), 8.1 (1H,
m, ArH ), 8.04 (1H, m, ArH ), 7.88 (2H, m, ArH ), 4.7 (1H, dd,
J = 5.5, 6.3 Hz, H-3), 3.82 (2H, m, H-4); m/z (CI) 215 (MHϩ,
15%); found MHϩ 215.0822. C12H10N2O2 requires M ϩ H
215.0820.
ϩ
5%); found MNH4 342.1893. C20H24O2Si (ϩ NH4) requires
M 342.1889. The spectroscopic data were exactly comparable
with those reported previously for this compound prepared by
mono-silylation of the corresponding diol.31
1-[2-(Dimethylaminomethyleneamino)-3-(2,2-dimethyl-
propanoyloxymethyl)-4-oxopteridin-6-yl]-3,4-bis(tert-
butyldiphenylsiloxy)but-1-yne 12a
3,4-Bis(tert-butyldiphenylsiloxy)but-1-yne 15b
To a stirred solution of alcohol 15a (3 g, 9.26 mmol), DMAP
(113 mg, 0.926 mol) and Et3N (5 ml) at 25 ЊC in dry CH2Cl2
(20 ml), was added tert-butyldiphenylsilyl chloride (3.31 g, 12.0
mmol). After 24 h, water (20 ml) was added and the organic
layer separated, the aqueous layer was then extracted with
CH2Cl2 (2 × 20 ml). The combined organic extracts were
washed with 12% citric acid solution (30 ml), brine (30 ml),
dried (MgSO4) and the solvent was evaporated. Purification by
flash chromatography (silica, 2.5 5% EtOAc in petroleum
ether) provided 15b (5.15 g, 99%) as a white crystalline solid,
mp 83–84 ЊC (previously prepared in 5% yield as a byproduct in
a preparation of 3-hydroxy-4-tert-butyldiphenylsiloxybut-1-yne
15a by silylation of the corresponding diol31); λmax(CHCl3)/nm
242, 262; νmax(film)/cmϪ1 3306, 3071, 3050, 2957, 2931, 2891,
To a degassed solution of 6-chloro-2-(dimethylaminomethylene-
amino)-3-(2,2-dimethylpropanoyloxymethyl)pteridin-4-one15
(1.0 g, 2.73 mmol), alkyne 15b (2.34 g, 4.10 mol) and Et3N
(7 ml) in MeCN (30 ml), was added Pd(OAc)2 (31 mg, 0.14
mmol), Ph3P (72 mg, 0.27 mmol) and CuI (52 mg, 0.27 mmol)
and the resulting mixture refluxed for 2 h. On cooling, the mix-
ture was concentrated and the residue partitioned between
water (50 ml) and EtOAc (50 ml). The layers were separated and
the aqueous layer re-extracted with EtOAc (2 × 25 ml). The
combined organic fractions were washed with brine (25 ml),
dried (MgSO4) and concentrated. Purification by flash chroma-
tography (silica, 30 50 100% EtOAc in petroleum ether)
provided 12a (1.95 g, 80%) as a yellow foam; λmax(CHCl3)/nm
256, 332, 374; νmax(film)/cmϪ1 2960, 2932, 2859, 1732, 1705,
1
1
2858, 1472, 1428,1112, 962, 823; H NMR (300 MHz, CDCl3)
1634, 1525, 1424, 1365, 1332, 1113, 755; H NMR (300 MHz,
δ 7.74 (8H, m, ArH ), 7.4 (12H, m, ArH ), 4.56 (1H, m, H-3), 3.8
(2H, m, H-4), 2.28 (1H, d, J = 2.1 Hz, H-1), 1.14 (9H, s, t-Bu),
1.07 (9H, s, t-Bu); 13C NMR (75 MHz, CDCl3) δ 136.1, 135.8,
135.6, 135.5, 133.4, 133.3, 129.6, 127.6, 127.5, 127.4, 83.0, 73.4,
68.1, 65.0, 26.9, 26.7, 19.3, 19.2; m/z (CI) 580 (MNH4ϩ, 30%),
485 (15), 267 (100); found C, 76.92; H, 7.76%; MNH4
580.3077. C36H42O2Si2 requires C, 76.82; H, 7.76%; M (ϩ NH4)
580.3067.
CDCl3) δ 8.95 (1H, s, H-7Ј), 8.12 (1H, s, CHNMe2), 7.75 (8H,
m, ArH ), 7.38 (12H, m, ArH ), 7.4 (8H, m, ArH ), 6.38 (2H, s,
NCH2OCOt-Bu), 4.84 (1H, m, H-3), 3.91 (2H, m, H-4), 3.25
(3H, s, NCH3), 3.17 (3H, s, NCH3), 1.17 (9H, s, t-Bu), 1.13 (9H,
s, t-Bu), 1.08 (9H, s, t-Bu); 13C NMR (75 MHz, CDCl3) δ 177.3,
160.8, 159.2, 157.3, 153.1, 152.8, 136.1, 135.8, 135.5, 135.2,
133.5, 133.1, 133.0, 129.7, 129.6, 127.6, 127.4, 92.6, 82.5, 68.0,
65.8, 65.6, 41.6, 38.8, 35.6, 27.0, 26.8, 26.7, 19.1, 19.2, 15.1;
m/z (ESϩ) 892 (Mϩ, 100%).
ϩ
1-(Quinoxalin-2-yl)-3-hydroxy-4-tert-butyldiphenylsiloxybut-1-
yne 11a
1-[2-(Dimethylaminomethyleneamino)-3-(2,2-dimethyl-
propanoyloxymethyl)-4-oxopteridin-6-yl]-3,4-dihydroxy-
but-1-yne 12b
To a degassed solution of 2-chloroquinoxaline (0.77 g, 4.66
mmol), alkyne 15a (1.78 g, 4.23 mmol) and Et3N (5 ml) in
MeCN (10 ml), was added Pd(OAc)2 (47 mg, 0.21 mmol), Ph3P
(111 mg, 0.423 mmol) and CuI (80 mg, 0.42 mmol). The result-
ing mixture was refluxed for 2 h, cooled to 25 ЊC and concen-
trated in vacuo. The residue was partitioned between water
(50 ml) and EtOAc (50 ml), the layers separated and the aqueous
layer extracted with EtOAc (2 × 50 ml). The combined organic
extracts were washed with brine (75 ml), dried (MgSO4) and
concentrated in vacuo. Purification by flash chromatography
(silica, 5 10% EtOAc in petroleum ether) provided 11a (1.40
g, 73%) as a coloured oil; λmax(CHCl3)/nm 256, 334; νmax(film)/
cmϪ1 3329, 2956, 2930, 2888, 2857, 1541, 1487, 1471, 1427,
1364, 1295, 1216, 1114, 824; 1H NMR (300 MHz, CDCl3) δ 8.85
(1H, s, H-3Ј), 8.08 (2H, m, ArH ), 7.74 (6H, m, ArH ), 7.36 (6H,
To a stirred solution of pteridine 12a (1.5 g, 1.68 mmol) in THF
(30 ml) at 0 ЊC was added TBAF (0.97 ml of a 1.0 M solution of
5% H2O in THF). The mixture was then allowed to warm to
room temperature. After 5 h the solution was diluted with
EtOAc (100 ml) and water (50 ml), the layers separated, the
organic layer washed with brine (50 ml), dried and concen-
trated. Purification by flash chromatography (silica,
0
2
5
10% MeOH in EtOAc) provided 12b (531 mg, 76%)
as a yellow solid, mp >230 ЊC; λmax(CHCl3)/nm 256, 334, 376;
νmax(film)/cmϪ1 3343, 2930, 1731, 1704, 1638, 1518, 1361, 1326,
1
1145, 1114; H NMR (300 MHz, CDCl3) δ 8.88 (1H, s, H-7Ј),
8.72 (1H, s, CHNMe2), 6.27 (2H, s, NCH2OCOt-Bu), 4.73 (1H,
t, J = 5.5 Hz, H-3), 3.83 (2H, m, H-4), 3.19 (3H, s, NCH3), 3.10
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 2 9 – 1 3 3
132

View Article Online
(3H, s, NCH3), 1.08 (9H, s, t-Bu); m/z (CI) 417 (MHϩ, 80%);
found MHϩ 417.1886. C19H24N6O5 requires M (ϩ H) 417.1886.
Acknowledgements
We gratefully acknowledge support for this work from the
EPSRC and latterly from the BBSRC in the form of post-
doctoral assistantships (BB).
4-(1-Hydroxyethyl)-5-(quinoxalin-2-yl)-1,3-dithiol-2-one 16
Alcohol 8 (2.0 g, 0.01 mol), disulfide 4 (3.0 g, 11 mmol), and
AIBN (0.75 g, 4.55 mmol) in toluene (1 ml) were heated to
reflux for 6 h. The cooled mixture was purified directly by flash
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2% MeOH in CH2Cl2) giving 18 (146 mg, 61%) as a yellow
solid, with physical and spectroscopic data identical to those
reported previously.15
5-(Quinoxalin-2-yl)-4-(1,2-dihydroxyethyl)-1,3-dithiol-2-one 19
A mixture of diol 11b (2.0 g, 0.01 mol), disulfide 4 (3.0 g,
0.011 mol), and AIBN (0.75 g, 4.55 mmol) in toluene (1 ml)
was heated to reflux for 6 h. The cooled mixture was puri-
fied directly by flash chromatography (silica, 0
5
10%
EtOAc in CH2Cl2) giving 19 (234 mg, 30%) as a yellow solid.
All spectroscopic data were identical to those previously
reported.14
5-[2-(Dimethylaminomethyleneamino)-3-(2,2-dimethyl-
propanoyloxymethyl)-4-oxopteridin-6-yl]-4-(1,2-di-
hydroxyethyl)-1,3-dithiol-2-one 20
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Diol 12b (30 mg, 0.072 mmol), disulfide 4 (21.4 mg, 0.079
mmol), AIBN (5.32 mg, 0.032 mmol) in toluene (0.1 ml) were
heated to reflux for 6 h. The cooled mixture was purified
directly by flash chromatography (silica, 0
2
5% EtOAc in
CH2Cl2) giving 20 (7 mg, 20%) as a yellow crystalline solid with
spectroscopic data identical to those reported previously.15
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 2 9 – 1 3 3
133