A bis(η5-cyclopentadienyl)cobalt complex of a bis-dithiolene: A chemical analogue of the metal centres of the DMSO reductase family of molybdenum and tungsten enzymes, in particular ferredoxin aldehyde oxidoreductase

Article abstract of DOI:10.1016/j.tet.2005.08.095

The synthesis is described of a bis-ene-1,2-dithiolate pro-ligand, designed to model the stereochemical situation in the cofactor of the tungsten enzyme ferredoxin aldehyde oxidoreductase from Pyrococcus furiosus. Each masked ene-1,2-dithiolate unit is mounted on a pyrano[2,3-b]tetrahydroquinoxaline tricycle, comparable to the pyrano[2,3-g]tetrahydropteridines found in all molybdoenzymes and tungsten analogues. Hydrolytic release of the bis-ligand was confirmed by its entrapment as a double (η⁵-C₅H ₅)Co complex.

Full text of DOI:10.1016/j.tet.2005.08.095

Tetrahedron 614 (2005) 11010–11019
5
A bis(h -cyclopentadienyl)cobalt complex of a bis-dithiolene:
a chemical analogue of the metal centres of the DMSO reductase
family of molybdenum and tungsten enzymes, in particular
ferredoxin aldehyde oxidoreductase
a
France-Aim e´ e Alphonse, Rehana Karim, C e´ line Cano-Soumillac, Marielle Hebray,
a
a
a
a
David Collison, C. David Garner and John A. Joule
b
a,
*
a
The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
b
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 14 June 2005; revised 11 August 2005; accepted 19 August 2005
Available online 21 September 2005
Abstract—The synthesis is described of a bis-ene-1,2-dithiolate pro-ligand, designed to model the stereochemical situation in the cofactor of
the tungsten enzyme ferredoxin aldehyde oxidoreductase from Pyrococcus furiosus. Each masked ene-1,2-dithiolate unit is mounted on a
pyrano[2,3-b]tetrahydroquinoxaline tricycle, comparable to the pyrano[2,3-g]tetrahydropteridines found in all molybdoenzymes and
5
tungsten analogues. Hydrolytic release of the bis-ligand was confirmed by its entrapment as a double (h -C
q 2005 Elsevier Ltd. All rights reserved.
5 5
H )Co complex.
1. Introduction
The nature of the cofactors of molybdenum and tungsten
enzymes that catalyse oxygen atom transfer has been
determined by a series of degradative and spectroscopic
1
investigations, notably by Rajagopalan et al., followed by
2
–6
several X-ray crystallographic structural studies.
These
investigations identified molybdopterin (1, RZH or a
nucleotide), present as the doubly S,S -dideprotonated ene-
0
7
dithiolate (dithiolene ), as the ubiquitous ligand for the
metal in these enzymes. Based on the nature of the metal
centre in the oxidized form of the enzymes, molybdenum
enzymes can be placed into one of three groups, known as
the xanthine oxidase, sulfite oxidase and DMSO reductase,
8
families. In some of the enzymes the molybdenum is co-
ordinated by just one ene-dithiolate unit, but intriguingly in
others—the DMSO-reductase family—by two MPT units;
Figure 1. Chem3D drawing of tungsten centre in ferredoxin aldehyde
oxidoreductase from X-ray co-ordinates, showing the linking of the two
MPT units via phosphate oxygens to a magnesium cation.
5
5,6,9
tungsten enzymes
also belong to this family. In the
tungsten enzyme ferredoxin aldehyde oxidoreductase from
Pyrococcus furiosus, the two MPTs (RZH), which ligand
tungsten are oriented via linkage, through a phosphate oxygen
in each case, to a magnesium cation, meaning that there is a
It has long been our supposition that the MPT unit in these
enzymes is not simply a spectator ligand, but is intimately
and actively involved in the mechanism of action of the
enzymes, and we have discussed how this could operate,
involving electronic interaction between the metal centre
and the pterin, initiated by cleavage of the C–O bond in the
5
nine-atom chain joining the two tricyclic ligands (Fig. 1).
Keywords: Aldehyde; Tungsten; Ligand; DMSO reductase family;
Pyrano[2,3-b]quinoxaline; Enedithiolate.
10
N–C–O unit. In order to gain experimental evidence for
this view through in vitro electrochemical studies on
*
Corresponding author Tel.: C44 (0)1612754633; fax: C44 (0)
612754939; e-mail addresses: john.joule@manchester.ac.uk;
dave.garner@nottingham.ac.uk
1
1
chemical analogues, we have developed flexible routes
1
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.095

F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
11011
for the synthesis of tricyclic pyrano[2,3-b]tetrahydro-
quinoxaline- and pyrano[2,3-g]tetrahydropteridine-1,3-
dithiol-2-one pro-ligands, which are amenable to modifi-
cation and variation, as might be required. We have
described the conversion of pro-ligands, such as 3, into
Our programme of organic synthetic chemistry culminated
in a synthesis of 2, MPT itself, in protected and masked
1
1l
form.
The development of the chemistry of metal
complexes of chemical relatives of MPT presents several
challenges; these include the binding of two ligands to a
metal centre, as occurs in the DMSO family of enzymes. As
a step towards the realisation of this latter goal, and with
specific reference to the structural relationship between the
two MPT ligands bound to tungsten in P. furiosus aldehyde
ferredeoxin oxidoreductase, we describe herein, the syn-
thesis of the bis-pro-ligand 5 and the release of the two
dithiolene moieties and their entrapment to form the double
5
neutral, easily purified, stable, diamagnetic (h -cyclopenta-
1
1f
dienyl)cobalt complexes such as 4 via hydrolysis of the
,3-dithiol-2-one unit and then trapping the released ene-
dithiolate group on a (h -C H )Co centre. The redox
1
5
5
5
5
properties of [(h -C H )Co(dithiolene)] complexes can be
5
5
investigated electrochemically and these studies have
provided valuable information concerning the electronic
communication between the metal centre and the ligand.
1
1n
5
(h -C H )Co complex 6 (Scheme 2).
5
5
The formation of such neutral cobalt complexes is also seen
as a necessary prelude to the synthesis of more labile,
paramagnetic Mo and W bis-enedithiolate salts (Scheme 1).
5
Using the published co-ordinates for the atoms around the
tungsten centre in ferredoxin aldehyde oxidoreductase, we
Scheme 1.
Scheme 2.

11012
F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
determined that a molecule with two pyrano-quinoxaline-
enedithiolate ligands, linked by a pentamethylene chain,
would be able to achieve an almost identical orientation
diol-diyne 10 and coupling it with 2 mol equiv of 2-
chloroquinoxaline to produce 11a. The starting diol-diyne
10 was made available by the reaction of pimeloyl chloride
7 with bis(trimethylsilyl)acetylene giving a diketone 8,
which was reduced with sodium borohydride, presumably
producing a mixture of meso and (G) forms of diol 9, from
which the trimethylsilyl groups were removed giving 10.
(
Fig. 2, hydrogens omitted for clarity), as that observed for
the two pyrano-pteridine-enedithiolate ligands in the
enzyme (Fig. 1, hydrogens omitted for clarity).
The radical-based process to generate the 1,3-dithiol-2-
thione units failed with 11a and so this was acetylated
giving 11b and from this the desired product 12 was
obtained, pure after careful chromatography, albeit in low
yield, by reaction with diisopropyl xanthogen disulfide
0
using 1,1 -azobis(cyclohexanecarbonitrile) (ACCN) as
initiator (Scheme 3). Unfortunately this strategy had to be
abandoned since conditions for the hydrolysis of the
acetates in 12 could not be identified, complex mixtures
being obtained, presumably reflecting competing attack on
the carbonyl of the five-membered heterocycle(s).
1
In the H NMR spectra of all the compounds with chiral
Figure 2. Chem3D drawing of proposed tungsten complex to be formed
from a synthetic ligand.
centres in this sequence, that is, 9–11b, except the final
product 12, all exhibit duplicate protons, accidentally
magnetically equivalent. However, in the H NMR
1
2. Synthesis
spectrum of 12, two one-hydrogen singlets at low field
correspond to the two quinoxaline a-protons in different
environments, perhaps signify the presence of a 1:1 mixture
of (G)- and meso-forms.
In our previous work, we utilised alkynes to synthesise 1,
1
1k
3
phenyl-1,3-dithiole-2-thione, and to prepare 1,3-dithiol-2-
-dithiole-2-thiones by reaction
with 4,5-dihydro-4-
1
1m
ones by a radical-based reaction
with diisopropyl
xanthogen disulfide. 1,3-Dithiole-2-thiones can be trivially
and efficiently transformed into the latter, which are the
actual pro-ligands, by reaction with mercuric acetate and
water. With this background, we began by synthesising
A brief examination was made of the possibility of arriving
at a diketone 13, which could then have been reduced to
diol-diyne 11a. The C-lithiated derivative of 2-ethynyl-
1
2
quinoxaline was treated with the double Weinreb amide,
Scheme 3. Reagents: (i) Me
BnMe NCl, MeCN, 0 8C (90%); (iv) 2-chloroquinoxaline, Pd(OAc)
vi) (i-PrOCSS) , ACCN, PhMe, reflux (62%); (vii) Me(MeO)NH, pyridine, rt/MeO(Me)NCO(CH
Qnx^H, LDA, THF, K78 8C.
3
SiC^CSiMe
3
, AlCl
3
, CS
2
, 0 8C/rt (ca. 100%); (ii) CeCl
, Ph P, CuI, Et N, MeCN, reflux (28%); (v) Ac
CON(Me)OMe (ca. 100%) then treatment of this with
3
$7H
2
O, MeOH, rt then NaBH
4
, 0 8C (59%); (iii) aqueous NaOH,
3
2
3
3
2
O, pyridine, 60 8C (ca. 100%);
(
2
2 5
)

F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
11013
2 2 2 2 5
Scheme 4. Reagents: (i) aqueous HCO H, CH Cl , rt (72%); (ii) 4,5-dihydro-4-phenyl-1,3-dithiole-2-thione, 40/80 8C (44%); (iii) BrMg(CH ) MgBr.
1
made easily from pimeloyl chloride, but this did not give
diketone 13.
3
cycle. This clearly speaks to the stabilisation of an anion at
that position, and this suggested a fourth strategy, namely
that lithiation of 19 could be followed by reaction with
either the double Weinreb amide derived from pimeloyl
chloride, or with heptane-1,7-dial.
Pursuing an alternative disconnection, reaction of the
1
4
aldehyde 15, obtained from acetal 14, with 4,5-dihydro-
-phenyl-1,3-dithiole-2-thione gave 16 in a moderate yield.
4
Attempted conversion of this into a diol 17a by reaction
with pentamethylenebis(magnesium bromide) failed under
several conditions of time and temperature, complex
product mixtures always being formed (Scheme 4).
A major practical difficulty emerged in our attempts to
1
1b,d,15
lithiate 19
improved cross-coupling
(prepared in this work by a much
16
of 2-iodoquinoxaline and
1
1g
4-tri-n-butylstannyl-1,3-dithiole-2-thione) in the form of
its very low solubility in the ethereal solvents normally
used for such processes. Since alkyl groups on the
benzene ring of the target pyrano-quinoxaline-ene-1,2-
dithiolates would be expected to influence the planned
electrochemical experiments only marginally, the dimethyl-
analogue 23 was synthesized and indeed proved to be much
more soluble, and amenable to lithiation in THF in the
usual way.
Yet a third alternative disconnection led us to the ketone
1
1
1l
8
in which it seemed possible that 2 equiv of an enolate,
formed by deprotonation at the methyl group, might react
with 1,3-diiodopropane to give diketone 17b. It was
disappointing to find that, using a range of bases, the only
transformation we were able to achieve, in yields of
4
(
0–70%, was deacetylation of 18, that is, formation of 19
Scheme 5). We assume that this must involve nucleophilic
addition to the carbonyl group and then C–C cleavage
leaving, formally, an anion on the five-membered hetero-
Reaction of 4,5-dimethyl-1,2-phenylenediamine with ethyl
glyoxylate gave 6,7-dimethylquinoxalin-2-one 20, which
Scheme 5.
2 3 2 2
Scheme 6. Reagents: (i) EtO CCHO, PhMe, EtOH, reflux (68%); (ii) POCl , reflux (96%); (iii) HI, NaI, H O, Me CO, 65 8C (62%); (iv) 4-(tri-n-butylstannyl)-
1,3-dithiole-2-thione 22, CuMeSal, THF, reflux (73%).

11014
F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
was converted via the 2-chloride 21a into 2-iodo-6,7-
dimethylquinoxaline 21b. Coupling the iodide with 4-(tri-n-
butylstannyl)-1,3-dithiole-2-thione 22 using copper(I)
3-methylsalicylate (CuMeSal) produced the quinoxa-
linyl-dithiole 23 in 73% yield (Scheme 6).
the two relevant hydrogens. At this stage, although we are
sure that the final products 5a and 5b are homogeneous with
regard to the relative stereochemistry around each indi-
vidual pyran ring (all cis), we cannot be sure whether these
bis-pro-ligands have the (desired) relative stereochemistry
shown in 5, that is, that they are derived from the (G)-form
of diols 24, or the undesired stereochemistry, which would
result from the meso-forms of diols 24, or indeed a mixture
of these. Certainly, the products 25 and 5 gave clean NMR
spectra and were homogeneous on chromatographic
examination. We take note that six one-hydrogen singlet
1
7
Heptane-1,7-dial was prepared by oxidation of heptane-1,7-
diol with the Dess-Martin periodinane and, on reaction with
lithiated 23, gave the diol 24a in 68% yield, conversion to
the 1,3-dithiol-2-one 24b being efficient and unexceptional.
Closure of the pyran ring followed our earlier developed
protocol involving reaction with a chloroformate and
intramolecular trapping of the resulting non-isolated
quinoxalinium salt by the alcohol giving 25a and 25b
1
H NMR signals were observed for the quinoxaline ring
protons in both 24a and 24b, and this would be consistent
1
with a 1:1 mixture of (G)- and meso-forms. The H NMR
using FmocCl and ClCO Bn, respectively. Reduction of the
2
spectra of the compounds, which followed the diols 24a and
24b in the sequence were too complex for a comparable
analysis (Scheme 7).
remaining imine using Na(CN)BH in the presence of acetic
3
1
1f,j-l
acid produced 5a and 5b. Our earlier experiences
with
these pyran-forming ring closures showed that the cis
stereoisomer is always the predominant product, and that
the subsequent imine reduction is totally stereoselective,
giving rise to pyrano-quinoxalines in which, at the three
chiral centres, the hydrogens are all on the same side. The
cis orientation in the ring closure forming 25a was
confirmed by the observation of an NOE effect between
Complications arose on attempted transformation of pro-
ligand 5a into a tetrathiolate by basic hydrolysis, probably
involving removal or partial removal of the Fmoc group(s).
However, hydrolysis of 5b with CsOH and addition to the
5
resulting solution of (h -C H )Co(CO)I ] led to the target
2
5
5
double cobalt complex 6.
Scheme 7. Reagents: (i) n-BuLi, K78 8C, OHC(CH
0 8C (42%); (iv) ClCO Bn, CH Cl , rt (22%); (v) Na(CN)BH
Co(cp)(CO)I (36%).
2
)
5
CHO, THF (68%); (ii) Hg(OAc)
2
, AcOH, Me
2
CO, rt (70%); (iii) FmocCl, NaHCO
3
, H
2
O, dioxane,
Cl , rt then
4
2
2
2
, MeOH, CH Cl , rt 5a, (70%); 5b, (95%); (vi) CsOH$H
3 2
2
2
O, MeOH, CH
2
2
2

F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
11015
1
1f,j-l
Summarising, we have shown that our earlier methods
of the residue over silica, eluting with EtOAc/hexane 1:4,
gave diol 10 (1.00 g, 90%) as a colourless oil; y
for the synthesis of pyrano-quinoxaline-enedithiolate
ligands can be used to prepare bis-pro-ligands, 5, from
which bis(ene-dithiolates) can be liberated and trapped. This
pro-ligand has the potential to generate complexes of
molybdenum and tungsten bound to two pyrano-quinoxa-
line-ene-1,2-dithiolate ligands, that is, analogous to the
catalytic centres of the DMSO reductase family of enzymes.
(film)/
max
K1
cm
3386, 3292, 2938, 2861, 2114, 1725, 1583, 1461,
1374, 1251, 1093, 1047, 1021; H NMR (300 MHz, CDCl )
1
3
d 4.39 (2H, t, JZ6.6 Hz, 2!CHOH), 2.50 (2H, s, 2!
C^CH), 1.95 (2H, br s, 2!OH), 1.79–1.71 (4H, m), 1.56–
1.40 (6H, m); C NMR (75 MHz, CDCl ) d 85.3, 73.2,
1
3
3
C
4
62.4, 37.7, 29.0, 25.1; m/z (CI) 198 (MCNH , 100%).
3
.1.4. 1,11-Bis(quinoxalin-2-yl)undeca-1,10-diyne-3,9-
3
. Experimental
diol 11a and 3,9-bis(acetoxy)-1,11-bis(quinoxalin-2-
yl)undeca-1,10-diyne 11b. To a degassed solution of
2-chloroquinoxaline (1.86 g, 11 mmol), diol 10 (0.85 g,
3
3
.1. General
5
Pd(OAc) (0.29 g, 1.25 mmol), Ph P (0.37 g, 1.42 mmol)
mmol), Et N (11 ml) in MeCN (30 ml) was added
3
.1.1. 1,11-Bis(trimethylsilyl)undeca-1,10-diyne-3,9-
2
3
dione 8. To a suspension of AlCl (4.50 g, 34 mmol) in
3
CS (8.5 ml) at 0 8C were added dropwise pimeloyl chloride
2
and CuI (0.30 g, 1.62 mmol) and the mixture heated at
reflux for 4 h when TLC showed that all the diol had been
consumed. The mixture was evaporated to dryness and
partial purification achieved by chromatography over silica,
eluting with EtOAc/hexane 3:7, yielding the diol 11a as a
dark brown thick oil (0.68 g), which was characterized by
acetylation.
(
(
2.80 ml, 17 mmol) and then bis(trimethylsilyl)acetylene
7.06 ml, 34 mmol). The mixture was stirred at 0 8C for a
further 30 min then allowed to warm to rt. An aqueous
solution of HCl (5%, 12 ml) was added slowly, the layers
separated, the aqueous layer re-extracted with Et O (3!
2
3
0 ml) and the combined organic extracts washed with
aqueous NaHCO (5%), H O, then dried (MgSO ), filtered
A solution of the diol 11a (0.68 g, 1.6 mmol) in Ac O–
2
3
2
4
and evaporated. Purification by chromatography over silica
eluting with EtOAc/hexane 1:9) gave the dione 8 as a
pyridine (1/1, 4.0 ml) was heated at 60 8C overnight. The
cooled reaction mixture was evaporated and the residue
purified by chromatography over silica, using EtOAc/
hexane 1:4, to give the diacetate 11b in essentially
mustard-coloured oil, in essentially quantitative yield; y
(
max
K1
film)/cm 2960, 2902, 2864, 2150, 1678, 1407, 1253,
104, 1058, 847, 762, 704; H NMR (300 MHz, CDCl ) d
1
1
2
7
2
4
quantitative yield, as a mustard-coloured oil; y
(film)/
max
3
K1
.52 (4H, t, JZ7.3 Hz, 2!CH CO), 1.69 (4H, quintet, JZ
cm
2935, 2861, 2236, 1742, 1541, 1486, 1369, 1229,
1130, 1021, 966, 920, 765; H NMR (300 MHz, CDCl ) d
2
1
.5 Hz, 2!CH CH CO), 1.42–1.32 (2H, m), 0.26 (18H, s,
2
2
3
1
!Si(CH ) ); C NMR (75 MHz, CDCl ) d 102.2, 98.0,
3
8.89 (2H, s, 2!Qnx-3-H), 8.10–8.05 (4H, ArH), 7.81–7.75
(4H, ArH), 5.71 (2H, t, JZ6.6 Hz, 2!CHOAc), 2.16 (6H, s,
3
3
3
C
4
C
5.2, 28.4, 23.8, K0.5; m/z (CI) 338 (MCNH , 38%), 321
C
13
(MH , 38), 303 (100); found, HRMS, M 320.1617.
C H O Si requires M 320.1622.
2!CH CO), 2.00–1.95 (4H, m), 1.65–1.45 (6H, m);
C
NMR (75 MHz, CDCl ) d 170.2, 147.4, 142.2, 141.4, 138.9,
3
1
7
28
2
2
3
1
31.0, 130.9, 129.5, 91.2, 83.0, 64.1, 34.6, 28.9, 25.2, 21.2;
C
C
3
9
.1.2. 1,11-Bis(trimethylsilyl)undeca-1,10-diyne-3,9-diol
. To the dione 8 (3.41 g, 11 mmol) dissolved in MeOH
m/z (CI) 521 ((MH , 50%), 401 (20); found, HRMS, M
520.2094. C31 requires M 520.2105.
H N O
28 4 4
(
the mixture stirred at rt for 15 min. The solution was cooled
to 0 8C then NaBH (3.00 g, 80 mml) added portionwise.
4
100 ml) was added CeCl $7H O (12.00 g, 32 mmol) and
3 2
3.1.5. 1,7-Bis(acetoxy)-1,7-bis(4-(quinoxalin-2-yl)-1,3-
dithiol-2-on-5-yl)heptane 12. The diacetate 11b (0.12 g,
0.23 mmol) was dissolved in PhMe (2 ml) and the solution
After completion of the reduction (TLC) aqueous satd
NH Cl was added then the solution brought to pH 1.0 by the
1
8
degassed for 15 min. Diisopropyl xanthogen disulfide
4
0
addition of cold aqueous HCl (0.5 M). Product was
extracted into EtOAc, the combined extracts dried
(88 mg, 0.33 mmol) and 1,1 -azobis(cyclohexanecarbo-
nitrile) (ACCN) (88 mg, 0.36 mmol) were added and the
reaction mixture heated at reflux for 2 h. Further portions of
the xanthogen (!3, 88 mg) and ACCN (!3, 88 mg) were
added at two-hourly intervals. After a total of 10 h relux, the
cooled mixture was evaporated to dryness and the residue
purified by chromatography over silica using EtOAc/hexane
(
MgSO ), filtered and evaporated and the residue purified
4
by chromatography over silica (EtOAc/hexane 1:4) to give
the diol 9 (2.05 g, 59%) as a pale yellow oil; y (film)/
max
K1
cm
1
3351, 2942, 2861, 2172, 1409, 1332, 1250, 1108,
019, 843, 760, 699; H NMR (300 MHz, CDCl ) d 4.40
1
3
(
1
2H, t, JZ6.5 Hz, 2!CHOH), 1.77–1.70 (5H, m), 1.55–
1:4, to give the bis-1,3-dithiole 12 (0.10 g, 62%) as a
mustard-coloured oil; H NMR (300 MHz, CDCl ) d 9.04
1
3
.42 (5H, m), 0.20 (18H, s, 2!Si(CH ) ); C NMR
1
3
3
3
(
m/z (CI) 342 (MCNH , 12%), 325 (MH , 10), 90 (90), 73
75 MHz, CDCl ) d 107.1, 89.7, 63.1, 37.8, 29.1, 25.3, 0.15;
(1H, s, Qnx-3-H), 8.97 (1H, s, Qnx-3-H), 8.16–8.03 (4H,
ArH), 7.86–7.74 (4H, ArH), 6.50–6.42 (2H, m, CHOAc),
2.09 (6H, s, 2!CH CO), 2.07–1.20 (10H, m).
3
C
4
C
C
100); found, HRMS, M 324.1929. C H O Si requires
(
M 324.1935.
1
7
32
2
2
3
3.1.6. 3-(Quinoxalin-2-yl)propynal 15. To a solution of
2-(3,3-diethoxypropyn-1-yl)quinoxaline 14 (450 mg,
1
2
3
.1.3. Undeca-1,10-diyne-3,9-diol 10. A solution of NaOH
12 M, 5.23 ml) was added dropwise to a solution of diol 9
(
(
1.76 mmol) in CH Cl (10 ml), was added formic acid
2
2
2.00 g, 6 mmol) and BnMe NCl (65 mg, 0.3 mmol) in
3
(32 ml) and the mixture was stirred at rt for 5 h. After
hydrolysis with water (30 ml) and seven extractions with
CH Cl , the combined organic extracts were washed with a
MeCN (10 ml), stirred at 0 8C over 10 min. The reaction
mixture was diluted with Et O, washed with H O then brine,
2
2
2
2
dried (MgSO ), filtered and concentrated. Chromatography
4
solution of NaHCO3 (0.3 N), dried (MgSO ) and
4

11016
F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
evaporated. The aldehyde 15 was obtained as a yellow solid
231 mg, 72%) sufficiently pure for further reaction. The
product was kept under nitrogen at K30 8C to prevent
NMR (300 MHz, DMSO-d ) d 9.56 (1H, s), 8.84 (1H, s),
6
(
8.14–8.09 (1H, m), 8.07–8.02 (1H, m), 7.92–7.86 (2H, m);
C (75 MHz, DMSO-d ) d 213.4, 144.0, 143.8, 142.3,
6
1
3
1
degradation; H NMR (300 MHz, CDCl ) d 9.52 (1H, s,
3
140.9, 140.5, 132.7, 131.4, 130.9, 129.0, 128.7; m/z (CI) 263
C
C
CHO), 9.00 (1H, s, Qnx-3-H), 8.15–8.10 (2H, m), 7.87–7.84
(
(MH , 100%); found, HRMS, M 261.9696. C H N S
11 6 2 3
1
3
2H, m); C NMR (75 MHz, CDCl ) d 175.9, 147.1, 142.3,
requires M 261.9688.
3
1
1
41.8, 136.4, 132.1, 131.3, 129.6, 129.4, 89.2, 88.1; m/z (CI)
83 (MH , 100%); found, HRMS, MH 183.0549.
C
C
3.1.10. 6,7-Dimethylquinoxalin-2-one 20. To a solution of
4,5-dimethyl-o-phenylenediamine (5 g, 36.7 mol) in abso-
lute ethanol (70 ml), ethyl glyoxylate (50% in toluene)
(11.2 ml, 1.5 equiv) was added dropwise with stirring. An
orange precipitate was formed and the mixture became hot.
After refluxing for 2 h, the solution was cooled to rt and
stirred for 1 h after which the solid product was filtered off,
rinsed with absolute ethanol and dried in vacuo. The
C H N O requires MCH 183.0553.
11 7 2
3
.1.7. 4-(Quinoxalin-2-yl)-1,3-dithiole-2-thion-5-ylcarb-
oxaldehyde 16. A solution of aldehyde 15 (218 mg,
.20 mmol) and 4,5-dihydro-4-phenyl-1,3-dithiole-2-thione
1,27 g, 5 equiv) in CH Cl (5 ml) was concentrated on a
1
(
2
2
rotary evaporator to produce a homogenous solid. The flask
was fitted with a condenser and then heated to 40 8C under
nitrogen for one night and then to 80 8C for 4 h. Flash
chromatography of the cooled reaction mixture (silica,
0–1% MeOH in CH Cl ) provided the quinoxalinyl-1,3-
dithiole-aldehyde 16 (153 mg, 44%) as a yellow solid. The
quinoxalinone 20 (5.01 g, 79%) was obtained pure as white
powder, mp 310–312 8C; H NMR (300 MHz, DMSO-d ) d
1
6
12.30 (1H, s), 8.06 (1H, s), 7.55 (1H, s), 7.06 (1H, s), 2.30
(3H, s), 2.28 (3H, s); C NMR (75 MHz, DMSO-d ) d
1
3
2
2
6
154.9, 150.2, 140.3, 131.9, 130.5, 129.7, 128.5, 115.6, 19.7,
18.8; m/z (CI) 175 (MH , 100%); found, HRMS, MH
C
C
product was kept under nitrogen at K30 8C to prevent
degradation; H NMR (500 MHz, CDCl ) d 10.17 (1H, s),
1
175.0866. C H N O requires MCH 175.0866.
10 11 2
3
8
7
.99 (1H, s), 8.20–8.18 (1H, m), 8.15–8.13 (1H, m), 7.93–
.90 (2H, m); m/z (CI) 291 (MH , 45%), 187 (100%).
C
3.1.11. 2-Chloro-6,7-dimethylquinoxaline 21a. 6,7-
Dimethylquinoxalin-2-one 20 (2.0 g, 11.5 mmol) was
heated under reflux in POCl (9 ml, 8 equiv) for 2 h with
protection from moisture. After cooling to rt, the mixture
was evaporated to dryness under vacuum. Some ice and
water (5 ml) were added to the black oil and the mixture
obtained was then poured into a large beaker and was
3.1.8. 4-Tri-n-butylstannyl-1,3-dithiole-2-thione 22. To a
solution of 1,3-dithiole-2-thione (300 mg, 2.23 mmol) in
3
dry THF (4 ml) under nitrogen cooled at K78 8C, LDA
(
1.8 M in hexane/THF/ethylbenzene, 1.5 ml, 1.2 equiv) was
added dropwise with efficient stirring. After 1 h at K78 8C,
tri-n-butylstannyl chloride (730 ml, 1.2 equiv) was added
with stirring and the resultant solution allowed to warm to rt
over 2 h. The reaction was quenched by the addition of satd
neutralized slowly with solid NaHCO . The aqueous layer
3
was filtered through Celite and then extracted with EtOAc
(3!10 ml). After drying (MgSO ), the solution was
4
aqueous NH Cl (10 ml), the layers separated and the
4
evaporated in vacuo to leave the 2-chloroquinoxaline 21a
(2.06 g, 94%) as a beige solid, essentially pure, mp
aqueous phase extracted with hexane (3!20 m). The
combined organic extracts were washed with brine (15 m),
dried and the solvent evaporated under vacuum leaving a
brown oil, which was purified by flash chromatography
K1
(film)/cm 2978, 2945, 1118, 1091, 960,
98–99 8C; y
753, 420; H NMR (300 MHz, CDCl ) d 8.66 (1H, s), 7.83
max
1
3
1
3
(1H, s), 7.74 (1H, s), 2.78 (6H, s); C NMR (75 MHz,
(silica, EtOAc/petroleum ether 5:95) to give the stannane 22
as a brown oil (690 mg, 73%). The product was kept under
CDCl ) d 146.4, 143.7, 142.0, 140.9, 140.8, 139.8, 128.2,
3
C
127.5, 20.4, 20.3; m/z (CI) 193/195 (MH , 100/53%);
1
nitrogen at K30 8C to minimise degradation; H NMR
C
found, HRMS, MH 193.0529. C H ClN requires MCH
193.0527.
1
0
10
2
3
(
300 MHz, CDCl ) d 6.99 (1H, d, J(Sn–H)Z13 Hz), 1.68–
3
1
0
1
2
4
.49 (6H, m), 1.38–1.26 (8H, m), 1.17–1.11 (4H, m), 0.93–
1
3
.87 (9H, m); C NMR (75 MHz, CDCl ) d 218.9, 147.8,
3
3.1.12. 2-Iodo-6,7-dimethylquinoxaline 21b. A mixture of
Me CO and H O (22 ml and 1 ml) was saturated at the
3
33.3, 133.2, 28.7 ( J
2
Z11 Hz), 27.1 ( J(Sn–C)Z50,
4 Hz), 17.5, 13.6, 11.4 ( J(Sn–C)Z176, 168 Hz); m/z (CI)
25 (M
(
Sn–C)
1
2
2
boiling point with NaI (w9 g). To the resulting hot solution,
2-chloro-6,7-dimethylquinoxaline 21a (1.0 g, 5 mmol) was
added with stirring. Then a solution of HI (57%, 0.5 ml) in
water (2 ml) was added and the mixture stirred at 65 8C for
2 h. The precipitate was filtered off and washed with
acetone. The filtrate was dried over anhydrous K CO /
Sn120 C
H , 100%).
3
.1.9. 4-(Quinoxalin-2-yl)-1,3-dithiole-2-thione 19. A
1
4
mixture 2-iodoquinoxaline (312 mg, 1.25 mmol), 4-tri-n-
butylstannyl-1,3-dithiole-2-thione (1.06 g, 2 equiv) and
copper(I) 3-methylsalicylate (539 mg, 2 equiv) under
nitrogen in dry THF (6 ml) was heated at reflux for 4 h
then cooled to rt. In order to break up the copper complexes,
2
3
MgSO then evaporated, the resultant residue was triturated
4
in Et O and the organic layer was filtered. The filtrate was
2
washed with a solution of Na S O (0.2 g in 35 ml of H O)
2
2
5
2
a solution of KCN in aqueous NH OH (35% v/v) (4 g/
4
and dried (MgSO ). Recrystallisation from pentane
4
5
for 30 min. CH Cl (50 ml) was added and the yellow
0 ml) was added and the resultant solution was stirred at rt
(w100 ml) provided the iodide 21b as a pale yellow solid
K1
(0.91 g, 62%), mp 128–130 8C; n (film)/cm
2988,
2935, 1517, 1067, 938, 424; H NMR (300 MHz, CDCl ) d
2
2
max
1
precipitate of the quinoxalinyl-1,3-dithiole 19, which
formed was washed twice with CH Cl and dried under
3
8.87 (1H, s), 7.79 (1H, s), 7.76 (1H, s), 2.47 (3H, s), 2.46
(3H, s); C NMR (75 MHz, CDCl ) d 151.3, 144.1, 141.9,
2
2
1
3
vacuum (236 mg, 72%). A further quantity (50 mg) was
obtained by extraction of the aqueous phase with CH Cl
but required purification by chromatography (silica, EtOAc/
3
141.5, 140.2, 128.7, 128.1, 117.0, 20.73, 20.72; m/z (CI)
285/286 (MH , 100/12%), 159/160 (82/7); found, HRMS,
2
2
C
1
C
MH 284.9892. C H IN requires MCH 284.9883.
petroleum ether 1:9 with 2% of Et N), mp 250–252 8C; H
3
10 10
2

F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
11017
3
.1.13. 4-(6,7-Dimethylquinoxalin-2-yl)-1,3-dithiole-2-
thione 23. A mixture 2-iodo-6,7-dimethylquinoxaline 21b
1.1 g, 3.87 mmol), 4-tri-n-butylstannyl-1,3-dithiole-2-
thione 22 (3.29 g, 2 equiv) and copper(I) 3-methylsalicylate
1.66 g, 2 equiv) under nitrogen in dry THF (22 m) was
(C), 140.7 (C), 140.7 (C), 139.9 (2CH), 135.4 (C), 135.4
(C), 128.3 (CH), 128.3 (CH), 127.8 (2CH), 68.4 (2CH), 36.5
(CH ), 28.8 (CH ), 28.7 (CH ), 25.9 (CH ), 25.8 (CH ),
20.5 (4CH ); m/z (ESK) 708 (M , 70%), 744 (MHCCl ,
3
100%).
(
2
2
2
2
2
K
K
(
heated at reflux for 4 h. After cooling to rt, in order to break
the copper complexes, a solution of KCN in aqueous
NH OH (35% v/v) (20 g/250 ml) was added together with
3
.1.16. 1,7-Bis(4-(6,7-dimethylquinoxalin-2-yl)-1,3-
dithiol-2-on-5-yl)heptane-1,7-diol 24b. To the diol 24a
4
CH Cl (250 ml) and the resultant solution was stirred at rt
2
2
(
(
(
166 mg, 0.234 mmol) dissolved/suspended in Me CO
2
8 ml) and acetic acid (1.9 ml) was added Hg(OAc)2
300 mg, 4 equiv) and the solution was stirred for 2 days
for 30 min. Then, the layers were separated and the aqueous
layer was extracted with CH Cl (3!100 ml). The
2
2
combined organic extracts were dried (MgSO ) and
4
at rt and then filtered through Celite and the filter cake
washed with a portion of EtOAc (8 ml). Satd aqueous
NaHCO3 was added to the filtrate, followed by solid
evaporated. Flash chromatography (silica, EtOAc/petro-
leum ether 1:9–6:4 using 2% of Et N) provided the
3
quinoxalinyl-dithiole 23 (815 mg, 73%) as a yellow solid,
mp 229–231 8C; H NMR (500 MHz, CDCl ) d 9.02 (1H, s,
Qnx-3-H), 7.86 (1H, s, ArH), 7.83 (1H, s, ArH), 7.78 (1H, s,
1
NaHCO until a neutral pH was attained. The organic layer
3
3
was separated and the aqueous layer was re-extracted with
EtOAc (2!10 ml), the combined organic extracts were
washed with brine (10 ml), dried and evaporated to leave the
bis(1,3-dithiol-2-one) 24b as an orange solid (110 mg,
70%); H NMR (500 MHz, CDCl ) d 8.77 (1H, s), 8.75
1
ArCH3); C NMR (125 MHz, CDCl ) d 212.6, 145.2,
,3-dithiole-thione-5-H), 2.53 (3H, s, ArCH ), 2.52 (3H, s,
3
1
3
3
1
1
42.9, 142.4, 142.1, 141.8, 140.6, 139.6, 128.3, 128.2,
26.3, 20.5, 20.4; m/z (CI) 291 (MH , 100%); found,
1
C
3
C
(1H, s), 7.85 (1H, s), 7.84 (1H, s), 7.76 (1H, s), 7.75 (1H, s),
.91–4.87 (2H, m), 2.51 (6H, s), 2.49 (6H, s), 1.86–1.82
2H, m), 1.77–1.73 (2H, m),1.57–1.51 (2H, m, OH), 1.42–
HRMS, M 290.0003. C H N S requires M 290.0001.
3 10 2 3
1
4
(
3
.1.14. Heptane-1,7-dial. To a suspension of the Dess-
13
1.30 (6H, m); C NMR (125 MHz, CDCl ) d 189.3 (2CO),
3
Martin periodinane (4 g, 2.35 equiv) in freshly distilled
CH Cl (80 ml) under nitrogen was added a solution a 1,7-
heptandiol (529 mg, 4 mmol) in freshly distilled CH Cl
1
44.0 (2C), 143.1 (2CH), 143.1 (2C), 142.5 (2C), 142.2
2
2
(2C), 140.2 (2C), 139.8 (2C), 128.0 (2CH), 127.8 (2CH),
2
2
1
25.4 (2C), 68.4 (2CH), 36.8 (2CH ), 28.8 (CH ), 25.9
2
2
(
for 40 min then Et O (200 ml) was added. The reaction
10 ml) within 10 min. The reaction mixture was stirred at rt
K
2CH ), 20.4 (2CH ), 20.4 (2CH ); m/z (ESK) 675 (M ,
(
2 3 3
K
0%), 711 (MCCl , 100%).
2
7
mixture was washed with NaOH (1 M, 2!50 ml) then with
satd aqueous NH Cl (50 ml). The organic layers were dried
4
(
MgSO ) and evaporated. Flash chromatography (silica,
4
3.1.17. 1,5-Bis(6(5aH)-(9H-fluoren-9-ylmethyloxycarbo-
nyl)-8,9-dimethyl-2-oxo-4H-1,3-dithiolo[4,5]pyrano[2,3-
b]quinoxalin-4-yl)pentane 25a. A stirred solution of diol
24b (130 mg, 0.192 mmol), 9H-fluoren-9-ylmethyl chloro-
formate (5.7 g, 115 equiv), solid NaHCO3 (1.85 g,
EtOAc/pentane 3:7) provided the dial (320 mg, 62%) as a
colourless oil. The dialdehyde was kept under nitrogen at
K30 8C to minimise degradation; H NMR (250 MHz,
CDCl ) d 9.76 (2H, s, 2!CHO), 2.49–2.40 (4H, m), 1.69–
3
1
1
C
.57 (4H, m), 1.40–1.34 (2H, m); m/z (CI) 146 (MNH ,
4
102 equiv) and 1,4-dioxane–H O (10 ml, 19/1) was heated
2
1
00%).
at 40 8C for 24 h. The reaction mixture was filtered with
suction and the filtrate evaporated under vacuum. A small
amount of hexane was added and the precipitate was
purified by extraction using a Soxhlet apparatus with hexane
for 2 days. The bis-pyrano-quinoxaline-imine 25a was
obtained as a yellow solid (90 mg, 42%). A NOE was
3
.1.15. 1,7-Bis(4-(6,7-dimethylquinoxalin-2-yl)-1,3-
dithiole-2-thion-5-yl)heptane-1,7-diol 24a. To a solution
of 4-(6,7-dimethylquinoxalin-2-yl)-1,3-dithiole-2-thione 23
(
275 mg, 0.948 mmol, 2.5 equiv) in dry THF (60 ml) cooled
at K78 8C under nitrogen, n-BuLi (1.57 M in hexane,
40 ml, 2.6 equiv) was added dropwise with efficient
stirring. After 45 min at K78 8C, heptane-1,7-dial (50 mg,
.385 mmol, 1.0 equiv) was added and the resultant solution
was stirred at K78 8C for 1 h and allowed to warm at rt over
h. The reaction was quenched by addition of satd aqueous
observed between NCHO and CH CHO confirming the cis
2
K1
6
orientation; n
482; H NMR (500 MHz, CDCl ) d 7.75–7.73 (3H, m), 7.70
(film)/cm 2924, 1733, 1685, 1257, 742,
max
1
3
0
(3H, m), 7.59–7.57 (2H, m), 7.53 (2H, d, JZ7.5 Hz), 7.40–
7.33 (4H, m), 7.32–7.29 (2H, m), 7.26–7.23 (2H, m), 7.15
1
(2H, s), 5.12–5.09 (2H, dd, JZ5, 11 Hz, CHCH OCON),
2
NH Cl (30 ml), the layers separated and the aqueous phase
4
5.07 (2H, br s, NCHO), 4.78–4.75 (2H, dd, JZ5, 11 Hz,
CHCH OCON), 4.26 (2H, m, CHCH OCON), 3.98–3.91
(2H, m, H-4), 2.21–2.20 (6H, m), 2.18 (6H, br s), 1.48–1.29
extracted with EtOAc (3!50 ml). The combined organic
phases were washed with brine (15 ml), dried and the
solvent evaporated under vacuum giving a brown solid,
which was purified by flash chromatography (alumina,
neutral, EtOAc/hexane: 1:9) to give the bis(1,3-dithiol-2-
2
2
1
3
(4H, m), 1.07 (6H, br s); C NMR (125 MHz, CDCl ) d
3
189.6 (2CO), 154.1 (2C), 149.2 (2C), 143.7 (2C), 142.9
(CH), 141.4 (2C), 141.3 (2C), 140.1 (2C), 138.0 (2C), 132.8
(2C), 131.1 (2C), 129.6 (2CH), 128.0 (2CH), 127.8 (2CH),
127.5 (2CH), 127.4 (2CH), 125.6 (2C), 124.5 (2CH), 124.4
(2CH), 121.4 (2CH), 120.0 (2CH), 119.9 (2CH), 77.1
(2CH), 76.2 (CH), 76.2 (CH), 67.1 (CH ), 66.99 (CH ), 47.4
1
one 24a as a yellow solid (185 mg, 68%); H NMR
(
300 MHz, CDCl ) d 8.70 (1H, s, Qnx-3-H), 8.64 (1H, s,
3
Qnx-3-H), 7.84 (1H, s, ArH), 7.82 (1H, s, ArH), 7.74 (1H, s,
ArH), 7.72 (1H, s, ArH), 5.00 (2H, br s, 2!OH), 4.99–4.92
2
2
(
2H, m), 2.51 (6H, s), 2.50 (6H, s), 1.90–1.75 (4H, m), 1.65–
(CH), 47.3 (CH), 35.5 (2CH ), 28.8 (CH ), 23.2 (2CH ),
2 2 2
1
.51 (2H, m),1.46–1.30 (4H, m); C NMR (75 MHz,
3
K
1
CDCl ) d 209.0 (2CS), 153.2 (C), 152.9 (C), 142.9 (C),
1
20.1 (2CH ), 18.8 (2CH ); m/z (ESK) 1155 (MCCl ,
3 3
C C
100%); m/z (ESC) 1121 (MH , 75%), 1143 (MCNa ,
100%).
3
42.9 (2C), 142.9 (C), 142.7 (C), 142.7 (C), 142.7 (C), 142.7

11018
F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
3
.1.18. 1,5-Bis(6(5aH)-(9H-fluoren-9-ylmethyloxycarbo-
(2H, br s, ArH), 7.39–7.34 (7H, m, ArH), 7.31–7.26 (2H, m,
ArH), 7.20–7.18 (2H, m, ArH), 7.12–1.09 (1H, m, ArH),
6.43 (2H, br s, 2!NH), 5.92 (2H, br s, 2!NCHO), 5.35–
5.20 (4H, br s, PhCH OCON), 4.66 (2H, br s, 2!CHCH ),
nyl)-11,11a-dihydro-8,9-dimethyl-2-oxo-4H-1,3-di-
thiolo[4,5]pyrano[2,3-b]quinoxalin-4-yl)pentane 5a. To a
stirred solution of the bis-pyrano-quinoxaline-imine 25a
2
2
(
90 mg, 0.08 mmol) in CH Cl (2 ml) and MeOH (2 ml) at
2
8C was added acetic acid (two drops) and after 5 min,
3.58 (2H, br s, 2!HNCH), 2.12–2.11 (12H, br s), 1.57 (4H,
br s), 1.22 (6H, br s); m/z (ESC) 971 (MCNa , 84%); m/z
2
C
0
NaB(CN)H (36 mg, 7 equiv) then the resulting mixture was
K
(ESK) 983 (MCCl , 100%); found, HRMS, MCNa
C
3
stirred for 24 h at rt. The mixture was diluted with CH Cl
2
971.2253. C H O N NaS requires M 971.2247.
4
2
49 48
8
4
(
NaHCO until a neutral pH was attained. Separation of the
5 ml), satd aqueous NaHCO was added followed by solid
3
3
3.1.21. The double cobalt complex 6. To a solution of
pyrano-tetrahydroquinoxaline 5b (12 mg, 0.013 mmol) in
CH Cl –MeOH (v/v, 2 ml) was added a solution of
aqueous layer and re-extraction with CH Cl (2!5 ml)
2
2
gave combined organic extracts, which were washed with
brine (10 ml), dried and evaporated to leave the pyrano-
tetrahydroquinoxaline 5a as a yellow oil (63 mg, 70%)
2
2
CsOH$H O (9 mg, 4.2 equiv) in MeOH (0.5 ml) and the
2
mixture was stirred for 20 min. Carbonyl(cyclopenta-
1
9
essentially pure. This compound proved to be very sensitive
to silica and alumina; H NMR (300 MHz, CDCl ) d 7.69–
dienyl)diiodocobalt (21 mg, 4 equiv) was then added
and the mixture was stirred for a further 15 min. The
reaction was quenched with water (5 ml) and extracted with
CH Cl (3!5 ml). After dried (MgSO ) and evaporated, the
1
3
7
.66 (4H, d, JZ7.5 Hz), 7.57 (2H, d, JZ7.2 Hz), 7.53 (2H,
d, JZ7.5 Hz), 7.48 (2H, br s), 7.41–7.32 (6H, m), 7.29–7.25
4H, m), 6.39 (2H, br s, NH), 5.07 (2H, br s, NCHO), 4.99–
.94 (2H, dd, JZ5, 11 Hz, CHCH OCON), 4.69–4.64 (2H,
2
2
4
(
4
crude was purified by flash chromatography (silica, 0–5%
MeOH in CH Cl ) to provide the double cobalt complex 6
2
2
2
1
(5.3 mg, 36%) as a night-blue solid; H NMR (500 MHz,
dd, JZ5, 11 Hz, CHCH OCON), 4.26–4.24 (2H, m,
2
CHCH OCON), 4.13–4.05 (2H, m, H-4), 3.47 (2H, br s,
H-11a), 2.11 (6H, br s), 2.09 (6H, br s), 1.49–1.38 (4H, m),
2
CDCl ) d 7.55 (2H, br s), 7.45–7.26 (12H, m), 7.12 (1H, s),
3
6
.28 (1H, s, NCHO), 6.25 (1H, s, NCHO), 5.69–5.66 (2H,
m, 2!NH), 5.34 (5H, s, cp), 5.33 (5H, s, cp), 5.29–5.23
2H, m, PhCH OCON), 5.16–5.13 (1H, d, JZ13 Hz,
C
.16–0.95 (6H, m); m/z (ESC) 1125 (MH , 100%), 1147
1
C
MCNa , 34%).
(
(
2
PhCH OCON), 5.14–5.12 (1H, d, JZ13 Hz, PhCH OCON),
2
2
3
.1.19. 1,5-Bis(6(5aH)-(phenylmethyloxycarbonyl)-8,9-
4.65–4.54 (2H, m, H-4), 4.45–4.37 (2H, m, H-11a), 2.08
(6H, br s), 2.04 (3H, s), 2.03 (3H, s), 1.66–1.51 (4H, m),
dimethyl-2-oxo-4H-1,3-dithiolo[4,5]pyrano[2,3-b]-
quinoxalin-4-yl)pentane 25b. To diol 24b (44 mg,
C
1.28–1.02 (6H, m); m/z (ESC) 1163 (MCNa , 100%); m/z
K
(ESK) 1140 (M , 74%).
0
.063 mmol) in CH Cl (1 ml) was added benzyl chloro-
2
2
formate (4 ml, excess) and the mixture was stirred for 24 h
at rt. The reaction mixture was diluted with hexane (100 ml)
and the resulting mixture was passed through a short column
of alumina, eluting with hexane to remove the excess
chloroformate. Elution of the column with 5–40% EtOAc in
hexane then 0–20% MeOH in CH Cl provided the bis-
Acknowledgements
We thank the BBSRC (R. K., F.-A. A. and C. C.-S.) for its
support of our work on the molybdoenzymes.
2
2
pyrano-quinoxaline-imine 25b as an orange oil (13 mg,
1
2%); H NMR (300 MHz, CDCl ) d 7.97 (1H, s, ArH),
.96 (1H, s, ArH), 7.38–7.20 (10H, m), 7.12 (1H, s, ArH),
.09 (1H, s, ArH), 6.00 (1H, s, NCHO), 5.96 (1H, s, NCHO),
2
7
7
5
3
.35 (2H, d, JZ12 Hz, PhCH OCON), 5.28–5.24 (1H, d,
References and notes
2
JZ12 Hz, PhCH OCON), 5.27–5.23 (1H, d, JZ12 Hz,
2
PhCH OCON), 4.87–4.83 (2H, q, JZ3.3, 3.9 Hz, H-4), 2.25
1. For recent work from this group and leading references see:
Nichols, J. D.; Rajagopalan, K. V. J. Biol. Chem. 2005, 280,
7817–7822. George, G. N.; Garrett, R. M.; Prince, R. C.;
Rajagopalan, K. V. Inorg. Chem. 2004, 43, 8456–8460.
Enemark, J. H.; Astashkin, A. V.; Raitsimring, A. M.; Feng,
C.; Wilson, H. L.; Rajagopalan, K. V. J. Inorg. Biochem. 2003,
96, 53.
2
(
1
3H, s), 2.23 (3H, s), 2.21 (6H, br s), 1.71–1.52 (4H, m),
C
.34–1.19 (6H, m); m/z (ESC) 967 (MCNa , 100%);
C
found, HRMS, MCNa 967.1940. C H O N NaS
4
4
9
44
8
4
requires M 967.1934.
3
1
.1.20. 1,5-Bis(6(5aH)-(phenylmethyloxycarbonyl)-11,
1a-dihydro-8,9-dimethyl-2-oxo-4H-1,3-dithiolo[4,5]-
2. Rom a˜ o, M. J.; Archer, M.; Moura, I.; Moura, J. J. G.; LeGall,
J.; Engh, E.; Schneider, M.; Hof, P.; Huber, R. Science 1995,
270, 1170–1176. Dobbek, H.; Huber, R. Met. Ions Biol. Syst.
2002, 39, 227–263.
pyrano[2,3-b]quinoxalin-4-yl)pentane 5b. To a stirred
solution of the bis-pyrano-quinoxaline-imine 25b (13 mg,
0.014 mmol) in CH Cl (2 ml) and MeOH (2 ml) at 0 8C
2 2
was added acetic acid (two drops) and after 5 min,
3. Schindelin, H.; Kisker, C.; Hilton, J.; Rajagopalan, K. V.;
Rees, D. C. Science 1996, 272, 1615–1621. Schneider, F.;
L o¨ we, J.; Huber, R.; Schindelin, H.; Kisker, C.; Kn a¨ blein, J.
J. Mol. Biol. 1996, 263, 53–69. Kisker, C.; Schindelin, H.;
Rees, D. C. Annu. Rev. Biochem. 1997, 66, 223–267.
4. Bertero, M. G.; Rothery, R. A.; Palak, M.; Hou, C.; Lim, D.;
Blasco, F.; Weiner, J. H.; Strynadka, N. C. J. Nat. Struct. Biol.
2003, 10, 681–687.
NaB(CN)H (30 mg, 7 equiv) then the resulting mixture
3
was stirred for 24 h at rt. The mixture was diluted with
CH Cl (5 ml), satd aqueous NaHCO was added followed
2
2
3
by solid NaHCO3 until a neutral pH was attained.
Separation of the aqueous layer and re-extraction with
CH Cl (2!5 ml) gave combined organic extracts, which
2
2
were washed with brine (10 ml), dried and evaporated to
leave the pyrano-tetrahydroquinoxaline 5b as a yellow oil
5. Chan, M. K.; Mukund, S.; Kletzin, A.; Adams, M. W. W.;
Rees, D. C. Science 1995, 267, 1463–1469.
1
12 mg, 95%) essentially pure. H (300 MHz, CDCl ) d 7.55
(
3

F.-A. Alphonse et al. / Tetrahedron 614 (2005) 11010–11019
11019
6
. Stewart, L. J.; Bailey, S.; Bennett, B.; Charnock, J. M.; Garner,
C. D.; McAlpine, A. S. J. Mol. Biol. 2000, 299, 593–600.
. McMaster, J.; Tunney, J. M.; Garner, C. D. Prog. Inorg. Chem.
Docrat, A.; Joule, J. A.; Wilson, C. R.; Garner, C. D. J. Chem.
Soc., Dalton Trans. 1998, 3647–3656. (j) Bradshaw, B.;
Collison, D.; Garner, C. D.; Joule, J. A. Chem. Commun. 2001,
123–124. (k) Bradshaw, B.; Dinsmore, A.; Collison, D.;
Garner, C. D.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 2001,
3232–3238. (l) Bradshaw, B.; Dinsmore, A.; Collison, D.;
Garner, C. D.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 2001,
3239–3244. (m) Bradshaw, B.; Collison, D.; Garner, C. D.;
Joule, J. A. Org. Biol. Chem. 2003, 1, 129–133. (n) Bhachu, T.
S.; Garner, C. D.; Joule, J. A., to be published.
7
2
. Hille, R. Chem. Rev. 1996, 96, 2757–2816.
003, 52, 539–583.
8
9
. Ellis, P. J.; Conrads, T.; Hille, R.; Kuhn, P. Structure 2001, 9,
1
25–132.
1
0. Armstrong, E. M.; Austerberry, M. S.; Birks, J. H.; Garner,
C. D.; Helliwell, M.; Joule, J. A.; Russell, J. R. J. Inorg.
Biochem. 1991, 43, 588. Armstrong, E. M.; Austerberry, M. S.;
Birks, J. H.; Beddoes, R. L.; Helliwell, M.; Joule, J. A.; Garner,
C. D. Heterocycles 1993, 35, 563–568. Greatbanks, S. P.;
Hillier, I. H.; Garner, C. D.; Joule, J. A. J. Chem. Soc., Perkin
Trans. 2 1997, 1529–1534. McNamara, J. P.; Joule, J. A.;
Hillier, I. H.; Garner, C. D. Chem. Commun. 2005, 177–179.
1. (a) Rowe, D. J.; Garner, C. D.; Joule, J. A. J. Chem. Soc.,
Perkin Trans. 1 1985, 1907–1910. (b) Larsen, L.; Garner,
C. D.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1989,
12. Armengol, M.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1
2001, 154–158.
13. Jones, G. B.; Wright, J. M.; Plourde, G.; Purohit, H. A. D.;
Wyatt, J. K.; Hynd, G.; Fouad, F. J. Am. Chem. Soc. 2000, 122,
9872–9873.
1
14. Armengol, M.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1
2001, 978–984.
15. Larsen, L.; Rowe, D. J.; Garner, C. D.; Joule, J. A. Tetrahedron
Lett. 1988, 29, 1453–1456.
2
311–2316. (c) Larsen, L.; Rowe, D. J.; Garner, C. D.; Joule,
J. A. J. Chem. Soc., Perkin Trans. 1 1989, 2317–2327.
d) Dinsmore, A.; Birks, J. H.; Garner, C. D.; Joule, J. A.
16. Lont, P. J.; van der Plas, H. C. Recl. Trav. Chim. Pays-Bas
1972, 91, 850. Sugimoto, O.; Mori, M.; Moriya, K.; Tanji, K.-i.
Helv. Chim. Acta 2001, 84, 1112–1118.
(
J. Chem. Soc., Perkin Trans. 1 1997, 801–807. (e) Davies,
E. S.; Beddoes, R. L.; Collison, D.; Dinsmore, A.; Docrat, A.;
Joule, J. A.; Wilson, C. R.; Garner, C. D. J. Chem. Soc., Dalton
Trans. 1997, 3985–3996. (f) Bradshaw, B.; Dinsmore, A.;
Garner, C. D.; Joule, J. A. Chem. Commun. 1998, 417–418.
17. Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3,
91–93.
18. Schroll, A. L.; Barany, G. J. Org. Chem. 1986, 51, 1866–1881.
19. Heck, R. F. Inorg. Chem. 1965, 4, 855. Moran, M. Z.
Naturforsch. B: Anorg. Chem. Org. Chem. 1981, 36, 431–433.
Bolinger, C. M.; Weatherill, T. D.; Rauchfuss, T. B.;
Rheingold, A. L.; Day, C. S.; Wilson, S. R. Inorg. Chem.
1986, 25, 634–643.
(
g) Dinsmore, A.; Garner, C. D.; Joule, J. A. Tetrahedron
998, 54, 3291–3302. (h) Dinsmore, A.; Garner, C. D.; Joule,
J. A. Tetrahedron 1998, 54, 9559–9568. (i) Davies, E. S.;
1
Aston, G. M.; Beddoes, R. L.; Collison, D.; Dinsmore, A.;