Synthesis of cyclic mono- and bis-disulfides and their selective conversion to mono- and bis-thiosulfinates

Article abstract of DOI:10.1016/j.tet.2007.01.002

Twelve-membered ring pseudopeptidic cyclic disulfides have been prepared by iodine oxidation of the parent dithiols. However, oxidation of N,N′-(1,2-phenylene)bis(2-mercapto-2-methylpropanamide) afforded a 25/75 mixture of cyclic mono- and bis-disulfides

Full text of DOI:10.1016/j.tet.2007.01.002

Tetrahedron 63 (2007) 2466–2471
Synthesis of cyclic mono- and bis-disulfides and their selective
conversion to mono- and bis-thiosulfinates
a
Emilie Bourles, Rodolphe Alves de Sousa, Erwan Galardon, Mohamed Selkti,
a
a
b
ꢀ
Alain Tomasb and Isabelle Artauda,
*
a
´
Laboratoire de Chimie et Biochimie Pharmacologique et Toxicologique, UMR 8601, CNRS Universite Paris 5,
45 rue des Saints Peꢀres, 75270 Paris Cedex 06, France
b
´
Laboratoire de Cristallographie et RMN Biologiques, UMR 8015, CNRS Universite Paris 5, 4 avenue de l’Observatoire,
75270 Paris cedex 06, France
Received 8 November 2006; revised 27 December 2006; accepted 2 January 2007
Available online 4 January 2007
Abstract—Twelve-membered ring pseudopeptidic cyclic disulfides have been prepared by iodine oxidation of the parent dithiols. However,
oxidation of N,N0-(1,2-phenylene)bis(2-mercapto-2-methylpropanamide) afforded a 25/75 mixture of cyclic mono- and bis-disulfides that
were separated by selective precipitation in CHCl3. The cyclic bis-disulfide was selectively prepared by iodine oxidation of the Ni complex
of this dithiol and crystallized. Its crystal structure was solved by X-ray diffraction. All these cyclic mono- or bis-disulfides were selectively
converted to cyclic mono- and bis-thiosulfinates upon stoichiometric oxidation with dimethyldioxirane at low temperature. 1H NMR of the
cyclic bis-thiosulfinate revealed the presence of four isomers, two couples of stereoisomers, as expected from the insertion of two oxygen
atoms in this compound, one on each disulfide bond. The two couples of cis/trans isomers were separated by preparative TLC and identified
after alkaline cleavage of the two S(O)–S bonds and metalation with Ni(II). As HOꢀ attack is selective for the sulfinyl sulfur, the nature of the
Ni complexes obtained is a signature of each couple of stereoisomers.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2a, 2b, and 2c, respectively. While the synthesis of 1b has
been previously described,4 the synthetic route for the dipep-
tide 1c is outlined in Scheme 2. Acylation of o-phenylenedi-
amine with 2 equiv of S-benzyl-protected N-Boc-cysteine
afforded the S-protected dithiol, which was further debenzyl-
ated with Na in liquid NH3. Compound 1a was prepared
Recently glutathion has been reported to be converted to di-
sulfide-S-oxides under oxidative stress conditions.1 These
reactive sulfur oxidized species can then react with nucleo-
philes in proteins such as free thiols2 or zinc bound thiolates
leading to glutathionylation of proteins or zinc metallothio-
neins.3 This finding emphasizes that more generally disul-
fide-S-oxides might play an important role in biology. This
requires developing the synthesis of new disulfide mono-
oxides (thiosulfinates) or dioxides (thiosulfonates). Herein
we report the synthesis of cyclic mono- and bis-disulfides
from the parent dithiols and their further oxidation into
cyclic disulfide-S-oxide and cyclic bis(disulfide-S-oxides)
(bis(thiosulfinates)).
O
O
O
O
NH HN
NH HN
SH HS
Et3N / I2
CHCl3
R1
R1 n
R2
R1
R1 n
R2
n
n
S
S
R
2R2
R
2R2
R2
R2
2a
2b
2c
1a, n = 0, R2 = Me
1b, n = 1, R1 = H, R2 = Me
1c, n = 1, R1 = NHBoc, R2 = H
+
2. Results and discussion
O
O
S
S
HN
HN
NH
NH
The linear dithiols N2S2H4, 1a, 1b, and 1c, shown in Scheme
1, are the precursors of 10- or 12-membered ring disulfides
S
S
O
O
Keywords: Cyclic disulfide; Disulfide-S-oxide; Thiosulfinate; Bis(disulfide-
S-oxides); Bis-thiosulfinates.
3a
* Corresponding author. Tel.: +33 (1) 42 86 21 89; fax: +33 (1) 42 86 83 87;
e-mail: isabelle.artaud@univ-paris5.fr
Scheme 1. Synthesis of disulfides.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.002

E. Bourleꢀs et al. / Tetrahedron 63 (2007) 2466–2471
2467
O
O
ii
i
S
NH HN
1c
O3
C10i
C11
C1
S2i
COOH
NHBoc
BocHN
NHBoc
S
S
C2
N1
C4
Ph
Ph
C5
C3
C12
S1
Scheme 2. Synthesis of dithiol 2c: (i) i-BuOCOCl/o-phenylenediamine/
NMP; (ii) Na/NH3.
C8
O4
C6
S1i
N2
C7
in situ from the bis(S-acetylated) form of 1a5 after depro-
tection with K2CO3 in MeOH.
C9
C10
S2
C14
C13
Oxidative cyclization of the dithiols 1 with iodine in CHCl3
in the presence of triethylamine6 affords cyclic mono-disul-
fides 2 and bis-disulfide 3a (Scheme 1) depending on the size
of the N2S2H4 chelate, while oxidation of 1b and 1c provides
2b and 2c as the only products identified by 1H NMR. At this
stage, we tried to remove the Boc protection of 2c by an
acidic treatment, but this results in a poorly soluble species
that was difficult to characterize further. Oxidation of 1a
leads to a mixture of the cyclic mono- and bis-disulfides
2a and 3a, in a 25/75 ratio.
Figure 1. ORTEP view of the cyclic bis(disulfide) 3a showing 50% proba-
˚
bility displacement ellipsoids. Selected bond distances (A): S1–C1:
1.856(2), S2–C10: 1.864(3); selected bond angles (ꢁ): C1–S1–S2i:
106.31(8), C10–S2–S1i: 105.65(8); [i: 1ꢀx, 1ꢀy, 1ꢀz].
˚
of 2.0294(9), 1.856(2), and 1.864(3) A, respectively; C1–
S1–S2i and C10–S2–S1i bond angles of 106.31(8)ꢁ and
105.65(8)ꢁ, respectively) compare well with those of struc-
turally related 20-membered ring disulfides such as a
tetrabenzo-tetrathia-tetraazacycloeicosane13 or an octa-
methyl-diperhydrobenzo-tetrathia-tetraazacycloeicosane.11
Fortunately, 2a and 3a could be easily separated by repeated
crystallizations from CHCl3, 2a being only sparingly soluble
in this solvent. The 10-atom chelate 1a does not favor the
ring closure into 2a whose structure appears to be rigid
and twisted in solution as shown by the lack of any symmetry
revealed by 1H NMR analysis. The methyl protons are split
into two groups (6H each) appearing at two different chem-
ical shifts. In contrast, the methyl protons of the bis(di-
sulfide) 3a are equivalent and appear as a single resonance,
showing the larger flexibility of the dimer in solution.
Two features characterize the structure of 3a, namely, (i) a
i
˚
very short cross cage distance S1–S1 of 3.393(1) A, which
puts the two sulfur atoms within van der Waals contact and
(ii) a quite large value of the C1–S1–S2i–C10i torsion angle
(111.9(1)ꢁ). This value, which has been established to be 80–
85ꢁ in strain-free disulfides,14 is indicative of the stability of
the disulfides. Torsion angles can be compared within cyclic
disulfides of the same size. In that regard, the value deter-
mined in 3a is slightly larger than that found in the structure
described by Fox et al. (110.1(2)ꢁ).11 Replacement of the
two 1,2-diamino-cyclohexyl groups in this structure by
two phthalamide groups in 3a is likely to account for the
increase of the torsion as well as for the short cross cage
distance revealed in 3a.
Oxidation of dithiols usually provides mixtures of cyclic di-
sulfides containing one or more disulfide bridges depending
on the reaction conditions. Thus, oxidation with iodine under
high-dilution conditions7 or using thiol-disulfide interchange
reactions8 are reported to provide monomeric disulfides
and higher disulfide-containing species, respectively, but
these reactions are either not very selective, or afford by-
products. Interestingly, selective synthesis of bis(disulfide)-
tetramine macrocycles from the parent dithiol/diamine
precursor has been described either when using vanadyl spe-
cies as oxidizing agent9 or by oxidative coupling of Ni(II) or
Cu(II) complexes of the linear tetradentate N2S2 ligand.10,11
In this latter case, the cleanest synthesis was described by
Fox et al.11 Iodine oxidation of the diamine/dithiolate
nickel(II) or copper(II) complexes followed by removal of
the metal led to the unique and selective formation of the
bis(disulfide) in high yield.11 To get a larger amount of 3a,
this method was applied to the oxidation of the diamidato
The second part of this work deals with the oxidation of di-
sulfides 2 and bis(disulfide) 3a into cyclic mono- and bis-
thiosulfinates. While oxidation of linear disulfides is well
documented, only a few papers describe the oxidation of
cyclic disulfides into cyclic thiosulfinates15 and to the best
of our knowledge, there is no report on the oxidation of
cyclic bis(disulfides).
Dimethyldioxirane (DMD) was chosen as a clean oxidant
since acetone was the only by-product after oxygen transfer.
The solvent used was either acetone or a mixture of CH2Cl2/
acetone, when the starting product was only sparingly
soluble in acetone at the low temperature required for the
reaction. In these conditions, the cyclic disulfides 2 were
completely and selectively converted with 1 equiv of DMD
to the monothiosulfinate 4 (Scheme 3).
dithiolato nickel(II) complex of 1a, prepared as previously
€
12
described by Kruger and Hanss. Compound 3a was iso-
lated in almost quantitative yield and subjected to crystalli-
zation by slow evaporation of a CH2Cl2 solution.
A view of its X-ray crystal structure is shown in Figure 1.
As other cyclic bis(disulfides),7 3a adopts a cage conforma-
tion with a center of symmetry. The metric parameters
of the disulfides (S1–S2i, S1–C1, and S2–C10 distances
Oxidation of the bis(disulfide) 3a was performed in a
CH2Cl2/acetone mixture at ꢀ50 ꢁC with 2 equiv of DMD
1
(Scheme 4). H NMR analysis of the raw material isolated

2468
E. Bourleꢀs et al. / Tetrahedron 63 (2007) 2466–2471
Despite several attempts, we did not succeed in separating
the four isomers but two clean fractions were isolated after
separation over preparative TLC (SiO2, RP-18). The upper
fraction contained two stereoisomers in a 1/1 ratio while
the lower fraction contained the other two stereoisomers in
a 35/65 ratio. The different ratio in both couples of stereoiso-
mers after separation arises from the slight difference in mi-
gration of the two slow-migrating isomers and by the quite
arbitrary cut-off, the in-between fraction being a mixture
of the four isomers.
O
O
O
O
NH HN
NH HN
DMD
acetone
R1
R2
R1
R1
R1
n
n
n
n
S
R2
S
R2
S
S
R
2R2
R2
R2
R2
O
4a
4b
4c
2a, n = 0, R2 = Me
2b, n = 1, R1 = H, R2 =Me
2c, n = 1, R1 = NHBoc, R2 = H
Scheme 3. Synthesis of mono-thiosulfinates.
1
A definitive assignment of the H NMR spectrum of each
fraction to cis/trans 5a or cis/trans 6a being difficult, we
used an indirect evidence to do this attribution. In a recent
paper,17 we have shown that alkaline cleavage of the S(O)–
S bond in 4b selectively takes place at the sulfinyl sulfur as
previously described for related compounds (Eq. 1),18 lead-
ing after insertion of Co(III) to the corresponding mixed
thiolate/sulfinate complex.17
after oxidation of 3a shows the existence of four different
products in the same amount. ESI+ MS analysis of this mix-
ture shows only two peaks at m/z 653 and 675, corresponding
to the incorporation of two oxygen atoms in the four products
(653, [M+H]+; 675 [M+Na]+). The IR spectrum does not
show strong bands in the range 1100–1300 cmꢀ1 as expected
for thiosulfonates RS(O2)–SR, but exhibits only one strong
stretching frequency at 1082 cmꢀ1 supporting the formation
of thiosulfinates. The two oxygens can be incorporated either
on both sulfur atoms of the same disulfide bond, or on one sul-
fur atom of each disulfide bond leading, respectively, to vic-
disulfoxides or bis(thiosulfinates). Only two stereoisomers
are expected in the case of vic-disulfoxides and four isomers,
as observed by 1H NMR, in the case of thiosulfinates. These
four isomers correspond to two couples of cis/trans stereoiso-
mers, resulting from the incorporation of one oxygen atom at
S1 and S3, or S1 and S4, leading to 5a (cis/trans) and 6a (cis/
trans), respectively. Moreover our compounds being stable at
rt, we can rule out definitively the possible involvement of
vic-disulfoxides, whose S–S bond is relatively weak, and
which are only stable at low temperature.16a Such com-
pounds have been isolated in unusual structures such as
bridged bicyclic a-disulfoxides16b and more recently as tetra-
thiolane-2,3-dioxides.15c,d
O
-H2O
ð1Þ
+ 2 HO-
RSO- + RS-
R
S
S
R
This reaction was then applied to the metalation of 4a
and 4b with Ni(II) with the same selectivity toward
mixed thiolate/sulfinate derivatives (paper in preparation).
To characterize and attribute the regioisomers to each
fraction, the two collected fractions were subjected to
alkaline cleavage of both S(O)–S bonds followed by Ni(II)
insertion in the opened structures. By comparison with
an authentic sample prepared from 4a, a unique square
planar complex with a mixed thiolate/sulfinate environment,
{Ni[N2S(SO2)]}2ꢀ, was obtained from the lower fraction,
indicating clearly that it corresponds to the mixture of
stereoisomers 6a cis and trans. Treatment of the upper
fraction leads to a 1/1 mixture of bis(thiolate) and bis(sulfi-
nate) nickel complexes consistent with the mixture of
stereoisomers 5a cis and trans. The IR spectra of
{Ni[N2S(SO2)]}2ꢀ and{Ni[N2S(SO2)]}2ꢀ displaytwobands
between 1000 and 1200 cmꢀ1, assigned to n(SO)asym and
n(SO)sym stretching typically observed in S-bonded metal
sulfinate complexes. For an O-bonded sulfinate, only one
strong vibration around 1000 cmꢀ1 is expected. Because
the yields of pure isomers 5a and 6a were very low, this
has hampered the attempts to get crystal structures of the re-
sulting Ni complexes. Finally, an assignment of the 1H NMR
signals to 6a1 and 6a2 (cis or trans isomer) was possible on
the basis of their relative intensities since these two com-
pounds are in 35/65 ratio. However, 5a1 and 5a2 being in
a 1/1 ratio, a complete attribution of the signals to 5a1 and
5a2 was not possible.
2-
O
O
S1
S3
HN
S2
NH
O
O
N
N
S
i) ii) iii)
O
O
Ni
S4
NH
HN
S
O
O
O
O
{Ni[N2(SO2)2]}2-
6a cis / trans
2-
O
O
N
N
O
O
Ni
S
S
O
O
S1
S2 HN
HN
NH
O
i) ii) iii)
O
O
O
{Ni[N2(SO2)2]}2-
3. Conclusion
NH S3 S4
2-
O
O
In conclusion, we have described efficient syntheses of
cyclic mono- and bis-disulfides and their selective conver-
sions to thiosulfinates and bis-thiosulfinates with dimethyl-
dioxirane as oxidant. In addition, we propose a simple
method to identify the two regioisomers derived from the
20-membered ring cyclic bis(thiosulfinates), which can be
applied to other cyclic pseudopeptidic bis(thiosulfinates).
O
O
5a cis / trans
N
S
N
S
Ni
[Ni(N2S2)]2-
Scheme 4. Cyclic bis(thiosulfinates) and their conversion to Ni complexes:
(i) 4 equiv Et4NOH, DMF, ꢀ40 ꢁC; (ii) 2 equiv NiCl2; (iii) 4 equiv Et4NOH.

E. Bourleꢀs et al. / Tetrahedron 63 (2007) 2466–2471
2469
4. Experimental
4.3.1. 7,7,10,10-Tetramethyl-5,12-dihydro-8,9-dithia-
5,12-diaza-benzocyclodecene-6,11-dione 2a. IR (ATR):
3300 (NH), 1653 (amide), 1503, 1441, 747. 1H NMR
(250 MHz; DMSO-d6) d 1.56 (s, 6H), 1.59 (s, 6H), 7.2 (m,
2H), 7.35 (m, 2H), 9.13 (s, 2HNH). Mass (ESI+) m/z 333
[M+Na]+. Anal. Calcd for C14H18N2O2S2$0.5H2O: C,
52.64; H, 6.00; N, 8.77. Found: C, 52.44; H, 5.56; N, 8.8.
Yield from 240 mg of 1a, 24% (58 mg).
4.1. Dithiol 1c
To a THF solution (20 mL) of S-benzyl-N-Boc-L-cysteine
(1.1 g, 3.53 mmol) and N-methylmorpholine (442 mL,
4 mmol), isobutyl chloroformate (521 mL, 4 mmol) was
added dropwise at 0 ꢁC and the mixture was stirred for
1 h. o-Phenylenediamine (173 mg, 1.6 mmol) in THF
(25 mL) was slowly added at rt. After stirring overnight,
the solution was filtered and the solvent evaporated to dry-
ness. Ethyl acetate was then added and the solution was
washed with water, saturated aq NaCl, water, dried over
Na2SO4, and concentrated in vacuo. Purification by column
chromatography over silica gel (CH2Cl2/AcOEt 95/5) gave
4.3.2. 8,8,11,11-Tetramethyl-5,7,8,11,12,14-hexahydro-
9,10-dithia-5,14-diaza-benzocyclododecene-6,13-dione
2b. 1H NMR (250 MHz, CDCl3) d 1.49 (s, 12H), 2.64 (s, 4H),
7.18 (m, 2H), 7.41 (m, 2H), 8.24 (s, 2HNH). Anal. Calcd for
C16H22N2O2S2: C, 56.77; H, 6.55; N, 8.28. Found: C, 56.76;
H, 6.48;N, 8.09. Yieldstartingfrom4.47 gof1b:61%(2.71 g).
1
the S-benzyl intermediate. Yield: 72% (800 mg). H NMR
(CDCl3, 250 MHz) d 1.46 (s, 18H), 2.9 (m, 4H), 3.74 (m,
4H), 4.39 (m, 2H), 5.39 (m, 2H), 7.17–7.46 (m, 16H), 8.46
(s, 2H). Mass (CI+, NH3) m/z 695 [M+1]+; 712 [M+NH+4].
Anal. Calcd for C36H48N4O6S2: C, 62.22; H, 6.67; N, 8.06.
Found: C, 62.09; H, 6.82; N, 8.17. The S-benzyl derivative
(800 mg, 1.15 mmol) dissolved in THF (3 mL) was stirred
with anhydrous ammonia (50 mL). An excess of sodium
(4–10 equiv) was then added until persistence of a blue color
for 1 h. After addition of NH4Cl, and removal of NH3 and
THF, aq HCl (0.1 M) was added and the acidic solution
was extracted with AcOEt. The organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo.
4.3.3. (12-tert-Butoxycarbonylamino-6,13-dioxo-
5,6,7,8,11,12,13,14-octahydro-9,10-dithia-5,14-diaza-
benzocyclododecen-7-yl)-carbamic acid tert-butyl ester
1
2c. H NMR (250 MHz, CDCl3) d 1.47 (s, 18H), 3.22–3.38
(m, 4H), 4.57 (m, 2H), 5.52 (s, 2HNH), 7.22–7.36 (m, 4H),
8.34 (s, 2H). Anal. Calcd for C22H32N4O6S2$AcOEt$H2O:
C, 50.47; H, 6.84; N, 9.05. Found: C, 50.71; H, 7.05; N,
8.86. Yield starting from 400 mg of 1c: 58% (231 mg).
4.3.4. 7,7,10,10,19,19,22,22-Octamethyl-5,12,17,24-tetra-
hydro-8,9,20,21-tetrathia-5,12,17,24-tetraaza-dibenzo-
[a,k]cycloeicosene-6,11,18,23-tetraone 3a. IR (ATR,
cmꢀ1): 3306 (NH), 1670 (amide), 1527, 1472, 747. 1H NMR
(250 MHz, CDCl3) d 1.66 (s, 24H), 7.0 (m, 4H), 7.26 (m, 4H),
8.73 (s, 4HNH). Anal. Calcd for C28H36N4O4S4$H2O: C,
52.64; H, 6.00; N, 8.77. Found: C, 53.36; H, 6.00; N, 8.77.
Mass (FAB+) m/z 621 [M+1]+. Yield from 240 mg of 1a,
75% (180 mg).
1
Yield: 86% (510 mg). Compound 1c: H NMR (250 MHz,
CDCl3) d 1.49 (s, 18H), 1.65 (m, 2H), 2.83–3.17 (m, 4H),
4.5 (m, 2H), 5.59 (m, 2H), 7.2 (m, 2H), 7.13–7.46 (m,
2H), 8.63 (s, 2H). Mass (CI+, NH3) m/z 515 [M+1]+; 532
[M+NH+4]. Anal. Calcd for C22H34N4O6S2: C, 51.34; H,
6.66; N, 10.89. Found: C, 51.14; H, 6.86; N, 10.77.
4.2. 2-Mercapto-N-[2-(2-mercapto-2-methyl-propionyl-
amino)-phenyl]-2-methyl-propionamide 1a
4.4. Typical procedure for synthesis of thiosulfinates 4
Disulfide 2 was dissolved in acetone (0.02 M for 2b) or in
a 60/40 v/v mixture of CH2Cl2/acetone (3 mM for 2a) and
DMD (0.08 M in acetone, 1 equiv) was added dropwise at
ꢀ40 ꢁC under argon. Removal of the solvents afforded the
thiosulfinates 4 in almost quantitative yields.
A 0.07 M methanol solution of thioacetic acid S-{1-[2-
(2-acetylsulfanyl-2-methyl-propionylamino)-phenyl-carba-
moyl]-1-methyl-ethyl} ester5 was deprotected in methanol
with K2CO3 (2.2 equiv). After stirring overnight under ar-
gon, the solution was acidified with an ethereal solution of
HCl(g) (2 equiv). After removal of the solvents and dissolu-
tion of the solid in a large volume of EtOAc, the solution
was washed with water and dried over MgSO4. Evaporating
4.4.1. 7,7,10,10-Tetramethyl-8-oxo-5,7,8,12-tetrahydro-
8l4,9-dithia-5,12-diaza-benzocyclodecene-6,11-dione 4a.
1
IR (ATR, cmꢀ1): 1662, 1506, 1089 (S]O), 749. H NMR
1
the solvent in vacuo afforded 1a in quantitative yield. H
(250 MHz, CDCl3) d 1.69 (s, 3H), 1.71 (s, 3H), 1.75 (s,
3H), 1.96 (s, 3H), 7.19 (m, 2H), 7.37 (m, 2H). Mass
(FAB+) m/z 327.2 [M+1]+. 1H NMR (250 MHz, DMSO-d6)
d 1.53 (s, 3H), 1.76 (s, 6H), 7.18 (m, 2H), 7.37 (m, 2H),
9.18 (s, 1HNH), 9.76 (s, 1HNH). 13C NMR (500 MHz,
DMSO-d6) d 16.32, 22.15, 25.57, 28.17, 54.78, 70.24,
128.27, 128.53, 129.23, 135.55, 167.63, 172.64. Mass (FAB+)
m/z 327 [M+1]+. Anal. Calcd for C16H22N2O3S2$1/6CH2Cl2:
C, 49.66; H, 5.40; N, 8.16. Found: C, 49.57; H, 5.24; N, 8.56.
Yield from 200 mg of 2a, 97% (217 mg).
NMR (250 MHz, CD2Cl2) d 1.31 (s, 3H), 1.60 (s, 6H),
1.71 (s, 6H), 7.28 (m, 2H), 7.42 (m, 2H). Yield from
443 mg of the thioacetic derivative, 95% (324 mg).
4.3. Typical procedure for synthesis of disulfides
0.13 M solutions of dithiol 1 and I2 (1 equiv relative to 1) in
CHCl3 were added dropwise and simultaneously, under
argon, into a 0.26 M solution of triethylamine (2 equiv relative
to 1) in CHCl3. Then the solution was washed with saturated
aq Na2S2O3, aq HCl (0.1 N), and water and the solvent was
removed. Inthecaseof1a, 2aand3awereisolatedbyselective
precipitation of 2a in CHCl3 leading to a 25/75 ratio of 2a/3a.
Compounds 2b and 2c were purified by column chromato-
graphy over silica gel using dichloromethane/ethyl acetate
mixtures as eluants (7/3 for 2b and 8/2 for 2c).
4.4.2. 8,8,11,11-Tetramethyl-9-oxo-5,8,9,11,12,14-hexa-
hydro-7H-9l4,10-dithia-5,14-diaza-benzocyclododecene-
6,13-dione 4b. IR (ATR, cmꢀ1): 1665, 1527, 1070 (S]O),
1
733. H NMR (250 MHz, DMSO-d6) d 1.45 (s, 3H), 1.61
(s, 3H), 1.65 (s, 6H), 2.78–2.9 (m, 2H), 3.1–3.2 (m, 2H),
7.17 (m, 2H), 7.3 (m, 2H), 8.95 (s, 1HNH), 9.67 (s, 1HNH).

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E. Bourleꢀs et al. / Tetrahedron 63 (2007) 2466–2471
13C NMR (500 MHz, CDCl3) d 24.04, 24.84, 30.70, 31.80,
45.66, 49.54, 52.36, 63.10, 126.46, 127.00, 130.96, 131.70,
167.30, 168.76. Anal. Calcd for C16H22N2O3S2$0.5H2O: C,
53.31; H, 6.34; N, 7.77. Found: C, 53.33; H, 6.16; N, 7.56.
Yield from 500 mg of 2b, 94% (508 mg).
4 equiv) to cleave the S(O)–S bonds and to produce the
sulfinates and the thiolates. A concentrated DMF solution
of NiCl2 (2 equiv) was then added and immediately 4 equiv
of Et4NOH to deprotonate the amides. The solution was
then allowed to warm to rt. After removal of the solvents
in vacuo, the complexes were isolated upon precipitation
at 0 ꢁC from CH3CN into diethylether and characterized
by 1H NMR. Synthesis and spectroscopic characterizations
of [Ni(N2S2)](Et4N)2 are described in Ref. 12.
4.4.3. (12-tert-Butoxycarbonylamino-6,10,13-trioxo-5,7,
8,10,11,12,13,14-octahydro-6H-9,10l4-dithia-5,14-di-
aza-benzocyclododecen-7-yl)-carbamic acid tert-butyl
ester 4c. The product was purified by flash chromatography
(SiO2, CH2Cl2/AcOEt 60/40). IR (ATR, cmꢀ1): 1692, 1660,
{Ni[N2S(SO2)]}(Et4N)2: IR (ATR, cmꢀ1): 1588 (C]O),
1154 and 1034 (SO2), 1173, 1001 (Et4N). 1H NMR
(250 MHz, CD3CN) d 1.18 (m, 24H), 1.27 (s, 6H), 1.45 (s,
6H), 3.24 (q, J¼7.3 Hz, 16H), 6.62 (m, 2H), 8.58 (m, 2H).
Anal. Calcd for C60H56N4NiO4S2$1.5H2O: C, 52.48; H,
8.66; N, 8.16. Found C, 52.57; H, 8.65; N, 8.37.
1
1076 (S]O), 756. H NMR (250 MHz, CDCl3) d 1.47 (s,
18H), 3.52–3.83 (m, 4H), 4.53–4.59 (m, 1H), 4.87 (s, 1H),
5.69–5.77 (m, 2HNH), 7.13–7.65 (m, 4HAr), 8.58 (s, 1HNH),
8.64 (s, 1HNH). 13C NMR (500 MHz, CDCl3) d 28.32,
37.36, 51.62, 53.70, 57.99, 80.81, 124.00, 125.39, 126.40,
127.00, 127.59, 128.31, 128.97, 130.74, 154.97, 167.00,
168.24. Anal. Calcd for C22H32N4O7S2$0.5AcOEt: C,
50.33; H, 6.34; N, 9.78. Found: C, 50.62; H, 6.42; N, 9.45.
Yield from 50 mg of 2c, 63% (35 mg).
{Ni[N2(SO2)2]}(Et4N)2: IR (ATR, cmꢀ1): 1599, 1562,
1180, 1170, 1057, 1031. 1H NMR (250 MHz, CD3OD)
d 1.26 (t, J¼7.3 Hz, 24H), 1.45 (s, 12H), 3.26 (q,
J¼7.3 Hz, 16H), 6.75 (m, 2H), 8.47 (m, 2H). Mass (ESIꢀ)
m/z 560 (50%) [{Ni[N2(SO2)2]}(Et4N)]ꢀ. Anal. Calcd for
C60H56N4NiO6S2$H2O$0.5CH3CN: C, 50.99; H, 8.21; N,
8.63. Found: C, 50.82; H, 8.09; N, 8.60.
4.5. Bis-thiosulfinates 5a and 6a
To a CH2Cl2/acetone (30/70 v/v mixture) solution of 3a,
cold DMD in acetone (2 equiv) was added dropwise at
4.7. X-ray crystallography for 3a
1
ꢀ50 ꢁC. H NMR analysis of the mixture isolated after re-
moval of the solvents revealed the unique presence of 5a
and 6a in a 1/1 ratio. Mass (ESI+) m/z 653 [M+H]+; 675
[M+Na]+. Anal. Calcd for C28H36N4O6S4$0.5H2O: C,
50.81; H, 5.63; N, 8.46. Found: C, 50.79; H, 5.88; N, 8.29.
Yield from 205 mg of 3a, 96% (260 mg of 5a and 6a). Com-
pounds 5a and 6a were separated by three successive migra-
tions on preparative TLC silica gel 60 F254 (1 mm) eluted
with hexane/AcOEt (4/6 v/v mixture).
Formula C28H36N4O4S4; monoclinic, space group
˚
P21/a; a¼11.958(2), b¼10.662(2), c¼13.373(2) A, b¼
3
ꢁ
˚
116.15(1) , V¼1530.4(4) A , Z¼2. The structure was solved
by SHELXS 9719 and refined using SHELXL 97.20 The hy-
drogen atoms were positioned geometrically and refined rid-
ing on their carrier atom with isotropic thermal displacement
parameters fixed at 1.2 times those of their parent atoms.
Convergence was reached at R1¼0.0636 for 2733 reflections
(I>2 s(I)), wR2¼0.186 for all data and S¼0.934 for 185 pa-
rameters. The residual electron density in the final difference
4.5.1. 7,7,10,10,19,19,22,22-Octamethyl-8,21-dioxo-5,7,
8,12,17,21,22,24-octahydro-8l4,9,20,21l4-tetrathia-5,
12,17,24-tetraaza-dibenzo[a,k]cycloeicosene-6,11,18,23-
tetraone 5a. Two isomers 5a1 and 5a2 unrespectively cis
and trans in a 1/1 ratio. 1H NMR (250 MHz, CDCl3)
d 1.93, 1.89, 1.87, 1.85, 1.76, 1.60 (s, 6ꢂ3H), 1.76 (s, 6H),
6.88, 6.95, 7.16, 7.61 (m, 8HAr 5a1), 6.86, 6.94, 7.65, 7.2
(m, 8HAr 5a2), 7.08 (m) not attributed, 8.40, 8.85 (s,
2ꢂ2HNH 5a1), 8.37, 8.90 (s, 2ꢂ2HNH 5a2). IR (ATR,
cmꢀ1): 3272, 1650 (amide), 1513, 1082 (S]O), 747. Yield
from 42 mg of the mixture 5a/6a, 14% (6 mg).
Fourier does not show any feature above 0.698 eAꢀ3 and be-
˚
low ꢀ0.571 eAꢀ3. An ORTEP21 view is given in Figure 1.
˚
Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Center as supplementary publication no. CCDC 249662.
Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[fax: +44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.
ac.uk]
4.5.2. 7,7,10,10,19,19,22,22-Octamethyl-8,20-dioxo-5,7,
8,12,17,19,20,24-octahydro-8l4,9,20l4,21-tetrathia-5,
12,17,24-tetraaza-dibenzo[a,k]cycloeicosene-6,11,18,23-
tetraone 6a. Two isomers 6a1 and 6a2 unrespectively cis
and trans in a 7/3 ratio. 1H NMR (250 MHz, CDCl3) d 6a1:
1.95, 1.78, 1.74, 1.72 (s, 4ꢂ3H), 7.14, 7.66 (m, 2ꢂ4H),
8.60 (m, 4H); d 6a2: 1.98, 1.84, 1.77, 1.66 (s, 4ꢂ3H),
7.66, 7.14 (m, 2ꢂ4H), 8.54 (s, 4H). Yield from 42 mg of
the mixture 5a/6a, 47% (20 mg).
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