Synthesis of polydentate ligands containing amides and thiols for biomimetic metal complexes

Article abstract of DOI:10.1081/SCC-100104041

Three pentadentate "N₂S₃" and one tetradentate "N₂S₂" new ligands with "N" = CONH and "S" = SH have been synthesized. The key step is the direct diamide formation from the malonyl diester and the amines in the p

Full text of DOI:10.1081/SCC-100104041

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SYNTHESIS OF POLYDENTATE
LIGANDS CONTAINING AMIDES
AND THIOLS FOR BIOMIMETIC
METAL COMPLEXES
Laurent Heinrich a , Jean-Claude Chottard a & Yun
Li b
a Université René Descartes , Laboratoire de
Chimie et Biochimie Pharmacologiques et
Toxicologiques (CNRS UMR8601), 45 rue des Saints
Péres, Paris Cedex 06, 75270, France
b Université René Descartes , Laboratoire de
Chimie et Biochimie Pharmacologiques et
Toxicologiques (CNRS UMR8601), 45 rue des Saints
Péres, Paris Cedex 06, 75270, France
Published online: 09 Nov 2006.
To cite this article: Laurent Heinrich , Jean-Claude Chottard & Yun Li (2001)
SYNTHESIS OF POLYDENTATE LIGANDS CONTAINING AMIDES AND THIOLS FOR
BIOMIMETIC METAL COMPLEXES, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 31:9, 1323-1333, DOI:
10.1081/SCC-100104041
To link to this article: http://dx.doi.org/10.1081/SCC-100104041
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SYNTHETIC COMMUNICATIONS, 31(9), 1323–1333 (2001)
SYNTHESIS OF POLYDENTATE LIGANDS
CONTAINING AMIDES AND THIOLS FOR
BIOMIMETIC METAL COMPLEXES
Laurent Heinrich, Jean-Claude Chottard, and Yun Li*
Laboratoire de Chimie et Biochimie Pharmacologiques et
Toxicologiques (CNRS UMR8601), Universite Rene
Descartes, 45 rue des Saints Peres, 75270
Paris Cedex 06, France
ABSTRACT
Three pentadentate ‘‘N2S3’’ and one tetradentate ‘‘N2S2’’ new
ligands with ‘‘N’’ ¼ CONH and ‘‘S’’ ¼ SH have been synthe-
sized. The key step is the direct diamide formation from the
malonyl diester and the amines in the presence of trimethyla-
luminum.
Nitrile hydratases (NHases) are metalloenzymes that contain a non-
heme iron(III) or a non-corrinoid cobalt(III) and catalyze the hydration of
nitriles to amides.1–3 Recent x-ray crystallographic structures of NHases
from Rhodococcus sp.R312 and Rhodococcus sp.N771 indicated that the
iron(III) is coordinated to two nitrogen atoms from peptide bonds of the
main chain and three cystein sulfur atoms, two of which are post-
translationally oxidized to cystein sulfinic ðRSOÀ2 Þ and sulfenic ðRSOÀÞ
moieties.4,5 Despite the structural information brought by x-ray diffraction
data, post-translational oxidation of bound cysteins remains to be
* Corresponding author.
1323
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1324
HEINRICH, CHOTTARD, AND LI
understood and it is not yet clear how NHases work. The study of relevant
mimetic complexes should help to answer these questions.
As part of our research program directed toward the synthesis of
biomimetic complexes of NHases, different iron(III) and cobalt(III) com-
plexes with thiolato and N-carboxamido ligands were to be studied.
Recently, some model complexes of NHases have been reported,6–8 but
none of them has the N2S3 (with ‘‘N’’ ¼ CONH and ‘‘S’’ ¼ SH) coordination
sphere present in the enzyme metal center. One of the major reasons for this
lack is probably the synthetic difficulty to accede to N2S3 ligands. To our
knowledge, the synthesis of polydentate ligands containing two amide and
three thiol groups has not been reported so far. Only a N2S2 ligand similar
to 4 has been prepared in low yield (37%).9
In this paper we report the synthesis of the following three N2S3
ligands 1–3 and the N2S2 ligand 4 (Fig. 1).
Our first route to the formation of the diamide moiety consisted of a
classical double-coupling reaction between a diacid and two equivalents of
an amino compound. The diacid 8 was prepared in good yield by condensa-
tion of diethyl 2-methylmalonate (6) with benzylchloromethylsulfide (5) in
anhydrous DMF in the presence of sodium hydride, followed by a double
saponification (Scheme 1). 5 was prepared by a smooth and high-yielding
method from bromochloromethane, benzyl mercaptan, and potassium
hydroxide using triethylbenzylammonium chloride (TEBAC),10 as phase-
transfer catalyst. It was more satisfactory than using benzyl mercaptan
and 1,3,5-trioxane in the presence of hydrogenchloride (gas).11
Figure 1. N2S3 and N2S2 ligands
Scheme 1.

POLYDENTATE LIGANDS
1325
The diacid 8, converted in situ into the dicarbonylchloride (SOCl2) and
then treated with 912 in the presence of Et3N in CH2Cl2 at 25ꢀC gave the
desired diamide 10 in 53% yield; surprisingly, the side-product 11, resulting
from the fragmentation of the malonic function was also formed in 18%
yield (Scheme 2); Lower temperature (0ꢀC) gave the mixture 10:11 in a 85:15
ratio. Other conventional coupling reagents13 such as 1,3-diclohexyl-
carbodiimide (DCC) and DCC / 1-hydroxybenzotriazole (HOBt) gave
similar results. Carbonyldiimidazole (CDI) gave the monoamide 11 (65%
yield) as the only isolable product. All efforts to separate the diamide 10
from the monoamide 11 failed. Even after total deprotection of the thiol
groups, the two compounds remained unseparable.
Scheme 2.
Since we needed highly pure ligands for metal complexation, the pres-
ence of the monoamide was not acceptable. Another strategy was then
adopted. The direct amidation of the diester 7 by the amine 9 in the presence
of trimethylaluminum14 in anhydrous CH2Cl2 at 40ꢀC afforded the diamide
10 as the unique product in 80% yield (Scheme 3). This reaction is very
sensitive to higher temperature: the use of toluene at 80ꢀC for 72 h gave
exclusively the monoamide 11 in 60% yield.
Scheme 3.
The procedure was successfully applied to the diester 12 and the amine
9 to afford the diamide 13 in 82% yield. The corresponding monoamide 16
(vide infra) was also obtained when the reaction was conducted in toluene
at 80ꢀC. A third diamide 15 was prepared from 7 and 14 in good yield
following the same methodology.

1326
HEINRICH, CHOTTARD, AND LI
The three N2S3 ligands 1, 2, and 3 were obtained, respectively, by
debenzylation of 10, 13, and 15 with sodium in liquid ammonia and anhy-
drous THF in good yields (Scheme 3).
The formation of the monoamides 11 and 16 is tentatively assigned to
a fragmentation of the malonic diamide under basic conditions assisted by
aluminum (Scheme 4).
Scheme 4.
Finally, the preparation of the N2S2 ligand 4 was rather straight-
forward from dimethylmalonyl dichloride (17) and 1-amino-2-methyl-2-
propanethiol hydrochloride (18) with triethylamine in anhydrous CH2Cl2
in 91% yield (Scheme 5). No trace of monoamide was detected under these
conditions.
Scheme 5.
Preliminary results using these ligands are already interesting: ligand 1,
upon deprotonation and complexation with Fe(III), followed by sponta-
neous air oxidation, afforded a pentacoordinated complex, with one sulfi-
nato ligand ðRSOÀ2 Þ [(N2S2S{O}O)Fe]2À. It is the first example of an
O-sulfinato-iron(III) complex obtained by O2 oxidation of a thiolato
ligand.15 Ligand 4, upon deprotonation and complexation with Co(III),
gave a rather rare, tetracoordinated, square-planar [(N2S2)Co]À complex.16
Other iron(III) or cobalt(III) complexes using 1–4 as ligands are currently
under investigation.

POLYDENTATE LIGANDS
1327
EXPERIMENTAL
Benzylchloromethylsulfide (BnSCH2Cl) (5): To a solution of benzyl-
thiol (15.6 g, 0.126 mol) in CH2ClBr (1 L) were added successively triethyl-
benzylammonium chloride (TEBAC, 3.05 g, 0.013 mol) and a fine powder of
potassium hydroxide (10.2 g, 0.182 mol) under argon. After vigorous stirring
at room temperature for 1 h, a saturated aq. solution of NH4Cl was added
to the mixture to reach pH ffi 7, the organic layer was washed with water
(100 mL), dried (Na2SO4), and evaporated to afford BnSCH2Cl (5) as a pure
(NMR), colorless oil (21.8 g, 100%). This product was used in the next step
without further purification. 1H NMR (250MHz, CDCl 3): ꢀ 7.34–7.26
(m, 5 H, Ar), 4.54 (s, 2H, SCH2Cl), 3.89 (s, 2H CH2Ph).
Diethyl 2-(benzylthiomethyl)-2-methylmalonate (7): NaH (60% in
mineral oil, 556 mg, 13.9 mmol) was added in small portions under Ar to
a solution of BnSCH2Cl (5) (2.168 g, 12.6 mmol) and diethyl 2-methyl-
malonate (6) (2.19 g, 12.6 mmol) in anhydrous DMF (55 mL) cooled to
À10ꢀC. After 1.5 h at À10ꢀC and 16 h at 25ꢀC, aq. HCl 1M was added
to reach pH ffi 7 and the solvents were evaporated under reduced pressure.
Water (30ml) was added and the mixture extracted with Et 2O (3 Â 30mL).
The organic layer was washed with water (2 Â 20mL) dried (Na 2SO4), and
evaporated. The crude product was purified by chromatography over silica
1
gel (1:9 EtOAc-cyclohexane) to afford 7 as a colorless oil (2.93 g, 75%). H
NMR (250MHz, CDCl 3): ꢀ 7.29–7.19 (m, 5H, Ar), 4.15 (q, 4H, J ¼ 7.1 Hz,
OCH2CH3), 3.70(s, 2H, SC H2Ph), 2.97 (s, 2H, CH2S), 1.45 (s, 3H, CH3),
1.21 (t, 6H, OCH2CH3); 13C NMR (63 MHz, CDCl3): ꢀ 171.06 (CO),
138.01 (Ar-C), 128.87 (Ar-CH), 128.45 (Ar-CH), 127.05 (Ar-CH), 61.48
(OCH2CH3), 54.81 (C(CO)2), 37.95 (SCH2Ph), 37.11 (SCH2), 19.72 (CH3),
13.94 (OCH2CH3); MS (CI/NH3): 311 (MHþ), 328 (MþNH4þ); IR (CHCl3):
ꢁ 1730cm À1 (CO); Anal. calc. for C16H22O4S (310.42): C 61.91, H 7.14.
Found: C 61.98, H 7.28.
2-methyl-2-(benzylthiomethyl)-malonic diacid (8): Aq. 2M potassium
hydroxide solution (58 mL) was added to a solution of the diester 7 (1.085 g,
3.5 mmol) in ethanol (95%, 80ml). After 3 days at 25 ꢀC, ethanol was
evaporated and aq. 1M HCl was added at 0ꢀC to reach pH ffi 1. The mixture
was extracted with Et2O (3 Â 100 mL). The organic layer was washed with
aq. saturated NaCl (50ml), dried (Na 2SO4), and evaporated to afford 8 as a
1
pure (NMR), colorless solid (882 mg, 99%). H NMR (250MHz, CDCl ):
3
ꢀ 8.96 (s br., 2H, D2O exchangeable, OH), 7.29–7.17 (m, 5H, Ar), 3.73 (s, 2H,
SCH2Ph), 2.98 (s, 2H, SCH2), 1.52 (s, 3H, CH3); 13C NMR (63 MHz,
CDCl3): ꢀ 177.03 (CO), 137.61 (Ar-C), 128.94 (Ar-CH), 128.56 (Ar-CH),
127.24 (Ar-CH), 55.18 (C(CO)2), 38.05 (SCH2Ph), 36.51 (SCH2),
19.66 (CH3); MS (CI/NH3): 228 (M-CO2þNHþ4 ); IR (CHCl3): ꢁ 3680,

1328
HEINRICH, CHOTTARD, AND LI
3500 cmÀ1 (OH), 1710, 1720 cmÀ1 (CO); Anal. calc. for C12H14O4S (254.31):
C 56.68, H 5.55, S 12.61. Found: C 56.71, H 5.59, S 12.41.
Diethyl 2-(2-benzylthioethyl)-2-methylmalonate (12): NaH (60% in
mineral oil, 1 g, 25 mmol) was added in small portions under Ar to a solution
of benzylthiol (2.912 g, 23.5 mmol) in anhydrous DMF (20mL) cooled to
À10ꢀC (ice–NaCl bath). After 0.5 h at À10ꢀC, the mixture was added drop-
wise to a solution of the diethyl 2-(2-bromoethyl)-2-methylmalonate17
(6.504 g, 23.1 mmol) in anhydrous DMF (20 mL) at 0ꢀC. After 16 h at
25ꢀC, aq. HCl 1M was added to the reaction to reach pH ffi 1 and the solvents
were evaporated under reduced pressure. Water (50mL) was added and the
mixture extracted with EtOAc (2 Â 100 mL). The organic layer was washed
with water (2 Â 50mL), dried (Na 2SO4), and evaporated. The crude product
was purified by chromatography on silica gel (1:1 CH2Cl2-cyclohexane) to
1
afford 12 as a colorless oil (5.781 g, 77%). H NMR (250MHz, CDCl 3): ꢀ
7.29–7.20(m, 5H, Ar), 4.13 (q, 4H, J ¼ 7.1 Hz, OCH2CH3), 3.70(s, 2H,
SCH2Ph), 2.37–2.31 (m, 2H, CH2CH2S), 2.10–2.15 (m, 2H, CH2CH2S),
1.35 (s, 3H, CH3), 1.20(t, 6H, OCH CH3); 13C NMR (63 MHz, CDCl3): ꢀ
2
171.73 (CO), 138.19 (Ar-C), 128.84 (Ar-CH), 128.44 (Ar-CH), 126.96 (Ar-
CH), 61.31 (OCH2CH3), 53.39 (C(CO)2), 35.96, 35.63 (SCH2Ph, SCH2),
26.01 (CH2CH2S), 19.89 (CH3), 13.94 (OCH2CH3); MS (CI/NH3): 342
(MþNHþ4 ), 325 (MHþ); IR (CHCl3): ꢁ 1728 cmÀ1 (CO); High Resolution
MS calc. for C17H25O4S (Mþ): 325.1474. Found: 325.1478.
GeneralProcedure for the Synthesis of Diamides
A solution of trimethylaluminum in heptane (2M, 7.2 mL, 14.4 mmol)
was added dropwise under argon to a solution of the amino compound
(11 mmol) in anhydrous CH2C12 (5 mL) cooled to À15ꢀC. After stirring at
25ꢀC until no more methane evolved, the reaction was cooled to 0ꢀC and a
solution of the starting diester (3.7 mmol) in anhydrous CH2Cl2 (3 mL) was
added. After 48 h at 40ꢀC (bath), the mixture cooled to À15ꢀC was carefully
acidified by conc. HCl (pH ffi 1), extracted with EtOAc (3 Â 40mL), and the
combined organic layers were washed with satured aq. NaHCO3 (to pH 8),
and water (2 Â 20mL), dried (MgSO 4) and evaporated. The crude product
was purified by chromatography on silica gel (1:4 EtOAc-cyclohexane) to
afford the corresponding diamide as a colorless oil. All of the following
compounds were prepared according to this procedure.
N,N0-bis-(2-benzylthio-2-methylpropyl)-2-(benzylthiomethyl)-2-methyl-
malonyl diamide (10): from 7 (450mg, 1.45 mmol) and amine 9 (850mg,
1
4.4 mmol); yield 706 mg (80%); H NMR (250MHz, CDCl 3): ꢀ 7.31–7.19
(m, 17H, ArþNH), 3.72 (s, 2H, SCH2Ph), 3.69 (s, 4H, 2 Â SCH2Ph), 3.25

POLYDENTATE LIGANDS
1329
(d, 4H, J ¼ 5.7 Hz, 2 Â CH2N), 2.97 (s, 2H, CH2S), 1.48 (s, 3H, CH3), 1.26
(s, 12H, 4 Â CH3); 13C NMR (63 MHz, CDCl3): ꢀ 171.58 (CO), 137.87 (Ar-
C) 137.80(Ar-C), 128.77 (CH-Ar), 128.63 (CH-Ar), 128.37 (CH-Ar), 126.83
(CH-Ar), 54.18 (C(CO)2), 47.61 (NCH2), 46.35 (Me2CS), 39.72 (CH2S),
37.70(CH SCH2Ph), 32.72 (Me2CSCH2Ph), 26.48 (4 Â CH3), 19.76 (CH3);
2
MS (CI/NH3): 609 (MHþ); High Resolution MS (CI/CH4): m/z calc. for
C34H45N2O2S3 (MHþ): 609.2643, found: 609.2641.
N,N0-bis-(2-benzylthio-2-methylpropyl)-2-(2-benzylthioethyl)-2-
methylmalonyl diamide (13): from 12 (1.192 g, 3.7 mmol) and amine 9
1
(2.112 g, 11 mmol); yield 1.872 g (82%); H NMR (250MHz, CDCl 3): ꢀ
7.35–7.20(m, 15H, Ar), 7.02 (t, 2H, J ¼ 6.8 Hz, D2O exchangeable, NH),
3.67 (s, 4H, 2 Â SCH2Ph), 3.66 (s, 2H, SCH2Ph), 3.20(d, 4H, CH 2N), 2.33–
2.27 (m, 2H, CH2CH2S), 2.12–2.06 (m, 2H, CH2CR2S), 1.32 (s, 3H, CH3),
1.22 (s, 12H, 4 Â CH3); 13C NMR (63 MHz, CDCl3): ꢀ 172.32 (CO), 138.17
(Ar-C), 128.90(CH-Ar), 128.80(CH-Ar), 128.62 (CH-Ar), 128.44 (CH-Ar),
127.07 (CH-Ar), 126.94 (CH-Ar), 53.23 (C(CO)2), 47.71 (NCH2), 46.58
(Me2CS), 39.07 (CH2S), 36.09 (CH2CH2S), 32.72 (SCH2Ph), 26.69
(4 Â CH3), 18.90(CH 3); MS (CI/NH3): 623 (MHþ); IR (CHCl3): ꢁ
1670cm À1 (CO); High Resolution MS (CI/CH4): m/z calc. for
C35H47N2O2S3 (MHþ): 623.2800. Found: 623.2802.
N,N0-bis-(2-benzylthioethyl-2-(benzylthiomethyl)-2-methylmalonyl di-
amide (15): from
7 (500 mg, 1.61 mmol) and amine 14 (685 mg,
4.10mmol); yield 670mg (75%); 1H NMR (250MHz, CDCl 3): ꢀ 7.29–7.17
(m, 15H, Ar), 7.03 (t, 2H, J ¼ 4.9 Hz, D2O exchangeable, NH), 3.70(s, 2H,
SCH2Ph), 3.68 (s, 4H, 2 Â CH2CH2SCH2Ph), 3.35 (m, 4H, 2 Â CH2N), 2.93
(s, 2H, CH2S), 2.52 (t, 4H, J ¼ 6.5 Hz, 2 Â CH2CH2S), 1.45 (s, 3H, CH3);
13C NMR (63 MHz, CDCl3: ꢀ 171.89 (CO), 137.99 (Ar-C), 128.95 (CH-Ar),
128.84 (CH-Ar), 127.16 (CH-Ar), 54.20( C(CO)2), 39.70(CH 2S), 38.40
(2 Â SCH2Ph), 37.88 (SCH2Ph), 35.77 (NCH2), 30.81 (2 Â CH2S), 20.24
(CH3); MS (CI/NH3): 553 (MHþ); High Resolution MS (CI/CH4): m/z
calc. for C30H37N2O2S3 (MHþ): 553.2017; found: 553.2018.
GeneralProcedure for Debenzyal tion
Sodium (ꢁ1.6 g, 70mmol) was added in small portions to a solution of
benzylated diamide (10.2 mmol) in anhydrous THF (50 mL) and liquid
ammonia (100 mL) until the deep blue color remained for 15 min. After
addition of solid ammonium chloride (6 g, 112 mmol) and evaporation of
ammonia under Ar, the mixture, cooled to 0ꢀC, was acidified by aq. 2M HCl
(pH ffi 1), extracted with EtOAc (3 Â 50mL), and the combined organic
layers were washed with saturated aq. NaCl, dried (MgSO4), and evaporated.

1330
HEINRICH, CHOTTARD, AND LI
The crude product was purified by chromatography on silica gel (1:1
EtOAc-cyclohexane) to afford the corresponding tris-thiol as a colorless
solid. All of the following compounds were prepared according to this
procedure.
N,N0-bis-(2-mercapto-2-methylpropyl)-2-(mercaptomethyl)-2-methyl-
malonyl diamide (1): from 10 (6.2 g, 10.2 mmol); yield 2.95 g (85%); m.p.
(cyclohexane): 84ꢀC; 1H NMR (250MHz, Me 2SO-d6): ꢀ 7.83 (t, 2H,
J ¼ 5.5 Hz, D2O exchangeable, NH), 3.25 (m, 4H, CH2N), 3.01 (d, 2H,
J ¼ 8.4 Hz, CH2SH), 2.72 (s, 2H, D2O exchangeable, Me2CSH), 2.15 (t,
1H. D2O exchangeable, CH2SH), 1.42 (s, 3H, CH3), 1.24 (s, 12H,
4 Â CH3); 13C NMR (63 MHz, CDCl3: ꢀ 171.61 (CO), 55.48 (C(CO)2),
52.44 (NCH2), 45.16 (Me2CSH), 33.05 (CH2S), 29.96 (4 Â CH3); 19.46
(CH3), MS (CI/NH3): 339 (MHþ); IR (CHCl3): ꢁ 1675 cmÀ1 (CO), 3440,
À1
3330cm
(CONH); High Resolution MS (CI/CH4): m/z calc. for
C13H27N2O2S3 (MHþ): 339.1235; found: 339.1234.
N,N0-bis-(2-mercapto-2-methylpropyl)-2-(2-mercaptoethyl)-2-methyl-
malonyl diamide (2): from 13 (1.793 g, 2.9 mmol); yield 975 mg (96%); m.p.
(cyclohexane): 93ꢀC; 1H NMR (250MHz, CDCl 3): ꢀ 7.16 (t, 2H, J ¼ 6.1 Hz,
D2O exchangeable, NH), 3.32 (d, 4H, 2 Â CH2NH), 2.53–2.44 (m, 2H,
CH2CH2S), 2.24–2.17 (m, 2H, CH2CH2S), 1.63 (s, 2H, D2O exchangeable,
2 Â Me2CSH), 1.49 (s, 3H, CH3), 1.42 (t, 1H, J ¼ 7.9 Hz, D2O exchangeable,
CH2SH), 1.32 (s, 12H, 4 Â CH3); 13C NMR (63 MHz, CDCl3): ꢀ 172.26
(CO), 53.51 (C(CO)2), 52.30(CH N), 45.08 (Me2CS), 43.86 (CH2S), 29.92
2
(4 Â CH3), 20.12 (CH2CH2S), 19.06 (CH3); MS (CI/NH3): 353 (MHþ); High
Resolution MS (CI/CH4): m/z calc. For C14H29N2O2S3 (MHþ): 353.l391.
Found: 353.1379.
N,N0-bis-(2-mercaptoethyl)-2-(mercaptomethyl)-2-(methylmalonyl
diamide (3): from 15 (639 mg, 1.16 mmol); yield 266 mg (82%); m.p. (cyclo-
hexane): 88ꢀC; 1H NMR (250MHz, CDCl 3): ꢀ 7.17 (s br, 2H, D2O
exchangeable, NH), 3.44–3.36 (m, 4H, 2 Â CH2N), 2.95 (d, 2H, J ¼ 9.0Hz,
CH2S), 2.67–2.59 (m, 4H, 2 Â CH2CH2S), 1.61 (t, 1H, D2O exchangeable,
SH), 1.48 (s, 3H, CH3), 1.37 (t, 2H, J ¼ 8.4 Hz, D2O exchangeable, 2 Â SH);
13C NMR (63 MHz, CDCl3): ꢀ 171.63 (CO), 55.15 (C(CO)2), 42.57 (CH2N),
33.01 (CH2S), 24.25 (2 Â CH2S), 19.16 (CH3); MS (CI/NH3). 283 (MHþ);
High Resolution MS (CI/CH4) m/z calc. For C9H19N2O2S3 (MHþ):
283.0609. Found: 283.0604.
N-(2-benzylthio-2-methylpropyl)-1-benzylthio-2-methylpropionamide
(11): Carbonyldiimidazole (CDI, 163 mg, 1 mmol) was added at room tem-
perature under argon to a solution of the diacid 8 (116 mg, 0.457 mmol) in
anhydrous THE (2 mL). After vigorous stirring at room temperature for 30
min, a solution of the amine 9 (95 mg, 1 mmol) in anhydrous THF (2 mL)
was added to the mixture. After 3 days at room temperature, aq. HCl 1M

POLYDENTATE LIGANDS
1331
was added to reach pH ffi 1 and the product extracted with EtOAc (3 Â 30
mL). The organic layer was washed with water (20mL), saturated aq.
NaHCO3 (pH ffi 10), saturated aq. NaCl (20 mL), dried (MgSO4), and eva-
1
porated to afford 11 as a pure (NMR), colorless oil (114 mg, 65%). H
NMR (250MHz, CDCl 3): ꢀ7.33–7.20(m, 10H, Ar), 5.80(s br, 1H, NH),
3.69 (s, 4H, 2 Â SCH2Ph), 3.25–3.20(m, 2H, CH 2N), 2.71 (dd, 1H,
JAB ¼ 13.1 Hz J ¼ 8.1 Hz, BnSCHAHB), 2.42 (dd, 1H, J ¼ 5.9 Hz,
SCHAHB), 2.19 (m, 1H, C(O)CHCH3), 1.23 (s, 6H, 2 Â CH3), 1.11 (d, 3H,
J ¼ 7 Hz, CHCH3); 13C NMR (63 MHz, CDCl3): ꢀ 174.55 (CO), 138.24 (Ar-
C), 138.04 (Ar-C), 128.66 (Ar-CH), 128.43 (Ar-CH), 128.35 (Ar-CH), 126.88
(Ar-CH), 47.11 (Me2CS), 46.59 (CH2N), 41.50( CHCO), 36.83 (SCH2Ph),
35.18 (SCH2Ph), 32.63 (CH2S), 26.53 (2 Â CH3), 17.50( CH3CH); MS (CI/
NH3): 388 (MHþ); High Resolution MS (CI/CH4): m/z calc. for
C22H30NOS2 (MHþ): 388.1769. Found: 388.1764.
N-(2-benzylthio-2-methylpropyl)-1-benzylthio-3-methylbutyramide
(16): A solution of trimethylaluminum in heptane (2M, 7.5 mL, 15 mmol)
was added dropwise under argon to a solution of the amine 9 (2.11 g,
10.8 mmol) in anhydrous toluene (7 mL) cooled to À15ꢀC. After stirring
at 25ꢀC until no more methane evolved, the reaction, cooled to 0ꢀC, was
added a solution of the diester 12 (1 g, 3.09 mmol) in anhydrous toluene
(4 ml). After 48 h at reflux, the mixture, cooled to À15ꢀC, was carefully
acidified by aq. 2M HCl (pH ffi 1), extracted with EtOAc (3 Â 40mL), and
the combined organic layers were washed with saturated aq. NaHCO3 (to
pH 8), and water (2 Â 20mL), dried (MgSO 4) and evaporated. The crude
product was purified by chromatography on silica gel (3:7 EtOAc-cyclohex-
1
ane) to give the monoamide 16 as a pale-yellow oil (590mg, 48%). H NMR
(250MHz, CDCl 3): ꢀ 7.36–7.20(m, 10H, Ar), 5.76 (t, 1H, J ¼ 5.8 Hz, NH),
3.68 (s, 2H, SCH2Ph), 3.67 (s, 2H, SCH2Ph), 3.20(d, 2H, NCH 2), 2.45–2.26
(m, 4H, CH2CH2S), 1.93 (m, 1H, C(O)CHCH3), 1.25 (s, 6H, 2 Â CH3), 1.07
(d, 3H, J ¼ 6.9 Hz, CHCH3); 13C NMR (63 MHz, CDCl3): ꢀ 175.59 (CO),
138.21 (Ar-C), 128.82 (Ar-CH), 128.67 (Ar-CH), 128.67 (Ar-CH), 128.49
(Ar-CH), 127.61 (Ar-CH), 127.13 (Ar-CH), 126.96 (Ar-CH), 47.14 (CH2N),
46.81 (Me2CS), 40.20 (CHCO), 36.12 (CH2S), 33.18 (SCH2Ph), 32.87
(SCH2Ph), 29.27 (CH2CH2S), 26.76 (CH3), 26.69 (CH3), 17.86 (CH3CH);
MS (CI/NH3): 402 (MHþ); High Resolution MS (CI/CH4): m/z calc. for
C23R32NOS2 (MHþ): 402.1925. Found: 402.1929.
N,N0 bis-(2-mercapto-2-methylpropyl)-2,2-dimethylmalonyl diamide
(4): To a suspension of 1-amino-2-methyl-2-propanethiol hydrochloride
(18) (184 mg, 1.3 mmol) in anhydrous CH2Cl2 (5 mL) were added succes-
sively triethylamine (346 mL, 2.49 mmol) and dimethylmalonyl dichloride
(17) (100 mg, 0.592 mmol) at 0ꢀC under argon. After vigorous stirring at
room temperature for 16 h, aq. HCl 1M was added to the mixture to reach

1332
HEINRICH, CHOTTARD, AND LI
pH ffi 1 and the product extracted with CH2Cl2 (2 Â 20ml). The organic
layer was washed with saturated aq. NaHCO3 (10ml), water (10ml), dried
(MgSO4), and evaporated to afford 4 as a pure (NMR), colorless solid
(165 mg, 91%). m.p. (cyclohexane) 92ꢀC; H NMR (250MHz, Me 2SO-d6):
1
ꢀ 7.60(t, 2H, J ¼ 6.3 Hz, D2O exchangeable, NH), 3.22 (d, 4H, CH2N), 2.71
(s, 2H, D2O exchangeable, SH), 1.35 (s, 6H, 2 Â CH3), 1.22 (s, 12H,
4 Â CH3); 13C NMR (63 MHz, CDCl3): ꢀ 173.41 (CO), 52.09 (CH2) 49.35
(C(CO)2), 45.09 (Me2CSH), 29.72 (4 Â CH3), 23.90(2 Â CH3); MS (CI/
À1
NH3): 307 (MHþ); IR (CHCl3): ꢁ 3320, 3450 cmÀ1 (CONH), 1670cm
(CO); Anal. calc. for C13H26N2O2S2 (306.49): C 50.95, H 8.55, N 9.14.
Found: C 50.97, H 8.59, N 9.25.
ACKNOWLEDGMENTS
This work was supported by the European Commission TMR-
NOHEMIP, contract no. ERBFMRX-CT98-0174.
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Received in the UK June 13, 2000