Desymmetrization reactions: A convenient synthesis of aromatic diamide diamines

Article abstract of DOI:10.1055/s-2001-16076

A two-step process for the synthesis of various diamide diamines derived from 1,n-diamino benzene compounds is described. The amidation reaction is simple, mild, involves readily available bis(N-acylthiazolidine-2-thione) derivatives as acylating agents and requires only stoichiometric equivalents of diamine and acylating agents.

Full text of DOI:10.1055/s-2001-16076

PAPER
1471
Desymmetrization Reactions: A Convenient Synthesis of Aromatic Diamide
Diamines
A
Convenient
Sy
l
nthesis
a
of Aromati
u
c
D
iamide
D
d
iamines e Picard,* Nathalie Arnaud,1 Pierre Tisnès
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique, CNRS UMR 5068, Université Paul Sabatier, 118 route de
Narbonne, 31062 Toulouse cedex 04, France
Fax +33(5)61556011; E-mail: picard@chimi.ups-tlse.fr
Received 29 January 2001; revised 27 March 2001
H
N
H
N
Abstract: A two-step process for the synthesis of various diamide
diamines derived from 1,n-diamino benzene compounds is de-
scribed. The amidation reaction is simple, mild, involves readily
available bis(N-acylthiazolidine-2-thione) derivatives as acylating
agents and requires only stoichiometric equivalents of diamine and
acylating agents.
NH2
NH2
R
Act
R
Act
+
2
O
O
O
O
NH2
H2N
1a, b
3a, b
2a
O
N
Key words: regioselectivity, aromatic diamines, acylation, dia-
mides, N-acylthiazolidine-2-thione
N
S
,
,
OCH3
Act = Cl, OCOtBu,
O
S
,
O
Me
O
Me
O
Aromatic diamide diamines are useful precursors for the
synthesis of several classes of compounds, which are
widely used in host guest chemistry for the selective rec-
ognition of metal ions or neutral molecules. Applications
of these building blocks include bis(benzimidazoyl) and
diamide diimide derivatives2,3 or dissymetrical tetraa-
R
=
O
1a
O
1b
O
O
O
O
O
Scheme 1
mides and tetralactams.4,5 They are also key intermediates Here we report a simple and mild method, which produces
for the access to amide-based catenanes.6 Aromatic dia- aromatic diamide diamines in good yields even when sto-
mide diamines themselves have been also tested as drug ichiometric equivalents of diamine and activated diacid
candidates,7 ion chelating agents8 or in asymmetric syn- are utilized. This procedure allows the efficient use of a
thesis.9
diamine without resorting to costly and time-consuming
procedures. Preliminary results of this work have been
previously published.13
The preparation of such compounds involves a strategy
based on the formation of amide bonds and on the differ-
entiation of two chemically equivalent aromatic amino In connection with our studies directed towards the syn-
groups. Amide bonds are generally formed quite simply thesis of macrocyclic polylactams,14 we needed an effi-
via the reaction of an activated acid with an amine,10 but cient method for the access to diamide diamines 3a,b
direct monoacylation of symmetrical diamines is fre- derived from 1,2-diaminobenzene and diglycolic acid or
quently complicated by the tendency to bis-acylation side 2,3-O-isopropylidene-L-tartaric
acid
respectively
reaction. The utilization of stoichiometric equivalents of (Scheme 1). In studies on the reaction of symmetrical ali-
an aromatic diamine and a diacid derivative usually gen- phatic diamines with iso(thio)cyanates15 or activated ac-
erates a mixture of the diamide diamine compound, cyclic ids,16 it has been shown that a decrease of the reactivity of
(polylactams) and polymeric products. To date this pitfall the electrophilic reagent leads to increased yields in
has been circumvented most easily by employing a large mono-substituted diamines. Thus, we carried out a study
excess of the starting diamine relative to the acylating in order to compare the yield of diamide diamines 3a,b as
agent.4–6,8a However, the low volatility of aromatic di- a function of the reactivity of the acylating group
amines makes the separation of the diamide diamine prod- (Table 1).
uct from unreacted diamine troublesome. Two indirect,
multistep methods have been also described to obtain this
family of compounds. They involve the use of a nitro-
Table 1 Comparison of the Yield (%) of Diamide Diamines 3a,b
from the Reaction of 1,2-Diaminobenzene with Various Acylating
Agentsa Derived from 1 (Scheme 1)
aromatic amine, followed by reduction of the nitro
group,2a–c,11 or the selective monoprotection of one nitro-
Act
3a
Cl
20
18
OCOBu-t OSu
TT
80
60
OMe
gen atom of the diamine, followed by acylation of the re-
29
24
0 (79)b
0 (75)b
0
0
maining nitrogen and finally deprotection.12
3b
Synthesis 2001, No. 10, 30 07 2001. Article Identifier:
1437-210X,E;2001,0,10,1471,1478,ftx,en;E01001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
a Abbreviations used: Su = succinimide, TT = 1,3-thiazolidine-2-
thione.
b Yield of bis(benzimidazolyl) product (See Figure).

1472
C. Picard et al.
PAPER
Table 2 Preparation of Diamide Diamines 3a–ua
monly used in peptide chemistry, has been reported to be
successful in the monoacylation of symmetrical aliphatic
diamines,16 but unsuccessful when 1,2-diaminobenzene
was used. Efforts to synthesize 3a,b via the hydroxysuc-
cinimide route were thwarted by the exclusive formation
(yields greater than 75%) of bis(benzimidazolyl) deriva-
tives (Figure). It should be noted that this reaction takes
place smoothly at room temperature, in sharp contrast
with other methodologies17 used for the preparation of
such compounds. Acylation was also attempted with less
active reagents, such as dimethyl esters. These esters are
known to react with aliphatic diamines,18 but owing to the
lesser nucleophilicity of the aromatic diamine, no reaction
occurred in these experiments, even after long reaction
time. Finally, the solution to the synthesis of diamide di-
amines 3a,b was found by the activation of the diacid as a
bis(2-mercaptothiazolide). As a matter of fact, acids acti-
vated with 1,3-thiazolidine-2-thione (TTH) react smooth-
ly with aromatic amines,19 their reactivity being much
lower than that of succinimide esters and higher than that
of methyl esters. Furthermore, these acylating agents are
stable and easy to handle in the open atmosphere at room
temperature, and form after aminolysis a stable byprod-
uct; the 1,3-thiazolidine-2-thione that will not induce salts
formation or side reactions. Reactions were carried out at
room temperature in dichloromethane by addition of mer-
captothiazolides 1a,b to two equivalents of 1,2-diami-
nobenzene. The target compounds 3a,b were isolated by a
simple filtration of the reaction mixture (3a) or by chro-
matography on silica gel (3b) with 80% and 60% yield,
respectively. It should be noted that the higher yield ob-
served with 3a does not reside in its precipitation from the
solution when it is formed (releasing it out of competition
from acylating agent). Similar yield was observed when a
better dissolving medium (DMF) was used.
Entry
Reagents
Diamide Diamine 3b
Yield (%)c
mp (°C)d
1
2
a
b
c
d
e
f
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
80 (93)e
60
169–170
168–169
208–210
189–190
164–165
158–159
216–218
228–230
236–237
200–201
193–194
192–193
171–173
163–165
213–214
175–177
236–238
154–156
amorphous solid
218–219
134–135
87
94
92
70
g
h
i
1g
1h
1i
52
68
91
j
1j
57 (75)e
81
k
l
1k
1a
1a
1a
1a
1a
1i
59f
63f
46f
55f
45
m
n
o
p
q
r
2f
69
1a
1a
1i
2g
2h
2h
2i
98f
90
s
t
98
91f
In order to demonstrate the easy access of the starting acy-
lating agents and to explore the usefulness of this method,
the selective functionalization of 1,2 diaminobenzene
with nine different bis(mercaptothiazolide) derivatives
was examined (Scheme 2 and Table 2, entries c–k).
Acylthiazolidinethiones may be prepared by the reaction
of 1,3-thiazolidine-2-thione with the carboxylic acid, in
the presence of (i) 1,3-dicyclohexylcarbodiimide (DCC)
with a catalytic amount of 4-dimethylaminopyridine
(DMAP),19,20 and (ii) 2-chloro-1-methylpyridinium chlo-
u
1a
a Reactions conditions: mercaptothiazolide (1 equiv), diamine (2
equiv), CH2Cl2 as solvent except for 3n (DMF) and 3o (MeCN).
b The alphabets a–u in the entry correspond to the numbering of the
products 3a–u. Elemental analysis (C, H, N) calculated and found
values were within 0.4% for all compounds 3 except for 3n (H,
0.49) and 3r (C, 0.45).
c Refers to isolated product.
d Recrystallization solvent: MeCN.
e Reactions conditions: mercaptothiazolide (1 equiv), diamine (3
equiv).
f For compounds 3l,m,r the methyl, chloro, or fluoro substituents are
in the 4,4' position. For compound 3o the methoxycarbonyl substitu-
ents are in the 5,5' position. For compound 3u the methyl substituents
are in the 3,3' position.
H
N
H
N
O
N
N
The reaction of diacid dichlorides 1a,b (Act = Cl) with
two equivalents of 1,2-diaminobenzene in anhydrous
THF in the presence of triethylamine afforded the corre-
sponding diamide diamines 3a,b after aqueous workup
and column chromatography in ~20% yield. Substitution
of an anhydride group for a chloro group in the diacid
dichloride (mixed pivalic anhydride activation) gave also
poor yields of the target products. The procedure involv-
ing N-hydroxysuccinimide (HOSu) active esters, com-
Me
O
Me
O
H
H
N
N
N
N
Figure Structures of bis(benzimidazolyl) derivatives isolated in the
diamide diamine formation reaction via the hydroxysuccinimide rou-
te
Synthesis 2001, No. 10, 1471–1478 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Synthesis of Aromatic Diamide Diamines
1473
ride,21 or with the acid chloride in the presence of thali-
um(I) salt19,20 or triethylamine.22 Compounds 1c–k were
easily prepared by using the first and the last methods and
were obtained in yields ranging from 58% to 99% de-
pending on the reagent (acyl chloride route giving the best
yields). These activated diacids were readily character-
ized by their yellow color and by their 1H NMR spectra.
As a matter of fact their formation was accompanied by a
characteristic downfield shift of the CH2N protons of the
R'
NH2
2
S
N
R
N
S
+
O
O
S
S
NH2
1
2
H
N
H
R'
R'
R
N
O
O
NH2
NH2
heterocyclic moiety (
0.6 ppm) as compared to the
R
3
starting thiazolidine-2-thione ( = 3.98). Table 2 shows
that these aliphatic or aromatic activated diacids gave the
corresponding diamide diamines 3c–k in moderate (52%)
to high yields (92%). These yields may be improved by
using larger amount of diamines. For instance, when the
reactions were carried out with mercaptothiazolides 1a or
1j in the presence of three equivalents of diamine 2a,
compounds 3a or 3j were obtained in 93% and 75% yield,
respectively, versus 80% and 57%, respectively, when
two equivalents of diamine were used. One can note that
this amidation reaction was also carried out with an amino
acid residue (L-glutamic acid) and afforded compound 3k
in a good yield (Table 2, entry k). This result is in agree-
ment with the successful application of mercaptothiaz-
olide activation in peptide synthesis.23
O
O
NH2
(CH2)3
(CH2)6
(CH2)12
1c
2a
2b
O
O
NH2
NH2
1d
O
O
NH2
NH2
H3C
Cl
2c
2d
1e
1f
O
O
NH2
NH2
O
2
O
O
NH2
NH2
F
Boc
N
MeOOC
2e
2f
1g
1h
As one can see from the other examples gathered in
Table 2, the diamide diamines derived from substituted
1,2-diaminobenzenes were obtained in reasonable yields
(entries l–o). For these acylation reactions an exclusive re-
gioselectivity was observed, accordingly with the activat-
ing or deactivating nature of the substituent on the ring. A
limitation of this method was found in acylation of 2,3-di-
aminonaphtalene. Owing to the less basic and less nucleo-
philic nature of this polyaromatic diamine, no reaction
occurred in this experiment. This suggests that, with 1,2-
diaminobenzene derivatives that are strongly deactivated,
a more reactive diacid derivative is required to have ac-
cess to the title compounds.
O
O
O
NH2
NH2
Boc
N
2
O
NH2
NH2
2g
1i
H3C
O
O
NH2
NH2
NH2
2h
2i
1j
N
H2N
H3C
O
O
O
NHBoc
1k
Our method is also applicable to other 1,n-diaminoben-
zenes under similar reaction conditions. When one equiv-
alent of activated diacids 1a,i was condensed with two
equivalents of 1,3- or 1,4-diaminobenzene derivatives the
corresponding diamide diamines were always the pre-
dominant products (Table 2, entries p–u). It is noteworthy
that the compounds derived from 1,4-diaminobenzene, a
core that is often used as a linker, were obtained with an
excellent yield (>90%).
H2N
O
Scheme 2
forms would be expected in the 1H and 13C NMR spectra
of these diamide compounds. With the exception of
3g,h,k, compounds 3 showed a single resonance in NMR
spectra for each chemically non-equivalent hydrogen or
carbon. This suggested the existence of several rotamers
in rapid interconversion (with respect to the time scale of
NMR), or more certainly the presence of a single rotamer
with N–H amide bond in the trans conformation.24 On the
contrary, the restricted rotation about the C–N bond of the
carbamate group(s)25 induced more complex NMR spec-
tra for symmetrical compounds 3g and 3h.
The structures proposed for new diamide diamine com-
pounds 3 are consistent with data derived from infrared
and nuclear magnetic resonance spectra in addition to sat-
isfactory combustion analysis and molecular weights de-
termined by mass spectrometry analyses (Table 3).
Owing to the phenomenon of hindered internal rotation
around the carbon–nitrogen bond of the amide group,24
the presence of signals corresponding to the trans and cis
Synthesis 2001, No. 10, 1471–1478 ISSN 0039-7881 © Thieme Stuttgart · New York

1474
C. Picard et al.
PAPER
Table 3 Spectroscopic Data for Diamide Diamines 3a–u
Prod- IR (KBr)
uct
1H NMR (200 MHz, DMSO-d6)a
, J (Hz)
13C NMR (50.3 MHz, DMSO-d6)a
MS
m/z (%)
(cm–1)
3a
3429, 3366, 3308 4.27 (s, 4 H, CH2), 4.94 (br s, 4 H, NH2), 6.58 (td, 70.7 (CH2), 115.8 (CH), 116.1 (CH),
(NH2, NH), 1679, 2 H, J = 8.0, 1.5, Ar-H), 6.76 (dd, 2 H, J = 8.0, 122.2 (C–NH), 126.2 (CH), 126.5
315 (100) [M + H]+
1653, 1612
(C=O)
1.5, Ar-H), 6.97 (td, 2 H, J = 8.0, 1.5, Ar-H), 7.18 (CH), 142.8 (C–NH2), 167.9 (C=O)
(dd, 2 H, J = 8.0, 1.5, Ar-H), 9.35 (s, 2 H, NH)
3bb
3446, 3380, 3343 1.54 (s, 6 H, CH3), 4.85 (s, 2 H, CH), 4.87 (br s, 26.3 (CH3), 77.9 (CH), 112.1
371 (100) [M + H]+
(NH2, NH), 1661 4 H, NH2), 6.59 (td, 2 H, J = 8.0, 1.5, Ar-H), 6.76 [C(CH3)2], 115.8 (CH), 116.1 (CH),
(C=O)
(dd, 2 H, J = 8.0, 1.5, Ar-H), 6.97 (td, 2 H,
J = 8.0, 1.5, Ar-H), 7.20 (dd, 2 H, J = 8.0, 1.5,
Ar-H), 9.37 (s, 2 H, NH)
122.2.(C–NH), 126.0 (CH), 126.6
(CH), 142.6 (C–NH2), 167.8 (C=O)
3c
3411, 3321, 3263 1.92 (quint, 2 H, J = 7.3, CH2), 2.41 (t, 4 H,
(NH2, NH), 1642 J = 7.3, CH2CO), 4.88 (br s, 4 H, NH2), 6.54 (td, 116.1 (CH), 123.4 (C–NH), 125.4
(C=O) 2 H, J = 8.0, 1.5, Ar-H), 6.73 (dd, 2 H, J = 8.0, (CH), 125.7 (CH), 141.9 (C–NH2),
21.4 (CH2), 35.0 (CH2), 115.8 (CH),
313 (100) [M + H]+
355 (100) [M + H]+
1.5, Ar-H), 6.90 (td, 2 H, J = 8.0, 1.5, Ar-H), 7.19 170.8 (C=O)
(dd, 2 H, J = 8.0, 1.5, Ar-H), 9.13 (s, 2 H, NH)
3d
3401, 3332, 3266 1.37 (m, 4H, CH2), 1.60 (m, 4H, CH2), 2.33 (t, 4 25.2 (CH2), 28.5 (CH2), 35.7 (CH2),
(NH2, NH), 1642 H, J = 7.3, CH2CO), 4.78 (br s, 4 H, NH2), 6.54 115.8 (CH), 116.1 (CH), 123.5 (C–
(C=O)
(td, 2 H, J = 8.0, 1.5, Ar-H), 6.72 (dd, 2 H,
NH), 125.2 (CH), 125.6 (CH), 141.8
J = 8.0, 1.5, Ar-H), 6.90 (td, 2 H, J = 8.0, 1.5, Ar- (C–NH2), 171.1 (C=O)
H), 7.17 (dd, 2 H, J = 8.0, 1.5, Ar-H), 9.04 (s, 2
H, NH)
3e
3428, 3345, 3286 1.29 (m, 16 H, CH2), 1.60 (m, 4 H, CH2), 2.31 (t, 25.2 (CH2), 28.6 (CH2), 28.75 (CH2), 439 (100) [M + H]+
(NH2, NH), 1649 4 H, J = 7.3, CH2CO), 4.80 (br s, 4 H, NH2), 6.55 28.8 (CH2), 29.0 (CH2), 35.7 (CH2),
(C=O)
(td, 2 H, J = 8.0, 1.5, Ar-H), 6.72 (dd, 2 H,
115.8 (CH), 116.1 (CH), 123.5 (C–
J = 8.0, 1.5, Ar-H), 6.90 (td, 2 H, J = 8.0, 1.5, Ar- NH), 125.2 (CH), 125.6 (CH), 141.8
H), 7.16 (dd, 2 H, J = 8.0, 1.5, Ar-H), 9.02 (s, 2 (C–NH2), 171.1 (C=O)
H, NH)
3f
3466, 3369, 3265 3.80 (s, 4 H, CH2), 4.15 (s, 4 H, CH2CO), 4.78 (br 70.1 (CH2), 70.2 (CH2), 116.0 (CH),
(NH2, NH), 1657, s, 4 H, NH2), 6.58 (td, 2 H, J = 8.0, 1.5, Ar-H), 116.3 (CH), 122.7 (C–NH), 125.6
1621 (C=O) 6.76 (dd, 2 H, J = 8.0, 1.5, Ar-H), 6.92 (td, 2 H, (CH), 126.1 (CH), 142.2 (C–NH2),
359 (100) [M + H]+
414 (100) [M + H]+
J = 8.0, 1.5, Ar-H), 7.22 (dd, 2 H, J = 8.0, 1.5,
168.1 (C=O)
Ar-H), 8.97 (s, 2 H, NH)
3g
3430, 3365, 3285 1.40 (s, 9 H, CH3), 4.13 (s, 4 H, CH2), 4.85 (br s, 27.8 (CH3), 52.9, 53.2 (CH2), 79.9
(NH2, NH), 1685 4 H, NH2), 6.57 (m, 2 H, Ar-H), 6.72 (dd, 2 H, [C(CH3)3)] 115.4, 115.7, 115.8, 116.0
J = 7.4, 1.5, Ar-H), 6.93 (td, 2 H, J = 7.4, 1.5, Ar- (CH), 122.2, 122.5 (C–NH), 125.2,
(C=O, Boc),
1650 (C=O)
amide)
H), 7.14 (m, 2 H, Ar-H), 9.80 (s, 2 H, NH)
126.0, 126.1, 126.4 (CH), 142.1, 142.7
(C–NH2), 154.7 (C=O, Boc), 168.8,
169.0 (C=O)
3h
3i
3434, 3359, 3274 1.38, 1.44 (2 s, 18 H, CH3), 3.42 (s, 4 H, CH2N), 27.9 (CH3), 45.7, 46.1 (CH2), 49.8,
(NH2, NH), 1687 3.99 (s, 4 H, CH2CO), 4.83 (br s, 4 H, NH2), 6.55 50.5 (CH2), 78.7, 78.9 [C(CH3)3],
557 (100) [M + H]+
(C=O, Boc),
1631 (C=O,
amide)
(td, 2 H, J = 7.5, 1.5, Ar-H), 6.73 (dd, 2 H,
J = 7.5, 1.5, Ar-H), 6.92 (td, 2 H, J = 7.5, 1.5, Ar- (C–NH), 125.3, 125.7, 126.0 (CH),
H), 7.14 (dd, 2 H, J = 7.5, 1.5, Ar-H), 9.15 (s, 2 142.1, 142.3 (C–NH2), 154.8, 155.0
115.5, 115.8, 116.1 (CH), 122.7, 123.0
H, NH)
(C=O, Boc), 167.8 (C=O, amide)
3441, 3360, 3319 4.97 (br s, 4 H, NH2), 6.63 (td, 2 H, J = 7.8, 1.5, 116.0, 116.2 (CH, a.b.m.), 123.0 (C– 347 (100) [M + H]+
(NH2, NH), 1655, a.b.m.), 6.81 (dd, 2 H, J = 7.8, 1.5, a.b.m.), 7.01 NH), 126.6, 126.7 (CH, a.b.m.),
1625 (C=O)
(td, 2 H, J = 7.8, 1.5, a.b.m.), 7.22 (dd, 2 H,
127.2, 128.3, 130.5 (CH, i.m.), 134.7
J = 7.8, 1.5, a.b.m.), 7.67 (t, 1 H, J = 7.7, i.m.), (C, i.m.), 143.1 (C–NH2), 164.9
8.17 (dd, 2 H, J = 7.7, 1.5, i.m.), 8.61 (t, 1 H,
J = 1.5, i.m.), 9.80 (s, 2 H, NH)
(C=O)
3j
3387, 3333, 3260 4.94 (br s, 4 H, NH2), 6.65 (td, 2 H, J = 8.0, 1.5, 115.8, 116.1 (CH, a.b.m.), 122.2 (C– 348 (100) [M + H]+
(NH2, NH), 1672 a.b.m.), 6.84 (dd, 2 H, J = 8.0, 1.5, a.b.m.), 7.05 NH), 124.7 (CH, py.m.), 127.2, 127.5
(C=O)
(td, 2 H, J = 8.0, 1.5, a.b.m.), 7.20 (dd, 2 H,
J = 8.0, 1.5, a.b.m.), 8.22–8.38 (m, 3 H, py.m.), 144.0 (C–NH2), 148.8 (C, py.m.),
10.67 (s, 2 H, NH) 161.9 (C=O)
(CH, a.b.m.), 139.5 (CH, py.m.),
Synthesis 2001, No. 10, 1471–1478 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Synthesis of Aromatic Diamide Diamines
1475
Table 3 Spectroscopic Data for Diamide Diamines 3a–u (continued)
Prod- IR (KBr)
uct
1H NMR (200 MHz, DMSO-d6)a
, J (Hz)
13C NMR (50.3 MHz, DMSO-d6)a
MS
m/z (%)
(cm–1)
3kc
3432, 3374, 3307 1.43 (s, 9 H, CH3), 2.05 (m, 2 H, CH2), 2.47 (m, 27.6 (CH2), 28.1 (CH3), 32.2 (CH2),
428 (100) [M + H]+
(NH2, NH), 1683 2 H, CH2CO), 4.16 (m, 1 H, CH), 4.81 (br s, 4 H, 54.5 (CH), 78.2 [C(CH3)3], 115.5,
((C=O, Boc)
1656,(C=O)
NH2), 6.56 (m, 2 H, Ar-H), 6.74 (m, 2 H, Ar-H), 115.7, 116.0 (CH), 122.7, 123.3 (C–
6.92 (m, 3 H, Ar-H and NH-Boc), 7.20 (m, 2 H, NH), 125.4, 125.7, 125.9, 126.2 (CH),
Ar-H), 9.05, 9.12 (2 s, 2 H, NH)
142.0, 142.5 (C–NH2), 155.5 ((C=O,
Boc), 170.5, 170.8 (C=O, amide)
3l
3429, 3370, 3309 2.18 (s, 6 H,CH3), 4.24 (s, 4 H, CH2), 4.77 (br s, 20.8 (CH3), 70.7 (CH2), 116.2, 116.9
(NH2, NH), 1678, 4 H, NH2), 6.39 (dd, 2 H, J = 8.0, 1.7, Ar-H5,5’), (CH3,3’, CH5,5’), 119.7 (C–NH), 126.2
343 (100) [M + H]+
383 (100) [M + H]+
1649, 1617
(C=O)
6.57 (d, 2 H, J = 1.7, Ar-H3,3’), 7.03 (d, 2 H,
J = 8.0, Ar-H6,6’), 9.27 (s, 2 H, NH)
(CH6,6’), 135.5 (C4,4’), 142.7 (C–NH2),
167.8 (C=O)
3m
3n
3430, 3366, 3306 4.26 (s, 4 H, CH2), 5.20 (br s, 4 H, NH2), 6.57 (dd, 70.6 (CH2), 114.4, 115.2 (CH3,3’
,
(NH2, NH), 1677, 2 H, J = 8.4, 2.4, Ar-H5,5’), 6.79 (d, 2 H, J = 2.4, CH5,5’), 120.9 (C–NH), 127.8 (CH6,6’),
1649, 1614
(C=O)
Ar-H3,3’), 7.16 (d, 2 H, J = 8.4, Ar-H6,6’), 9.33 (s, 130.5 (C4,4’), 144.5 (C–NH2), 168.2
2 H, NH) (C=O)
3438, 3366, 3315 4.22 (s, 4 H, CH2), 5.26 (br s, 4 H, NH2), 6.33 (td, 70.6 (CH2), 101.1 (d, J = 25.0, CH3,3’), 351 (100) [M + H]+
(NH2, NH), 1681, 2 H, J = 8.6, 2.9, Ar-H5,5’), 6.50 (dd, 2 H, 101.8 (d, J = 23.0, CH5,5’), 118.0 (C–
J = 11.2, 2.9, Ar-H3,3’), 7.05 (dd, 2 H, J = 8.6, 6.3 NH), 128.4 (d, J = 10.5, CH6,6’), 145.4
1651, 1621
(C=O)
Ar-H6,6’), 9.32 (s, 2 H, NH)
(d, J = 12.0, C–NH2), 161.1 (d,
J = 239.0, C4,4’), 168.2 (C=O)
3°
3428, 3337, 3287 3.76 (s, 6 H,CH3), 4.28 (s, 4 H, CH2), 5.77 (br s, 54.1 (CH3), 73.4 (CH2), 117.0 (CH3,3’), 431 (52)
(NH2, NH), 1715 4 H, NH2), 6.76 (d, 2 H, J = 8.5, Ar-H3,3’), 7.58
118.7 (C5,5’), 123.4 (C–NH), 131.3,
131.4 (CH4,4’, CH6,6’), 151.0 (C–NH2),
168.8, 171.2 (C=O)
[M + H]+
(C = O ester),
1669, 1632
(C=O)
(dd, 2 H, J = 8.5, 2.0, Ar-H4,4’), 7.79 (d, 2 H,
J = 2.0, Ar-H6,6’), 9.34 (s, 2 H, NH)
3p
3q
3432, 3345, 3308 4.21 (s, 4 H, CH2), 5.04 (br s, 4 H, NH2), 6.32 (m, 71.0 (CH2), 105.2 (CH), 107.5 (CH),
315 (100) [M + H]+
(NH2, NH), 1673, 2 H, Ar-H), 6.77 (m, 2 H, Ar-H), 6.96 (m, 4 H,
1611 (C=O) Ar-H), 9.75 (s, 2 H, NH)
109.7 (CH), 128.9 (CH), 138.8 (C–
NH), 149.0 (C–NH2), 167.7 (C=O)
3454, 3373, 3229 5.13 (br s, 4 H, NH2), 6.34 (m, 2 H, a.b.m.), 6.95 106.0, 108.3, 109.8 (CH, a.b.m.),
(NH2, NH), 1636, (m, 4 H, a.b.m.), 7.14 (t, 2 H, J = 2.0, a.b.m.), 126.8, 128.4 (CH, i.m.), 128.8 (CH
364 (100) [M +
NH4]+
1621, 1607
(C=O)
7.66 (t, 1 H, J = 7.7, i.m.), 8.09 (dd, 2 H, J = 7.7, a.b.m.), 130.3 (CH, i.m.), 135.4 (C,
1.6, i.m.), 8.45 (t, 1 H, J = 1.6, i.m.), 10.12 (s, 2 i.m.), 139.6 (C–NH), 148.9 (C–NH2),
H, NH)
164.8 (C=O)
3r
3457, 3364, 3281 2.01 (s, 6 H, CH3), 4.18 (s, 4 H, CH2), 4.89 (br s, 16.9 (CH3), 71.0 (CH2), 105.5, 107.9
(NH2, NH), 1673 4 H, NH2), 6.72 (dd, 2 H, J = 8.0, 2.0, Ar-H6,6’), (CH2,2’, CH6,6’), 116.7 (C4,4’), 129.8
343 (100) [M + H]+
315 (100) [M + H]+
(C=O)
6.85 (d, 2 H, J = 8.0, Ar-H5,5’), 7.01 (d, 2 H,
J = 2.0, Ar-H2,2’), 9.79 (s, 2 H, NH)
(CH5,5’), 136.7 (C–NH), 146.6 (C–
NH2), 167.4 (C=O)
3s
3t
3437, 3348, 3310 4.15 (s, 4 H, CH2), 4.95 (br s, 4 H, NH2), 6.53 (d, 70.9 (CH2), 113.9 (CH), 121.7 (CH),
(NH2, NH), 1663 4 H, J = 8.7, Ar-H), 7.26 (d, 4 H, J = 8.7, Ar-H), 127.4 (C–NH), 144.8 (C–NH2), 166.9
(C=O)
9.70 (s, 2 H, NH)
(C=O)
3463, 3363, 3319 4.88 (br s, 4 H, NH2), 6.58 (d, 4 H, J = 8.7,
114.0, 122.0 (CH, a.b.m.), 126.5,
364 (100) [M +
NH4]+
(NH2, NH), 1640 a.b.m.), 7.40 (d, 4 H, J = 8.7, a.b.m.), 7.62 (t, 1 128.3 (CH, i.m.), 128.4 (C–NH),
(C=O) H, J = 7.7, i.m.), 8.07 (dd, 2 H, J = 7.7, 1.6, i.m.), 130.0 (CH, i.m.), 135.3 (C, i.m.),
8.46 (t, 1 H, J = 1.6, i.m.), 9.93 (s, 2 H, NH) 144.5 (C–NH2), 164.2 (C=O)
3u
3411, 3384, 3289 2.05 (s, 6 H, CH3), 4.15 (s, 4 H, CH2), 4.71 (br s, 17.5 (CH3), 70.8 (CH2), 113.7 (CH5,5’
)
343 (100) [M + H]+
(NH2, NH), 1662 4 H, NH2), 6.57 (d, 2 H, J = 8.3, Ar-H5,5’), 7.14
119.4 (CH6,6’), 121.0 (C3,3’), 122.8
(CH2,2’), 127.3 (C–NH), 143.2 (C–
NH2), 166.8 (C=O)
(C=O)
(dd, 2 H, J = 8.3, 2.4, Ar-H6,6’), 7.19 (d, 2 H,
J = 2.4, Ar-H2,2’), 9.65 (s, 2 H, NH)
a Abbreviations used: a.b.m.: aminobenzene moiety, i.m.: isophtalic moiety, py.m.: pyridinyl moiety.
b [ ]D20 –21.3 (c = 1, DMSO).
c [ ]D20 +6.3 (c = 1, DMSO).
In conclusion, a two-step method was developed to pre- aminobenzene compounds, which are important
pare in good yields diamide diamines derived from 1,n-di- intermediates in organic synthesis. This method can be
Synthesis 2001, No. 10, 1471–1478 ISSN 0039-7881 © Thieme Stuttgart · New York

1476
C. Picard et al.
PAPER
line) was purchased from Lancaster Chemical Company, and used
without further purification.
carried out by a very simple procedure under mild and
neutral conditions and is convenient for the preparation of
large amounts of products. As a matter of fact, only sto-
ichiometric equivalents of diamine and acylating agent
are needed. The results presented here illustrate further
the potential of thiazolidine-2-thione amide for mediating
selective functional group transformation.26
Bis(2-mercaptothiazolides) 1a–k; General Procedure
Method A: To a stirred solution of 1,3-thiazolidine-2-thione (15
mmol) and Et3N (22 mmol) in anhyd THF (100 mL) was added
dropwise the suitable diacid dichloride (7.5 mmol) in anhyd THF
(30 mL) at 50°C. The reaction mixture was stirred for 2 h, and then
cooled to r.t. The triethylamine hydrochloride was filtered off and
washed with THF. The filtrate was washed with 0.5 N NaOH solu-
tion (50 mL), then brine (50 mL) and dried (Na2SO4). After removal
of the solvent, the yellow solid obtained was purified by filtration
through a silica gel plug (CH2Cl2–acetone).
Melting points were taken on a Kofler apparatus. 1H (200 MHz) and
13C (50.3 MHz) NMR spectra were recorded on a Bruker AC-200
spectrometer. IR spectra were determined with a Perkin-Elmer 883
spectrometer. Positive ES-MS spectra were performed with a Ner-
mag R10–10C spectrometer using the Desorption Chemical Ioniza-
tion (DCI/NH3) technique. Optical rotations were measured with a
Perkin Elmer 241 polarimeter. Elemental analyses were carried out
by the “Service Commun de Microanalyse élémentaire UPS-INP”
in Toulouse. Chromatographic purifications were performed by fil-
tration through Merck silica gel (15 m) or by column chromatog-
raphy (Amicon silica gel 70–200 m).
Method B: Dicyclohexylcarbodiimide (15 mmol) and a catalytic
amount of 4-dimethylaminopyridine were added to a solution of the
suitable diacid (7.5 mmol) and 1,3-thiazolidine-2-thione (15 mmol)
in CH2Cl2 (100 mL). The mixture was stirred at r.t. for 24 h and the
precipitate formed in the reaction was filtered off and washed with
CH2Cl2. The filtrate was washed with 0.5 N NaOH solution (2 40
mL) then brine (2 40 mL), dried and concentrated in vacuo to give
a yellow product, which was purified by filtration through a plug of
silica gel (CH2Cl2–acetone).
2,3-O-Isopropylidene-L-tartaric acid chloride was prepared as de-
scribed previously.14a The other diacid dichlorides were synthesized
from diacids using standard oxalyl chloride method. 1,4-Diami-
nobenzene, 2,5-diaminotoluene and 3,4-diaminotoluene were puri-
fied prior to use by recrystallization from benzene in the presence
of activated carbon. 1,3-Thiazolidine-2-thione (2-mercaptothiazo-
The yields, physical and spectroscopic data of bis (2-mercaptothia-
zolide) 1a–k are gathered in Table 4.
Table 4 Preparation and Spectroscopic Data for Bis(2-mercaptothiazolide) Derivatives 1a–k
Prod-
uct
Yield (%)a
(Method)b
Mp (°C)c
145–147d
not isolated
94–95
IR (CHCl3)
C=O(cm–1)
1H NMR (200 MHz,CDCl3)
, J (Hz)
13C NMR (50.3 MHz, CDCl3)
1a
1b
1c
95 (A)
76 (B)
1710
3.38 (t, 4 H, J = 7.5, CH2S), 4.61 (t, 4 H,
J = 7.5, CH2N), 5.12 (s, 4 H, CH2O)
29.3 (CH2S), 55.7 (CH2N), 71.9
(CH2O), 171.1 (C=O), 201.9 (C=S)
60 (A)e
45 (B)e
-
1.55 (s, 6 H, CH3), 3.45 (m, 4 H, CH2S),
4.55 (m, 4 H, CH2N), 6.57 (s, 2 H, CH)
-
97 (A)
1700
2.07 (quint, 2 H, J = 7.0, CH2), 3.28 (t, 4
H, J = 7.5, CH2S), 3.33 (t, 4 H, J = 7.0,
CH2CO), 4.57 (t, 4 H, J = 7.5, CH2N)
19.9 (CH2), 28.4 (CH2S), 37.5
(CH2CO), 56.1 (CH2N), 174.1(C=O),
201.7 (C=S)
1d
1e
87 (A)
109–110
107–108f
1699
1699
1.35 (m, 4 H, CH2), 1.67 (m, 4H, CH2),
3.22 (t, 4 H, J = 7.2, CH2CO), 3.27 (t, 4 H, 38.4 (CH2CO), 56.1 (CH2N), 174.8
J = 7.5, CH2S), 4.56 (t, 4 H, J = 7.5,
CH2N)
24.6 (CH2), 28.4 (CH2S), 28.8 (CH2),
(C=O), 201.6 (C=S)
89 (A)
1.26 (m, 16 H, CH2), 1.67 (m, 4 H, CH2), 24.8 (CH2), 28.4 (CH2S), 29.1, 29.4,
3.23 (t, 4 H, J = 7.2, CH2CO), 3.26 (t, 4 H, 29.5, 29.6 (CH2), 38.6 (CH2CO), 56.1
J = 7.5, CH2S), 4.56 (t, 4 H, J = 7.5,
(CH2N), 175.0 (C=O), 201.6 (C=S)
CH2N)
1f
92 (A)
62 (B)
134–135
152–154
1710
1706
3.37 (t, 4 H, J = 7.5, CH2S), 3.80 (s, 4 H, 29.6 (CH2S), 55.6 (CH2N), 71.1, 73.6
CH2O), 4.59 (t, 4 H, J = 7.5, CH2N), 5.02 (CH2O), 171.9 (C=O), 201.2 (C=S)
(s, 4 H, CH2CO)
1g
79 (B)
1.42 (s, 9 H, CH3), 3.35 (t, 4 H, J = 7.5,
28.3 (CH3), 29.4 (CH2S), 54.9, 55.2,
CH2S), 4.57 (t, 4 H, J = 7.5, CH2N), 4.91, 55.8, 55.9 (CH2CO, CH2N), 81.1 (C-
4.92 (2 s, 4 H, CH2CO)
(CH3)3), 155.2 (C=O, Boc), 171.1
(C=O, amide), 201.5, 201.6 (C=S)
1h
76 (B)
197–200
1698
1.39, 1.46 (2 s, 18 H, CH3), 3.34 (m, 8 H, 28.3, 28.5 (CH3), 29.3, 29.4 (CH2S),
CH2S, CH2NBoc), 4.57 (t, 4 H, J = 7.5,
CH2N), 4.83 (m, 4 H, CH2CO)
47.1, 47.4, 47.5 (CH2NBoc), 54.8, 55.4,
55.5, 55.6, 55.9 (CH2CO, CH2N), 80.4,
80.6, 80.7 [C(CH3)3], 155.2, 155.5
(C=O, Boc), 171.3, 171.5 (C=O,
amide), 201.4, 201.6 (C=S)
Synthesis 2001, No. 10, 1471–1478 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convenient Synthesis of Aromatic Diamide Diamines
1477
Table 4 Preparation and Spectroscopic Data for Bis(2-mercaptothiazolide) Derivatives 1a–k (continued)
Prod-
uct
Yield (%)a
(Method)b
Mp (°C)c
98–100
IR (CHCl3)
C=O(cm–1)
1H NMR (200 MHz,CDCl3)
, J (Hz)
13C NMR (50.3 MHz, CDCl3)
1i
91 (A)
1602
3.46 (t, 4 H, J = 7.4, CH2S), 4.52 (t, 4 H,
J = 7.4, CH2N), 7.43 (t, 1 H, J = 7.8, Ar-
H), 7.81 (dd, 2 H, J = 7.8, 1.7, Ar-H),
7.97(t, 1 H, J = 1.7, Ar-H)
29.9 (CH2S), 56.5 (CH2N), 128.4,
130.3, 133.1 (CH-Ar), 134.1 (C-Ar),
170.2 (C=O), 201.9 (C=S)
1j
99 (A)
58 (B)
104–105
170–172
1695
1698
3.51 (t, 4 H, J = 7.5, CH2S), 4.58 (t, 4 H,
J = 7.5, CH2N), 7.85 (m, 3 H, Ar-H)
30.6 (CH2S), 56.2 (CH2N), 126.5 (CH-
Ar), 138.1 (CH-Ar), 151.1 (C-Ar),
168.3 (C=O), 201.9 (C=S))
1kg
1.42 (s, 9 H, CH3), 1.97, 2.32 (m, 2 H,
28.0 (CH2), 28.4 (CH3), 28.5, 28.6
CH2), 3.38 (m, 6 H, CH2S, CH2CO), 4.56 (CH2S), 34.8 (CH2CO), 53.2 (CH),
(m, 4 H, CH2N), 5.29 (m, 1 H, CH), 6.18 56.1, 56.4 (CH2N), 80.2 [C(CH3)3],
(m, 1 H, NH)
155.4(C=O, Boc), 173.9, 174.2 (C=O,
amide), 201.3, 201.6 (C=S)
a Refers to isolated product unless otherwise noted.
b See experimental section.
c Solvent for recrystallization: EtOAc.
d Lit.14d mp 145–147°C.
e Determined from 1H NMR spectroscopy.
f Lit.20b mp 109–112°C.
g [ ]D20 –26.9 (c = 1, CHCl3).
Diamide Diamines 3a–u; General Procedure
(4) (a) Chin, T.; Gao, Z.; Lelouche, I.; Shin, Y.-G. K.;
Purandare, A.; Knapp, S.; Isied, S. S. J. Am. Chem. Soc.
1997, 119, 12849. (b) Tecilla, P.; Jubian, V.; Hamilton, A.
D. Tetrahedron 1995, 51, 435. (c) Aoki, I.; Kawahara, Y.;
Sakaki, T.; Harada, T.; Shinkai, S. Bull. Chem. Soc. Jpn.
1993, 66, 927. (d) Chang, S.-K.; Hamilton, A. D. J. Am.
Chem. Soc. 1988, 110, 1318.
(5) (a) Adams, H.; Carver, F. J.; Hunter, C. A.; Osborne, N. J.
Chem. Commun. 1996, 2529. (b) Kluger, R.; Tsao, B. J. Am.
Chem. Soc. 1993, 115, 2089. (c) Chang, S.-K.; VanEngen,
D.; Fan, E.; Hamilton, A. D. J. Am. Chem. Soc. 1991, 113,
7640. (d) Hunter, C. A. J. Chem. Soc., Chem. Commun.
1991, 749.
(6) (a) Vögtle, F.; Jäger, R.; Händel, M.; Ottens-Hildebrandt, S.
Pure Appl. Chem. 1996, 68, 225. (b) Carver, F. J.; Hunter,
C. A.; Shannon, R. J. J. Chem. Soc., Chem. Commun. 1994,
1277. (c) Ottens-Hildebrandt, S.; Meier, S.; Schmidt, W.;
Vögtle, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1767.
(d) Hunter, C. A. J. Am. Chem. Soc. 1992, 114, 5303.
(7) (a) Domagala, J. M.; Bader, J. P.; Gogliotti, R. D.; Sanchez,
J. P.; Stier, M. A.; Song, Y.; Prasad, J. V. N. V.; Tummino,
P. J.; Scholten, J.; Harvey, P.; Holler, T.; Gracheck, S.;
Hupe, D.; Rice, W. G.; Schultz, R. Bioorg. Med. Chem.
1997, 5, 569. (b) Bonsignore, L.; Loy, G.; Secci, D.; Logu,
A.; Palmieri, G. Farmaco 1990, 45, 1245. (c) Waisser, K.;
Odlerova, Z.; Gruenert, R. Pharmazie 1989, 44, 162.
(8) (a) Brooker, S.; deGeest, D. J.; Dunbar, G. S. Inorg. Chim.
Acta 1998, 282, 222. (b) Lu, Y. W. Tetrahedron 1997, 53,
16721.
To a stirred solution of 1,n-diaminobenzene derivative 2 (10 mmol)
in CH2Cl2 (25 mL) was added dropwise a solution of bis(2-mercap-
tothiazolide) 1 (5 mmol) in CH2Cl2 (90 mL) at r.t. After the addition
was complete (2 h), the mixture was allowed to stir until no further
disappearance of yellowish color was observed (3–5 d).
Diamide diamines 3a,c–e,l,o,p,r,t: were isolated by a simple filtra-
tion of the reaction mixture. The solid was washed with CH2Cl2 and
dried in vacuo.
Diamide diamines 3b,f–h,j,n,u: the reaction mixture was washed
with 2 N NaOH solution (2 50 mL), brine (2 50 mL), and dried
(Na2SO4). After the evaporation of the solvent under reduced pres-
sure, the crude product was purified on a silica gel column using
CH2Cl2–MeOH (95:05 for 3b,f,j; 90:10 for 3h), MeCN (3n) or
MeCN–MeOH (95:05 for 3g; 90:10 for 3u) as eluent.
Diamide diamines 3i,k,m,q,s: were isolated mainly by filtration.
Additional product was obtained after aqueous workup of the fil-
trate as mentioned above and chromatography on a silica gel col-
umn using CH2Cl2–acetone (70:30) (3i), CH2Cl2–MeOH (90:10)
(3k), CH2Cl2–acetone (70:30
50:50) (3m, s) or MeCN (3q) as
eluent.
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