From targeted aza-Michael addition to linked azaheterocyclic scaffolds

Article abstract of DOI:10.1016/j.tet.2014.07.038

A straightforward method for the synthesis of spaced, phenyl-linked bis(thiohydantoin) derivatives and (thio)hydantoins spiro-fused to pyrroline ring has been developed. All the synthetic strategies here presented rely on initial aza-Michael addition followed by acylation/regioselective ring-closure step involving DD, primary amine and iso(thio)cyanate in a 3-CR providing 1,3,5-trisubstituted (thio)hydantoins. The choice of opportune acyclic reagents in the sequential 3-CR followed by 1,4-nucleophilic addition/intramolecular ring closing and 1,3-dipolar cycloaddition permits a number of C–N and C–C formation that realizes different kind of linkage between several pharmacophores.

Full text of DOI:10.1016/j.tet.2014.07.038

Tetrahedron 70 (2014) 7336e7343
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
From targeted aza-Michael addition to linked azaheterocyclic
scaffolds
Orazio A. Attanasi a, Lucia De Crescentini a, Paolino Filippone a, Gianluca Giorgi b,
,
Simona Nicolini a, Francesca R. Perrulli a, Stefania Santeusanio a
*
a
ꢀ
Department of Biomolecular Science, Section of Organic Chemistry and Organic Natural Compounds, Universita degli Studi di Urbino “Carlo Bo”, Via I
Maggetti 24, 61029 Urbino, Italy
b
ꢀ
Department of Chemistry, Universita degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward method for the synthesis of spaced, phenyl-linked bis(thiohydantoin) derivatives and
(thio)hydantoins spiro-fused to pyrroline ring has been developed. All the synthetic strategies here
presented rely on initial aza-Michael addition followed by acylation/regioselective ring-closure step
involving DD, primary amine and iso(thio)cyanate in a 3-CR providing 1,3,5-trisubstituted (thio)hydan-
toins. The choice of opportune acyclic reagents in the sequential 3-CR followed by 1,4-nucleophilic ad-
dition/intramolecular ring closing and 1,3-dipolar cycloaddition permits a number of CeN and CeC
formation that realizes different kind of linkage between several pharmacophores.
Received 30 April 2014
Received in revised form 30 June 2014
Accepted 9 July 2014
Available online 15 July 2014
Keywords:
Aza-Michael addition
Multi-component reaction
Hydantoin
Ó 2014 Elsevier Ltd. All rights reserved.
Thiohydantoin
Heteroannulation
Spiro compounds
1. Introduction
2-thiohydantoins7b from 1,2-diaza-1,3-dienes (DDs)8 as readily
available building blocks.
The structural diversity of natural and synthetic heterocycles
has become a key topic in organic, bioorganic and medicinal
chemistry. As a result, there is an increasing need to access new
areas of chemical space with the aim to discover biologically rele-
vant heterocyclic molecules in a rapid and economic fashion. Multi-
component reactions (MCRs)1 have gained much importance in
synthetic organic chemistry as they produce the target compounds
in a single step avoiding the isolation of intermediates. MCRs can
use domino reactions or sequential reactions and have proved to be
efficient for the construction of many different types of
heterocycles.2
Since MCRs that afford products with reactive functional
groups capable of being utilized in a further reaction are powerful
methods for generating diverse collections of functionalized
heterocyclic templates,9 we envisioned the extension of our pre-
vious results to allow the synthesis of linked azaheterocyclic
architectures.
In a continuation of recent studies, we herein describe synthetic
strategy to spiro-fused as well as spaced azaheterocyclic scaffolds
based on initial 3-CR.
Specifically hydantoin and 2-thiohydantoin-based scaffolds ex-
hibit a wide array of properties ranging from bioscience materials3
to bioactive compounds;4 therefore, numerous synthetic strategies
both on solid support5 and in solution phase6 have been reported in
the literature.
2. Results and discussion
The aza-Michael reaction can be considered a hydroamination
process and it has been largely applied to DDs by our group as
a strategic starting point to produce different heterocyclic tem-
In this field our research group has recently developed a se-
plates.10 The
a-aminohydrazone A, resulted from the nucleophilic
quential 3-CR to afford selectively substituted hydantoins7a and
addition of primary amine 2 to DD 1, is a densely functionalized
derivative, which accounts for its chemical versatility through the
simultaneous presence of both electrophilic (i.e., ester and hydra-
zone functions) and nucleophilic (i.e., secondary amine) centres
(Scheme 1).
* Corresponding author. Tel.: þ39 (0)722 303442; fax: þ39 (0)722 303441;
e-mail address: stefania.santeusanio@uniurb.it (S. Santeusanio).
http://dx.doi.org/10.1016/j.tet.2014.07.038
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

O.A. Attanasi et al. / Tetrahedron 70 (2014) 7336e7343
7337
temperature leads to nucleophilic 1,4-addition to another DD 1
molecule affording 5,5-disubstituted intermediate 5 (Scheme 3). By
heating the crude reaction mixture, the two hydrazone side chains
of 5 co-operate in the heteroannulation process by means of
intramolecular nucleophilic attack. According to this synthetic ap-
proach, a (thio)hydantoin spiro-fused to a pyrroline ring (Scheme
3) can be generated. So, after removal of dioxane and purification
of the crude reaction mixture by flash chromatography, 6aei were
obtained in good yields (60e77%, Table 2). Moreover, this domino
process allows diversified substitution pattern at N-1 and N-3 of
the 2-thiohydantoin ring of 6aee with respect to those present in
similar compounds obtained from the reactivity of DDs with N,N0-
dialkylthioureas.11
Scheme 1. Proposed mechanism for the formation of 1,3,5-trisubstituted hydantoins
and 2-thio analogues 4.
The acylation process involving the secondary amine moiety of
A with isothiocyanate or isocyanate 3 generates the requisite
asymmetric thiourea or urea derivative B that in turn provides
regioselective nucleophilic attack at the terminal ester function of
the azo-ene system of 1 concluding in the 2-thiohydantoin or
hydantoin ring 4 formation (Scheme 1).
Using this consolidated sequential 3-CR protocol, regiose-
lectively 1,3,5-substituted hydantoins and 2-thio analogues 4aei
have been successfully prepared in good yields (63e86%)
(Scheme 2, Table 1).
Scheme 3. Synthetic pathway affording spiro-fused azaheterocycles 6aei.
The spiro-fused heterobicyclic structure has been confirmed by
single-crystal X-ray diffraction study of compound 6c12 (Fig. 1)
allowing the stereochemical assignment of the two asymmetric
carbons. By comparison of the 1H NMR chemical shifts values of
spiro derivatives 6aei, C5(R/S),C6(R/S) resulted the prevalent di-
astereomer isolable (60e77%). Only in the case of the reaction
affording compound 6c, it was possible to obtain the minor di-
astereomer C5(R/S),C6(S/R) in very small amount (9%) By virtue of
the yields recorded for the major diastereomer of 6aei, we can
conclude that in all cases the reaction proceeds with high
diastereoselectivity.
Hence, we reasoned that the propargylic appendage at N-1 of
the hydantoin core of 6h,i would give us a handle to enrich the
structure with an additional biologically active heterocycle.
Therefore, the optimized13 CuI-catalyzed Huisgen 1,3-dipolar
cycloaddition involving azides 7a,b and the propargyl function of
6h,i provides 1,4-disubstituted 1,2,3-triazole derivatives 8a,b in
Scheme 2. Sequential 3-CR protocol leading to 1,3,5-trisubstituted hydantoins and
2-thio analogues 4aei.
Both the heterocyclic structures possess reactive groups, namely
the hydrazone chain at C5-position of the ring, that can be utilized
for the preparation of spiro azaheterocyclic architectures. Thus, the
base-promoted carbanion formation from 4 in dioxane at room
Table 1
Results of the synthesis of 1,3,5-trisubstituted 2-thiohydantoin and hydantoin derivatives 4aei
Entry
DD 1
Amine 2
Isothiocyanate or isocyanate 3
Solvent
2-Thiohydantoin or hydantoin 4
Yielda (%)
R1
R2
X
R3
1
2
3
4
5
6
7
8
9
1a
1b
1b
1c
1c
1a
1b
1a
1c
CO2Et
COt2Bu
COt2Bu
CO2Me
CO2Me
CO2Et
COt2Bu
CO2Et
CO2Me
2a
2b
2a
2b
2a
2a
2b
2c
2c
n-Bu
n-Pr
n-Bu
n-Pr
n-Bu
n-Bu
n-Pr
Propargyl
Propargyl
3a
3b
3a
3b
3a
3c
3c
3d
3c
S
S
S
S
Ph
Me
Ph
Me
Ph
Ph
Ph
3-ClePh
Ph
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
EtOH
EtOH
EtOH
4a
4b
4c
4d
4e
4f
4g
4h
4i
71
63
69
64
S
88
O
O
O
O
67b
76b
63b
63b
a
Yield of pure isolated product.
See Ref. 7a.
b

7338
O.A. Attanasi et al. / Tetrahedron 70 (2014) 7336e7343
Table 2
Results of the synthesis of spiro azaheterobicyclic compounds 6aei
Entry
Starting 2-thiohydantoin or hydantoin 4
DD 1
C5(R/S),C6(R/S) Spiro derivative 6
X
R1
R2
R3
R4
R5
R6
Yielda (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
S
S
S
S
CO2Et
COt2Bu
COt2Bu
CO2Me
CO2Me
CO2Et
COt2Bu
CO2Et
CO2Me
n-Bu
n-Pr
n-Bu
n-Pr
n-Bu
n-Bu
n-Pr
Propargyl
Propargyl
Ph
Me
Ph
Me
Ph
Ph
Ph
3-Cl-Ph
Ph
1d
1e
1e
1f
1g
1e
1e
1e
1h
CO2Bn
CO2Me
CO2Me
CO2Bn
COt2Bu
CO2Me
CO2Me
CO2Me
CO2Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
6a
6b
6c
6d
6e
6f
6g
6h
6i
77
70
Me
Me
Me
Me
Me
Me
Me
Me
68 (9)b
76
S
70
68
69
66
O
O
O
O
60
a
Yield of pure isolated diastereomer.
Referred to the minor diastereomer C5(R/S),C6(S/R) identified.
b
excellent yields and high regioselectivity (Scheme 4). It is note-
worthy that by the choice of opportune acyclic reagents the se-
the yields of 10aei (73e84%) were obtained by easy filtration in
vacuo.
quential
3-CR,
followed
by
1,4-nucleophilic
addition/
intramolecular ring closing and 1,3-dipolar cycloaddition, allows
a number of CeC and CeN formation that realizes different kind of
linkage between several pharmacophores.
Scheme 5. Results of the sequential 3-CR to obtain spaced bis(2-thiohydantoin) de-
rivatives 10aei.
The sequential 3-CR strategy was also successfully applied to
produce phenyl-linked 2-thiohydantoin derivatives. As an example,
DD 1c (2 equiv) was reacted with amines 2b,d (2 equiv) in DCM at
room temperature affording the aza-Michael adduct intermediates
(TLC check) to be combined with 1,4-diisothiocyanatobenzene (11)
(1 equiv). The regioselective heteroannulation process at ester
function of DD took place during the night has provided 12a,b that
were collected by filtration from the reaction medium (Scheme 6).
Scheme 4. Results of the assembly of the 1,2,3-triazole moiety linked to spirocyclic
hydantoin ring.
Then, intrigued by the possibility to synthesize spaced 2-
thiohydantoin rings, we applied our sequential 3-CR procedure by
employing diamines. So, DDs 1b,c,i (2 equiv) quickly reacted with
diamines 9a,b (1 equiv) in CH2Cl2 at room temperature by means of
a double aza-Michael addition. After the discolouring of the re-
action mixture, isothiocyanates 3a,b (2 equiv) were added and the
reaction mixture was left at room temperature. TLC wasn’t helpful
in determining the reaction time, but gratifyingly the precipitation
of spaced bis(2-thiohydantoins) 10aei (Scheme 5, Table 3) from the
medium allowed us to establish the completion of the reaction and
Scheme 6. 3-CR synthesis of phenyl-linked 2-thiohydantoin derivatives 12a,b.
Table 3
Results of the synthesis of spaced bis(2-thiohydantoins) 10aeh
Entry DD 1
R1
Diamine 9 Isothiocyanate 3 Bis(2-thiohydantoin) 10
n
R3
Yielda (%)
1
2
3
4
5
6
7
8
9
1b COt2Bu
1b COt2Bu
1b COt2Bu
1c CO2Me
1c CO2Me
1c CO2Me
1i CONHPh 9a
1i CONHPh 9b
1i CONHPh 9a
9a
9b
9b
9a
9b
9b
1
4
4
1
4
4
1
4
1
3a
3a
3b
3a
3a
3b
3a
3a
3b
Ph
Ph
Me
Ph
Ph
Me
Ph
Ph
Me
10a
10b
10c
10d
10e
10f
10g
10h
10i
79
75
84
82
73
65
65
77
81
Fig. 1. ORTEP diagram of one molecule of the asymmetric unit of compound 6c. El-
lipsoids enclose 50% probability.
a
Yield of pure isolated product.

O.A. Attanasi et al. / Tetrahedron 70 (2014) 7336e7343
7339
3. Conclusions
NCH2CH2CH2CH3), 1.82 (3H, s, CH3), 3.35e3.44 (1H, m,
NCHaHbCH2CH2CH3), 3.94e4.01 (1H, m, NCHaHbCH2CH2CH3), 4.17
(2H, q, J¼7.2 Hz, OCH2CH3), 5.16 (1H, s, CH), 7.32 (2H, d, J¼7.0 Hz,
ArH), 7.41e7.55 (3H, m, ArH), 10.38 (1H, s, NH). 13C NMR (100 MHz,
In summary, as an extension of our previous results, we de-
veloped efficient synthetic pathways to build different kinds of
linkages between azaheterocyclic scaffolds of pharmacological
relevance (i.e., hydantoin, 2-thiohydantoin, 1,2,3-triazole). All the
strategies here presented rely on initial aza-Michael addition fol-
lowed by acylation/regioselective ring-closure involving DD, pri-
mary amine and iso(thio)cyanate in a 3-CR.
DMSO-d6) d: 12.5, 13.5, 14.5, 19.4, 28.4, 45.2, 60.8, 68.8, 128.7, 128.8,
133.6, 143.9, 153.9, 169.9, 181.9. MS (EI): m/z (%)¼376 (Mþ, 2), 361
(1), 288 (5), 149 (58), 137 (34), 125 (59), 111 (100). Anal. Calcd for
C18H24N4O3S (376.47): C, 57.43; H, 6.43; N,14.88. Found: C, 57.28; H,
6.51; N, 14.99.
The hydrazone functionality introduced by DD at the 5-position
of the hydantoin or 2-thiohydantoin ring combined with the elec-
trophilicity of the heterodiene system of DD framework, enable an
alternative route to assemble spiro (thio)hydantoins-based archi-
tectures14 as valuable compounds due to the biological activity
associated with these templates.15
4 . 2 . 2 . t e r t - B u t yl 2 - [ 1 - ( 1 - m e t hyl - 5 - o x o - 3 - p r o p yl - 2 -
thioxoimidazolidin-4-yl)ethylidene]hydrazinecarboxylate
(4b). Yield: 206.9 mg (63%). White powder, mp: 170e172 ꢁC
(dec) (from EtOAc/cyclohexane). IR (Nujol) nmax 3357, 3006, 2962,
1750, 1735, 1508 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 0.84 (3H, t,
J¼7.2 Hz, NCH2CH2CH3), 1.49e1.65 (11H, m, NCH2CH2CH3 and OtBu),
1.67 (3H,
s CH3), 3.13 (3H, s, NCH3), 3.21e3e30 (1H, m,
4. Experimental
NCHaCHbCH2CH3), 3.84e3.93 (1H, m, NCHaCHbCH2CH3), 4.96 (1H, s,
CH),10.03 (1H, s, NH).13C NMR (100 MHz, DMSO-d6)
d: 11.0,12.6,19.8,
4.1. General experimental section
28.0, 28.1, 46.8, 68.3, 79.8, 143.4, 152.7, 170.5, 182.4. MS (EI): m/z (%)
328 (Mþ, 3), 272 (35), 255 (18), 228 (35), 212 (62), 197 (9), 172 (100).
Anal. Calcd for C14H24N4O3S (328.43): C, 51.20; H, 7.37; N, 17.06.
Found: C, 51.39; H, 7.20; N, 17.12.
All chemicals and solvents were purchased from commercial
suppliers and used as received. 1,2-Diaza-1,3-dienes were pre-
pared as reported8 and used as EE/EZ isomer mixtures. Melting
points were determined in open capillary tubes and are un-
corrected. FTIR spectra were obtained as Nujol mulls. Mass spectra
(MS) were carried out by electron ionization (EI, 70 eV). 1H
(400 MHz) and 13C (100 MHz) spectra were recorded in DMSO-d6.
Chemical shifts (dH) are reported in parts per million (ppm), rel-
ative to TMS as internal standard. All coupling constant (J values)
are given in hertz (Hz). Chemical shifts (dC) are reported in parts
per million (ppm), relative to the central peak of DMSO-d6 as in-
ternal standard. The abbreviations used are as follows: s, singlet;
d, doublet; dd, double-doublet; t, triplet; q, quartet; m, multiplet;
br, broad; ArH, aromatic hydrogen. All the NH exchanged with
D2O. Precoated silica gel plates 0.25 mm were employed for an-
4 . 2 . 3 . t e r t - B u t y l 2 - [ 1 - ( 3 - b u t y l - 5 - o x o - 1 - p h e n y l - 2 -
thioxoimidazolidin-4-yl)ethylidene]hydrazinecarboxylate
(4c). Yield: 279.1 mg (69%). White powder, mp: 172e173 ꢁC
(dec) (from EtOH). IR (Nujol) nmax 3330, 1755, 1716, 1706, 1504 cmꢂ1
.
1H NMR (400 MHz, DMSO-d6)
d:
0.90 (3H, t, J¼7.2 Hz,
NCH2CH2CH2CH3), 1.26e1.40 (2H, m, NCH2CH2CH2CH3), 1.45 (9H, s,
OtBu), 1.49e1.66 (2H, m, NCH2CH2CH2CH3), 1.80 (3H, s, CH3),
3.34e3.43 (1H, m, NCHaHbCH2CH2CH3), 3.94e4.03 (1H, m,
NCHaHbCH2CH2CH3), 5.13 (1H, s, CH), 7.31 (2H, d, J¼7.0 Hz, ArH),
7.45e7.55 (3H, m, ArH), 10.11 (1H, s, NH). 13C NMR (100 MHz, DMSO-
d6) d: 12.6, 13.6, 19.4, 28.0, 28.5, 45.1, 68.9, 79.9, 128.7, 128.8, 133.6,
143.3, 152.7, 170.0, 181.8. MS (EI): m/z (%)¼404 (Mþ, 2), 348 (8), 316
(15), 304 (8), 288 (15), 219 (46), 149 (69), 125 (57), 111 (100).
Anal. Calcd for C20H28N4O3S (404.53): C, 59.38; H, 6.98; N, 13.85.
Found: C, 59.13; H, 7.12; N, 13.97.
alytical thin layer chromatography and silica gel 35e70
mm for
column chromatography. Compounds 4fej are previous synthe-
sized and characterized.7a All new compounds showed satisfac-
tory
The nomenclature was generated using ACD/IUPACName (version
3.50, Apr. 1998), Advanced Chemistry Development Inc.,
elemental
analysis
(Cꢀ0.35;
Hꢀ0.30;
Nꢀ0.30).
4.2.4. Methyl 2-[1-(1-methyl-5-oxo-3-propyl-2-thioxoimidazolidin-
4-yl)]ethylidene]hydrazinecarboxylate (4d). Yield: 183.2 mg (64%).
White powder, mp: 152e155 ꢁC (dec) (from EtOAc/cyclohexane). IR
(Nujol) nmax 3198, 3035, 1746, 1707, 1541 cmꢂ1. 1H NMR (400 MHz,
5
Toronto, ON (Canada).
4.2. General one-pot procedure for the synthesis of 1,3,5-
trisubstituted hydantoins and 2-thio analogous 4aej
DMSO-d6)
d
: 0.84 (3H, t, J¼7.6 Hz, NCH2CH2CH3), 1.45e1.63 (2H, m,
NCH2CH2CH3), 1.68 (3H, s, CH3), 3.13 (3H, s, NCH3), 3.22e3.31 (1H,
m, NCHaHbCH2CH3), 3.69 (3H, s, OCH3), 3.82e3.96 (1H, m,
NCHaHbCH2CH3), 4.99 (1H, s, CH), 10.36 (1H, s, NH). 13C NMR
To a stirred solution of the corresponding DD 1aec (1 mmol) in
CH2Cl2 or EtOH the appropriate amine derivative 2aec (1 mmol)
was added at room temperature. After the disappearance of 1
(0.1e0.5 h) (TLC check), isothiocyanate or isocyanate derivative
3aed was added and the reaction mixture was allowed to stand at
room temperature (12e24 h). In some cases, solid derivative 4 was
obtained by precipitation from the reaction medium or by crys-
tallization from appropriate solvents. In other cases, after the re-
moval of the reaction solvent in vacuo, chromatographic
purification (cyclohexane/ethyl acetate mixtures) followed by
crystallization from appropriate solvents was necessary to obtain
pure derivatives 4aei.
(100 MHz, DMSO-d6) d: 11.7, 13.1, 20.5, 28.9, 47.5, 52.8, 69.0, 144.1,
156.4, 170.4, 182.5. MS (EI): m/z (%)¼286 (Mþ, 10), 254 (6), 212 (51),
171 (27), 111 (35), 97 (53), 83 (100), 69 (64), 57 (99). Anal. Calcd for
C11H18N4O3S (286.35): C, 46.14; H, 6.34; N,19.57. Found: C, 46.22; H,
6.12; N, 19.68.
4.2.5. Methyl 2-[1-(3-butyl-5-oxo-1-phenyl-2-thioxoimidazolidin-4-
yl)]ethylidene]hydrazinecarboxylate (4e). Yield: 318.9 mg (88%).
White powder, mp: 176e178 ꢁC (dec) (from EtOAc/cyclohexane). IR
(Nujol) nmax 3326,1744, 1731, 1507 cmꢂ1. 1H NMR (400 MHz, DMSO-
d6)
d
: 0.89 (3H, t, J¼7.6 Hz, NCH2CH2CH2CH3), 1.26e1.37 (2H, m,
NCH2CH2CH2CH3), 1.49e1.67 (2H, m, NCH2CH2CH2CH3), 1.82 (3H, s,
CH3), 3.35e3.46 (1H, m, NCHaHbCH2CH2CH3), 3.71 (3H, s, OCH3),
3.90e4.03 (1H, m, NCHaHbCH2CH2CH3), 5.16 (1H, s, CH), 7.32 (2H, d,
J¼7.0 Hz, ArH), 7.43e7.52 (3H, m, ArH), 10.43 (1H, s, NH). 13C NMR
4.2.1. Ethyl 2-[1-(3-butyl-5-oxo-1-phenyl-2-thioxoimidazolidin-4-
yl)]ethylidene]hydrazinecarboxylate (4a). Yield: 267.3 mg (71%).
White powder, mp: 162e163 ꢁC (from EtOAc/cyclohexane). IR
(Nujol) nmax 3227, 1751, 1708, 1507 cmꢂ1. 1H NMR (400 MHz, DMSO-
(100 MHz, DMSO-d6) d: 12.5, 13.6, 19.4, 28.5, 45.2, 52.1, 68.9, 128.7,
d6)
d
: 0.90 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.25 (3H, t, J¼7.2 Hz,
128.9, 133.6, 144.0, 154.4, 169.9, 181.9. MS (EI): m/z (%)¼362 (Mþ,
OCH2CH3), 1.28e1.37 (2H, m, NCH2CH2CH2CH3), 1.50e1.65 (2H, m,

7340
O.A. Attanasi et al. / Tetrahedron 70 (2014) 7336e7343
39), 330 (10), 288 (100), 274 (23), 259 (5). Anal. Calcd for
17H22N4O3S (362.45): C, 56.33; H, 6.12; N, 15.46. Found: C, 56.42;
H, 6.18; N, 15.31.
s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.4, 13.3, 15.5, 19.6, 28.0,
C
28.9, 44.8, 51.1, 53.0, 77.4, 80.4, 87.9, 92.8, 128.7, 128.9, 129.0, 133.6,
155.9, 156.7, 163.5, 166.9, 171.8, 179.1. MS (EI): m/z (%) 590 (Mþ, 2),
459 (20), 340 (37), 252 (100). Anal. Calcd for C27H38N6O7S (590.69):
C, 54.90; H, 6.48; N, 14.23. Found: C, 55.09; H, 6.31; N, 14.32.
4.3. General one-pot procedure for the synthesis of spiro
derivatives 6aeg
4.3.4. 5R/S,6S/R Methyl 6-[2-(tert-butoxycarbonyl)hydrazino]-1-
butyl-7-[(methoxycarbonyl)amino]-6,8-dimethyl-4-oxo-3-phenyl-2-
A catalytic amount of sodium methoxide was added to a mag-
netically stirred solution of derivatives 4aei (1 mmol) in dioxane,
followed by the addition of DD 1deh (1 mmol). The reaction
mixture was allowed to stand at room temperature until the dis-
appearance of 1 (0.1e0.5 h) (TLC check) and then it was refluxed for
6e12 h. The solvent was removed at reduced pressure and the
crude reaction mixture was purified by flash chromatography
eluting with cyclohexane/ethyl acetate mixtures to obtain pure
spiro derivatives 6aei.
thioxo-1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
(6c). Minor
diastereomer. Yield: 53.1 mg (9%). White powder, mp: 164e166 ꢁC
(dec) (from Et2O/light petroleum ether). IR (Nujol) nmax 3388, 3280,
3256, 1755, 1737, 1726, 1712, 1692, 1598 cmꢂ1 1H NMR (400 MHz,
.
DMSO-d6)
d
: 0.84 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.08e1.25 (5H,
m, NCH2CH2CH2CH3 and CH3), 1.38 (9H, s, OtBu), 1.94e2.09 (2H, m,
NCH2CH2CH2CH3), 2.19 (3H, s, CH3), 3.55e3e70 (7H, m,
NCHaCHbCH2CH2CH3 and 2ꢃOCH3), 4.00e4.13 (1H,
m,
NCHaCHbCH2CH2CH3), 4.88 (1H, br s, NH), 7.29 (2H, d, J¼7.2 Hz, ArH),
4.3.1. 5R/S,6R/S Methyl 7-{[(benzyloxy)carbonyl]amino}-1-butyl-6-
[2-(ethoxycarbonyl)hydrazino]-8-ethyl-6-methyl-4-oxo-3-phenyl-2-
7.41e7.51 (3H, m, ArH), 8.21 (1H, br s, NH), 9.76 (1H, s, NH). 13C NMR
(100 MHz, DMSO-d6) d: 11.9, 13.4, 16.6, 19.9, 28.2, 29.0, 45.3, 50.9,
thioxo-1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
(6a). Major
52.6, 75.9, 79.2, 88.2, 93.9, 128.4, 128.6, 128.9, 134.4, 156.2, 157.5,
163.9, 164.2, 170.4, 180.3. Anal. Calcd for C27H38N6O7S (590.69): C,
54.90; H, 6.48; N, 14.23. Found: C, 54.70; H, 6.56; N, 14.36.
diastereomer. Yield: 502.6 mg (77%). White powder, mp:
160e161 ꢁC (from EtOAc/cyclohexane). IR (Nujol) nmax 3375, 3337,
3247, 1752, 1740, 1717, 1697, 1669, 1604 cmꢂ1 1H NMR (400 MHz,
.
DMSO-d6)
d
: 0.84 (3H, t, J¼7.6 Hz, NCH2CH2CH2CH3), 0.97e1.28
4.3.5. 5R/S,6R/S Methyl 7-{[(benzyloxy)carbonyl]amino}-6-[2-(me-
thoxycarbonyl)hydrazino]-3,6,8-trimethyl-4-oxo-1-propyl-2-thioxo-
(11H, m, CH2CH3, NCH2CH2CH2CH3, OCH2CH3 and CH3), 1.94e2.04
(2H, m, NCH2CH2CH2CH3), 2.53e2.58 (1H, CHaHbCH3), 2.65e2.70
(1H, CHaHbCH3), 3.42e3.50 (1H, m, NCHaHbCH2CH2CH3), 3.63 (3H,
s, OCH3), 3.90e4.04 (3H, m, NCHaHbCH2CH2CH3 and OCH2CH3),
5.20 (1H, d, J¼12.0 Hz, CHaHbPh), 5.25 (1H, d, 12.0 Hz, CHaHbPh),
6.41 (1H, s, NH), 7.29e7.56 (11H, m, NH and ArH), 8.79 (1H, s, NH).
1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
astereomer. Yield: 416.9 mg (76%). Whitish foam. IR (Nujol) nmax
3313, 3286, 3194, 1738, 1725, 1712, 1685, 1606 cmꢂ1 1H NMR
(400 MHz, DMSO-d6)
: 0.77 (3H, t, J¼7.2 Hz, NCH2CH2CH3), 1.07
(6d). Major
di-
.
d
(3H, s, CH3), 1.76e1.91 (2H, m, NCH2CH2CH3), 2.16 (3H, s, CH3), 3.18
(3H, s, NCH3), 3.35e3.41 (1H, m, NCHaHbCH2CH3), 3.51 (3H, s,
OCH3), 3.59 (3H, s, OCH3), 3.81e3.87 (1H, m, NCHaHbCH2CH3), 5.17
(1H, d, J¼12.0 Hz, CHaHbPh), 5.22 (1H, d, J¼12.0 Hz, CHaHbPh), 6.26
(1H, s, NH), 7.36e7.41 (5H, m, ArH), 7.60 (1H, s, NH), 8.70 (1H, s,
13C NMR (100 MHz, DMSO-d6)
d: 11.0, 13.4,14.4,15.5,18.5,19.7, 29.0,
44.9, 51.1, 61.3, 67.1, 77.4, 88.2, 92.1, 128.0, 128.3, 128.6, 128.7, 129.3,
133.5,135.1, 135.9,155.8,156.1,156.7,163.2,171.9,179.0. MS (EI): m/z
(%)¼653 (Mþ, 1), 549 (23), 430 (46), 342 (100). Anal. Calcd for
C
32H40N6O7S (652.76): C, 58.88; H, 6.18; N, 12.87. Found: C, 58.81;
NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.3,11.7,15.3, 26.3, 28.2, 46.7,
H, 6.42; N, 12.69.
51.7, 52.7, 67.1, 77.1, 87.7, 92.6, 128.0, 128.6, 128.9, 135.9, 155.9, 157.0,
163.3,166.6,172.4,179.8 MS (EI): m/z (%)¼548 (Mþ, 4), 459 (76), 402
(45), 328 (100). Anal. Calcd for C24H32N6O7S (548.61): C, 52.54; H,
5.88; N, 15.32. Found: C, 52.61; H, 6.03; N, 15.20.
4.3.2. 5R/S,6R/S Methyl 6-[2-(tert-butoxycarbonyl)hydrazino]-7-
[(methoxycarbonyl)amino]-3,6,8-trimethyl-4-oxo-1-propyl-2-thioxo-
1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
(6b). Major
di-
astereomer. Yield: 360.2 mg (70%). White powder, mp:
4.3.6. 5R/S,6R/S Methyl 7-[(tert-butoxycarbonyl)amino]-1-butyl-6-
[2-(methoxycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-3-phenyl-2-
151e153 ꢁC (EtOAc/cyclohexane). IR (Nujol) nmax 3368, 3349, 3294,
1754, 1728, 1717, 1697, 1673, 1653, 1636, 1606 cmꢂ1
.
1H NMR
thioxo-1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
(6e). Major
(400 MHz, DMSO-d6)
d
: 0.77 (3H, t, J¼7.2 Hz, NCH2CH2CH3), 1.06
diastereomer. Yield: 413.5 mg (70%). White powder, mp:
177e178 ꢁC (dec) (from EtOAc/cyclohexane). IR (Nujol) nmax 3384,
3344, 3316, 1741, 1720, 1662, 1597 cmꢂ1. 1H NMR (400 MHz, DMSO-
(3H, s, CH3), 1.39 (9H, s, OtBu), 1.82e1.88 (2H, m, NCH2CH2CH3), 2.18
(3H, s, CH3), 3.20 (3H, s, NCH3), 3.24e3.30 (1H, m, NCHaHbCH2CH3),
3.52 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.80e3.86 (1H, m,
NCHaHbCH2CH3), 6.13 (1H, s, NH), 7.35 (1H, s, NH), 8.76 (1H, s, NH).
d6)
d
: 0.84 (3H, t, J¼7.6 Hz, NCH2CH2CH2CH3), 1.02e1.47 (14H, m,
NCH2CH2CH2CH3, CH3 and OtBu), 1.94e2.02 (2H, m,
NCH2CH2CH2CH3), 2.17 (3H, s, CH3), 3.46e3.54 (1H, m,
NCHaHbCH2CH2CH3), 3.60 (3H, s, OCH3), 3.62 (3H, s, OCH3),
3.86e4.04 (1H, m, NCHaHbCH2CH2CH3), 6.38 (1H, s, NH), 7.32 (2H,
d, J¼7.6 Hz, ArH), 7.46e7.56 (4H, m, ArH and NH), 8.39 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6)
d: 11.3, 11.4, 15.4, 20.6, 28.0, 28.2,
46.6, 50.9, 52.9, 71.2, 80.4, 87.7, 92.5, 155.9, 156.5,163.3,166.6, 172.4,
179.8 MS (EI): m/z (%)¼514 (Mþ, 5), 383 (58), 326 (48), 252 (100).
Anal. Calcd for C21H34N6O7S (514.60): C, 49.01; H, 6.66; N, 16.33.
Found: C, 49.12; H, 6.53; N, 16.20.
13C NMR (100 MHz, DMSO-d6)
d: 11.2, 13.2, 15.3, 19.6, 26.3, 27.8,
44.7, 51.0, 52.6, 77.4, 81.1, 87.9, 92.3, 128.8, 128.9, 133.6, 154.9, 157.0,
163.5, 166.9, 171.9, 179.0 MS (EI): m/z (%)¼590 (Mþ, 4), 501 (31), 445
(28), 326 (100), 238 (66). Anal. Calcd for C27H38N6O7S (590.69): C,
54.90; H, 6.48; N, 14.23. Found: C, 54.79; H, 6.53; N, 14.32.
4.3.3. 5R/S,6R/S Methyl 6-[2-(tert-butoxycarbonyl)hydrazino]-1-
butyl-7-[(methoxycarbonyl)amino]-6,8-dimethyl-4-oxo-3-phenyl-2-
thioxo-1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
(6c). Major
diastereomer. Yield: 401.7 mg (68%). Colourless crystals, mp:
171e172 ꢁC (dec) (from Et2O/cyclohexane). IR (Nujol) nmax 3383,
3282, 3259, 1746, 1703, 1689, 1603 cmꢂ1. 1H NMR (400 MHz, DMSO-
4.3.7. 5R/S,6R/S Methyl 1-butyl-6-[2-(ethoxycarbonyl)hydrazino]-7-
[(methoxycarbonyl)amino]-6,8-dimethyl-2,4-dioxo-3-phenyl-1,3,7-
triazaspiro[4.4]non-8-ene-9-carboxylate (6f). Major diastereomer.
Yield: 371.6 mg (68%). White foam. IR (Nujol) nmax 3306, 3255, 3198,
1775, 1751, 1718, 1703, 1684, 1610 cmꢂ1. 1H NMR (400 MHz, DMSO-
d6)
d
: 0.84 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.04e1.37 (14H, m,
NCH2CH2CH2CH3, CH3 and OtBu), 1.96e2.03 (2H, m,
NCH2CH2CH2CH3), 2.20 (3H, s, CH3), 3.42e3e50 (1H, m,
NCHaCHbCH2CH2CH3), 3.63 (3H, s, OCH3), 3.74 (3H, s, OCH3),
3.88e3.96 (1H, m, NCHaCHbCH2CH2CH3), 6.28 (1H, s, NH), 7.26 (1H,
s, NH), 7.31 (2H, d, J¼7.8 Hz, ArH), 7.45e7.56 (3H, m, ArH), 8.82 (1H,
d6)
d: 0.82 (3H, t, J¼7.2 Hz, NCH2CH2CH2CH3), 1.13e1.23 (8H, m,
OCH2CH3, NCH2CH2CH2CH3 and CH3), 1.62e1.65 (2H, m,
NCH2CH2CH2CH3), 2.16 (3H, s, CH3), 3.19e3.24 (1H, m,

O.A. Attanasi et al. / Tetrahedron 70 (2014) 7336e7343
7341
NCHaHbCH2CH2CH3), 3.40e3.48 (1H, m, NCHaHbCH2CH2CH3), 3.60
(3H, s, OCH3), 3.73 (3H, s, OCH3), 4.03e4.07 (2H, m, OCH2CH3), 6.22
(1H, s, NH), 7.38 (1H, s, NH), 7.40e7.46 (3H, m, ArH), 7.53 (2H, t,
diluted with CH2Cl2 and washed with satd NH4Cl and with brine.
After anhydrification and evaporation of the organic phase, the
residue was purified by flash chromatography eluting with cyclo-
hexane/EtOAc mixtures to obtain pure derivatives 8a,b.
J¼8.0 Hz, ArH), 8.68 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d:
11.2, 13.3, 14.5, 15.6, 19.5, 30.4, 40.9, 50.8, 52.8, 61.1, 74.5, 87.5, 93.6,
126.8, 128.2, 128.8, 131.9, 153.4, 156.4, 156.6, 163.6, 166.4, 171.2. MS
(EI): m/z (%)¼546 (Mþ, 1), 515 (4), 443 (39), 410 (20), 324 (100), 266
(32). Anal. Calcd for C25H34N6O8 (546.57): C, 54.94; H, 6.27; N,
15.38. Found: C, 54.80; H, 6.39; N, 15.51.
4.4.1. Methyl 3-(3-chlorophenyl)-6-[2-(ethoxycarbonyl)hydrazino]-
1-{[1-(2-fluorobenzyl)-1H-1,2,3-triazol-5-yl]methyl}-7-[(methox-
ycarbonyl)amino]-6,8-dimethyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-
8-ene-9-carboxylate (8a). Yield: 599.8 mg (84%). White powder,
mp: 178e179 ꢁC (dec) (from EtOAc/cyclohexane). IR (Nujol) nmax
3310, 3237, 3184, 3157, 1777, 1753, 1729, 1701, 1670, 1615 cmꢂ1. 1H
4.3.8. 5R/S,6R/S Methyl 6-[2-(tert-butoxycarbonyl)hydrazino]-7-
[(methoxycarbonyl)amino]-6,8-dimethyl-2,4-dioxo-3-phenyl-1-
NMR (400 MHz, DMSO-d6) d: 1.08e1.19 (3H, m, OCH2CH3), 1.33 (3H,
propyl-1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
(6g). Major
s, CH3), 2.09 (3H, s, CH3), 3.12 (3H, s, OCH3), 3.75 (3H, s, OCH3),
3.99e4.08 (2H, m, OCH2CH3), 4.39 (1H, d, J¼16.0 Hz, NCHaHbHet),
4.87 (1H, d, J¼16.0 Hz, NCHaHbHet), 5.61 (2H, s, NCH2Ar), 6.22 (1H,
s, NH), 7.17e7.59 (5H, m, ArH and NH), 7.89 (1H, s, HetH), 8.70 (1H,
diastereomer. Yield: 386.8 mg (69%). White powder, mp: 163e165 ꢁC
(dec) (from Et2O/light petroleum ether). IR (Nujol) nmax 3330, 3245,
3195, 1771, 1734, 1716, 1684, 1662, 1616 cmꢂ1 1H NMR (400 MHz,
.
DMSO-d6)
d
: 0.78 (3H, t, J¼7.6 Hz, NCH2CH2CH3),1.23 (3H, s, CH3),1.38
s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.4, 14.5, 15.9, 36.1, 46.6,
(9H, s, OtBu), 1.51e1.66 (2H, m, NCH2CH2CH3), 2.19 (3H, s, CH3),
3.02e3.10 (1H, m, NCHaHbCH2CH3), 3.36e3.44 (1H, m,
NCHaHbCH2CH3), 3.60 (3H, s, OCH3), 3.73 (3H, s, OCH3), 6.14 (1H, s,
NH), 7.36 (1H, s, NH), 7.38e7.46 (3H, m, ArH), 7.53 (2H, t, J¼7.6 Hz,
50.2, 52.8, 61.1, 74.5, 87.4, 93.7, 115.5 (d, 2J¼20.5 Hz), 122.8 (d,
2J¼14.4 Hz), 122.9, 123.8, 124.6, 124.7, 125.4, 126.5, 128.4, 128.4,
130.6, 131.9 (d, 1J¼235.2 Hz), 132.9, 142.7, 153.1, 156.5, 158.8, 161.2,
162.9, 166.0, 170.8. Anal. Calcd for C31H33ClFN9O8 (714.10): C, 52.14;
H, 4.66; N, 17.65. Found: C, 52.34; H, 4.45; N, 17.50.
ArH), 8.80 (1H, s, NH).13C NMR (100 MHz, DMSO-d6)
d: 11.4,15.8, 21.9,
28.0, 43.1, 50.8, 52.8, 74.5, 80.2, 87.5, 93.5, 126.8, 128.2, 128.9, 131.9,
153.4, 155.9, 156.5, 163.7, 166.5, 171.2. MS (EI): m/z (%)¼560 (Mþ, 1),
530 (8), 429 (34), 310 (100), 266 (19). Anal. Calcd for C26H36N6O8
(560.60): C, 55.70; H, 6.47; N,14.99. Found: C, 55.80; H, 6.24; N,15.04.
4.4.2. Methyl 1-[(1-benzyl-1H-1,2,3-triazol-5-yl)methyl]-7-[(ethox-
ycarbonyl)amino]-6-[2-(methoxycarbonyl)hydrazino]-6,8-dimethyl-
2,4-dioxo-3-phenyl-1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate
(8b). Yield: 508.9 mg (77%). White powder, mp: 133e135 ꢁC (from
EtOAc/cyclohexane). IR (Nujol) nmax 3331, 3238, 3198, 1769, 1752,
4.3.9. 5R/S,6R/S Methyl 3-(3-chlorophenyl)-6-[2-(ethoxycarbonyl)
hydrazino]-7-[(methoxycarbonyl)amino]-6,8-dimethyl-2,4-dioxo-3-
phenyl-1-(2-propynyl)-1,3,7-triazaspiro[4.4]non-8-ene-9-
carboxylate (6h). Yield: 371.5 mg (66%). White powder, mp:
161e162 ꢁC (from EtOAc-Cyclohexane). IR (Nujol) nmax 3381, 3289,
3263, 2121, 1773, 1744, 1696, 1604 cmꢂ1. 1H NMR (400 MHz, DMSO-
1719, 1671, 1605 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.27 (3H, t,
J¼7.2 Hz, OCH2CH3), 1.32 (3H, s, CH3), 2.09 (3H, s, CH3), 3.12 (3H, s,
OCH3), 3.58 (3H, s, OCH3), 4.14e4.25 (2H, m, OCH2CH3), 4.42 (1H, d,
J¼16.0 Hz, NCHaCHbHet), 4.86 (1H, d, J¼16.0 Hz, NCHaCHbHet), 5.54
(2H, s, NCH2Ar), 6.25 (1H, s, NH), 7.20e7.60 (11H, m, ArH and NH),
d6)
d
: 1.15 (3H, s, J¼7.2 Hz, OCH2CH3), 1.23 (3H, s, CH3), 2.16 (3H, s,
7.86 (1H, s, Het), 8.61 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d:
CH3), 3.16 (1H, s, NCH2C^CH), 3.58 (3H, s, OCH3), 3.73 (3H, s, OCH3),
3.83 (1H, d, J¼18.0 Hz, NCHaHbC^CH), 3.98e4.09 (2H, m,
OCH2CH3), 4.44 (1H, d, J¼18.0 Hz, NCHaHbC^CH), 6.21 (1H, s, NH),
7.38e7.61 (5H, m, ArH and NH), 8.67 (1H, s, NH). 13C NMR (100 MHz,
11.3, 14.3, 15.8, 36.1, 50.1, 52.3, 52.5, 61.7, 74.3, 87.4, 93.8, 123.6,
126.8, 127.9, 128.0, 128.3, 128.6, 128.9, 131.9, 136.0, 142.9, 153.6,
156.1, 157.0, 162.9, 166.2, 171.1. Anal. Calcd for C30H35N9O8 (661.67):
C, 56.27; H, 5.33; N, 19.05. Found: C, 56.20; H, 5.37; N, 19.29.
DMSO-d6) d: 11.3, 14.5, 15.7, 29.7, 50.9, 52.9, 61.1, 73.8, 74.3, 78.3,
87.1, 93.6, 125.4, 126.5, 128.4, 130.7, 132.9, 133.0, 152.7, 156.1, 156.5,
163.4, 166.0, 170.6. Anal. Calcd for C24H27ClN6O8 (562.96): C, 51.20;
H, 4.83; N, 14.93. Found: C, 51.28; H, 4.60; N, 15.17.
4.5. General one-pot procedure for the synthesis of spaced
bis(thiohydantoins) 10aei
To a stirred solution of the corresponding DD 1b,c,i (2 mmol) in
CH2Cl2 (4 mL), diamine derivative 9 (1 mmol) solved in CH2Cl2
(2 mL) was added at room temperature. After the disappearance of
1 (0.5e1 h) (TLC check), isothiocyanates 3a,b were added and the
reaction mixture was allowed to stand at room temperature
(24e120 h) until the precipitation of derivatives 10aei from the
reaction mixture. The crude product so obtained was then recrys-
tallized from CH2Cl2/Et2O or from CH2Cl2/light petroleum ether.
4.3.10. 5R/S,6R/S Methyl 7-[(ethoxycarbonyl)amino]-6-[2-(methox-
ycarbonyl)hydrazino]-6,8-dimethyl-2,4-dioxo-3-phenyl-1-(2-
propynyl)-1,3,7-triazaspiro[4.4]non-8-ene-9-carboxylate (6i). Yield:
317.1 mg (60%). White powder, mp: 156e159 ꢁC (from Et2O/light
petroleum ether). IR (Nujol) nmax 3361, 3321, 3310, 3272, 3261, 2120,
1773, 1745, 1705, 1684, 1612 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d:
1.12e1.30 (6H, m, CH3 and OCH2CH3), 2.16 (3H, s, CH3), 3.14 (1H, s,
NCH2C^CH), 3.57 (3H, s, OCH3), 3.59 (3H, s, OCH3), 3.84 (1H, d,
J¼18.0 Hz, NCHaHbC^CH), 4.17 (2H, q, J¼7.2 Hz, OCH2CH3), 4.43 (1H,
d, J¼18.0 Hz, NCHaHbC^CH), 6.25 (1H, s, NH), 7.30e7.58 (5H, m, ArH
4.5.1. tert-Butyl
2-{1-[3-(3-{5-[2-(tert-butoxycarbonyl)ethanhy-
drazonoyl]-4-oxo-3-phenyl-2-thioxo-1-imidazolidinyl}propyl)-5-
oxo-1-phenyl-2-thioxo-4-imidazolidinyl]ethylidene}-1-
hydrazinezinecarboxylate (10a). Yield: 582.1 mg (79%). White
powder, mp: 215e217 ꢁC (CH2Cl2/Et2O). IR (Nujol) nmax 3200, 1748,
and NH), 8.58 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.2, 14.3,
15.7, 29.6, 50.1, 52.5, 61.8, 73.7, 74.2, 78.4, 87.1, 93.6, 126.8, 128.4,
128.9, 131.7, 153.3, 156.1, 157.0, 163.4, 166.0, 170.9. Anal. Calcd for
C24H28N6O8 (528.51): C, 54.54; H, 5.34; N, 15.90: Found: C, 54.30; H,
1723, 1593 cmꢂ1 1H NMR (400 MHz, DMSO-d6)
. d: 1.41 (18H, s,
5.34; N, 16.13.
2ꢃOtBu), 1.84 (6H, s, 2ꢃCH3), 2.01e2.07 (2H, m, CH2), 3.45e3.55
(2H, m, CH2), 4.07e4.14 (2H, m, CH2), 5.17 (2H, s, 2ꢃCH), 7.28e7.48
4.4. General one-pot procedure for the synthesis of 8a,b
(10H, m, ArH),10.07 (2H, s, 2ꢃNH). 13C NMR (100 MHz, DMSO-d6)
d:
12.9, 24.6, 26.4, 28.2, 43.0, 43.2, 68.9, 80.1, 128.9, 129.1, 133.7, 143.3,
152.9, 153.1, 170.1, 182.4. Anal. Calcd for C35H44N8O6S2 (736.90): C,
57.05; H, 6.02; N, 15.21. Found: C, 56.90; H, 6.11; N, 15.38.
Spiro compounds 6h,i (1 mmol), CuSO4$5H2O (0.06 mmol) and
sodium ascorbate (0.16 mmol) were suspended in a CH2Cl2 (3 mL)/
H2O (0.5 mL) mixture. Under magnetic stirring azide 7a or 7b was
added at room temperature. Magnetic stirring was maintained at
the same temperature for 24e32 h, then the reaction mixture was
4.5.2. tert-Butyl
2-{1-[3-(6-{5-[2-(tert-butoxycarbonyl)ethanhy-
drazonoyl]-4-oxo-3-phenyl-2-thioxo-1-imidazolidinyl}hexyl)-5-oxo-

7342
O.A. Attanasi et al. / Tetrahedron 70 (2014) 7336e7343
1 - p h e n yl - 2 - t h i o x o - 4 - i m i d a z o l i d i n yl ] e t h y l i d e n e } - 1 -
hydrazinezinecarboxylate (10b). Yield: 584.2 mg (75%). White
powder, mp: 195e197 ꢁC (CH2Cl2/Et2O). IR (Nujol) nmax 3321, 1760,
(570.68): C, 46.30; H, 6.01; N, 19.63. Found: C, 46.41; H, 6.18; N,
19.52.
1711, 1665 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d
: 1.36e1.64 (26H,
4.5.7. N1-Phenyl-2-{1-[3-(3-{5-[2-(anilinocarbonyl)ethanhy-
drazonoyl]-4-oxo-3-phenyl-2-thioxo-1-imidazolidinyl}propyl)-5-
oxo-1-phenyl-2-thioxo-4-imidazolidinyl]ethylidene}-1-
hydrazinecarboxamide (10g). Yield: 503.7 mg (65%). White powder,
mp: 179e181 ꢁC (CH2Cl2/light petroleum ether). IR (Nujol) nmax
m, 4ꢃCH2 and 2ꢃOtBu), 1.80 (6H, s, 2ꢃCH3), 3.30e3.37 (2H, m,
CH2), 3.95e4.02 (2H, m, CH2), 5.10 and 5.11 (2H, 2s, 2ꢃCH),
7.28e7.50 (10H, m, ArH), 10.11 (2H, s, 2ꢃNH). 13C NMR (100 MHz,
DMSO-d6) d: 12.6, 12.8, 25.0, 25.9, 26.4, 28.2, 44.9, 45.4, 69.0, 80.0,
81.0, 128.9, 129.0, 133.8, 143.4, 143.7, 152.9, 170.2, 170.7, 181.9, 182.0.
Anal. Calcd for C38H50N8O6S2 (778.98): C, 58.59; H, 6.47; N, 14.38.
Found: C, 58.63; H, 6.69; N, 14.44.
3354, 3200, 1750, 1699, 1600 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d:
1.89 (6H, s, 2ꢃCH3), 2.08e2.16 (2H, m, CH2), 3.48e3.59 (2H, m, CH2),
4.14e4.25 (2H, m, CH2), 5.30 and 5.37 (2H, 2s, 2ꢃCH), 7.02 (2H, t,
J¼7.6 Hz, ArH), 7.26e7.35 (8H, m, ArH), 7.43e7.48 (6H, m, ArH), 7.55
4.5.3. tert-Butyl
2-{1-[3-(6-{5-[2-(tert-butoxycarbonyl)ethanhy-
(4H, d, J¼7.6 Hz, ArH), 8.85 (2H, s, 2ꢃNH), 10.14 (2H, s, 2ꢃNH). 13
C
drazonoyl]-3-methyl-4-oxo-2-thioxo-1-imidazolidinyl}hexyl)-1-
methyl-5-oxo-2-thioxo-4-imidazolidinyl]ethylidene}-1-
hydrazinezinecarboxylate (10c). Yield: 550.0 mg (84%). White
powder, mp: 175e177 ꢁC (CH2Cl2/Et2O). IR (Nujol) nmax 3311, 1759,
NMR (100 MHz, DMSO-d6) d: 12.3, 25.0, 42.4, 43.0, 68.5, 119.5,
122.6, 128.6, 128.7, 128.9, 133.5, 133.6, 138.8, 139.8, 140.0, 152.8,
153.0, 169.9, 170.0, 182.3, 182.5. Anal. Calcd for C39H38N10O4S2
(774.91): C, 60.45; H, 4.94; N, 18.08. Found: C, 60.61; H, 4.91; N,
17.89.
1725, 1675 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.26e1.53 (26H,
m, 4ꢃCH2 and 2ꢃOtBu), 1.65 and 1.67 (6H, 2s, 2ꢃCH3), 3.12 and 3.14
(6H, 2s, 2ꢃCH3), 3.23e3.27 (2H, m, CH2), 3.91e3.97 (2H, m, CH2),
4.5.8. N1-Phenyl-2-{1-[3-(6-{5-[2-(anilinocarbonyl)ethanhy-
drazonoyl]-4-oxo-3-phenyl-2-thioxo-1-imidazolidinyl}hexyl)-5-oxo-
1 - p h e n y l - 2 - t h i o x o - 4 - i m i d a z o l i d i n y l ] e t h y l i d e n e } - 1 -
hydrazinecarboxamide (10h). Yield: 629.0 mg (77%). White powder,
mp: 157e159 ꢁC (CH2Cl2/light petroleum ether). IR (Nujol) nmax
4.95 and 5.30 (2H, 2s, 2ꢃCH), 10.01 and 10.04 (2H, 2s, 2ꢃNH). 13
C
NMR (100 MHz, DMSO-d6) d: 12.3, 12.6, 23.6, 25.5, 26.2, 28.0, 44.1,
44.9, 68.1, 68.4, 79.8, 79.9, 143.2, 143.4, 152.7, 170.5, 170.9, 182.3.
Anal. Calcd for C28H46N8O6S2 (654.84): C, 51.36; H, 7.08; N, 17.11.
Found: C, 51.51; H, 7.13; N, 17.27.
3401, 3204, 1763, 1716, 1601 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d:
1.35e1.70 (8H, m, 4ꢃCH2), 1.82 and 1.85 (6H, 2s, 2ꢃCH3), 3.36e3.44
(2H, m, CH2), 3.98e4.06 (2H, m, CH2), 5.23 and 5.26 (2H, 2s, 2ꢃCH),
7.02 (2H, t, J¼7.2 Hz, ArH), 7.27e7.50 (14H, m, ArH), 7.56 (4H, d,
J¼7.2 Hz, ArH), 8.93 and 8.96 (2H, 2s, 2ꢃNH), 10.09 and 10.11 (2H,
4.5.4. Methyl
2-{1-[3-(3-{5-[2-(methoxycarbonyl)ethanhy-
drazonoyl]-4-oxo-3-phenyl-2-thioxo-1-imidazolidinyl}propyl)-5-
oxo-1-phenyl-2-thioxo-4-imidazolidinyl]ethylidene}-1-
hydrazinezinecarboxylate (10d). Yield: 535.2 mg (82%). White
powder, mp: 206e210 ꢁC (CH2Cl2/Et2O). IR (Nujol) nmax 3245, 1759,
2s, 2ꢃNH). 13C NMR (100 MHz, DMSO-d6)
d: 12.2, 25.6, 25.7, 26.1,
43.7, 45.2, 67.0, 68.7, 119.5, 122.6, 128.6, 128.7, 128.8, 133.6, 138.8,
139.6, 152.9, 170.1, 180.2, 181.8. Anal. Calcd for C42H44N10O4S2
(816.99): C, 61.74; H, 5.43; N,17.14. Found: C, 61.81; H, 5.55; N,17.00.
1738, 1595 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.85 and 1.86 (6H,
2s, 2ꢃCH3), 1.94e2.04 (2H, m, CH2), 3.45e3.55 (2H, m, CH2), 3.68
(6H, s, 2ꢃCH3), 4.03e4.11 (2H, m, CH2), 5.14 and 5.20 (2H, 2s,
2ꢃCH), 7.29e7.51 (10H, m, ArH), 10.44 (2H, s, 2ꢃNH). 13C NMR
4.5.9. N1-Phenyl-2-{1-[3-(6-{5-[2-(anilinocarbonyl)ethanhy-
drazonoyl]-3-methyl-4-oxo-2-thioxo-1-imidazolidinyl}hexyl)-1-
methyl-5-oxo-2-thioxo-4-imidazolidinyl]ethylidene}-1-
hydrazinecarboxamide (10i). Yield: 527.1 mg (81%). White powder,
mp: 209e212 ꢁC (CH2Cl2/Et2O). IR (Nujol) nmax 3401, 3217, 1759,
(100 MHz, DMSO-d6) d: 12.7, 12.8, 24.6, 42.9, 43.1, 52.2, 68.7, 128.7,
128.9, 133.5, 143.9, 154.4, 169.8, 182.3, 182.5. Anal. Calcd for
29H32N8O6S2 (652.74): C, 53.36; H, 4.94; N, 17.17. Found: C, 53.41;
C
H, 5.13; N, 17.21.
1720, 1601 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.72 and 1.73 (6H,
4.5.5. Methyl
2-{1-[3-(3-{5-[2-(methoxycarbonyl)ethanhy-
2s, 2ꢃCH3), 1.94e1.99 (2H, m, CH2), 3.14 (6H, s, 2ꢃCH3), 3.37e3.45
(2H, m, CH2), 4.03e4.11 (2H, m, CH2), 5.11 and 5.13 (2H, 2s, 2ꢃCH),
6.99e7.16 (2H, m, ArH), 7.27e7.31 (4H, m, ArH), 7.53e7.57 (4H, m,
ArH), 8.80 and 8.84 (2H, 2s, 2ꢃNH), 10.08 (2H, s, 2ꢃNH). 13C NMR
drazonoyl]-4-oxo-3-phenyl-2-thioxo-1-imidazolidinyl}propyl)-5-
oxo-1-phenyl-2-thioxo-4-imidazolidinyl]ethylidene}-1-
hydrazinezinecarboxylate (10e). Yield: 507.2 mg (73%). White
powder, mp: 209e211 ꢁC (CH2Cl2/Et2O). IR (Nujol) nmax 3218, 1740,
(100 MHz, DMSO-d6) d: 12.2, 24.4, 24.5, 28.1, 42.6, 68.0, 68.8, 119.4,
1712, 1700, 1648 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.26e1.62
122.6, 128.5, 138.7, 140.0, 140.1, 152.9, 170.4, 182.7. Anal. Calcd for
C29H34N10O4S2 (650.77): C, 53.52; H, 5.27; N, 21.52. Found: C, 53.61;
H, 5.21; N, 21.68.
(8H, m, 4ꢃCH2), 1.80 (6H, s, 2ꢃCH3), 3.32e3.37 (2H, m, CH2), 3.70
(6H, s, 2ꢃOCH3), 3.96e4.01 (2H, m, CH2), 5.16 (2H, s, 2ꢃCH),
7.31e7.53 (10H, m, ArH), 10.44 (2H, s, 2ꢃNH). 13C NMR (100 MHz,
DMSO-d6) d: 12.7, 25.5, 25.9, 26.4, 45.2, 45.4, 52.3, 69.1, 128.9, 129.1,
4.6. General one-pot procedure for the synthesis of phenyl-
linked 2-thiohydantoins 12a,b
133.8, 144.2, 154.6, 154.8, 170.1, 170.2, 182.1. Anal. Calcd for
32H38N8O6S2 (694.82): C, 55.32; H, 5.51; N, 16.13. Found: C, 55.08;
C
H, 5.60; N, 16.22.
To a stirred solution of DD 1c (2 mmol) in CH2Cl2 (8 mL), amine
derivative 2b or 2d (2 mmol) solved in CH2Cl2 (2 mL) was added at
room temperature. After the disappearance of 1 (0.5e1 h) (TLC
check), 1,4-diisothiocyanatobenzene (11) (1 mmol) was added and
the reaction mixture was allowed to stand overnight at room
temperature. Pure derivatives 12a,b crystallized from the reaction
medium and were isolated by filtration in vacuo washing with
CH2Cl2/Et2O.
4.5.6. Methyl
2-{1-[3-(6-{5-[2-(methoxycarbonyl)ethanhy-
drazonoyl]-3-methyl-4-oxo-2-thioxo-1-imidazolidinyl}hexyl)-1-
methyl-5-oxo-2-thioxo-4-imidazolidinyl]ethylidene}-1-
hydrazinezinecarboxylate (10f). Yield: 370.9 mg (65%). White
powder, mp: 207e209 ꢁC (CH2Cl2/light petroleum ether). IR
(Nujol) nmax 3208, 1744, 1712 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d
: 1.25e1.58 (8H, m, 4ꢃCH2), 1.67 (6H, s, 2ꢃCH3), 3.12 (6H, s,
2ꢃCH3), 3.21e3.27 (2H, m, CH2), 3.68 (6H, s, 2ꢃOCH3), 3.87e3.98
(2H, m, CH2), 4.97 and 5.01 (2H, 2s, 2ꢃCH), 10.34 (2H, s, 2ꢃNH).
4.6.1. Methyl
2-{1-[1-(4-{4-[2-(methoxycarbonyl)ethanhy-
drazonoyl]-5-oxo-3-propyl-2-thioxo-1-imidazolidinyl}phenyl)-5-
oxo-3-propyl-2-thioxo-4-imidazolidinyl]ethilidene}-1-
hydrazinecarboxylate. (12a). Yield: 408.3 mg (66%). White powder,
13C NMR (100 MHz, DMSO-d6)
d: 12.4, 25.5, 26.2, 28.2, 44.9, 52.0,
68.2, 144.0, 154.3, 170.4, 182.4. Anal. Calcd for C22H34N8O6S2

O.A. Attanasi et al. / Tetrahedron 70 (2014) 7336e7343
7343
mp: 221e222 ꢁC (dec) (CH2Cl2/Et2O). IR (Nujol) nmax 3331, 3297,
Murdoch, M. C. G.; Green, S. B.; Heim, D. R. Pestic. Biochem. Physiol. 1996, 55,
210e217.
3200, 3030, 1752, 1730, 1711, 1680 cmꢂ1. 1H NMR (400 MHz, DMSO-
5. (a) Lamothe, M.; Lannuzel, M.; Perez, M. J. Comb. Chem. 2002, 4, 73e78; (b) Kita,
R.; Svec, F.; Frechet, J. M. J. J. Comb. Chem. 2001, 3, 564e571; (c) Park, K.-H.; Kurt,
M. J. Tetrahedron Lett. 2000, 41, 7409e7413; (d) Dorwald, F. Z. Organic Synthesis
on Solid Phase; Wiley-VCH: Weinheim, Germany, 2000; pp 363e366; (e)
Mattheus, J.; Rivero, R. A. J. Org. Chem. 1997, 62, 6090e6092; (f) Kim, S. W.; Ahn,
S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y. Tetrahedron Lett. 1997, 38, 4603e4606.
6. (a) Beller, M.; Eckert, M.; Moradi, W. A.; Neumann, H. Angew. Chem., Int. Ed.
1999, 38, 1454e1457; (b) Ignacio, J. M.; Macho, S.; Marcaccini, S.; Pepino, R.;
Torroba, T. Synlett 2005, 3051e3054; (c) Miura, T.; Mikano, Y.; Murakami, M.
Org. Lett. 2011, 13, 3560e3563; (d) Baccolini, G.; Boga, C.; Delpivo, C.; Micheletti,
G. Tetrahedron Lett. 2011, 52, 1713e1717; (e) Olimpieri, F.; Bellucci, M. C.; Mar-
celli, T.; Volonterio, A. Org. Biomol. Chem. 2012, 10, 9538e9555; (f) Gosling, S.; El
d6)
d
: 0.89 (6H, t, J¼7.2 Hz, 2ꢃNCH2CH2CH3), 1.53e1.70 (4H, m,
2ꢃNCH2CH2CH3), 1.83 (6H, s, 2ꢃCH3), 3.30e3.44 (2H, m,
2ꢃNCHaHbCH2CH3), 3.71 (6H, s, 2ꢃOCH3), 3.86e3.97 (2H, m,
2ꢃNCHaHbCH2CH3), 5.17 (2H, s, 2ꢃCH), 7.49 (4H, s, ArH), 10.43 (2H,
s, 2ꢃNH). 13C NMR (100 MHz, DMSO-d6)
d: 11.1, 12.5, 19.8, 47.2, 52.1,
68.9, 126.4, 129.1, 130.3, 133.6, 143.9, 154.4, 169.8, 181.5. Anal. Calcd
for C26H34N8O6S2 (618.73): C, 50.47; H, 5.54; N, 18.11. Found: C,
50.77; H, 5.64; N, 18.34.
€
Amri, C.; Tatibouet, A. Synthesis 2014, 46, 1079e1084.
4.6.2. Methyl
drazonoyl]-5-oxo-2-thioxo-1-imidazolidinyl}phenyl-5-oxo-2-thioxo-
4-imidazolidinyl]ethilidene}-1-hydrazinecarboxylate (12b). Yield:
540.9 mg (88%). White powder, mp: 228 ꢁC (charcoals) (CH2Cl2/
Et2O). IR (Nujol) nmax 3288, 3244, 3170, 3034, 1753, 1717, 1674 cmꢂ1
1H NMR (400 MHz, DMSO-d6)
2-{1-[3-allyl-1-{4-[2-(methoxycarbonyl)ethanhy-
7. (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Nicolini, S.; Perrulli, F. R.; San-
teusanio, S. Org. Lett. 2011, 13, 353e355; (b) Attanasi, O. A.; Bartoccini, S.; Favi,
G.; Giorgi, G.; Perrulli, F. R.; Santeusanio, S. J. Org. Chem. 2012, 77, 1161e1167.
8. For a review on the synthesis and chemistry of DDs see: Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S.
Eur. J. Org. Chem. 2009, 3109e3127 and reference cited therein (b) Attanasi, O.
A.; De Crescentini, L.; Filippone, P.; Mantellini, F.; Santeusanio, S. ARKIVOC 2002,
xi, 274e292 and references cited therein.
.
d
: 1.81 (6H, s, 2ꢃCH3), 3.71 (6H, s,
2ꢃOCH3), 4.17 (2H, dd, J¼6.0, 16.0 Hz, 2ꢃNCHaHb), 4.56 (2H, dd,
J¼6.0, 16.0 Hz, 2ꢃNCHaHb), 5.11 (2H, s, 2ꢃCH), 5.21e5.30 (4H, m,
2ꢃCH]CH2), 5.79e5.90 (2H, m, 2ꢃCH]CH2), 7.51 (4H, s, ArH),
€
9. (a) Beck, B.; Picard, A.; Herdtweck, E.; Domling, A. Org. Lett. 2004, 6, 39e42; (b)
Hulme, C.; Morrissette, M. M.; Volz, F. A.; Burns, C. J. Tetrahedron Lett. 1998, 39,
1113e1116.
10.41 (2H, s, 2ꢃNH). 13C NMR (100 MHz, DMSO-d6)
d: 12.8, 47.9,
10. For selected recent papers on the heterocycles syntheses via aza-Michael ad-
dition see: (a) Attanasi, O. A.; Bartoccini, S.; Giorgi, G.; Mantellini, F.; Perrulli, F.
R.; Santeusanio, S. Tetrahedron 2010, 66, 5121e5129; (b) Attanasi, O. A.; Bar-
toccini, S.; Favi, G.; Giorgi, G.; Perrulli, F. R.; Santeusanio, S. Tetrahedron 2012,
69, 608e613; (c) Attanasi, O. A.; Favi, G.; Mantellini, F.; Moscatelli, G.; San-
teusanio, S. Adv. Synth. Catal. 2011, 353, 1519e1524; (d) Attanasi, O. A.; Bar-
toccini, S.; Favi, G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S. J. Org. Chem. 2012,
77, 9338e9342; (e) Attanasi, O. A.; Bianchi, L.; Campisi, L. A.; De Crescentini, L.;
Favi, G.; Mantellini, F. Org. Lett. 2013, 15, 3646e3649.
52.1, 68.9, 69.0, 119.3, 126.5, 129.2, 130.8, 133.7, 143.7, 154.4, 169.8,
181.7. Anal. Calcd for C26H30N8O6S2 (614.70): C, 50.80; H, 4.92; N,
18.23. Found: C, 50.61; H, 5.08; N, 18.20.
Acknowledgements
11. Attanasi, O. A.; Filippone, P.; Foresti, E.; Guidi, B.; Santeusanio, S. Tetrahedron
1999, 55, 13423e13444.
12. CCDC-783240 contains the supplementary crystallographic data for compound
6c described in this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
Financial support from the Ministero dell’Istruzione,
ꢀ
dell’Universita e della Ricerca (MIUR)-Roma and from the Univer-
sity of Urbino “Carlo Bo” is gratefully acknowledged.
References and notes
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~
€
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