Study of the nucleophilic behaviour of N-phenylbenzamidine towards 1,2-diaza-1,3-dienes: Domino reactions for imidazole scaffolds

Article abstract of DOI:10.1016/j.tet.2010.04.108

Depending on the nature of the solvent, alcohol or DMF, N-phenylbenzamidine shows different nudeophilic behaviour towards the conjugated azoene system of 1,2-diaza-1,3-dienes. In alcohol it reacts as a nucleophile through the N-phenyl imino nitrogen affording spiro pyrroloimidazoles and 1,3-diphenyl- IH-imidazoles. In DMF, by contrast, it behaves as nucleophile mainly by means of the imino amidino nitrogen providing 2-phenylimidazole derivatives by loss of the aniline molecule.

Full text of DOI:10.1016/j.tet.2010.04.108

Tetrahedron 66 (2010) 5121e5129
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Tetrahedron
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Study of the nucleophilic behaviour of N-phenylbenzamidine towards 1,2-diaza-
1,3-dienes: domino reactions for imidazole scaffolds
Orazio A. Attanasi a, Silvia Bartoccini a, Gianluca Giorgi b, Fabio Mantellini a, Francesca R. Perrulli a,
,
Stefania Santeusanio a
*
a Institute of Organic Chemistry, Università degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy
b Department of Chemisrty, Università 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:
Depending on the nature of the solvent, alcohol or DMF, N-phenylbenzamidine shows different nucle-
ophilic behaviour towards the conjugated azoeene system of 1,2-diaza-1,3-dienes. In alcohol it reacts as
a nucleophile through the N-phenyl imino nitrogen affording spiro pyrroloimidazoles and 1,3-diphenyl-
1H-imidazoles. In DMF, by contrast, it behaves as nucleophile mainly by means of the imino amidino
nitrogen providing 2-phenylimidazole derivatives by loss of the aniline molecule.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 24 February 2010
Received in revised form 8 April 2010
Accepted 26 April 2010
Available online 22 May 2010
Keywords:
1,2-Diaza-1,3-dienes
Tautomerism
Michael addition
Nitrogen heterocycles
Spiro compounds
1. Introduction
that the predominant tautomer of PBA has the C]N double bond
conjugated with the phenyl group (Fig. 1, amino form B). Since each
The development of new methods for the synthesis of azahe-
terocycles1 is of particular interest in organic chemistry since they
occur in awide variety of natural products.2 This is especially true for
nitrogen-containing five-membered ring, such as imidazoles,3
which are core components of a large number of substances that
possess a wide range of interesting biological activities.4 In particu-
lar, 2-arylimidazoles represent an important class of structures be-
cause of their reported antifungal,5 NPY5 receptor antagonism6 and
macromolecular ligand7 properties. Due to their importance, many
methods have been developed for assembling the imidazole ring.8 In
connectionwith ourongoinginterestto employ 1,2-diaza-1,3-dienes
(DDs) as building blocks for heterocyclic skeletons,9 recently we
reported the Michael addition of arylamidinestoazoeenesystem for
the synthesis of 2-arylimidazole derivatives and spirocyclic com-
pounds including the imidazole framework.10 Starting from these
results, we envisaged the opportunity to investigate the nucleophilic
behaviour of N-phenylbenzamidine (PBA)11 towards DDs in order to
enlarge our approach for the synthesis of imidazole-containing
compounds. Even if two tautomeric forms can be expected for PBA
(Fig.1), previously reported IR spectra12 and 15N NMR studies13 show
tautomeric form possesses potential nucleophilic sites, we hypoth-
esized that, depending on the reaction solvent (alcohol or DMF), the
nucleophilic behaviour of such a bidentate molecule could change
and thus influence the results of the reaction with DDs.
Nu
NH
NH2
N
Ph
Ph
Ph
N
Ph
H
2
Nu
imide form A
amino form B
Figure 1. Tautomeric equilibrium of N-phenylbenzamidine with potential nucleophilic
centres.
2. Results and discussion
On the basis of our previous results,10 in which arylamidines
reacted with DDs 1 in 1:2 ratios to afford spiro pyrroloimidazoles,
we planned to perform a one-pot reaction of DDs 1aed (2 equiv)
and PBA 2 (1 equiv) in MeOH or EtOH, firstly at room temperature
until the disappearance of the reagents and then under reflux to
promote the conversion of the intermediates (Scheme 1). By
* Corresponding author. Tel.: þ39 0722 303445; fax: þ39 0722 303441; e-mail
address: stefania.santeusanio@uniurb.it (S. Santeusanio).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.108

5122
O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
O
R2
Ph
N
R1
O
O
O
O
1
N
H
N
R2
H
R2
B
R1
1) R2OH, r.t.
O
_
O
R1
NHNH2
O
N
N
N
O
N
+
Ph
HN
Ph
NH2
N
2) Δ
route A
Ph
Ph
A
Ph
3
4
2
_
R2OH
route B
O
R1
O
O
O
NH
R1
HN R1
HN R1
HN
R1
H
N
O
O
HN NH
O
N
H
R1
H
N
1
O
N
N
O
OR2
N
N
N
O
N
N
O
N
N
N
Ph
Ph
N
H
O
Ph
Ph
Ph
Ph
O
5
7
6
5'
Ph
R2
Ph
Scheme 1. Reaction pathway between 1 (2 equiv) and 2 (1 equiv) in MeOH or EtOH.
column chromatography of the crude reaction mixture, we found
two main products: 4 and 7 (Table 1). As shown in Scheme 1, the
replacement with an amide residue could allow the regioselective
ring closure according to route A and the unambiguous assignment
Table 1
Results of the reactions of DDs 1 and PBA 2 in MeOH or EtOH
Entry
DD 1
1,3-Diphenyl-1H-imidazole 4
Spiro Pyrroloimidazole 7
4H-Imidazol-5-one 5/50
R1
R2
R2
Yieldb (%)
Yielda (%) C4(S/R),C6(S/R)
Yielda (%) C4(S/R),C6(R/S)
R1
1
2
3
4
1a
1b
1c
1d
OMe
OMe
OtBu
OtBu
Me
Et
Me
Et
4a
4b
4a
4b
Me
Et
Me
Et
15
16
8
7a
7b
7c
7d
20
26
30
32
32
29
35
33
50a
OMe
10
a
Yield of pure isolated diastereomer based on 2.
Yield of pure isolated product based on 2.
b
reaction pathway proceeds via nucleophilic attack of PBA 2 through
the imino N-phenyl nitrogen at the terminal carbon atom of the
conjugated azoeene system of 1 to give hydrazone intermediate 3
by Michael-type addition. At this point two different internal cy-
clization routes are possible for the intermediate 3: one (route A) in
which the imino amidino function provides a nucleophilic attack at
the hydrazono moiety affording 1,2-diphenyl-1H-imidazole de-
rivative 4 by loss of a hydrazinecarboxylic ester residue, the other
(route B), in which the same function attacks the ester group at C4
producing 4H-imidazol-5-one derivative 5 by loss of an alcohol
molecule, According to our previous results,10 the carbanion for-
mation from 5, catalyzed by the amidine itself, gives rise to nu-
cleophilic 1,4-addition to another molecule of 1 furnishing the
intermediate 6. Finally, the two hydrazone side chains of 5 co-
operate in the pyrroline ring closure producing spiro pyrroloimi-
dazole derivative 7 as a diastereomeric mixture (ranging from 52 to
65%, see Table 1).
Figure 2. X-ray molecular structure of 7a with EtOAc molecule enclosed.
Confirmation of this reaction pathway is given by means of the
occasional isolation of the hydrazino tautomeric form 50a and by
the X-ray structure determination of the diastereomer 4S/R,6S/R of
7a (Table 1) (Fig. 2).14
The structure of imidazole 4, arising from the loss of the hy-
drazide residue, was deduced by comparison of 4a with its
regioisomer, which appeared in the literature.15 Since the ester
function at C4 of 1 played a key role in route B, we thought that its
of the structure 4. In fact, the reaction in EtOH between 1e and 2 in
equimolar ratio (Scheme 2), afforded 4e (70%).
The X-ray study of 4e (Fig. 3)16 confirmed the hypothesized
structure obtained from intermediate 3 through route A. Both de-
rivatives 4 and 7 establish, thus, the involvement of the N-phenyl
nitrogen of PBA 2 in the nucleophilic addition on DDs in alcoholic
medium.

O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
5123
Next, based on NMR studies carried out by Clement,13 we
decided to investigate the reactions between DDs 1aeh (2 equiv)
and PBA 2 (1 equiv) in DMF under the same conditions: at room
temperature, until the disappearance of the reagents and then
under reflux. After the removal of DMF and chromatographic pu-
rification of the crude products, imidazole derivatives 4aed
(14e38%) and new alkyl 1-[(alkoxycarbonyl)amino]-5-methyl-2-
phenyl-1H-imidazole-4-carboxylate derivatives 10aeh (57e70%)
were obtained (see Scheme 3 and Table 2). The prevalent formation
of these last compounds requires the nucleophilic attack by the
unsubstituted nitrogen of 2 at the azoeene system resulting in the
Michael adduct 8. The subsequent intramolecular nucleophilic at-
tack of the sp2 hydrazone nitrogen at the imino function of the
amidine residue, affords intermediate 9 that in turn provides 2-
phenylimidazole derivative 10 by extrusion of an aniline molecule.
In DMF, therefore, both the imino nitrogen of PBA 2 (Fig. 1) are
operative in the nucleophilic addition.
O
t
N
OBu
O
H
N
N
N
H
t
OBu
O
N
N
1e
1) EtOH, r. t.
N
NH O
NH2
N
Ph
Ph
2) Δ
3e
Ph
Ph
2
H
N
t
OBu
_
H2N
O
O
N
N
N
Ph
4e 70%
Ph
Scheme 2.
Both reaction pathways, in protic and non protic polar medium,
implicate the role of the amidine derivative as nucleophile as well
as base in a domino heterocyclization process. Besides, the different
imidazole derivatives obtained allows us to assert that PBA 2 acts as
a nucleophile by the N-substituted imino group of the amino form
in alcohol; on the contrary, the nucleophilic attack through the N-
unsubstituted imino function of the imide form is favoured in DMF.
In order to extend the scope for the cascade spiro annulation
process, the reaction of DDs 1 with N,N0-diphenylguanidine (DPG)
11,11 under the optimized stoichiometric conditions, was then ex-
amined. All the reactions carried out in alcohol were exothermic
and 11, being a stronger base with respect to PBA 2, worked so well
to rapidly produce spiroheterocycles 15 that these were often
obtained by precipitation (15c,d) from the reaction medium at
room temperature (Scheme 4, Table 3). In some cases, 2-anilino-1-
phenylimidazol-4-one derivative intermediate 13 (Table 3) was
separated by chromatography. The formation of 15 can be
Figure 3. Crystal structure of 4e.
Scheme 3. Reaction pathway between DDs 1 and PBA 2 in DMF.
Table 2
Results of the reactions between DDs 1 and PBA 2 in DMF
Entry
DD 1
1,2-Diphenyl-1H-imidazole 4
Alkyl 1-[(alkoxycarbonyl)amino]-5-methyl-2-phenyl-1H-imidazole-4-carboxylate 10
R1
R2
R2
Yielda (%)
Yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
OMe
OMe
OtBu
OtBu
OEt
Me
Et
Me
Et
4a
4b
4a
4b
4b
4c
4a
4d
Me
Et
Me
Et
14
17
26
25
21
38
29
20
10a
10b
10c
10d
10e
10f
58
70
59
60
63
58
66
57
Et
Et
OtBu
OBn
OMe
i-Pr
Me
Allyl
i-Pr
Me
Allyl
1g
1h
10g
10h
a
Yield of pure isolated product based on 2.

5124
O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
Scheme 4. Reaction pathway between 1 (2 equiv) and 11 (1 equiv) in MeOH or EtOH.
Table 3
Results of the reactions of DDs 1 and DPG 11 in MeOH or EtOH
Entry
DD 1
2-Anilino-1-phenylimidazol-4-one 13
Spiro pyrroloimidazole 15
Yielda (%) C4(S/R),C6(R/S)
36
R1
R2
R1
Yielda (%) C4(S/R),C6(S/R)
1
2
3
4
5
1a
1b
1c
1d
1e
OMe
OMe
OtBu
OtBu
OEt
Me
Et
Me
Et
13a
13a
OMe
OMe
40
38
15a
15b
15c
15d
15e
41
47
49
49
23
24
Et
13b
OEt
37
a
Yield of pure isolated product based on 11.
explained by the attack of N-phenyl imino group of DPG 11 at the
terminal carbon of the conjugated azoeene system of DDs 1 to give
hydrazone derivative 12 that in turn, by formal [3þ2] cyclization,
affords 13 by loss of an alcohol molecule. This last one, by DPG-
promoted carbanion formation, adds to another DD molecule in
a Michael fashion providing the intermediate 14. Subsequent
intramolecular cyclization between the two hydrazone side chains
finally produces spiro pyrroloimidazole derivative 15.
The X-ray diffraction study of 15a confirmed the structure hy-
pothesized by spectroscopic data (Fig. 4)17 and allowed us to es-
tablish the stereochemical assignement of the two stereogenic
carbons of the major diastereomer.
3. Conclusions
In summary, based on the products, which resulted from the
study of the reactivity of PBA 2 with DDs 1 in different polar solvents,
we can conclude that 2 behaves as a nucleophile with the N-phenyl
imino group in alcoholic solvents, whereas the imino amidino ni-
trogen prevailes as the nucleophile in DMF. The choice of solvent is,
therefore, strategic in influencing the nucleophilic behaviour of PBA,
allowing the acquisition of structurally different imidazole scaffolds.
Inboth routes, moreover, PBA playsa critical rolein the successof the
reaction by serving as base for the intramolecular ring closure and
for the spirocyclization process. Similarly, DPG 11 realizes carbon/
nitrogen bond formation with DDs 1 by nucleophilic attack of the
substituted imino nitrogen in alcoholic solvents, and acts as base for
the construction of complex spiro azaheterocycles through a dom-
ino process.
Conversely, complicated reaction mixtures were obtained when
DPG 11 was tested to react with DDs in DMF.
4. Experimental
4.1. General experimental section
N-Phenylbenzamidine and N,N0-diphenylguanidine were com-
mercial materials and were used without further purification. 1,2-
Diaza-1,3-dienes were prepared as reported9 and solvents were
used without further purification. Melting points were determined
in open capillary tubes and are uncorrected. FTIR spectra were
obtained as Nujol mulls. Mass spectra (MS) were carried out by
electron impact (EI) at an ionizing voltage of 70 eV. 1H (400 MHz)
and 13C (100 MHz) spectra were recorded in CDCl3 or in DMSO-d6,
as specified below. Chemical shifts (dH) are reported in parts per
Figure 4. X-ray molecular structure of 15a.

O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
5125
million (ppm), relative to TMS as internal standard. All coupling
constant (J values) are given in hertz (Hz). The abbreviations for the
multiplicity are used as follows: s, singlet; d, doublet; dd, double-
doublet; t, triplet; q, quartet; sept, septet; m, multiplet; br, broad;
ArH, aromatic hydrogen. All the NH exchanged with D2O. Chemical
shifts (dC) are reported in parts per million (ppm), relative to the
central peak of CDCl3 or DMSO-d6 as internal standard. Precoated
silica gel plates 0.25 mm were employed for analytical thin layer
J¼8.4 Hz, ArH), 7.55 (1H, t, J¼8.4 Hz, ArH), 7.64 (2H, d, J¼8.4 Hz,
ArH), 7.99 (1H, s, NH), 8.92 (1H, s, NH). 13C NMR (100 MHz, DMSO-
d6) d: 11.0, 15.7, 50.4, 52.5, 52.8, 81.7, 89.6, 93.4, 127.7, 128.4, 128.7,
129.0, 130.2, 132.9, 137.5, 156.8, 162.9, 167.6, 179.8, 189.7. MS (EI): m/
z (%)¼536 (Mþ, 1), 447 (100), 415 (6), 340 (5), 312 (4), 284 (5). Anal.
Calcd for C26H28N6O7 (536.53): C, 58.20; H, 5.26; N, 15.66. Found: C,
58.42; H, 5.23; N, 15.48.
4S/R,6R/S isomer: Yield: 171.7 mg (32%). Beige solid, mp:
chromatography and silica gel 35e70 mm for column chromatog-
123e125 ꢀC dec (from THF/n-pentane). IR (Nujol) nmax 3349, 3331,
raphy. All new compounds showed satisfactory elemental analysis
(Cþ0.35; Hþ0.30; Nþ0.30). The nomenclature was generated using
ACD/IUPACName (version 3.50, 5 Apr. 1998), Advanced Chemistry
Development Inc., Toronto, ON (Canada).
3290, 1740, 1735, 1720, 1600 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d:
1.28 (3H, s, CH3), 1.83 (3H, s, CH3), 3.56 (3H, s, OCH3), 3.69 (3H, s,
OCH3), 3.75 (3H, s, OCH3), 5.61 (1H, br s, NH), 7.14 (5H, br s, Ph), 7.35
(2H, t, J¼7.6 Hz, ArH), 7.46 (1H, t, J¼7.6 Hz, ArH), 7.65 (2H, d,
J¼7.6 Hz, ArH), 9.68 (1H, br s, NH), 10.39 (1H, br s, NH). 13C NMR
4.2. General procedure for the reactions of PBA in alcohol
(100 MHz, DMSO-d6) d: 11.6, 17.1, 50.3, 51.6, 52.6, 79.2, 88.7, 95.1,
127.1,127.9,128.0,129.6,130.2, 130.7,132.2,138.7,154.4, 157.2,163.9,
165.0, 180.1, 187. 7. MS (EI): m/z (%)¼536 (Mþ, 1), 447 (100), 415 (7),
340 (6), 312 (5), 284 (5). Anal. Calcd for C26H28N6O7 (536.53): C,
58.20; H, 5.26; N, 15.66. Found: C, 58.32; H, 5.33; N, 15.48.
In a 25-mL flask, PBA 2 (1 mmol) was dissolved in MeOH or
EtOH (2 mL) and a solution of DD 1aed (2 mmol) in the same
solvent (4 mL) was added dropwise quickly. The reaction mixture
was stirred at room temperature until the disappearance of DD was
confirmed by TLC (0.3e1.0 h). Upon completion, the reaction mix-
ture was heated under reflux (1e4 h) until its colour turned purple
and the intermediates evolved in two major spots (by TLC). After
removal of the solvent in vacuo, the residue was purified by chro-
matography (silica gel, DCM/EtOAc) to give 4a,b and 7aed.
4.2.5. Ethyl
7-[(methoxycarbonyl)amino]-6-[2-(methoxycarbonyl)
hydrazino]-6,8-dimethyl-4-oxo-1,2-diphenyl-1,3,7-triazaspiro[4.4]
nona-2,8-diene-9-carboxylate
(7b):
4S/R,6S/R
isomer. Yield:
143.1 mg (26%). White solid, mp: 219e220 ꢀC dec (from MeOH). IR
(Nujol) nmax 3302, 3236, 3190, 1743, 1721, 1687, 1601, 1553 cmꢁ1. 1H
NMR (400 MHz, CDCl3)
d
: 1.17 (3H, t, J¼7.2 Hz, OCH2CH3), 1.73 (3H,
4.2.1. Methyl
(4a). Yield: 43.8 mg (15%). White powder, mp: 144e147 ꢀC (from
EtOAc). IR (Nujol) nmax 1713, 1600, 1538, 1499 cmꢁ1 1H NMR
(400 MHz, CDCl3) : 2.63 (3H, s, CH3), 3.71 (3H, s, OCH3), 7.19e7.22
(5H, m, ArH), 7.31e7.33 (2H, m, ArH), 7.39e7.41 (3H, m, ArH). 13C
4-methyl-1,2-diphenyl-1H-imidazole-5-carboxylate
s, CH3), 1.97 (3H, s, CH3), 3.63 (3H, s, OCH3), 3.85 (3H, s, OCH3),
3.88e4.01 (2H, m, OCH2CH3), 4.69 (1H, br s, NH), 7.18 (5H, br s, Ph),
7.28 (2H, t, J¼8.4 Hz, ArH), 7.43 (1H, t, J¼8.4 Hz, ArH), 7.69 (2H, d,
J¼8.4 Hz, ArH), 7.94 (1H, s, NH), 8.99 (1H, s, NH). 13C NMR (100 MHz,
.
d
DMSO-d6) d: 11.7, 14.6, 16.6, 53.1, 53.4, 60.0, 82.8, 90.5, 95.0, 128.3,
NMR (100 MHz, CDCl3)
d
: 16.1, 51.6, 122.0, 128.5, 128.6, 129.2, 129.3,
128.9, 129.3, 129.6, 131.2, 133.1, 138.2, 158.1, 158.3, 163.8, 169.1, 180.7,
190.3. MS (EI): m/z (%)¼550 (Mþ, 1), 461 (27), 279 (30), 252 (100).
Anal. Calcd for C27H30N6O7 (550.56): C, 58.90; H, 5.49; N, 15.26.
Found: C, 58.76; H, 5.52; N, 15.43.
129.4, 129.9, 138.3, 148.2, 150.3, 161.4. MS (EI): m/z (%)¼292 (Mþ,
100), 261 (18), 233 (8), 130 (35). Anal. Calcd for C18H16N2O2
(292.33): C, 73.95; H, 5.52; N, 9.58. Found: C, 74.30; H, 5.48; N, 9.72.
4S/R,6R/S isomer: yield: 159.7 mg (29%). Beige solid, mp:
119e122 ꢀC dec (from Et2O/light petroleum ether). IR (Nujol) nmax
3536, 3276, 3220, 1738, 1725, 1703, 1608 cmꢁ1. 1H NMR (400 MHz,
4.2.2. Ethyl
(4b). Yield: 52.1 mg (52%). White powder, mp: 111e114 ꢀC (from
DCM/n-pentane). IR (Nujol) nmax 1699, 1681, 1597, 1562, 1500 cmꢁ1
1H NMR (400 MHz, DMSO-d6)
: 0.98 (3H, t, J¼7.2 Hz, OCH2CH3),
2.48 (3H, s, CH3), 4.00 (2H, q, J¼7.2 Hz, OCH2CH3), 7.20e7.30 (7H, m,
ArH), 7.38e7.43 (3H, m, ArH). 13C NMR (100 MHz, DMSO-d6)
: 13.7,
15.3, 59.7, 121.5, 128.1, 128.3, 128.7, 128.8, 128.9, 129.0, 129.5, 137.7,
146.6, 148.9, 159.6. MS (EI): m/z (%)¼306 (Mþ, 100), 277 (24), 261
(17), 234 (29), 130 (33). Anal. Calcd for C19H18N2O2 (306.35): C,
74.49; H, 5.92; N, 9.14. Found: C, 74.56; H, 6.02; N, 9.10.
4-methyl-1,2-diphenyl-1H-imidazole-5-carboxylate
.
DMSO-d6)
d
: 1.09 (3H, t, J¼6.8 Hz, OCH2CH3), 1.30 (3H, s, CH3), 1.81
d
(3H, s, CH3), 3.66e3.85 (8H, m, 2CH3 and OCH2CH3), 5.62 (1H, br s,
NH), 7.14 (5H, br s, Ph), 7.35 (2H, t, J¼7.6 Hz, ArH), 7.46 (1H, t,
J¼7.6 Hz, ArH), 7.63 (2H, d, J¼7.6 Hz, ArH), 8.18 (1H, br s, NH), 9.66
d
(1H, br s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.5,14.0,17.08, 51.6,
52.7, 58.9, 79.3, 88.8, 95.4, 127.2, 128.1, 128.9, 129.7, 130.6, 132.3,
138.6, 157.3, 163.5, 165.0, 180.1, 187.8. Anal. Calcd for C27H30N6O7
(550.56): C, 58.90; H, 5.49; N, 15.26. Found: C, 58.69; H, 5.53; N,
15.34.
4.2.3. Methyl 2-[1-(5-oxo-2,3-diphenyl-3,5-dihydro-4H-imidazol-4-
ylidene)ethyl]hydrazinecarboxylate (50a). Yield: 35 mg (10%). Beige
solid, mp: 217e218 ꢀC (from MeOH). IR (Nujol) nmax 3220, 3085,
4.2.6. Methyl
7-[(tert-butoxycarbonyl)amino]-6-[2-(tert-butox-
ycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-1,2-diphenyl-1,3,7-tri-
azaspiro[4.4]nona-2,8-diene-9-carboxylate (7c): 4S/R,6S/R isomer.
Yield: 186.2 mg (30%). White solid, mp: 222e223 ꢀC dec (from
MeOH). IR (Nujol) nmax 3347, 3227, 3075, 1747, 1729, 1711, 1690,
1746, 1714, 1605, 1534 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.97
(3H, s, CH3), 3.72 (3H, s, OCH3), 7.14e7.27 (5H, m, Ph), 7.36 (2H, t,
J¼8 Hz, ArH), 7.47 (1H, t, J¼8 Hz, ArH), 7.54 (2H, d, J¼8 Hz, ArH),
10.23 (1H, s, NH),11.41 (1H, br s, NH). 13C NMR (100 MHz, DMSO-d6)
1609, 1598 cmꢁ1. 1H NMR (400 MHz, DMSO-d6) : 1.37 (9H, s, OtBu),
d
d: 13.6, 52.0, 94.1, 128.0, 128.5, 128.6, 129.2, 130.0, 132.3, 138.1, 148.7,
1.49 (3H, s, CH3), 1.52 (9H, s, OtBu), 1.85 (3H, s, CH3), 3.38 (3H, s,
OCH3), 6.19 (1H, s, NH), 7.19 (5H, br s, Ph), 7.41 (2H, t, J¼7.6 Hz, ArH),
7.54 (1H, t, J¼7.6 Hz, ArH), 7.65 (2H, d, J¼7.6 Hz, ArH), 7.78 (1H, s,
155.0, 160.2, 178.1, 186.94. Anal. Calcd for C19H18N4O3 (350.37): C,
65.13; H, 5.18; N, 15.99. Found: C, 64.89; H, 5.30; N, 16.06.
NH), 8.77 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.2, 15.8,
4.2.4. Methyl 7-[(methoxycarbonyl)amino]-6-[2-(methoxycarbonyl)
hydrazino]-6,8-dimethyl-4-oxo-1,2-diphenyl-1,3,7-triazaspiro[4.4]
27.9, 28.0, 50.4, 79.9, 80.8, 81.9, 89.7, 92.9, 127.6, 128.4, 128.7, 129.1,
130.2, 132.9, 137.6, 155.6, 155.7, 163.1, 167.6, 179.8, 189.8. MS (EI): m/
z (%)¼489 ([MꢁNHNHBoc]þ, 55), 433 (100), 389 (6), 340 (5). Anal.
Calcd for C32H40N6O7 (620.69): C, 61.92; H, 6.50; N, 13.54. Found: C,
61.84; H, 6.61; N, 13.63.
nona-2,8-diene-9-carboxylate
(7a):
4S/R,6S/R
isomer. Yield:
107.3 mg (20%). Colourless crystals, mp: 212e213 ꢀC dec (from
EtOAc). IR (Nujol) nmax 3434, 3209, 3089, 1752, 1732, 1722, 1683,
1610, 1588, 1550 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d
: 1.51 (3H, s,
4S/R,6R/S isomer: yield: 217.2 (35%). Beige solid, mp: 189e191 ꢀC
dec (from EtOAc/n-pentane). IR (Nujol) nmax 3360, 3330, 3206, 1752,
CH3), 1.85 (3H, s, CH3), 3.39 (3H, s, OCH3), 3.59 (3H, s, OCH3), 3.78
(3H, s, OCH3), 6.38 (1H, s, NH), 7.20 (5H, br s, Ph), 7.42 (2H, t,
1680, 1599 cmꢁ1. 1H NMR (400 MHz, DMSO-d6) : 1.24 (9H, s, OtBu),
d

5126
O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
1.40 (9H, s, OtBu), 1.77 (3H, s, CH3), 1.85 (3H, s, CH3), 3.36 (3H, s,
OCH3), 5.63 (1H, br s, NH), 7.13 (5H, br s, Ph), 7.34 (2H, t, J¼7.6 Hz,
ArH), 7.45 (1H, t, J¼7.6 Hz, ArH), 7.73 (2H, d, J¼7.6 Hz, ArH), 8.96
4.4. General procedure for the reactions of PBA in DMF
In a 5-mL flask, PBA 2 (1 mmol) was dissolved in DMF (1 mL) and
a solution of DD 1aeh (2 mmol) in DMF (2 mL) was then added at
room temperature with stirring. After the disappearance of DD
(0.2e0.5 h), monitored by TLC, the crude reaction mixture was
heated (0.5 h) until its colour turned brown (0.5e1 h). After partial
evaporation of DMF in vacuo, the crude was dissolved in EtOAc
(20 mL) and washed with H2O (5ꢂ5 mL). The organic layer was
dried (Na2SO4), filtered and the filtrate was concentrated in vacuo.
The residue was purified by chromatography (silica gel, cyclohex-
ane/EtOAc) to separate 4aed from 10aeh.
(1H, br s, NH), 9.41 (1H, br s, NH). 13C NMR (100 MHz, DMSO-d6)
d:
11.5, 16.9, 27.8, 28.1, 50.3, 79.8, 80.8, 81.7, 88.7, 94.8, 127.2, 128.1,
128.9, 129.7, 130.7, 132.3, 138.6, 155.1, 156.0, 163.8, 165.3, 179.9,
187.3. MS (EI): m/z (%)¼489 ([MꢁNHNHBoc]þ, 74), 433 (100), 389
(7), 340 (5). Anal. Calcd for C32H40N6O7 (620.69): C, 61.92; H, 6.50;
N, 13.54. Found: C, 61.88; H, 6.64; N, 13.66.
4.2.7. Ethyl
7-[(tert-butoxycarbonyl)amino]-6-[2-(tert-butoxy-
carbonyl)hydrazino]-6,8-dimethyl-4-oxo-1,2-diphenyl-1,3,7-tri-
azaspiro[4.4]nona-2,8-diene-9-carboxylate (7d): 4S/R,6S/R isomer.
Yield: 203.1 mg (32%). White solid, mp: 214e215 ꢀC dec (from
EtOH). IR (Nujol) nmax 3337, 3220, 3079, 1736, 1718, 1687, 1613,
4.4.1. Isopropyl 4-methyl-1,2-diphenyl-1H-imidazole-5-carboxylate
(4c). Yield: 121.7 mg (38%). White powder, mp: 113e115 ꢀC (from
1563 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
: 1.16 (3H, t, J¼7.2 Hz,
Et2O/n-pentane). IR (Nujol) nmax 1700, 1600, 1559, 1495 cmꢁ1 1H
.
OCH2CH3), 1.40 (9H, s, OtBu), 1.54 (9H, s, OtBu), 1.66 (3H, s, CH3), 1.97
(3H, s, CH3), 3.86e4.00 (2H, m, OCH2CH3), 4.38 (1H, br s, NH),
7.12e7.17 (5H, br s, Ph), 7.29 (2H, t, J¼7.6 Hz, ArH), 7.43 (1H, t,
J¼7.6 Hz, ArH), 7.69 (2H, d, J¼7.6 Hz, ArH), 7.71 (1H, s, NH), 8.70 (1H,
NMR (400 MHz, DMSO-d6)
d
: 0.97 (6H, d, J¼6.0 Hz, CH3CHCH3),
2.48 (3H, s, CH3) 4.84 (1H, sept, J¼6.0 Hz, CH3CHCH3), 7.22e7.31
(7H, m, ArH), 7.40e7.44 (3H, m, ArH). 13C NMR (100 MHz, DMSO-d6)
d
: 15.2, 21.3, 67.1, 121.5, 128.7, 128.0, 128.3, 128.6, 128.7, 128.8, 128.9,
s, NH). 13C NMR (100 MHz, CDCl3)
d: 11.8, 14.6, 16.6, 28.7, 28.8, 59.8,
129.5, 137.8, 146.5, 148.7, 159.0. MS (EI): m/z (%)¼320 (Mþ, 75), 278
(71), 233 (13), 130 (30), 125 (60), 111(100). Anal. Calcd for
C20H20N2O2 (320.38): C, 74.98; H, 6.29; N, 8.74. Found: C, 74.87; H,
6.35; N, 8.81.
81.2, 81.5, 83.0, 90.2, 94.0, 128.1, 128.9, 129.2, 131.3, 133.3, 138.2,
156.6, 156.8, 163.90, 180.5, 190.0. MS (EI): m/z (%)¼503
([MꢁNHNHBoc]þ, 75), 447 (100), 403 (5), 375 (3), 340 (6). Anal.
Calcd for C33H42N6O7 (634.72): C, 62.45; H, 6.67; N, 13.24. Found: C,
62.58; H, 6.75; N, 13.50.
4.4.2. Allyl
4-methyl-1,2-diphenyl-1H-imidazole-5-carboxylate
4S/R,6R/S isomer: yield: 209.5 mg (33%). White solid, mp:
(4d). Yield: 63.7 mg (20%). White powder, mp: 70e78 ꢀC (from
DCM/light petroleum ether). IR (Nujol) nmax 1718, 1670, 1651, 1599,
184e185 ꢀC dec (from Et2O/light petroleum ether). IR (Nujol) nmax
3277, 3181, 3067, 1753, 1725, 1703, 1657, 1607 cmꢁ1
.
1H NMR
1546, 1502 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d: 2.64 (3H, s, CH3),
(400 MHz, DMSO-d6)
d
: 1.05 (3H, t, J¼6.8 Hz, OCH2CH3), 1.24 (9H, s,
4.59e4.61 (2H, m, OCH2), 5.15e5.23 (2H, m, CH2]CH), 5.75e5.85
(1H, m, CH2]CH), 7.17e7.26 (5H, m, ArH), 7.32e7.36 (2H, m, ArH),
OtBu), 1.28 (3H, s, CH3), 1.41 (9H, s, OtBu), 1.77 (3H, s, CH3),
3.74e3.86 (2H, m, OCH2CH3), 5.64 (1H, br s, NH), 7.13 (5H, br s, Ph),
7.34 (2H, t, J¼7.6 Hz, Ar), 7.47 (1H, t, J¼7.6 Hz, Ar), 7.72 (2H, d,
J¼7.6 Hz, Ar), 8.40 (1H, br s, NH), 9.40 (1H, br s, NH). 13C NMR
7.38e7.42 (3H, m, ArH). 13C NMR (100 MHz, CDCl3)
d: 16.2, 65.2,
118.5, 122.0, 128.5, 128.6, 129.2, 129.3, 129.4, 130.0, 132.4, 138.4,
148.5, 150.3, 160.5. MS (EI): m/z (%)¼318 (Mþ, 100), 277 (26), 234
(64), 219 (3), 193 (29). Anal. Calcd for C20H18N2O2 (318.36): C, 75.45;
H, 5.70; N, 8.80. Found: C, 75.30; H, 5.78; N, 8.64.
(100 MHz, DMSO-d6) d: 11.5, 14.0, 16.9, 58.7, 78.7, 79.4, 80.5, 89.0,
93.8, 127.1, 127.7, 127.9, 129.6, 130.8, 132.1, 138.4, 154.9, 156.0, 163.3,
165.1, 180.0, 187.5. MS (EI): m/z (%)¼503 ([MꢁNHNHBoc]þ, 70), 447
(100), 403 (6), 375 (4), 340 (7). Anal. Calcd for C33H42N6O7 (634.72):
C, 62.45; H, 6.67; N, 13.24. Found: C, 62.61; H, 6.59; N, 13.36.
4.4.3. Methyl 1-[(methoxycarbonyl)amino]-5-methyl-2-phenyl-1H-
imidazole-4-carboxylate (10a). Yield: 167.8 mg (58%). Beige pow-
der, mp: 188e191 ꢀC (from Et2O/light petroleum ether). IR (Nujol)
nmax 3475, 1740, 1720, 1580, 1550 cmꢁ1. 1H NMR (400 MHz, DMSO-
d6)
(3H, t, J¼7.0 Hz, ArH), 7.72 (2H, d, J¼7.0 Hz, ArH), 11.21 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6)
: 9.1, 51.1, 53.2, 125.7, 127.5, 128.5,
d: 2.38 (3H, s, CH3), 3.70 (3H, s, OCH3), 3.79 (3H, s, OCH3), 7.48
4.3. General procedure for the synthesis of N5,N5-diethyl-4-
methyl-1,2-diphenyl-1H-5-imidazolecarboxamide (7e)
d
128.6, 129.4, 129.9, 138.2, 145.4, 155.3, 163.2. MS (EI): m/z (%)¼289
(Mþ, 100), 257 (82), 229 (39), 155 (77), 104 (56). Anal. Calcd for
C14H15N3O4 (289.29): C, 58.13; H, 5.23; N, 14.53. Found: C, 58.42; H,
5.12; N, 14.72.
In a 25-mL flask, PBA 2 (1 mmol) was dissolved in EtOH (2 mL)
and a solution of DD 1e (1 mmol) in the same solvent (4 mL) was
added dropwise quickly. The reaction mixture was stirred at room
temperature until the disappearance of 1e was confirmed by TLC
(6.0 h). Upon completion, the reaction mixture was heated under
reflux (8 h) until the polar intermediates evolved into a major non
polar spot (by TLC). After removal of the solvent in vacuo, the res-
idue was purified by chromatography (silica gel, DCM/EtOAc mix-
tures) to obtain 4e.
4.4.4. Ethyl
1-[(methoxycarbonyl)amino]-5-methyl-2-phenyl-1H-
imidazole-4-carboxylate (10b). Yield: 212.3 mg (70%). Beige pow-
der, mp: 169e171 ꢀC dec(from EtOAc/n-pentane). IR (Nujol) nmax
3390, 1755, 1708, 1590, 1560 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d:
1.30 (3H, t, J¼7.2 Hz, OCH2CH3), 2.38 (3H, s, CH3), 3.70 (3H, s, OCH3),
4.27 (2H, q, J¼7.2 Hz, OCH2CH3), 7.48 (3H, t, J¼8.0 Hz, ArH), 7.73
(2H, d, J¼8.0 Hz, ArH), 11.19 (1H, s, NH). 13C NMR (100 MHz, DMSO-
4.3.1. N5,N5-Diethyl-4-methyl-1,2-diphenyl-1H-5-imidazolecarbox-
amide (4e). Yield: 233.4 mg (70%). Colourless crystals, mp:
140e141 ꢀC (from EtOAc/light petroleum ether). IR (Nujol), nmax
d6) d: 9.9, 15.0, 53.9, 60.4, 126.5, 128.2, 129.2, 129.3, 130.1, 138.8,
146.1, 156.0, 163.5. MS (EI): m/z (%)¼303 (Mþ, 79), 257 (64), 229
(36), 155 (52), 125 (57), 111 (100). Anal. Calcd for C15H17N3O4
(303.31): C, 59.40; H, 5.65; N, 13.85. Found: C, 59.61; H, 5.69; N,
13.68.
1655, 1637, 1595, 1498 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d: 0.82
(3H, br s, NCH2CH3), 0.92 (3H, br s, NCH2CH3), 2.18 (3H, s, CH3), 3.19
(4H, br s, 2 NCH2CH3), 7.22e7.29 (7H, m, ArH), 7.40e7.43 (3H, m,
ArH). 13C NMR (100 MHz, DMSO-d6)
d: 12.1, 12.9, 13.9, 37.7, 42.2,
126.4, 127.2, 128.1, 128.3, 128.6, 129.2, 129.9, 134.4, 136.6, 145.4,
161.2. MS (EI): m/z (%)¼333 (Mþ, 88), 261 (100), 234 (95), 193 (22),
130 (51). Anal. Calcd for C21H23N3O (333.43): C, 75.65; H, 6.95; N,
12.60. Found: C, 75.50; H, 6.71; N, 12.58.
4.4.5. Methyl 1-[(tert-butoxycarbonyl)amino]-5-methyl-2-phenyl-
1H-imidazole-4-carboxylate (10c). Yield: 195.5 (59%). Beige pow-
der, mp: 177e179 ꢀC dec (from THF/n-pentane). IR (Nujol) nmax
3342, 1745, 1710, 1595, 1550 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d:

O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
5127
1.41 (9H, s, OtBu), 2.36 (3H, s, CH3), 3.79 (3H, s, OCH3), 7.47 (3H, t,
(3H, t, J¼7.6 Hz, ArH), 7.72 (2H, d, J¼7.6 Hz, ArH), 11.21 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6)
: 9.2, 53.1, 64.1, 117.9, 125.5, 127.4,
128.4, 128.6, 129.4, 132.9, 138.3, 145.4, 155.3, 162.3. MS (EI): m/z
(%)¼315 (Mþ, 7), 274 (3), 258 (4), 125 (54), 111 (100). Anal. Calcd for
C16H17N3O4 (315.32): C, 60.94; H, 5.43; N, 13.33. Found: C, 60.96; H,
5.28; N, 13.41.
J¼7.2 Hz, ArH), 7.72 (2H, d, J¼7.2 Hz, ArH), 10.83 (1H, s, NH). 13C
d
NMR (100 MHz, DMSO-d6)
d: 9.1, 27.7, 50.9, 81.6, 125.5, 127.4, 128.5,
128.6, 129.2, 138.1, 145.4, 153.8, 163.2. MS (EI): m/z (%)¼331 (Mþ,
28), 275 (100), 243 (92), 215 (35), 155 (40), 111 (34), 104 (56). Anal.
Calcd for C17H21N3O4 (331.36): C, 61.62; H, 6.39; N, 12.68. Found: C,
61.55; H, 6.49; N, 12.79.
4.5. General procedure for the reactions of DPG in alcohol
4.4.6. Ethyl 1-[(tert-butoxycarbonyl)amino]-5-methyl-2-phenyl-1H-
imidazole-4-carboxylate (10d). Yield: 207.2 mg (60%). Pink powder,
mp: 143e145 ꢀC dec (from DCM/light petroleum ether). IR (Nujol)
nmax 3330, 1735, 1715, 1600, 1560 cmꢁ1. 1H NMR (400 MHz, DMSO-
In a 25-mL flask, DPG 11 (1 mmol) was dissolved in MeOH or
EtOH (2 mL) and a solution of DD 1aee (2 mmol) in the same sol-
vent (4 mL) was added dropwise quickly under magnetic stirring at
room temperature. The reaction mixture became warm and the
disappearance of DD (by TLC) was fast (0.1e03 h). After removal of
the solvent in vacuo, the residue was purified by chromatography
(silica gel, DCM/EtOAc) to give 13a,b and 15aee.
d6)
d
: 1.30 (3H, t, J¼7.2 Hz, OCH2CH3), 1.41 (9H, s, OtBu), 2.36 (3H, s,
CH3), 4.26 (2H, q, J¼7.2 Hz, OCH2CH3), 7.47 (3H, t, J¼7.2 Hz, ArH),
7.71 (2H, d, J¼7.2 Hz, ArH), 10.81 (1H, s, NH). 13C NMR (100 MHz,
DMSO-d6) d: 9.1,14.3, 27.7, 59.5, 81.5,125.7,127.4,128.4,128.7,129.2,
137.9, 145.4, 153.8, 163.7. MS (EI): m/z (%)¼345 (12), 289 (40), 243
(33), 199 (22), 125 (60), 111 (100). Anal. Calcd for C18H23N3O4
(345.39): C, 62.59; H, 6.71; N, 12.17. Found: C, 62.80; H, 6.58; N,
12.29.
4.5.1. Methyl 2-[1-(2-anilino-4-oxo-1-phenyl-4,5-dihydro-1H-imi-
dazol-5-yl)ethylidene]hydrazinecarboxylate (13a). Yield: 146.1 mg
(40%). White powder, mp: 138e142 ꢀC dec (from EtOAc/Et2O). IR
(Nujol) nmax 3243, 3197, 3152, 1734, 1718, 1700, 1610, 1570,
4.4.7. Ethyl 1-[(ethoxycarbonyl)amino]-5-methyl-2-phenyl-1H-im-
idazole-4-carboxylate (10e). Yield: 199.9 mg (63%). White powder,
mp: 148e150 ꢀC dec (from EtOAc/n-pentane). IR (Nujol) nmax 3345,
1560 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.70 (3H, s, CH3), 3.64
(3H, s, OCH3), 4.92 (1H, s, CH), 7.12 (1H, t, J¼7.6 Hz, ArH), 7.30e7.47
(7H, m, ArH), 7.57 (2H, d, J¼8.0 Hz, ArH), 9.47 (1H, s, NH), 10.10 (1H,
1735, 1710, 1595, 1570 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d
: 1.20
s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 12.1, 51.8, 73.2, 122.6, 126.9,
(3H, t, J¼6.8 Hz, OCH2CH3), 1.30 (3H, t, J¼6.8 Hz, OCH2CH3), 2.38
(3H, s, CH3), 4.17 (2H, q, J¼6.8 Hz, OCH2CH3), 4.27 (2H, q, J¼6.8 Hz,
OCH2CH3), 7.48 (3H, t, J¼6.8 Hz, ArH), 7.71 (2H, d, J¼6.8 Hz, ArH),
127.6, 128.2, 129.7, 136.3, 138.0, 146.5, 154.3, 167.8, 182.9. MS (EI): m/
z (%)¼365 (Mþ, 100), 333 (35), 291 (90), 276 (49), 273 (84), 251 (30),
241 (18). Anal. Calcd for C19H19N5O3 (365.39): C, 62.46; H, 5.24; N,
19.17. Found: C, 62.59; H, 5.50; N, 19.34.
11.12 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 9.9, 15.0, 60.3,
62.7, 126.6, 128.2, 129.3, 130.0, 138.7, 146.1, 155.6, 163.5. MS (EI): m/z
(%)¼317 (Mþ, 100), 271 (62), 245 (50), 172 (34), 155 (51), 111 (38),
105 (69). Anal. Calcd for C16H19N3O4 (317.33): C, 60.56; H, 6.03; N,
13.24. Found: C, 60.61; H, 6.12; N, 13.48.
4.5.2. Ethyl 2-[1-(2-anilino-4-oxo-1-phenyl-4,5-dihydro-1H-imida-
zol-5-yl)ethylidene]hydrazinecarboxylate (13b). Yield: 140.3 mg
(37%). White powder, mp: 164e167 ꢀC dec (from Et2O/light petro-
leum ether). IR (Nujol) nmax 3259, 3203, 3154, 3112, 1733, 1717, 1617,
4.4.8. Isopropyl 1-[(tert-butoxycarbonyl)amino]-5-methyl-2-phenyl-
1H-imidazole-4-carboxylate (10f). Yield: 208.5 mg (58%). Beige
powder, mp: 154e156 ꢀC dec (from EtOAc/n-pentane). IR (Nujol)
nmax 3290, 1740, 1710, 1590, 1560 cmꢁ1. 1H NMR (400 MHz, DMSO-
1570, 1559 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
. d: 1.20 (3H, t,
J¼7.2 Hz, OCH2CH3), 1.70 (3H, s, CH3), 4.10 (2H, q, J¼7.2 Hz,
OCH2CH3), 4.92 (1H, s, CH), 7.12 (1H, t, br s, ArH), 7.30e7.55 (9H, m,
ArH), 9.47 (1H, s, NH), 10.05 (1H, s, NH). 13C NMR (100 MHz, DMSO-
d6)
d
: 1.30 (6H, t, J¼6.4 Hz, 2 CH3), 1.41 (9H, s, OtBu), 2.36 (3H, s,
d6) d: 12.1, 14.5, 60.4, 73.1, 122.5, 124.3, 126.9, 127.6, 128.3, 129.6,
CH3), 5.11 (1H, sept, J¼6.4 Hz, OCH), 7.47 (3H, t, J¼7.2 Hz, ArH), 7.70
136.4, 138.0, 146.4, 153.8, 167.8, 182.9. MS (EI): m/z (%)¼379 (Mþ,
100), 333 (44), 291 (77), 287 (67), 276 (56), 251 (45). Anal. Calcd for
C20H21N5O3 (379.16): C, 63.31; H, 5.58; N, 18.46. Found: C, 63.51; H,
5.39; N, 18.56.
(2H, d, J¼7.2 Hz, ArH), 10.83 (1H, s, NH). 13C NMR (100 MHz, DMSO-
d6) d: 9.2, 21.8, 27.7, 66.8, 81.5, 126.0, 127.4, 128.4, 128.7, 129.2, 137.7,
145.4, 153.8, 162.2. MS (EI): m/z (%)¼359 (Mþ, 34), 303 (74), 243
(55), 199 (41), 155 (29), 125 (61), 111 (100). Anal. Calcd for
C19H25N3O4 (359.41): C, 63.49; H, 7.01; N, 11.69. Found: C, 63.54; H,
6.95; N, 11.75.
4.5.3. Methyl 2-anilino-7-[(methoxycarbonyl)amino]-6-[2-(methoxy-
carbonyl)hydrazino]-6,8-dimethyl-4-oxo-1-phenyl-1,3,7-triazaspiro
[4,4]nona-2,8-diene-9-carboxylate (15a). 4S/R,6S/R isomer: yield:
198.6 mg (36%). White powder, mp: 178e179 ꢀC dec (from THF/n-
pentane). IR (Nujol) nmax 3293, 3252, 3230, 1748, 1730, 1717, 1702,
4.4.9. Methyl 1-{[(benzyloxy)carbonyl]amino}-5-methyl-2-phenyl-
1H-imidazole-4-carboxylate (10g). Yield: 241.2 mg (66%). White
powder, mp: 135e138 ꢀC (from EtOAc/n-pentane). IR (Nujol) nmax
1617, 1606, 1559 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.40 (3H, s,
3350, 1730, 1708, 1595, 1560 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d:
CH3), 1.82 (3H, s, CH3), 3.37 (3H, s, OCH3), 3.55 (3H, s, OCH3), 3.76
(3H, s, OCH3), 6.14 (1H, s, NH), 7.11 (1H, t, J¼6.8 Hz, ArH), 7.23e7.35
(7H, m, ArH), 7.58 (2H, br s, ArH), 8.39 (1H, s, NH), 8.86 (1H, s, NH),
2.63 (3H, s, CH3), 3.79 (3H, s, OCH3), 5.19 (2H, q, J¼12.4 Hz, OCH2Ph),
7.32e7.46 (8H, m, ArH), 7.68 (2H, d, J¼7.6 Hz, ArH),11.32 (1H, s, NH).
13C NMR (100 MHz, DMSO-d6)
d: 9.1, 67.1, 125.7, 127.5, 127.8, 128.3,
10.00 (1H, br s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 10.9, 15.8,
128.4,128.5,128.6,129.4,135.9,138.1,145.4,154.8,163.2. MS (EI): m/
z (%)¼365 (Mþ, 13), 288 (19), 274 (8), 230 (14), 216 (29), 149 (69),
125 (55), 111 (100). Anal. Calcd for C20H19N3O4 (365.38): C, 65.74; H,
5.24; N, 11.50. Found: C, 65.63; H, 5.31; N, 11.32.
50.2, 52.2, 52.6, 80.4, 80.8, 94.3, 121.6, 124.1, 126.3, 126.8, 128.5,
136.9, 138.0, 156.8, 163.2, 167.1, 168.1, 186.3. MS (EI): m/z (%)¼551
(Mþ, 3), 462 (100), 430 (26), 387 (23), 355 (23). Anal. Calcd for
C26H29N7O7 (551.55): C, 56.62; H, 5.30; N, 17.78. Found: C, 56.48; H,
5.36; N, 17.82.
4.4.10. Allyl
1-[(methoxycarbonyl)amino]-5-methyl-2-phenyl-1H-
imidazole-4-carboxylate (10h). Yield: 179.7 mg (57%). White pow-
der, mp: 138e140 ꢀC (from DCM/light petroleum ether). IR (Nujol)
nmax 3306, 1748, 1710, 1660, 1605 cmꢁ1. 1H NMR (400 MHz, DMSO-
4.5.4. Ethyl 2-anilino-7-[(methoxycarbonyl)amino]-6-[2-(methoxy-
carbonyl)hydrazino]-6,8-dimethyl-4-oxo-1-phenyl-1,3,7-triazaspiro
[4,4]nona-2,8-diene-9-carboxylate (15b). 4S/R,6S/R isomer: yield:
231.9 mg (41%). White powder, mp: 167e168 ꢀC dec (from Et2O). IR
(Nujol) nmax 3307, 3227, 3186, 3067, 1734, 1718, 1697, 1668, 1605,
d6)
d
: 2.38 (3H, s, CH3), 3.70 (3H, s, OCH3), 4.76 (2H, d, J¼5.6 Hz,
OCH2), 5.26 (1H, dd, 2J¼1.6 Hz, 3J¼10.4 Hz, CH2]CH), 5.38 (1H, dd,
2J¼1.6 Hz, 3J¼17.2 Hz, CH2]CH), 5.99e6.09 (1H, m, CH2]CH), 7.48
1559 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6)
d
: 1.07 (3H, t, J¼7.2 Hz,

5128
O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
OCH2CH3), 1.40 (3H, s, CH3), 1.82 (3H, s, CH3), 3.56 (3H, s, OCH3),
3.76 (3H, s, OCH3), 3.77e3.89 (2H, m, OCH2CH3), 6.13 (1H, s, NH),
7.11 (1H, br s, ArH), 7.25e7.33 (7H, m, ArH), 7.59 (2H, br s, ArH), 8.41
(1H, s, NH), 8.86 (1H, s, NH),10.01 (1H, br s, NH). 13C NMR (100 MHz,
4.5.7. Ethyl
2-anilino-7-[(ethoxycarbonyl)amino]-6-[2-(ethox-
ycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-1-phenyl-1,3,7-triazaspiro
[4,4]nona-2,8-diene-9-carboxylate (15e). Yield: 290.9 mg (49%).
White powder, mp: 183e184 ꢀC dec (from EtOAc). IR (Nujol) nmax
3362, 3282, 3238, 3191, 1742, 1706, 1660, 1614, 1569 cmꢁ1. 1H NMR
DMSO-d6) d: 10.8, 13.9, 15.8, 52.3, 58.6, 80.4, 88.4, 94.4, 121.5, 124.1,
126.2, 126.8, 128.5, 136.8, 138.1, 156.8, 162.8, 167.0, 168.1, 186.4. Anal.
Calcd for C27H31N7O7 (565.58): C, 57.34; H, 5.52; N, 17.34. Found: C,
57.48; H, 5.62; N, 17.29.
(400 MHz, DMSO-d6)
d
: 1.07 (3H, t, J¼7.2 Hz, OCH2CH3), 1.12 (3H, t,
J¼7.2 Hz, OCH2CH3), 1.27 (3H, t, J¼7.2 Hz, OCH2CH3), 1.40 (3H, s,
CH3), 1.82 (3H, s, CH3), 3.76e3.88 (2H, m, OCH2CH3), 3.98e4.05 (2H,
m, OCH2CH3), 4.18e4.23 (2H, m, OCH2CH3), 6.09 (1H, s, NH), 7.11
(1H, t, J¼8.0 Hz, ArH), 7.25e7.34 (7H, m, ArH), 7.58 (2H, br s, ArH),
8.37 (1H, s, NH), 8.85 (1H, s, NH), 9.98 (1H, br s, NH). 13C NMR
4.5.5. Methyl 2-anilino-7-[(tert-butoxycarbonyl)amino]-6-[2-(tert-
butoxycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-1-phenyl-1,3,7-tri-
azaspiro[4,4]nona-2,8-diene-9-carboxylate (15c). 4S/R,6S/R isomer:
yield: 298.8 mg (47%). White powder, mp: 200e202 ꢀC dec (from
MeOH). IR (Nujol) nmax 3372, 3263, 3208, 3154, 1732, 1716, 1706,
(100 MHz, DMSO-d6) d: 10.9, 13.2, 13.9, 14.5, 15.8, 58.6, 60.7, 61.4,
80.5, 88.9, 94.4, 121.5, 124.1, 126.8, 127.8, 128.5, 136.8, 138.1, 156.4,
162.8, 166.9, 168.1, 186.4. MS (EI): m/z (%)¼489 ([MꢁNHNHCO2Et]þ,
100), 401 (75), 355 (79). Anal. Calcd for C29H35N7O7 (593.63): C,
58.67; H, 5.94; N, 16.52. Found: C, 58.39; H, 6.08; N, 16.58.
1706, 1610, 1571 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.35 (9H, s,
OtBu), 1.38 (3H, s, CH3), 1.50 (9H, s, OtBu), 1.82 (3H, s, CH3), 3.36 (3H,
s, OCH3), 5.94 (1H, s, NH), 7.11 (1H, t, J¼7.2 Hz, ArH), 7.24e7.33 (7H,
m, ArH), 7.58 (2H, br s, ArH), 8.12 (1H, s, NH), 8.70 (1H, s, NH), 9.94
4.6. X-ray crystallography
(1H, br s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.1, 15.9, 27.9, 28.0,
50.0, 79.5, 80.5, 88.9, 93.7, 121.7, 124.1, 126.4, 126.8, 128.4, 128.5,
137.0, 138.0, 155.6, 163.3, 166.9, 168.2, 186.3. MS (EI): m/z (%)¼635
(Mþ, 1), 504 (88), 472 (8), 448 (100), 416 (17), 405 (40), 387 (28),
355 (34). Anal. Calcd for C32H41N7O7 (635.71): C, 60.46; H, 6.50; N,
15.42. Found: C, 60.54; H, 6.36; N, 15.64.
Single crystals of 7aꢂEtOAc, 15aꢂTHF and 4e were submitted to
X-ray data collections. A Siemens P4 four-circle (for 7aꢂEtOAc and
15aꢂTHF) and a BrukereNonius FR591 rotating anode diffractom-
eters (for 7e) with graphite monochromated Mo-K
a radiation
ꢀ
(l
¼0.71073 A) were used for data collections. The structures were
4S/R,6R/S, isomer: yield: 146.2 mg (23%). White solid, mp:
solved by direct methods implemented in the SHELXS-97 pro-
gram.18 The refinements were carried out by full-matrix anisotropic
least-squares on F2 for all reflections for non-H atoms by using the
SHELXL-97 program.19
161e162 ꢀC dec (from EtOAc/Et2O). IR (Nujol) nmax 3434, 3369,
3268, 3238, 1745, 1717, 1701, 1636, 1610, 1570 cmꢁ1 1H NMR
.
(400 MHz, DMSO-d6) d
: 1.30 (3H, s, CH3), 1.41 (9H, s, OtBu), 1.50
(9H, s, OtBu), 1.80 (3H, s, CH3), 3.31 (3H, s, OCH3), 5.25 (1H, br s,
NH), 7.05e7.19 (1H, m, ArH), 7.21e7.47 (7H, m, ArH), 7.56e7.63
(2H, m, ArH), 8.34 (1H, br s, NH), 8.62 (1H, br s, NH), 9.27 (1H,
Acknowledgements
br s, NH), 9.43 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.6,
Financial support from the Ministero dell’Istruzione, dell’Uni-
versità e della Ricerca (MIUR)-Roma and from the University of
Urbino ‘Carlo Bo’ is gratefully acknowledged.
17.0, 27.8, 27.9, 49.5, 77.9, 80.2, 86.8, 91.9, 120.8, 123.5, 126.1,
126.5, 128.0, 137.4, 137.7, 154.4, 164.0, 166.7, 168.3, 186.4. MS (EI):
m/z (%)¼635 (Mþ, 1), 504 (94), 389 (7), 472 (14), 448 (100), 416
(35), 405 (93), 388 (44), 355 (51). Anal. Calcd for C32H41N7O7
(635.71): C, 60.46; H, 6.50; N, 15.42. Found: C, 60.57; H, 6.39; N,
15.38.
References and notes
1. Chebanov, A. V.; Desenko, S. M.; Gurley, T. W. Azaheterocycles Based on
Unsaturated Carbonyls; Springer: Berlin Heidelberg, 2008.
2. Jin, Z. Nat. Prod. Rep. 2009, 26, 382.
a,b-
4.5.6. Ethyl 2-anilino-7-[(tert-butoxycarbonyl)amino]-6-[2-(tert-bu-
toxycarbonyl)hydrazino]-6,8-dimethyl-4-oxo-1-phenyl-1,3,7-tri-
azaspiro[4,4]nona-2,8-diene-9-carboxylate (15d). 4S/R,6S/R isomer:
yield: 318.4 mg (49%). White powder, mp: 203e204 ꢀC dec (from
EtOH). IR (Nujol) nmax 3371, 3260, 3233, 3152, 1731,1715,1706,1690,
3. Grimmet, M. R. Imidazoles In. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. W., Eds.; Pergamon: Oxford, 1996; Vol. 3.
4. De Luca, L. Curr. Med. Chem. 2006, 13, 1.
5. Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M. L.; Conte, L.;
Ramis, J.; Merlos, M.; Garcia-Rafanell, J.; Forn, J. J. Med. Chem. 1998, 41, 1855.
6. Elliot, R. L.; Oliver, R. M.; LaFlamme, J. A.; Gillaspy, M. L.; Hammond, M.; Hank,
R. F.; Maurer, T. S.; Baker, D. L.; DaSilva-Jardine, P. A.; Steveson, R. W.; Mack, C.
M.; Cassella, J. V. Bioorg. Med. Chem. Lett. 2003, 13, 3593.
1611, 1570, 1509 cmꢁ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.04e1.07
(3H, m, OCH2CH3), 1.35 (9H, s, OtBu), 1.37 (9H, s, OtBu), (3H, s, CH3),
1.56 (3H, s, CH3), 1.82 (3H, s, CH3), 3.78e3.86 (2H, m, OCH2CH3),
5.93 (1H, s, NH), 7.11 (1H, t, J¼7.4 Hz, ArH), 7.22e7.35 (7H, m, ArH),
7.58 (2H, br s, ArH), 8.16 (1H, s, NH), 8.70 (1H, s, NH), 9.93 (1H, br s,
7. Street, J. P. Tetrahedron Lett. 1991, 32, 3333.
8. (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932; (b) Abbiati,
G.; Arcadi, A.; Canevari, V.; Rossi, E. Tetrahedron Lett. 2007, 48, 8491; (c) Yoburn,
J. C.; Baskaran, S. Org. Lett. 2005, 7, 3801; (d) Guillemet, M.; Robert, A.; Baudy-
Floc’h, M. Tetrahedron Lett. 1995, 36, 547; (e) Shilcrat, S. C.; Mokhallalati, M. K.;
Fortunak, J. M. D.; Pridgen, L. N. J. Org. Chem. 1997, 62, 8449.
NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.0, 13.9, 15.9, 27.9, 28.0,
9. (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Per-
rulli, F. R.; Santeusanio, S. Eur. J. Org. Chem. 2009, 3109; (b) Attanasi, O. A.; De
Crescentini, L.; Filippone, P.; Mantellini, F.; Santeusanio, S. ARKIVOC 2002, xi.
10. Attanasi, O. A.; Giorgi, G.; Favi, G.; Filippone, P.; Lillini, S.; Perrulli, F. R.; San-
teusanio, S. Synlett 2007, 1691.
58.5, 79.5, 80.4, 88.9, 93.8, 121.5, 124.1, 126.4, 126.7, 128.5, 137.0,
138.1, 155.6, 162.9, 166.9, 168.1, 186.8. Anal. Calcd for C33H43N7O7
(649.74): C, 61.00; H, 6.67; N, 15.09. Found: C, 61.13; H, 6.58; N,
15.29.
€
11. (a) Hafelinger, G.; Fodor, G.; Phillips, B. A. In The Chemistry of Amidines and
4S/R,6R/S isomer: yield: 155.9 mg (24%). White solid, mp:
182e185 ꢀC dec (from EtOAc/light petroleum ether). IR (Nujol) nmax
3343, 3241, 3201, 3149, 1729, 1715, 1697, 1676, 1617, 1568,
Imidates; Patai, S., Ed.; Wiley: New York, NY, 1975, Chapter 1e2; (b) Gautier, J.;
Miocque, M.; Farnoux, C. C. In The Chemistry of Amidines and Imidates; Patai, S.,
Ed.; Wiley: New York, NY, 1975, Chapter 7.
ꢁ
12. Prevosek, D. C. J. Phys. Chem. 1962, 66, 769.
1508 cmꢁ1
.
1H NMR (400 MHz, DMSO-d6)
d
: 1.04 (3H, t, J¼7.4 Hz,
€
13. Clement, B.; Kampchen, T. Chem. Ber. 1986, 119, 1101.
OCH2CH3), 1.30 (3H, s, CH3), 1.41 (9H, s, OtBu), 1.50 (9H, s, OtBu), 1.80
(3H, s, CH3), 3.72e3.85 (2H, m, OCH2CH3), 5.23 (1H, br s, NH), 7.07
(1H, br s, ArH), 7.28e7.56 (9H, m, ArH), 8.29 (1H, br s, NH), 8.60 (1H,
14. Crystallographic data for compound 7a have been deposited with the Cam-
bridge Crystallographic Data Centre with deposit number CCDC-745801. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif
(or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: þ44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
br s, NH), 9.43 (1H, br s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 11.4,
ꢁ
ꢁ
15. BratusekRecnik, S.; Svete, J.; Meden, A.; Stanovnik, B. Heterocycles 2003, 60,
1161.
14.0, 17.0, 28.0, 28.1, 58.1, 78.8, 79.4, 86.8, 91.7, 121.0, 121.2, 122.6,
126.5, 127.0, 128.3, 129.7, 137.7, 138.4, 156.0, 163.6, 164.5, 168.5,
184.1. Anal. Calcd for C33H43N7O7 (649.74): C, 61.00; H, 6.67; N,
15.09. Found: C, 60.92; H, 6.85; N, 15.23.
16. Crystallographic data for compound 4e have been deposited with the
Cambridge Crystallographic Data Centre with deposit number CCDC-745802.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_

O.A. Attanasi et al. / Tetrahedron 66 (2010) 5121e5129
5129
request/cif (or from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: (þ44) 1223-336-033; or e-mail: deposit@
ccdc.cam.ac.uk.
from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: þ44 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
18. Sheldrick, G. M. SHELXS-97, A Program for Automatic Solution of Crystal Struc-
€
€
17. Crystallographic data compound 15a have been deposited with the Cambridge
Crystallographic Data Centre with deposit number CCDC-745803. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif (or
tures (Release 97e2); University of Gottingen: Gottingen, Germany, 1997.
19. Sheldrick, G. M. SHELXL-97, A Program for Crystal Structure Refinement (Release
€
€
97e2); University of Gottingen: Gottingen, Germany, 1997.