Simple route to multisubstituted tetrahydropyrimidines

Article abstract of DOI:10.1016/j.tet.2015.06.100

Abstract As part of our ongoing investigation into the synthetic application of nitroenamines several new densely substituted pyrimidine and pyrrolo-pyrimidine derivatives were prepared. Thus, 2-nitromethylenepyrrolidine and some open chain nitroenamines of phenyl-(2-nitro-1-phenyl-vinyl)-amine type were reacted with ethyl glyoxylate and a substituted aniline usually in a one-pot procedure to furnish the key intermediates for a subsequent cyclization. These compounds including a molecular fragment of 1,3-diamine type were subjected to a simple ring closure with formaldehyde to give the title compounds in good yields. The protocol reported has the advantages of mild reaction conditions, easy workup and inexpensive reagents. In an attempted removal of the 4-methoxy-phenyl protecting group from the 4-methoxy-phenyl substituted hexahydropyrrolo[1,2-c]pyrimidine derivative, an unexpected periodic acid mediated ring cleavage and phenyl group migration was discovered. The structures of the synthesized new compounds were confirmed by spectral data, and, particularly, the hindered rotation and the unusual ¹H NMR characteristics of 4-(4-nitro-phenyl)-but-3-enoic acid ethyl ester derivative were discussed.

Full text of DOI:10.1016/j.tet.2015.06.100

Tetrahedron 71 (2015) 6135e6142
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Simple route to multisubstituted tetrahydropyrimidines
a
a
a
a
b
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Zoltan Vincze , Mihaly V. Pilipecz , Pal Scheiber , Tamas R. Varga , Gabor Toth ,
a
,
*
ꢀ
Peter Nemes
a
ꢀ
Department of Chemistry, Faculty of Veterinary Science, Szent Istvan University, H-1400 Budapest, PO Box 2, Hungary
Department of Inorganic and Analytical Chemistry, NMR Group, Budapest University of Technology and Economics, H-1111 Budapest, Szt. Gellert ter 4,
b
ꢀ
ꢀ
Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of our ongoing investigation into the synthetic application of nitroenamines several new densely
substituted pyrimidine and pyrrolo-pyrimidine derivatives were prepared. Thus, 2-nitromethy
lenepyrrolidine and some open chain nitroenamines of phenyl-(2-nitro-1-phenyl-vinyl)-amine type
were reacted with ethyl glyoxylate and a substituted aniline usually in a one-pot procedure to furnish the
key intermediates for a subsequent cyclization. These compounds including a molecular fragment of 1,3-
diamine type were subjected to a simple ring closure with formaldehyde to give the title compounds in
good yields. The protocol reported has the advantages of mild reaction conditions, easy workup and
inexpensive reagents.
Received 3 February 2015
Received in revised form 17 June 2015
Accepted 29 June 2015
Available online 3 July 2015
Keywords:
Nitroenamines
Mannich reaction
In an attempted removal of the 4-methoxy-phenyl protecting group from the 4-methoxy-phenyl
substituted hexahydropyrrolo[1,2-c]pyrimidine derivative, an unexpected periodic acid mediated ring
cleavage and phenyl group migration was discovered. The structures of the synthesized new compounds
were confirmed by spectral data, and, particularly, the hindered rotation and the unusual 1H NMR
characteristics of 4-(4-nitro-phenyl)-but-3-enoic acid ethyl ester derivative were discussed.
Ó 2015 Elsevier Ltd. All rights reserved.
Hexahydro-pyrrolo-pyrimidines
Tetrahydropyrimidines
Multifunctional compounds
1. Introduction
As many naturally occurring compounds contain a pyrimidine
skeleton as a key structural motif1 in the last two decades we were
witnesses to a tremendous increase in the number of publications
dealing with the synthesis of multifunctionalized dihydropyr-
imidines (‘Biginellii compounds’) and tetrahydropyrimidines2,3
representing remarkable pharmacological efficiency.4
A wide
range of biological effects,5 including anticancer,6 calcium channel
modulation,7 muscarinic agonist,8 antiviral, antimicrobial,9 and
anti-inflammatory10 activities have been attributed to this class of
heterocyclic compounds.
Scheme 1. Mannich reaction with enaminonitrile and nitroenamine.
In our earlier work11,12 we demonstrated that enaminonitriles
and nitroenamines with primary amines and formaldehyde
undergo ‘double’ Mannich reactions to afford tetrahydropyr-
imidines and hexahydro-pyrrolo-pyrimidines in good yields
(Scheme 1).
glyoxylate and differently substituted anilines13 to give the adducts
2 (Scheme 2). Our protocol offers considerable benefits, like simple
reactants, synthetic work carried out on gram-scale, and access to
a large number of new multi-functional compounds for further
transformations to polysubstituted heterocyclic scaffolds.
These results prompted us to investigate similar ring closing
reactions of 2 with formaldehyde and to synthesize new multi-
substituted tetrahydropyrimidines starting from different
nitroenamines.1
Recently we have also reported the multi-component catalyst-
free reactions of 2-nitromethylenepyrrolidine (1) with ethyl
* Corresponding author. Tel.: þ36 1 478 4176; fax: þ36 1 478 4268; e-mail
address: Nemes.Peter@aotk.szie.hu (P. Nemes).
http://dx.doi.org/10.1016/j.tet.2015.06.100
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

6136
Z. Vincze et al. / Tetrahedron 71 (2015) 6135e6142
nitroenamines according to known procedures.15 Substituted
benzaldehydes were reacted with nitromethane at room temper-
ature to give the addition products 4aec. The replacement of the
imidazole catalyst by potassium fluoride simplified the workup
procedure, and after evaporation of the solvent the product could
be used in the next step. After oxidation of 4aec to the corre-
sponding acetophenones 5aec, the nitroenamines 6aee were ob-
tained with anilines in acceptable yields (Scheme 4, Table 2).
Scheme 2. Three-component reaction with nitroenamine 1.
2. Results and discussion
First we prepared five Mannich adducts 2aee according to the
procedure described earlier.13 The products underwent ring clo-
sures in ethanol at reflux temperature using 35% formaldehyde
solution resulting in 3aee in low to acceptable yields (Scheme 3,
Table 1). Attempts to carry out the reactions with para-
formaldehyde were unsuccessful. The Z arrangement around the
C]C double bond of 2aee confirmed in the preceding paper13 has
been changed in the ring closure process, which can be evidenced
by the unique bonding structure of the pushepull alkenes. In fact,
previous studies of nitroenamine models revealed14 that the low
energy barrier (about 15 kcal/mol) of the ZeE interconversion leads
to an equilibrium with the predominance of the former one due to
the stabilization through H-bonding. The easy formation of 3aee
can be understood by this relatively free rotation around the C]C
bond providing a suitable geometrical position both NH groups to
be cyclized with formaldehyde, irrespective of the type of the
possible iminium intermediates with either of the NH
functionalities.
Scheme 4. Synthesis of nitroenamines 6aee (R1, R2, R3 see Table 2).
Table 2
Open chain nitroenamines 6aee
Entry
R1
R2
R3
Yield (%)
6a
6b
6c
6d
6e
CH3
F
CH3
H
CH3
H
CH3
H
4-NO2
4-NO2
H
4-NO2
3-NO2
65
67
66
74
62
CH3
CH3
The new aryl substituted nitroenamines 6aed readily un-
derwent Mannich reactions with ethyl glyoxylate and anilines to
afford the desired products 7aef in one-pot reactions with ac-
ceptable yields (Scheme 5, Table 3).
Scheme 3. Ring closure of 2aee with formaldehyde.
Table 1
Pyrrolo-pyrimidines prepared from 2aee
R1
R2
Yield (%)
Scheme 5. Synthesis of 7aef with three-component reactions.
Entry
3a
3b
3c
3d
3e
OCH3
H
CH3
CH3
OPh
H
H
H
CH3
H
40
30
60
25
58
Table 3
Mannich products 7aef from the open chain nitreoenamines 6aed
Entry
R1
R2
R3
R4
R5
Yield (%)
7a
7b
7c
7d
7e
7f
CH3
F
CH3
CH3
H
CH3
H
CH3
CH3
H
NO2
NO2
H
H
NO2
NO2
F
F
F
CH3
F
H
H
H
CH3
H
62
82
70
69
76
82
Having this reaction in hand, we attempted to prepare these
pyrrolo-pyrimidines in a four-component reaction. After the for-
mation of 2aee from the three starting materials in tri-
fluoroethanol, without isolation of the intermediate formaldehyde
solution was added to the reaction mixture. The desired products
3aee could be detected by TLC, but after purification the yields
were somewhat lower than in the sequential process.
H
H
CH3
CH3
The new compounds 7aef were fully characterized by NMR
spectroscopy. However, an unexpected NMR spectral observation,
not found so far according to our knowledge, made a detailed study
of 7f necessary. The 200-H/600-H and 300-H/500-H atoms of the 3-(p-
In order to broaden the scope of the Mannich reaction and the
subsequent ring closure we synthesized new open chain

Z. Vincze et al. / Tetrahedron 71 (2015) 6135e6142
6137
nitrophenyl) group of 7f gave, surprisingly, four signals with dd
(8.5 Hz, 2.0 Hz) multiplicity at 7.38/7.93 and 8.16/8.35 ppm, re-
spectively, instead of the expected AA0XX0 spectrum pattern. From
this observation it can be concluded that the 200-H/600-H and 300-H/
500-H hydrogens became pair-wise diastereotopic showing huge
differences, i.e., Dd¼329 Hz and 114 Hz, that cannot be explained
with the effect of the C-2 stereocenter of the chiral compound 7f.
Interaction of this type, however, manifested itself in the signals of
the geminal hydrogen atoms of the ethyl group, resulting in the
chemical shifts 4.32dq and 4.25dq ppm (10.7 and 7.1 Hz) in the
600 MHz spectrum with the difference Dd¼40 Hz.
Scheme 6. Ring closure with formaldehyde to 1,2,3,4-tetrahydro-pyrimidines 8aef.
In the two-dimensional NOESY spectrum of 7f (mixing
time¼300 ms) we managed to observe the NOESY (blue) as well as
the exchange (red) cross-peaks separately. The extreme chemical
Table 4
Tetrahydropyrimidines from 7aef
shift of one of the NH hydrogens, i.e., d 12.05 ppm, indicates a planar
Entry
R1
R2
R3
R4
R5
Yield (%)
structure of chelate type of the nitroenamine moiety that, owing to
the extended conjugation, is arranged coplanar with the 4-(p-
nitrophenyl) ring. The H-600 signal and its steric proximity to 2-H
was assigned by the 4.57/7.93 NOESY peak. Due to steric reasons,
confirmed also by models, the aniline-phenyl group is nearly per-
pendicular to the chelate ring and, consequently, the 200-H and 300-H
hydrogens are located above the plane of this C6H5 ring, explaining
their detected diamagnetic shifts (Figs. 1 and 2).
8a
8b
8c
8d
8e
8f
CH3
F
CH3
CH3
H
CH3
H
CH3
CH3
H
NO2
NO2
H
H
NO2
NO2
F
F
F
CH3
F
H
H
H
CH3
H
73
71
76
67
82
77
H
H
CH3
CH3
Unfortunately, these experiments led to complex mixtures from
which pure products could not be separated. On the other hand, use
of cyclopentyl-, cyclohexyl-, adamantyl-, and tert-butylamine fur-
nished new compounds, which were isolated and purified with
column chromatography in moderate yields. The missing 1H NMR
signals of the ethyl protons indicated a spontaneous cyclization
leading to formation of 1,5-dihydropyrrolones 9aef and not
allowing the isolation of the expected intermediate (Scheme 7,
Table 5). The ring closure was accompanied with a double bond
shift, which is evidenced by a strong HMBC cross peak, e.g., H-5(
5.87s)/C-200,600( 5.98s)/C-200(
127.8) for compound 9a and H-5(
122.7) and C-600(
134.0) for compound 9e.
d
d
d
d
d
Fig. 1. Stereostructure, 1H chemical shifts, and characteristic NOESY responses of
7f (Only one of the enantiomeric forms is depicted.).
Fig. 2. Section of the NOESY spectrum of 7f. Blue cross-peaks correspond to the NOESY
responses whereas the red ones refer to the exchanges.
The 7.38/7.93 and 8.16/8.35 ppm exchange (red) cross-peaks
reveals that during the 300 ms mixing time a slow rotation takes
place around the C-100eC-4 bond that accelerates upon heating.
Thus, in a DMSO-d6 solution we observed a coalescence of the 200-H/
600-H and 300-H/500-H signals, and at about 100 ꢀC a spectrum of
AA0XX00 type was registered, accompanied, unfortunately, by
a considerable thermal decomposition.
Scheme 7. Spontaneous ring closure to 1,5-dihydropyrrolone derivatives 9aef.
Table 5
1,5-Dihydropyrrolones formed from 6aee
Entry
R1
R2
R3
R4
Yield (%)
Products 7aef were utilized in cyclizations with formaldehyde
according to the procedure described above to give 5-nitro-1,3,6-
triphenyl-1,2,3,4-tetrahydro-pyrimidine-4-carboxylic acid esters
8aef (Scheme 6, Table 4).
Next we tried to replace the anilines by aliphatic and aralkyl
primary amines such as butylamine and benzylamine.
9a
9b
9c
9d
9e
9f
CH3
CH3
F
F
CH3
H
CH3
CH3
H
H
CH3
H
H
Cyclohexyl
Cyclohexyl
Cyclopentyl
tert-Butyl
Adamantyl
Adamantyl
52
38
20
17
44
32
4-NO2
4-NO2
4-NO2
3-NO2
4-NO2

6138
Z. Vincze et al. / Tetrahedron 71 (2015) 6135e6142
As our attempts to prepare the N-benzyl derivatives of 3 were
hand, in a periodic acid solution without sulfuric acid the reaction
took place slower, but also with excellent yield.
unsuccessful we tried to remove the PMP moiety of 3a in order to
prepare pyrimidines with a secondary nitrogen in the ring, thus
opening the route to further functionalization. Strictly adapting the
standardized reaction conditions of the oxidative deprotection with
periodic acid/sulfuric acid the expected product was, however, not
obtained. Instead a ring opening accompanied by phenyl group
migration took place, and a compound of aldimine type 10 was
formed as a single product in excellent yield (Scheme 8), whose
structure was proven by detailed NMR measurements.
3. Conclusion
In summary, an efficient and simple synthesis was elaborated
for the preparation of highly substituted tetrahydropyrimidines
and hexahydropyrrolo-pyrimidines. These new compounds were
obtained from the Mannich adducts of versatile nitroenamines,
ethyl glyoxylate, and anilines in a simple ring closure with form-
aldehyde. The products are suitable for further transformations to
afford complex heterocyclic scaffolds and alkaloid analogues. An
interesting with N/C phenyl migration accompanied acid cata-
lyzed ring opening reaction of a hexahydropyrrolo-pyrimidine de-
rivative was discovered.
4. Experimental section
4.1. General methods
1H and 13C NMR spectra were recorded at room temperature on
Bruker Avance 300, 500, 600 and Varian Unity 300 spectrometers.
Scheme 8. Formation of 10 through ring opening rearrangement of 3a. Characteristic
NOESY steric proximity is indicated with red, the HMBC correlations with black arrows.
Chemical shifts, given on the d scale, were referenced to the solvent
The cyclic structure of 3a is proven by the presence of the
characteristic NMR signals of the NCH2N moiety at 60.2; 4.77d/
4.50dd. The absence of these signals and the appearance of a new
NH singlet at 9.68s in the spectra of 10 indicate the opening of the
tetrahydropyrimidine ring and simultaneously the emergence of
a hydrogen bonding with the nitro group. The Z-configuration
around the C]C double bond is further proven by the 2-H/30-H2
NOESY cross-peaks. The presence of a N]CH aldimine moiety in
compound 10 is verified by the characteristic shifts (8.23s, 1H,
163.3) and coupling constant (1J(C,H)¼200 Hz). Furthermore, the
HMBC cross-peaks (8.23/130.4 (C-200,600) and 8.23/55.5(C-2)) and
the NOESY response (8.23/7.20(200,600-H)) provided unambiguous
evidences that the carbon atom of the azomethine group is directly
connected to the 4-methoxyphenyl group.
(CDCl3: dC¼77.0 and dH¼7.27). In the 1D measurements (1H, 13C,
DEPTQ, DEPT-135, sel-NOE), 64K data points were used for the FID.
The pulse programs (gradient-selected HSQC, HMBC, and NOESY)
were taken from the Bruker software library. The NMR signals of
the products were assigned by comprehensive one- and two-
dimensional NMR methods using widely accepted strategies.16
The HRMS analyses were performed with an Agilent 5230 TOF in-
strument. IR spectra were recorded on a Perkin Elmer 1600 FT IR
spectrometer. TLC precoated sheets (Merck DC-Alufolien Kieselgel
60F254) were used. Melting points were determined on an Elec-
trothermal 9100 apparatus.
4.2. General procedure for the synthesis of 3aee
A plausible proposal for the mechanism of this transformation is
depicted in Scheme 9. It can be supposed that, due to the decreased
basicity, the enamine-nitrogen in the ring cannot tolerate pro-
tonation and leads to the cleavage of the tetrahydropyrimidine ring
followed by the phenyl migration adopting the favored Z-configu-
ration as explained above.
A solution of formaldehyde (37% w/w aq solution, 0.2 mL,
3.2 mmol), and 2aee (1.0 mmol) in EtOH (6 mL) were heated at
reflux temperature until the starting material was consumed. The
reaction mixture was concentrated under reduced pressure and the
oily residue was dissolved in CH2Cl2 (10 mL). The solution was
washed with H2O (3ꢁ10 mL), dried over Na2SO4, and then evapo-
rated under reduced pressure to give the crude product.
4.2.1. 2-(4-Methoxy-phenyl)-4-nitro-1,2,3,5,6,7-hexahydro-pyrrolo
[1,2-c]pyrimidine-3-carboxylic acid ethyl ester (3a). Purification of
the product by column chromatography (n-hexane/EtOAc/iPr-
amine 59:33:8) gave yellowish solid (278 mg, 40%), mp 86e88 ꢀC
(decomp.); Rf (n-hexane/EtOAc/iPr-amine 59:33:8) 0.40. nmax (KBr)
1737, 1592, 1511, 1342, 1288, 1229, 1093, 836 cmꢂ1
; dH (500 MHz,
CDCl3) 6.92 (2H, d, J 10.0 Hz, 20-H, 60-H), 6.82 (2H, d, J 10.0 Hz, 30-H,
50-H), 5.24 (1H, s, 3-H), 4.77 (1H, d, J 13.1 Hz, 1-H), 4.50 (1H, d, J
13.1 Hz, 1-H), 4.28e4.20 (2H, m, CH2eCH3), 3.76 (3H, s, OCH3),
3.64e3.58 (2H, m, 7-H), 3.54e3.50 (2H, m, 5-H), 2.18e2.08 (2H, m,
6-H), 1.28 (3H, t, J 7.0 Hz, CH2eCH3); dC (125 MHz, CDCl3) 170.6,
160.9,155.8,142.2,121.0,114.6,114.0, 61.6, 61.0, 60.2, 55.5, 52.1, 34.3,
20.1, 14.1. HRMS (ITTOF) m/z: [MþH]þ calcd for C17H22N3O5:
348.1559. Found: 348.1563.
4.2.2. 4-Nitro-2-phenyl-1,2,3,5,6,7-hexahydro-pyrrolo[1,2-c]pyrimi-
dine-3-carboxylic acid ethyl ester (3b). Purification of the product
by column chromatography (tBu-Me-ether/iPr-amine 9:1) gave
white solid (190 mg, 30%), mp 123e125 ꢀC (decomp.); Rf (tBu-Me-
ether/iPr-amine 9:1) 0.70. nmax (KBr) 1739, 1597, 1342, 1285, 1233,
Scheme 9. Mechanistic proposal for the ring opening rearrangement process.
Since no oxidation occurred, we tried to carry out the reaction
without periodic acid, either in an aqueous solution of sulfuric or
trifluoroacetic acid, but 3a remained unchanged. On the other
1098, 1026 cmꢂ1
; dH (500 MHz CDCl3) 7.30e6.98 (5H, m, Ar), 5.43

Z. Vincze et al. / Tetrahedron 71 (2015) 6135e6142
6139
(1H, s, 3-H), 4.81 (1H, d, J 9.0 Hz, 1-H), 4.62 (1H, d, J 9.0 Hz, 1-H),
4.28e4.22 (2H, m, CH2eCH3), 3.64e3.58 (2H, m, 7-H), 3.54e3.50
(2H, m, 5-H), 2.20e2.09 (2H, m, 6-H),1.30 (3H, t, J 7.0 Hz, CH2eCH3);
dC (125 MHz, CDCl3) 170.6, 160.9, 148.3, 129.5, 122.9, 118.8, 114.1,
61.7, 59.9, 59.7, 52.1, 34.3, 20.1, 14.1. HRMS (ITTOF) m/z: [MþH]þ
calcd for C16H20N3O4: 318.1454. Found: 318.1452.
(1H, d, J 8.0 Hz, Ph(3,4e(CH3)2)), 2.15 (3H, s, CH3), 2.12 (3H, s, CH3);
dC (75 MHz, CDCl3) 153.3, 149.0, 138.5, 138.3, 135.6, 134.7, 130.5,
130.0, 125.5, 124.2, 121.9, 114.3, 19.9, 19.4. HRMS (ITTOF) m/z:
[MþH]þ calcd for C16H16N3O4: 314.1140. Found: 314.1144.
4.3.2. (4-Fluoro-phenyl)-[2-nitro-1-(4-nitro-phenyl)-vinyl]-amine
(6b). Yellow solid (5.07 g, 67%), mp 183 ꢀC; Rf (hexane/EtOAc 5:2)
4.2.3. 4-Nitro-2-p-tolyl-1,2,3,5,6,7-hexahydro-pyrrolo[1,2-c]pyrimi-
dine-3-carboxylic acid ethyl ester (3c). Purification of the product by
column chromatography (EtOAc/n-hexane 1:1) gave white solid
(400 mg, 60%), mp 114e115 ꢀC; Rf (EtOAc) 0.70. nmax (KBr) 1737,
0.54. nmax (KBr) 1584, 1529, 1512, 1349, 1193, 860 cmꢂ1
; dH
(300 MHz, CDCl3) 11.21 (1H, br s, NH), 8.18 (2H, d, J 8.4 Hz, Ph(p-
NO2)), 7.47 (2H, d, J 8.4 Hz, Ph(p-NO2)), 6.88e6.80 (4H, m, Ph(p-F)),
6.72 (1H, s, ]CHeNO2); dC (75 MHz, CDCl3) 162.6, 159.3, 153.2,
149.1, 137.9, 133.3, 133.2, 130.1, 126.5, 126.3, 124.4, 116.8, 116.6, 114.8.
HRMS (ITTOF) m/z: [MþH]þ calcd for C14H11FN3O4: 304.0734.
Found: 304.0737.
1592, 1513, 1342, 1290, 1229, 1098 cmꢂ1
; dH (500 MHz CDCl3) 7.09
(2H, d, J 10.0 Hz, 30-H, 50-H), 6.88 (2H, d, J 10.0 Hz, 20-H, 60-H), 5.37
(1H, s, 3-H), 4.78 (1H, d, J 12.0 Hz, 1-H), 4.60 (1H, d, J 12.0 Hz, 1-H),
4.27e4.21 (2H, m, CH2eCH3), 3.64e3.58 (2H, m, 7-H), 3.54e3.50
(2H, m, 5-H), 2.29 (3H, s, CH3), 2.19e2.09 (2H, m, 6-H), 1.29 (3H, t, J
7.0 Hz, CH2eCH3); dC (125 MHz, CDCl3) 170.6, 160.9, 146.0, 132.6,
130.0, 119.0, 114.1, 61.6, 60.3, 59.8, 52.1, 34.3, 22.8, 20.5, 14.1. HRMS
(ITTOF) m/z: [MþH]þ calcd for C17H22N3O4: 332.1610. Found:
332.1611.
4.3.3. (3,4-Dimethyl-phenyl)-(2-nitro-1-phenyl-vinyl)-amine
(6c). Yellow solid (4.42 g, 66%), mp 167 ꢀC; Rf (hexane/EtOAc 5:2)
0.69. nmax (KBr) 2367, 1700, 1596, 1568, 1358, 1200 cmꢂ1
; dH
(300 MHz, CDCl3) 11.51 (1H, br s, NH), 8.35e7.24 (5H, m, Ph), 6.85 (1H,
d, J 8.1 Hz, Ph(3,4-(CH3)2)), 6.73 (1H, s, ]CHeNO2), 6.64 (1H, s,
Ph(3,4-(CH3)2)), 6.43 (1H, d, J 8.1 Hz, Ph(3,4-(CH3)2)), 2.13 (3H, s, CH3),
2.09 (3H, s, CH3); dC (75 MHz, CDCl3) 156.1, 137.8, 135.3, 134.8, 131.9,
130.9, 130.2, 129.1, 128.7, 125.1, 121.4, 113.9, 19.9, 19.4. HRMS (ITTOF)
m/z: [MþH]þ calcd for C16H17N2O2: 269.1290. Found: 269.1288.
4.2.4. 2-(3,4-Dimethyl-phenyl)-4-nitro-1,2,3,5,6,7-hexahydro-pyr-
rolo[1,2-c]pyrimidine-3-carboxylic acid ethyl ester (3d). Purification
of the product by column chromatography (EtOAc/cyclohexane 6:4)
gave white solid (173 mg, 25%), mp 176e178 ꢀC; Rf (EtOAc/cyclo-
hexane 1:1) 0.40. nmax (KBr) 1737, 1588, 1518, 1344, 1285, 1242, 1211,
4.3.4. [2-Nitro-1-(4-nitro-phenyl)-vinyl]-phenyl-amine (6d). Yellow
solid (5.28 g, 74%), mp 179 ꢀC; Rf (hexane/EtOAc 5:2) 0.32. nmax (KBr)
1096 cmꢂ1 dH (300 MHz, CDCl3) 7.04 (1H, d, J 8.1 Hz, 50-H), 6.81
;
(1H, s, 20-H), 6.69 (1H, dd, J 8.1, 2.1 Hz, 60-H), 5.39 (1H, s, 3-H), 4.79
(1H, d, J 13.2 Hz, 1-H), 4.62 (1H, d, J 13.2 Hz, 1-H), 4.31e4.20 (2H, m,
CH2eCH3), 3.65 (2H, m, 7-H), 3.53 (2H, m, 5-H), 2.14e2.06 (2H, m,
6-H), 2.24 (3H, s, PheCH3), 2.21 (3H, s, PheCH3), 1.31 (3H, t, J 7.1 Hz,
CH2eCH3); dC (75 MHz, CDCl3) 170.8, 161.0, 146.4, 137.9, 131.4, 130.5,
120.7, 116.0, 114.2, 61.8, 60.4, 59.8, 52.2, 34.4, 20.2, 20.1, 19.0, 14.2.
HRMS (ITTOF) m/z: [MþH]þ calcd for C18H24N3O4: 346.1769. Found:
346.1765.
1581, 1529, 1351, 1288, 1197, 857 cmꢂ1
; dH (300 MHz, CDCl3) 11.28
(1H, br s, NH), 8.18 (2H, d, J 8.7 Hz, Ph(p-NO2)), 7.51 (2H, d, J 8.7 Hz,
Ph(p-NO2)), 7.20e7.13 (3H, m, Ph), 6.82e6.73 (2H, m, Ph), 6.73 (1H,
s, ]CHeNO2); dC (75 MHz, CDCl3) 153.0, 149.1, 138.2, 137.2, 130.1,
129.7, 126.8, 124.4, 124.3, 114.9. HRMS (ITTOF) m/z: [MþH]þ calcd
for C14H12N3O4: 286.0828. Found: 286.0835.
4.3.5. (3,4-Dimethyl-phenyl)-[2-nitro-1-(3-nitro-phenyl)-vinyl]-
amine (6e). Yellow solid (4.43 g, 62%), mp 168 ꢀC; Rf (hexane/EtOAc
4.2.5. 4-Nitro-2-(4-phenoxy-phenyl)-1,2,3,5,6,7-hexahydro-pyrrolo
[1,2-c]pyrimidine-3-carboxylic acid ethyl ester (3e). Purification of
the product by column chromatography (EtOAc/cyclohexane 1:5)
gave white solid (456 mg, 58%), mp 129e130 ꢀC; Rf (EtOAc/cyclo-
hexane 1:9) 0.55. nmax (KBr) 1739, 1592, 1506, 1342, 1290, 1233,
5:2) 0.52. nmax (KBr) 1580, 1529, 1349, 1288, 1194, 865 cmꢂ1
; dH
(300 MHz, CDCl3) 11.28 (1H, br s, NH), 8.25 (1H, d, J 8.2 Hz, 40-H), 8.20
(1H, s, 20-H), 7.62 (1H, d, J 8.2 Hz, 60-H), 7.53 (1H, t, J 7.8 Hz, 50-H), 6.89
(1H, d, J 7.8 Hz, 500-H), 6.73 (1H, s, ]CHeNO2), 6.70 (1H, d, J 2.1 Hz, 200-
H), 6.46 (1H, dd, J 7.8, 2.1 Hz, 600-H), 2.15 (3H, s, CH3), 2.13 (3H, s, CH3);
dC (75 MHz, CDCl3) 153.2, 148.4, 138.4, 135.6, 134.7, 134.6, 130.9,
130.5,130.3,125.6,125.5,123.8,122.1,114.3,19.9,19.5. HRMS (ITTOF)
m/z: [MþH]þ calcd for C14H12N3O4: 314.1141. Found: 314.1145.
1093 cmꢂ1
; dH (300 MHz, CDCl3) 7.36e7.28 (2H, m, AreH),
7.12e7.07 (1H, m, AreH), 6.99e6.97 (5H, m, AreH), 5.33 (1H, s, 3-
H), 4.81 (1H, d, J 12.9 Hz, 1-H), 4.57 (1H, d, J 12.9 Hz, 1-H),
4.29e4.22 (2H, m, CH2eCH3), 3.68e3.62 (2H, m, 7-H), 3.56e3.52
(2H, m, 5-H), 2.23e2.11 (2H, m, 6-H), 1.31 (3H, t, J 7.1 Hz, CH2eCH3);
dC (75 MHz, CDCl3) 170.6, 161.0, 157.6, 152.7, 144.4, 129.8, 123.2,
120.8, 120.2, 118.4, 114.1, 61.8, 60.5, 60.3, 52.1, 34.4, 20.2, 14.2. HRMS
(ITTOF) m/z: [MþH]þ calcd for C22H24N3O5: 410.1716. Found:
411.1708.
4.4. General procedure for the one-pot synthesis of com-
pounds 7aef
Nitroenamine 6aed (2 mmol), ethyl glyoxylate (1.1 mL 50% so-
lution in toluene, 5.5 mmol), and the corresponding aniline
(5.5 mmol) were stirred in 8 mL trifluoroethanol at 70 ꢀC until the
nitroenamine was consumed. The solvent was then removed in
vacuum and the crude product was purified by column chroma-
tography on silica gel using hexane/EtOAc (5:2) as eluent to give
a crystalline product.
4.3. General procedure for the synthesis of 6aee
A mixture of a-nitro ketone 5aec (25 mmol), substituted aniline
(50 mmol), and acetic acid (50 mmol) was stirred at 80 ꢀC under
nitrogen atmosphere until TLC indicated the total consumption of
the
a
-nitro ketone. The reaction mixture was concentrated at re-
4.4.1. 4-(3,4-Dimethyl-phenylamino)-2-(4-fluoro-phenylamino)-3-
nitro-4-(4-nitro-phenyl)-but-3-enoic acid ethyl ester (7a). Yellow
solid (629 mg, 62%), mp 158 ꢀC; Rf (hexane/EtOAc 5:2) 0.50. nmax
duced pressure and the residue was purified by column chroma-
tography (hexane/EtOAc 5:2).
(KBr) 2364, 1752, 1700, 1652, 1559, 1509, 1350 cmꢂ1
; dH (300 MHz,
4.3.1. (3,4-Dimethyl-phenyl)-[2-nitro-1-(4-nitro-phenyl)-vinyl]-
CDCl3) 12.06 (1H, s, NH), 8.32 (1H, dd, J 8.5, 2.1 Hz, Ph(p-NO2)), 8.15
(1H, dd, J 8.5, 2.1 Hz, Ph(p-NO2)), 7.85 (1H, dd, J 8.5, 1.5 Hz, Ph(p-
NO2)), 7.35 (1H, dd, J 8.5, 1.5 Hz, Ph(p-NO2)), 6.84 (1H, d, J 8.0 Hz,
Ph(CH3)2), 6.76 (1H, d, J 8.5 Hz, Ph(p-F)), 6.72 (1H, d, J 8.5 Hz, Ph(p-
F)), 6.68 (1H, s, Ph(CH3)2), 6.42 (1H, d, J 8.0 Hz, Ph(CH3)2), 6.14 (1H, d,
J 8.8 Hz, Ph(p-F)), 6.12 (1H, d, J 8.5 Hz, Ph(p-F)), 4.87 (1H, d, J 9.9 Hz,
amine (6a). Yellow solid (5.09 g, 65%), mp 150 ꢀC; Rf (hexane/EtOAc
5:2) 0.63. nmax (KBr) 2362, 1700, 1652, 1578, 1526, 1350, 1202 cmꢂ1
;
dH (300 MHz, CDCl3) 11.28 (1H, br s, NH), 8.17 (2H, d, J 8.6 Hz, Ph(p-
NO2)), 7.49 (2H, d, J 8.6 Hz, Ph(p-NO2)), 6.88 (1H, d, J 8.0 Hz, Ph(3,4-
(CH3)2)), 6.70 (1H, s, ]CHeNO2), 6.68 (1H, s, Ph(3,4e(CH3)2)), 6.43

6140
Z. Vincze et al. / Tetrahedron 71 (2015) 6135e6142
NH), 4.46 (1H, d, J 9.9 Hz, CHeCOOEt), 4.25 (2H, q, J 7.1 Hz, CH2eCH3),
2.13 (3H, s, CH3), 2.10 (3H, s, CH3), 1.14 (3H, t, J 7.1 Hz, CH2eCH3); dC
(75 MHz, CDCl3) 170.5, 155.3, 149.1, 142.7, 142.6, 138.4, 138.3, 136.4,
134.7, 131.2, 131.1, 130.7, 126.5, 124.4, 124.2, 123.6, 122.8, 116.2, 116.2,
116.0, 115.9, 62.7, 58.5, 20.1, 19.6, 14.6. HRMS (ITTOF) m/z: [MꢂH]þ
calcd for C26H26FN4O6: 509.1836. Found: 509.1840.
1529, 1348, 1134, 857 cmꢂ1
; dH (600 MHz, CDCl3) 12.05 (1H, s, NH),
8.35 (1H, dd, J 8.5, 2.0 Hz, 300-H), 8.16 (1H, dd, J 8.5, 2.0 Hz, 500-H), 7.93
(1H, dd, J 8.5, 2.0 Hz, 200-H), 7.38 (1H, dd, J 8.5, 2.0 Hz, 600-H), 7.18 (2H,
t, J 7.3 Hz, 30,50-H), 7.12 (1H, t, J 7.3 Hz, 40-H), 6.81 (2H, d, J 7.3 Hz, 20,60-
H), 6.79 (1H, d, J 8.1 Hz, 5þ-H), 5.96 (1H, d, J 2.0 Hz, 2þ-H), 5.93 (1H,
dd, J 8.1, 2.0 Hz, 6þ-H), 4.82 (1H, br, NH), 4.57 (1H, s, CHeCOOEt),
4.32, 4.25 (2H, dq, J 10.7, 7.1 Hz, CH2eCH3), 2.14 (3H, s, 4þeCH3), 2.04
(3H, s, 3þ-CH3), 1.33 (3H, t, J 7.1 Hz, CH2eCH3); dC (150 MHz, CDCl3)
170.3 (C]þO), 154.1 (C-4), 148.7 (C-400), 143.8 (C-1þ), 137.8 (C-1þ00),
137.2 (C-2 ), 136.8 (C-10), 131.1 (C-600), 130.9 (C-200), 130.1 (C-5 ),
129.3 (C-30,50), 127.1 (C-4þ), 127.0 (C-40), 125.0 (C-20,60), 124.2 (C-3),
124.1 (C-300),123.8 (C-500),115.8 (C-1þ),111.7 (C-6þ), 62.3 (OCH2), 57.4
(C-2), 19.8 (CH3-5þ), 18.6 (CH3-4þ), 14.2 (CH3CH2). HRMS (ITTOF)
m/z: [MþH]þ calcd for C26H27N4O6: 491.1931. Found: 491.1937.
4.4.2. 2,4-Bis-(4-fluoro-phenylamino)-3-nitro-4-(4-nitro-phenyl)-
but-3-enoic acid ethyl ester (7b). Yellow solid (817 mg, 82%), mp
129 ꢀC; Rf (hexane/EtOAc 5:2) 0.51. nmax (KBr) 2362, 1700, 1652,
1578, 1526, 1350, 1202 cmꢂ1
; dH (300 MHz, CDCl3) 11.93 (1H, s, NH),
8.32 (1H, dd, J 8.5,1.9 Hz, Ph(p-NO2)), 8.17 (1H, dd, J 8.5,1.9 Hz, Ph(p-
NO2)), 7.83 (1H, dd, J 8.2, 1.3 Hz, Ph(p-NO2)), 7.35 (1H, dd, J 8.2,
1.3 Hz, Ph(p-NO2)), 6.90e6.72 (6H, m, Ar), 6.15e6.12 (2H, m, Ar),
4.85 (1H, d, J 10.0 Hz, NH), 4.47 (1H, d, J 10.0 Hz, CHeCOOEt), 4.26
(2H, q, J 7.0 Hz, CH2eCH3), 1.30 (3H, t, J 7.0 Hz, CH2eCH3); dC
(75 MHz, CDCl3) 170.2, 162.9, 159.6, 158.5, 155.3, 154.9, 149.1, 142.5,
142.4, 137.7, 133.1, 133.0, 131.1, 130.9, 127.5, 127.3, 124.5, 124.1, 116.8,
116.5,116.1, 116.0,115.8, 62.6, 58.3,14.4. HRMS (ITTOF) m/z: [MþH]þ
calcd for C24H21F2N4O6: 499.1429. Found: 499.1429.
4.5. Compounds 8aef were prepared as described above for
3aee
4.5.1. 1-(3,4-Dimethyl-phenyl)-3-(4-fluoro-phenyl)-5-nitro-6-(4-
nitro-phenyl)-1,2,3,4-tetrahydro-pyrimidine-4-carboxylic acid ethyl
ester (8a). Recrystallization of the crude product (EtOAc) gave
a yellow solid (380 mg, 73%), mp 168 ꢀC; Rf (hexane/EtOAc 5:2) 0.51.
4.4.3. 4-(3,4-Dimethyl-phenylamino)-2-(4-fluoro-phenylamino)-3-
nitro-4-phenyl-but-3-enoic acid ethyl ester (7c). Yellow solid
(649 mg, 70%), mp 115 ꢀC;Rf (hexane/EtOAc 5:2)0.45. nmax (KBr) 2362,
nmax (KBr) 2362, 1700, 1652, 1578, 1526, 1350, 1202 cmꢂ1
; dH
(300 MHz, CDCl3) 8.05 (2H, d, J 7.6 Hz, Ph(p-NO2)), 7.33 (2H, d, J
7.6 Hz, Ph(p-NO2)), 7.01e6.98 (4H, m, Ar), 6.79 (1H, d, J 7.9 Hz,
Ph(CH3)2), 6.48 (1H, s, Ph(CH3)2), 6.33 (1H, d, J 7.9 Hz, Ph(CH3)2),
5.55 (1H, s, CHeCOOEt), 5.33 (1H, d, J 13.1 Hz, NeCH2eN), 4.83 (1H,
d, J 13.1 Hz, NeCH2eN), 4.31 (2H, q, J 7.1 Hz, CH2eCH3), 2.09 (3H, s,
CH3), 2.05 (3H, s, CH3), 1.34 (3H, t, J 7.1 Hz, CH2eCH3); dC (75 MHz,
CDCl3) 170.1, 161.0, 157.2, 154.3, 148.2, 144.2, 144.1, 139.8, 139.6,
138.5, 136.9, 130.8, 130.3, 128.0, 124.6, 123.8, 121.4, 120.9, 120.8,
116.7, 116.4, 67.9, 62.5, 61.7, 20.0, 19.7, 14.5. HRMS (ITTOF) m/z:
[MþH]þ calcd for C27H26FN4O6: 521.1836. Found: 521.1839.
1699, 1650, 1557, 1539, 1522, 1505 cmꢂ1
; dH (300 MHz, CDCl3) 12.40
(1H, s, NH), 7.64 (1H, d, J 8.0 Hz, Ph(CH3)2), 7.52e7.49 (2H, m, Ph),
7.39e7.32 (1H, m, Ph), 7.16 (1H, d,J 7.5 Hz, Ph(p-F)), 6.85 (1H, d, J 7.5 Hz,
Ph(p-F)), 6.73 (1H, d, J 8.5 Hz, Ph(p-F)), 6.70 (1H, d, J 8.5 Hz, Ph(p-F)),
6.62 (1H, s, Ph(CH3)2), 6.43 (1H, d, J 7.5 Hz, Ph(CH3)2), 6.14e6.10 (2H,
m, Ph), 4.93 (1H, d, J 9.6 Hz, NH), 4.70 (1H, d, J 9.6 Hz, CHeCOOEt), 4.27
(2H, q, J 7.1 Hz, CH2eCH3), 2.14 (3H, s, CH3), 2.10 (3H, s, CH3),1.31 (3H, t,
J 7.1 Hz, CH2eCH3); dC (75 MHz, CDCl3) 170.7,158.0,157.3,154.9,142.9,
137.6, 135.1, 135.0, 131.7, 130.8, 130.0, 129.4, 129.2, 129.1, 129.0, 125.5,
123.3,121.7,115.6,115.5,115.3, 62.1, 58.0,19.7.19.2,14.3. HRMS (ITTOF)
m/z: [MþH]þ calcd for C26H27FN3O4: 464.1986. Found: 464.1978.
4.5.2. 1,3-Bis-(4-fluoro-phenyl)-5-nitro-6-(4-nitro-phenyl)-1,2,3,4-
tetrahydro-pyrimidine-4-carboxylic
acid
ethyl
ester
(8b).
4.4.4. 2,4-Bis-(3,4-dimethyl-phenylamino)-3-nitro-4-phenyl-but-3-
enoic acid ethyl ester (7d). Yellow solid (653 mg, 69%), mp 134 ꢀC; Rf
(hexane/EtOAc 5:2) 0.53. nmax (KBr) 2367, 1734, 1701, 1652, 1559,
Recrystallization of the crude product (EtOAc) gave a yellow solid
(724 mg, 71%), mp 184 ꢀC; Rf (hexane/EtOAc 5:2) 0.56. nmax (KBr)
1737, 1572, 1511, 1348, 1297, 1231, 839 cmꢂ1
; dH (300 MHz, CDCl3)
1540, 1509 cmꢂ1
;
dH (300 MHz, CDCl3) 12.40 (1H, s, NH), 7.72e5.97
8.04 (2H, d, J 7.1 Hz, Ph(p-NO2)), 7.33 (2H, d, J 7.6 Hz, Ph(p-NO2)),
7.00e6.60 (8H, m, Ph(p-F)), 5.53 (1H, s, CHeCOOEt), 5.32 (1H, d, J
13.0 Hz, NeCH2eN), 4.80 (1H, d, J 13.0 Hz, NeCH2eN), 4.29 (2H, q, J
7.1 Hz, CH2eCH3), 1.31 (3H, t, J 7.1 Hz, CH2eCH3); dC (75 MHz, CDCl3)
169.8, 162.9, 160.6, 159.6, 157.4, 153.5, 148.1, 143.8, 143.7, 139.2,
138.0, 137.9, 130.1, 129.0, 128.9, 123.8, 122.1, 120.8, 120.7, 116.9, 116.7,
116.6, 116.4, 68.1, 62.5, 61.2, 14.3. HRMS (ITTOF) m/z: [MþH]þ calcd
for C25H21F2N4O6: 511.1429. Found: 511.1430.
(11H, m, Ar), 4.91 (1H, d, J 9.5 Hz, NH), 4.83 (1H, d, J 9.5 Hz,
CHeCOOEt), 4.26 (2H, q, J 7.1 Hz, CH2eCH3), 2.19 (3H, s, CH3), 2.15
(3H, s, CH3), 2.11 (3H, s, CH3), 2.06 (3H, s, CH3), 1.34 (3H, t, J 7.1 Hz,
CH2eCH3); dC (75 MHz, CDCl3) 170.4, 157.0, 144.5, 137.2, 137.1, 135.1,
134.9, 131.8, 130.7, 130.2, 130.1, 129.9, 129.7, 126.5, 125.4, 123.8,
121.6, 115.7, 111.9, 62.0, 57.5, 19.8, 19.7. 19.2, 19.0, 14.3. HRMS (ITTOF)
m/z: [MþH]þ calcd for C28H32N3O4: 474.2393. Found: 474.2394.
4.4.5. 2-(4-Fluoro-phenylamino)-3-nitro-4-(4-nitro-phenyl)-4-
phenylamino-but-3-enoic acid ethyl ester (7e). Recrystallization of
the crude product (EtOAc) gave a yellow solid (730 mg, 76%), mp
168 ꢀC; Rf (hexane/EtOAc 5:2) 0.50. nmax (KBr) 2361, 1751, 1574, 1511,
4.5.3. 1-(3,4-Dimethyl-phenyl)-3-(4-fluoro-phenyl)-5-nitro-6-
phenyl-1,2,3,4-tetrahydro-pyrimidine-4-carboxylic acid ethyl ester
(8c). Recrystallization of the crude product (EtOAc) gave a yellow
solid (722 mg, 76%), mp 158 ꢀC; Rf (hexane/EtOAc 5:2) 0.30. nmax
1350, 1141 cmꢂ1
;
dH (300 MHz, CDCl3) 12.07 (1H, s, NH), 8.33 (1H,
(KBr) 1737, 1558, 1508, 1292, 1208, 737 cmꢂ1
; dH (300 MHz, CDCl3)
dd, J 8.4, 2.0 Hz, Ph(p-NO2)), 8.16 (1H, dd, J 8.4, 2.0 Hz, Ph(p-NO2)),
7.88 (1H, dd, J 8.3,1.3 Hz, Ph(p-NO2)), 7.36 (1H, dd, J 8.3,1.3 Hz, Ph(p-
NO2)), 7.21e7.13 (3H, m, Ph), 6.83e6.73 (4H, m, Ph(p-F)), 6.17e6.11
(2H, m, Ph), 4.89 (1H, d, J 10.2 Hz, NH), 4.50 (1H, d, J 10.2 Hz,
CHeCOOEt), 4.28 (2H, q, J 7.1 Hz, CH2eCH3), 1.32 (3H, t, J 7.1 Hz,
CH2eCH3); dC (75 MHz, CDCl3) 170.1, 158.3, 155.1, 154.6, 148.9, 142.3,
142.2, 137.8, 136.8, 131.0, 130.8, 129.5, 127.2, 125.2, 124.2, 123.9,
123.8, 115.9, 115.8, 115.7, 115.6, 62.5, 58.1, 14.3. HRMS (ITTOF) m/z:
[MþH]þ calcd for C24H22FN4O6: 481.1523. Found: 481.1531.
7.11e6.97 (9H, m, Ar), 6.79 (1H, d, J 7.8 Hz, Ph(CH3)2), 6.37 (1H, s,
Ph(CH3)2), 6.34 (1H, d, J 7.8 Hz, Ph(CH3)2), 5.56 (1H, s, CHeCOOEt),
5.34 (1H, d, J 13.0 Hz, NeCH2eN), 4.85 (1H, d, J 13.0 Hz, NeCH2eN),
4.33 (2H, q, J 7.1 Hz, CH2eCH3), 2.10 (3H, s, CH3), 2.05 (3H, s, CH3),
1.36 (3H, t, J 7.1 Hz, CH2eCH3); dC (75 MHz, CDCl3) 170.0, 160.2,
156.9, 156.6, 144.1, 144.0, 140.3, 137.6, 135.5, 132.4, 130.0, 129.3,
129.1, 1283, 127.6, 124.1, 120.8, 120.5, 120.4, 116.2, 115.9, 67.4, 62.0,
61.8, 19.6, 19.3, 14.2. HRMS (ITTOF) m/z: [MþH]þ calcd for
C27H27FN3O4: 476.1986. Found: 476.1979.
4.4.6. 2-(3,4-Dimethyl-phenylamino)-3-nitro-4-(4-nitro-phenyl)-4-
phenylamino-but-3-enoic acid ethyl ester (7f). Yellow solid (800 mg,
82%), mp 152 ꢀC; Rf (hexane/EtOAc 5:2) 0.40. nmax (KBr) 2362, 1572,
4.5.4. 1,3-Bis-(3,4-dimethyl-phenyl)-5-nitro-6-phenyl-1,2,3,4-
tetrahydro-pyrimidine-4-carboxylic acid ethyl ester (8d).
Recrystallization of the crude product (EtOAc) gave a yellow solid

Z. Vincze et al. / Tetrahedron 71 (2015) 6135e6142
6141
(650 mg, 67%), mp 136 ꢀC; Rf (hexane/EtOAc 5:2) 0.50. nmax (KBr)
2368, 1736, 1699, 1650, 1555, 1542, 1507, 1458, 1285 cmꢂ1
dH
(ITTOF) m/z: [MþH]þ calcd for C24H28N3O3: 406.2131. Found:
;
406.2138.
(300 MHz, CDCl3) 7.20e6.43 (11H, m, Ar), 5.68 (1H, s, CHeCOOEt),
5.34 (1H, d, J 13.0 Hz, NeCH2eN), 4.93 (1H, d, J 13.0 Hz,
NeCH2eN), 4.34 (2H, q, J 7.0 Hz, CH2eCH3), 2.21 (3H, s, CH3), 2.18
(3H, s, CH3), 2.12 (3H, s, CH3), 2.06 (3H, s, CH3), 1.37 (3H, t, J 7.0 Hz,
CH2eCH3); dC (75 MHz, CDCl3) 170.3, 156.7, 145.6, 140.4, 137.7,
137.4, 135.4, 132.7, 130.7, 130.5, 129.9, 129.2, 129.1, 128.2, 127.8,
124.3, 120.9, 120.2, 115.8, 66.7, 61.9, 61.8, 20.1, 19.6, 19.3, 18.4, 14.2.
HRMS (ITTOF) m/z: [MþH]þ calcd for C29H32N3O4: 486.2393.
Found: 486.2398.
4.6.2. 3-Cyclohexylamino-1-(3,4-dimethyl-phenyl)-4-nitro-5-(4-
nitro-phenyl)-1,5-dihydro-pyrrol-2-one (9b). Purification by column
chromatography (hexane/EtOAc 5:2), yellow solid (684 mg, 38%),
mp 124 ꢀC; Rf (hexane/EtOAc 5:2) 0.54. nmax (KBr) 1714, 1645, 1520,
1458, 1350 cmꢂ1
; dH (300 MHz, CDCl3) 8.47 (1H, s, NH), 8.07 (2H, d, J
8.4 Hz, Ph(p-NO2)), 7.42 (2H, d, J 8.4 Hz, Ph(p-NO2)), 7.14e6.97 (3H,
m, Ph(CH3)2), 5.98 (1H, s, H-5), 4.96e4.93 (1H, m, NHeCH), 2.15
(3H, s, CH3), 2.13 (3H, s, CH3), 1.81e1.23 (10H, m, C6H11); dC (75 MHz,
CDCl3) 160.8, 148.0, 142.4, 142.3, 137.9, 136.2, 132.4, 130.3, 128.8,
128.7, 124.8, 123.8, 120.9, 60.7, 51.7, 34.7, 34.2, 26.9, 25.1, 24.6, 19.9,
19.3. HRMS (ITTOF) m/z: [MþH]þ calcd for C24H27N4O5: 451.1981.
Found: 451.1983.
4.5.5. 3-(4-Fluoro-phenyl)-5-nitro-6-(4-nitro-phenyl)-1-phenyl-
1,2,3,4-tetrahydro-pyrimidine-4-carboxylic acid ethyl ester (8e).
Recrystallization of the crude product (EtOAc) gave a yellow solid
(807 mg, 82%), mp 110 ꢀC; Rf (hexane/EtOAc 5:2) 0.44. nmax (KBr)
1739, 1565, 1511, 1351, 1299, 1215, 861 cmꢂ1
;
dH (300 MHz, CDCl3)
4.6.3. 3-Cyclopentylamino-1-(4-fluoro-phenyl)-4-nitro-5-(4-nitro-
phenyl)-1,5-dihydro-pyrrol-2-one (9c). Purification by column
chromatography (hexane/EtOAc 2:1) gave an oil (342 mg, 20%); Rf
(cyclohexane/EtOAc 2:1) 0.51; dH (300 MHz, CDCl3) 8.50 (1H, d, J
9.0 Hz, NH), 8.15e6.98 (8H, m, Ar), 5.99 (1H, s, H-5), 5.38e5.35 (1H,
m, NHeCH), 1.85e1.13 (8H, m, C5H9); dC (75 MHz, CDCl3) 162.9,
161.3, 159.6, 148.4, 142.4, 141.9, 131.0, 129.0, 125.8, 125.7, 124.2,
122.7, 116.8, 116.5, 61.2, 61.1, 54.9, 35.4, 34.9, 24.1, 24.0. HRMS
(ITTOF) m/z: [MþH]þ calcd for C21H20FN4O5: 427.1418. Found:
427.1414.
8.07 (2H, d, J 6.9 Hz, Ph(p-NO2)), 7.35 (2H, d, J 6.9 Hz, Ph(p-NO2)),
7.15e7.00 (7H, m, Ar), 6.70e6.65 (2H, m, Ph), 5.58 (1H, s,
CHeCOOEt), 5.38 (1H, d, J 13.0 Hz, NeCH2eN), 4.89 (1H, d, J
13.0 Hz, NeCH2eN), 4.34 (2H, q, J 7.1 Hz, CH2eCH3), 1.37 (3H, t, J
7.1 Hz, CH2eCH3); dC (75 MHz, CDCl3) 169.7, 160.4, 157.2, 153.5,
147.9, 143.7, 143.6, 141.7, 139.2, 130.1, 129.6, 127.7, 126.9, 123.5,
121.7, 120.5, 120.4, 116.5, 116.2, 67.5, 62.3, 61.3, 14.2. HRMS
(ITTOF) m/z: [MþH]þ calcd for C25H22FN4O6: 493.1523. Found:
493.1529.
4.5.6. 3-(3,4-Dimethyl-phenyl)-5-nitro-6-(4-nitro-phenyl)-1-
phenyl-1,2,3,4-tetrahydro-pyrimidine-4-carboxylic acid ethyl ester
(8f). Recrystallization of the crude product (EtOAc) gave a yellow
solid (773 mg, 77%), mp 113 ꢀC; Rf (hexane/EtOAc 5:2) 0.54. nmax
4.6.4. 3-tert-Butylamino-1-(4-fluoro-phenyl)-4-nitro-5-(4-nitro-
phenyl)-1,5-dihydro-pyrrol-2-one (9d). Purification by column
chromatography (hexane/EtOAc 2:1) gave an oil (114 mg, 17%); Rf
(cyclohexane/EtOAc 2:1) 0.55; dH (300 MHz, CDCl3) 9.15 (1H, s, NH),
8.15e7.01 (8H, m, Ar), 5.99 (1H, s, H-5), 1.68 (9H, s, C4H9); dC
(75 MHz, CDCl3) 162.9, 161.3, 148.4, 144.6, 142.0, 131.1, 128.9, 125.9,
125.8, 124.2, 122.7, 116.8, 116.5, 61.5, 56.3, 30.8. HRMS (ITTOF) m/z:
[MþH]þ calcd for C20H20FN4O5: 415.1418. Found: 415.1417.
(KBr) 2368, 1736, 1700, 1650, 1550, 1539, 1502, 1460, 1288 cmꢂ1
; dH
(300 MHz, CDCl3) 8.05 (1H, d, J 7.1 Hz, Ph(p-NO2)), 7.34 (2H, d, J
7.1 Hz, Ph(p-NO2)), 7.06e6.71 (8H, m, Ar), 5.65 (1H, s, CHeCOOEt),
5.37 (1H, d, J 13.0 Hz, NeCH2eN), 4.95 (1H, d, J 13.0 Hz, NeCH2eN),
4.35 (2H, q, J 7.1 Hz, CH2eCH3), 2.18 (3H, s, CH3), 2.14 (3H, s, CH3),
1.37 (3H, t, J 7.1 Hz, CH2eCH3); dC (75 MHz, CDCl3) 170.2, 153.5,
147.8, 145.2, 141.9, 139.4, 138.0, 131.3, 130.6, 130.1, 129.4, 127.6, 127.0,
123.5, 121.9, 120.1, 115.7, 66.8, 62.1, 61.4, 20.2, 18.9, 14.2. HRMS
(ITTOF) m/z: [MþH]þ calcd for C27H27N4O6: 503.1931. Found:
503.1928.
4.6.5. 3-(Adamant-1-ylamino)-1-(3,4-dimethyl-phenyl)-4-nitro-5-
(3-nitro-phenyl)-1,5-dihydro-pyrrol-2-one (9e). Purification by col-
umn chromatography (hexane/EtOAc 2:1), yellow solid (442 mg,
44%), mp 221 ꢀC; Rf (cyclohexane/EtOAc 2:1) 0.60. nmax (KBr) 1716,
1640, 1520, 1457, 1352 cmꢂ1
; dH (600 MHz, CDCl3) 9.14 (1H, s, NH),
8.10 (1H, d, J 8.3 Hz, 40-H), 8.09 (1H, s, 20-H), 7.60 (1H, d, J 8.3 Hz, 60-
H), 7.46 (1H, t, J 8.3 Hz, 50-H), 7.12 (1H, d, J 2.0 Hz, 200-H), 7.05 (1H, d, J
8.3 Hz, 500-H), 6.97 (1H, dd, J 8.3, 2.0 Hz, 600-H), 5.98 (1H, s, 5-H), 2.19
(3H, s, 300-CH3), 2.16 (3H, s, 400-CH3), adamantyl: 2.32/2.28 (6H, d, J
12.0 Hz, CH2), 1.78e1.72 (6H, d, J 12.0 Hz, CH), 2.19 (3H, s); dC
(150 MHz, CDCl3) 160.3 (C-2), 148.3 (C-30), 145.2 (C-3), 138.0 (C-300),
137.3 (C-20), 136.4 (C-400), 134.0 (C-60), 132.3 (C-100), 130.4 (C-500),
129.5 (C-50),125.4 (C-200),123.8 (C-4),123.8 (C-40),122.7 (C-20),121.5
(C-600), 19.9 (CH3-300), 19.3 (CH3-400), adamantyl: 56.6 (CeN), 42.6
and 35.7 (CH2), 29.7 (CH) (The C-4 and C-40 appeared as overlapped
signals at 123.8 ppm, proven by ed-HSQC and HMBC measure-
ments. For differentiation of 300-CH3 and 400-CH3 signals selective
NOESYexperiment (irradiation at 7.12) was applied.). HRMS (ITTOF)
m/z: [MþH]þ calcd for C28H31N4O5: 503.2294. Found: 503.2301.
4.6. General procedure for the one-pot synthesis of com-
pounds 9aef
Nitroenamine 6aee (2 mmol), ethyl glyoxylate (1.1 mL 50% so-
lution in toluene, 5.5 mmol), and the corresponding primary amine
(5.5 mmol) were stirred in 8 mL trifluoroethanol at 70 ꢀC until the
nitroenamine was consumed. The solvent was then removed in
vacuum and the crude product was purified by column chroma-
tography on silica.
4.6.1. 3-Cyclohexylamino-1-(3,4-dimethyl-phenyl)-4-nitro-5-phenyl-
1,5-dihydro-pyrrol-2-one (9a). Purification by column chromatog-
raphy (hexane/EtOAc 5:1), yellow solid (842 mg, 52%), mp 156 ꢀC; Rf
(hexane/EtOAc 5:2) 0.73. nmax (KBr) 1703, 1647, 1513, 1454,
4.6.6. 3-(Adamant-1-ylamino)-1-phenyl-4-nitro-5-(4-nitro-phenyl)-
1,5-dihydro-pyrrol-2-one (9f). Purification by column chromatog-
raphy (hexane/EtOAc 2:1), yellow solid; (304 mg, 32%), mp 213-
214 ꢀC; Rf (cyclohexane/EtOAc 5:2) 0.63. nmax (KBr) 1712,1638,1522,
1396 cmꢂ1
; dH (500 MHz, CDCl3) 8.47 (1H, d, J 8.6 Hz, NH),
7.35e7.20 (5H, m, Ph-5), 7.17 (1H, d, J 2.0 Hz, 200-H), 7.03 (1H, d, J
8.3 Hz, 500-H), 7.00 (1H, dd, J 8.3, 2.0 Hz, 600-H), 5.87 (1H, s, 5-H), 2.18
(3H, s, 300-CH3), 2.16 (3H, s, 400-CH3), cyclohexyl: 4.99 (1H, m, CHeN),
2.20e1.20 (10H, m, C6H11); dC (125 MHz, CDCl3) 161.3 (C-2), 142.4
(C-3), 137.5 (C-300), 135.7 (C-400), 134.7 (C-10), 133.0 (C-100), 130.2 (C-
500), 128.8 (C-40), 128.6 (C-30,50), 127.8 (C-20,60), 125.2 (C-200), 123.6
(C-4), 121.3 (C-600), 61.9 (C-5), 20.0 (CH3-300), 19.4 (CH3-400), cyclo-
hexyl: 51.6 (CeN), 34.9/34.4, 24.7/24.6 and 25.2 (CH2). HRMS
1457, 1357 cmꢂ1
; dH (300 MHz, CDCl3) 9.10 (1H, s, NH), 8.12 (2H, d, J
8.7 Hz, Ph(p-NO2)), 7.43 (2H, d, J 8.7 Hz, Ph(p-NO2)), 7.35e7.29 (3H,
m, Ph), 7.21e7.16 (2H, m, Ph), 6.03 (1H, s, 5-H), adamantyl: 2.30/
2.25 (6H, d, J 12.0 Hz, CH2), 1.78e1.75 (6H, d, J 12.0 Hz, CH), 2.19
(3H, s); dC (75 MHz, CDCl3) 160.7, 148.3, 142.3, 135.2, 129.6, 128.9,
127.6, 124.1, 68.6, 61.5, 56.8, 42.9, 36.0, 30.0, 23.1, 20.3. HRMS

6142
Z. Vincze et al. / Tetrahedron 71 (2015) 6135e6142
(ITTOF) m/z: [MþH]þ calcd for C26H26N4O5. 475.1981. Found:
are indebted to Mrs. Valeria M. Szekely and Mrs. Klara M. Ocskay for
their technical help.
ꢀ
ꢀ
ꢀ
475.1988.
4.7. 2-[(4-Methoxy-benzylidene)-amino]-3-nitro-3-
pyrrolidin-2-ylidene-propionic acid ethyl ester (10)
References and notes
1. (a) Endo, T.; Tsuda, M.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2007, 70, 423; (b)
Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman, L. E.; Shak, A. J. J. Org. Chem.
1999, 64, 1512.
2. Kappe, C. O. Tetrahedron 1993, 49, 6937.
3. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
4. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
5. Haggarty, S. J.; Mayer, T. U.; Miyamoto, D. T.; Fathi, R.; King, R. W.; Mitchison, T.
J.; Schreiber, S. L. Chem. Biol. 2000, 7, 275.
6. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.; Mitch-
ison, T. J. Science 1999, 286, 971.
7. Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland, S.; Gou-
goutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35,
3254.
8. Messer, W. S.; Abuh, Y. F.; Liu, Y.; Periyasamy, S.; Ngur, D. O.; Edgar, M. A. N.; El-
Assadi, A. A.; Sbeih, S.; Dunbar, P. G.; Roknich, S.; Rho, T.; Fang, Z.; Ojo, B.;
Zhang, H.; Huzl, J. J.; Nagy, P. I. J. Med. Chem. 1997, 40, 1230.
9. (a) Nair, V.; Chi, G.; Ptak, R.; Neamati, N. J. Med. Chem. 2006, 49, 445; (b) Zhou,
S.; Kern, E. R.; Gullen, E.; Cheng, Y. C.; Drach, J. C.; Matsumi, S.; Mitsuya, H.;
Zemlicka, J. J. Med. Chem. 2004, 47, 6964.
A mixture of 3a (300 mg 0.86 mmol), periodic acid (197 mg
0.86 mmol), and sulfuric acid (0.86 mL, 1 M, 0.86 mmol) in acetoni-
trile/water (16 mL 1:1) was stirred at room temperature. The com-
plete conversion was indicated by TLC analysis after 48 h reaction
time. Then, potassium carbonate (3 g) was added, and the organic
phase was separated. The aqueous phase was extracted with diethyl
ether, and the combined organic phases were treated with charcoal,
dried (Na2SO4), and evaporated to furnish a fairly pure product
(290 mg, 97%) as a red oil that solidified upon standing. Flash column
chromatography on silica (tert-butyl-methyl-ether/EtOAc/iso-
propylamine 72:20:8) gave an analytical sample; yellow solid, mp
>200 ꢀC dec; Rf (tert-butyl-methyl-ether/isopropylamine 9:1) 0.31.
dH (600 MHz, CDCl3) 9.68 (1H, br s, NH), 8.23 (1H, s, CH]), 7.20 (2H, d,
20,60-H), 6.81 (2H, d, 30,50-H), 6.11 (1H, s, C(2)-H), 4.24 (2H, m,
CH3CH2), 3.81 (2H, t, t, J 7.2 Hz, 500-H2), 3.78 (3H, s, OCH3), 3.00 and
2.86 (2H, m, 300-H2), 2.22 (2H, m, 400-H2),1.28 (3H, t, J 7.2 Hz, CH3CH2);
dC (150 MHz, CDCl3) 167.9, 164.6, 163.3, 159.6, 130.4, 130.3, 114.0,
113.2, 62.0, 55.5, 55.3, 49.2, 32.7, 21.4, 14.1. HRMS (ITTOF) m/z:
[MþH]þ calcd for C17H20N3O5: 347.1481. Found: 347.1478.
10. Bahekar, S. S.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2004, 14, 1733.
11. Vincze, Z.; Nemes, P. Tetrahedron 2013, 69, 6269.
ꢀ
12. Scheiber, P.; Toth, G.; Pilipecz, M. V.; Varga, T. G.; Nemes, P. Heterocycles 2011,
83, 2001.
ꢀ
13. Pilipecz, M. V.; Scheiber, P.; Vincze, Z.; Varga, T. G.; Toth, G.; Nemes, P. Tetra-
hedron 2014, 70, 4355.
14. Bakhmutov, V. I.; Babievskii, K. K. Bull. Acad. Sci. USSR 1978, 27, 2125.
15. Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417.
ꢀ
16. (a) Duddeck, H.; Dietrich, W.; Toth, G. Structure Elucidation by Modern NMR;
Acknowledgements
ꢀ
SpringereSteinkopff: Darmstadt, Germany, 1998; (b) Pretsch, E.; Toth, G.;
Munk, M. E.; Badertscher, M. Computer-aided Structure Elucidation. Spectra
Interpretation and Structure Generation; Wiley-VCH: Weinheim, Germany,
2002.
ꢀ
Financial support from the Veterinary Faculty of the Szent Istvan
University (KK-UK 15281) is gratefully acknowledged. The authors