Diastereoselective synthesis of 1-alkyl-2,4,6-trioxoperhydropyrimidine-5- spiro-3′-(1′,2′,3′,4′-tetrahydroquinolines)

Article abstract of DOI:10.1016/j.tet.2010.06.015

Knoevenagel products formed by the condensation of N-monoalkyl barbituric acids with o-tert-amino benzaldehydes undergo tert-amino effect reactions (T-reactions) yielding 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-3′- (1′,2′,3′,4′-tetrahydroquinoline) derivatives as a mixture of (S*,S*)- and (S*,R*)-diastereomers. Mostly, the major diastereomer has the S*,S*-configuration. According to X-ray diffraction data in the solid form and NOE data in solution, diastereoselectivity of the T-reactions can be associated with the structure of the Knoevenagel products whose conformation is fixed by the strong intramolecular C-H?π interaction.

Full text of DOI:10.1016/j.tet.2010.06.015

Tetrahedron 66 (2010) 6054e6061
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Diastereoselective synthesis of 1-alkyl-2,4,6-trioxoperhydropyrimidine-5-spiro-
30-(10,20,30,40-tetrahydroquinolines)
,
b
c,
Konstantin A. Krasnova , Victor G. Kartsev , Victor N. Khrustalev
*
*
a FGUN ‘Institute of Toxicology’ of the Federal Medical-Biological Agency, 1, Bekhterev St., St., Petersburg 192019, Russian Federation
b InterBioScreen Ltd., Chernogolovka, PO Box 218, Moscow 142432, Russian Federation
c A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28, Vavilov St., Moscow 119991, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Knoevenagel products formed by the condensation of N-monoalkyl barbituric acids with o-tert-amino
benzaldehydes undergo tert-amino effect reactions (T-reactions) yielding 1-alkyl-2,4,6-trioxoperhy-
Received 18 January 2010
Received in revised form 17 May 2010
Accepted 7 June 2010
dropyrimidine-5-spiro-30-(10,20,30,40-tetrahydroquinoline) derivatives as a mixture of (S
*
,S
*
)- and (S
*
,R )-
*
diastereomers. Mostly, the major diastereomer has the S
* *
,S -configuration. According to X-ray diffraction
Available online 12 June 2010
data in the solid form and NOE data in solution, diastereoselectivity of the T-reactions can be associated
with the structure of the Knoevenagel products whose conformation is fixed by the strong intra-
Keywords:
molecular CeH/
p interaction.
Knoevenagel products
tert-Amino effect reaction
Diastereoselective synthesis
Trioxoperhydropyrimidine-5-spiro-30-
tetrahydroquinoline
Ó 2010 Elsevier Ltd. All rights reserved.
Intramolecular CeH/
p interaction
1. Introduction
Recently, the synthetic potential of the tert-amino effect
has been considerably extended due to the use of the cyclic
The concept of the tert-amino effect formulated by Meth-Cohn
and Suschitsky1 refers to a great number of cyclization reactions
involving o-substituted tertiary aromatic amines. One of the most
important manifestations of the tert-amino effect includes the
thermal isomerization of 2-vinyl-N,N-dialkylanilines leading to the
annealed 1,2,3,4-tetrahydroquinoline systems (Scheme 1).2,3 De-
spite the demanding conditions of the tert-amino effect reactions
(T-reactions), the examples of diastereodirected and enantiodir-
ected courses of isomerization have been described.4,5
b-dicarbonyl reagents, which allow T-reactions to proceed under
surprisingly mild conditions.6,7 Furthermore, most of 1,2,3,4-tet-
rahydroquinoline derivatives containing spirocyclic barbituric acid,
Meldrum’s acid, or cyclohexene-1,3-dione moieties were prepared
in this fashion (Scheme 2).6e10
If an asymmetric carbon atom is present in the tert-amino
group, the T-reactions may proceed diastereoselectively.8,10 In such
cases, the enantiomerically pure 1,2,3,4-tetrahydroquinolinic sys-
tems may be obtained from the chiral substrates (Scheme 2).11
In continuation of our previous studies on the stereochemical
aspects of the tert-amino effect, herein we describe stereoselective
T-reactions that result in the formation of compounds with two
new chiral centers.
R2
R3
R1
N
R3
R1
N
R2
R4
4
X
R
X
H
2. Results and discussion
Knoevenagel condensation of 1-methylbarbituric (1a) or
1-tert-butylbarbituric (1k) acids with 2-(tert-amino) benzalde-
hydes (2aej) yields 1-alkyl-5-(2-(tert-amino)benzylidene)barbi-
turates (3aet) as useful precursors for the syntheses of
corresponding 5-spiro barbiturates (4aet) (Scheme 3). In this
case, the T-reaction leads to the formation of compounds with
two new asymmetric centers. Hence, the final products 4aet may
Scheme 1. Thermal isomerization of 2-vinyl-N,N-dialkylanilines into 1,2-annelated
1,2,3,4-tetrahydroquinolines.
* Corresponding authors. Tel.: þ7 499 135 9343; fax: þ7 499 135 5085 (V.N.K.);
tel.: þ7 812 365 0680; fax: þ7 812 412 9163 (K.A.K.); e-mail addresses:
krasnov_tox@mail.ru (K.A. Krasnov), vkh@xray.ineos.ac.ru (V.N. Khrustalev).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.015

K.A. Krasnov et al. / Tetrahedron 66 (2010) 6054e6061
6055
be obtained either as diastereomeric pairs with (S
*
,S
*
) or (S
*
,R )-
*
O
O
O
X
relative configuration of these centers, or as their mixture.
X
X
X
X
Condensation of acids 1a,k with 2-(N-4-phenylpiperazino)
benzaldehyde 2a in 90%-ethanol afforded unstable Knoevenagel
products 3a,k, which undergo rapid isomerization into spirocyclic
derivatives 4a,k at room temperature. 1-Methyl-substituted
X
O
R
R
R
R
N
O
N
derivative 4a was obtained as a 9:1 mixture of (S
diastereomers, whereas 1-tert-butyl derivative 4k was isolated
almost quantitatively as the (S ,S )-diastereomer (Table 1). The
*
,S
*
)- and (S
*
,R )-
*
R
R
*
*
relative configurations of the major diastereomers of 4a and 4k
were established by X-ray diffraction analysis (Fig. 1).
X
X
X
O
R
O
Table 1
T-reaction
Overall yield and diastereomeric ratio of spirocyclic derivatives 4aet
N
R
Starting R1
reagents
R2
X
Product Methoda Overall (S
*
,S
*
)/(S
*
*
,R ),
yield, %
%
R
1aþ2a
1aþ2b
1aþ2c
1aþ2d
1aþ2e
1aþ2f
1aþ2g
1aþ2h
1aþ2i
3j
Me
Me
Me
H
H
H
NePh
NeMe
NeCH2Ph 4c
d
4a
4b
A
A
A
A
A
A
A
A
B
C
D
A
A
A
A
A
A
A
A
B
C
87
86
85
84
71
84
82
84
82
96
100
85
85
85
80
83
83
74
79
65
95
90/10
64/36
52/48
53/47
100/0
50/50
91/9
89/11
54/46
50/50
74/26
96/4
Scheme 2. Isomerization of 2-vinyl-N,N-dialkylanilines into 1,2-annelated 1,2,3,4-
tetrahydroquinolines.
Me NO2
Me NO2 CH2
Me CH2CH2
Me NO2 CH2CH2
Me
Me NO2 NeMe
4d
4e
4f
4g
4h
4i
H
X
R
H
O
O
H
O
O
N
N
H
N
Me NO2
O
4j
O
+
O
1kþ2a
1kþ2b
1kþ2c
1kþ2d
1kþ2e
1kþ2f
1kþ2g
1kþ2h
1kþ2i
3t
t-Bu
t-Bu
t-Bu
H
H
H
NePh
NeMe
NeCH2Ph 4m
d
4k
4l
N
N
N
R1
100/0
93/7
O
R1
X
O
R
t-Bu NO2
t-Bu NO2 CH2
t-Bu CH2CH2
t-Bu NO2 CH2CH2
t-Bu
t-Bu NO2 NeMe
t-Bu NO2
4n
4o
4p
4q
4r
4s
4t
78/22
100/0
100/0
100/0
100/0
100/0
70/30
2a-j
1a, k
3a-t
H
R
R
H
O
O
O
O
H
N
H
N
O
H
O
H
a
+
O
See Experimental section.
N
N
N
N
R
R
O
X
X
Similarly, the condensation of acids 1a,k with aldehydes 2beh is
accompanied by rapid T-reaction leading directly to spirocyclic
derivatives 4beh, ler through the one-pot synthesis (method A,
Table 1). The reaction rate is limited by the Knoevenagel conden-
sation step, whereas highly reactive intermediatesd1-alkyl-5-
arylidene barbiturates 3aeh, ler formed in situ undergo immediate
isomerization into the final spirocyclic systems.
4a-t (S*,S*)
4a-t (S*,R*)
Scheme 3. The formation of 5-spiro barbiturates from 1-alkylbarbituric acids and
2-(tert-amino) benzaldehydes. R1¼Me (aej), t-Bu (ket); R2¼H (aec, f, h, kem, p, r),
NO2 (d, e, g, i, j, n, o, q, s, t); X¼NPh (a, k), NMe (b, i, l, s), NCH2Ph (c, m), d(d, n), CH2
(e, o), CH2CH2 (f, g, p, q), O (h, j, s, t).
Figure 1. Molecular structures of 4a, 4j, and 4k.

6056
K.A. Krasnov et al. / Tetrahedron 66 (2010) 6054e6061
To distinguish the (S
and 4k in their 1H NMR spectra, we used the authentic samples of
(S ,S )-diastereomers, whose configuration was previously con-
*
,S
*
)- and (S
*
,R
*
)-diastereomers of 4a, 4j,
These observations are indicative of the very strong CeH/p
interaction arising due to increased electron-withdrawing ability of
the C]C vinyl bond in 5-benzylidene barbiturates. We proposed
*
*
firmed by X-ray diffraction study (Fig. 1). For other compounds, the
proton signals of diastereomers 4 were identified by the charac-
teristic chemical shifts of NH and NMe (NCMe3) groups. Thus, for
5-spiro-derivatives of 1-methylbarbituric acid 4a and 4j, the NH
that such a strong CeH/p interaction can be used to explain the
facile initiation of the T-reactions in compounds 3aet as well as in
other 5-(2-dialkylaminobenzylidene) barbiturates and related
compounds.
signals from (S
11.40 and 11.55 ppm, whereas the NH signals from the corre-
sponding (S ,R )-isomers are shifted downfield by 0.19 ppm and
*
,S
*
)-diastereomers (in DMSO-d6) are observed at
Isomerization of 3t into the spirocyclic derivative 4t (Scheme 4)
proceeds via a zwitterionic intermediate 6 formed by uptake of
1,5-hydride. In this case, the CeH/p interaction observed in
*
*
observed at 11.59 and 11.74 ppm, respectively.
compound 3t and its analogs (Fig. 2) both stabilizes the starting
conformation, and creates the necessary prerequisites for the
subsequent migration of the hydride from the NCH2 group.
In contrast to aldehydes 2aeh, 5-nitro-2-(4-N-methylpiper-
azino)benzaldehyde 2i and 5-nitro-2-(N-morpholino)benzalde-
hyde 2j react with acids 1a,k to yield relatively stable 5-arylidene
barbiturates (derivatives 3j, t have been isolated). The isomeriza-
tion of 3j into 4j in solution exhibited a lower diastereoselectivity,
while heating of 3j in the solid state (without solvent) yielded an
O
O
H
O
N
O
O
N
H
O
H
H
H
excess of the (S
*
*
,S )-diastereomer of 4j. The latter was isolated and
N
N
N
N
H
characterized by NMR spectroscopy and single-crystal X-ray anal-
ysis. As for the isomerization of 1-tert-butyl-5-arylidenebarbiturate
3t into 4t, diastereoselectivity of the T-reaction was moderate
(Table 1).
O
'
O
N
H
N
H
H
H
O
O
O
H
O
H
'
H
3t (E)
3t (Z)
Thus, the isomerization of 1-tert-butyl-5-arylidene barbiturates
3ket predominantly results in the (S
*
,S )-diastereomers of the
*
O
corresponding spirocyclic 4-compounds. The diastereodirected
T-reaction was also observed for 1-methyl substituted substrates
3a,b,e,gei (for 3t in solid phase), however, in the case of 3c,d,f,i,
diastereoselectivity was completely absent.
O
N
O
O
N
-
N
(S*S*)
4t
+
In order to rationalize the above trend toward the predominant
O
N
(S
*
,S )-diastereomer of 4, we rigorously investigated the structure
*
O
of Knoevenagel products (substrates of the T-reaction) using 1-tert-
butyl-[5-nitro-2-(N-morpholino)benzylidene]barbituric acid 3t
and 1,3-dimethyl-[5-nitro-2-(N-morpholino)benzylidene]barbitu-
ric acid 56 as model compounds.
6
Scheme 4. Tautomeric E/Z equilibrium in compound 3t and mechanism of the for-
mation of the (S ,S )-diastereomer 4t.
*
*
Previously,7 we reported that 5-(2-dimethylamino-5-nitro-
benzylidene)barbituric acid exhibited a very short CeH/p(C]C)
In fact, the intramolecular CeH/p interaction can be regarded
intramolecular contact between the hydrogen atom of one of the
two methyl group of the amino substituent and the exocyclic car-
bon atom of the vinyl fragment, with the H/C interatomic distance
as the initial stage of the process: the abstraction of hydride ion by
the polar C]C bond. Interestingly, this hydride uptake resembles
the well-known reactions of nucleophilic addition of amines and
OHꢀ to 5-benzylidene barbiturates.12 The only difference is that in
3t the reaction proceeds intramolecularly and the labile Hꢀ ion acts
as a nucleophile.
ꢀ
of 2.34 A. The X-ray structural data for compounds 3t and 5 reveal
the presence of similar contacts with the corresponding H/C in-
ꢀ
teratomic distances of 2.26 and 2.35 A, respectively (Fig. 2).
Figure 2. Molecular structure of compounds 3t and 5.

K.A. Krasnov et al. / Tetrahedron 66 (2010) 6054e6061
6057
X-ray structural and 1H NMR spectroscopy data for 3t suggest
that the crystals of 3t are formed by the E-isomer only, whereas in
solution, this compound is present as a mixture of E- and Z-iso-
mers, the former being predominant. In the crystal, due to the
T-reaction that involves a hydride uptake and determines the ste-
reochemical ratio of the formed products 4aet. The stronger
CeH/
p
interaction occurs in 3(E)-isomers, and facilitates the
,S )-diastereomers of 4.
predominant formation of (S
*
*
strong CeH/
p
interaction, the molecule of 3t (E) adopts the
It is interesting to note that, for slowly isomerizing substrates 3j
and 3t, diastereoselectivity of the T-reactions is low, whereas their
unstable and highly reactive analogs 3aeh, ker mostly react stereo-
conformation in which the morpholine moiety is located as far
from the tert-butylated nitrogen atom as possible (Fig. 2). Such
a conformation of the starting molecule 3t(E), in view of its sub-
sequent disrotational isomerization via zwitterion 6, favors the
selectively yielding the (S
*
,S )-diastereomers 4 in quantitative yield.
*
formation of (S
starting conformation of 3t(Z)-isomer should favor the formation
of (S ,R )-diastereomer 4t.
*
,S
*
)-diastereomer 4t (Scheme 4). Accordingly, the
4. Experimental section
4.1. General
*
*
The molecule of 3t(E)-isomer (Fig. 2, Scheme 4) was confirmed,
with the use of the Overhauser method, to retain its spatial struc-
ture both in solid state and in solution. During several hours after
dissolution of 3t in CDCl3, the 1H spectrum exhibited the following
The 1H and 13C NMR spectra were recorded on a AM-500 Bruker
spectrometer (500 and 200 MHz, respectively). The purity of syn-
thesized compounds was determined by elemental analysis and 1H
set of signals from 3t(E)-isomer (500 MHz,
d, ppm, numeration of
NMR spectroscopy. The relative amounts of (S
*
,S
*
)- and (S
*
*
,R )-di-
protons is given in Scheme 4): 1.70 (9H, s, C(CH3)3), 3.16 (4H, m, N
(CH2)2), 3.91 (4H, m, O(CH2)2), 7.04 (1H, d, J 9.2 Hz, H5), 8.00 (1H, s,
NH), 8.26 (1H, dd, J 9.2, 2.4 Hz, H4), 8.36 (1H, s,]CH), 8.80 (1H, d, J
2.4 Hz, H3). 1He1H NOE correlations for this compound (Table 2) are
very close to theoretically expected values for the E-isomer, judging
from the relevant H/H distances in its crystal structure.
astereomers in products (4aet) were derived from the intensity of
proton signals of NH groups (in 1H NMR spectra), at the integration
accuracy better than 2%. The relevant data are collected in Table 1.
Starting aldehydes 2aec were prepared from o-fluo-
robenzaldehyde and corresponding amines by use of the method
described in,2 while derivatives 2f, 2h in a similar way following the
methods.3,5 Aldehydes 2d, 2e, 2g, 2i, 2j were prepared from
2-chloro-5-nitrobenzaldehyde
and
corresponding
amines
Table 2
by method.6 Compound 5 was synthesized from aldehyde 2j and
NOE correlations in (E)- and (Z)-isomers of compound 3t in CDCl3
1,3-dimethylbarbituric acid by method.6
Crystals of compounds 3t, 4a, 4j, 4k, and 5 suitable for X-ray
structural analysis were grown from water-ethanol solutions.
Interacting protons
HeH distances
in 3t(E), A
NOE correlations,
% for 3t(E) for 3t(Z)
in 3t(E) and 3t(Z)a
b
ꢀ
H4eH5
2.29
2.15 and 2.68
2.30
3
100
45
dc
100
18
0
H5eH6 and H5eH6
0
H2eH7
4.2. X-ray structure determination
H2eH8
2.49
31
<5
a
For numeration of protons, see Scheme 4.
In solid state (from X-ray diffraction data).
Obscured by signal from the E form.
Data for 3t, 4a, 4j, 4k, and 5 were collected on a Bruker SMART
b
c
1 K CCD diffractometer
(lMo Ka-radiation, graphite mono-
chromator, and scan mode). For details, see Table 3. The
u
4
structures were determined by direct methods and refined by full-
matrix least squares technique on F2 with anisotropic displacement
parameters for non-hydrogen atoms. The hydrogen atoms of the
amino-groups in 3t were objectively located in the difference
Fourier map and refined isotropically. The hydrogen atoms of the
amino-groups in 4a and 4j were objectively located in the differ-
ence Fourier map and refined with fixed positional and isotropic
displacement parameters. The other hydrogen atoms in 3t, 4a, and
4j and all hydrogen atoms in 4k and 5 were placed in calculated
positions and refined in riding model with fixed isotropic dis-
placement parameters [Uiso(H)¼1.5Ueq(C) for the CH3 groups and
Uiso(H)¼1.2Ueq(C) for the other groups]. All calculations were car-
ried out using the SHELXTL program.13 Crystallographic data for 3t,
4a, 4j, 4k, and 5 have been deposited with the Cambridge Crys-
tallographic Data Center, CCDC 665417-665421. Copies of this in-
formation may be obtained free of charge from the Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223 336033;
e-mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk).
If 3t(E) is kept in CDCl3 solution at 20 ꢁC for prolonged periods of
time, the 1H NMR spectrum changes due to partial conversion of
the starting compound into 3t(Z)-isomer and exhibits the following
set of signals: (500 MHz, d, ppm, numeration of protons is given in
Scheme 4): 1.71 (9H, s, C(CH3)3), 3.16 (4H, m, N(CH2)2), 3.91 (4H, m,
O(CH2)2), 7.06 (1H, d, J 9.2 Hz, H5), 8.14 (1H, s, NH), 8.28 (1H, dd, J
9.2, 2.4 Hz, H4), 8.29 (1H, s,]CH), 8.43 (1H, d, J 2.4 Hz, H3). The E/Z-
isomerization around the C]C bond is reversible: equilibrium in
the system was achieved in 10 days. According to our 1H NMR data,
the equilibrium mixture contained 65% 3t(E)- and 35% 3t(Z)-
isomer.
0
The NOE correlations (Table 2) show that the H2/H7 distance in
ꢀ
3t(E)-isomer is within 2.30e2.40 A, whereas it increases up to
2.70e2.80 A in 3t(Z)-isomer; therefore, the 3t(E)/3t(Z) trans-
ꢀ
formation is accompanied by significant weakening of a remarkable
CeH/p interaction.
Based on the above considerations we conclude that the more
stable 3t(E)-isomer enters into the T-reaction more readily because
its starting conformation is more favorable for the hydride uptake
as compared to that of the 3t(Z)-isomer. The predisposition of 3t(E)-
4.3. General method Adthe procedure for synthesis of
5-spiro barbiturates 4aeh, ker (Table 1)
isomer for conversion into (S
*
*
,S )-diastereomer 4t provides a logical
4.3.1. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(30-phe-
nyl-10,20,30,3a0,40,50-hexahydro-1H-pyrazino[1,2-a]quinoline)) (4a). A
solution of 5 mmol (0.71 g) acid 1a in 50% ethanol (10 ml) was
added to a solution of 5 mmol (1.32 g) aldehyde 2a in 90% ethanol
(20 ml) at 50 ꢁC, and the reaction mixture was stirred for 5 min.
After staying at room temperature for 1 h, water (10 ml) was added.
The precipitated colorless crystals were separated, washed with
explanation for the predominance of the latter in the products of
the T-reaction.
3. Conclusion
We have rationalized the tendency of 1-monoalkyl 5-(2-dia-
lkylaminobenzylidene)barbituric acids 3 to isomerize into products
4
with the predominant (S
*
,S
*
)-configuration. The CeH/
p
50% ethanol, and air dried to give a mixture of (S
,S
* *
)- and (S
*
*
,R )-
interaction in the intermediates 3 seems to be a crucial factor of the
diastereomers 4a; dH (500 MHz, DMSO-d6) 11.59 and 11.40

6058
K.A. Krasnov et al. / Tetrahedron 66 (2010) 6054e6061
Table 3
Crystallographic data for 3t, 4a, 4j, 4k, and 5
Compound
3t
4a
4k
4j
5
Empirical formula
Fw
C19H22N4O6
402.41
C22H22N4O3
390.44
C25H28N4O3
432.51
C16H16N4O6
360.33
C17H18N4O6
374.35
T, K
120 (2)
120 (2)
120 (2)
120 (2)
120 (2)
Crystal size, mm
Crystal system
Space group
0.24ꢂ0.21ꢂ0.15
0.30ꢂ0.30ꢂ0.05
Orthorhombic
Pca21
15.718 (3)
16.583 (4)
7.3072 (16)
90
0.21ꢂ0.18ꢂ0.12
Orthorhombic
Pbca
12.376 (4)
17.568 (5)
20.348 (7)
90
90
90
4424 (2)
8
1.299
0.24ꢂ0.21ꢂ0.18
Monoclinic
P21/c
9.700 (3)
11.588 (4)
13.849 (4)
90
99.471(7)
90
1535.6 (8)
4
0.24ꢂ0.21ꢂ0.18
Monoclinic
P21/n
7.3557 (8)
8.5607 (10)
26.757 (3)
90
95.215 (5)
90
1677.9 (3)
4
Triclinic
P-1
ꢀ
a, A
7.697 (3)
11.824 (5)
12.033 (5)
63.323 (8)
84.427 (8)
71.561 (8)
927.0 (7)
2
ꢀ
b, A
ꢀ
c, A
a
, deg
, deg
b
90
90
g
, deg
3
ꢀ
V, A
1904.6 (7)
4
1.362
824
0.093
Z
dc, gꢂcmꢀ3
F (000)
1.442
424
0.109
1.559
752
0.122
1.482
784
0.114
1840
0.087
m
, mmꢀ1
2qmax, deg
50
56
50
52
56
Index range
ꢀ9<¼h<¼9
ꢀ14<¼k<¼14
ꢀ13<¼l<¼14
6521
ꢀ20<¼h<¼20
ꢀ21<¼k<¼21
ꢀ9<¼l<¼9
18,733
ꢀ14<¼h<¼14
ꢀ18<¼k<¼20
ꢀ24<¼l<¼24
22,758
ꢀ11<¼h<¼11
ꢀ14<¼k<¼14
ꢀ17<¼l<¼15
8783
ꢀ9<¼h<¼9
ꢀ11<¼k<¼11
ꢀ35<¼l<¼34
16,774
No. of rflns collected
No. of unique rflns
No. of rflns with I>2
Data/restraints/parameters
R1; wR2 (I>2 (I))
3188 (Rint¼0.064)
4571 (Rint¼0.053)
3890 (Rint¼0.077)
3002 (Rint¼0.032)
4033 (Rint¼0.026)
s(I)
1762
3342
2038
1948
3020
3188/0/266
0.074; 0.159
0.132; 0.179
1.015
4571/1/263
0.054; 0.114
0.074; 0.122
1.004
3890/0/289
0.067; 0.132
0.124; 0.146
1.036
3002/0/236
0.053; 0.124
0.077; 0.137
1.002
4033/0/246
0.046; 0.102
0.062; 0.108
1.002
s
R1; wR2 (all data)
GOF on F2
Tmin; Tmax
0.976; 0.988
0.969; 0.996
0.982; 0.990
0.970; 0.980
0.970; 0.983
(0.1Hþ0.9H, sþs, NH (S
*
,R
*
and S
*
,S
*
)), 7.18 (2H, dd, J 7.4 Hz, Harom),
DMSO-d6) 11.60 and 11.41 (0.48Hþ0.52H, sþs, NH (S
*
,R
*
and S ,
*
7.04 (1H, dd, J 7.4 Hz, Harom), 6.94 (1H, d, J 6.9 Hz, Harom), 6.87 (1H, d,
J 7.9 Hz, Harom), 6.82 (2H, dd, J 7.5 Hz, Harom), 6.76 (1H, dd, J 6.8 Hz,
Harom), 6.64 (1H, dd, J 6.9 Hz, Harom), 4.06 and 2.70 (1Hþ1H, mþm, J
10.7 Hz, NCHaHb), 3.74 (1H, dd, J 9.5, 3.1 Hz, NCH), 3.60 and 3.38
(1Hþ1H, m, J 10.6 Hz, NCHaHb), 3.24 and 3.08 (0.3Hþ2.7H, sþs, NMe
S
*
)), 7.33e7.20 (5H, m, Ph), 6.99 (1H, m, Harom), 6.91 (1H, m,
Harom), 6.80 (1H, m, Harom), 6.64 (1H, m, Harom), 3.81 (1H, dd, J 9.5,
3.9 Hz, NCH), 3.54e3.30 (3H, m, NCH2Ar and CHH), 3.26 and 3.09
(1Hþ1H, dþd, J 16.9 Hz, CHaHbAr), 3.19 and 3.11 (1.59Hþ1.41H,
sþs, NMe (S
NCHH).
*
,R
*
and S
*
,S )), 2.08e2.36 (4H, m, 2NCH2), 1.93 (1H, m,
*
(S
and 2.96 (1Hþ1H, mþm, J 11.0 Hz, NCHaHbCH).
The pure (S ,S )-diastereomer of 4a was obtained by re-
,R
* *
and S
*
,S
*
)), 3.27 and 3.18 (2H, dþd, J 16.6 Hz, CHaHbAr), 3.17
*
*
4.3.4. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(70-nitro-
crystallization from 10:1 ethanol/DMF solution as colorless plate-
like crystals, mp 239e242 ꢁC; [found: C 67.44; H 5.60; N 14.19.
C22H22N4O3 requires C 67.68; H 5.68; N 14.35%]; dC (200 MHz,
DMSO-d6) 170.72, 168.08, 150.56, 150.38, 144.11, 129.22, 128.61,
126.74, 121.39, 119.56, 117.93, 115.60, 113.17, 59.24, 50.37, 48.33,
47.62, 46.31, 33.48, 27.48.
10,20,30,3a0,40,50-hexahydropyrrolo[1,2-a]quinoline)) (4d). Mixture of
(S
*
,S
*
)- and (S
*
,R
)-diastereomers. Yellow crystals, mp 301e305 ꢁC
*
(decomp.); [found: C 55.57; H 4.77; N 16.09. C16H16N4O5 requires
C 55.81; H 4.68; N 16.27%]; dH (500 MHz, DMSO-d6) 11.78 and
11.51 (0.47Hþ0.53H, sþs, NH (S
*
,R
*
and S
*
,S )), 8.92 (1H, d, J
*
8.8 Hz, Harom), 7.83 (1H, d, J 2.4 Hz, Harom), 6.55 (1H, dd, J 8.8,
2.4 Hz, Harom), 3.89 (1H, m, NCH), 3.70 (1H, t, J 11.1 Hz, NCHH-eq),
3.37 (3H, m, NCHHþCH2Ar), 3.22 and 3.06 (1.41Hþ1.59H, sþs,
4.3.2. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(30-
methyl-10,20,30,3a0,40,50-hexahydro-1H-pyrazino[1,2-a]quinoline))
NMe (S
*
,R
*
and S
*
,S
*
)), 2.20e1.95 (3H, m, CH2þCHH-eq), 1.53 (1H,
(4b). Mixture of (S
*
,S
*
)- and (S
*
*
,R )-diastereomers. Colorless
m, CHH-ax).
powder, mp 213e216 ꢁC; [found: C 62.31; H 5.69; N 16.93.
C17H20N4O3 requires C 62.18; H 6.14; N 17.06%]; dH (500 MHz,
4.3.5. (S
*
,S
)-1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(80-
*
DMSO-d6) 11.61 and 11.49 (0.36Hþ0.64H, sþs, NH (S
*
,R
*
and S
*
,S
*
)),
nitro-10,20,30,3a0,40,50-hexahydropyrido[1,2-a]quinoline)) (4e). Yellow
acicular crystals, mp 310e312 ꢁC (decomp.); [found, C 56.74; H
5.21; N 15.50. C17H18N4O5 requires C 56.98; H 5.06; N 15.63%]; dH
(500 MHz, DMSO-d6) 11.48 (1H, s, NH), 7.90 (1H, dd, J 9.2, 2.3 Hz,
Harom), 7.85 (1H, d, J 2.3 Hz, Harom), 6.91 (1H, d, J 9.2 Hz, Harom),
4.21 (1H, dd, J 9.9, 4.6 Hz, NCH), 3.73 and 3.08 (1Hþ1H, dþd, J
12.5 Hz, NCHaHb), 3.39 and 3.05 (1Hþ1H, dþd, J 17.2 Hz, CHaH-
bAr), 3.12 (3H, s, NCH3), 1.84e1.23 (6H, m, 3CH2); dC (200 MHz,
DMSO-d6) 170.22, 168.36, 150,66, 149.60, 136.55, 124.20, 123.46,
121.77, 111.60, 60.76, 51.94, 48.58, 29.03, 27.88, 26.89, 23.86,
23.28.
7.01 (1H, dd, J 7.9 Hz, Harom), 6.92 (1H, d, J 8.9 Hz, Harom), 6.82 (1H,
m, Harom), 6.64 (1H, m, Harom), 3.88 (1H, m, NCH), 3.39 and 2.74
(2H, mþm, NCHaHb), 3.26 and 3.09 (1Hþ1H, dþd, J 16.5 Hz,
CHaHbAr), 3.24 (3H, s, NMe), 2.90 and 2.09 (1Hþ1H, mþm,
NCHaHb), 2.55 and 1.79 (1Hþ1H, m, J 9.5 Hz, AB-system, NCH2),
2.21 (3H, s, NMe); dC (200 MHz, DMSO-d6) 172.20, 171.64, 168.17,
167.53, 150,03, 141.79, 129.12, 126.80, 122.05, 117.98, 113.76, 59.25,
58.79, 50.73, 50.46, 47.62, 47.48, 46.60, 46.44, 45.76, 45.65, 33.63,
33.48, 28.04, 27.41.
4.3.3. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(30-ben-
zyl-10,20,30,3a0,40,50-hexahydro-1H-pyrazino[1,2-a]quinoline)) (4c).
4.3.6. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-
(50,60,6a0,70,80,90,100,110-octahydroazepino[1,2-a]quinoline)) (4f). Mix-
Mixture of (S
*
,S
*
)- and (S
*
,R
*
)-diastereomers. Colorless acicular
crystal, mp 225e229 ꢁC; [found: C 68.42; H 6.01; N 13.79.
C23H24N4O3 requires C 68.30; H 5.98; N 13.85%]; dH (500 MHz,
ture of (S
*
,S
*
)- and (S
*
,R
*
)-diastereomers. Colorless powder, mp
66.19; 6.56; 12.68. C18H21N3O3
229e233 ꢁC; [found:
C
H
N

K.A. Krasnov et al. / Tetrahedron 66 (2010) 6054e6061
6059
requires C 66.04; H 6.47; N 12.84%]; dH (500 MHz, DMSO-d6) 11.37
,S and S ,R )), 6.98 (2H, m,
118.08, 113.94, 60.83, 59.51, 53.83, 52.53, 50.40, 48.14, 45.75,
28.72, 25.99.
and 11.25 (0.5Hþ0.5H, sþs, NH (S
*
*
*
*
Harom), 6.60 (2H, m, Harom), 3.60 (1H, m, NCH), 3.59 and 3.22
(1Hþ1H, mþm, NCHaHb), 3.35 and 3.01 (1Hþ1H, dþd, J 17.4 Hz,
4.3.11. 1-tert-Butyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(30-
benzyl-10,20,30,3a0,40,50-hexahydro-1H-pyrazino[1,2-a]quinoline))
CHaHbAr), 3.17 and 3.11 (1.5Hþ1.5H, sþs, NMe (S
1.40e1.95 (8H, m, 4CH2).
*
,S
*
and S
*
*
,R )),
(4m). Mixture of (S
*
,S
*
)- and (S
*
,R
*
)-diastereomers; dH (500 MHz,
,R and S ,S )), 7.17
CDCl3) 8.44 and 7.73 (0.07Hþ0.93H, sþs, NH (S
*
*
* *
4.3.7. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(30-nitro-
50,60,6a0,70,80,90,100,110-octahydroazepino[1,2-a]quinoline)) (4g). Mix-
(2H, dd, J 8.3, 7.2 Hz, Harom), 7.04 (2H, m, Harom), 6.90 (1H, d, J 8.3 Hz,
Harom), 3.92 (1H, dd, J 10.1, 5.4 Hz, NCH), 4.00 and 3.21 (1Hþ1H,
mþm, J 14.0 Hz, NCHaHb), 3.66 and 3.26 (1Hþ1H, ddþdd, J 12.5 Hz,
NCHaHb), 2.73 and 2.59 (1Hþ1H, dd, J 11.1, 5.9 Hz, NCHaHb), 1.51 and
ture of (S
*
,S
*
)- and (S
*
,R )-diastereomers. Yellow powder, mp
*
299e301 ꢁC; [found: C 58.00; H 5.53; N 14.94. C18H20N4O5 requires
C 58.06; H 5.41; N 15.05%]; dH (500 MHz, DMSO-d6) 11.41 and 11.25
1.47 (8.37Hþ0.63H, sþs, t-Bu (S
*
,S
*
and S
*
*
,R )).
(0.91Hþ0.09H, sþs, NH (S
*
,S
*
and S
*
,R
*
)), 7.94 (1H, d, J 2.6 Hz, Harom),
The pure (S ,S )-diastereomer 4m was isolated by re-
*
*
6.98 (2H, m, Harom), 6.66 (1H, d, J 9.0 Hz, Harom), 3.95 (1H, dd, J 8.0,
4.6 Hz, NCH), 3.87 and 3.25 (1Hþ1H, mþm, NCHaHb), 3.49 and 2.96
(1Hþ1H, dþd, J 17.7 Hz, CHaHbAr), 3.14 and 3.06 (2.73Hþ0.27H, sþs,
crystallization from ethanol as colorless acicular crystals, mp 225 ꢁC
(decomp.); [found, C 70.11; H 6.84; N 16.39. C26H30N4O3 requires C
69.93; H 6.77; N 12.55%]; dC (200 MHz, DMSO-d6) 172.35, 167.43,
149.77, 142.20, 137.67, 129.05, 128.33, 127.18, 126.82, 122.14, 118.25,
118.16, 113.84, 62.27, 60.91, 59.64, 53.70, 51.10, 49.05, 48.08,
28.74, 26.95.
NMe (S
*
,S
*
and S
*
,R )), 1.33e1.99 (8H, m, 4CH2); dC (200 MHz,
*
DMSO-d6) 170.53, 168.67, 150,45, 149.81, 136.13, 123.80, 123.04,
121.23, 112.36, 60.15, 51.28, 48.11, 29.10, 27.82, 27.19, 24.22,
23.24, 22.90.
4.3.12. 1-tert-Butyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(70-
nitro-10,20,30,3a0,40,50-hexahydropyrrolo[1,2-a]quinoline)) (4n). Mix-
4.3.8. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-
(10,30,40,90,100,10a0-hexahydro-2-oxa-4a-phenanthrene)) (4h). Mix-
ture of (S
*
,S
*
)- and (S
*
,R )-diastereomers. Yellow acicular crystals,
*
ture of (S
*
,S
*
)- and (S
*
,R
*
)-diastereomers. Colorless acicular
mp 240 ꢁC (decomp.); [found: C 58.97; H 5.80; N 14.39. C19H22N4O5
crystals, mp 224e226 ꢁC; [found: C 60.89; H 5.46; N 13.31.
C16H17N3O4 requires C 60.94; H 5.43; N 13.33%]; dH (500 MHz,
requires C 59.06; H 5.74; N 14.50%]; dH (500 MHz, DMSO-d6) 11.42
and 11.20 (0.22Hþ0.78H, sþs, NH (S
Harom), 6.50 (1H, m, Harom), 3.98 and 3.81 (0.22Hþ0.78H, ddþdd, J
12.2 Hz, NCH (S ,R and S ,S )), 3.70 (1H, m, NCHH-eq), 3.29 (3H, m,
NCHHþCH2Ar), 1.98e2.22 (3H, m, CH2þCHH-eq), 1.56 (1H, m, CHH-
,S and S ,R ); dC
*
,R
*
and S
*
,S
*
)), 7.91 (2H, m,
DMSO-d6) 11.64 and 11.45 (0.11Hþ0.89H, sþs, NH (S
*
,S
*
and S ,
*
R
*
)), 7.04 (1H, dd, J 7.7 Hz, Harom), 6.94 (1H, d, J 7.8 Hz, Harom),
*
*
* *
6.83 (1H, d, J 7.7 Hz, Harom), 6.67 (1H, dd, J 7.8 Hz, Harom), 3.74
(1H, dd, J 9.4, 4.8 Hz, NCH), 3.87þ3.79þ3.41þ3.32þ3.10þ3.04
(1Hþ1Hþ1Hþ1Hþ1Hþ1H, m, NCHaHbþ2OCHaHb), 3.32 and 2.99
(1Hþ1H, dþd, J 17.2 Hz, CHaHbAr), 3.28 and 3.19 (0.33Hþ2.67H,
ay), 1.54 and 1.36 (7.03þ1.97H, sþs, t-Bu, S
*
*
*
*
(200 MHz, DMSO-d6) 172.67, 166.96, 149.64, 148.59, 137.21, 124.68,
123.46, 122.22, 112.34, 62.38, 59.50, 54.25, 49.48, 28.67, 26.00,
25.31, 24.20.
sþs, NCH3 (S
*
,R
*
and S
*
,S )); dC (200 MHz, DMSO-d6) 171.14,
*
167.96, 150.33, 142.22, 129.40, 126.56, 122.87, 118.64, 113.41,
64.98, 63.25, 59.72, 52.47, 48.39, 28.82, 27.51.
4.3.13. (S
*
*
,S )-1-tert-Butyl-2,4,6-trioxospiro(perhydropyrimidino-
5,50-(80-nitro-10,20,30,3a0,40,50-hexahydropyrido[1,2-a]quinoline))
(4o). Yellow acicular crystals, mp 244 ꢁC (decomp.); [found: C
60.06, H 5.98, N 13.91. C20H24N4O5 requires C 59.99, H 6.04, N
13.99%]; dH (500 MHz, DMSO-d6) 11.17 (1H, s, NH), 7.98 (1H, d, J
2.2 Hz, Harom), 7.89 (1H, dd, J1 9.2, 2.2 Hz, Harom), 6.92 (1H, d, J
9.2 Hz, Harom), 4.21 (1H, dd, J 9.8, 5.0 Hz, NCH), 3.92 and 3.11
(1Hþ1H, mþm, J 12.2 Hz, NCHaHb), 3.32 and 2.94 (1Hþ1H, dþd, J
17.0 Hz, CHaHbAr), 1.49 (9H, s, t-Bu), 1.87e1.25 (6H, m, 3CH2); dC
(200 MHz, DMSO-d6) 171.53, 168.01, 150,12, 149.50, 136.08, 124.96,
123.23, 122.15, 112.27, 60.94, 52.58, 51.90, 48.61, 29.34, 28.52, 26.66,
24.04, 23.75.
4.3.9. 1-tert-Butyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(30-
phenyl-10,20,30,3a0,40,50-hexahydro-1H-pyrazino[1,2-a]quinoline))
DMSO-d6) 11.30 and 11.18 (0.04Hþ*0.96H, sþs, NH (S
,R
* *
and S
*
*
,S )),
(4k). Mixture of (S
*
,S
*
)- and (S ,R )-diastereomers; dH (500 MHz,
*
7.17 (2H, dd, J 8.3, 7.2 Hz, Harom), 7.04 (2H, m, Harom), 6.90 (1H, d, J
8.3 Hz, Harom), 6.81 (2H, d, J 8.2 Hz, Harom), 6.76 (1H, t, J 7.2 Hz,
Harom), 6.69 (1H, t, J 7.2 Hz, Harom), 4.23 and 3.27 (1Hþ1H, m, J
14.3 Hz, NCHaHb), 3.99 (1H, dd, J 10.7, 2.9 Hz, NCH), 3.42 and 2.94
(1Hþ1H, d, J 16.7 Hz, CHaHbAr), 3.40 and 3.26 (1Hþ1H, m, J 12.0 Hz,
NCHaHb), 2.81 and 2.61 (1Hþ1H, m, J 11.4 Hz, NCHaHb),1.53 and 1.48
(8.6Hþ0.4H, sþs, t-Bu (S
,S
* *
and S
*
,R
*
)).
The pure (S ,S
*
*
)-diastereomer 4k was obtained by re-
4.3.14. (S
*
*
,S )-1-tert-Butyl-2,4,6-trioxospiro(perhydropyrimidino-
crystallization from ethanol as colorless acicular crystals, mp
226e227 ꢁC; [found, C 69.60; H 6.41; N 12.73. C25H28N4O3 re-
quires C 69.42; H 6.53; N 12.95%]; dC (200 MHz, DMSO-d6) 172.36,
167.48, 150.79, 149.73, 141.60, 129.18, 126.91, 122.10, 119.81,
118.29, 115.79, 114.04, 59.89, 59.59, 53.80, 47.72, 46.74, 44.81,
28.77, 26.69.
5,50-(50,60,6a0,70,80,90,100,110-octahydroazepino[1,2-a]quinoline))
(4p). Colorless acicular crystals, mp 222e223 ꢁC; [found: C 68.04,
H 7.45, N 11.28. C21H27N3O3 requires C 68.27, H 7.37, N 11.37%]; dH
(500 MHz, DMSO-d6) 11.92 (1H, s, NH), 7.03 (1H, d, J 8.4 Hz,
Harom), 6.94 (1H, dd, J 8.4, 7.0 Hz, Harom), 6.59 (1H, dd, J 8.4, 7.0 Hz,
Harom), 6.49 (1H, d, J 8.4 Hz, Harom), 3.88 and 3.10 (1Hþ1H, mþm, J
14.0 Hz, NCHaHb), 3.82 (1H, dd, J 9.6, 6.0 Hz, NCH), 3.41 and 2.82
(1Hþ1H, dþd, J 16.8 Hz, CHaHbAr), 2.13 (1H, m, CHH), 1.64e1.30
(7H, m, 3CH2þCHH), 1.50 (9H, s, t-Bu); dC (200 MHz, DMSO-d6)
172.89, 168.00, 149.96, 142.06, 128.85, 126.64, 119.36, 116.38,
110.82, 64.42, 59.42, 55.25, 49.75, 30.00, 28.79, 26.58, 24.92,
24.87, 24.44.
4.3.10. (S
*
*
,S )-1-tert-Butyl-2,4,6-trioxospiro(perhydropyrimidino-
5,50-(30-methyl-10,20,30,3a0,40,50-hexhydro-1H-pyrazino[1,2-a]quino-
line)) (4l). Colorless acicular crystals, mp 219e221 ꢁC; [found, C
64.99; H 7.15; N 15.06. C20H26N4O3 requires C 64.85; H 7.07; N
15.12%]; dH (500 MHz, DMSO-d6) 11.17 (1H, s, NH), 7.01 (2H, m,
Harom), 6.81 (1H, dd, J 7.6, 5.2 Hz, Harom), 6.67 (1H, dd, J 7.1, 4.9 Hz,
Harom), 4.06 and 3.08 (1Hþ1H, ddþdd, J 14.7 Hz, NCHaHb), 3.76 (1H,
dd, J 9.7 Hz, NCH), 3.22 and 2.85 (1Hþ1H, dþd, J 17.1 Hz, CHaHbAr),
2.49 and 2.42 (1Hþ1H, m, NCHaHb), 2.14 (3H, s, NMe), 2.04 and 1.84
(1Hþ1H, ddþdd, J 11.3 Hz, NCHaHb), 1.49 (9H, s, t-Bu); dC (200 MHz,
DMSO-d6) 172.51, 167.44, 149.78, 141.83, 129.16, 126.85, 122.06,
4.3.15. (S
*
*
,S )-1-tert-Butyl-2,4,6-trioxospiro(perhydro-pyrimidino-
5,50-(30-nitro-50,60,6a0,70,80,90,100,110-octahydro-azepino[1,2-a]quino-
line)) (4q). Yellow acicular crystals, mp 256 ꢁC (decomp.); [found: C
60.98, H 6.40, N 13.42. C21H26N4O5 requires C 60.86, H 6.32, N
13.52%]; dH (500 MHz, DMSO-d6) 10.94 (1H, s, NH), 7.94 (1H, d, J

6060
K.A. Krasnov et al. / Tetrahedron 66 (2010) 6054e6061
2.5 Hz, Harom), 7.89 (1H, dd, J 8.3, 2.5 Hz, Harom), 6.65 (1H, d, J 8.3 Hz,
Harom), 3.97 and 3.36 (1Hþ1H, mþm, NCHaHb), 3.94 (1H, dd, J 9.5,
5.0 Hz, NCH), 3.42 and 2.86 (1Hþ1H, dþd, J 17.4 Hz, CHaHbAr), 1.99
(1H, m, CHH), 1.60 (9H, s, t-Bu), 1.57e1.30 (7H, m, 3CH2þCHH); dC
(200 MHz, DMSO-d6) 171.96, 166.62, 150.23, 148.16, 136.40, 124.08,
123.19, 121.74, 112.97, 61.15, 59.48, 54.11, 49.23, 29.65, 28.67, 26.49,
24.88, 24.62, 24.21.
8.23þ8.20 (1H, sþs, ]CH, EþZ), 7.18 (1H, d, J 8.4 Hz, Harom), 3.80
(4H, t, J 5.5 Hz, 2 OCH2), 3.27þ3.22 (3H, sþs, NMe, EþZ), 3.18 (4H, t,
J 5.0 Hz, 2NCH2).
4.5.2. 1-tert-Butyl-5-(2-morpholin-4-yl-5-nitrobenzylidene)-pyrimi-
dine-2,4,6-trione (3t). It was prepared from aldehyde 2j and acid 1k
in 82% yield. Yellow-orange prismatic crystals, mp 160 ꢁC. For 1H
NMR, see the above text. Found, %: C 56.63, H 5.60, N 13.86.
C19H22N4O6. Requires C 56.71, H 5.51, N 13.92%].
4.3.16. (S
*
*
,S )-1-tert-Butyl-2,4,6-trioxospiro(perhydro-pyrimidino-
5,50-(10,30,40,90,100,10a0-hexahydro-2-oxa-4a-phenanthrene)) (4r).
Colorless acicular crystals, mp 198e199 ꢁC; [found: C 63.97, H 6.56,
N 11.69. C19H23N3O4 requires C 63.85, H 6.49, N 11.76%]; dH
(500 MHz, DMSO-d6) 11.13 (1H, s, NH), 7.03 (2H, m, Harom), 6.79
4.6. General method Cdthe procedure for synthesis of 5-
spiro barbiturates 4j,t (Table 1)
(1H, d,
J
8.3 Hz, Harom), 6.68 (1H, dd,
J
7.5 Hz, Harom),
4.6.1. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(80-nitro-
10,30,40,90,100,10a0-hexahydro-2-oxa-4a-phenanthrene)) (4j). A solu-
tion of 5 mmol (0.71 g) acid 1a in 20 ml 50% ethanol were added to
a solution of 2 mmol (0.72 g) compound 3t in 40 ml 94% ethanol
containing 0.5 ml of dimethylacetamide. The reaction mixture was
refluxed for 6 h, cooled down, after which 40 ml water was added.
A precipitate was filtered out, washed with 50% ethanol and dried
3.95þ3.83þ3.54þ3.52þ3.34þ3.19 (1Hþ1Hþ1Hþ1Hþ1Hþ1H, m,
NCH2þ2 ꢁCH2), 3.64 (1H, dd, J 7.9, 5.0 Hz, NCH), 3.20 and 2.92
(1Hþ1H, dþd, J 16.5 Hz, CHaHbAr), 1.53 (9H, s, t-Bu); dC (200 MHz,
DMSO-d6) 172.20, 167.26, 149.68, 142.27, 129.05, 126.96, 121.98,
118.21, 113.78, 65.00, 63.42, 60.22, 59.72, 52.83, 48.83, 28.72, 28.10.
4.4. General method Bdthe procedure for synthesis of 5-
spiro barbiturates 4i,s (Table 1)
in air to give compound 4j as a mixture of (S
*
,S
*
)- and (S
*
,R )-di-
*
astereomers, pale-yellow acicular crystals, mp 301e303 ꢁC; [found:
C 53.20, H 4.57, N 15.36. C16H16N4O5 requires C 53.33, H 4.48, N
15.56%]; dH (500 MHz, DMSO-d6) 11.74 and 11.55 (0.5Hþ0.5H, sþs,
4.4.1. 1-Methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(30-
methyl-80-nitro-10,20,30,3a0,40,50-hexahydro-1H-pyrazino[1,2-a]quino-
line)) (4i). A solution of 5 mmol (0.71 g) of acid 1a in 50% ethanol
(10 ml) was added to a solution of 5 mmol (1.24 g) aldehyde 2i in hot
90% ethanol (20 ml). The reaction mixture was heated to reflux for
6 h, then water (10 ml) was added, and the solution was allowed to
stand at 20 ꢁC overnight. A precipitate was filtered out, washed with
NH (S
*
,S
*
and S
*
,R )), 7.95 (1H, dd, J 9.5, 2.4 Hz, Harom), 7.82 (1H, d, J
*
2.4 Hz, Harom), 6.95 (1H, d, J 9.5 Hz, Harom), 4.07þ3.75þ3.56
(1Hþ2Hþ1H, mþmþm, OCHaHbþNCHaHb), 3.93 (1H, m, NCH),
3.35e3.18 (4H, m, CH2ArþOCH2), 3.20 and 3.10 (1.5Hþ1.5H, sþs,
NMe, S
*
,S
*
and S
*
*
,R ).
50% ethanol, and dried in air to give a mixture of (S
diastereomers 4i as yellow crystals, mp 289e291 ꢁC; dH (500 MHz,
,R and S ,S ),
*
,S
*
)- and (S
*
,R
*
)-
4.6.2. 1-tert-Butyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(80-ni-
tro-10,30,40,90,100,10a0-hexahydro-2-oxa-4a-phenanthrene)) (4t). Mix-
DMSO-d6) 11.69 and 11.53 (0.46Hþ0.54H, sþs, NH, S
*
*
*
*
ture of (S
(decomp.); dH (500 MHz, DMSO-d6) 11.39 and 11.20 (0.3Hþ0.7H, sþs,
NH, S ,R and S ,S ), 7.90 (2H, m, Harom), 6.93 (1H, d, J 9.0 Hz,
,S )- and (S ,R
* * * *
)-diastereomers, mp 245e248 ꢁC
7.92 (1H, m, Harom), 7.79 (1H, d, J 2.4 Hz, Harom), 6.97 (1H, m, Harom),
4.15 (1H, m, NCH), 3.71 and 3.34 (2H, m, NCHaHb), 3.26 and 3.09
(1Hþ1H, dþd, J 16.5 Hz, CHaHbAr), 3.20 and 3.10 (1.38Hþ1.62H, sþs,
*
*
* *
Harom), 4.10þ3.78þ3.52þ3.35 (2Hþ1Hþ2Hþ1H, mþmþmþm,
NMe, S
*
,R
*
and S
*
,S
*
), 2.81 and 2.05 (1Hþ1H, m, NCHaHb), 2.64 and
2OCHaHbþNCHaHb), 3.98 (1H, m, NCH), 3.31 and 3.05 (1Hþ1H, dþd,
1.77 (1Hþ1H, m, J 9.0 Hz, NCHaHb), 2.22 (3H, s, NMe).
J 16.7 Hz, CHaHbAr), 1.55 and 1.49 (6.3Hþ2.7H, sþs, t-Bu, S
*
,S
*
, and
* *
S ,R ).
4.4.2. (S ,S )-1-tert-Butyl-2,4,6-trioxospiro(perhydro-pyrimidino-
*
*
Recrystallzation from ethanol gave the pure (S
* *
,S
)-di-
5,50-(30-methyl-80-nitro-10,20,30,3a0,40,50-hexahydro-1H-pyrazino[1,2-
a]quinoline)) (4s). Yellow acicular crystals, mp 260 ꢁC (decomp.);
[found: C 57.75, H 6.23, N 16.92. C20H25N5O5 requires C 57.82, H
6.07, N 16.86%]; dH (500 MHz, DMSO-d6) 11.22 (1H, s, NH), 7.95 (1H,
d, J 2.2 Hz, Harom), 7.91 (1H, dd, J 9.3, 2.2 Hz, Harom), 6.95 (1H, d, J
9.3 Hz, Harom), 4.23 and 3.20 (2H, m, J 13.5 Hz, NCHaHb), 3.89 (1H,
dd, J 9.4, 5.0 Hz, NCH), 3.35 and 3.05 (1Hþ1H, dþd, J 16.4 Hz,
CHaHbAr), 2.66 and 1.84 (1Hþ1H, m, J 10.5 Hz, NCHaHb), 2.59 and
2.04 (1Hþ1H, m, NCHaHb), 2.20 (3H, s, NMe), 1.51 (9H, s, t-Bu); dC
(200 MHz, DMSO-d6) 172.05, 166.84, 149.57, 148.49, 137.45, 124.67,
123.44, 122.08, 112.63, 59.84, 59.77, 54.34, 52.64, 51.96, 48.28,
45.44, 28.69, 27.57.
astereomer 4t as pale-yellow acicular crystals, mp 248 ꢁC
(decomp.); [found: C 56.60, H 5.50, N 13.88. C19H22N4O6 requires C
56.71, H 5.51, N 13.92%]; dC (200 MHz, DMSO-d6); 170.54, 167.69,
149.88, 136.45, 124.03, 124.22, 121.36, 111.14, 66.65, 66.23, 57.71,
54.47, 48.84, 46.15, 28.72, 27.66.
4.7. Method Ddthe procedure for synthesis of (S
*
,S )-1-
*
methyl-2,4,6-trioxospiro(perhydropyrimidino-5,50-(80-nitro-
10,30,40,90,100,10a0-hexahydro-2-oxa-4a-phenanthrene)) (4j)
(Table 1) in the solid phase
Crystals 3t (2 mmol (0.72 g)) were kept in a sealed ampoule at
120 ꢁC for 72 h to obtain a mixture of (S
*
,S
*
)- and (S
*
*
,R )-di-
4.5. General procedure for synthesis of 5-arylidene
barbiturates 3j,t
astereomers 4j (see Table 1). This mixture was boiled in 50%
ethanol (50 ml) for 10 min and then hot-filtered. A precipitate
was recrystallized from glacial acetic acid and vacuum-dried over
4.5.1. 1-Methyl-5-(2-morpholin-4-yl-5-nitrobenzylidene)-pyrimi-
dine-2,4,6-trione (3j). A solution of 5 mmol (0.71 g) acid 1a in 50%
ethanol (20 ml) was added to a hot solution of 5 mmol (1.18 g)
aldehyde 2j in 94% ethanol (50 ml). The reaction mixture was
allowed to stand at 20 ꢁC for 5 days. A precipitate was filtered out,
washed with 50% ethanol, and dried in air to give 1.50 g (84%)
compound 3t as yellow-orange prismatic crystals, mp 185 ꢁC;
[found: C 53.14, H 4.65, N 15.21. C16H16N4O6 requires C 53.33, H
KOH to give 0.21 g (29%) the (S
*
,S )-diastereomer of 4j as pale-
*
yellow acicular crystals, mp 305e307 ꢁC (decomp.); [found: C
53.25, H 4.53, N 15.50. C16H16N4O6 requires C 53.33, H 4.48,
N 15.56%]; dH (500 MHz, DMSO-d6) 11.55 (1H, s, NH), 7.95 (1H,
dd, J 8.5, 2.2 Hz, Harom), 7.82 (1H, d, J 2.2 Hz, Harom), 6.95 (1H,
d,
J
8.5 Hz, Harom), 4.07þ3.80þ3.77þ3.56 (1Hþ1Hþ1Hþ1H,
mþmþmþm, OCHaHbþNCHaHb), 3.93 (1H, dd, J 9.5, 4.6 Hz, NCH),
3.35e3.23 (4H, m, CH2ArþOCH2), 3.20 (3H, s, NMe); dC (200 MHz,
DMSO-d6) 170.15, 167.44, 149.99, 136.92, 124.20, 123.71, 120.78,
111.25, 66.68, 66.04, 58.14, 48.64, 46.38, 34.41, 28.10.
4.48, N 15.55%]; dH 1H NMR (500 MHz, DMSO-d6)
dþd, J 2.6 Hz, Harom, EþZ), 8.25 (1H, dd, J 8.4, 2.6 Hz, Harom),
d
8.73þ8.70 (1H,

K.A. Krasnov et al. / Tetrahedron 66 (2010) 6054e6061
6061
5. Nijhuis, W. H. N.; Verboom, W.; El-Fadl, A. A.; van Hummel, G. J.; Reinhoudt, D.
N. J. Org. Chem. 1989, 54, 209.
Supplementary data
6. Krasnov, K. A.; Kartsev, V. G. Russ. J. Org. Chem. 2005, 41, 920.
7. Krasnov, K. A.; Kartsev, V. G.; Khrustalev, V. N. Mendeleev Commun. 2006, 1, 52.
8. Sherry, D.; Thomasco, L.M.; Toogood, P.L. WO Patent 031,195, 2004.
9. D’yachenko, E. V.; Glukhareva, T. V.; Nikolaeva, E. F.; Tkachev, A. V.; Morzherin,
Yu. Yu. Russ. Chem. Bull. 2004, 6, 1240.
10. Krasnov, K. A.; Kartsev, V. G. In The Chemistry and Biological Activity of Synthetic
and Natural Compounds. Nitrogen-Containing Heterocycles; Kartsev, V. G., Ed.;
ICSPF: Moscow, 2006; Vol. 1, p 76.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.06.015.
References and notes
1. Meth-Cohn, O. Adv. Heterocycl. Chem. 1996, 65, 1.
11. Krasnov, K. A.; Kartsev, V. G. Heterocycles 2007, 71, 19.
12. Haslinger, E.; Reithmaier, M.; Robien, W.; Wolschann, P. Monatsh. Chem. 1984,
115, 375.
2. Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S. J. Org. Chem. 1984, 49, 269.
3. Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N. Synthesis 1987, 7, 641.
4. Nijhuis, W. H. N.; Verboom, W.; El-Fadl, A. A.; Harkema, S.; Reinhoudt, D. N. J.
Org. Chem. 1989, 54, 199.
13. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.