Diastereoselective t-reaction of 1-alkyl-5-(5-nitro-2- n-morpholino- benzylidene)barbituric acids in the solid state: Synthesis of 1-alkyl-2,4,6-trioxoperhydropyrimidino-5- spiro -10'-(7'-nitro-1',3',4',9',10', 10a'-hexahydro-2'-oxa)-4a'-azaphenanthrenes and their 2'-thia analogues

Article abstract of DOI:10.1021/cg500570u

1-Alkyl-5-(5-nitro-2-N-morpholinobenzylidene) barbituric acids undergo tert-amino effect reactions (T-reactions) yielding 1-alkyl-2,4,6- trioxoperhydropyrimidino-5-spiro-10'-(7'-nitro-1',3',4',9',10', 10a'-hexahydro-2'-oxa)-4a'-azaphenanthrene derivatives as a mixture of (S*,S*)- and (S*,R*)-diastereomers. A novel heterophase modification of the T-reaction is proposed, which makes it possible to afford nearly pure (S*,S*)-diastereomers in high yields, whereas rearrangement reactions in solutions usually lack stereoselectivity. To our best knowledge, this is the first example of deliberate tuning stereodirection of a T-reaction by external conditions. Using X-ray diffraction analysis, we demonstrate that this diastereoselectivity of the solid state T-reaction is due to a peculiar crystal structure of starting 5-arylidene barbiturates, which accommodates only one specific conformation fixed by a strong intramolecular C-H···π interaction.

Full text of DOI:10.1021/cg500570u

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Article
Diastereoselective T-reaction of 1-alkyl-(5-nitro-2-N-morpholino-
benzyliden)barbituric acids in the solid state: synthesis of 1-alkyl-2,4,6-
trioxoperhydropyrimidino-5-spiro-5'-(8'-nitro-1',3',4',9',10',10#'-
hexahydro-2-oxa)-4a-phenanthrenes and their thia analogues
Konstantin A. Krasnov, and Victor Nikolayevich Khrustalev
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg500570u • Publication Date (Web): 10 Jul 2014
Downloaded from http://pubs.acs.org on July 12, 2014
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Diastereoselective Tꢀreaction of 1ꢀalkylꢀ(5ꢀnitroꢀ2ꢀNꢀmorpholinoꢀ
benzyliden)barbituric acids in the solid state: synthesis of 1ꢀalkylꢀ
2,4,6ꢀtrioxoperhydropyrimidinoꢀ5ꢀspiroꢀ5’ꢀ(8’ꢀnitroꢀ
1’,3’,4’,9’,10’,10а’ꢀhexahydroꢀ2ꢀoxa)ꢀ4aꢀphenanthrenes and their thia
analogues
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Published as part of the Crystal Growth & Design Mikhail Antipin Memorial virtual spesial issue
Konstantin A. Krasnov,*,† Victor N. Khrustalev*,‡,§
†Institute of Toxicology, 1, Bekhterev St., St. Petersburg, 192019, Russian Federation;
‡NRC «Kurchatov Institute», 1, Acad. Kurchatov Sq., Moscow, 123182, Russian Federation;
§A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28, Vavilov St., Moscow, 119991 Russian Federation
ABSTRACT: 1ꢀAlkylꢀ(5ꢀnitroꢀ2ꢀNꢀmorpholinobenzylidene) barbituric acids undergo tertꢀamino
effect reactions (Tꢀreactions) yielding 1ꢀalkylꢀ2,4,6ꢀtrioxoperhydropyrimidinoꢀ5ꢀspiroꢀ5’ꢀ(8’ꢀnitroꢀ
1’,3’,4’,9’,10’,10а’ꢀhexahydroꢀ2ꢀoxa)ꢀ4aꢀphenanthrene derivatives as a mixture of (S*,S*)ꢀ and
(S*,R*)ꢀdiastereomers. A novel heterophase modification of the Tꢀreaction is proposed, which
makes it possible to afford nearly pure (S*,S*)ꢀdiastereomers in high yields, whereas rearrangement
reactions in solutions usually lack stereoselectivity. To our best knowledge, this is the first example
of deliberate tuning stereodirection of a Tꢀreaction by external conditions. Using Xꢀray diffraction
analysis we demonstrate that this diastereoselectivity of the solid state Tꢀreaction is due to peculiar
crystal structure of starting 5ꢀarylidene barbiturates, which accommodates only one specific
conformation fixed by a strong intramolecular CꢀH…π interaction.
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INTRODUCTION
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The concept of the tertꢀamino effect as formulated by MethꢀCohn and Suschitsky1 refers to a
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great number of cyclization reactions involving oꢀsubstituted tertiary aromatic amines. One of the
most important manifestations of the tertꢀamino effect includes the thermal isomerization of
2ꢀvinylꢀN,Nꢀdialkylanilines giving rise to annelated 1,2,3,4ꢀtetrahydroquinoline systems2ꢀ6
(Scheme 1).
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Scheme 1. Isomerization (Tꢀreaction) of 2ꢀvinylꢀN,Nꢀdialkylanilines into 1,2ꢀannelated 1,2,3,4ꢀ
tetrahydroquinolines.
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R
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1
R
R
N
R
1
2
2
R
N
R
R
4
X
R
X
1
H
2
X
1
O
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2
1
X
X
N
X
2
3
O
X
R
O
2
R
O
N
3
R
3
R
1
1
R
R
tertꢀAmino effect reactions (Tꢀreactions) typically require harsh conditions and can be
promoted by microꢀwave irradiation.7,8
Recently, the synthetic potential of the tertꢀamino effect has been considerably extended due
to the use of cyclic βꢀdicarbonyl reagents, which allow such isomerizations to proceed under
surprisingly mild conditions.9,10 A number of 1,2,3,4ꢀtetrahydroquinoline derivatives bearing
spirocyclic barbituric acid, Meldrum’s acid, or cyclohexeneꢀ1,3ꢀdione moieties have been prepared
in this fashion.4,11,12
Stereoselective intramolecular cyclizations are of special interest. A few examples of
diastereodirected and enantiodirected Tꢀreactions have been described so far even for cyclization
reactions proceeding under harsh conditions.13,14
If an asymmetric carbon atom is present in the tertꢀamino group, the isomerizations may
proceed diastereoselectively.4,12,15 In some cases, a new chiral center is formed and enantiomerically
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pure 1,2,3,4ꢀtetrahydroquinolinic systems can be afforded from chiral substrates.16ꢀ18 In all the
above examples, the stereoselectivity of the Tꢀreactions was due to the presence of an asymmetric
carbon atom in a starting reactant.
Recently, we have described a stereoselective Tꢀreaction that gives rise to the formation of
compounds with two new asymmetric centers. 1ꢀAlkylꢀ5ꢀarylidenebarbiturates (1) obtained by the
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Knoevenagel
condensation
of
1ꢀalkylbarbituric
acids
with
corresponding
oꢀdialkylaminobenzaldehydes were further cyclized into spirocyclic derivatives (2) (Scheme 2)19.
Compounds 1 for R2=H were highly reactive so as we were unable to isolate them due to the
spontaneous intramolecular cyclization that readily proceeded already at room temperature.
Scheme 2. Formation of 5ꢀspiro barbiturates (2) from 5ꢀarylideneꢀbarbituric acids (1).
2
R
O
H
N
O
N
N
1
O
X
R
R1= Me, tꢀBu; R2=H, NO2; X= ꢀ, (CH2)1ꢀ2, NꢀPh, O
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2
2
R
R
O
O
H
N
H
N
H
H
O
O
+
N
N
N
N
X
O
1
O
1
R
R
X
2 (S*, R*)
2 (S*, S*)
The «rapid» Тꢀreactions typically proceed stereoselectively to afford predominantly (S*,S*)ꢀ
diastereomers of 5ꢀspiro barbituric acid derivatives 2. In some cases, the diastereomeric purity was
as high as 90ꢀ100%. To the contrary, 5ꢀarylidenebarbiturates 1 with R2=NO2 and X=O were quite
stable, their rearrangement required heating and proceeded non stereoselectively.
In this paper, we apply a new procedure to improve diastereoselectivity of the Тꢀreactions by
conducting them in the solid state. The study is performed for a series of 1ꢀalkylꢀ5ꢀ(2ꢀmorpholinꢀ4ꢀ
ylꢀ5ꢀnitrobenzylidene)barbiturates (5aꢀi) synthesized from 2ꢀmorpholinꢀ4ꢀylꢀ5ꢀnitrobenzaldehyde
(3) and 1ꢀalkylbarbituric acids (4) (Scheme 3).
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Scheme 3. Synthesis of 1ꢀalkylꢀ5ꢀ(2ꢀmorpholinꢀ4ꢀylꢀ5ꢀnitrobenzylidene)barbiturates (5aꢀi) and their
isomerization into 5ꢀspiro barbituric acid derivatives (6aꢀi) (S*,S*).
O
O
5
6
HN
7
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9
- H2O
O
O
N+
+
X
N
O
N
R
O
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4 a-h
3 a, b
O
N+
O
O
O
N+
O
O
H
H
N
N
H
N
O
O
N
N
N
R
O
R
O
X
X
5 a-i
6 a-i (S*,S*)
■
EXPERIMENTAL SECTION
The Н and 13C NMR spectra were recorded on a АМꢀ500 Bruker spectrometer (500 and
1
200 MHz, respectively). The purity of synthesized compounds was determined by elemental
analysis and 1Н NMR spectroscopy. The relative amounts of (S*,S*)ꢀ and (S*,R*)ꢀdiastereomers in
1
products 6aꢀi were derived from relative intensities of proton signals of NH groups (in H NMR
spectra) at the integration accuracy better than 2%. The relevant data are collected in Table 1.
Starting aldehyde 3a was prepared from 2ꢀchloroꢀ5ꢀnitrobenzaldehyde and morpholine by the
standard method.9 4ꢀNitroꢀ2ꢀ(1,4ꢀthiazinanꢀ4ꢀyl)benzaldehyde 3b was synthesized by a similar
method from 2ꢀchloroꢀ5ꢀnitrobenzaldehyde and thiomorpholine in a yield of 90%, M.p. 117 °С.
Starting 1ꢀalkylbarbituric acids 4аꢀh were synthesized from 2ꢀchloroꢀ5ꢀnitrobenzaldehyde and
morpholine by the general method.20
Single crystals of compound 5f suitable for Xꢀray structural analysis were grown from the
reaction mixture. Single crystals of compound 6a were obtained by recrystallization from ethanol.
Single crystals of compound 6f were obtained by a slow evaporation of a solution of 6f in a
CH2Cl2ꢀmethanol 1:1 mixture.
Spirocyclic products 6 as mixtures of (S*,S*)ꢀ and (S*,R*)ꢀdiastereomers were synthesized
by method C.
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________________________________________________________________________________
Table 1. Synthesis of spirocyclic derivatives 6aꢀi under different conditions: overall yields and
diastereomeric purities.
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Product
R
X
O
Procedurea Overall yield, %
(S*,S*), %
A
С
D
A
A
A
A
B
B
B
B
99
95
90
98
98
98
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99
94
96
97
>99
50
77
95
98
93
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99
90
94
96
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Me
6a
Me
Et
S
6b
6c
6d
6e
6f
O
O
O
O
O
O
O
nꢀPr
CH2CH=CH2
nꢀBu
iꢀPr
6g
6h
6i
CH2Ph
CH2CH2Ph
a See experimental section
________________________________________________________________________________
Xꢀray Single Crystal Structure Analysis. Data were collected on a Bruker SMART APEXꢀII
CCD diffractometer (λ(MoKα)ꢀradiation, graphite monochromator, ω and φ scan mode) and
corrected for absorption using the SADABS program21. For details, see Table 2. The structures were
solved by direct methods and refined by a fullꢀmatrix least squares technique on F2 with anisotropic
displacement parameters for nonꢀhydrogen atoms. The hydrogen atoms of the NHꢀgroups were
localized in the differenceꢀFourier map and included in the refinement with fixed positional and
isotropic displacement parameters. The other hydrogen atoms in both compounds were placed in
calculated positions and refined within the riding model with fixed isotropic displacement
parameters (Uiso(H) = 1.5Ueq(C) for the CH3ꢀgroups and Uiso(H) = 1.2Ueq(C) for the other groups).
All calculations were carried out using the SHELXTL program package22. Crystallographic data for
5f and 6f have been deposited with the Cambridge Crystallographic Data Center. CCDC 997090
and CCDC 997091 contain the supplementary crystallographic data for this paper. These data can
be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax: +44 1223 336033; eꢀmail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk).
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Table 2. Crystallographic data for 5f and 6f.
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compound
empirical formula
fw
5f
6f
C19H22N4O6
402.41
C19H22N4O6
402.41
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T, K
100(2)
100(2)
crystal size, mm
crystal system
space group
a, Å
0.30 x 0.24 x 0.01
monoclinic
P21/n
0.28 x 0.22 x 0.20
triclinic
Pꢀ1
12.065(5)
11.414(5)
13.752(5)
90
6.7833(3)
11.0656(5)
13.3501(6)
70.2880(10)
87.0620(10)
84.8850(10)
939.36(7)
2
b, Å
c, Å
α
, deg.
, deg.
, deg.
β
92.538(7)
90
γ
V, Å3
1891.9(13)
4
Z
dc, g · cmꢀ3
1.413
1.423
F(000)
848
424
1
ꢀ
, mm−
0.107
0.108
2
θmax, deg.
56.2
56.0
index range
ꢀ15 < = h < = 15
ꢀ14 < = k < = 15
ꢀ18 < = l < = 18
20614
ꢀ8 < = h < = 8
ꢀ14 < = k < = 14
ꢀ17 < = l < = 17
10726
no. of rflns collected
no. of unique rflns
no. of rflns with I > 2
4579
4535
σ(I)
2758
3783
data/restraints/parameters
R1; wR2 (I > 2 (I))
4579 / 0 / 266
0.0552; 0.1006
0.1114; 0.1168
1.000
4535 / 0 / 266
0.0397; 0.1019
0.0479; 0.1071
1.001
σ
R1; wR2 (all data)
GOF on F2
Tmin; Tmax
0.969; 0.999
0.971; 0.979
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General procedure for the synthesis of 5ꢀarylidene barbiturates 5a-f
.
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Synthesis of 1ꢀmethylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hexahydroꢀ2,4,6ꢀ
pyrimidinetrione (5a). A solution of 5 mmol (0.71 g) 1ꢀmethylbarbituric acid 4а in 50% ethanol
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(20 ml) was added to a hot solution of 5 mmol (1.18 g) aldehyde 2a in 96% ethanol (30 ml). The
o
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reaction mixture was stirred at 50 C for 10 min and allowed to stand at 20
°С for 12 h. A
precipitate was filtered out, washed with 50% ethanol and dried in air to give 1.45 g (81%)
compound 5a as yellowꢀorange prismatic crystals, m.p. 197ꢀ198 С; [Found: С 53.14, Н 4.65, N
°
15.21. C16H16N4O6 required С 53.33, Н 4.48, N 15.55%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.56
+ 11.50 (1H, s+s, NH, E + Z), 8.75+8.71 (1Н, d+d, J 2.6 Hz, Harom, E + Z), 8.25 (1Н, dd, J 8.4, 2.6
Hz, Harom), 8.23+8.20 (1H, s+s, =CH, E + Z), 7.18 (1Н, d, J 8.4 Hz, Harom), 3.80 (4Н, t, J 5.5 Hz,
2ОCH2), 3.27+3.22 (3H, s+s, NMe, E + Z), 3.18 (4Н, t, J 5.0 Hz, 2NCH2).
The same method was used to synthesize:
1ꢀMethylꢀ5ꢀ(1ꢀ[4ꢀnitroꢀ2ꢀ(1,4ꢀthiazinanꢀ4ꢀyl)phenyl]methylidene)hexahydroꢀ2,4,6ꢀ
pyrimidinetrione (5b). From 1ꢀmethylbarbituric acid 4а and aldehyde 2b (yield 86%) as yellowꢀ
orange prismatic crystals, m.p. 220 °С (Dec.); [Found: С 50.93, Н 4.35, N 14.81. C16H16N4O5S
required С 51.06, Н 4.28, N 14.89%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.52 + 11.64 (1H, s+s,
NH, E + Z), 8.65 (1Н, d, J 2.6 Hz, Harom,), 8.23 + 8.20 (1Н, d+d, J 2.6 Hz, Harom, E + Z), 8.09+8.06
(1H, s+s, =CH, E + Z), 7.22 (1Н, d, J 8.3 Hz, Harom), 3.40 (4Н, m, 2NCH2), 3.21+3.16 (3H, s+s,
NMe, E + Z), 2.45 (4Н, m, 2SCH2).
1ꢀEthylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehahydroꢀ2,4,6ꢀpyrimidineꢀtrione
(5c). From 1ꢀethylbarbituric acid 4b and aldehyde 2a (yield 79%) as yellowꢀorange prismatic
crystals, m.p. 189ꢀ191 °С; [Found: С 54.64, Н 4.80, N 14.88. C17H18N4O6 required С 54.54, Н 4.85,
N 14.97%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.56 + 11.49 (1H, s+s, NH, E + Z), 8/74 + 8.69
(1Н, d+d, J 2.6 Hz, Harom, E + Z), 8.23 (1Н, dd, J 8.2, 2.6 Hz,, Harom,), 8.12+8.09 (1H, s+s, =CH, E
+ Z), 7.20 (1Н, d, J 8.2 Hz, Harom), 3.79 (4Н, m, 2 ОCH2), 3.75 (2Н, m, NCH2CH3), 3.17 (4Н, m,
2NCH2), 1.14 (3H, t, J 5.9 Hz, CH3).
1ꢀ
(5d). From 1ꢀnꢀpropylbarbituric acid 4c and aldehyde 2a (yield 87%) as yellowꢀorange prismatic
crystals, m.p. 192ꢀ194 С; [Found: С 55.75, Н 5.22, N 14.32 C18H20N4O6 required С 55.67, Н 5.19,
nꢀPropylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehahydroꢀ2,4,6ꢀpyrimidinetrione
°
N 14.43%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.56 + 11.48 (1H, s+s, NH, E + Z), 8/73 + 8.70
(1Н, d+d, J 2.6 Hz, Harom, E + Z), 8.20 (1Н, dd, J 8.4, 2.6 Hz,, Harom,), 8.11+8.08 (1H, s+s, =CH, E
+ Z), 7.24 (1Н, d, J 8.4 Hz, Harom), 3.80 (2Н, m, NCH2), 3.77 (4Н, m, 2 ОCH2), 3.16 (4Н, m,
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2NCH2), 1.52 (2Н, m, CH2CH3), 1.11 (3H, t, J 6.7 Hz, CH3).
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1ꢀAllylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehahydroꢀ2,4,6ꢀpyrimidineꢀtrione
(5e). From 1ꢀallylbarbituric acid 4d and aldehyde 2a (yield 89%) as yellowꢀorange prismatic
crystals, m.p. 203ꢀ205 °С (Dec.); [Found: С 55.88, Н 4.76, N 14.39. C18H18N4O6 required С 55.96,
Н 4.70, N 14.50%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.69 + 11.53 (1H, s+s, NH, E + Z), 8.72 +
8.69 (1Н, d+d, J 2.7 Hz, Harom,), 8.24 (1Н, m, Harom), 8.10+8.09 (1H, s+s, =CH, E + Z), 7.23 (1Н, d,
J 8.4 Hz, Harom), 5.83 (2Н, m, CH=CH2), 5.16 (2Н, m, =CH2), 4.41+4.35 (2H, d+d, J 4.9 Hz, NCH2,
E + Z), 3.73 (4Н, m, 2 ОCH2), 3.18 (4Н, m, 2NCH2).
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1ꢀnꢀButylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehahydroꢀ2,4,6ꢀpyrimidinetrione
(5f). From 1ꢀbuthylbarbituric acid 4e and aldehyde 2a (yield 88%) as yellowꢀorange prismatic
crystals, m.p. 196ꢀ198 °С; [Found: С 56.59, Н 5.45, N 13.80. C19H22N4O6 required С 56.71, Н 5.51,
N 13.92%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.57 + 11.44 (1H, s+s, NH, E + Z), 8.72 + 8.68
(1Н, d+d, J 2.6 Hz, Harom,), 8.25 (1Н, m, Harom), 8.09 + 8.08 (1H, s+s, =CH, E + Z), 7.23 (1Н, d.d, J
8.2, 2.6 Hz, Harom), 3.80 (2Н, t, J 6.2 Hz, OCH2), 3.74 (4Н, m, 2NCH2), 3.17 (4Н, m, 2NCH2), 1.53
(2Н, m, CH2CH2), 1.32 (2Н, m, CH2CH3), 0.90 (3H, t, J 6.9 Hz, CH3).
1ꢀ
(5g). From 1ꢀiꢀpropylbarbituric acid 4f and aldehyde 2a (yield 73%) as yellowꢀorange prismatic
crystals, m.p. 184ꢀ186 С; [Found: 55.79, Н 5.13, N 14.29 C18H20N4O6 required С 55.67, Н 5.19, N
iꢀPropylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehahydroꢀ2,4,6ꢀpyrimidinetrione
°
14.43%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.48 + 11.36 (1H, s+s, NH, E + Z), 8.56 (1Н, d, J
2.8 Hz, Harom,), 8.25 (1Н, m, Harom), 8.08+8.06 (1H, s+s, =CH, E + Z), 7.23 (1Н, d.d, J 8.8, 2.8 Hz,
Harom, E + Z), 4.95 (Н, m, NCH), 3.75 (2Н, t, J 6.2 Hz, OCH2), 3.18 (4Н, m, 2NCH2), 1.40 + 1.38
(3H + 3H, d+d, J 7.0 Hz, 2CH3, E + Z).
1ꢀBenzylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehahydroꢀ2,4,6ꢀpyrimidinetrione
(5h). From 1ꢀbenzylbarbituric acid 4g and aldehyde 2a (yield 94%) as redꢀorange powder, m.p.
144ꢀ148 °С; [Found: 60.36, Н 4.71, N 12.66 C22H20N4O6 required С 60.55, Н 4.62, N 12.84%]; δН
1Н NMR (500 MHz, DMSOꢀd6): 11.71 + 11.57 (1H, s+s, NH, E + Z), 8.76 + 8.71 (1Н, d+d, J 2.9
Hz, Harom, E + Z), 8.25 (1Н, d.d, J 8.9, 2.9 Hz, Harom), 8.13 + 8.10 (1H, s+s, =CH, E + Z), 7.29 (6Н,
m, 6 Harom), 5.02 + 4.96 (2H, s+s, ArCH2N, E + Z), 3.74 (4Н, m, 2OCH2), 3.18 (4Н, m, 2NCH2).
Synthesis of 1ꢀ(2ꢀphenylethyl)ꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehaꢀ
hydroꢀ2,4,6ꢀpyrimidinetrione (5i). 5 mmol (1.16 g) of 1ꢀphenylethylbarbituric acid 4h and 5
mmol (1.18 g) aldehyde 2a were dissolved in dimethylsulfoxide (2 ml) at 50
°С and stirred at 50 °С
for 10 min. The reaction mixture was cooled to 20 С, diluted by waterꢀethanol 50% mixture (30
°
ml) and stirred for 10 min. Then water (20 ml) was added, the precipitate was filtered out and
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washed with water. The crude product was workedꢀup by adding of water (70 ml) and stirring for 1
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h at 20
°С. The precipitate was filtered out, washed with water and dried in air at room temperature
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to give 2.15 g (95%) of compound 5i as redꢀorange powder, m.p. 187ꢀ189
°С; [Found: С 61.19, Н
4.96, N 12.32. C23H22N4O6 required С 61.33, Н 4.92, N 12.44%]; δН 1Н NMR (500 MHz, DMSOꢀ
d6): 11.66 + 11.53 (1H, s+s, NH, E + Z), 8.72 + 8.66 (1Н, d+d, J 3.0 Hz, Harom, E + Z), 8.26 (1Н, m,
Harom), 8.11 + 8.09 (1H, s+s, =CH, E + Z), 7.26 (6Н, m, 6 Harom), 3.99 (2H, m, CH2N), 3.75 (4Н, m,
2OCH2), 3.17 (4Н, m, 2NCH2), 2.85 (2H, m, CH2Ph).
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General Method A – the procedure for the synthesis of 5ꢀspiro barbiturates 6aꢀe.
Synthesis
of
(S*,S*)ꢀ1ꢀmethylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ
1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (4a). 0.72 г (2 ммоль) of 1ꢀmethylꢀ5ꢀ[1ꢀ
(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hehahydroꢀ2,4,6ꢀpyrimidinetrione (5a) was dissolved in
о
water (20 ml) and stirred at 90 С 3 h. Then the reaction mixture was stirred under reflux for 4 h.
Then the mixture was cooled for 20
ethanol 25% and dried in air at a room temperature to give 0.70 g (97%) of compound 6a as paleꢀ
yellow acicular crystals, m.p. 301 С; [Found: С 53.29, Н 4.50, N 15.52. C16H16N4O6 requires
°С, the precipitate was filtered out, washed with aqueous
°
С 53.33, Н 4.48, N 15.56%]; δН (500 MHz, DMSOꢀd6) 11.55 (1Н, s, NH), 7.95 (1Н, dd, J 8.5, 2.2
Hz, Harom), 7.82 (1Н, d, J 2.2 Hz, Harom), 6.95 (1Н, d, J 8.5 Hz, Harom), 4.07 + 3.80 + 3.77 + 3.56
(1Н+1Н+1Н+1Н, m + m + m + m, ОCHaHb+NCHaHb), 3.93 (1Н, dd, J 9.5, 4.6 Hz, NCH), 3.35ꢀ
3.23 (4Н, m, CH2Ar+ОCH2), 3.20 (3Н, s, NMe); δC (200 MHz, DMSOꢀd6) 170.15, 167.44, 150,17,
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.
The same method was used to synthesize:
(
S*,S*)ꢀ1ꢀmethylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'
hexahydroꢀ2ꢀthiaꢀ4aꢀphenanthrene) (4b). From 1ꢀmethylꢀ5ꢀarylidene barbiturate (5b) as yellow
prismatic crystals, m.p. 278ꢀ279 С; [Found: С 51.09, Н 4.26, N 14.85. C16H16N4O5S requires С
ꢀ
°
51.06, Н 4.28, N 14.89%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.51 (1Н, s, NH), 7.97 (1Н, d, J
2.0 Hz, Harom), 7.94 (1Н, dd, J 8.9, 2.0 Hz, Harom), 6.98 (1Н, d, J 8.9 Hz, Harom), 4.50 + 3.60
(1Н+1Н, m + m, J1 13.1 Hz, NCHaHb), 4.30 (1Н, dd, J 10.4 Hz, NCH), 3.44 + 2.98 (1H + 1H, d+d,
J 17.2 Hz, CH2Ar), 3.03 (3Н, s, NMe), 2.77 + 2.36 (1Н+1Н, m + m, J1 13.5 Hz, SCHaHb), 2.62 +
2.19 (1Н+1Н, d.d + d.d, J1 13.3 Hz, SCHaHb); δC (200 MHz, DMSOꢀd6) 169.82, 168.88, 151.06,
148.15, 137.65, 124.85, 123.73, 122.85, 112.59, 62.20, 52.91, 51.26, 28.34, 27.19, 26.34, 22.95.
(S*,S*)ꢀ1ꢀEthylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀ
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hexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (4c). From 1ꢀethylꢀ5ꢀarylidene barbiturate (5c) as yellow
crystals, m.p. 287ꢀ288 С; [Found: С 54.59, Н 4.87, N 14.94. C17H18N4O6 requires С 54.54, Н 4.85,
°
N 14.97%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.74 (1Н, s, NH), 7.99 (1Н, dd, J 8.6, 2.2 Hz,
Harom), 7.84 (1Н, d, J 2.2 Hz, Harom), 7.03 (1Н, d, J 8.6 Hz, Harom), 4.09 + 3.82 + 3.74 + 3.43
(1Н+1Н+1Н+1Н, m + m + m + m, 2 ОCHaHb), 3.90 (1Н, dd, J 11.9, 3.3 Hz, NCH), 3.67 (2Н, q, J
6.7 Hz, NCH2), 3.38 + 3.20 (1Н + 1H, d+d, J 16.2, ArCHaHb), 3.22 (2Н, m, NCHaHb), 1.03 (3Н, t,
J 6.7 Hz, CH3); δC (200 MHz, DMSOꢀd6) 170.00, 167.67, 150,38, 150.16, 137.29, 124.53, 124.03,
121.27, 111.66, 66.22, 66.00, 58.49, 48.88, 46.67, 36.12, 34.35, 13.31.
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(S*,S*)-1ꢀ
hexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (4d). From 1ꢀ nꢀpropylꢀ5ꢀarylidene barbiturate (5d) as yellow
crystals, m.p. 247ꢀ248 С; [Found: С 55.62, Н 5.20, N 14.38 C18H20N4O6 required С 55.67, Н 5.19,
nꢀPropylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀ
°
N 14.43%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.73 (1Н, s, NH), 7.96 (1Н, dd, J 8.6, 2.4 Hz,
Harom), 7.81 (1Н, d, J 2.4 Hz, Harom), 7.02 (1Н, d, J 8.6 Hz, Harom), 4.07 (1H, m, J 13.0 Hz, OCHH),
3.90 (1H, dd, J 11.2, 2.5 Hz NCH), 3.84 (1H, dd, J 10.1, 2.8 Hz, OCHH), 3.70 (1H, m, OCHH),
3.59 (2H, t, J 6.7 Hz NCH2), 3.37 + 3.20 (1Н + 1H, d+d, J 16.1, ArCHaHb), 3.19 (2Н, m, NCHaHb),
1.46 (2H, m, CH3CH2), 0.80 (3Н, t, J 6.7 Hz, CH3); δC (200 MHz, DMSOꢀd6) 170.01, 167.79,
150,34, 150.25, 137.29, 124.53, 124.06, 121.13, 111.59, 66.24, 66.02, 58.34, 48.88, 46.62, 42.49,
34.66, 21.11, 11.55.
(S*,S*)ꢀ1ꢀAllylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀ
hexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (4e). From 1ꢀallylꢀ5ꢀarylidene barbiturate (5e) as yellow
crystals, m.p. 240ꢀ241
N 14.50%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.61 (1H, s, NH), 7.95 (1Н, dd, J 8.6, 2.4 Hz,
arom), 7.84 (1Н, d, J 2.4 Hz, Harom), 6.94 (1Н, d, J 8.6 Hz, Harom), 5.83 (1H, m, =CH), 5.18 (2H, m,
°С; [Found: С 55.99, Н 4.68, N 14.48. C18H18N4O6 required С 55.96, Н 4.70,
H
=CH2), 4.38 (2H, d, J 5.8 Hz, NCH2CH=), 3.89 (1H, m, J 13.1 Hz, OCHH), 3.89 (1H, dd, J 12.1,
2.5 Hz NCH), 4.09 + 3.82 + 3.74 + 3.43 (1Н+1Н+1Н+1Н, m + m + m + m, 2 ОCHaHb), 3.90 (1Н,
dd, J 11.9, 3.3 Hz, NCH), 3.73 (1H, m, J 11.1 Hz, OCHH), 3.40 + 3.24 (1Н + 1H, d+d, J 16.1,
ArCHaHb), 3.20 (2Н, m, NCH2); δC (200 MHz, DMSOꢀd6) 170.01, 167.63, 150,31, 150.03, 137.33,
132.62, 124.62, 124.08, 123.00, 117.25, 111.62, 66.29, 66.00, 58.48, 49.08, 46.72, 43.49, 34.75.
General Method B – the procedure for the synthesis of 5ꢀspiro barbiturates 6fꢀi.
Synthesis
of
(S*,S*)ꢀ1ꢀbuthylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ
1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (6f). 20 ml of water was added
to 0.99 g (2 mmol) 1ꢀbuthylꢀ5ꢀ[1ꢀ(2ꢀmorpholinoꢀ4ꢀnitrophenyl)methylidene]hexahydroꢀ2,4,6ꢀ
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pyrimidinetrione (5a) and the mixture was stirred at 60 С for 4 hrs. Then the temperature was
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increased to 70 С and further to 100 С at a heating rate of 5 С/hr under constant stirring. The
reaction mixture was boiled for 4 h. Then the mixture was cooled to 20 С, the precipitate was
filtered out, washed with aqueous ethanol 25% and dried in air at room temperature to give 0.70 g
(97%) of compound 6f as yellow crystals, m.p. 209ꢀ210 С; [Found: С 56.66, Н 5.49, N 13.88.
°
°
C19H22N4O6 required С 56.71, Н 5.51, N 13.92%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.63 (1Н,
s, NH), 7.95 (1Н, dd, J 8.6, 2.4 Hz, Harom), 7.80 (1Н, d, J 2.4 Hz, Harom), 7.02 (1Н, d, J 8.6 Hz,
Harom), 4.09 (1H, m, J 12.6 Hz, OCHH), 3.90 (1H, m, J 12.5 Hz, OCHH), 3.85 (1H, dd, J 11.1, 2.5
Hz NCH), 3.71 (3H, m, NCH2 + OCHH), 3.46 (1H, m, J 12.6 Hz, OCHH), 3.39 + 3.22 (1Н + 1H,
d+d, J 16.5, ArCHaHb), 1.46 (2H, m, CH3CH2CH2), 1.28 (2H, m, CH3CH2), 0.88 (3Н, t, J 6.7 Hz,
CH3); δC (200 MHz, DMSOꢀd6) 170.30, 167.71, 150.28, 150.20, 137.33, 124.59, 124.08, 121.11,
111.66, 66.27, 65.96, 58.54, 49.08, 46.76, 41.25, 34.63, 29.81, 19.98, 14.07.
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The same method was used to synthesize:
(S*,S*)ꢀ1ꢀ
hexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (6g). From 1ꢀiꢀpropylꢀ5ꢀarylidene barbiturate (5f) as yellow
crystals, m.p. 218ꢀ219 С; [Found: С 55.69, Н 5.21, N 14.36 C18H20N4O6 required С 55.67, Н 5.19,
iꢀPropylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀ
°
N 14.43%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.64 (1Н, s, NH), 7.94 (1Н, dd, J 8.1, 2.4 Hz,
Harom), 7.84 (1Н, d, J 2.4 Hz, Harom), 6.98 (1Н, d, J 8.1 Hz, Harom), 4.78 (1H, m, CHMe2), 4.07 (1H,
m, J 12.7 Hz, OCHH), 3.92 (1H, dd, J 11.3, 2.4 Hz NCH), 3.76 (2H, m, OCH2), 3.51 (1H, m,
NCHH), 3.28 (4H, m, ArCH2 + NCHH + OCHH), 1.34 + 1.31 (3H + 3H, d+d, J 6.9 Hz,
CH3CHCH3); δC (200 MHz, DMSOꢀd6): 169.86, 168.17, 150.29, 150.17, 137.39, 124.52, 123.96,
121.54, 111.76, 66.25, 65.98, 58.47, 49.48, 46.83, 45.96, 34.26, 19.83, 19.60.
(S*,S*)ꢀ1ꢀBenzylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀ
hexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (6h). From 1ꢀbenzylꢀ5ꢀarylidene barbiturate (5h) as yellow
crystals, m.p. 216ꢀ217 °С; [Found: 60.43, Н 4.66, N 12.81 C22H20N4O6 required С 60.55, Н 4.62, N
12.84%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.95 (1H, s, NH), 7.96 (1Н, dd, J 8.2, 2.4 Hz, Harom),
7.83 (1Н, d, J 2.4 Hz, Harom), 7.26 (6Н, m, 6 Harom), 7.02 (1Н, d, J 8.2 Hz, Harom), 4.84 (2H, ABꢀ
system, J 14.6 Hz, ArHaHbN), 4.07 (1H, m, J 12.4 Hz, OCHH), 3.87 (2H, m, OCHH + NCH), 3.67
(1H, m, J 11.3 Hz, NCHH), 3.41 + 3.24 (1Н + 1H, d+d, J 16.4, NCHaHbAr), 3.32 (1H, m, J 12.5,
OCHH), 3.20 (1H, m, J 11.7, OCHH), 3.10 (1H, m, J 10.8, NCHH), δC (200 MHz, DMSOꢀd6):
170.35, 167.82, 150.53, 150.29, 137.41, 136.96, 128.76, 128.10, 127.87, 124.62, 124.05, 121.19,
111.70, 66.19, 65.95, 58.64, 49.22, 46.82, 44.61, 34.77.
(S*,S*)ꢀ1ꢀ(2ꢀPhenylethyl)ꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ
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1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene) (6i). From 1ꢀ(2ꢀphenylethyl)ꢀ5ꢀarylidene
barbiturate (5i) as yellow crystals, m.p. 255ꢀ256 С; [Found: 60.43, Н 4.66, N 12.81 C22H20N4O6
°
requires С 60.55, Н 4.62, N 12.84%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.83 (1H, s, NH), 7.96
(1Н, dd, J 8.2, 2.4 Hz, Harom), 7.77 (1Н, d, J 2.4 Hz, Harom), 7.26 (6Н, m, 6 Harom), 6.91 (1Н, d, J 8.2
Hz, Harom), 4.90 + 4.83 (!H + 1H, d+d, J 13.7 Hz, ArHaHbN), 3.98 (1H, m, J 12.4 Hz, OCHH), 3.87
(1H, dd, J 11.2, 2.6 Hz NCH), 3.75 (1H, m, J 12.0 Hz, OCHH), 3.67 (1H, m, NCHH), 3.28 (4H, m,
ArCHH + OCHH), 3.07 (1H, m, NCHH), δC (200 MHz, DMSOꢀd6): [Found: С 61.41, Н 4.90, N
12.42. C23H22N4O6 requires С 61.33, Н 4.92, N 12.44%]; δН 1Н NMR (500 MHz, DMSOꢀd6): 11.90
(1H, s, NH), 7.95 (1Н, dd, J 8.3, 2.3 Hz, Harom), 7.81 (1Н, d, J 2.3 Hz, Harom), 7.24 (6Н, m, 6 Harom),
7.03 (1Н, d, J 8.3 Hz, Harom), 4.06 (1H, m, J 12.5 Hz, OCHH), 3.88 (4Н, m, NCH + NCH2CH2 +
OCHH), 3.61 (1H, m, J 12.3 Hz, NCHH), 3.39 (1H, m, J 11.1 Hz, NCHH), 3.32 + 3.19 (1Н + 1H,
d+d, J 16.2, ArCHaHb), 3.16 (1H, m, OCHH), 2.97 (1H, m, J 11.2, NCHH), 2.79 (2Н, t, J 6.8 Hz,
NCH2CH2); δC (200 MHz, DMSOꢀd6): 170.22, 167.81, 150.15, 150.01, 138.84, 137.56, 129.01,
128.76, 126.76, 124.63, 123.92, 120.91, 111.49, 67.17, 66.99, 58.16, 48.83, 46.49, 42.22, 34.84,
33.76.
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Method C – the procedure for the synthesis of a diastereomeric mixture ((
1ꢀalkylꢀ2,4,6ꢀtrioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀ
oxaꢀ4 ꢀphenanthrene)s (6).
S*,S*)ꢀ and (S*,R*)ꢀ
a
Synthesis of the mixture of (S*,S*)ꢀ and (S*,R*)ꢀ diastereomers of 1ꢀmethylꢀ2,4,6ꢀ
trioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀoxaꢀ4aꢀ
phenanthrene) 6a (Table 1). 2 mmol (0.72 g) of 1ꢀmethylꢀ5ꢀarylidene barbiturate 5a was dissolved
o
in dimethylacetamide 7 ml and heated at 100 C for 4 h. After cooling, the reaction mixture was
diluted by 50 ml of water. A precipitate was filtered out, washed with 50% ethanol and dried in air
to give compound 6a as a mixture of (S*,S*)ꢀ and (S*,R*)ꢀdiastereomers, paleꢀyellow acicular
crystals, m.p. 299ꢀ300 °С; [Found: С 53.20, Н 4.57, N 15.36. C16H16N4O5 requires С 53.33, Н 4.48,
N 15.56%]; δН (500 MHz, DMSOꢀd6) 11.74 and 11.55 (0.5Н+0.5Н, s+s, NH (S*,S* and S*,R*)),
7.95 (1Н, dd, J 9.5, 2.4 Hz, Harom), 7.82 (1Н, d, J 2.4 Hz, Harom), 6.95 (1Н, d, J 9.5 Hz, Harom), 4.07
+ 3.75 + 3.56 (1Н+2Н+1Н, m+m+m, ОCHaHb+NCHaHb), 3.93 (1Н, m, NCH), 3.35ꢀ3.18 (4Н, m,
CH2Ar+ОCH2), 3.20 and 3.10 (1.5Н+1.5Н, s+s, NMe, S*,S* and S*,R*).
Synthesis
of
the
diastereomeric
mixtures
of
other
1ꢀalkylꢀ2,4,6ꢀ
trioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀoxaꢀ4aꢀphenanthrene)
derivatives (6) were carried out similarly from respective 1ꢀalkyl 5ꢀarylidene barbiturates in
dimethlyacetamide solution. Yields 95ꢀ97%. Ratio of diastereomers in mixtures ca. 1:1.
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Method
D
–
the procedure for the synthesis of
(S*,S*)ꢀ1ꢀmethylꢀ2,4,6ꢀ
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trioxospiro(perhydropyrimidinoꢀ5,5'ꢀ(8'ꢀnitroꢀ1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀoxaꢀ4
phenanthrene) (6a) (Table 1) in the solid phase. 1 mmol (0.36 g) of 1ꢀmethylꢀ5ꢀarylidene
barbiturate 5a were kept in a sealed ampoule at 100 С for 15 days. A substance was washed with
ethanol, chloroform and dried in air to give a mixture of (S*,S*)ꢀ and (S*,R*)ꢀdiastereomers 6a (see
Table 1) as yellow powder, m.p. 293ꢀ293 С.
aꢀ
°
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■
RESULTS AND DISCUSSION
As it has been established, the isomerization of 5ꢀnitrobenzylidene barbiturates (5aꢀi) under
conditions typically applied (viz. heating of solutions in organic solvents, such as AcOH, EtOH,
DMF) proceeds non stereoselectively giving rise to respective spirocyclic derivatives (6aꢀi) as a
mixture of (S*,S*) and (S*,R*) diastereomers in a nearly 1:1 ratio.
Under alternative conditions, upon heating polycrystalline powder of 5a in water (Procedure
A, see Experimental section) we found that the spirocyclic product 6a (Scheme 3) is afforded in an
excellent yield as a nearly pure (S*,S*)ꢀdiastereomer (>99%, Table 1). This is indeed surprising
since no successful example of tuning stereoselectivity of a Tꢀreaction by external conditions has
been reported so far.
Figure 1. Molecular structure of 6a (S*,S*).
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The relative configuration of compound 6a was reliably established by Xꢀray crystalloꢀ
graphic analysis (its molecular structure is depicted in Figure 1), and its diastereomeric purity was
determined by 1H NMR using the intensity ratio of peaks attributed to NH protons.19
It is well known that (S*,S*)ꢀ and (S*,R*)ꢀdiasteromers of 5ꢀspiro barbituric acid derivatives
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are characterized by distinctly different positions of signals of NH protons that makes H NMR
spectroscopy a very straightforward technique to assess diasteromeric purity of such compounds.19
The surprising diastereospecificity of our new approach to the isomerization of 5a is
explained by the fact that the reaction proceeds in the heterogeneous mode since both the reactant
and product are virtually insoluble in water. To our best knowledge, such an approach to Tꢀreactions
has not been attempted so far although it is known that isomerizations can be accomplished in the
solid state without any solvent.7,19 In particular, we19 synthesized the spirocyclic product 6a by
heating 5a as a dry powder but the reaction was very slow (72 h at 120 °С, which is roughly 200
times more slowly than in solutions) and characterized by a low stereoselectivity giving rise to a
mixture of (S*,S*)ꢀ and (S*,R*)ꢀdiastereomers in a 3:1 ratio. As a part of this work, we performed
an analogous experiment on the isomerization of dry 5a under less harsh conditions (100 °С,
Procedure D, see Experimental section) but the reaction decelerated a lot (a 90% conversion was
achieved within 15 days) and no significant improvement in the diastereomeric purity of 6а was
achieved (Table 1).
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In the case of the new method, despite the heterogeneous character, the Тꢀreaction proceeds
nearly as fast as in solutions. Indeed, the heterophase isomerization of 5a upon heating to 100 °С in
water (Procedure A, see Experimental section) takes 3 hrs, whereas it requires 2 hrs at the same
temperature in acetic solutions. But, as it has been mentioned before, the Tꢀreaction with 5a in
solution proceeds nonꢀstereospecifically, whereas the diastereoslectivity of the heterophase reaction
is virtually 100%.
Therefore, the use of a twoꢀphase system involving water and crystalline reactant 5а has
proven to be ultimately efficient in term of both reaction rate and stereospecificity. The
implementation of this method is also very simple since only water is used as a solvent and the
product afforded does not require any additional purification.
The heterophase rearrangement of (5b) that can be regarded as a thia analogue of 1ꢀmethylꢀ5ꢀ
arylidenebarbiturates 5a (Procedure A, see Experimental section) afforded the spirocyclic derivative
(6b, (S*,S*) with a diastereomeric purity of 93 % (Table 1).
A
more detailed investigation into rearrangements of 1ꢀalkylsubstituted 5ꢀ
arylidenebarbiturates 5cꢀi into respective spirocyclic derivatives (6aꢀi) demonstrated that the
heterophase Тꢀreactions always proceed stereoselectively giving rise to predominance of the (S*,S*)
diastereomers (Table 1). Especially high diastereomeric purities were achieved provided that both
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reactant and product remained solid throughout the reaction process. The diastereoselectivity
degraded a lot if the reaction mass underwent melting or coagulation of powder grains.
Compounds 5aꢀe survived boiling in water and remained crystalline so as is was possible to
о
accomplish the isomerization at 100 С (Procedure A, see Experimental section) and afford the
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respective spirocyclic derivatives (6aꢀe) as highly pure (S*,S*)ꢀdiastereomers (Table 1).
In the case of 1ꢀbutyl 5ꢀarylidenebarbiturate 5f, temperature 100 оС appears to be too high for
the initial stage of the reaction, since the precipitate starts to coagulate within approximately
0.5 h of stirring in boiling water. In order to avoid that we started the heterophase isomerization of
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5f at a lower temperature and gradually increased it to 100 С in the course of the reaction
(Procedure B, see Experimental section). As a result, the spirocyclic derivative 6f was afforded with
a diastereomeric purity of 99 %.
A similar stepwise temperature increase was used to isomerize 1ꢀisopropylꢀ (5g), 1ꢀbenzylꢀ
(5h), and 2ꢀphenylethyl (5i) 5ꢀarylidenebarbiturates to afford the respective spirocyclic derivatives
(6g) and (6h) with diastereomeric purities above 90 % (Table 1).
Despite deliberate adjustment of the temperature regime we were unable to completely
suppress coagulation of powder particles in the course of isomerization of 1ꢀiꢀpropylꢀ5ꢀ
arylidenebarbiturate (5g). That is why the diastereomeric purity of spirocyclic product (6g) was
lower than for other analogues.
Taking into account the results obtained it would be reasonable to suggest that the high
stereoselectivity of the Тꢀreactions under heterophase conditions is due to the fact that the primary
reaction proceeds at the interface between the crystals of starting 5ꢀarylidenebarbiturates 5 and
water. Typically, several reactive conformations coexist in equilibrium in solutions but only one of
them can be stabilized in the crystal structure. To get insight into this problem we grown single
crystals of 1ꢀnꢀbutylꢀ[5ꢀnitroꢀ2ꢀ(Nꢀmorpholino)benzylidene]barbituric acid 5f and of its
rearrangement product, spirocyclic derivative 6f and determined their structure by Xꢀray diffraction
analysis (Table 2). The molecular structures of above compounds are depicted in Figures 2 and 3.
First of all, it is clearly seen that molecules of 1ꢀnꢀbutyl 5ꢀenzylidenebarbiturate 5f are present
in the crystal exclusively as (E)ꢀisomers although two (E)ꢀ and (Z)ꢀisomers relative to the double
С=С bond are possible. Similarly, as it has been found before19, only one (E)ꢀisomer is present in
the
crystal
structure
of
another
related
compound,
1ꢀtertꢀbutylꢀ[5ꢀnitroꢀ2ꢀ(Nꢀ
morpholino)benzylidene]barbituric acid. Apparently, (E)ꢀisomers of similar compounds are
energetically favorable in crystals with respect to (Z)ꢀisomers. Indeed, in the crystal, the (E)ꢀisomers
of 5f are additionally stabilized by the extended system of intermolecular hydrogen bonds. As it can
be seen from Figure 4, the molecules of 5f form the zigzagꢀlike chains towards [1 01] by the strong
intermolecular NꢀH...O hydrogen bonds (Table 3).
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Figure 2. Molecular structure of 5f (the structureꢀ forming СꢀН…π contact is shown as dashed line)
Figure 3. Molecular structure of 6f (S*,S*)
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Figure 4. A portion of crystal packing of 5f demonstrating the zigzagꢀlike Hꢀbonded chains along the
direction [1 01] (two projections are shown). The strong intermolecular NꢀH...O hydrogen bonds are drawn
by dashed lines.
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Table 3. Intermolecular hydrogen bonds (Å and deg.) for 5f.
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7
8
D*ꢀH...A*
d(DꢀH)
d(H...A)
d(D...A)
∠(DꢀH...A)
9
N3ꢀH3...O7a
0.90(2)
0.95
1.93(2)
2.43
2.824(3)
3.130(3)
3.259(3)
171.8(14)
130.0
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C14ꢀH14...O2b
C21ꢀH21B...O6c
0.99
2.32
158.5
*D – proton donor; A – proton acceptor.
Symmetry transformation used to generate equivalent atoms:
: (xꢀ0.5, ꢀy+1.5, z+0.5); : (x+1, y, z); : (ꢀx+1.5, yꢀ0.5, ꢀz+1.5).
a
b
c
________________________________________________________________________________
Further, the zigzagꢀlike chains are linked by the intermolecular CꢀH...O hydrogen bonds
(Figure 4, Table 3) into threeꢀdimensional framework.
1
Meanwhile, according to Н NMR spectroscopy, both (E)ꢀ and (Z)ꢀisomers of 1ꢀalkyl 5ꢀ
benzylidenebarbiturates 5 occur in solutions in nearly equal proportions due to the fast reversible
isomerization around the С=С bond.
Secondly, a relatively short intramolecular СꢀН…π (C=C) contact between the hydrogen atom
of ꢀCH2ꢀN group and the exocyclic carbon atom of the vinyl fragment is of note in the crystal
structure of 5ꢀbenzylidenebarbiturate 5f. The respective H…C interatomic distance is only 2.31 Å.
We reported on similar СꢀН…π
contacts in crystal structures of related compounds earlier10,19, but
in the present case, this specific interaction plays a special role hindering the free rotation within the
molecule and fixing a unique conformation of 5f with the morpholine ring tilted towards the NH
group and away from the nꢀbutyl group. Importantly, exactly the same mutual arrangement of
groups is observed in the actual reaction product, (S*,S*)ꢀdiastereomer 6f, whereas the opposite
orientation is realized in the (S*,R*)ꢀdiastereomer. Therefore, we may conlcude that the initial
molecular conformation of 5f in the crystal state is prone to rearrangement exactly into (S*,S*)ꢀ
rather than (S*,R*)ꢀdiastereomer of 6f.
This conclusion fully corresponds to currently adopted common mechanism of such
reactions1. It is believed that the Тꢀreaction in 5 started with the intramolecular transfer of hydrideꢀ
ion from the αꢀalkylamino group to the vinyl carbon atom with the formation of a zwitterꢀionic
intermediate 7 (Scheme 4). The detachment of a hydrideꢀion is promoted by the nonꢀtypically
strong СꢀН…
π
interaction observed in 5ꢀ(оꢀdialkylamino)arylidene derivatives of barbituric acid.10
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Scheme 4. The currently adopted mechanism of the Tꢀreaction.
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5
O
O
O
N+
N+
O
H
N
6
7
O
O
H
O
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9
N
N
N
(S*S*)
6
R
O
N
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H
+
O
N
H
H
O
R
O
O
5
7
Further, the intermediate 7 undergoes cyclization into the final spirocyclic derivative 6. The
cyclization is characterized by nearly zero energy barrier and apparently proceeds too fast for the
molecule to change its initial conformation with a specific mutual orientation of moieties, which
explains the reaction stereoselectivity. Probably, interface water present in the heterophase process
also plays an important role stabilizing the zwitterꢀion 7 by its specific hydration at the crystal
surface.
In total contrast, different conformations of 5 coexist in equilibrium in solutions and thus its
rearrangement affords (S*,S*)ꢀ and (S*,R*)ꢀdiastereomers of 6 with equal probabilities.
■
CONCLUSIONS
A new efficient approach to stereodirected Тꢀreactions is proposed, which is based on the
heterophase isomerization of 1ꢀalkylꢀ5ꢀ(2ꢀmorpholinꢀ4ꢀylꢀ5ꢀnitrobenzylidene)barbiturates 5aꢀi
conformationally confined in the crystal state. Spirocyclic derivatives of barbituric acid 6aꢀi were
successfully synthesized by this method in the diastereomerically pure (S*,S*)ꢀform. We believe
that the application of the method to other types of Tꢀreactions will extend their synthetic potential
as stereodirected rearrangements.
■
ASSOCIATED CONTENT
Supporting Information
Crystallographic information files. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Authors
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*(K.A.K.) Eꢀmail: krasnov_tox@mail.ru.
*(V.N.K.) Eꢀmail: vkh@xray.ineos.ac.ru.
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Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGEMENTS
The authors thank the Russian Academy of Sciences in the framework of the program “Theoretical
and experimental study of chemical bonding and mechanisms of chemical reactions and processes”
for partial financial support of this work.
■
REFERENCES
(1) MethꢀCohn, O. Adv. Heterocycl. Chem. 1996, 65, 1‒37.
(2) Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S. J. Org. Chem. 1984, 49, 269‒276.
(3) Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N. Synthesis 1987, 7, 641‒645.
(4) Sherry, D.; Thomasco, L. M.; Toogood, P. L. WO Patent 031195, 2004.
(5) Tverdokhlebov, A. V.; Gorulya, A. P.; Tolmachev, A. A.; Kostyuk, A. N.; Chernega, A. N.;
Rusanov, E. B. Tetrahedron 2006, 62, 9146‒9152.
(6) Gorulya, A. P.; Tverdokhlebov, A. V.; Tolmachev, A. A.; Shishkin, O. V.; Shishkina, S. V.;
Tetrahedron 2011, 67, 1030‒1035.
(7) Kaval, N.; HalaszꢀDajka, B.; VoꢀThanh, G.; Dehaen, W.; Van der Eycken, J.; Mátyus, P.;
Loupy, A.; Van der Eycken, E. Tetrahedron 2005, 61, 9052‒9057.
(8) Dunkel, P.; Túrós, G.; Bényei, A.; Ludányi, K.; Mátyus, P. Tetrahedron 2010, 66, 2331‒2339.
(9) Krasnov, K. A.; Kartsev, V. G. Russ. J. Org. Chem. 2005, 41, 920‒925.
(10) Krasnov, K. A.; Kartsev, V. G.; Khrustalev, V. N. Mendeleev Commun. 2006, 1, 52‒54.
(11) D’yachenko, E. V.; Glukhareva, T. V.; Nikolaeva, E. F.; Tkachev, A. V.; Morzherin, Yu.
Yu. Russ. Chem. Bull. 2004, 53, 1240‒1247.
(12) Krasnov, K. A.; Kartsev, V. G. in The Chemistry and Biological Activity of Synthetic and
Natural Compounds. NitrogenꢀContaining Heterocycles, Ed. by Kartsev V. G., Moscow, ICSPF
Press 2006, 1, 76.
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(13) Nijhuis, W. H. N.; Verboom, W.; ElꢀFadl, A. A.; Harkema, S.; Reinhoudt, D. N. J. Org.
Chem. 1989, 54, 199‒209.
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(14) Nijhuis, W. H. N.; Verboom, W.; ElꢀFadl, A. A.; van Hummel, G. J.; Reinhoudt, D. N. J.
Org. Chem. 1989, 54, 209‒216.
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(15) Deeva, E. V.; Glukhareva, T. V.; Tkachev, A. V.; Morzherin, Yu. Yu. Mendeleev Commun.
2006, 16, 82‒83.
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(16) Krasnov, K. A.; Kartsev, V. G. Heterocycles 2007, 71, 19‒25.
(17) Rabong, C.; Valla, C.; Kartsev, V. G.; Jordis, U. Mendeleev Commun. 2007, 17, 318‒320.
(18) Rabong, C.; Hametner, C.; Jordis, U.; Mereiter, K.; Kartsev, V. G. Heterocycles 2008, 75,
799‒838.
(19) Krasnov, K. A.; Kartsev, V. G.; Khrustalev, V. N. Tetrahedron 2010, 66, 6054‒6061.
(20) Stein, A.; Gregor, M. P.; Spoerri, P. E. J. Am. Chem. Soc. 1956, 78, 6185‒6188.
(21) Sheldrick, G. M. SADABS, v. 2.03, Bruker/Siemens Area Detector Absorption Correction
Program, Bruker AXS, Madison, Wisconsin, 2003.
(22) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112‒122.
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Diastereoselective Tꢀreaction of 1ꢀalkylꢀ(5ꢀnitroꢀ2ꢀNꢀmorpholinoꢀbenzyliden)barbituric acids
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in the solid state: synthesis of 1ꢀalkylꢀ2,4,6ꢀtrioxoperhydropyrimidinoꢀ5ꢀspiroꢀ5'ꢀ(8'ꢀnitroꢀ
1',3',4',9',10',10а'ꢀhexahydroꢀ2ꢀoxa)ꢀ4aꢀphenanthrenes and their thia analogues
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Konstantin A. Krasnov, Victor N. Khrustalev
A new efficient approach to stereodirected Тꢀreactions is proposed, which is based on the
heterophase isomerization of 1ꢀalkylꢀ5ꢀ(2ꢀmorpholinꢀ4ꢀylꢀ5ꢀnitrobenzylidene)barbiturates 5aꢀi
conformationally confined in the crystal state. Spirocyclic derivatives of barbituric acid 6aꢀi were
successfully synthesized by this method in the diastereomerically pure (S*,S*)ꢀform. It has been
demonstrated by Xꢀray diffraction study that this diastereoselectivity of the solid state Tꢀreaction is
due to peculiar crystal structure of starting 5ꢀarylidene barbiturates, which accommodates only one
specific conformation fixed by a strong intramolecular CꢀH…π interaction.
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