A simple synthesis of aplysinopsin analogues by dimethylamine substitution in N,N-(dimethylamino)methylidene derivatives of five-membered heterocycles

Article abstract of DOI:10.1016/S0040-4020(01)00838-9

Some new aplysinopsin analogues were prepared by a simple coupling of N,N-(dimethylamino)methylidene substituted hydantoin, thiohydantoin, and thiazolone derivatives, with indole derivatives. Configuration around the exocyclic C=C double bond was determined on the basis of long-range heteronuclear coupling constants using 2D HMBC correlation technique.

Full text of DOI:10.1016/S0040-4020(01)00838-9

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 8395±8403
A simple synthesis of aplysinopsin analogues by dimethylamine
substitution in N,N-ꢀdimethylamino)methylidene derivatives of
®ve-membered heterocycles
p
Renata Jakse, Simon Recnik, Jurij Svete, Amalija Golobic, Ljubo Golic and Branko Stanovnik
p
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Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O. Box 537, 1000 Ljubljana, Slovenia
Received 5 June 2001; revised 16July 2001; accepted 8 August 2001
AbstractÐSome new aplysinopsin analogues were prepared by a simple coupling of N,N-)dimethylamino)methylidene substituted
hydantoin, thiohydantoin, and thiazolone derivatives, with indole derivatives. Con®guration around the exocyclic CvC double bond was
determined on the basis of long-range heteronuclear coupling constants using 2D HMBC correlation technique. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
novel and stereoselective synthetic approaches towards
aplysinopsins have been developed: )a) a three-step
synthesis from alkyl 3-dimethylamino-2-[)2,2-disubstituted
1-vinyl)amino]propenoates and, )b) a one-step synthesis
from 5-[)dimethylamino)methylidene]hydantoin deriva-
tives and analogues.13 In this manner, aplysinopsins, thio-
aplysinopsins, and analogues in which the hydantoin
moiety is replaced with 1,4,5,6-tetrahydro-1,2,4-)1H,4H)-
Since their isolation from various marine organisms,1±6
aplysinopsins )1) )Fig. 1) have attracted considerable
interest, especially due to their cytotoxicity towards
cancer cells3 and their ability to affect neurotransmitters.2
Synthetic routes towards aplysinopsins are generally
based on two approaches: )a) condensation reaction
between the 3-formylindole derivative and a suitable
hydantoin derivative4±7 and )b) condensation reaction
between the 3-formylindole derivative and ethyl azido-
acetate to give the corresponding 2-azido-3-)indol-3-yl)pro-
penoate, followed by tandem Staudinger/aza-Wittig
reaction and subsequent cyclisation.8,9
triazin-6-one
and
2,4,6-)1H,3H,5H)-pyrimidinetrione
have been prepared )Fig. 1).13,14 As an extension of our
work in this ®eld, we now report the synthesis and
structural characterisation of some novel aplysinopsin
analogues.
Recently, a series of alkyl 2-substituted 3-)dimethylamino)-
propenoates have been prepared as versatile reagents for the
synthesis of various heterocyclic systems and fuctionalized
heterocycles, such as heteroaryl substituted a-amino- and
a-hydroxy acid derivatives.10±12 In this connection, two
2. Results and discussion
In this paper, we present further examples of formation of
aplysinopsin analogues by the procedure including
5-)dimethylamino)methylidene derivatives of some ®ve
Figure 1. R1, R2ˆH, Me; XˆO, NH; YˆH, Br.
Keywords: aplysinopsins; enamines; hydantoins; indoles; NMR.
Corresponding authors. Tel.: 1386-1-2419-100; fax: 1386-1-2419-220; e-mail: jurij.svete@uni-lj.si; branko.stanovnik@uni-lj.si
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00838-9

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R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8396
membered heterocycles, such as imidazolones, imidazo-
lethiones, and thiazolones as the key intermediates.
3-Substituted thiohydantoins )2-thiooxoimidazolidin-4-
ones) 2a±d were converted with tert-butoxy-bis)dimethyl-
amino)methane )Bredereck's reagent) into the correspond-
ing 5-[)dimethylamino)methylidene]-2-thiooxo-4-imidazolidi-
nones 3a±d in 57±83% yield, while with N,N-dimethyl-
formamide dimethyl acetal )DMFDMA) also methylation
at the exocyclic sulfur took place to give 5-[)dimethyl-
amino)methylidene]-3-substituted-2-)methylsulfanyl)-3H-
imidazol-4)5H)-ones 4a±d in 7±65% yield. Compound 3d
was transformed with DMFDMA into 4d, identical with the
compound prepared from 2d. 2-Amino-1,3-thiazol-4)5H)-
one )7) gave by treatment with Bredereck's reagent in
DMF 2-dimethylamino-5-[)dimethylamino)methylidene]-
1,3-thiazol-4)5H)-one )8) in 65% yield. Treatment of 5-
[)dimethylamino)methylidene]imidazole derivatives 3a±d,
4b,d with 2-methylindole in acetic acid in the presence of
small amounts of hydrogen bromide at room temperature
produced the corresponding 5-[)2-methyl-1H-indol-3-
yl)methylidene]imidazole derivatives 5a±d, 6b,d as thio-
aplysinopsin analogues in 15±79% yield. Methylation of
5d with DMFDMA took place at the sulfur atom to give
6d in 51% yield. Upon reaction of 8 with 2-methylindole,
2-)dimethylamino)-5-[)Z)-1-)2-methyl-1H-indol-3-yl)methyl-
idene]-1,3-thiazol-4)5H)-one )9) in the form of hydrobro-
mide salt was isolated in 48% yield. )Scheme 1).
1-Methylimidazolidine-2,4-dione )1-methylhydantoin) )10)
was transformed with tert-butoxy-bis)dimethylamino)-
methane into 5-[)dimethylamino)methylidene]-1-methyl-
imidazolidine-2,4-dione )11) in 54% yield, while with
DMFDMA also methylation occurred at the 3-position to
give the corresponding 1,3-dimethyl derivative )12) in 98%
yield. Compound 11 coupled with indole derivatives to give
5-[)1H-indol-3-yl)methylidene]-1-methylimidazolidine-
2,4-diones 13a±d in 38±81% yield. Similarly, treatment of
compound 12 with indole and 2-methylindole furnished the
corresponding 1,3-dimethyl derivatives 14a,b in 65 and
61% yield, respectively. )Scheme 2).
Scheme 1. )i) tert-BuOCH)NMe2)2, MeCN or DMF, re¯ux; )ii) DMFDMA, MeCN or DMF, re¯ux; )iii) 2-methylindole, AcOH, HBr, rt±508.

Ï
R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8397
Scheme 2. )i) tert-BuOCH)NMe2)2, MeCN, re¯ux; )ii) DMFDMA, MeCN, re¯ux; )iii) indole derivative, AcOH, re¯ux.
3. Structure determination: ꢀZ)- and/or ꢀE)-orientation
around the exocyclic double bond
nation of the con®gurations around the exocyclic CvC
double bonds in this study.
3.1. Structure of 5-[ꢀdimethylamino)methylidene]azol-4-
one derivatives 3, 4, 8, 11
Compounds 3±6, 8, 9, 11±14 can exist in )Z)- and/or )E)
isomeric forms with respect to the exocyclic CvC double
bond. Since most of these compounds exist as single
isomers, differentiation between )Z)- and )E)-form is not
possible on the basis of chemical shifts or J values.
However, the two isomeric forms can easily be differen-
tiated on the basis of the magnitude of the long-range
3
The long-range coupling constants, JC±H, between the
methylidene protons )H±C)50)) and the carbonyl carbon
atoms )OvC)4)) in compounds 3a, 4b,d, 8, 11 were
measured from the antiphase splitting of cross peaks in
the HMBC spectrum. In the case of compounds 3a, 4b,d,
8, the magnitude of coupling constants, 3JC±Hˆ2.7±3.9 Hz,
showed that these compounds exist in the )Z)-form, while
for compound 11, 3JC±Hˆ8.6Hz, the ) E)-con®guration was
established )Table 1).
3
heteronuclear 13C±1H coupling constants, JC±H, which
have been used for determination of conformations and
con®gurations in various systems.15±17 Several methods
3
for measuring JC±H, such as TOCSY-based methods18±20
and methods based on HMBC correlation techniques,21±26
have been described in the literature. Recently, the orienta-
tion around the double bond in alkyl 2,3-)diamino)propeno-
ates has been determined using the 2D HMBC method.27
3.2. Structure of aplysinopsin analogues 5, 6, 9, 13, 14
3
Generally, the magnitude of coupling constant JC±H for
Orientation around the exocyclic double bond was deter-
mined analogously as for compounds 3, 4, 8, 11 on the
basis of the long-range heteronuclear coupling constants,
3JC±H. Compounds 5d, 6d, 9, 13a, and 14a were obtained
in isomerically pure form. Thus, for compounds 5d, 6d, 9,
nuclei with cis-con®guration around the CvC double
bond is smaller )2±6Hz) than that for trans-oriented nuclei
)8±12 Hz).25,27,28 Similar coupling constants have also been
observed in some oxazolone derivatives with an analogous
structural element.29 For this reason, HMBC correlation
technique was selected as the most suitable for the determi-
3
the )Z)-con®guration, JC±Hˆ4.9±5.7 Hz, was established,
while for compounds 13a and 14a the )E)-con®guration,

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R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8398
Table 1. Con®gurations and 3JC±H coupling constants for compounds 3±6, 8, 9, 11, 13, 14
Compound
3JC±H )Hz)
Z or E
Compound
3JC±H )Hz)
Z or E
3.6
Z
8.6
E
3.1
2.7
3.9
5.1
Z
Z
Z
Z
10.9
10.2
5.4
E
E
Z
E
10.8
4.9
Z
11.0
E
5.7
Z
5.5
Z
3JC±Hˆ10.8±10.9 Hz, was determined )Table 1). The struc-
ture of 14a was con®rmed by X-ray analysis )Fig. 2, Table
1). On the other hand, compounds 13b and 14b were
4. Conclusion
Aplysinopsin analogues can be easily prepared by one-step
synthesis from indole derivatives by dimethylamine substi-
tution in substituted 5-[)dimethylamino)methylidene]azol-
4-ones such as imidazolidine-2,4-diones, 2-thiooxoimidazo-
lidin-4-ones, and 2-amino-5,6-dihydrothiazol-4-one, gener-
ally in good yields. The )Z)- and/or )E)-orientations around
the methylidene )exocyclic) double bond were determined
by 2D HMBC correlation technique, supported by NOE
effect and X-ray analysis. Total assignment of 13C signals
for compound 14b was achieved by means of HMQC,
HMBC and NOESY. In conclusion, indole derivatives,
3
obtained as mixtures of isomers with JC±Hˆ5.4±5.5 Hz
3
for the )Z)-isomers and with JC±Hˆ10.2±11.0 Hz for the
)E)-isomers )Table 1). In the case of compound 14b, both
isomers were separated by medium pressure liquid chroma-
tography )MPLC). Total assignment for H- and C-atoms in
the )E)-isomer of compound 14b has been done by means of
HMBC, HMQC, and NOESY techniques. Furthermore,
con®guration of the )E)-isomer of 14b was also con®rmed
by NOE-effect between the methylidene proton H±C)50)
and the Me±N)1) methyl group )Fig. 3).

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R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8399
²
with detection on silica gel )Merck, silica gel 40, 0.015±
0.035 mm); column dimensions )dry ®lled): 15£460 mm;
backpressure: 10±15 bar; detection: UV 254 nm.
3-Substituted-2-thiohydantoins 2a±d were prepared accord-
ing to the procedure described in the literature.30
5.2. General procedure for the preparation of 3-
substituted 5-[ꢀZ)-ꢀdimethylamino)methylidene]- 2-
thiooxoimidazolidin-4-ones ꢀ3a±d), 2-dimethylamino-5-
[ꢀZ)-ꢀdimethylamino)methylidene]-1,3-thiazol-4ꢀ5H)-one
ꢀ8), and 5-[ꢀE)-ꢀdimethylamino)methylidene]-1-methyl-
imidazolidine-2,4-dione ꢀ11)
Figure 2. Ortep view of the asymmetric unit of compound 14a with label-
ling of nonhydrogen atoms. )Ellipsoids are at 50% probability level.)
A mixture of compound 2a±d, 7, or 10 )3 mmol), aceto-
nitrile )10 mL) or DMF )10 mL), and tert-butoxy-bis)di-
methylamino)methane )783 mg, 4.5 mmol) was heated
under re¯ux for 2±4 h. Volatile components were evapo-
rated in vacuo, ethanol )10 mL) was added to the residue,
and the precipitate was collected by ®ltration and washed
with ethanol. Compounds 3a±d, 8, 11 were prepared in this
manner.
5.2.1.
5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-ethyl-2-
thiooxoimidazolidin-4-one ꢀ3a). Prepared from compound
2a in acetonitrile, 4 h, 412 mg )69%) of a pale yellow solid;
mp 201±2038C )EtOH). 1H NMR )DMSO-d6): d 1.10 )3H,
t, Jˆ7.2 Hz, CH3CH2), 3.11 )6H, s, NMe2), 3.74 )2H, q,
Jˆ7.2 Hz, CH2CH3), 6.76 )1H, s, H±C)50)), 11.29 )1H, s,
H±N)1)). 13C NMR )CDCl3): d 13.5, 36.7, 43.3, 103.9,
132.0, 164.4, 171.3. )Found: C, 48.47; H, 6.75; N, 20.85.
C8H13N3OS requires: C, 48.22; H, 6.58; N, 21.09.); nmax
)KBr) 3275, 2970, 1705, 1630, 1500, 1445 cm21; m/z )EI)
199 )M1).
Figure 3. NOESY spectrum of the )E)-isomer of 14b was taken in DMSO-
d6 at 302 K.
unsubstituted at position 2, reacted with 5-[)dimethyl-
amino)methylidene]-1-methylimidazolidine-2,4-dione )11)
and 5-[)dimethylamino)meth-ylidene]-1,3-dimethylimida-
zolidine-2,4-dione )12), affording only the )E)-aplysinopsin
analogues 13a,c,d 14a, while with 2-methylindole mixtures
of )Z)- and )E)-isomers of 13b and 14b were formed.
However, when 2-methylindole reacted with 5-[)Z)-
)dimethylamino)methylidene]-2-thiooxoimidazolidin-4-one
derivatives 3, 4 and 5-[)Z)-)dimethylamino)-methylidene]-
1,3-thiazol-4)5H)-one )8), the )Z)-aplysinopsin analogues
5a±d, 6a±d, and 9 were formed stereoselectively.
5.2.2.
5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-allyl-2-
thiooxoimidazolidin-4-one ꢀ3b). Prepared from compound
2b in acetonitrile, 2 h, 361 mg )57%) of a white solid; mp
188±1908C )EtOH). H NMR )DMSO-d6): d 3.12 )6H, s,
1
NMe2), 4.32 )2H, ddd, Jˆ1.5, 1.7, 5.3 Hz, CH2CHvCH2),
4.99 )1H, ddd, Jˆ1.5, 1.7, 17.3 Hz, 1H of CHvCH2), 5.07
)1H, ddd, Jˆ1.5, 1.7, 10.2 Hz, 1H of CHvCH2), 5.81
)1H, ddt, Jˆ5.3, 10.2, 17.3 Hz, CHvCH2), 6.84 )1H, s,
H±C)50)), 11.36)1H, s, H±N)1)); 13C NMR )CDCl3): d
43.4, 43.6, 103.5, 117.9, 131.7, 132.8, 164.4, 171.0. Anal.
)Found: C, 51.41; H, 6.29; N, 20.12. C9H13N3OS requires:
C, 51.16; H, 6.20; N, 19.89.); nmax )KBr) 3215, 2990, 1705,
1640, 1495, 1480 cm21; m/z )EI) 211 )M1).
5. Experimental
5.1. General
Melting points were determined on a Ko¯er micro hot stage.
1
The H NMR, 13C NMR, HMQC, HMBC, and NOESY
5.2.3. 5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-phenyl-2-
thiooxoimidazolidin-4-one ꢀ3c). Prepared from compound
2c in acetonitrile, 4 h, 437 mg )59%) of a pinkish solid; mp
spectra were obtained on a Bruker Avance DPX 300 at
300 MHz for 1H and 75.5 MHz for 13C nucleus with
DMSO-d6 or CDCl3 as solvents as stated and TMS as the
internal standard. Mass spectra were recorded on an Auto-
SpecQ spectrometer and IR spectra on a Perkin±Elmer
Spectrum BX FTIR spectrophotometer. Microanalyses
were performed on a Perkin±Elmer CHN Analyser 2400.
TLC was performed on alu foils coated with silica gel 60,
0.2 mm )Merck). Column chromatography )CC) was
performed on silica gel )Fluka, silica gel 60, 0.04±
0.06mm). Medium pressure liquid chromatography
)MPLC) was performed with a BuÈchi isocratic system
1
241±2438C )decomp.) )EtOH). H NMR )DMSO-d6): d
3.17 )6H, s, NMe2), 6.85 )1H, s, H±C)50)), 7.26±7.49
)5H, m, Ph), 11.56)1H, s, H±N)1)); 13C NMR )DMSO-
d6): d 42.5, 102.0, 127.9, 128.5, 128.7, 133.1, 134.4,
163.3, 169.7. )Found: C, 58.16; H, 5.32; N, 16.82.
C12H13N3OS requires: C, 58.28; H, 5.30; N, 16.99.); nmax
)KBr) 3015, 2930, 1685, 1620, 1510, 1495 cm21; m/z )EI)
247 )M1).
²
Donation of Alexander von Humboldt Foundation, Germany.

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R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8400
5.2.4. 5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-ꢀ4-methyl-
phenyl)-2-thiooxoimidazolidin-4-one ꢀ3d). Prepared from
compound 2d in acetonitrile, 3.5 h, 650 mg )83%) of a pink-
5.3.2.
5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-allyl-2-
ꢀmethylsulfanyl)imidazolidin-4-one ꢀ4b). Prepared from
compound 2b in DMF; 2.5 h, trituration with ethyl acetate,
324 mg )48%) of a pale yellow solid; mp 98±1008C
1
ish solid; mp 2568C )decomp.) )EtOH). H NMR )DMSO-
1
d6): d 2.35 )3H, s, Me±Ar), 3.16)6H, s, NMe ), 6.83 )1H, s,
)EtOAc). H NMR )CDCl3): d 2.56)3H, s, SMe), 3.15
2
H±C)50)), 7.13 )2H, dd, Jˆ1.9, 7.9 Hz, 2H of Ar), 7.26)2H,
dd, Jˆ1.9, 7.9 Hz, 2H of Ar), 11.52 )1H, s, H±N)1)). 13C
NMR )CDCl3): d 21.7, 43.4, 103.6, 128.5, 130.1, 131.6,
133.0, 139.1, 164.5, 171.5. )Found: C, 60.07; H, 5.93; N,
15.97. C13H15N3OS requires: C, 59.75; H, 5.79; N, 16.08.);
nmax )KBr) 3225, 2965, 1700, 1640, 1655, 1515, 1475,
1440 cm21; m/z )EI) 261 )M1).
and 3.55 )6H, 2s, 1:1, NMe2), 4.32 )2H, ddd, Jˆ1.5, 1.7,
5.3 Hz, CH2CHvCH2), 5.00 )1H, ddd, Jˆ1.5, 1.7, 17.3 Hz,
1H of CHvCH2), 5.08 )1H, ddd, Jˆ1.5, 1.7, 10.2 Hz,
1H of CHvCH2), 5.81 )1H, ddt, Jˆ5.3, 10.2, 17.3 Hz,
CHvCH2), 6.94 )1H, s, H±C)50)). 13C NMR )DMSO-
d6): d 13.2, 42.5, 46.4, 115.1, 117.1, 133.9, 139.6, 147.0,
168.8. )Found: C, 53.37; H, 6.79; N, 18.44. C10H15N3OS
requires: C, 53.31; H, 6.71; N, 18.65.); nmax )KBr) 2925,
2900, 2815, 1680, 1620, 1510, 1425, 1410 cm21; m/z )EI)
225 )M1).
5.2.5. 2-Dimethylamino-5-[ꢀZ)-ꢀdimethylamino)methyl-
idene]-1,3-thiazol-4ꢀ5H)-one
ꢀ8).
Prepared
from
compound 7 in DMF, 3 h, 388 mg )65%) of a white solid;
mp 187±1908C )decomp.) )EtOH). 1H NMR )DMSO-d6): d
3.06)H6 , s, NMe 2), 3.09 )6H, s, NMe2), 7.40 )1H, s,
H±C)50)) 13C NMR )DMSO-d6): d 42.2, 46.2, 94.5, 145.3,
174.3, 181.3. )Found: C, 48.31; H, 6.54; N, 21.20.
C8H13N3OS requires: C, 48.22; H, 6.58; N, 21.09.); nmax
5.3.3. 5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-phenyl-2-
ꢀmethylsulfanyl)imidazolidin-4-one ꢀ4c). Prepared from
compound 2c in DMF, 2 h, trituration with ethanol,
110 mg )14%) of a pinkish solid; mp 237±2408C )decomp.)
1
)EtOH). H NMR )CDCl3): d 2.53 )3H, s, SMe), 3.18 and
)KBr) 3005, 2915, 2815, 1665, 1595, 1560, 1435 cm21
m/z )EI) 199 )M1).
;
3.60 )6H, 2s, 1:1, NMe2), 7.01 )1H, s, H±C)50)), 7.26±7.40
)5H, m, Ph). 13C NMR )DMSO-d6): d 31.3, 40.1, 44.7,
105.1, 127.9, 128.4, 128.9, 134.9, 140.7, 158.1, 167.0.
)Found: C, 59.76; H, 5.83; N, 16.26. C13H15N3OS requires:
C, 59.74; H, 5.79; N, 16.08.); nmax )KBr) 3035, 3010, 2915,
2810, 1695, 1610, 1505, 1430, 1415, 1390 cm21; m/z )EI)
261 )M1).
5.2.6.
5-[ꢀE)-ꢀDimethylamino)methylidene]-1-methyl-
imidazolidine-2,4-dione ꢀ11). Prepared from compound
10 in acetonitrile, 4 h, 274 mg )54%) of a white solid; mp
1
200±2028C )EtOH). H NMR )DMSO-d6): d 2.90 )3H, s,
Me±N)1)), 3.15 )6H, s, NMe2), 6.47 )1H, s, H±C)50)), 10.31
)1H, s, NH). 13C NMR )DMSO-d6): d 27.1, 44.8, 106.0,
135.7, 152.9, 161.4. )Found: C, 49.65; H, 6.81; N, 25.13.
C7H11N3O2 requires: C, 49.70; H, 6.55; N, 24.84.); nmax
5.3.4. 5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-ꢀ4-methyl-
phenyl)-2-ꢀmethylsulfanyl)imidazolidin-4-one ꢀ4d). Pre-
pared from compound 2d in acetonitrile, 4 h, trituration
with ethyl acetate, 536mg )65%) of a pinkish solid; mp
)KBr) 3145, 3015, 2800, 2720, 1690, 1610, 1485 cm21
m/z )EI) 169 )M1).
;
1
173±1758C )decomp.) )EtOAc). H NMR )CDCl3): d 2.38
)3H, s, Me±Ar), 2.52 )3H, s, SMe), 3.17 and 3.99 )6H, 2s,
1:1, NMe2), 7.00 )1H, s, H±C)50)), 7.18 )2H, dd, Jˆ1.9,
7.9 Hz, 2H of Ar), 7.21 )2H, dd, Jˆ1.9, 7.9 Hz, 2H of
Ar). 13C NMR )DMSO-d6): d 12.4, 20.7, 41.3, 45.5,
114.4, 127.0, 129.5, 131.2, 137.6, 139.0, 145.8, 167.8.
)Found: C, 61.33; H, 6.21; N, 15.54. C14H17N3OS
requires: C, 61.07; H, 6.22; N, 15.26.); nmax )KBr) 3020,
2970, 2920, 2795, 1685, 1620, 1510, 1410 cm21; m/z )EI)
275 )M1).
5.3. General procedure for the preparation of 5-[ꢀZ)-
ꢀdimethylamino)methylidene]-3-substituted-2-ꢀmethyl-
sulfanyl)imidazolidin-4-ones ꢀ4a±d) and 5-[ꢀE)-
ꢀdimethylamino)methylidene]-1,3-dimethyl-imidazo-
lidine-2,4-dione ꢀ12)
A mixture of compound 2a±d or 10 )3 mmol), acetonitrile
)10 mL) or DMF )10 mL), and DMFDMA )94%, 608 mg,
4.8 mmol), was heated under re¯ux for 2±6h. Volatile
components were evaporated in vacuo, and the residue
was triturated with an appropriate solvent )10 mL). The
precipitate was collected by ®ltration and washed with the
same solvent. Compounds 4a±d, 12 were prepared in this
manner.
Compound 4d was also prepared by methylation of 3d with
DMFDMA:
A mixture of 3d )46mg, 0.18 mmol),
DMFDMA )94%, 36mg, 0.3 mmol), and acetonitrile
)3 mL) was heated under re¯ux for 4 h. Volatile components
were evaporated in vacuo, and the residue was triturated
with ethyl acetate )3 mL). The precipitate was collected
by ®ltration and washed with EtOAc to give 4d, 40 mg
)81%).
5.3.1.
5-[ꢀZ)-ꢀDimethylamino)methylidene]-3-ethyl-2-
ꢀmethylsulfanyl)imidazolidin-4-one ꢀ4a). Prepared from
compound 2a in acetonitrile, 4 h, trituration with ethanol/
isopropanol, 45 mg )7%) of a pale yellow solid; mp
5.3.5. 5-[ꢀE)-ꢀDimethylamino)methylidene]-1,3-dimethyl-
imidazolidine-2,4-dione ꢀ12). Prepared from 10 in aceto-
nitrile, 6h, trituration with chloroform/ n-hexane 538 mg
)98%) of a white solid; mp 49±518C )chloroform/n-hexane).
1H NMR )DMSO-d6): d 2.85 and 2.98 )6H, 2s, 1:1,
Me±N)3) and Me±N)1)), 3.18 )6H, s, NMe2), 6.59 )1H, s,
H±C)50)); 13C NMR )DMSO-d6): d 24.9, 27.5, 44.8, 104.6,
136.3, 152.6, 160.0. nmax )KBr) 3230, 1720, 1680, 1615,
1465 cm21; m/z )EI) 183 )M1). HRMS: Calcd for
C8H13N3O2: 183.100777, Found: 183.101500.
1
85±888C )ethanol/isopropanol, 1:1). H NMR )DMSO-d6):
d 1.09 )3H, t, Jˆ7.2 Hz, CH3CH2), 2.52 )3H, s, SMe), 3.14
and 3.46)H6 , 2s, 1:1, NMe 2), 3.47 )2H, q, Jˆ7.2 Hz,
CH2CH3), 6.91 )1H, s, H±C)50)); 13C NMR )CDCl3): d
13.1, 14.8, 35.7, 40.1, 46.4, 116.3, 138.8, 148.2, 170.0.
)Found: C, 50.43; H, 7.21; N, 19.59. C9H15N3OS requires:
C, 50.68; H, 7.09; N, 19.70.); nmax )KBr) 2970, 2930, 2815,
1685, 1640, 1610, 1510, 1440, 1415 cm21; m/z )EI) 213
)M1).

Ï
R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8401
5.4. General procedure for the preparation of 5-[ꢀZ)-ꢀ2-
methyl-1H-indol-3-yl)methylidene]-3-substituted-2-
thiooxoimidazolidin-4-ones ꢀ5a±d), 3-substituted 5-[ꢀZ)-
ꢀ2-methyl-1H-indol-3-yl)methylidene]-2-ꢀmethyl-
sulfanyl)imidazolidin-4-ones ꢀ6b,d), and 2-ꢀdimethyl-
amino)-5-[ꢀZ)-1-ꢀ2-methyl-1H-indol-3-yl)methylidene]-
1,3-thiazol-4ꢀ5H)-one hydrobromide ꢀ9)
5.4.4. 5-[ꢀZ)-ꢀ2-Methyl-1H-indol-3-yl)methylidene]-3-ꢀ4-
methylphenyl)-2-thiooxoimidazolidin-4-one ꢀ5d). Pre-
pared from compound 3d, rt, 48 h, 132 mg )77%) of an
1
orange solid; mp 208±2118C )EtOH). H NMR )DMSO-
d6): d 2.43 and 2.63 )6H, 2s, 1:1, Me±Ar and Me±C)200)),
6.98 )1H, s, H±C)50)), 7.15±7.24 )2H, m, H±C)500) and
H±C)600)), 7.32 )2H, dd, Jˆ1.9, 8.3 Hz, 2H of Ar), 7.38
)2H, dd, Jˆ1.9, 8.3 Hz, 2H of Ar), 7.42 )1H, dd, Jˆ1.9,
6.8, Hz, H±C)700)), 7.65 )1H, dd, Jˆ2.3, 6.8 Hz,
H±C)400)), 11.74 and 11.98 )2£1H, 2s, H±N)1) and
H±N)100)). 13C NMR )DMSO-d6): d 13.6, 21.6, 107.3,
110.1, 112.0, 120.0, 121.0, 122.4, 125.0, 127.7, 129.4,
130.1, 132.0, 136.7, 139.0, 140.9, 164.2, 177.4. Found: C,
67.91; H, 5.30; N, 10.91. C20H17N3OS´0.5 H2O requires: C,
68.08; H, 5.44; N, 11.34.); nmax )KBr) 3290, 1735, 1715,
1640, 1515, 1465, 1400 cm21; m/z )EI) 347 )M1).
Hydrobromic acid )33% in acetic acid, 4.1 M, 5±6drops,
,0.4 mmol) was added to a mixture of compound 3a±d,
4b,d, or 8 )0.5 mmol), 2-methylindole )66 mg, 0.5 mmol),
and acetic acid )2 mL) and the mixture was stirred at rt±508
for 6±72 h. Volatile components were evaporated in vacuo,
ethanol )3 mL) was added to the residue, and the precipitate
was collected by ®ltration. Compounds 5a±d, 6b,d, 9 were
prepared in this manner.
5.4.5.
5-[ꢀZ)-ꢀ2-Methyl-1H-indol-3-yl)methylidene]-3-
5.4.1.
5-[ꢀZ)-ꢀ2-Methyl-1H-indol-3-yl)methylidene]-3-
allyl-2-ꢀmethylsulfanyl)imidazolidin-4-one ꢀ6b). Prepared
from compound 4b, rt, 24 h, 48 mg )31%) of a yellow solid;
mp 217±2198C )EtOH); 1H NMR )CDCl3): d 2.66 and 2.77
)6H, 2s, 1:1, SMe and Me±C)200)), 4.26)2H, ddd, Jˆ1.7,
5.3 Hz, CH2CHvCH2), 5.21 )1H, ddd, Jˆ1.1, 1.7, 17.3 Hz,
1H of CHvCH2), 5.25 )1H, ddd, Jˆ1.1, 1.5, 6.8 Hz, 1H of
CHvCH2), 5.86)1H, ddt, Jˆ5.3, 6.8, 17.3 Hz, CHvCH2),
7.16±7.30 )3H, m, H±C)5 0), H±C)500), and H±C)600)), 8.32
)1H, d, Jˆ8.3 Hz, H±C)700)), 9.07 )1H, dd, Jˆ7.9 Hz,
H±C)400)), NH is exchanged. 13C NMR )DMSO-d6): d
13.0, 13.6, 43.1, 110.1, 111.9, 117.7, 120.0, 121.2, 123.1,
124.4, 127.1, 132.1, 133.3, 137.1, 145.4, 158.5, 169.4.
Found: C, 65.31; H, 5.48; N, 13.28. C17H17N3OS requires:
C, 65.57; H, 5.51; N, 13.50.); nmax )KBr) 3220, 2930, 1680,
1605, 1575, 1485, 1460 cm21; m/z )EI) 311 )M1).
ethyl-2-thiooxoimidazolidin-4-one ꢀ5a). Prepared from
compound 3a, rt, 24 h, 21 mg )15%) of a yellow solid; mp
178±1808C )MeOH). H NMR )DMSO-d6): d 1.18 )3H, t,
1
00
Jˆ6.8 Hz, CH3CH2), 2.46)3H, s, Me±C)2 )), 3.84 )2H, q,
Jˆ6.8 Hz, CH2CH3), 6.87 )1H, s, H±C)50)), 7.06±7.16 )2H,
m, H±C)500) and H±C)600)), 7.35 )1H, dd, Jˆ1.5, 6.0 Hz,
H±C)700)), 7.53 )1H, dd, Jˆ1.9, 6.4 Hz, H±C)400)), 11.66
and11.69 )2H, 2s, 1:1, H±N)1) and H±N)100)). 13C NMR
)DMSO-d6): d 13.2, 13.5, 36.0, 106.9, 109.6, 111.7,
119.6, 120.6, 122.1, 124.6, 127.3, 136.4, 140.5, 163.8,
176.8. )Found: C, 63.34; H, 5.32; N, 14.50. C15H15N3OS
requires: C, 63.14; H, 5.30; N, 14.74.); nmax )KBr) 3285,
1685, 1620, 1460, 1430 cm21; m/z )EI) 285 )M1).
5.4.2.
5-[ꢀZ)-ꢀ2-Methyl-1H-indol-3-yl)methylidene]-3-
allyl-2-thiooxoimidazolidin-4-one ꢀ5b). Prepared from
compound 3b, rt, 24 h, 71 mg )48%) of a yellow solid; mp
128±1308C )EtOH); H NMR )DMSO-d6): d 2.37 )3H, s,
5.4.6. 5-[ꢀZ)-ꢀ2-Methyl-1H-indol-3-yl)methylidene]-3-ꢀ4-
methylphenyl)-2-ꢀmethylsulfanyl)imidazolidin-4-one
ꢀ6d). Prepared from compound 4d, rt, 48 h, 81 mg )45%) of
a yellow solid; mp 269±2728C )decomp.) )EtOH). 1H NMR
)CDCl3): d 2.41, 2.67, and 2.73 )9H, 3s, 1:1:1, Me±Ar,
Me±C)200), and SMe), 7.19±7.31 )6H, m, H±C)500),
H±C)600), and 4H of Ar), 7.35 )1H, s, H±C)50)), 8.40 )1H,
m, H±C)700)), 9.11 )1H, m, H±C)400)), NH is exchanged. 13C
NMR )DMSO-d6): d 13.0, 13.8, 21.6, 110.2, 111.9, 120.3,
121.3, 123.1, 124.4, 127.2, 128.2, 130.7, 131.4, 132.0,
137.1, 139.3, 145.5, 158.4, 169.2. )Found: C, 70.07; H,
5.25; N, 11.68. C21H19N3OS requires: C, 69.78; H, 5.30;
N, 11.63.); nmax )KBr) 3190, 2920, 1680, 1605, 1575,
1515, 1460 cm21; m/z )EI) 361 )M1).
1
Me±C)200)), 3.92±4.08 )3H, m, CH2CHvCH2 and 1H of
CHvCH2), 4.59 )1H, d, Jˆ10.2 Hz, 1H of CHvCH2),
4.95±5.20 )1H, m, CHvCH2), 6.98 )1H, s, H±C)50)),
6.95±7.07 )2H, m, H±C)500) and H±C)600)), 7.47 )1H, dd,
Jˆ8.3 Hz, H±C)700)), 7.77 )1H, dd, Jˆ7.9 Hz, H±C)400)),
10.42 and 11.44 )2H, 2s, 1:1, H±N)1) and H±N)100)). 13C
NMR )DMSO-d6): d 13.4, 43.3, 107.2, 110.2, 112.0, 117.8,
119.9, 121.0, 122.4, 124.7, 127.6, 132.7, 136.7, 140.9,
164.0, 177.1. )Found: C, 64.48; H, 5.13; N, 14.26.
C16H15N3OS requires: C, 64.63; H, 5.09; N, 14.14.); nmax
)KBr) 3260, 1705, 1620, 1580, 1530, 1465 cm21; m/z )EI)
297 )M1).
Compound 6d was also prepared by methylation of 5d with
A mixture of 5d )174 mg, 0.5 mmol),
5.4.3.
5-[ꢀZ)-ꢀ2-Methyl-1H-indol-3-yl)methylidene]-3-
DMFDMA:
phenyl-2-thiooxoimidazolidin-4-one ꢀ5c). Prepared from
compound 3c, rt, 48 h, 132 mg )79%) of a yellow solid;
mp 2818C )decomp.) )EtOH). 1H NMR )DMSO-d6): d
2.58 )3H, s, Me±C)200)), 6.93 )1H, s, H±C)50)), 7.09±7.18
)2H, m, H±C)500) and H±C)600)), 7.35±7.55 )6H, m,
H±C)700) and Ph), 7.62 )1H, dd, Jˆ1.9, 6.4 Hz, H±C)400)),
11.69 and 11.95 )2H, 2s, 1:1, H±N)1) and H±N)100)). 13C
NMR )DMSO-d6):d 13.6, 107.3, 110.2, 112.0, 120.0, 121.0,
122.4, 125.0, 127.7, 129.4, 129.6, 129.7, 134.6, 136.7,
140.9, 164.2, 177.2. )Found: C, 68.82; H, 4.44; N, 12.23.
C19H15N3OS requires: C, 68.45; H, 4.54; N, 12.61.); nmax
)KBr) 3265, 1715, 1630, 1595, 1495, 1455 cm21; m/z )EI)
333 )M1).
DMFDMA )94%, 95 mg, 0.8 mmol), and acetonitrile
)2 mL) was stirred at rt for 72 h. Volatile components
were evaporated in vacuo, ethyl acetate )3 mL) was added
and the precipitate was collected by ®ltration to give 6d,
92 mg )51%).
5.4.7. 2-ꢀDimethylamino)-5-[ꢀZ)-1-ꢀ2-methyl-1H-indol-3-
yl)methylidene]-4,5-dihydro-1,3-thiazol-4-one hydro-
bromide ꢀ9). Prepared from compound 8, 508, 6h, 88 mg
1
)48%) of an orange solid; mp 247±2508C )MeOH); H
NMR )DMSO-d6): d 3.20 )3H, s, SMe), 5.10 )6H, s,
NMe2), 7.12 )1H, dt, Jˆ1.5, 6.8, 7.1 Hz, H±C)500)), 7.15

Ï
R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8402
)1H, dt, Jˆ1.5, 6.8, 7.1 Hz, H±C)600)), 7.38 )1H, ddd,
Jˆ0.8, 1.5, 6.8 Hz, H±C)700)), 7.78 )1H, dd, Jˆ1.5,
7.1 Hz, H±C)400)), 7.82 )1H, s, H±C)50)), 11.82 )1H, s,
H±N)100)). 13C NMR )DMSO-d6): d 13.2, 40.2, 108.3,
112.6, 119.2, 120.1, 121.5, 123.0, 125.8, 128.4, 136.9,
143.8, 172.2, 175.8. )Found: C, 49.45; H, 4.69; N, 11.43.
C15H15N3OS´HBr requires: C, 49.31; H, 4.42; N, 11.51.);
nmax )KBr) 3120, 3085, 2955, 2765, 1720, 1655, 1595,
1520, 1460 cm21; m/z )EI) 285 )M12HBr).
5.5.3.
5-[ꢀE)-ꢀ5-Bromo-1H-indol-3-yl)methylidene]-1-
methylimidazolidine-2,4-dione ꢀ13c). Prepared from
compound 11 and 5-bromoindole, 5 h, 61 mg )38%) of a
yellow solid; mp 341±3448C )AcOH). H NMR )DMSO-
d6): d 3.19 )3H, s, Me±N)1)), 6.69 )1H, s, H±C)50)), 7.28
1
00
)1H, dd, Jˆ1.9, 8.6Hz, H±C)6 )), 7.42 )1H, d, Jˆ8.6Hz,
H±C)700)), 7.24 )1H, d, Jˆ1.9 Hz, H±C)400)), 8.79 )1H, d,
00
Jˆ2.6Hz, H±C)2 )), 11.19 and 11.74 )2£1H, 2s, H±N)3)
and H±N)100)). 13C NMR )DMSO-d6): d 25.9, 106.9, 108.4,
112.7, 113.8, 120.9, 124.4, 126.2, 129.5, 129.6, 134.3,
153.0, 163.3. )Found: C, 48.70; H, 3.04; N, 13.01.
C13H10BrN3O2 requires: C, 48.77; H, 3.15; N, 13.13.);
nmax )KBr) 3405, 3155, 3050, 2740, 1780, 1705, 1630,
1515, 1450 cm21; m/z )EI) 319 )79Br), 321 )81Br) )M1).
5.5. General procedure for the preparation of 5-
[ꢀsubstituted 1H-indol-3-yl)methylidene]-1-methyl-2,4-
diones ꢀ13a±d) and 5-[ꢀ1H-indol-3-yl)methylidene]-1,3-
dimethylimidazolidine-2,4-dione ꢀ14a)
5.5.4.
5-[ꢀE)-ꢀ5-Fluoro-1H-indol-3-yl)methylidene]-1-
A mixture of compound 11 or 12 )0.5 mmol), indole
derivative )indole, 2-methylindole, 5-bromoindole, or
5-¯uoroindole) )0.5 mmol), and acetic acid )10 mL) was
heated under re¯ux for 3±9 h. The volatile components
were evaporated in vacuo, ethanol )3 mL) was added to
the residue, and the precipitate was collected by ®ltration.
Compounds 13a±d, 14a were prepared in this manner.
methylimidazolidine-2,4-dione ꢀ13d). Prepared from
compound 11 and 5-¯uoroindole, 6h, 89 mg )69%) of a
yellow solid; mp 354±3568C )AcOH); H NMR )DMSO-
1
d6): d 3.18 )3H, s, Me±N)1)), 6.64 )1H, s, H±C)50)), 7.09
)1H, ddd, Jˆ2.4, 8.8, 9.4 Hz, H±C)600)), 7.45 )1H, dd,
Jˆ4.7, 8.8 Hz, H±C)700)), 7.81 )1H, dd, Jˆ2.4, 10.6Hz,
H±C)400)), 8.82 )1H, d, Jˆ1.9 Hz, H±C)200), 11.18 and
11.66 )2H, 2s, 1:1, H±N)3) and H±N)100)). 13C NMR
)DMSO-d6): d 25.9, 103.3, 103.6, 107.2, 108.9, 109.0,
109.9, 110.2, 112.9, 113.0, 125.9, 128.3, 130.3, 132.2,
153.0, 156.2, 159.2, 163.4. )Found: C, 60.00; H, 3.80; N,
16.27. C13H10FN3O2 requires: C, 60.21; H, 3.89; N, 16.22.);
5.5.1. 5-[ꢀE)-ꢀ1H-Indol-3-yl)methylidene]-1-methylimi-
dazolidine-2,4-dione ꢀ13a). Prepared from compound 11
and indole, 3 h; 70 mg )58%) of a yellow solid; mp
1
310±3138C )EtOH). H NMR )DMSO-d6): d 3.19 )3H, s,
Me±N)1)), 6.68 )1H, s, H±C)50)), 7.14 )1H, ddd, Jˆ1.1,
7.2, 7.9, 8.3 Hz, H±C)500)), 7.19 )1H, ddd, Jˆ1.1, 7.2, 7.9,
8.3 Hz, H±C)600)), 7.47 )1H, dd, Jˆ1.1, 8.3 Hz, H±C)700)),
7.93 )1H, dd, Jˆ1.1, 7.2 Hz, H±C)400)), 8.78 )1H, d,
Jˆ3.0 Hz, H±C)200)), 11.17 and 11.59 )2H, 2s, 1:1,
H±N)3) and H±N)100)). 13C NMR )DMSO-d6): d 26.6,
108.3, 109.4, 112.8, 119.0, 120.7, 122.9, 126.6, 128.6,
129.4, 136.5, 153.9, 164.2. )Found: C, 64.59; H, 4.32; N,
17.16. C13H11N3O2 requires: C, 64.71; H, 4.60; N, 17.43.);
nmax )KBr) 3355, 3155, 3050, 2735, 1740, 1700, 1625,
1515 cm21; m/z )EI) 241 )M1).
nmax )KBr) 3350, 3155, 3050, 2735, 1760, 1705, 1625, 1580,
1515, 1480, 1440, 1380 cm21; m/z )EI) 259 )M1).
5.5.5. 5-[ꢀE)-ꢀ1H-Indol-3-yl)methylidene]-1,3-dimethyl-
imidazolidine-2,4-dione ꢀ14a). Prepared from compound
12 and indole, 2 h; 83 mg )65%) of a yellow solid; mp
1
270±2728C )AcOH). H NMR )DMSO-d6): d 3.01 and
3.25 )6H, 2s, 1:1, Me±N)3) and Me±N)1)), 6.77 )1H, s,
H±C)50)), 7.14 )1H, dt, Jˆ0.8, 7.2 Hz, H±C)600)), 7.19
)1H, dt, Jˆ1.1, 7.2 Hz, H±C)500)), 7.46)1H, dd, Jˆ1.1,
7.2 Hz, H±C)700)), 7.96)1H, dd, Jˆ0.8, 7.2 Hz, H±C)400)),
00
8.84 )1H, d, Jˆ2.6Hz, H±C)2 )), 11.66 )1H, s, H±N)100)).
5.5.2. 5-[ꢀ2-Methyl-1H-indol-3-yl)methylidene]-1-methyl-
imidazolidine-2,4-dione ꢀ13b). Prepared from compound
11 and 2-methylindole, 9 h, 103 mg )81%) of a yellow
solid; mp 250±2598C )EtOH), Z/Eˆ62:38. )Found: C,
66.05; H, 5.03; N, 16.34. C14H13N3O2 requires: C, 65.86;
H, 5.14; N, 16.47., nmax )KBr) 3310, 3155, 3055, 2725,
1750, 1700, 1655, 1615, 1460 cm21; m/z )EI) 255 )M1).
13C NMR )DMSO-d6): d 25.2, 27.0, 109.0, 109.4, 112.8,
119.0, 120.7, 122.9, 125.3, 128.6, 129.5, 136.5, 153.6,
162.8. )Found: C, 65.84; H, 5.10; N, 16.22. C14 H13N3O2
requires: C, 65.86; H, 5.14; N, 16.47.); nmax )KBr) 3300,
1740, 1690, 1620, 1515, 1495, 1460, 1430, 1405 cm21; m/z
)EI) 255 )M1).
5.5.6.
methylimidazolidine-2,4-dione ꢀ14b).
5-[ꢀ1H-2-Methylindol-3-yl)methylidene]-1,3-di-
mixture of
NMR data for the major 0Z)-isomer. 1H NMR )DMSO-d6): d
2.37 )3H, s, Me±C)200)), 3.16)3H, s, Me±N)1)), 6.67 )1H, s,
H±C)50)), 6.96±7.10 )2H, m, H±C)500) and H±C)600)),
7.27±7.38 )2 H, m, H±C)400) and H±C)700)), 11.14 and
11.40 )2H, 2s, 1:1, H±N)3) and H±N)100)). 13C NMR
)DMSO-d6): 13.1, 29.6, 105.5, 106.7, 111.9, 119.8, 120.5,
122.0, 129.0, 131.1, 136.2, 137.5, 157.1, 165.3.
A
compound 12 )92 mg, 0.5 mmol), 2-methylindole )66 mg,
0.5 mmol), and in acetic acid )10 mL) was heated under
re¯ux for 2.5 h. Volatile components were evaporated in
vacuo and the residue was puri®ed by CC )chloroform/
ethyl acetate, 5:1). Fractions containing the product were
combined and evaporated in vacuo to give crude 14b,
³
82 mg )61%) of a yellow solid; mp 94±998C, Z/Eˆ28:72.
NMR data for the minor 0E)-isomer. 1H NMR )DMSO-d6):
d 2.29 )3H, s, Me±C)200)), 2.74 )3H, s, Me±N)1)), 6.54 )1H,
s, H±C)50)), 6.96±7.10 )2H, m, H±C)500) and H±C)600)),
7.27±7.38 )2H, m, H±C)400) and H±C)700)), 11.14 and
11.28 )2H, 2s, 1:1, H±N)3) and H±N)100)). 13C NMR
)DMSO-d6): d 14.1, 26.8, 105.3, 108.1, 111.9, 119.3,
120.0, 121.6, 128.4, 128.7, 136.0, 138.2, 154.2, 163.0.
)Found: C, 66.92; H, 5.51; N, 15.39. C15H15N3O2 requires:
C, 66.89; H, 5.62; N, 15.61.); nmax )KBr) 3255, 1760, 1700,
1650, 1540, 1460 cm21; m/z )EI) 269 )M1). The isomers
were separated by MPLC )chloroform/ethyl acetate )5:1),
³
TLC: chloroform/ethyl acetate, 5:1, Rf [)E)-isomer]ˆ0.18, Rf [)Z)-
isomer]ˆ0.27.

Ï
R.Jaks e et al./ Tetrahedron 57 02001) 8395±8403
8403
Reagents; Beal, J. L., Reinhard, E., Eds.; Hippokrates:
Stuttgart, 1981; pp. 299±303.
Rt [)Z)-isomer]ˆ5.4 min, Rt [)E)-isomer]ˆ8.4 min). Frac-
tions containing single isomers were evaporated in vacuo
to give the )Z)- and the )E)-isomer of 14b.
3. Hollenbeak, K. H.; Schmitz, F. J. Lloydia 1977, 40, 479±481.
4. Djura, P.; Faulkner, D. J. J.Org.Chem. 1980, 45, 735±737.
5. Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv.Chim.
Acta 1988, 71, 773±782.
Data for the 0Z)-isomer. 32 mg )24%); mp 144±1478C.1H
NMR )DMSO-d6): d 2.38 )3H, s, Me±C)200)), 2.78 )3H, s,
Me±N)3)), 2.99 )3H, s, Me±N)1)), 6.79 )1H, d, Jˆ0.8 Hz,
H±C)50)), 7.02 )1H, dt, Jˆ1.5, 7.2 Hz, H±C)500)), 7.08 )1H,
dt, Jˆ1.5, 7.2 Hz, H±C)600)), 7.32 )1H, dd, Jˆ1.5, 7.2 Hz,
H±C)700)), 7.38 )1H, dd, Jˆ1.5, 7.2 Hz, H±C)400)), 11.44
)1H, s, H±N)100)). 13C NMR )DMSO-d6): d 13.0, 25.5,
30.1, 105.4, 106.5, 111.9, 119.3, 120.6, 122.0, 128.9,
130.0, 136.3, 137.9, 157.1, 164.3.
6. Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv.Chim.
Acta 1989, 72, 1444±1450.
7. Dalkafuoki, A.; Ardisson, J.; Kunesch, N.; Lacombe, L.;
Poisson, J. E. Tetrahedron Lett. 1991, 5325±5328.
8. For
a review on iminophosphoranes see: Molina, P.;
Vilaplana, M. J. Synthesis 1994, 1197±1218.
9. Molina, P.; Almendros, P.; Fresneda, P. M. Tetrahedron 1994,
50, 2241±2254.
1
10. Stanovnik, B.; Svete, J. Synlett 2000, 1077±1091.
11. Stanovnik, B.; Svete, J. Targets Heterocycl.Syst. 2000, 4,
105±137.
Ï
12. Smodis, J.; Stanovnik, B. Tetrahedron 1998, 54, 9799±9810.
Ï Ï Ï Ï Ï
13. Selic, L.; Jakse, R.; Lampic, K.; Golic, L.; Golic-Grdadolnik,
Data for the 0E)-isomer. 47 mg )35%); mp 176±1788C. H
NMR )DMSO-d6): 2.30 )3H, s, Me±C)200)), 2.94 )3H, s,
Me±N)3)), 3.22 )3H, s, Me±N)1)), 6.64 )1H, d, Jˆ0.8 Hz,
H±C)50)), 6.99 )1H, dt, Jˆ1.1, 7.2 Hz, H±C)500)), 7.06)1H,
dt, Jˆ1.1, 7.2 Hz, H±C)600)), 7.29 )1H, dd, Jˆ1.1, 7.2 Hz,
H±C)700)), 7.37 )1H, dd, Jˆ1.1, 7.2 Hz, H±C)400)), 11.32
)1H, s, H±N)100)). 13C NMR )DMSO-d6): d 14.1 )Me±
C)200)), 25.2 )Me±N)3)), 27.2 )Me±N)1)), 106.8 )C)300)),
109.0 )C)5000)), 111.5 )C)700)), 119.9 )C)500)), 120.1 )C)400)),
121.7 )C)6 )), 127.5 )C)5)), 128.4 )C)3a)), 136.0 )C)7a)),
138.5 )C)200)), 154.1 )C)2)), 161.7 )C)4)).
S.; Stanovnik, B. Helv.Chim.Acta 2000, 83, 2802±2811.
Ï
14. Selic, L.; Stanovnik, B. Tetrahedron 2001, 57, 3159±3164.
15. Martins, J. C.; Willem, R.; Biesemans, M. J.Chem.Soc,.
Perkin Trans.2 1999, 1513±1520.
16. Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.;
Tachibana, K. J.Org.Chem. 1999, 64, 866±876.
17. Nagatsu, A.; Tanaka, R.; Mizukami, H.; Ogihara, Y.;
Sakakibara, J. Tetrahedron 2001, 57, 3369±3372.
18. Kurz, M.; Schmieder, P.; Kessler, H. Angew.Chem,. Int.Ed.
Engl. 1991, 30, 1329±1331.
5.6. X-Ray structure analysis for compound 14a
Diffraction data were processed by DENZO31 program.
Structure was solved by direct methods using SIR9732
program. The structure re®nement and interpretation was
done by Xtal3.433 program. ORTEP-II34 picture of the
asymmetric unit of compound 14a is presented in Fig. 3.
The crystallographic data have also been deposited with the
Cambridge Crystallographic Data Center as supplementary
material with the deposition number: 164527. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
19. Wollborn, U.; Willker, W.; Leibfritz, D. J.Magn.Reson., Ser.
A 1993, 103, 86±89.
20. Kozminski, W. J.Magn.Reson. 1999, 137, 408±412.
21. Bax, A.; Freeman, R. J.Am.Chem.Soc.
1100.
1982, 104, 1099±
22. Furihata, K.; Seto, H. Tetrahedron Lett. 1999, 40, 6271±6275.
23. Seki, H.; Tokunaga, T.; Utsumi, H.; Yamaguchi, K.
Tetrahedron 2000, 56, 2935±2939.
24. Willker, W.; Leibfritz, D. Magn.Reson.Chem. 1995, 33, 632±
638.
25. Fischer, P.; Schweizer, E.; Langner, J.; Schmidt, U. Magn.
Reson.Chem. 1994, 32, 567±568.
26. Ding, K. Magn.Reson.Chem. 2000, 38, 321±323.
Acknowledgements
Ï
27. Golic Grdadolnik, S.; Stanovnik, B. Magn.Reson.Chem.
1997, 35, 482±486.
The ®nancial support from the Ministry of Science and
Technology, Slovenia, is gratefully acknowledged. The
authors wish to express their gratitude to the Alexander
von Humboldt Foundation, Germany, for the donation of a
BuÈchi medium pressure liquid chromatograph. The crystal-
lographic data were collected on the Kappa CCD Nonius
diffractometer in the Laboratory of Inorganic Chemistry,
Faculty of Chemistry and Chemical Technology, University
of Ljubljana, Slovenia. We acknowledge with thanks the
®nancial contribution of the Ministry of Science and Tech-
nology, Republic of Slovenia through grants X-2000 and
PS-511-103, which thus made the purchase of the apparatus
possible.
28. Ando, T.; Koseki, N.; Toia, R. F.; Casida, J. E. Magn.Reson.
Chem. 1993, 31, 90±93.
29. Titman, J. J.; Foote, J.; Jarvis, J.; Keeler, J.; Neuhaus, D.
J.Chem.Soc,. Chem.Commun.
1991, 419±421.
30. Marckwald, W.; Neumark, M.; Stelzner, R. Berichte 1891, 24,
3278±3298.
31. Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276,
307±326.
32. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Polidori, G. J.Appl.Cryst.
1994, 27, 435.
33. Hall, S. R.; King, G. S. D.; Stewart, J. M. The Xtal3.4 User's
Manual; University of Western Australia: Lamb, Perth, 1995.
34. Johnson, C. K. ORTEPII.Report ORNL-5138 ; Oak Ridge
National Laboratory: Tennessee, USA, 1976.
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