Synthesis of naturally occurring pyrazine and imidazole alkaloids from Botryllus leachi

Article abstract of DOI:10.1007/s00706-003-0085-2

The synthesis of the naturally occurring and biologically active alkaloids 1 and 2, first isolated from the red ascidian Botryllus leachi by Duran et al. [1], is described and the structure proposed for Botryllazine B (1) is confirmed. The analytical data

Full text of DOI:10.1007/s00706-003-0085-2

Monatshefte f€ur Chemie 135, 333–342 (2004)
DOI 10.1007/s00706-003-0085-2
Synthesis of Naturally Occurring
Pyrazine and Imidazole Alkaloids
from Botryllus Leachi#
Siavosh Mahboobi1;ꢀ, Andreas Sellmer1, Thomas Burgemeister1,
Alexei Lyssenko1, and Dieter Schollmeyer2
1
Faculty of Chemistry and Pharmacy, University of Regensburg, D-93040 Regensburg,
Germany
2
Institute of Organic Chemistry, University of Mainz, D-55099 Mainz, Germany
Received June 12, 2003; accepted July 3, 2003
Published online December 23, 2003 # Springer-Verlag 2003
Abstract. The synthesis of the naturally occurring and biologically active alkaloids 1 and 2, first
isolated from the red ascidian Botryllus leachi by Duran et al. [1], is described and the structure
proposed for Botryllazine B (1) is confirmed. The analytical data for 2-(p-hydroxybenzoyl)-4-(p-
hydroxyphenyl)imidazole (2) are discussed and compared with the literature. With special emphasis
1
of H NMR data the tautomerism of aroylimidazolemethanones is described.
Keywords. Pyrazine and imidazole alkaloids; Annular tautomers; Botryllus leachi; Biologically
active compounds.
Introduction
The pyrazine and imidazole derivatives 1 and 2, the synthesis of which was
studied in the following, belong to a class of naturally occurring alkaloids which
were first isolated from the red ascidian Botryllus leachi by Duran et al. [1].
Furthermore, the authors described cytotoxicity against different human tumor
cell lines. In order to obtain these alkaloids by synthesis, so getting the chance
of more information on their respective pharmacological activities, Botryllazine
B (1) and 2-(p-hydroxybenzoyl)-4-(p-hydroxyphenyl)imidazole (2) (Fig. 1) were
synthesized.
#
Dedicated to Prof. G. M€arkl on the occasion of his 75th birthday
Corresponding author. E-mail: siavosh.mahboobi@chemie.uni-regensburg.de
ꢀ

334
S. Mahboobi et al.
Fig. 1. Chemical structures of Botryllazine B (1) and 2-(p-hydroxybenzoyl)-4-(p-hydroxyphenyl)
imidazole (2)
Results and Discussion
Syntheses
The pyrazine alkaloid 1 was synthesized according to Scheme 1: Oxidation of the
acetophenone 3 with SeO2 in methanolic solution [2] and ring closure [3] by
reaction of 4 with racemic 2,3-diaminopropionic acid hydrobromide in methanolic
NaOH solution [4] resulted in a mixture of the two regio-isomeric pyrazine car-
boxylic acids 5 and 6, which were separated by the different solubility of their
sodium salts and crystallization of the carboxylic acids. Separation of the isomers
can not be recommended. Transformation of 6 to the respective morpholine deri-
vative 7 via the carboxylic acid chloride [5] and condensation [6] with 4-methoxy-
t
phenyllithium, obtained from 1-bromo-4-methoxybenzene (8) and BuLi, yielded
the alkaloid precursor 9. The methoxy groups of 9 could be cleaved by hydrobro-
mic acid [7]. Because brominated phenols were found as an impurity by mass
Scheme 1. Synthesis of Botryllazine B (1)

Alkaloids from Botryllus Leachi
335
Scheme 2. Synthesis of 2-(p-hydroxybenzoyl)-4-(p-hydroxyphenyl)imidazole (2)
spectroscopy, bromine was removed from the compound by treatment of crude
alkaloid 1 with hydrogen=Pd on charcoal in 1 N NaOH solution [8].
The substitution pattern of 1 was characterized with special emphasis to the 4J
and J-values [9] of the pyrazine carboxylic acids 5 and 6. Whereas the 5-substi-
5
5
tuted compound 5 showed J ¼ 1.5 Hz, the signals of 6 showed no coupling and
only a small broadening of the respective singlets, similar to the 1H NMR pyrazine
signals of 1 [1]. Furthermore, the identity of the synthetically obtained compound 1
and the naturally occurring alkaloid described by Duran et al. [1] as Botryllazine B
was proved by comparison of the 1H NMR, 13C NMR, and EI MS data with those
reported, although a difference in IR spectra can be observed (cf. Exp.).
The imidazole alkaloid 2 was synthesized according to Scheme 2 by condensa-
tion of p-methoxyphenylglyoxale (4) [2] with ammonium acetate according to
Schubert [10], resulting in 10 [11] followed by cleavage of the methoxy groups
[7] as described for alkaloid 1. In the case of compound 2, the analytical data
reported for the natural product by Duran et al. [1] differ more significantly from
1
our H NMR, 13C NMR, and IR spectroscopic data.
Tautomerism of 2-(Aroyl)-4-arylimidazoles
Annular tautomerism at imidazole systems is well known [12]. Also in the synthe-
sized 2-(aroyl)-4-arylimidazoles 10 and 2 tautomerism was well observable by
1H NMR spectroscopy in CD3OD solution. Additional measurements in DMSO-
d6 solution were performed, in order to obtain resonance signals for the imidazole
N–H and phenolic hydrogens. The tautomeric equilibrium constants K were deter-
mined, respecting the integral intensities of the well separated phenolic and aro-
matic hydrogen atoms as shown in Fig. 2. The signals of the tautomeric structures
of 10 were characterized by the coupling constants of the imidazole nucleus
4
(3JA ¼ 2.4 Hz, JB ¼ 1.6 Hz) and their relations in intensity, after identification of
the respective N–H signals by H=D exchange in DMSO-d6 solution. Analogously,
the tautomeric equilibrium of 2 in DMSO-d6 solution was determined (Fig. 2). In
order to confirm the assignment of the tautomers, a NOE experiment was per-
formed in case of 2. The resonance signals for the imidazole N–H of tautomer
2A exhibit a well observable NOE effect to the related imidazolyl hydrogen. The
tautomer 2B exclusively shows relation to the AA0 system of the phenyl hydrogens
of B at 7.76 ppm. In pure CD3OD solution no duplication of the resonance signals
as in DMSO-d6 solution but very broadened signals were observed, indicating fast
interconversion. Furthermore, the formation of the tautomeric equilibrium of 2 was
accelerated by addition of a catalytic amount of CF3COOD, resulting in a coalesc-

336
S. Mahboobi et al.
Fig. 2. 1H NMR spectrum of 2 (DMSO-d6, c ¼ 8 mg=cm3); the tautomerism constants of 2-aroyl-4-
1
arylimidazoles 2 and 10 were determined according to the respective signal intensities in the H
NMR spectra; after addition of a catalytic amount of acid the coalescence spectra are observed (not
shown)
ence of the 1H NMR spectra, independent of the solvent used for measurement (not
shown).
Surprisingly, Duran et al. [1] report no duplication and no broadening of
1H NMR signals, indicating fast interconversion of tautomers – a result we could
obtain by addition of catalytic amounts of acid only.
Although the coalescence spectra we obtained, exhibit all the characteristics
described by Duran et al. [1], aberrations of the respective chemical shifts in the
1H NMR as well as in the 13C NMR spectra occurred. These aberrations may be
explained by different concentrations in measurement, as a strong concentration
1
dependent shift of H NMR signals for 2 has been observed by us in CD3OD
solution. A direct comparison of NMR spectral data with those of the literature
was not possible, for the concentration used by Duran et al. [1] is not reported.
A comparison of the respective analytical data of natural 2 and of 2 obtained by
synthesis is shown in Table 1.
Concerning the aberrations in the 13C NMR spectra, especially the shift of the
weak resonance signals caused by the quarternary C-atoms of the imidazole
nucleus at ꢀ ¼ 140.9 (lit. 155.9, C-4) and 145.1 ppm (lit. 158.3, C-2) is surprising

Alkaloids from Botryllus Leachi
337
Table 1. Analytical data of natural and synthetic 2
Data from Ref. [1]
Data of synthetic 2
1H NMR, ꢀ ppm
13C NMR, ꢀ ppm
6.84 (d, 2H), 6.89 (d, 2H),
7.59 (s, 1H), 7.71 (d, 2H),
8.38 (d, 2H)
6.90 (AA0, 2H), 6.97 (BB0, 2H),
7.67 (AA0, 2H), 7.77 (s, 1H),
8.13 (XX0, 2H)
117.1 (d, 2C), 117.2 (d, 2C),
119.5 (s, 1C), 122.9 (d, 1C),
126.8 (s, 1C), 128.1 (d, 2C),
134.8 (d, 2C), 155.9 (s, 1C),
158.3 (s, 1C), 160.8 (s, 1C),
167.7 (s, 1C), 172.2 (s, 1C)
116.4 (d, 2C), 116.8 (d, 2C),
120.5 (d, 1C), 122.7 (s, 1C),
128.4 (d, 2C), 128.6 (s, 1C),
134.6 (d, 2C), 140.9 (s, 1C),
145.1 (s, 1C), 159.4 (s, 1C),
164.5 (s, 1C), 180.8 (s, 1C)
IR, ꢁꢀ=cmꢂ1
3380, 3290, 1590, 1470,
1260 cmꢂ1
3388, 3251, 1617, 1602, 1440,
1273 cmꢂ1
EI-MS (70 eV)
281 (15) ½M þ 1ꢃþꢄ, 121 (100),
281 (16) ½M þ 1ꢃþꢄ, 280 (100)
½Mꢃþꢄ, 252 (66), 121 (70),
93 (18), 65 (16)
m=z (%)
93 (13), 65 (14)
as well as the lack of a carbonyl group in the IR spectral data. Furthermore, Duran
et al. [1] do not give a signal in the EI-MS for the molecular ion – a signal that is
the most intensive of our measurements. Nevertheless, the fragmentation pattern
seems to be in good correlation.
To confirm the structure of the synthetically obtained imidazole derivative 2 we
decided to perform an X-ray structure analysis. On sublimation in vacuum at 0.2
Torr=200ꢁC suitable crystals for X-ray structure analysis were obtained. The X-ray
data revealed that compound 2 is indeed the described imidazole derivative,
existing obviously exclusively as the 2-(p-hydroxybenzoyl)-5-(p-hydroxyphenyl)
imidazole tautomer in solid state – in contrast to DMSO-d6 solution where the
2-(p-hydroxybenzoyl)-4-(p-hydroxyphenyl)imidazole tautomer is the predominant
observable tautomer (Fig. 3).
In order to exclude the possibility, that compound 2 isolated by Duran et al.,
exhibiting the analytical characteristics of a disubstituted imidazole nucleus, might
be the isomeric 4-(p-hydroxybenzoyl)-2-(p-hydroxyphenyl)imidazole (14), this
compound was synthesized and characterized in addition (Scheme 3).
Fig. 3. Structure of 2 in the crystal according to X-ray structure analysis

338
S. Mahboobi et al.
Scheme 3. Synthesis of 4-(p-hydroxybenzoyl)-2-(p-hydroxyphenyl)imidazole (14)
1
The H NMR spectra of 14 exhibit two AA0BB0 systems and no observable
tautomerism in DMSO-d6 as well as in CD3OD solution as described for the sample
isolated by Duran et al. This may be due to fast interconversion or possibly to the
stabilization of the tautomeric 5-(p-hydroxybenzoyl)-2-(p-hydroxyphenyl)imid-
azole by an intramolecular hydrogen bond between the carbonyl group and the
N–H hydrogen. Nevertheless, comparison of the respective 1H NMR and 13C NMR
data obtained for 14 with the data given for 2, excludes a mistake in interpretation
because they differ significantly.
Conclusion
The structure of alkaloid Botryllazine B (1) obtained from Botryllus leachi was
confirmed by synthesis and comparison with data from the literature [1]. 2-(p-
Hydroxybenzoyl)-4-(p-hydroxyphenyl)imidazole (2) was synthesized, the analyti-
cal data were discussed and compared with data from the literature. The possibility
of an identity with the isomeric 5-(p-hydroxybenzoyl)-2-(p-hydroxyphenyl)imid-
azole (14) was excluded by synthesis and characterization of 14. Therefore,
although there are deviations of the analytical data from the natural compound
and the synthetic sample, it seems reasonable that the structure proposed by Duran
et al. [1] is in agreement with structure 2. Compounds 2 and 10 exhibit annular
1
tautomerism observable by H NMR spectroscopy and can be characterized by
their tautomeric equilibrium constants K.
Experimental
1H NMR 250 MHz and 13C NMR 62.5MHz spectra were recorded with a Bruker AC 250 F spectro-
meter at 300 K, using TMS as an internal standard. The 1H NMR signals of the tautomeric phenyl(ar-
ylimidazol-2-yl)methanones are characterized using the indices A or B according to Table 1 as far as an

Alkaloids from Botryllus Leachi
339
exact identification was possible with respect to intensity (cf. K values in Table 1), NOE experi-
ments, and=or coupling constants. Signals which result from both tautomers are given both indices.
AA0BB0 and AA0XX0 spectra are characterized by the center of the respective AA0, BB0, or XX0 part.
In order to confirm quaternary (s) and H bound carbon atoms (d), DEPT-135 experiments were
1
performed additionally in case of 13C NMR spectra. H NMR NOE experiments were recorded with
a Bruker BioSphere Avance 600 MHz spectrometer. – Elemental analyses were performed by the
Analytical Lab. Univ. Regensburg; results were in favorable agreement with the calculated values.
Melting points were determined with a Reichert hot-stage microscope. IR spectra (KBr) were
measured with a FT Nicolet 510 spectrometer, MS spectra were measured with a Finnigan MAT
95 (EI, 70eV).
5- and 6-(p-Methoxyphenyl)pyrazine-2-carboxylic acid (5 and 6)
To a stirred solution of 11.2g of NaOH (280mmol) and 13.0g of 2,3-diaminopropionic acid hydro-
bromide (70.0 mmol) [5] in 0.7 dm3 of MeOH, 11.5g of p-methoxyphenylglyoxal (70.0 mmol) [2]
were added at 20ꢁC. Air was bubbled through the solution (12 h), and the solvent was removed under
reduced pressure. The residue of sodium salts was extracted with 140 cm3 of cold water. Acidification
of the aqueous solution with conc. HCl afforded 6 which was purified by CC (SiO2, EtOH) and
crystallized (EtOH). The remaining sodium salt of 5 was dissolved in 560cm3 of hot water. The
carboxylic acid was liberated as mentioned above and crystallized (Rf of 5<Rf of 6, butyl acetate: Ac
OH: H2O ¼ 40:10:2).
5-(p-Methoxyphenyl)pyrazine-2-carboxylic acid (5, C12H10N2O3)
Yield 3.51 g (22%) white crystals, mp 228–230ꢁC; IR: ꢁꢀ¼ 1692 cmꢂ1; 1H NMR (DMSO-d6): ꢀ ¼ 3.86
(s, 3H), 7.13 (AA0, 2H, aromat.), 8.22 (XX0, 2H, aromat.), 9.17 (d, 1H, pyrazine, 5J ¼ 1.4 Hz), 9.33 (d,
ꢄ
5
1H, pyrazine, J ¼ 1.4Hz), 13.57 (s, br, 1H, exchangeable) ppm; EI-MS: m=z (%) ¼ 230 (97) [M]þ ,
186 (100), 133 (26), 132 (55).
*
6-(p-Methoxyphenyl)pyrazine-2-carboxylic acid (6, C12H10N2O3 1=6 H2O)
1
Yield 3.69g (23%) light yellowish crystals, mp 211–213ꢁC; IR: ꢁꢀ¼ 1732, 1611cmꢂ1; H NMR
(DMSO-d6): ꢀ ¼ 3.85 (s, 3H), 7.13 (AA0, 2H, aromat.), 8.20 (XX0, 2H, aromat.), 9.05 (s, 1H, pyrazine),
ꢄ
9.41 (s, 1H, pyrazine), 13.70 (s, br, 1H, exchangeable) ppm; EI-MS: m=z (%) ¼ 230 (100) [M]þ , 186
(84), 133 (19), 132 (17).
[6-(p-Methoxyphenyl)pyrazin-2-yl](morpholin-4-yl)methanon (7, C16H17N3O3)
A solution of 3.68g of the carboxylic acid 6 (16.0 mmol) in 50cm3 of SOCl2 was refluxed for 1 h.
The excess of SOCl2 was removed under reduced pressure and the resulting crude product was
dried in vacuo. Then it was dissolved in 50cm3 of CH2Cl2, and a solution of 4.20cm3 of
morpholine (48.0 mmol) in 20 cm3 of CH2Cl2 was added at 0ꢁC. The mixture was stirred at
20ꢁC for 12 h, 50 cm3 of 2% aqueous Na2CO3 solution were added, the organic layer was
separated, washed with 50cm3 of water, dried (Na2SO4), and the solvent was removed. The
product was crystallized from Et2O: petroleum ether (1:1) yielding 3.88g of 6 (81%) as white
1
crystals. Mp 105–106ꢁC; IR: ꢁꢀ¼ 2844, 1636, 1609 cmꢂ1; H NMR (CDCl3): ꢀ ¼ 3.76 (s, br, 4H),
3.86 (m, 4H), 3.89 (s, 3H), 7.04 (AA0, 2H, aromat.), 7.98 (XX0, 2H, aromat.), 8.82 (d, 1H,
4J ¼ 0.5 Hz, pyrazine), 9.03 (d, 1H, 4J ¼ 0.5 Hz, pyrazine) ppm; EI-MS: m=z (%) ¼ 299 (43)
ꢄ
[M]þ , 186 (70), 158 (16), 86 (100).

340
S. Mahboobi et al.
[6-(p-Methoxyphenyl)pyrazin-2-yl](p-methoxyphenyl)methanone (9, C19H16N2O3)
To a vigorously stirred solution of 0.66cm3 of 1-bromo-4-methoxybenzene (8) (5.25 mmol) in 90cm3
of dry THF a 1.5M solution of tBuLi (10.5mmol) in n-pentane was added at ꢂ100ꢁC. After 15min a
solution of 1.57g of 7 (5.25 mmol) in 30cm3 of THF, pre-cooled to ꢂ78ꢁC, was added at once, and the
mixture was stirred for 1.5 h. Hydrolysis of the yellowish to red coloured solution with 100 cm3 of a
2% aqueous Na2CO3 and extraction with 3 ꢅ 50cm3of CH2Cl2 afforded the product 9, which was
purified by CC (SiO2, ethyl acetate) and crystallization (Et2O: petroleum ether ¼ 1:1). Yield 1.26g
(75%) white crystals, mp 120.5–121.5ꢁC; IR: ꢁꢀ¼ 2837, 1649, 1604cmꢂ1; 1H NMR (CDCl3): ꢀ ¼ 3.89
(s, 3H), 3.92 (s, 3H), 7.01 (AA0, 2H, aromat.), 7.04 (BB0, 2H, aromat.), 8.04 (AA0, 2H, aromat.), 8.23
(BB0, 2H, aromat.), 9.04 (s, 1H, pyrazine), 9.15 (s, 1H, pyrazine) ppm.
Botryllazine B (1, C17H12N2O3)
A mixture of 1.10g of 9 (3.43 mmol), 25 cm3 acetic acid, and 40 cm3 of 48% HBr was refluxed for
12h. Half of the solvent was removed under reduced pressure, the mixture was cooled to room
temperature, and the precipitate was filtered off. The solid was dissolved in 50 cm3 of 1 N NaOH, a
small amount of Pd=C (10%) was added, and the mixture was stirred at room temperature under
hydrogen at atmospheric pressure overnight. The solution was filtered, neutralized with dil. HCl, and
the product was removed. Crystallization from ethanol=water yielded 0.432 g (43%) of yellow crystals.
1
Mp 206–208ꢁC; IR: ꢁꢀ¼ 3400, 3253, 1644, 1603cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.92 (AA0, 2H,
aromat.), 6.93 (BB0, 2H, aromat.), 7.98 (AA0, 2H, aromat.), 8.02 (BB0, 2H, aromat.), 8.89 (s, 1H,
pyrazine), 9.35 (s, 1H, pyrazine), 9.98 (s, 1H, exchangeable), 10.57 (s, 1H, exchangeable) ppm;
1H NMR (CD3OD): ꢀ ¼ 6.90 (AA0, 2H, aromat.), 6.91 (BB0, 2H, aromat.), 7.98 (AA0, 2H, aromat.),
8.06 (BB0, 2H, aromat.), 8.84 (s, 1H, pyrazine), 9.16 (s, 1H, pyrazine) ppm; 13C NMR (CD3OD):
ꢀ ¼ 116.3 (d, 2C), 117.1 (d, 2C), 128.1 (s, 1C), 128.7 (s, 1C), 129.8 (d, 2C), 134.9 (d, 2C), 142.8 (d,
1C), 143.5 (d, 1C), 151.4 (s, 1C), 152.4 (s, 1C), 161.3 (s, 1C), 164.4 (s, 1C), 192.4 (s, 1C) ppm; EI-MS:
ꢄ
m=z (%) ¼ 292 (33) [M]þ , 121 (100), 93 (23).
2-(p-Methoxybenzoyl)-4-(p-methoxyphenyl)imidazole (10, C18H16N2O3)
Compound 10 was synthesized from p-methoxyphenylglyoxal (4) [2] according to Ref. [10]. The
1H NMR data by Kong et al. [11] who give only the data for the predominant tautomer are completed
as follows: 1H NMR (DMSO-d6), c ¼ 8 mg=cm3): ꢀ ¼ 3.79 (s, 3HA), 3.81 (s, 3HB), 3.88 (s, 3HB), 3.89
(s, 3HA), 6.99 (AA0, 2HA, aromat.), 7.02 (AA0, 2HB, aromat.), 7.10 (BB0, 2HB, aromat.), 7.14 (BB0,
2HA, aromat.), 7.65 (d, 1HB, 4J ¼ 1.6 Hz), 7.85 (AA0, 2HA, 2HB, aromat.), 7.91 (d, 1HA, 3J ¼ 2.4 Hz),
8.55 (XX0, 2HB, aromat.), 8.69 (XX0, 2HA, aromat.), 13.42 (s, 1HA, NH, exchangeable), 13.55 (s, 1HB,
NH, exchangeable) ppm. The ꢀ values of the coalescence spectra – after addition of a catalytical
amount of CF3COOH – are as follows: 1H NMR (DMSO-d6, c ¼ 8 mg=cm3): ꢀ ¼ 3.81 (s, 3H), 3.90 (s,
3H), 7.04 (AA0, 2H, aromat.), 7.17 (BB0, 2H, aromat.), 7.86 (AA0, 2H, aromat.), 8.52 (XX0, 2H,
aromat.) ppm.
2-(p-Hydroxybenzoyl)-4-(p-hydroxyphenyl)imidazole (2, C16H12N2O3)
Synthesis by cleavage of the methoxy groups of 0.48g of 10 (1.56 mmol) as described for Botryllazine
B (1) without use of acetic acid as a co-solvent by heating for 4 h. Yield 0.33g (75%) of a yellow
powder, mp 295–297ꢁC; IR: ꢁꢀ¼ 3388, 3251, 1617 cmꢂ1
;
1H NMR (DMSO-d6, c ¼ 8 mg=cm3):
ꢀ ¼ 6.81 (AA0, 2HA, 2HB, aromat.), 6.90 (BB0, 2HB, aromat.), 6.93 (BB0, 2HA, aromat.), 7.56 (s,
1HB), 7.73 (AA0, 2HA, aromat.), 7.76 (AA0, 2HB, aromat.), 7.80 (d, 1HA, J ¼ 2.2 Hz), 8.47 (XX0,
3
2HB, aromat.), 8.60 (XX0, 2HA, aromat.), 9.46 (s, 1HA, exchangeable), 9.74 (s, 1HB, exchangeable),

Alkaloids from Botryllus Leachi
341
10.38 (s, 1HB, exchangeable), 10.43 (s, 1HA, exchangeable), 13.31 (s, 1HA, exchangeable), 13.40 (s,
1HB, exchangeable) ppm. The ꢀ values of the coalescence spectra – after addition of a catalytical
1
amount of CF3COOH – are as follows: H NMR (CD3OD, c ¼ 9 mg=cm3): ꢀ ¼ 6.90 (AA0, 2H,
aromat.), 6.97 (BB0, 2H, aromat.), 7.67 (AA0, 2H, aromat.), 7.77 (s, 1H), 8.13 (XX0, 2H, aromat.)
1
ppm; H NMR (DMSO-d6, 8 mg=cm3): ꢀ ¼ 6.87 (AA0, 2H, aromat.), 6.97 (BB0, 2H, aromat.), 7.77
(AA0, 2H, aromat.), 7.90 (s, 1H, aromat.), 8.37 (XX0, 2H, aromat.) ppm; 13C NMR (CD3OD,
c ¼ 18 mg=cm3): ꢀ ¼ 116.4 (d, 2C), 116.8 (d, 2C), 120.5 (d, 1C), 122.7 (s, 1C), 128.4 (d, 2C), 128.6
(s, 1C), 134.6 (d, 2C), 140.9 (s, 1C), 145.1 (s, 1C), 159.4 (s, 1C), 164.5 (s, 1C), 180.8 (s, 1C) ppm; EI-
MS: m=z (%) ¼ 281 (16) [Mþ 1]þ, 280 (100) ½Mꢃþꢄ, 93 (18), 65 (16).
Crystal structure analysis of compound 2. The data were collected on an Enraf Nonius CAD4
diffractometer, using graphite-monochromated Cu-Kꢂ radiation. Data were corrected using Lorentz-
and polarisation correction. Loss of intensity (10%) corrected with cubic spline function. The structure
was solved by a SIR-92 program (direct methods), refinement performed with a SHELXL97 pro-
gram (full matrix refinement) by 205 refined parameters. Weighting schema: w ¼ 1=[(ꢃ2(Fo) þ
2
ꢀ
ꢀ
2
ꢀ
2
(0.1019 P) þ 0.45 P] with P ¼ (Max(Fo ,0) þ 2 Fc )=3.0. H-atoms placed at calculated positions
and refined isotrop with riding motion. OHs and NH found in diff. Fourier maps. Non H-atoms were
refined anisotropic. R-values wR2 ¼ 0.2152 (R1 ¼ 0.0735 for 1679 reflections with Fo > 4ꢃ(Fo)). Good-
ꢀ
ness of fit: S ¼ 1.020. Flack parameter x ¼ ꢂ0.06(68). Maximal deviation of parameters: 0.001 e.s.d.
ꢂ3
˚
Maximal peak height in diff. Fourier map 0.76, ꢂ0.17 eA
.
Crystal data for C16H12N2O3: Weight 280.28gmolꢂ1; crystal size 0.032ꢅ 0.096 ꢅ 0.576 mm yel-
low needle; absorption ꢄ ¼ 0.82mmꢂ1; space group Pna21 (orthorhombic); lattice parameters (calcu-
ꢁ
ꢁ
˚
˚
˚
lated from 25 reflections with 25 <ꢅ<27 ), a ¼ 19.547(4) A, b ¼ 12.237(12) A, c ¼ 5.5049(8) A;
3
V ¼ 1317(1) A ; z ¼ 4; F(000) ¼ 584; temperature 295 K, density dX ¼ 1.414 g cmꢂ3. Anisotropic dis-
˚
placement parameters and complete lists of final coordinates and equivalent displacement parameters
have been deposited with the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK. The data are available on request on quoting CCDC 215662.
2-p-Methoxyphenyl-1-phenylsulfonyl-1H-imidazole (12, C16H14N2O3S)
To a solution of 1.70g of 2-p-methoxyphenyl-1H-imidazole (11) [7] (9.76 mmol) in 30cm3 of THF an
equimolar amount of NaH (60% in paraffin) was added in portions at 0ꢁC during 1 h. The mixture was
allowed to reach room temperature, stirred for 1 h, and after cooling to 0ꢁC, 1.25cm3 of benzenesulfonyl
chloride (9.76 mmol) was added. After 1 h the mixture was poured into a 2% aqueous NaCO3 solution
and the product was extracted with 3 ꢅ 100 cm3 of methylene chloride. The combined organic layers
were dried (Na2SO4) and the product was purified by CC (SiO2, CH2Cl2: ethyl acetate ¼ 1:1). Yield
2.16g (70%) of a colourless solid, mp 79.5–80ꢁC; 1H NMR (CDCl3): ꢀ ¼ 3.87 (s, 3H), 7.33 (AA0, 2H,
aromat.), 7.09 (d, 1H, J ¼ 1.6 Hz), 7.30–7.43 (m, 6H, aromat.), 7.51–7.58 (m, 1H, aromat.), 7.62 (d,
1H, J ¼ 1.6 Hz) ppm;. EI-MS: m=z (%) ¼ 314 (8) ½Mꢃþꢄ, 173 (100), 158 (6), 77 (5).
4-(p-Methoxybenzoyl)-2-(p-methoxyphenyl)-3H-imidazole (13, C18H16N2O3)
To 1.90 g of 12 (6.05 mmol) in 30 cm3 of dry THF 6.35mmol of tBuLi (1.5M in pentane) were added
at ꢂ100ꢁC. After 5 min 0.86 cm3 of a solution of p-methoxybenzoyl chloride (6.35 mmol) in THF,
cooled to ꢂ78ꢁC, was added at once. The mixture was allowed to reach room temperature over night.
Tetrabutylammonium fluoride trihydrate (2.05 g, 6.50 mmol) was added, the mixture was stirred for 1 h
and poured into a 2% aqueous NaCO3 solution. The product was extracted with 3ꢅ100 cm3 of ethyl
acetate. The combined organic layers were dried (Na2SO4), and the product was purified by crystal-
lization from ethyl acetate. One-pot synthesis by use of 11 without isolation of 12 also yielded the
desired product in the same amount. Yield 0.48g (26%) of colourless crystals, mp 226ꢁC; IR:
1
ꢁꢀ¼ 3245, 1611 cmꢂ1; H NMR (MeOD, CF3COOD, sat. solution): ꢀ ¼ 3.93 (s, 3H), 3.94 (s, 3H),

342
S. Mahboobi et al.: Alkaloids from Botryllus Leachi
7.14 (AA0, 2H, aromat.), 7.23 (BB0, 2H, aromat.), 8.00 (AA0, 2H, aromat.), 8.05 (BB0, 2H, aromat.),
8.26 (s, 1H) ppm; EI-MS: m=z (%) ¼ 308 (100) ½Mꢃþꢄ, 201 (7), 200 (21), 135 (15), 107 (1).
*
4-(p-Hydroxybenzoyl)-2-(p-hydroxyphenyl)-3H-imidazole (14, C16H12N2O3 H2O)
Synthesis by cleavage of the methoxy groups of 0.69g of 13 (2.24 mmol) as described for Botryllazine
B (1) without use of acetic acid as a co-solvent. Yield 0.58g (92%) of yellow crystals, mp 289–295ꢁC;
1
IR: ꢁꢀ¼ 3261, 1610 cmꢂ1; H NMR (CD3OD): ꢀ ¼ 6.91 (AA0, 2H, aromat.), 6.93 (BB0, 2H, aromat.),
1
7.72 (s, 1H, aromat.), 7.86 (AA0, 2H, aromat), 7.93 (BB0, 2H, aromat) ppm; H NMR (DMSO-d6):
ꢀ ¼ 6.87 (AA0, 2H, aromat.), 6.90 (BB0, 2H, aromat.), 7.82 (s, 1H, aromat.), 7.95 (AA0, 2H, aromat.),
8.06 (BB0, 2H, aromat.), 9.84 (s, 1H, exchangeable), 10.25 (s, 1H, exchangeable), 13.24 (s, 1H,
exchangeable) ppm; 13C NMR (CD3OD): ꢀ ¼ 116.4 (d, 2C), 116.9 (d, 2C), 121.3 (s, 1C), 129.3 (d,
2C), 130.7 (s, 1C), 132.8 (d, 2C), 133.7 (s, 1C), 135.9 (s, 1C), 151.7 (s, 1C), 160.8 (s, 1C), 163.8 (s,
1C), 186.0 (s, 1C) ppm; EI-MS: m=z (%) ¼ 280 (100) ½Mꢃþꢄ, 251 (6), 187 (13), 186 (22), 132 (21).
Acknowledgements
We thank Dr. Holger Fleischer, Institute of Inorganic and Analytical Chemistry, University of Mainz,
Germany, for growing crystals suitable for a single crystal X-ray diffraction analysis.
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Verleger: Springer-Verlag KG, Sachsenplatz 4–6, A-1201 Wien. – Herausgeber: Osterreichische Akademie der Wissenschaften,
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Dr.-Ignaz-Seipel-Platz 2, A-1010 Wien, und Gesellschaft Osterreichischer Chemiker, Eschenbachgasse 9, A-1010 Wien. –
Redaktion: Wa¨hringer Straꢁe 38, A-1090 Wien. – Satz und Umbruch: Thomson Press Ltd., Chennai, India. – Offsetdruck:
Manz Crossmedia, A-1051 Wien. – Verlagsort: Wien. – Herstellungsort: Wien. – Printed in Austria.