Total synthesis of phorbazole C

Article abstract of DOI:10.1016/S0040-4020(01)00425-2

The first total synthesis of the marine natural product phorbazole C 1 occurring in the sea sponge Phorbas aff. clathrata is reported. In the key steps of the convergent approach the 3,4-dichloro-5-ethoxycarbonyl-pyrrole-2-carboxylic acid (4) forms an ami

Full text of DOI:10.1016/S0040-4020(01)00425-2

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 4867±4871
Total synthesis of phorbazole C
Alexander Radspieler and JuÈrgen Liebscherp
È È
Institut fur Chemie, Humboldt-Universitat zu Berlin, Hessische Strasse 1-2, D-10115Berlin, Germany
Dedicated to Professor Dr Siegfried HuÈnig on the occasion of his 80th birthday
Received 15 February 2001; revised 12 April 2001; accepted 13 April 2001
AbstractÐThe ®rst total synthesis of the marine natural product phorbazole C 1 occurring in the sea sponge Phorbas aff. clathrata is
reported. In the key steps of the convergent approach the 3,4-dichloro-5-ethoxycarbonyl-pyrrole-2-carboxylic acid 24) forms an amide 9 with
protected 4-22-amino-1-hydroxyethyl)phenol 3 and the central oxazole is established by cyclodehydration of the acylaminoketone 2. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
in the synthesis of an isomer of phorbazole A.3 We report
here the ®rst total synthesis of phorbazole C 1.
Phorbazole C 1 belongs to a family of four compounds ®rst
isolated by Kashman et al.1 from the sea sponge Phorbas aff.
clathrata collected at Sodwana Bay, South Africa in 1994.
These compounds have in common a unique structure of a
pyrrole-, an oxazole- and a phenol ring, but differ in number
and positions of chloro atoms. Little is known about the
physiological properties of phorbazoles. For further exam-
inations, it would be necessary to ®nd easy access to these
materials. To the best of our knowledge a total synthesis of
phorbazole C is not known so far. A synthetic study reported
an approach to the backbone-structure, i.e. crucial substitu-
ents were missing in the product.2 Recently, we succeeded
2. Results and discussion
The structure was approached in a convergent retrosynthetic
manner according to Scheme 1with formation of an amide 2
starting from the aminoethanol 3 and the dichloropyrrole-
carboxylic acid 4 and formation of the oxazole ring by
cyclodehydration of the acylaminoketone 2 as key steps.
4-Hydroxybenzaldehyde 25) was protected as ethoxyethyl-
acetal 6 according to a literature procedure4 followed by
Scheme 1. Retrosynthetic analysis of phorbazole C 21).
Keywords: total synthesis; phorbazole C; natural product; oxazole.
Corresponding author. Tel.: 149-30-2093-9039; fax: 149-30-2093-8907; e-mail: liebscher@chemie.hu-berlin.de
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)00425-2

4868
A. Radspieler, J. Liebscher / Tetrahedron 57 /2001) 4867±4871
Scheme 2. 2a) EtO±CHCH2, MOM-Cl [cat], Et2O, 78%; 2b) MeNO2, NEt3, DMSO, rt, 84%; 2c) H2, 20 bar, Pd/C, NEt3HCl, EtOH, rt, 88%; 2d) 1. SO2Cl2, Et2O,
re¯ux; 2. H2O, dioxane, 908C, 47%; 2e) DCC, HOBt, EtNiPr2, CH2Cl2, rt., 65%; 2f) DMP, CH2Cl2, rt, 98%; 2g) PPh3, C2Cl6, NEt3, CH2Cl2, rt, 87%; 2h) HCl
21M), EtOH, THF, rt, 77%; 2i) NaOH 22 M), EtOH, re¯ux, 84%; 2j) H 2NC2H4OH, 1708C, 85%; 2k) MeI, K2CO3.
homologation using a Henry reaction with nitromethane and
triethylamine in DMSO 2Scheme 2). The resulting nitro-
aldol 7 was catalytically hydrogenated to the aminoethanol
3 under mild conditions 220 bar, room temperature) in the
presence of triethylamine hydrochloride as weak proton
source. The pyrrolecarboxylic acid 4 was accessible from
known ethyl 5-methylpyrrole-2-carboxylate 5 28) by oxida-
tive chlorination with sulfuryl chloride. The crude product
was hydrolysed in a dioxan solution at 908C. The amide
formation of the resulting pyrrolecarboxylic acid 4 with
the aminoethanol 3 was achieved with DCC as coupling
reagent in the presence of HOBt and ethyldiisopropylamine
in dichloromethane in 65% yield. Other commonly used
reagents 2SOCl2, BuOCOCl, BOP-Cl) failed to effect this
transformation or provided considerably lower yields 2EDC,
DPPA, TBTU, HATU). The acylaminoalcohol 9 could be
oxidised to the ketone 2 in excellent yields by Dess±Martin
periodinane 2DMP).6 Cyclodehydration of the acylamino-
ketone 2 to the oxazole 10 was successful using a modi®ed
Wipf protocol 2triphenylphosphine, perchloroethane, triethyl-
amine).7,8 The yield could even be slightly increased by the
use of polymer bound triphenylphosphine 287% versus
81%). Classical reagents for oxazole syntheses by cyclo-
dehydration9 such as SOCl2, POCl3 or Ac2O did not afford
formation of the oxazole ring but resulted in deprotection of
the phenolic hydroxy group of 2 instead. The oxazole 10

A. Radspieler, J. Liebscher / Tetrahedron 57 /2001) 4867±4871
4869
7.75 2d, 2H, Jˆ8.7 Hz, OphCphCHphCH), 9.812s, H1,
HCvO); 13C NMR 275 MHz, CDCl3): d 15.1 2CH3CH2O),
19.9 2CH3CHO2), 61.1 2CH3CH2O), 99.12CH 3CHO2), 116.8
2OphCphCH), 130.4 2phCCHvO), 131.8 2OphCphCHphCH),
162.1 2OphC), 190.8 2HCvO).
3.2.2. 1-[4-)1-Ethoxyethoxy)phenyl]-2-nitro-1-ethanol )7).
To a solution of 6 23.88 g, 0.02 mol) and nitromethane
23.2 mL, 0.06 mmol) in dry DMSO 215 mL) NEt3
22.79 mL, 0.02 mol) was added. After standing at room
temperature for 14 h, the mixture was poured into a satu-
rated aqueous NH4Cl solution. The pH was brought to 7 by
adding 0.1M hydrochloric acid and the mixture was
extracted with Et2O 22£150 mL). The combined organic
layers were washed with brine, dried 2MgSO4) and concen-
trated with a rotatory evaporator. Column chromatography
with hexane/EtOAc 29:1) afforded starting material
2349 mg, 9%). Further eluation with hexane/EtOAc 28:2)
gave 4.29 g 284%) of product 7 as colorless oil. Rfˆ0.25
Figure 1. A molecule of O-methylated phorbazole C 13 in the crystal.11
was deprotected by treatment with diluted hydrochloric
acid10 and the ester moiety of resulting ethyl hydroxy-
phenyloxazolylpyrrolecarboxylate 11 was saponi®ed with
diluted NaOH. Final decarboxylation of the resulting
pyrrole-2-carboxylic acid 12 was achieved by heating in
1,2-aminoethanol at 1708C, while re¯ux with sodium
hydroxide in ethanol or glycol was not forcing enough for
this transformation.
1
2hexane/EtOAcˆ7:3); H NMR, CDCl3) d 1.18 2t, 3H, Jˆ
7.1Hz, C H3CH2O), 1.48 2d, 3H, Jˆ5.3 Hz, CH3CHO2),
2.93 2brs, 1H, OH), 3.54 2dq, 1H, Jˆ9.3, 7.1Hz,
CH3CHH0O), 3.75 2dq, 1H, Jˆ9.3, 7.1Hz, CH 3CHH0O),
4.46 2dd, 1H, Jˆ13.6, 3.2 Hz, CHH0NO2), 4.58 2dd, 1H,
Jˆ13.5, 9.5 Hz, CHH0NO2), 5.35±5.42 2m, 2H, CHOH,
CH3CHO2), 7.00 2d, 2H, Jˆ8.7 Hz, OphCphCH), 7.29 2d,
2H, Jˆ8.6 Hz, OphCphCHphCH); 13C NMR CDCl3): d 15
2CH3CH2O), 20.5 2CH3CHO2), 61.7 2CH3CH2O), 71.0
2HOCH), 81.6 2NO2CH2), 99.8 2CH3CHO2), 118.1
2OphCphCH), 127.7 2OphCphCHphCH), 131.7 2phCCHOH),
157.8 2OphC).
High yields were obtained in all steps. Thus the total yield of
the transformation of 4-hydroxybenzaldehyde 5 into phor-
bazole C 1 via 9 steps was 18%. The material 1 obtained in
this synthetic pathway showed spectroscopic data identical
with those of natural phorbazole C.1 The structure was
further veri®ed by X-ray analysis of the O-methyl derivative
13 2Fig. 1).11
3. Experimental
3.1. General
3.2.3. 2-Amino-1-[4-)1-ethoxyethoxy)phenyl]-ethanol )3).
A mixture of 7 25.10 g, 0.02 mol), triethylammonium
chloride 22.75 g, 0.02 mmol), 10% Pd/C 2200 mg), EtOH
270 mL) and water 27 mL) was hydrogenated in an auto-
clave 2coated with glass) at 20 bar under stirring for 5 h.
Eventually more hydrogen gas must be provided if the pres-
sure drops too much. The reaction mixture was ®ltered and
the residue was washed with EtOH 230 mL). The combined
®ltrate was diluted with saturated aqueous K2CO3 2100 mL).
The volume of the mixture was reduced to its half by a
rotatory evaporator. After extraction with EtOAc 23£
70 mL) and drying 2MgSO4) the solvent was removed
under vacuum and the residue was puri®ed by column
chromatography CH2Cl2/MeOH/NEt3 29:1:0.5) affording 3
23.965 g, 88%) as pale yellow oil. Rfˆ0.25 2CH2Cl2/MeOH/
NEt3ˆ9:1:0.5); 1H NMR, CDCl3): d 1.19 2t, 3H, Jˆ7.1Hz,
CH3CH2O), 1.47 2d, 3H, Jˆ5.3 Hz, CH3CHO2), 2.74 2dd,
1H, Jˆ12.8, 7.6 Hz, CHH0NH2), 2.82 2dd, 1H, Jˆ12.8,
4.2 Hz, CHH0NH2), 3.03 2br s, 3H, OH, NH2), 3.54 2dq,
1H, Jˆ9.3, 7.1Hz, CH 3CHH0O), 3.77 2dq, 1H, Jˆ9.3,
7.1Hz, CH 3CHH0O), 4.54 2dd, 1H, Jˆ7.6, 4.2 Hz,
CHOH), 5.35 2q, 1H, Jˆ5.3 Hz, CH3CHO2), 6.95 2d, 2H,
Jˆ8.6 Hz, OphCphCH), 7.22 2d, 2H, Jˆ8.6 Hz,
OphCphCHphCH); 13C NMR, CDCl3): d 1 5 C2H3CH2O),
20.2 2CH3CHO2), 49.2 2NH2CH2), 61.3 2CH3CH2O), 73.7
2HOCH), 99.6 2CH3CHO2), 117.2 2OphCphCH), 127.0
2OphCphCHphCH), 136.2 2phCCHOH), 156.2 2OphC).
Reagents and materials were obtained from commercial
suppliers and were used without further puri®cation unless
otherwise mentioned. Flash chromatography, silica gel 60
20.040±0.063 mm), Merck; TLC, silica gel 60 F254 with
¯uorescent indicator, Merck, aluminium plates, melting
points 2uncorrected), Boetius heating block; H and 13C
1
NMR, DPX 300 2Bruker) and AC 300 2Bruker); d in
ppm; J in [Hz]; HRMS MAT 711 2Varian) bei 70 eV.
X-Ray crystal analysis STOE Ipds diffractometer.
3.2. Syntheses
3.2.1. 4-)1-Ethoxyethoxy)benzaldehyde )6). To a suspen-
sion of 4-hydroxybenzaldehyde 212.21 g, 0.10 mol) and
ethoxyethene 28.65 g, 0.12 mol) in Et2O 250 mL) a catalytic
amount of chloromethoxymethane 20.1mL) was added.
After 48 h of re¯ux the clear solution was cooled to room
temperature and was washed with 1M aqueous NaOH
22£50 mL). The aqueous phase was extracted with Et2O
22£50 mL). The combined organic phases were washed
with brine 230 mL) and dried 2MgSO4), concentrated and
distilled under vacuum 2bp 91±968C, 2£1022 mbar) afford-
ing 15.21 g 278%) of product 6 as colorless oil. Rfˆ0.32
2hexane/EtOAcˆ8:2); 1H NMR 2300 MHz, CDCl3): d
1.12 2t, 3H, Jˆ7.1Hz, C H3CH2O), 1.47 2d, 3H, Jˆ5.3 Hz,
CH3CHO2), 3.47 2dq, 1H, Jˆ9.3, 7.1Hz, CH 3CHH0O), 3.68
2dq, 1H, Jˆ9.3, 7.1Hz, CH 3CHH0O), 5.45 2q, 1H, Jˆ
5.3 Hz, CH3CHO2), 7.02 2d, 2H, Jˆ8.7 Hz, OphCphCH),
3.2.4. Ethyl 5-methyl-1H-pyrrole-2-carboxylate )8). A
solution of NaNO2 282.80 g, 1.20 mol) in water 2125 mL)
was slowly added to a solution of ethyl acetoacetate

4870
A. Radspieler, J. Liebscher / Tetrahedron 57 /2001) 4867±4871
2130.14 g, 1.00 mol) in acetic acid 2350 mL) under stirring
and ice cooling while the temperature was maintained
below 108C. After 12 h stirring at room temperature, 4,4-
dimethoxy-2-butanone 2132.3 g, 1.0 mol) was added. Zinc
dust 2142.6 g, 2.2 mol) was added under vigorous stirring as
fast as foaming allowed. The mixture was heated to 1208C
for 10 min. After the mixture had cooled down below 508C
it was poured into ice water 21L). The mixture was stirred at
08C for 1h. The precipitating orange solid was ®ltered off,
washed thoroughly with ice water and dried in a desiccator
2CaCl2). It was puri®ed by distillation via a short air conden-
ser under high vacuum 2bp 110±1208C, 0.7£1021 mbar) and
recrystallized from hexane affording 33.7 g 222%) of color-
less crystals. Mpˆ98±1008C, Rfˆ0.67 2hexane/EtOAcˆ
9:1); 1H NMR 2DMSO-d6): d 1.23 2t, 3H, Jˆ7.1Hz,
CH3CH2O), 2.18 2s, 3H, CH3pyC), 4.16 2q, 2H, Jˆ7.1Hz,
CH3CH2O), 5.83 2m, 1H, HpyC), 6.63 2m, 1H, HpyC), 11.53
2br s, 1H, NH); 13C NMR DMSO-d6): d 12.7 2CH3pyC), 14.5
2CH3CH2O), 59.2 2CH3CH2O), 108.3 2HpyC), 115.7 2HpyC),
120.6 2pyCCvO), 134.3 2pyCCH3), 160.4 2CvO).
OphCphCHphCH), 7.27 2br s, 1H, NHCvO), 10.62 2br s,
1H, pyNH); 13C NMR, CDCl3): d 14.2 2CH3CH2O), 15.1
2CH3CH2O), 20.2 2CH3CHO2), 47.0 2NHCH2), 61.3
2CH3CH2O), 61.5 2CH3CH2O), 72.12HOCH), 99.5
2CH3CHO2), 112.8 2pyCCl), 117.4 2OphCphCH), 117.7
2pyCCl), 119.8 2pyCCvO), 123.4 2pyCCvO), 127.1
2OphCphCHphCH), 134.9 2phCCHOH), 156.7 2OphC), 158.5
2pyCCvO), 158.9 2pyCCvO).
3.2.7. Ethyl 3,4-dichloro-5-[){2-[4-)1-ethoxyethoxy)phenyl]-
2-oxoethyl}amino)carbonyl]-1H-pyrrole-2-carboxylate )2).
Dess±Martin periodinane6 2509 mg, 1.11 mmol) was added
to a solution of 9 2459 mg, 1.00 mmol) in dry CH2Cl2
215 mL). The mixture was stirred at room temperature
until the reactant disappeared 2,45 min). The mixture was
quenched by adding a solution of 8 g Na2S2O3 in saturated
aqueous NaHCO3 230 mL) and intensive stirring for 5 min.
The organic layer was separated and the aqueous phase was
extracted with CH2Cl2 23£15 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 and
brine, dried 2MgSO4) and concentrated under vacuum.
The remaining solid was recrystallized from EtOH affording
3 2420 mg, 98%) as colorless crystals. Mp 199±2008C,
Rfˆ0.6 2CH2Cl2/acetoneˆ9:1); 1H NMR 2DMSO-d6): d
1.09 2t, 3H, Jˆ7.1Hz, C H3CH2OCHO), 1.31 2t, 3H, Jˆ
7.1Hz, C H3CH2OCvO), 1.43 2d, 3H, Jˆ5.1Hz,
CH3CHO2), 3.49 2dq, 1H, Jˆ9.3, 7.1Hz, CH 3CHH0OCHO),
3.66 2dq, 1H, Jˆ9.4, 7.1Hz, CH 3CHH0OCHO), 4.32 2q,
2H, Jˆ7.1Hz, CH 3CH2OCvO), 4.79 2d, 1H, Jˆ5.2 Hz,
CHH0NH), 5.65 2q, 1H, Jˆ5.1Hz, CH 3CHO2), 7.13 2d,
2H, Jˆ8.7 Hz, OphCphCH), 7.99 2d, 2H, Jˆ8.7 Hz,
OphCphCHphCH), 8.54 2t, 1H, Jˆ5.2 Hz, NHCvO), 12.97
2br s, 1H, pyNH); 13C NMR 2DMSO-d6): d 14.2 2CH3CH2O),
15.2 2CH3CH2O), 20.12 CH3CHO2), 46.0 2NHCH2), 61.0
2CH3CH2O), 61.2 2CH3CH2O), 98.8 2CH3CHO2), 113.9
2pyCCl), 116.3 2pyCCl), 116.4 2OphCphCH), 119.2 2pyCCvO),
124.4 2pyCCvO), 128.3 2phCCvO), 130.3 2OphCphCHphCH),
157.9 2OphC), 158.5 2pyCCvO), 161.2 2pyCCvO), 193.1
2OvCCH2). Anal. calcd for C20H24Cl2N2O6 2457.31): C,
52.53; H, 4.85; N, 6.13; Cl, 15.51. Found: C, 52.20; H,
4.83; N, 6.12; Cl, 15.65.
3.2.5. 3,4-Dichloro-5-ethoxycarbonylpyrrol-2-carboxylic
acid )4). SO2Cl2 240.55 g, 0.30 mol) was added dropwise to
a solution of 8 27.66 g, 0.05 mol) in dry Et2O 2250 mL)
under stirring and ice cooling. After stirring at room
temperature for 3 h volatile components were removed
under vacuum and the remainder was dissolved in dioxane
2130 mL) and water 220 mL). The mixture was heated to
90±958C for 2 h and was concentrated to dryness under
vacuum. The remainder was recrystallized from acetic
acid affording 5.92 g 247%) of slightly yellow crystals.
1
Mpˆ1808C 2decomp.); H NMR 2DMSO-d6): d 1.30 2t,
3H, Jˆ7.1Hz, C H3CH2O), 4.27 2q, 2H, Jˆ7.1Hz,
CH3CH2O), 13.11 2br s, 1H, NH); 13C NMR 2DMSO-d6) d
14.1 2CH3CH2O), 61.0 2CH3CH2O), 116.4 2pyCCl), 117.2
2pyCCl), 120.6 2pyCCO2), 122.0 2pyCCO2), 158.3 2pyCCO2),
159.7 2pyCCO2).
3.2.6. Ethyl 3,4-dichloro-5-[){2-[4-)1-ethoxyethoxy)phenyl]-
2-hydroxyethyl}amino)carbonyl]-1H-pyrrole-2-carboxyl-
ate )9). To a solution of 4 21240 g, 5.50 mmol) in dry
CH2Cl2 230 mL) 1-hydroxybenzotriazole 2HOBt) 2768 mg,
5.50 mmol), ethyldiisopropyamine 2646 mg, 5.50 mmol)
and 3 21260 mg, 5.00 mmol) were added. The mixture
was stirred until it gave a clear solution. After the addition
of DCC 21035 mg, 5.50 mmol) the mixture was stirred at
room temperature for 4 h. After cooling to 08C N,N0-di-
cyclohexylurea was ®ltered off and the ®ltrate was diluted
with CH2Cl2 230 mL), washed twice with saturated aqueous
NH4Cl, twice with half-concentrated aqueous K2CO3 and
with phosphate buffer pHˆ7. After drying 2MgSO4) the
solvent was removed under vacuum and the remainder
was puri®ed by column chromatography with CHCl3/
MeOH 298:2) affording 1493 mg 265%) of the product 9
as colorless solid. Rfˆ0.30 2CH2Cl2/acetoneˆ9:1); 1H
NMR, CDCl3): d 1.12 2t, 3H, Jˆ7.1Hz, C H3CH2OCHO),
1.30 2t, 3H, Jˆ7.1Hz, C H3CH2OCvO), 1.41 2d, 3H, Jˆ
5.3 Hz, CH3CHO2), 3.40±3.48 2m, 2H, CHH0NH,
CH3CHH0OCHO), 3.68 2dq, 1H, Jˆ9.3, 7.1Hz,
CH3CHH0OCHO), 3.812m, 1H, CH H0NH), 3.97 2br s, 1H,
OH), 4.29 2q, 2H, Jˆ7.1Hz, CH 3CH2OCvO), 4.80 2m, 1H,
CHOH), 5.29 2q, 1H, Jˆ5.3 Hz, CH3CHO2), 6.90 2d,
2H, Jˆ8.6 Hz, OphCphCH), 7.23 2d, 2H, Jˆ8.6 Hz,
3.2.8. Ethyl 3,4-dichloro-5-{5-[4-)1-ethoxyethoxy)phenyl]-
1,3-oxazol-2-yl}-1H-pyrrole-2-carboxylate )10). To a
solution of triphenylphosphine 2787 mg, 3.00 mmol) in
dry CH2Cl2 215 mL), hexachloroethane 2592 mg, 2.50
mmol), triethylamine 2607 mg, 6.00 mmol) and a solution
of 2 2457 mg, 1.00 mmol) in CH2Cl2 25 mL) were added.
After stirring at room temperature, the clear solution was
washed with saturated aqueous NH4Cl 210 mL), saturated
aqueous NaHCO3 210 mL) and with water 210 mL). After
drying 2MgSO4), removing the solvent under vacuum and
column chromatography hexane/EtOAc 26:4) 10 2356 mg,
81%) was obtained as colorless solid. Mp 199±2008C,
Rfˆ0.2 2hexane/EtOAcˆ6:4); 1H NMR 2DMSO-d6): d
1.10 2t, 3H, Jˆ7.0 Hz, CH3CH2OCHO), 1.33 2t, 3H, Jˆ
7.1Hz, C H3CH2OCvO), 1.42 2d, 3H, Jˆ5.1Hz,
CH3CHO2), 3.50 2dq, 1H, Jˆ9.4, 7.0 Hz, CH3CHH0OCHO),
3.67 2dq, 1H, Jˆ9.4, 7.0 Hz, CH3CHH0OCHO), 4.34 2q, 2H,
Jˆ7.1Hz, CH 3CH2OCvO), 5.55 2q, 1H, Jˆ5.1Hz,
CH3CHO2), 7.12 2d, 2H, Jˆ8.8 Hz, OphCphCH), 7.75 2s,
1H, oxCH), 7.83 2d, 2H, Jˆ8.7 Hz, OphCphCHphCH), 13.51
2br s, 1H, pyNH); 13C NMR 2DMSO-d6): d 14.2 2CH3CH2O),

A. Radspieler, J. Liebscher / Tetrahedron 57 /2001) 4867±4871
4871
15.2 2CH3CH2O), 20.2 2CH3CHO2), 61.0 2CH3CH2O), 61.1
2CH3CH2O), 98.9 2CH3CHO2), 112.3 2pyCCl), 117.1 2pyCCl),
117.4 2OphCphCH), 119.7, 119.8, 120.6 2pyCCvO, pyCoxC,
phCoxC), 122.6 2oxCH), 126.1 2OphCphCHphCH), 150.7, 151.4
2OoxC,OoxCN), 157.3 2OphC), 158.6 2pyCCvO).
9.83 2br s, 1H, HOphC), 12.51 2br s, 1H, pyNH); 13C
NMR 2DMSO-d6):
d
110.0 2pyCClpyCClpyCH), 111.1
2pyCClpyCClpyCH), 116.0 2OphCphCH), 116.3 2pyCoxC), 118.5
2phCoxC), 119.1 2pyCH), 121.1 2oxCH), 125.7 2OphCphCHphCH),
150.2 2OoxCphC), 152.4 2OoxCN), 158.0 2OphC). HRMS 2EI)
calcd for C13H8Cl2N2O2 293.99628, found 293.9963.
3.2.9. Ethyl 3,4-dichloro-5-[5-)4-hydroxyphenyl)-1,3-
oxazol-2-yl]-1H-pyrrole-2-carboxylate )11). 1M hydro-
chloric acid 21mL) was added to a solution of 10
2439 mg, 1.00 mmol) in THF 27 mL). The solution was
stirred at room temperature until all 10 disappeared 2,5 h,
TLC). The solution was diluted with brine 210 mL), neutra-
lized with NaHCO3 and extracted with EtOAc 23£15 mL).
The combined organic layers were washed with water, dried
2MgSO4) and evaporated under vacuum. After column
chromatography hexane/EtOAc 21:1) 11 2282 mg, 77%)
was obtained as colorless solid. Mp 227±2298C; Rf:0.19
2hexane/EtOAcˆ1:1); 1H NMR 2DMSO-d6): d 1.33 2t,
3H, Jˆ7.1Hz, C H3CH2OCvO), 4.34 2q, 2H, Jˆ7.1Hz,
CH3CH2OCvO), 6.87 2d, 2H, Jˆ8.8 Hz, OphCphCH), 7.66
2s, 1H, oxCH), 7.72 2d, 2H, Jˆ8.8 Hz, OphCphCHphCH), 9.87
2s, 1H, HOphC), 13.47 2br s, 1H, pyNH); 13C NMR 2DMSO-
d6): d 14.3 2CH3CH2O), 61.0 2CH3CH2O), 112.2 2pyCCl),
115.9 2OphCphCH), 117.0 2pyCCl), 118.3, 119.6, 119.8
2pyCCvO, pyCoxC, phCoxC), 121.7 2oxCH), 126.2
2OphCphCHphCH), 151.0, 151.3 2OoxC oxCH, OoxCN),
158.3 2OphC), 158.7 2pyCCvO).
3.2.12. 2-)3,4-Dichloro-1H-pyrrol-2-yl)-5-)4-methoxy-
phenyl)-1,3-oxazole )13). Crystals of the derivative 13
suitable for X-ray crystal analysis 2crystal system: triclinic,
Ê
space group P-1, unit cell dimensions: aˆ7.8283214) A, aˆ
Ê
Ê
77.9023)8, bˆ8.1721216) A, bˆ82.1622), cˆ12.33623) A,
Ê 3
2gˆ67.376213)8, volume 710.923) A , Zˆ2, calculated
density: 1.510 mg/m3, crystal size: 0.92£0.85£0.20 mm)
were obtained from a solution of 1 210 mg), MeI 2100 mg)
and K2CO3 2100 mg) in acetone 21 mL) after 20 min of stir-
ring at room temperature. The following parameters were
used for C-ray crystal analysis: Temperature: 18022) K;
Ê
wavelength: 0.71073 A; theta range for data collection:
1.69±25.088; limiting indices: 29#h#9, 29#k#9,
214#l#14; re¯ections collected/unique 3835/2529
[R2int)ˆ0.0510]; completeness to uˆ25.08 100.0%; max.
and min. transmission: 0.9134 and 0.6762; re®nement
method: Full-matrix least-squares on F2; data/restraints/
parameters: 2529/0/239; goodness-of-®t on F2: 0.986; Final
R indices [I.2s2I)], R1ˆ0.0485, vR2ˆ0.1245; R indices
2all data): R1ˆ0.0934, vR2ˆ0.1596; extinction coef®cient:
Ê 23
0.00223); largest diff. peak and hole 0.373 and 20.318e A
.
3.2.10. 3,4-Dichloro-5-[5-)4-hydroxyphenyl)-1,3-oxazol-
2-yl]-1H-pyrrole-2-carboxylic acid )12). 11 2352 mg,
1.00 mmol) was dissolved in a mixture of EtOH 28 mL)
and 2N NaOH 22 mL). After re¯uxing for 2 h 2TLC), the
solution was concentrated under vacuum and carefully
neutralized with 0.5 M hydrochloric acid. After dilution
with saturated aqueous NH4Cl 250 mL) the mixture was
extracted with THF 25£15 mL). The combined organic
layers were washed with brine, dried 2MgSO4) and concen-
trated under vacuum affording 12 2295 mg, 87%) as color-
less solid which was further used without prior puri®cation.
Acknowledgements
We gratefully acknowledge ®nancial support by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie. We thank Dr Burkhard Ziemer, Insti-
tut fu
Èr Chemie, Humboldt-UniversitaÈt Berlin for the X-ray
crystal analysis.
1
Mp 1808C 2decomp.); Rf: 0.15 2CH2Cl2/EtOHˆ7:3); H
References
NMR 2DMSO-d6): d 6.87 2d, 2H, Jˆ8.7 Hz, OphCphCH),
7.62 2s, 1H, oxCH), 7.72 2d, 2H, Jˆ8.7 Hz, OphCphCHphCH);
13C NMR 2DMSO-d6): d 112.0 2pyCCl), 115.9 2OphCphCH),
116.7 2pyCCl), 118.3, 119.2, 120.6 2pyCCvO, pyCoxC,
phCoxC), 121.6 2oxCH), 126.2 2OphCphCHphCH), 151.1 2OoxC
oxCH), 158.3 2OoxCN), 160.0 2OphC), 172.1 2pyCCvO).
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23£40 mL). The combined organic layers were washed
with brine, dried 2MgSO4) and concentrated under vacuum.
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bazole C was obtained as colorless solid 2248 mg, 84%). All
analytical data correspond to those reported in the litera-
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11. Full details have been deposited at the Cambridge Crystallo-
graphic Data Centre, reference number CCDC 156638. Copies
of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
1
EtOAcˆ6:4). H NMR 2DMSO-d6): d 6.87 2d, 2H, Jˆ
8.7 Hz, OphCphCH), 7.27 2d, 1H, Jˆ3.2 Hz, pyNHpyCH),
7.56 2s, 1H, oxCH), 7.612d, 2H, Jˆ8.7 Hz, OphCphCHphCH),