Chemo- and regioselectivity in the reactions of polyfunctional pyrroles

Article abstract of DOI:10.1016/j.tet.2010.06.006

The chemo- and regioselectivity of the reduction, oxidation and Wittig reaction of polyfunctional pyrroles, containing a variety of reactive centres was investigated. The reaction of 3,5-dichloropyrrole-2,4-dicarboxaldehydes with potassium permanganate leads to regioselective oxidation of the 2-formyl group, while the Wittig reaction with 1 equiv of a triphenylphosphorane produced the 2-alkenyl substituted pyrroles. The chemo- and regioselectivity of the reactions of polyfunctional pyrroles, containing a variety of reactive centres is described. Regioselective reduction, oxidation or Wittig reactions give a range of pyrroles suitable for further synthetic transformations.

Full text of DOI:10.1016/j.tet.2010.06.006

Tetrahedron 66 (2010) 6113e6120
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemo- and regioselectivity in the reactions of polyfunctional pyrroles
, ,
y
Gabriella Marth a, Rosaleen J. Anderson a, Barry G. Thompson b, Mark Ashton b, Paul W. Groundwater a
*
a Sunderland Pharmacy School, University of Sunderland, Sunderland, SR1 3SD, UK
b High Force Research Ltd., Bowburn North Industrial Estate, Bowburn, Durham, DH6 5PF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemo- and regioselectivity of the reduction, oxidation and Wittig reaction of polyfunctional pyr-
roles, containing a variety of reactive centres was investigated. The reaction of 3,5-dichloropyrrole-2,4-
dicarboxaldehydes with potassium permanganate leads to regioselective oxidation of the 2-formyl
group, while the Wittig reaction with 1 equiv of a triphenylphosphorane produced the 2-alkenyl
substituted pyrroles.
Received 26 March 2010
Received in revised form 15 May 2010
Accepted 1 June 2010
Available online 9 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyrroles
Chemoselectivity
Regioselectivity
Wittig
Reduction
Oxidation
1. Introduction
containing a number of functional groups are relatively difficult to
prepare and the selective reactions of polyfunctional pyrrole in-
Polyfunctional pyrroles represent important examples of syn-
thetic agrochemicals and pharmaceuticals and many naturally oc-
curring compounds also contain this structural moiety. Examples of
polysubstituted pyrroles include; Atorvastatin (LipitorÒ) 1,1 the
insecticide, Chlorfenapyr 22 and the anti-bacterial natural product,
Pentabromopseudilin 3, isolated from the marine bacterium Pseu-
doalteromonas luteoviolaceus,3 (Fig. 1). These pyrroles are also in-
teresting heterocyclic intermediates as they have a range of reactive
centres and the chemo- and regioselectivity of their reactions un-
der a range of conditions is, therefore, of much interest. Pyrroles
termediates would allow the preparation of a wide variety of these
substituted heterocyclic compounds. We now report the results of
our studies on the chemo- and regioselective reduction, oxidation
and Wittig reaction of multi-substituted pyrroles.
2. Results and discussion
For our study of the chemo- and regioselectivity of the reactions
of polyfunctional pyrroles we employed the 3,5-dichloro-1H-pyr-
role-2,4-dicarboxaldehydes 4 as the starting materials, as we have
Br
CONHPh
NC
Br
CF3
OEt
OH
Br
Br
Br
CHMe2
N
N
OH
F
Cl
Br
N
H
OH
CO2
Ca2+
2
3
1
2
Figure 1.
previously described the reactivity of these multi-functional pyr-
roles with a range of nucleophiles.4 These pyrroles are particularly
interesting as they contain a number of reactive sites and allow for
the study of regioselectivity through the comparison of the
* Corresponding author. Tel.: þ61 (0)2 9114 1232; fax: þ61 (0)2 9351 4391;
e-mail address: paul.groundwater@sydney.edu.au (P.W. Groundwater).
y
Present address: Faculty of Pharmacy, Pharmacy Building A15, University of
Sydney, NSW 2006, Australia.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.006

6114
G. Marth et al. / Tetrahedron 66 (2010) 6113e6120
reactivity of substituents at different positions on the pyrrole ring e.
g., through the comparison of the reactivity of the aldehyde groups
at the a-(C-2) and b-positions (C-4) of the ring.
the 2-formyl group with the milder reducing agent presumably
arises as a result of the greater electrophilicity of the carbonyl car-
bon, comparedtothatof the C-4 formyl group, due to its proximity to
the nitrogen of the pyrrole ring.
Cl
CHO
3
4
2.2. Oxidation
OHC
5 Cl
2
N
R
We next turned our attention to the investigation of the selective
oxidation of the 2-formyl group of the unsubstituted pyrrole 4a. The
reaction with KMnO4 in aqueous acetone was unsuccessful, with
only starting material recovered, as was the oxidation of the N-
methylpyrrole 4b with KMnO4 in aqueous acetone, at room tem-
perature in the presence of a crown ether. Refluxing this mixture
without the crown ether resulted in the formation of the 4-for-
mylpyrrole-2-carboxylic acid 8a, while under the same conditions
the ethyl-substituted pyrrole 4c always gave an inseparable mixture
of the mono-8b and dicarboxylic acids 9b (R¼Et), (Scheme 3). The
use of 4 equiv of KMnO4 resulted in the oxidation of both aldehyde
groups of the N-methylpyrrole 4b to give the dicarboxylic acid 9a.
Having achieved the regioselective oxidation of the N-methyl-
pyrrole 4b to the 4-formyl-1-methyl-1H-pyrrole-2-carboxylic acid
4a
R = H
4b R = Me
4c
R = Et
2.1. Reduction
We first examined the catalytic hydrogenation of these pyrro-
lesdcomplete dechlorination of 3,5-dichloro-1H-pyrrole-2,4-
dicarboxaldehyde 4a was observed with hydrogen (1 atm) over 10%
Pd/C catalyst, in Et3N and MeOH, to give the 1H-pyrrole-2,4-
dicarboxaldehyde 5a in 70% yield, Scheme 1, but the reaction of the
methyl substituted pyrrole 4b under similar conditions resulted in
H
2 (1 atm.)
H2 (1 atm.)
10% Pd/C, Et3N
MeOH, RT, 4 h
10% Pd/C, Et3N
MeOH, 60 oC, 4 h
CHO
Cl
OHC
CHO
Cl
OHC
CHO
Cl
OHC
N
H
N
Me
N
R
R = Me
R = H
4
5b
5a
(94%)
(70%)
Scheme 1.
the selective dehalogenation at C-5, to give the 3-chloro derivative
5b in an excellent yield. In each case, the structure of the aldehyde
could be confirmed by spectroscopic analysis, for example, the 1H
NMR spectrum of the 3-chloro derivative 5b showed the appear-
8a, the functional group interconversion of the acid to the amides
12 and esters 13 was achieved using standard conditions, (Scheme
4). The 4-formyl-pyrrole-2-carboxylic acid 8a and SOCl2 were
refluxed in toluene for 4 h to give the acid chloride 10, which
without purification, was dissolved in DCM and a solution of an
amine 11 and Et3N in DCM was added dropwise at 0 ꢀC. After stir-
ring at room temperature for 2 h, the amides 12 were obtained in
good to high yields. The preparation of the ester derivatives of acid
8a was again achieved via the acid chloride 10, which was reacted
with dry MeOH or EtOH or benzyl alcohol (and Et3N in DCM) to give
the esters, 13aec. Further oxidation of the methyl 4-formyl-pyr-
role-2-carboxylate 13a resulted in the dicarboxylic acid monoester
14, in which the two carboxyl groups are capable of further in-
dependent tranformations. An alternative route to amide 12d in-
volved the in situ generation and reaction of an acyl bromide 15
from the dicarboxaldehyde 4b,5 (Scheme 5).
ance of a singlet for H-5 at
showed a new CH signal at
d
¼7.36 and the DEPT 135 spectrum
d
¼132.7, while it is obvious from the
HMBC spectrum that the dehalogenation has taken place at the C-5
position, since the new H-5 proton shows connectivities to C-4 (2J;
H-C5-C4), at
d
¼127.0 and the NCH3 (3J; H-C5-NeCH3), at
¼38.4.
d
We next attempted the reduction of the aldehyde groups in these
pyrroles 4 with complex metal hydridesdreduction with lithium
aluminium hydride gave an uncharacterisable product upon re-
action with either the N-methylpyrrole 4b or the N-ethylpyrrole 4c,
while the reduction of 4c with sodium borohydride in methanol
gave the diol 6 (surprisingly, even when using only 0.5 equiv of
NaBH4), Scheme 2. Selective reduction of the 2-formyl group in the
Cl
HOH2C
CHO
Cl
Cl
OHC
CHO
Cl
Cl
HOH2C
CH2OH
Cl
NaBH3CN, MeOH
RT
NaBH4, MeOH
R = Et
N
R
N
R
N
Et
7a R = Me (42%)
4b R = Me
6 (75%)
7b R = Et (53%)
4c
R = Et
Scheme 2.
methyl-4b and ethyl-substituted pyrroles 4c was, however, ach-
ieved, using sodium cyanoborohydride in aqueous HCl/methanol
(pH 3e4), to give the mono-hydroxymethylpyrrolecarboxaldehydes
7a,b, (Scheme 2). Once again, the regioisomers were identified
through indicative HMBC correlations. This selective reduction of
2.3. Wittig reaction and oxime formation
The Wittig reaction of the pyrroles 4 with 1.05 equiv of the
phosphoranes 16 once again highlights the greater reactivity of the 2-
formyl compared to the 5-formyl group, as the 2-alkenyl substituted

G. Marth et al. / Tetrahedron 66 (2010) 6113e6120
6115
4 equiv. KMnO4
acetone, water
2 equiv. KMnO4
acetone, water
Cl
HOOC
COOH
Cl
Cl
OHC
CHO
Cl
Cl
HOOC
CHO
Cl
N
R
N
R
N
R
R = Me
R = Me
9a
4b,c
8a
R = Me (39%)
R = Me (55%)
Scheme 3.
Cl
CHO
HOOC
Cl
N
Me
8a
SOCl2, PhCH3, 4h
Cl
Cl
CHO
Cl
N
Me
O
10
R1R2NH 11
Et3N, DCM
ROH
PhCH2OH
Et3N, DCM
Cl
CHO
Cl
CHO
Cl
Cl
CHO
Cl
R1R2N
Cl
N
RO2C
PhCH2O2C
N
Me
N
Me
O
Me
12a R1 = H, R2 = Ph (80%)
13a R = Me (80%)
13c (38%)
1
2
i
13b
R = Et (86%)
12b
R = R = Pr (68%)
12c R1 = H, R2 = CH2CH=CH2 (54%)
1
2
n
12d
R = H, R = Bu (68%)
KMnO4
acetone, water
18-crown-6
Cl
COOH
Cl
MeO2C
N
Me
14
(40%)
Scheme 4.

6116
G. Marth et al. / Tetrahedron 66 (2010) 6113e6120
NBS, AIBN
CCl4
Cl
OHC
CHO
Cl
Cl
CHO
Cl
Cl
CHO
Cl
nBuNH2
Δ
H
N
Br
nBu
N
Me
N
Me
N
Me
O
O
4b
15
12d (45%)
Scheme 5.
pyrroles 17aec were the sole regioisomers obtained, with only trace
amounts of the 2,5-alkenyl adducts detectable in the 1H NMR spectra
and TLC; while treatment with 1.75 equiv gave the 2,5-dialkenyl ad-
ducts 18aec, with only trace amounts of the mono-alkenyl adducts
being evident in this case, (Scheme 6).
polyfunctional pyrroles 4 through their reactions with nucleophiles,
which we have previously reported,4 the two carboxaldehyde groups
in the pyrroles 4 can also be differentiated successfully through
a number of regioselective functional group interconversions, with
a sequential oxidation/esterification/oxidation leading to the di-
R2
Ph3P
CO2Et
16a R2 = H
16b R2 = Me
16
(1.75 equiv.)
acetonitrile
(1.05 equiv.)
CO2Et
R2
Cl
Cl
OHC
CHO
Cl
Cl
CHO
Cl
acetonitrile
R2
R2
Δ
Δ
, 12 h
, 12 h
EtO2C
Cl
EtO2C
N
N
R
N
R1
R1
4
1
1 = R2 = H (39%)
18b R1 = Me, R2 = H (45%)
18c
17a
18a
R
= H, R2 = Me (35%)
R
17b R1 = Me, R2 = H (35%)
1
= Et, R2 = H (43%)
R
1 = Et, R2 = H (64%)
17c
R
Scheme 6.
Finally, the differentiation of the two aldehyde groups in pyrroles
4a couldalsobe achieved viathe synthesis of the bisoxime 19, through
the chemoselective nucleophilic reaction with both aldehyde groups
rather than the nucleophilic substitution of the chloro groups and its
regioselective dehydration to give the nitrileeoxime 20, (Scheme 7).
Once again the regioisomer obtained was confirmed by 2D NMR, with
carboxylic acid monoester 14, in which both carbonyl-containing
groups are capable of further, independent, transformation. The
combination of regioselective nucleophilic substitution with regio-
selective functional group interconversion of the aldehyde groups
thus opensupthepossibilityforthesynthesisofarangeofsubstituted
pyrroles.
O
Me
N
H
COOH
1 POCl3, DMF
4 h, 90 oC
2 NH2OH, 4 h, RT
45%
Ac2O
Cl
OHC
CHO
Cl
NH2OH.HCl, EtOH, pyridine
Cl
CN
Cl
Cl
HON=HC
CH=NOH
Cl
1.5 h, Δ
2 h, Δ
HON=HC
N
H
N
H
N
H
72%
19
20
4a
Scheme 7.
a key correlation in the HMBC spectrum being that from the NH to the
oxime CH. This nitrileeoxime 20 was also the only regioisomer
obtained in a one-pot synthesis from N-acetylglycine using an adap-
tation of the method employed by Reddy and co-workers, Scheme 7.6
4. Experimental
4.1. General
Melting points were determined using an Electrothermal
9100, a Gallenkamp melting point apparatus, or a Reichert hot
stage microscope and are uncorrected. Microanalyses were
carried out on an Exeter Analytical CE 440 Elemental Analyzer
instrument. Infra-red spectra of liquid or solid samples were
3. Conclusion
The transformations outlined in Schemes 3e7 show that, in ad-
dition to the differentiation of the two chloro substituents in the

G. Marth et al. / Tetrahedron 66 (2010) 6113e6120
6117
obtained on a SpectrumBX fitted with PIKE MIRacleÔ. 1H and
13C NMR spectra were obtained on a Bruker AVANCE DPX-300
(chemiSPEC, University of Sunderland). Chemical shifts are
(0.037 g, 0.97 mmol) then the reaction mixture was stirred for
5 min at room temperature. 3,5-Dichloro-1-ethyl-1H-pyrrole-2,4-
dicarboxaldehyde 4c (0.40 g, 1.82 mmol) was added to the solution
which was then refluxed for 4 h. After completion of the reaction, as
indicated by TLC, the solvent was evaporated under reduced pres-
sure and the residue quenched with water (20 mL), extracted with
ether (3ꢁ30 mL) and the combined organics dried over MgSO4.
After filtration, the solvent was evaporated under reduced pressure
and the crude product was purified by column chromatography on
silica, eluting with ethyl acetate/petroleum ether (60e80 ꢀC)
(50:50) to give pyrrole 6 as a white solid (0.23 g, 75%), mp
139e140 ꢀC; 1H NMR (300 MHz, DMSO-d6): 1.25 (3H, t, J¼7.2 Hz,
CH3), 4.01 (2H, q, J¼7.2 Hz, CH2), 4.24 (2H, s, 4-CH2), 4.42 (2H, s, 2-
CH2), 4.71 (1H, br s, OH), 5.13 (1H, br s, OH); 13C NMR (75.5 MHz,
DMSO-d6): 16.3 (CH3), 39.9 (CH2), 52.3 (4-CH2), 53.1 (2-CH2), 109.8
(quat., C3), 114.2 (quat., C5), 116.8 (quat., C4), 128.1 (quat., C2); IR
(cmꢂ1): 3338 (broad OH). HRMS m/z calcd for C8H1235Cl2NO2
[MHþ]: 224.0240, found: m/z 224.0244.
reported in
d units relative to internal tetramethylsilane (TMS)
or the deuterated solvent. 1H NMR spectra were recorded at
300 MHz and 13C NMR spectra at 75.5 MHz. Homonuclear cor-
relation spectroscopy (1He1H COSY) and heteronuclear
(1He13C) correlation spectroscopy (HMQC and HMBC) were
obtained using the standard Bruker pulse sequences. Low-res-
olution electrospray mass spectra were obtained on an Esquire
3000þ ion trap mass spectrometer (chemiSPEC, University of
Sunderland) in positive ion mode and high-resolution spectra
were obtained by means of ESI-TOF-MS on a Synapt HDMS in-
strument (University of Warwick, UK). An internal standard of
sodiated maltose in methanol was added at an appropriate level
for mass correction using the ion at m/z 365.1060. Thin layer
chromatography (TLC) was performed on Merck silica gel 60F254
plates and the components were detected under UV light
(254 nm). Kieselgel 60 (Merck) was used for flash column
chromatography.
4.1.4. 3,5-Dichloro-1-methyl-2-hydroxymethyl-1H-pyrrole-4-carbox-
All crude reaction mixtures were analyzed by 1H NMR spec-
troscopy prior to purification and, unless stated otherwise, no ev-
idence was obtained for the formation of other regioisomers and
only starting materials or uncharacterisable products were formed,
in addition to the compounds listed below. All yields quoted are
isolated yields, after purification.
aldehyde
(7a). 3,5-Dichloro-1-methyl-1H-pyrrole-2,4-dicarbox-
aldehyde 4b (0.50 g, 2.43 mmol) and sodium cyanoborohydride
(0.15 g, 2.3 mmol) were dissolved in methanol (10 mL) and 2 M aq
HCl/methanol (3 mL, 20:80) was added dropwise, with stirring, to
the solution. Stirring was continued for an additional 1 h then the
methanol was evaporated under reduced pressure, the residue was
taken up in water (7 mL), saturated with sodium chloride, extracted
with ether (3ꢁ20 mL) and the combined organics dried over MgSO4.
After filtration, the solvent was evaporated under reduced pressure
and the crude product was purified by column chromatography on
silica, eluting with ethyl acetate/petroleum ether (60e80 ꢀC)
(30:70) to give 7a as a yellow solid (0.21 g, 42%), mp 129e130 ꢀC; 1H
NMR (300 MHz, DMSO-d6): 3.72 (3H, s, CH3), 4.54 (2H, s, CH2), 5.38
(1H, br s, OH), 9.84 (1H, s, CHO); 13C NMR (75.5 MHz, DMSO-d6):
31.9 (CH3), 51.8 (CH2), 109.8 (quat., C3), 115.3 (quat., C4), 124.7 (quat.,
C5), 131.8 (quat., C2), 182.7 (CHO); IR (cmꢂ1): 3353 (broad OH), 1710
(C]O), 1511 (C]C). C7H835Cl2NO2 [MHþ]: 207.9927, found: m/z
207.9937.
4.1.1. 1H-Pyrrole-2,4-dicarboxaldehyde (5a). 3,5-Dichloro-1H-pyr-
role-2,4-dicarboxaldehyde 4a (0.80 g, 4.16 mmol), 10% palladium
on carbon (0.024 g) and Et3N (0.71 mL, 5.10 mmol) were dissolved
in methanol (80 mL) then stirred under hydrogen (1 atm) at am-
bient temperature (ca. 23 ꢀC). After 4 h the reaction mixture was
filtered through Celite and the solution was removed in vacuo. The
residue was extracted with ethyl acetate (3ꢁ40 mL) and the com-
bined organic layer was washed with brine (70 mL) and dried over
MgSO4. After filtration, the solvent was evaporated under reduced
pressure and the crude product was purified by column chroma-
tography on silica, eluting with ethyl acetate/petroleum ether
(60e80 ꢀC) (30:70) to give 5a (0.36 g, 70%) as a white solid, mp
103e104 ꢀC; 1H NMR (300 MHz, DMSO-d6): 7.42 (1H, s, H3), 7.97
(1H, s, H5), 9.62 (1H, s, CHO), 9.81 (1H, s, CHO), 12.85 (1H, br s, NH);
13C NMR (75.5 MHz, DMSO-d6): 118.9 (CH, C3), 127.6 (quat., C2),
133.5 (CH, C5), 134.6 (quat., C4), 181.5 (CHO), 186.4 (CHO); IR
(cmꢂ1): 3117 (NH), 1666 (C]O), 1637 (C]O), 1540 (C]C). HRMS m/
z calcd for C6H6NO2 [MHþ]: 124.0393, found: m/z 124.0395.
4.1.5. 3,5-Dichloro-1-ethyl-2-hydroxymethyl-1H-pyrrole-4-carbox-
aldehyde
(7b). 3,5-Dichloro-1-ethyl-1H-pyrrole-2,4-dicarbox-
aldehyde 4c (0.40 g, 1.82 mmol) and sodium cyanoborohydride
(0.08 g, 1.84 mmol) were dissolved in methanol (15 mL) and 2 M aq
HCl/methanol (3 mL, 2:8) was added dropwise, with stirring, to the
solution. Stirring was continued for an additional 1 h then the
methanol was evaporated under reduced pressure, the residue was
taken up in water (10 mL), saturated with sodium chloride,
extracted with ether (3ꢁ20 mL) and the combined organics dried
over MgSO4. After filtration, the solvent was evaporated under re-
duced pressure and the crude product was purified by column
chromatography on silica, eluting with ethyl acetate/petroleum
ether (60e80 ꢀC) (30:70) to give pyrrole 7b as a yellow solid (0.21 g,
53%), mp 122e123 ꢀC; 1H NMR (300 MHz, CDCl3): 1.24 (3H, t,
J¼7.2 Hz, CH3), 4.38 (2H, q, J¼7.2 Hz, CH2), 4.50 (2H, s, CH2), 9.60
(1H, s, CHO); 13C NMR (75.5 MHz, CDCl3): 15.8 (CH3), 41.3 (CH2CH3),
52.5 (CH2), 119.1 (quat., C4 or C5), 120.3 (quat., C3), 124.7 (quat., C4
or C5), 126.3 (quat., C2), 176.9 (CHO); IR (cmꢂ1): 3350 (broad OH),
1662 (C]O). HRMS m/z calcd for C8H1035Cl2NO2 [MHþ]: m/z
222.0083, found: m/z 222.0092.
4.1.2. 3-Chloro-1-methyl-1H-pyrrole-2,4-dicarboxaldehyde
(5b). 3,5-Dichloro-1-methyl-1H-pyrrole-2,4-dicarboxaldehyde 4b
(1.01 g, 4.90 mmol), 5% palladium on charcoal (0.024 g) and Et3N
(0.71 mL, 5.1 mmol) were dissolved in methanol (80 mL) then
stirred in an autoclave under hydrogen (4 bar) at 60 ꢀC. After 4 h the
reaction mixture was filtered through Celite and the methanol was
concentrated in vacuo. The residue was extracted with ethyl acetate
(3ꢁ40 mL) and the combined organic layer was washed with brine
(70 mL) and dried over MgSO4. After filtration, the solvent was
evaporated under reduced pressure and recrystallised from petro-
leum ether (60e80 ꢀC) to give 5b as a white powder (0.79 g, 94%),
mp 100e101 ꢀC; 1H NMR (300 MHz, CDCl3): 3.91 (1H, s, CH3), 7.36
(1H, s, H5), 9.80 (1H, s, CHO), 9.83 (1H, s, CHO); 13C NMR (75.5 MHz,
CDCl3): 38.4 (CH3), 121.6 (quat., C3), 127.0 (quat., C4), 127.6 (quat.,
C2), 132.7 (CH, C5), 178.6 (4-CHO), 183.4 (2-CHO); IR (cmꢂ1): 1715
(C]O), 1653 (C]O), 1508 (C]C). Anal. Calcd for C7H6NO2Cl: C,
49.0; H, 3.5; N, 8.2. Found: C, 48.8; H, 3.5; N, 8.0%.
4.1.6. 3,5-Dichloro-4-formyl-1-methyl-1H-pyrrole-2-carboxylic acid
(8a). 3,5-Dichloro-1-methyl-1H-pyrrole-2,4-dicarboxaldehyde 4b
(0.50 g, 2.43 mmol) was dissolved in acetone (40 mL) and treated
with a solution of KMnO4 (0.78 g, 4.9 mmol) in H2O (13 mL). The
reaction mixture was refluxed for 12 h then decolourised with
charcoal. After filtration, the solvent was evaporated under reduced
4.1.3. 3,5-Dichloro-1-ethyl-2,4-bis(hydroxymethyl)-1H-pyrrole (6).
Methanol (15 mL) was added dropwise to sodium borohydride

6118
G. Marth et al. / Tetrahedron 66 (2010) 6113e6120
pressure, acidified with 2 M aq HCl and the crude product was
recrystallised from methanol to give pyrrole 8a as a white solid
(0.30 g, 55%), mp 173e175 ꢀC; 1H NMR (300 MHz, DMSO-d6): 3.87
(3H, s, CH3), 9.72 (1H, s, CHO), 13.15 (1H, br s, OH); 13C NMR
(75.5 MHz, DMSO-d6): 33.6 (CH3), 111.4 (quat., C4), 125.1 (quat., C3),
126.5 (quat., C5), 130.7 (quat., C2), 162.1 (C]O), 178.4 (CHO); IR
(cmꢂ1): 2588 (broad OH), 1662 (C]O). HRMS m/z calcd for
C7H637Cl2NO3 [MHþ]: m/z 225.9665, found: m/z 225.9657.
125.7 (quat.), 129.4 (quat.), 133.8 (]CH), 160.1 (C]O), 177.6 (CHO);
IR (cmꢂ1): 3262 (NH), 1668 (aldehyde C]O), 1635 (amide C]O),
1535 (C]C). HRMS m/z calcd for C10H1135Cl2N2O2 [MHþ]: 261.0193,
found: m/z 261.0203.
4.2.4. N-Butyl-3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-2-car-
boxamide (12d). 4.2.4.1. Method A. 3,5-Dichloro-1-methyl-1H-
pyrrole-2,4-dicarboxaldehyde 4b (0.40 g, 1.96 mmol) was dissolved
in dry CCl4 (10 mL). To this solution was added AIBN (0.005 g,
0.033 mmol) and NBS (0.45 g, 2.52 mmol). The reaction mixture
was refluxed for 15 min then cooled to 0 ꢀC (ice-water bath) and n-
butylamine (0.33 g, 4.50 mmol) was added dropwise. The ice-bath
was removed and the suspension was stirred at room temperature
for 10 min. The solid material was removed by filtration and
washed with CCl4 (10 mL). The filtrate was extracted with water
(2ꢁ10 mL) and the combined organics dried over MgSO4. After
filtration, the solvent was evaporated under reduced pressure and
the crude product was purified by column chromatography on
silica, eluting with ethyl acetate/petroleum ether (60e80 ꢀC)
(20:80) to give 12d as a yellow solid (0.24 g, 45%).
4.1.7. 3,5-Dichloro-1-methyl-1H-pyrrole-2,4-dicarboxylic acid (9a).
This pyrrole was prepared, as described above, but using 4 M equiv
of KMnO4, to give pyrrole 9a as a white solid (0.23 g, 39%), mp
179e180 ꢀC; 1H NMR (300 MHz, DMSO-d6): 3.84 (3H, s, CH3); 13C
NMR (75.5 MHz, DMSO-d6): 34.6 (CH3), 111.3 (quat., C4), 118.9
(quat., C3), 121.5 (quat., C5), 126.7 (quat., C2), 160.8 (COOH), 162.6
(COOH); IR (cmꢂ1): 2591 (broad OH), 1661 (C]O). Anal. Calcd for
C7H5Cl2NO4: C, 35.5; H, 2.1; N 5.9. Found: C, 35.9; H, 2.3; N, 5.5%.
4.2. General procedure for preparation of compounds
(12aed) and (13c)
A
solution of 3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-2-
4.2.4.2. Method B. A solution of 3,5-dichloro-4-formyl-1-
methyl-1H-pyrrole-2-carboxylic acid 8a (0.30 g, 1.35 mmol) and
SOCl2 (0.49 mL) in toluene (5 mL) was refluxed for 4 h. After
evaporation of the solvent, the crude mixture was dissolved in DCM
(5 mL) and a solution of n-butylamine (0.31 mL, 3.1 mmol) and TEA
(0.19 mL) in DCM (2 mL) was added dropwise at 0 ꢀC. The mixture
was stirred for 2 h at room temperature then washed sequentially
with 5% aq HCl (10 mL) and 5% aq NaOH (10 mL). The organic layer
was dried over MgSO4 and, after filtration, the solvent was evapo-
rated under reduced pressure and the residue purified by column
chromatography on silica, eluting with ethyl acetate/petroleum
ether (60e80 ꢀC) (30:70) to give 12d as a yellow solid (0.28 g, 68%),
mp 134e135 ꢀC; 1H NMR (300 MHz, DMSO-d6): 0.89 (3H, t,
J¼7.1 Hz, CH3), 1.34 (2H, sextet, J¼7.1 Hz, CH2), 1.47 (2H, quintet,
J¼7.1 Hz, CH2), 3.20 (2H, q, J¼7.1 Hz, NCH2), 3.86 (3H, s, CH3), 8.21
(1H, br s, NH), 9.66 (1H, s, CHO); 13C NMR (75.5 MHz, DMSO-d6):
14.1 (CH3), 19.9 (CH2), 31.5 (CH2), 33.4 (NCH3), 39.0 (CH2), 118.1
(quat.), 122.1 (quat.), 125.5 (quat.), 126.2 (quat.), 160.0 (C]O), 177.9
(CHO); 3273 (NH),1671 (C]O),1637 (C]O),1554 (C]C). HRMS m/z
calcd for C11H1535Cl2N2O2 [MHþ]: 277.0505, found: m/z 277.0515.
carboxylic acid 8a (1.35 mmol) and SOCl2 (0.49 mL) in toluene
(5 mL) was refluxed for 4 h. After evaporation of the solvent, the
crude mixture was dissolved in DCM (5 mL) and a solution of an
amine 11 or benzyl alcohol (2.01 mmol) and TEA (0.19 mL) in DCM
(1.6 mL) was added dropwise at 0 ꢀC. The mixture was stirred for
2 h at room temperature then washed sequentially with 5% aq HCl
(10 mL) and 5% aq NaOH (10 mL). The organic layer was dried over
MgSO4 and, after filtration, the solvent was evaporated under re-
duced pressure and purified by column chromatography or
recrystallised.
4.2.1. N-Phenyl-3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-2-car-
boxamide (12a). The crude product was recrystallised from meth-
anol to give 12a as colourless needles (0.32 g, 80%), mp 165e167 ꢀC;
1H NMR (300 MHz, CDCl3): 3.91 (3H, s, CH3), 7.11 (1H, m, ArH), 7.31
(2H, m, ArH), 7.53 (2H, m, ArH), 7.91 (1H, br s, NH), 9.70 (1H, s,
CHO); 13C NMR (75.5 MHz, CDCl3): 33.3 (CH3), 114.5 (quat.), 120.2
(CH, Ar), 120.4 (quat.), 120.5 (CH, Ar), 122.8 (quat.), 124.9 (CH, Ar),
125.2 (quat.), 125.9 (quat.), 129.1 (CH, Ar), 129.2 (CH, Ar), 137.4 (C]
O), 177.6 (CHO); IR (cmꢂ1): 3276 (NH), 1713 (aldehyde C]O), 1660
(amide C]O). Anal. Calcd for C13H10Cl2N2O2: C, 52.6; H, 3.4; N, 9.4.
Found: C, 52.9; H, 3.8; N, 9.0%.
4.2.5. Benzyl 3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-2-carboxy-
late (13c). This pyrrole was prepared, as described above, from
benzyl alcohol and the crude product was purified by column
chromatography on silica, eluting with ethyl acetate/petroleum
ether (60e80 ꢀC) (50:50) to give 13c as a white solid (0.15 g, 38%),
mp 124e125 ꢀC; 1H NMR (300 MHz, DMSO-d6): 3.89 (3H, s, CH3),
5.34 (2H, s, CH2), 7.39e7.45 (5H, m, ArH), 9.73 (1H, s, CHO); 13C NMR
(75.5 MHz, DMSO-d6): 33.7 (CH3), 66.4 (CH2), 110.2 (quat.), 124.9
(quat.), 126.7 (quat.), 128.3 (2ꢁCH), 128.5 (CH), 128.9 (2ꢁCH), 130.9
(quat.), 136.3 (quat., C10), 160.5 (C]O), 178.5 (CHO); IR (cmꢂ1): 1707
(C]O), 1664 (C]O). Anal. Calcd for C14H11Cl2NO3: C, 53.9; H, 3.6; N,
4.5. Found: C, 53.5; H, 3.8; N, 4.2%.
4.2.2. N,N-Diisopropyl-3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-
2-carboxamide (12b). The crude product was recrystallised from
methanol to give 12b as white crystals (0.28 g, 68%), mp
141e142 ꢀC; 1H NMR (300 MHz, CDCl3): 1.13 (6H, m, 2ꢁCH3), 1.47
(6H, m, 2ꢁCH3), 3.45 (1H, m, CH), 3.76 (1H, m, CH), 3.85 (3H, s, CH3),
9.62 (1H, s, CHO); 13C NMR (75.5 MHz, CDCl3): 20.4 (CH3), 20.5
(CH3), 21.2 (CH3), 21.3 (CH3), 33.2 (NCH3), 46.3 (CH), 51.7 (CH), 119.5
(quat., C3 or C4), 122.4 (quat., C3 or C4), 124.5 (quat., C5), 125.4
(quat., C2), 160.9 (C]O), 177.3 (CHO); IR (cmꢂ1): 1675 (aldehyde
C]O), 1635 (amide C]O), 1536 (C]C). Anal. Calcd for
C13H18Cl2N2O2: C, 51.2; H, 5.9; N, 9.2. Found: C, 51.1; H, 5.9; N, 8.9%.
4.2.6. Methyl 3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-2-carbox-
ylate (13a). A solution of 3,5-dichloro-4-formyl-1-methyl-1H-pyr-
role-2-carboxylic acid 8a (0.26 g, 1.16 mmol) and SOCl2 (0.49 mL) in
toluene (5 mL) was refluxed for 4 h. After evaporation of the sol-
vent, the crude mixture was cooled to 0 ꢀC. Dry methanol (10 mL)
was added and the solution stirred at 40 ꢀC for 2 h. The solvent was
evaporated under reduced pressure and the crude mixture was
diluted with water (10 mL), extracted with EtOAc (3ꢁ20 mL) and
the combined organic layers dried over MgSO4. The product was
purified by column chromatography on silica, eluting with petro-
leum ether/diethyl ether (60e80 ꢀC) (60:40) to give a solid, which
4.2.3. N-Allyl-3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-2-carbox-
amide (12c). This pyrrole was prepared, as described above and the
crude product was purified by column chromatography on silica,
eluting with ethyl acetate/petroleum ether (60e80 ꢀC) (40:60) to
give 12c as an orange solid (0.19 g, 54%), mp 125e126 ꢀC; 1H NMR
(300 MHz, DMSO-d6): 3.88 (3H, s, CH3), 4.01 (2H, m, CH2), 5.13 (1H,
t, J¼1.8 Hz,¼CHaH), 5.19 (1H, t, J¼1.8 Hz,¼CHbH), 5.86 (1H, m, CH),
6.27 (1H, br s, NH), 9.69 (1H, s, CHO); 13C NMR (75.5 MHz, DMSO-
d6): 33.2 (CH3), 41.9 (CH2), 114.3 (quat.), 116.7 (]CH2), 123.0 (quat.),

G. Marth et al. / Tetrahedron 66 (2010) 6113e6120
6119
was recrystallised from methanol to give 13a as a white solid
(0.22 g, 80%), mp 108e110 ꢀC; 1H NMR (300 MHz, DMSO-d6): 3.87
(3H, s, NCH3), 3.94 (3H, s, OCH3), 9.79 (1H, s, CHO); 13C NMR
(75.5 MHz, DMSO-d6): 33.7 (NCH3), 52.2 (OCH3), 110.4 (quat.), 124.8
(quat.), 126.7 (quat.), 130.7 (quat.), 161.1 (C]O), 178.5 (CHO); IR
(cmꢂ1): 1711 (C]O), 1654 (C]O), 1511 (C]C). Anal. Calcd for
C8H7Cl2NO3: C, 40.7; H, 3.0; N, 5.9. Found: C, 40.5; H, 2.9; N, 5.7%.
114e116 ꢀC; 1H NMR (300 MHz, CDCl3): 1.27 (3H, t, J¼7.2 Hz, CH3),
3.89 (3H, s, NCH3), 4.19 (2H, q, J¼7.2 Hz, CH2), 6.61 (1H, d, J¼16.0 Hz,
H2), 7.48 (1H, d, J¼16.0 Hz, H3), 9.69 (1H, s, CHO); 13C NMR
(75.5 MHz, CDCl3): 14.4 (CH3), 33.5 (CH3), 60.6 (CH2), 114.6 (quat.,
C30), 119.1 (CH, C2), 125.3 (quat., C50), 126.5 (quat., C3), 128.8 (quat.,
C40), 131.8 (CH, C3), 167.1 (C]O), 177.5 (CHO); IR (cmꢂ1): 1701 (C]
O), 1660 (C]O), 1634 (C]C). HRMS m/z calcd for C11H1235Cl2NO3
[MHþ]: 276.0189, found: m/z 276.0196.
4.2.7. Ethyl 3,5-dichloro-4-formyl-1-methyl-1H-pyrrole-2-carboxyl-
ate (13b). This ester was prepared as above and purified by column
chromatography on silica, eluting with petroleum ether/diethyl
ether (60e80 ꢀC) (60:40) to give 13b as white solid (0.25 g, 86%),
mp 78e80 ꢀC; 1H NMR (300 MHz, DMSO-d6): 1.35 (3H, t, J¼7.2 Hz,
CH2CH3), 3.93 (3H, s, NCH3), 4.35 (2H, q, J¼7.2 Hz, CH2), 9.76 (1H, s,
CHO); 13C NMR (75.5 MHz, DMSO-d6): 14.5 (CH2CH3), 33.6 (NCH3),
60.9 (CH2), 110.5 (quat., C3 or C4), 124.8 (quat., C3 or C4), 126.6
(quat., C5), 130.6 (quat., C2), 160.6 (C]O), 178.4 (CHO); IR (cmꢂ1):
1706 (C]O), 1662 (C]O), 1512 (C]C). Anal. Calcd for C9H9Cl2NO3:
C, 43.2; H, 3.6; N, 5.6. Found: C, 43.3; H, 3.8; N, 5.4%.
4.3.3. Ethyl 3-(30,50-dichloro-10-ethyl-40-formyl-1H-pyrrol-20-yl)ac-
rylate (17c). The crude product was purified by column chroma-
tography on silica, eluting with ethyl acetate/petroleum ether
(60e80 ꢀC) (20:80), to give 19c as a pale yellow solid (0.20 g, 43%),
mp 108e109 ꢀC; 1H NMR (300 MHz, CDCl3): 1.25 (3H, t, J¼7.2 Hz,
OCH2CH3), 1.28 (3H, t, J¼6.9 Hz, NCH2CH3), 4.19 (2H, q, J¼7.2 Hz,
OCH2CH3), 4.41 (2H, q, J¼6.9 Hz, NCH2CH3), 6.66 (1H, d, J¼16.2 Hz,
H2), 7.49 (1H, d, J¼16.2 Hz, H3), 9.68 (1H, s, CHO); 13C NMR
(75.5 MHz, CDCl3): 14.4 (CH3), 15.3 (CH3), 41.8 (NCH2), 60.6 (OCH2),
114.6 (quat., C-20),119.1 (CH, C2),125.6 (quat., C30 or C50),125.8 (quat.,
C30 or C50),127.9 (quat., C40),131.8 (CH, C3),167.1 (C]O),177.2 (CHO);
IR (cmꢂ1): 1706 (C]O),1665 (C]O),1634 (C]C),1525 (C]C). HRMS
m/z calcd for C12H1435Cl2NO3 [MHþ]: 290.0346, found: m/z 290.0359.
4.2.8. Methyl 3,5-dichloro-4-carboxylic acid-1-methyl-1H-pyrrole-
2-carboxylate (14). Methyl 3,5-dichloro-4-formyl-1-methyl-1H-
pyrrole-2-carboxylate 13a (0.15 g, 0.64 mmol) was dissolved in
acetone (15 mL) and treated with a solution of KMnO4 (0.23 g,
1.5 mmol) in H2O (5 mL). The reaction mixture was refluxed for
12 h then decolourised with charcoal. After filtration, the solvent
was evaporated under reduced pressure, acidified with 2 M aq HCl
and the crude product was recrystallised from methanol to give 14
as a white solid (0.064 g, 40%), mp 138e140 ꢀC; 1H NMR (300 MHz,
DMSO-d6): 3.64 (3H, s, NCH3), 3.70 (3H, s, OCH3); 13C NMR
(75.5 MHz, DMSO-d6): 34.7 (NCH3), 52.0 (OCH3), 110.3 (quat.), 118.7
(quat.), 121.8 (quat.), 136.9 (quat.), 160.6 (C]O), 161.6 (C]O); IR
(cmꢂ1): 1723 (ester C]O), 1659 (acid C]O), 1521 (C]C). Anal.
Calcd for C8H7Cl2NO4: C, 38.1; H, 2.8; N, 5.6. Found: C, 37.9; H, 2.8;
N, 5.5%.
4.3.4. 3,5-Dichloro-2,4-bis(20-ethoxycarbonylethenyl)-1H-pyrrole
(18a). Thecrudeproductwaspurifiedbycolumnchromatographyon
silica, eluting with ethyl acetate/petroleum ether (60e80 ꢀC) (20:80),
to give diester 18a as a pink solid (0.42 g, 39%), mp 168e169 ꢀC; 1H
NMR (300 MHz, DMSO-d6): 1.29 (6H, t, J¼6.9 Hz, 2ꢁCH3), 4.22 (4H, q,
J¼6.9 Hz, 2ꢁCH2), 6.46 (1H, d, J¼16.0 Hz,]CH), 6.59 (1H, d,
J¼16.0 Hz,]CH), 7.39 (2H, m,]CH), 13.18 (1H, s, NH); 13C NMR
(75.5 MHz,DMSO-d6):14.6(2ꢁCH3), 60.5(2ꢁCH2),113.7(quat.),115.5
(CH), 115.6 (quat.), 116.7 (CH), 122.3 (quat.), 125.5 (quat.), 128.7 (CH),
132.6 (CH), 166.5 (C]O), 166.7 (C]O); IR (cmꢂ1): 3208 (NH), 1704
(C]O), 1667 (C]O), 1624 (C]C), 1542 (C]C). HRMS m/z calcd for
C14H1635Cl2NO4 [MHþ]: 332.0451, found: m/z 332.0438.
4.3. General procedure for the Wittig reactions
4.3.5. 3,5-Dichloro-2,4-bis(20-ethoxycarbonylethenyl)-1-methyl-1H-
pyrrole (18b). The crude product was purified by column chroma-
tography on silica, eluting with ethyl acetate/petroleum ether
(60e80 ꢀC) (20:80), to give 18b as a yellow solid (0.38 g, 45%), mp
113e114 ꢀC; 1H NMR (300 MHz, DMSO-d6): 1.30e1.36 (6H, m,
2ꢁCH3), 3.79 (3H, s, NCH3), 4.24e4.28 (4H, m, 2ꢁCH2), 6.64 (1H, d,
J¼16.2 Hz,]CH), 6.67 (1H, d, J¼16.2 Hz,]CH), 7.49 (1H, d,
J¼16.2 Hz,]CH), 7.57 (1H, d, J¼16.2 Hz,]CH); 13C NMR (75.5 MHz,
DMSO-d6): 14.7 (2ꢁCH3), 33.1 (NCH3), 60.6 (CH2), 60.7 (CH2), 113.6
(quat.), 114.6 (quat.), 116.9 (CH), 117.4 (CH), 123.8 (quat.), 125.8
(quat.),129.4 (CH),132.6 (CH),166.7 (2ꢁC]O); IR (cmꢂ1): 1698 (C]
O), 1624 (C]C). HRMS m/z calcd for C15H1835Cl2NO4 [MHþ]
346.0607, found: m/z 346.0618.
The appropriate aldehyde 4b or 4c (2.91 mmol) was dissolved in
CH3CN (30 mL) and treated with (carbethoxymethylene)triphe-
nylphosphorane 16a (3.06 or 5.09 mmol) or (carbethoxyethylidene)
triphenylphosphorane 16b (3.06 or 5.09 mmol). The reaction mix-
ture was refluxed for 9e12 h, then the solvent was removed under
reduced pressure and the residue was treated with water (20 mL),
extracted with EtOAc (3ꢁ30 mL) and the combined organic layers
dried over MgSO4. After filtration, the solvent was evaporated un-
der reduced pressure and the crude product was purified by col-
umn chromatography.
4.3.1. Ethyl 3-(30,50-dichloro-40-formyl-1H-pyrrol-20-yl)methacrylate
(17a). The crude product was purified by column chromatography
on silica, eluting with ethyl acetate/petroleum ether (60e80 ꢀC)
(20:80), to give 17a as a yellow solid (0.20 g, 35%), mp 149e150 ꢀC;
1H NMR (300 MHz, DMSO-d6): 1.35 (3H, t, J¼7.2 Hz, CH3), 2.13 (3H,
d, J¼1.5 Hz, CH3), 4.28 (2H, q, J¼7.2 Hz, CH2), 7.37 (1H, q, J¼1.5 Hz,¼
CH), 9.88 (1H, s, CHO), 12.96 (1H, br s, NH); 13C NMR (75.5 MHz,
DMSO-d6): 14.6 (CH3), 15.2 (CH3), 61.3 (CH2), 114.3 (quat., C40), 116.7
(quat., C30), 123.8 (CH, C3), 125.5 (quat., C50), 126.1 (quat., C20), 128.5
(quat., C2), 167.5 (C]O), 182.9 (CHO); IR (cmꢂ1): 3180 (NH), 1717
(C]O), 1666 (C]O). Anal. Calcd for C11H11Cl2NO3: C, 47.9; H, 4.0; N,
5.1. Found: C, 47.8; H, 4.0; N, 5.0%.
4.3.6. 3,5-Dichloro-2,4-bis(20-ethoxycarbonylethenyl)-1-ethyl-1H-
pyrrole (18c). The crude product was purified by column chroma-
tography on silica, eluting with ethyl acetate/petroleum ether
(60e80 ꢀC) (20:80), to give 18c as an orange solid (0.42 g, 64%), mp
84e86 ꢀC; 1H NMR (300 MHz, DMSO-d6): 1.30e1.36 (9H, m, 3ꢁCH3),
4.24e4.28 (6H, m, 3ꢁCH2), 6.65 (1H, d, J¼16.0 Hz,]CH), 6.68 (1H, d,
J¼16.4 Hz,]CH), 7.49 (1H, d, J¼16.0 Hz,]CH), 7.57 (1H, d,
J¼16.4 Hz,]CH); 13C NMR (75.5 MHz, DMSO-d6): 14.6 (2ꢁCH3), 15.6
(CH3), 40.8 (CH2), 60.6 (CH2), 60.8 (CH2), 113.8 (quat.), 114.8 (quat.),
117.2 (CH), 117.6 (CH), 122.8 (quat.), 124.6 (quat.), 129.1 (CH), 132.5
(CH),166.7 (2ꢁC]O);IR(cmꢂ1):1704(C]O),1624(C]C). Anal. Calcd
for C16H19Cl2NO4: C, 53.4; H, 5.3; N, 3.9. Found: C, 53.5; H, 5.4; N, 3.8%.
4.3.2. Ethyl
3-(30,50-dichloro-40-formyl-10-methyl-1H-pyrrol-20-yl)
acrylate (17b). The crude product was purified by column chro-
matography on silica, eluting with ethyl acetate/petroleum ether
(60e80 ꢀC) (20:80), to give 17b as a pink solid (0.24 g, 35%), mp
4.3.7. 3,5-Dichloro-4-cyano-1H-pyrrole-2-carboxaldehyde
oxime
(20). 4.3.7.1. Method A. POCl3 (2.92 mL) was added dropwise to
dry DMF (10 mL) at 0 ꢀC. To this solution, N-acetylglycine (1.00 g,

6120
G. Marth et al. / Tetrahedron 66 (2010) 6113e6120
8.54 mmol) was added and the mixture stirred for 1 h at room
temperature then 4 h at 90 ꢀC. After completion of the reaction, as
indicated by TLC, the reaction mixture was diluted with DCM
(12 mL), cooled to 0 ꢀC and hydroxylamine hydrochloride (1.77 g,
25.5 mmol) in DMF (5 mL) was added. The mixture was stirred for
4 h at room temperature. After the reaction was complete, it was
diluted with water (8 mL) and extracted with DCM (2ꢁ15 mL). The
combined organic phases were washed with water (2ꢁ10 mL),
saturated aq NaHCO3 solution (8 mL) and water (15 mL) and dried
over MgSO4. After filtration, the solvent was evaporated under re-
duced pressure and the crude product was purified by column
chromatography on silica, eluting with ethyl acetate/petroleum
ether (60e80 ꢀC) (30:70) to give 20 (0.72 g, 45%) as a yellow solid
with identical spectral data to those given below.
4.98 (1H, s, NH), 7.89 (1H, s, CH]N), 11.53 (1H, s, OH); 13C NMR
(75.5 MHz, DMSO-d6): 100.3 (quat., C4 or C5),111.7 (quat., C4 or C5),
112.6 (quat., C2 or C3), 120.2 (quat., C2 or C3), 139.2 (CH]N); IR
(cmꢂ1): 3170 (broad NH and OH), 2234 (C^N). HRMS m/z calcd for
C6H435Cl2N3O [MHþ]: 203.9726, found: m/z 203.9732.
Acknowledgements
The receipt of a U.K. Engineering and Physical Sciences Research
Council (EPSRC) CASE studentship (G.M.) with High Force Research
Ltd. is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.06.006.
4.3.7.2. Method
B. 3,5-Dichloro-1H-pyrrole-2,4-dicarbox-
aldehyde 4a (1.00 g, 5.21 mmol), hydroxylamine hydrochloride
(0.38 g, 5.47 mmol) and pyridine (0.43 g, 5.43 mmol) were refluxed
in EtOH for 2 h, to give the crude bisoxime 19. To this solution was
added Ac2O (15 mL), the mixture was heated under reflux for 1.5 h,
cooled, stirred with water (100 mL), extracted with DCM
(3ꢁ30 mL) and dried over MgSO4. After filtration, the solvent was
evaporated under reduced pressure and the crude product was
purified by column chromatography on silica, eluting with ethyl
acetate/petroleum ether (60e80 ꢀC) (30:70) to give 20 as a yellow
solid (0.78 g, 72%), mp 158e159 ꢀC; 1H NMR (300 MHz, DMSO-d6):
References and notes
1. Pandey, P. S.; Srinivasa Rao, T. Bioorg. Med. Chem. Lett. 2004, 14, 129e131.
2. Watanabe, E.; Baba, K.; Eun, H.; Arao, T.; Ishii, Y.; Ueji, M.; Endo, S. J. Chromatogr.,
A 2005, 1074, 145e153.
3. Raimondi, M. V.; Cascioferro, S.; Schillaci, D.; Petruso, S. Eur. J. Med. Chem. 2006,
41, 1439e1445.
4. Zaytsev, A. V.; Anderson, R. J.; Meth-Cohn, O.; Groundwater, P. W. Tetrahedron
2005, 61, 5831e5836.
5. Markó, I. E.; Mekhalfia, A. Tetrahedron Lett. 1990, 31, 7237e7240.
6. Reddy, G.J.;Latha,D.;Thirupathaiah,C.;Rao,S.K. Tetrahedron Lett. 2004,45,847e848.