Investigations into the parallel synthesis of novel pyrrole-oxazole analogues of the insecticide pirate

Article abstract of DOI:10.1055/s-2006-942390

Investigations into the parallel synthesis of selected analogues of a structurally unique pyrrole-oxazole analogue of the pyrrole insecticide pirate, are reported. Acylaminoketone salts were obtained from ketobromides in moderate to high yields and excell

Full text of DOI:10.1055/s-2006-942390

PAPER
1975
Investigations into the Parallel Synthesis of Novel Pyrrole-Oxazole Analogues
of the Insecticide Pirate
Investigations into the
P
e
arallel Synt
n
hesis of Pyr
r
d
ole-Oxazole
y
s
A. Loughlin,*a,b Luke C. Henderson,a Kathryn E. Elson,a Michelle E. Murphya
a
School of Science, Griffith University, Brisbane, QLD, 4111, Australia
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, QLD, 4111, Australia
Fax +61(7)37357656; E-mail: w.loughlin@griffith.edu.au
b
Received 12 January 2006
As part of a study aimed at identifying new potential in-
secticides, we sought to synthesize novel, structurally
unique analogues of pirate 2, that might ultimately deliver
improved dosage rates and selectivity in the field, while
Abstract: Investigations into the parallel synthesis of selected ana-
logues of a structurally unique pyrrole-oxazole analogue of the pyr-
role insecticide pirate, are reported. Acylaminoketone salts were
obtained from ketobromides in moderate to high yields and excel-
lent purity. A number of N-tosyl pyrroles were obtained; however, reducing negative ecological impact. Previously7 we gen-
formation of the target acyl tosyl pyrroles was thwarted by the ste-
reoelectronic effects of the pyrrole substituents. During the pyrrole
subunit chemistry, an interesting pyrrole derivative, vinyl pyrrole,
was isolated. By restricting diversity to the aryl subunit, the parallel
erated simple pyrrole-oxazoles 4 and 5, and established
that they displayed moderate cytotoxicity.
During these investigations,7 we established a viable syn-
thetic route to pyrrole-oxazole 5 via coupling of 6 and 7a
and subsequent conversion to the target pyrrole-oxazole 5
(Scheme 1) without any purification steps, in 21% yield
(cf. 10% with purification steps).7 This suggested that the
sequence was robust enough for the generation of ana-
logues using solution-phase parallel synthesis. In the
present work we wish to report the results of our investi-
gations on the parallel synthesis of selected analogues of
pyrrole-oxazole 5.
synthesis of selected pyrrole-oxazoles in moderate purity, was
achieved when electron-donating or no groups were present on the
aryl ring.
Key words: pyrroles, oxazoles, amines, cyclizations, parallel syn-
thesis
The natural product antibiotic, dioxapyrrolomycin (1) iso-
lated from Streptomyces MG796-AF7,1 displays moder-
ate insecticidal and acaricidal activity against arachnids,
mites and ticks2 and has been found to be a potent uncou-
pler of oxidative phosphorylation.3 Using 1 as a lead com-
pound, 2-arylpyrroles, have been developed through
QSAR studies4 and identified as a novel class of insecti-
cides and acaricides. In particular, Pirate™ 2 has been
commercially developed as a broad-spectrum insecticide/
miticide.3 The N-dealkylated analogue 3, of pirate, is the
metabolically active compound,5 where the activity of the
pyrrole insecticides is primarily a function of lipophilicity
(Log P) and acidity (pKa).2,6
O
O
Br–
N
DMAP, Et3N,
CH2Cl2, 36%
H3N
Cl
7a
Ts
6
O
O
N
HN
Ts
8
POCl3, 55%
O
N
Cl
N
Br
CN
R
Cl
NO2
(i) n-BuLi, THF-hexane
9a R = Ts
4 R = CH2OEt
5a R = H
NaOH, CH3OH
52%
(ii) ClCH2OEt,DMSO
89%
F3C
N
R
Cl
Cl
N
H
O
O
Cl
Scheme 1
2 R = CH2OEt
3 R = H
1
O
We examined the parallel synthesis of acylaminoketone
salts, choosing commercially available ketobromides
10a–k, which varied in the steric and electronic influences
of the group a to the ketone. Acylaminoketone salts 7a–k
were obtained, in moderate to high yields and excellent
purity (with the exception of 7j which, though high yield-
ing, was impure), via a Delépine reaction in which the
ketobromides 10a–k were reacted with hexamethyl-
enetetramine9 followed by cleavage of the resulting salt
11a–k with hydrobromic acid (Scheme 2).10
N
R
4 R = CH2OEt
5a R = H
N
Figure 1 Structures of known insecticides 1–3 and potential lead
compounds 4 and 5
SYNTHESIS 2006, No. 12, pp 1975–1980
Advanced online publication: 11.05.2006
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DOI: 10.1055/s-2006-942390; Art ID: P00406SS
© Georg Thieme Verlag Stuttgart · New York

1976
W. A. Loughlin et al.
PAPER
pyrroles can be coupled with amines,14 we treated acetyl
dimethylpyrrole 14 with trichloroacetyl chloride in THF
at room temperature for 3 hours and found that, along with
trichloroacetyl pyrrole 25 (19%), the vinyl pyrrole 26 was
also formed, albeit in low yield (7%). The structure of 26
was unambiguously assigned using g-COSY, g-HMBC,
g-HSQC, GC-Mass spectrometry and micro analysis. A
key correlation between protons at d = 5.29 and 5.71 ppm
(2J = 1 Hz) and the carbon at d = 118.2 ppm in the g-
HSQC indicated a disubstituted olefinic group external to
the pyrrole ring. Chlorine isotope peaks were observed for
fragments at 182 [M – CCl3] and 264 [M – Cl] in the GC-
MS (+) spectrum. Reaction of the enol of trichloroacetyl
pyrrole 25 with trichloroacetyl chloride followed by dis-
placement of trichloroacetate ion with a chloride ion
would account for formation of vinyl pyrrole 26.
N
48% HBr,
CH3OH,
r.t., 5 d
hexamethylene-
tetramine, CHCl3,
r.t., 18 h
N
N
Br–
Br
NH3
N
O
O
Br
O
R
10a–k
R
R
89% overall
7a–k
11a–k
where R =
R'
d; R' = OCH3
e; R' = NO2
f; R' = Cl
g; R' = Br
h; R' = Ph
i
j
a; R' = H
b; R' = OCH3
c; R' = NO2
R'
k
where yield = 7a, 63%; 7b, 93%; 7c, 99%; 7d, 67%; 7e, 99%; 7f, 54%;
7g, 99%; 7h, 50%; 7i, 68%; 7j, 97% (impure); 7k, 76%.
O
O
Cl
Scheme 2
O
Cl3C
Cl
CCl3
CCl3
Synthesis of selected pyrrole subunits was examined us-
ing commercially available pyrroles with representative
combinations of electron donating and withdrawing
groups.
C
O
C
O
r.t., 3 h
THF
N
N
H
N
H
H
+
14
25
26
Generation of the potassium anion of pyrroles 12–14, fol- Scheme 4
lowed by treatment with tosyl chloride11 gave the corre-
sponding N-tosyl pyrroles 17–19 (Scheme 3). A modified
As side products were observed in the formation of 25,
trichloroacetyl pyrrole 16 was used for a trial tosylation
reaction. Treatment of 16 with potassium and tosyl chlo-
ride, however, gave complex mixtures and none of N-to-
syl pyrrole 21. A modified procedure using butyllithium
in DMSO–THF (~1:1) also gave a mixture of which start-
ing pyrrole 13 was the major component (~90%).
procedure, using methyllithium and DMSO (to aid solu-
bility of 15), was used to generate N-tosyl pyrrole 20
(35%) from 15. Acylation of N-tosyl pyrroles 17–20 was
then examined. Unfortunately, though the unsubstituted
pyrrole 17 underwent regioselective AlCl3-catalyzed
Friedel–Crafts acylation12 to give N-tosylpyrrolecarbonyl
chloride (6) (Scheme 3), pyrroles 18–20 were not acylated
to the corresponding acylpyrroles 22–24, with only start-
ing materials being recovered. Pyrrole 19 was also quan-
titatively recovered even upon heating at reflux for 48
hours. These results suggest the balance of steroelectronic
effects deactivate the 2-position to direct acylation.
With the complications of substituent effects and the side
reactions observed for the pyrrole subunit, we pursued the
parallel synthesis of the carboxamides, incorporating rep-
resentative points of diversity only in the aryl subunit. A
set of acylaminoketone salts was selected with a range of
substituents; phenyl (7a), methoxyphenyl (7d), nitrophe-
nyl (7e), and chlorophenyl (7f). A parallel set of reactions
were carried out using the sequence of coupling, cycliza-
tion and deprotection (Scheme 1, 7 to 5).
oxalyl
chloride,
AlCl3
R2
R3
R2
R2
R3
R3
base,
TsCl
O
R1
R1
R1
N
To streamline the parallel synthesis, purification of inter-
mediate compounds was not carried out, reactions were
carried out on a smaller scale and minimal reaction work-
up steps were used. Aliquots were taken at the conclusion
of some steps for analysis by mass spectrometry to moni-
tor the progress of the synthesis. After the coupling step,
it was found necessary to thoroughly dry the crude car-
boxamides (8a–d) so as to prevent hydrolysis of phospho-
rus oxychloride during the subsequent cyclodehydration.
N
N
H
Cl
Ts
Ts
6, 22–24
17–21
12–16
6,12,17; R1 = R2 = R3 = H 13,18,22; R1 = R3 = CH3, R2 = H
14,19,23; R1 = R3 = CH3, R2 = C(O)CH3 15,20,24; R1 = H, R2 = R3 = CO2Et
16,21; R1 = C(O)CCl3, R2 = R3 = H
Scheme 3
At this point the synthetic route to N-tosylpyrrolecarbonyl
chloride 6 was reconsidered. We previously showed that
conversion of N-tosylpyrrole carboxylic acid to 6 was
complicated by decomposition of the starting material.7 In
contrast, it has been reported13 that acylation of 2-methyl-
3-ethylpyrrole carboxylate with trichloroacetyl chloride
does occur upon heating at 65 °C. Since trichloroacetyl
Using acylaminoketone salts 7a, 7d and 7f, coupling with
acylpyrrole 6 gave carboxamides 8a, 8b and 8d, which
were successfully cyclized to the tosyl pyrrole-oxazoles
9a, 9b and 9d, deprotection of which gave the correspond-
ing pyrrole-oxazoles 5a, 5b and 5d, as confirmed by mass
spectrometry (Figure 2). Mass spectral monitoring also
provided evidence that coupling of acylaminoketone salt
Synthesis 2006, No. 12, 1975–1980 © Thieme Stuttgart · New York

PAPER
Investigations into the Parallel Synthesis of Pyrrole-Oxazoles
Arylamino Ketone Salts 7a–k; General Procedure
1977
7e with 6 did not proceed under standard conditions to
form the carboxamide 8c. The purity of the crude products
(5a, 5b and 5d) was estimated by 1H NMR spectroscopy
and by comparison with the spectra of authentic samples
where possible (5a and 5b). The lower overall yield (eg:
7a to 5a, ~12% cf. larger scale 21%) was attributed to the
smaller scale of reaction used in the parallel procedure.
Typical purity of the final pyrrole-oxazole was only mod-
erate (50–65%) with complex mixtures of by-products be-
ing observed, particularly for chloropyrrole-oxazole 5d.
Full characterization was not carried out due to the mod-
erate purities observed. Notably, when carboxamide 8d
was purified by column chromatography before the dehy-
In parallel, each bromo ketone (1.0 equivalent; 10a, 20.0 g, 0.1 mol;
10b, 2.0 g, 8.76 mmol; 10c, 0.5g, 2.0 mmol; 10d, 2.0 g, 8.7 mmol;
10e, 2.0 g, 8.2 mmol; 10f, 1.0 g, 4.3 mmol; 10g, 1.0 g, 3.6 mmol;
10h, 1.0 g, 3.6 mmol; 10i, 1.0 g, 4.5 mmol; 10j, 1.5 g, 9.9 mmol;
10k, 2.0 g, 11.2 mmol) was added to a solution of hexamethylene-
tetramine (1.1 equiv) dissolved in CHCl3 (10a, 200 mL; 10b,d,e,k
20 mL; 10j, 15 mL; 10f–i, 10 mL; 10c, 5 mL). After stirring at r.t.
for 12 h a precipitate formed. tert-Butyl methyl ether (10a, 100 mL;
10b, d,e,k 10 mL; 10j, 7.5 mL; 10f–i, 5 mL; 10c, 2.5 mL) was added
to the suspension and the solid was filtered, washed with a minimal
amount of Et2O and dried under high vacuum to give the quaternary
salts 11a–k. The salts 11a–k were then added to a solution of
MeOH (11a, 200 mL; 11b,d,e, 20 mL; 11j, 17 mL; 11f, h–i, k 10
mL; 11g, 8 mL; 11c, 5 mL) and HBr (48%; 11a, 38.82 mL; 11b, 3.3
dration and deprotection steps were carried out (with no mL; 11c 0.73 mL; 11d, 3.5 mL; 11e, 3.6 mL; 11f, 1.92 mL; 11g,
1.32 mL; 11h, 1.6 mL; 11i, 1.72 mL; 11j, 3.11 mL; 11k, 1.04 mL).
The mixtures were stirred at r.t. for 5 d then the solvent volume was
reduced in vacuo to a slurry, which was cooled to –15 °C. The re-
sultant solid was filtered, washed with sat. aq KBr and air dried. The
solid was recrystallised from n-BuOH and dried under high vacuum
to give the arylamino ketone salts 7a–k.
further purification and minimal workup) the purity of
pyrrole-oxazole 5d increased to 74%.
R
8a R = H
O
O
8b R = OCH3
8c R = NO2
8d R = Cl
N
HN
(2-Phenyl-2-oxoethyl)ammonium Bromide (7a)
Yield: 13.52 g (63%); white solid; mp 234–235 °C (Lit.16 198–
200 °C [HBr + HCl salt]).
1H NMR (200 MHz, CDCl3–TFA): d = 4.8 (br s, 2 H, CH2), 7.55
(dd, J = 8.2, 8.2 Hz, 2 H, H-3¢, H-5¢), 7.75 (dd, J = 7.1, 7.1 Hz, 1 H,
H-4¢), 7.94 (d, J = 7.1 Hz, 2 H, H-2¢, H-6¢).
Ts
R
5a R' = H, R = H
9a R' = Ts, R = H
O
5b R' = H, R = OCH3
5c R' = H, R = NO2
5d R' = H, R = Cl
9b R' = Ts, R = OCH3
9c R' = Ts, R = NO2
9d R' = Ts, R = Cl
N
N
R'
Figure 2 Carboxamides and pyrrole-oxazoles
NH3 not observed.
MS (ESI, +): m/z (%) = 136 (100) [M + H]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (99) [Br]–.
In summary, the parallel synthesis of the arylamino salt
subunit 7a–k has been achieved in moderate to high yields
and excellent purity (with the exception of 7j). The syn-
thetic route constitutes a reliable methodology for access
to such salts. Whereas the N-tosyl pyrroles 17–19 were
synthesized, the pyrrole acyl chloride subunits 22–24
could not be obtained using parallel chemistry, as this was
thwarted by the stereoelectronic effects of the pyrrole sub-
stituents. Examination of an alternate route to the pyrrole
subunit revealed the formation of the interesting pyrrole
derivative, vinyl pyrrole 26.
[2-(2¢-Methoxyphenyl)-2-oxoethyl]ammonium Bromide (7b)
Yield: 1.19 g (93%); orange solid; mp 249–250 °C.
IR (KBr): 1671, 1399 cm–1.
1H NMR (200 MHz, CDCl3–TFA): d = 4.01 (s, 3 H, OCH3), 4.67
(br s, 2 H, CH2), 7.05–7.18 (m, 2 H, H-3¢, H-5¢), 7.71 (dd, J = 7.0,
7.0 Hz, 1 H, H-4¢), 7.98 (dd, J = 7.5, <1.0 Hz, 1 H, H-6¢).
NH3 not observed.
13C NMR (50 MHz, CDCl3–TFA): d = 49.2, 56.8, 113.8, 122.2,
124.4, 131.8, 137.6, 162.1, 198.4.
MS (ESI, +): m/z (%) = 166 (100) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (98) [Br]–.
By restricting diversity to the aryl subunit, the parallel
synthesis of target pyrrole-oxazoles 5a, 5b and 5d with
either no groups, or electron-donating groups on the aryl
ring, was achieved. The parallel synthesis of these pyr-
role-oxazoles, easily monitored by mass spectrometry,
exploited modified workup procedures with no intermedi-
ate purification steps and gave moderate purity of the tar-
get compounds. Using one example, purification after the
coupling step was shown to increase the purity of the final
pyrrole-oxazole. From the above preliminary study, the
scope and limitations for the parallel synthesis of arylami-
no salts, pyrrole acyl chlorides and pyrrole-oxazole units
were assessed and presented for organic chemists consid-
ering using such methodology.
+
HRMS: m/z calcd for C9H12NO2 : 166.0863; found 166.0841.
[2-(2¢-Nitrophenyl)-2-oxoethyl]ammonium Bromide (7c)
Yield: 0.296 g (67%); beige solid; mp 209–211 °C.
IR (KBr): 1723, 1524, 1399, 1343 cm–1.
1H NMR (200 MHz, CDCl3–TFA): d = 4.57 (br s, 2 H, CH2), 7.56
(d, J = 6.9 Hz, 1 H, H-4¢), 7.75–7.92 (m, 2 H, H-5¢, H-6¢), 8.26 (d,
J = 6.9 Hz, 1 H, H-3¢).
NH3 not observed.
13C NMR (50 MHz, CDCl3–TFA): d = 48.8, 125.2, 129.9, 132.6,
132.9, 135.6, 145.6, 194.9.
MS (ESI, +): m/z (%) = 181 (100) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (98) [Br]–.
Instrumental details, the preparation of compounds 4, 5a, 5b, 6, 7a,
8a, 8b, 9a, 9b and the parallel synthesis procedures used, are de-
scribed elsewhere.7,11,15
+
HRMS: m/z calcd for C8H9N2O3 : 181.0608; found 181.0606.
Synthesis 2006, No. 12, 1975–1980 © Thieme Stuttgart · New York

1978
W. A. Loughlin et al.
PAPER
[2-(4¢-Methoxyphenyl)-2-oxoethyl]ammonium Bromide (7d)
Yield: 1.99 g (99%); pale yellow solid; mp 207.5–209 °C (Lit.10
204–205 °C).
1H NMR (200 MHz, CDCl3–TFA): d = 3.92 (s, 3 H, OCH3), 4.7 (br
s, 2 H, CH2), 7.01 (d, J = 9.75 Hz 2 H, H-3¢, H-5¢), 7.92 (d, J = 9.75
Hz, 2 H, H-2¢, H-6¢).
IR (KBr): 1693, 1486 cm–1.
1H NMR (200 MHz, CDCl3–TFA): d = 4.91 (br s, 2 H, CH2), 7.60–
7.80 (m, 3 H, H-5¢, H-6¢, H-7¢), 7.90–8.05 (m, 3 H, H-3¢, H-4¢, H-
8¢), 8.52 (br s, 1 H, H-1¢).
NH3 not observed.
13C NMR (50 MHz, CD3OD): d = 46.36, 124.0, 128.3, 128.9, 130.0,
130.8, 131.8, 132.3, 133.9, 137.6, 193.1.
MS (ESI, +): m/z (%) = 116 (7) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (96) [Br]–.
HRMS: m/z calcd for C9H12NO+: 186.0913; found 186.0912.
NH3 not observed.
MS (ESI, +): m/z (%) = 166 (100) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (98) [Br]–.
[2-(4¢-Nitrophenyl)-2-oxoethyl]ammonium Bromide (7e)
Yield: 0.296 g (67%); brown solid; mp 258–260 °C (dec.).
IR (KBr): 1683, 1520, 1472, 1340 cm–1.
1H NMR (200 MHz, CDCl3–TFA): d = 4.76 (br s, 2 H, CH2), 8.16
(d, J = 9.1 Hz, 2 H, H-2¢, H-6¢), 8.44 (d, 2 H, J = 9.1 Hz, 2 H, H-3¢,
H-5¢).
(2-Ethyl-2-oxoethyl)ammonium Bromide (7j)
Yield: 1.045 g (97%); brown solid; mp 372–373 °C (dec.).
IR (KBr): 1638, 1399 cm–1.
1H NMR (200 MHz, CDCl3–TFA): d = 1.16 (t, J = 7.4 Hz, 3 H,
CH3), 2.62 (q, J = 7.2 Hz, 2 H, CH2CH3), 4.11 (br s, 2 H, CH2).
NH3 not observed.
13C NMR (50 MHz, CDCl3–TFA): d = 46.3, 124.6, 129.8, 136.8,
149.0, 190.3.
MS (ESI, +): m/z (%) = 181 (100) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (98) [Br]–.
NH3 not observed.
13C NMR (50 MHz, CD3OD): d = 14.4, 26.4, 58.2, 173.3.
MS (ESI, +): m/z (%) = 188 (100) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (99) [Br]–.
HRMS: m/z calcd for C9H12NO+: 188.0768; found: [M + H]+ peak
unable to be measured.
+
HRMS: m/z calcd for C8H9N2O3 : 181.0608; found 181.0600.
[2-(4¢-Chlorophenyl)-2-oxoethyl]ammonium Bromide (7f)17
(2-tert-Butyl-2-oxoethyl)ammonium Bromide (7k)
Yield: 1.045 g (97%); white solid; mp 390 °C (dec.).
1H NMR (200 MHz, CD3OD): d = 1.20 (s, 9 H, 3 × CH3), 4.14 (br
s, 2 H, CH2).
Yield: 0.608 g (54%); white solid; mp 279–280 °C.
IR (KBr): 1682, 1464, 826 cm–1.
1H NMR (200 MHz, CDCl3–TFA): d = 4.74 (br s, 2 H, CH2), 7.56
(d, J = 6.5 Hz, 2 H, H-2¢, H-6¢), 7.90 (d, J = 6.5 Hz, 2 H, H-3¢, H-
5¢).
NH3 not observed.
MS (ESI, +): m/z (%) = 186 (100) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (95) [Br]–.
NH3 not observed.
13C NMR (50 MHz, CD3OD): d = 45.7, 122.8, 129.9, 143.4, 154.8,
191.5.
Tosyl Pyrroles; General Procedure
MS (ESI, +): m/z (%) = 172 (34) [M]+, 170 (100).
Potassium [(a) 1.369 g, 35 mmol; (b) 0.891 g, 23 mmol; 1.1 equiv]
was added to a solution of pyrrole [(a) 13, 3.000 g, 32 mmol; (b) 14,
3.006 g, 22 mmol; 1 equiv] in THF [(a) 25 mL, (b) 17 mL]. The so-
lution was gently heated at reflux until all of the potassium had re-
acted. A solution of TsCl [(a) 6.101 g, 32 mmol; (b) 3.516 g, 22
mmol; 1 equivalent] in THF [(a) 15 mL; (b) 11 mL] was added
dropwise over 20 minutes. The reaction was stirred at r.t. for 12 h.
H2O (10 mL) was added and the aqueous layer was extracted with
Et2O (3 × 10 mL). The combined organic layers were dried
(MgSO4), filtered and evaporated to dryness in vacuo. The crude
product was recrystallised (MeOH–hexane) and dried under high
vacuum.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (98) [Br]& ndash;
.
[2-(4¢-Bromophenyl)-2-oxoethyl]ammonium Bromide (7g)
Yield: 0.81 g (99%); white solid; mp 267 °C (dec.) [Lit.18 273–277
(dec.); Lit.10 260 °C (dec.)].
1H NMR (200 MHz, CDCl3–TFA): d = 4.71 (br s, 2 H, CH2), 7.73
(d, J = 8.7 Hz, 2 H, H-3¢, H-5¢), 7.82 (d, J = 8.3 Hz, 2 H, H-2¢, H-
6¢).
NH3 not observed.
MS (ESI, +): m/z (%) = 216 (38) [M]+, 214 (38).
MS (ESI, –): m/z (%) = 81 (99) [Br]–, 79 (100) [Br]–.
2,4-Dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole (18)
Yield: 6.761 g (84%); light brown solid; mp 80.1–82.0 °C (Lit.21
85 °C).
1H NMR (200 MHz, CDCl3): d = 2.00 (d, J = 1 Hz, 3 H, 2-CH3),
2.26 (d, J = 1 Hz, 3 H, 4-CH3), 2.41 (s, 3 H, PhCH3), 5.80 (br s, 1 H,
H3), 7.00 (br s, 1 H, H5), 7.29 (d, J = 8.2 Hz, 2 H, m-SO2C6H4),
7.66 (d, J = 8.2 Hz, 2 H, o-SO2C6H4).
2-[1,1¢-Biphenyl]-4-yl-2-oxoethylammonium Bromide (7h)
Yield: 1.04 g (50%); beige solid; mp 271–273 °C (dec.) (Lit.19
240 °C char, not melted at 300 °C).
1H NMR (200 MHz, CDCl3,/TFA): d = 4.77 (br s, 2 H, CH2), 7.40–
7.65 (m, 5 H, H-2¢¢, H-3¢¢, H-4¢¢, H-5¢¢, H-6¢¢), 7.80 (d, J = 8.1 Hz,
2 H, H-3¢, H-5¢), 8.03 (d, J = 8.1 Hz, 2 H, H-2¢, H-6¢).
NH3 not observed.
1-{2,4-Dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-
yl}ethanone (19)
A residue of 19 (66%) and starting material 14 (34%) was obtained.
Purification by column chromatography (CH2Cl2–hexane, 2:1) gave
pure 19.
MS (ESI, +): m/z (%) = 212 (100) [M]+.
MS (ESI, –): m/z (%) = 81 (100) [Br]–, 79 (99) [Br]–.
[2-(2¢-Naphthalyl)-2-oxoethyl]ammonium Bromide (7i)
Yield: 0.7 g (68%); white solid; mp 236–238 °C.
Yield: 1.34 g (26%); colourless crystals; mp 111–112 °C.
IR (KBr): 2926, 1670, 1365, 1174 cm–1.
Synthesis 2006, No. 12, 1975–1980 © Thieme Stuttgart · New York

PAPER
Investigations into the Parallel Synthesis of Pyrrole-Oxazoles
1979
1H NMR (200 MHz, CDCl3): d = 2.20 (d, J = 1 Hz, 3 H, 4-CH3),
2.38 (s, 3 H, 2-CH3), 2.41 (s, PhCH3, 3 H), 2.52 (s, 3 H, COCH3),
7.08 (d, J = 1 Hz, 1 H, H5), 7.31 (d, J = 8.1 Hz, 2 H, m-SO2C6H4),
7.70 (d, J = 8.1 Hz, 2 H, o-SO2C6H4).
13C NMR (100 MHz, CDCl3): d = 12.8 (2-CH3), 13.3 (4-CH3), 21.6
(PhCH3), 31.6 (COCH3), 119.4 (C5), 120.6 (C3), 126.5 (C4), 127.1
(o-SO2C6H4), 130.1 (m-SO2C6H4), 135.7 (i-SO2C6H4), 141.7 (2),
145.4 (p-SO2C6H4), 196.8 (C=O).
MS (ESI, +): m/z (%) = 301 (30) [M + 1]+.
GCMS: (%) = 182 (100) [M – CCl3].
Anal. Calcd for C10H9Cl4NO: C, 39.90; H, 3.01; N, 4.65. Found: C,
40.29; H, 3.10; N, 4.36.
Parallel Synthesis; Coupling Step
N-Tosylpyrrole-2-carbonyl chloride 6 (80 mg, 0.28 mmol), DMAP
(0.15 mg, 1.2 mmol) and Et3N (85 mg, 0.84 mmol, 0.12 mL) in
CH2Cl2 (3 mL) were added to each of four reacti-vials containing
one arylamino ketone salt in each. Vial A, 7a (60 mg, 0.28 mmol);
vial B, 7d (69 mg, 0.28 mmol); vial C 7e (73 mg, 0.28 mmol); vial
D, 7f (70 mg, 0.28 mmol). The solutions were stirred for 48 h at r.t.
then H2O (2 mL) was added to each reacti-vial and the aqueous
phase was removed by pasteur pipette. The organic phase from each
vessel was passed through a separate column of anhydrous Na2SO4
and the organic phases were collected and evaporated in vacuo.
MS (ESI, +): m/z (%) = 292 (23) [M]+.
HRMS: m/z calcd for C15H18NO3S+: 292.1002; found 292.1002.
Diethyl 1-[(4-Methylphenyl)sulfonyl]-1H-pyrrole-3,4-dicarbox-
ylate (20)
n-Methyllithium (5.90 mL, 7.1 mmol) was added dropwise at 0–
5 °C to a solution of diethyl 3,4-pyrrole dicarboxylate 15 (1.5 g, 1.5
mmol) in dry THF (15 mL) under an atmosphere of nitrogen. The
reaction mixture was stirred at 0 °C for 15 min, and warmed to r.t.
Dry DMSO (30 mL) was added, followed by dropwise addition of
TsCl (1.22 g, 6.39 mmol) in THF (10 mL). The solution was stirred
at r.t. for 12 h then H2O was added and the reaction mixture was
worked up according to the reference given in the general proce-
dure.
Compound 8a
MS (ESI, +): m/z (%) = 405 (100) [M + Na]+.
Compound 8b
MS (ESI, +): m/z (%) = 435 (100) [M + Na]+.
Compound 8c
Yield: 0.9 g (35%) (~95% purity); amber oil; Lit.22 mp 67–68 °C.
IR (KBr): 1747, 1380, 1066 cm–1.
No peaks detected in the MS (ESI, +).
1H NMR (200 MHz, CDCl3): d = 1.33 (t, J = 8.0 Hz, 6 H, 2 × CH3),
2.45 (s, 3 H, 4¢-CH3), 4.29 (q, J = 8.6 Hz, 4 H, 2 × CH2), 7.37 (d,
J = 10.3 Hz, 2 H, H3¢, H5¢), 7.65 (s, 2 H, H2, H5), 7.83 (d, J = 10.3
Hz, 2 H, H2¢, H6¢).
13C NMR (50 MHz, CDCl3): d = 14.25, 21.75, 61.0, 119.9, 125.5,
127.6, 130.5, 134.5, 149.5, 164.7.
(2¢-(4¢¢-Chlorophenyl-2¢-oxoethyl)-1-tosyl-1H-pyrrole-2-car-
boxamide (8d)
Obtained as a crude product.
1H NMR (200 MHz, CDCl3): d = 2.41 (s, 3 H, CH3), 4.85 (d, 2 H,
H1¢), 6.30 (dd, 1 H, H4), 6.82 (dd, 1 H, H3), 7.31 (d, 2 H, m-
SO2C6H4), 7.49 (m, 2 H, H3¢¢, H5¢¢), 7.54 (dd, 1 H, H5), 7.91 (d,
2 H, o-SO2C6H4), 7.93 (d, 2 H, H2¢¢, H6¢¢).
MS (GCMS): m/z (%) = 365 (8) [M]+.
NH not apparent.
MS (ESI, +): m/z (%) = 423 (100) [M + Li]+.
Pyrroles 25 and 26
3-Acetyl-2,4-dimethylpyrrole 14 (100 mg, 0.78 mmol) in THF (10
mL) was added dropwise over 20 min to a solution of trichloro-
acetyl chloride (0.162 g, 0.78 mmol, 0.1 mL) in dry THF (10 mL).
The solution was stirred at r.t. for 3 h, then a sat. soln of NaHCO3
(50 mL) was added dropwise over 1 h. The organic phase was col-
lected and washed with brine (3 × 10 mL), dried (MgSO4) and the
solvent removed in vacuo. The crude product mixture was purified
by silica column chromatography (EtOAc–CH2Cl2, 4:94).
Parallel Synthesis; Cyclodehydration
Phosphorus oxychloride (3 mL) was added to each reacti-vial (A–
D) containing the residues from the coupling step described above,
and the solutions were heated at reflux for 2 h. The reacti-vials were
allowed to cool to r.t. and stirred for a further 2 h before H2O (2 mL)
was added, and the solutions made basic by the addition of aq NH3
(28%) and worked up as described above.
1-(4-Acetyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trichloro-
ethanone (25)
Yield: 28 mg (13%); yellow solid; mp 125–127 °C.
1H NMR (200 MHz, CDCl3): d = 2.49 (s, 3 H, 3-CH3), 2.59 (s, 3 H,
5-CH3), 2.69 (s, 3 H, C(O)CH3), 9.10 (br s, Wh/2 = 20 Hz, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 14.0 (3-CH3), 15.7 (5-CH3), 31.8
(C(O)CH3), 96.17 (CCl3), 118.4 (C4), 124.9 (C3), 139.0 (C2), 140.6
(C5), 170.3 (C(O)CCl3), 195.3 (C(O)CH3).
5-(4¢¢-Chlorophenyl)-2-(1¢-tosyl-1H-pyrrol-2¢-yl)-1,3-oxazole
(9d)
Obtained as a crude product.
1H NMR (200 MHz, CDCl3): d = 2.40 (s, 3 H, CH3), 6.40 (dd, 1 H,
H4¢), 6.90 (dd, 1 H, H3¢), 7.27 (m, 2 H, H4 of m-SO2C6H4), 7.41 (m,
2 H, H3¢¢, H5¢¢), 7.53–7.56 (m, 2 H, H5¢, H2¢¢, H6¢¢), 7.77 (d, 2 H,
o-SO2C6H4).
Parallel Synthesis; Deprotection
MS (ESI, +): m/z (%) = 281 (100) [M + 1]+.
MeOH (3 mL) and NaOH (5M, 0.5 mL) were added to each reacti-
vial (A-D) containing the residues from the cyclodehydration. The
solutions were heated at reflux for 3 h then H2O (1 mL) was added
and the aqueous phase worked up with CH2Cl2 (3 × 3 mL). The
combined organic layers were washed with brine (3 × 3 mL), dried
(MgSO4) and the solvent removed in vacuo. The crude residues
were obtained as black solids; vial A (5a, 7 mg, ~12% from 6), vial
B (complex mixture, 12 mg), vial C (5b, 10 mg, ~15% from 6), vial
D (5d, 8 mg, ~12% from 6). The crude residues were analysed by
mass spectrometry and 1H NMR spectroscopy.
HRMS: m/z calcd for C10H10Cl3NO2: 280.9777; found 280.9775.
2,2,2-Trichloro-1-[4-(1-chlorovinyl)-3,5-dimethyl-1H-pyrrol-2-
yl]ethanone (26)
Yield: 15 mg (7%); colorless solid; mp 138–140 °C.
1H NMR (200 MHz, CDCl3): d = 2.40 (s, 3 H, 5-CH3), 2.45 (s, 3 H,
3-CH3), 5.29 (d, J = 1 Hz, 1 H, C=CHH), 5.71 (d, J = 1 Hz, 1 H,
C=CHH), 8.90 (br s, Wh/2 = 25 Hz, 1 H, NH).
13C NMR (50 MHz, CDCl3): d = 12.9 (CH3), 13.0 (CH3), 96.2
(CCl3), 118.2 (=CCl), 118.7 (=CH2), 124.0 (C3), 132.2 (C4), 135.2
(C2), 136.9 (C5), 169.8 (C=O).
Synthesis 2006, No. 12, 1975–1980 © Thieme Stuttgart · New York

1980
W. A. Loughlin et al.
PAPER
1
Purity as estimated by H nmr of crude product: 5a7 (55%); 5b11
(65%); 5d (50% without purification of 8d); 5d (74% with purifica-
tion of 8d)
(6) Gange, D. M.; Donovan, S.; Lopata, R. J.; Henegar, K. In
Classical and Three-Dimensional QSAR in Agrochemistry;
ACS Symposium Series 606, American Chemical Society:
Washington DC, 1995, 199.
5-(4¢¢-Chlorophenyl)-2-(1H-pyrrol-2¢-yl)-1,3-oxazole (5d)
Obtained as a crude product.
(7) Loughlin, W. A.; Murphy, M. E.; Elson, K. E.; Henderson,
L. C. Aust. J. Chem. 2004, 57, 227.
(8) Gale, P. A.; Camiolo, S.; Tizzard, G. J.; Chapman, C. P.;
Light, M. E.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem.
2001, 66, 7849.
(9) Blazevic, N.; Kolbah, D.; Belin, B.; Sunjic, V.; Kajez, F.
Synthesis 1979, 161.
1H NMR (200 MHz, CDCl3): d = 6.32–6.38 (m, 1 H, H4¢), 6.90–
6.95 (m, 1 H, H3¢), 6.95–6.01 (m, 1 H, H5¢), 7.33 (s, 1 H, H4), 7.40
(2 H, d, H2¢¢, H6¢¢, 7.61 (d, 2 H, H3¢¢ H5¢¢), 9.48 (br s, 1 H, NH).
(10) Hall, J. H.; Chien, J. Y.; Kauffman, J. M.; Litak, P. T.;
Adams, J. K.; Henry, R. A.; Hollins, R. A. J. Heterocycl.
Chem. 1992, 29, 1245.
(11) Loughlin, W. A.; Muderawan, I. W.; McCleary, M. A.;
Volter, K. E.; King, M. D. Aust. J. Chem. 1999, 52, 231.
(12) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org.
Chem. 1983, 48, 3214.
(13) Treibs, A.; Kreuzer, F. H. Justus Liebigs Ann. Chem. 1969,
721, 105.
(14) Sosa, A. C. B.; Yakushijin, K.; Horne, D. A. J. Org. Chem.
2002, 67, 4498.
Acknowledgment
We gratefully acknowledge financial support from the Australian
Research Council (Small Scheme) and Griffith University and the
support of CSIRO (Molecular Sciences).
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Synthesis 2006, No. 12, 1975–1980 © Thieme Stuttgart · New York