Synthesis and fungicidal activity of novel pimprinine analogues

Article abstract of DOI:10.1016/j.ejmech.2012.04.012

A simple and efficient synthetic protocol for 5-(3-indolyl)-oxazoles has been developed and further used to synthesize a series of novel analogues of natural product pimprinine. All new compounds were identified by ¹H NMR, high resolution mass

Full text of DOI:10.1016/j.ejmech.2012.04.012

European Journal of Medicinal Chemistry 53 (2012) 283e291
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and fungicidal activity of novel pimprinine analogues
,
Ming-Zhi Zhang a, Qiong Chen a, Nick Mulholland b, David Beattie b, Dianne Irwin b, Yu-Cheng Gu b
**
,
,
b
Guang-Fu Yang a , John Clough
*
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
b Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthetic protocol for 5-(3-indolyl)-oxazoles has been developed and further used
to synthesize a series of novel analogues of natural product pimprinine. All new compounds were
identified by 1H NMR, high resolution mass spectrometry, and the structures of 10 and 18o were further
confirmed by X-ray crystallographic diffraction analysis. Bioassay conducted at Syngenta showed that
several of the synthesized compounds exhibited fungicidal activity. Compounds 10, 17, 18h, 18o, 19h, 19i
and 19l all showed effective control of three out of the seven tested phytopathogenic fungi at the highest
rate screened. Compounds 17 and 19h in particular showed activity against the four pathogens screened
in artificial media; Pythium dissimile, Alternaria solani, Botryotinia fuckeliana and Gibberella zeae.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Received 10 January 2012
Received in revised form
6 April 2012
Accepted 10 April 2012
Available online 19 April 2012
Keywords:
Pimprinine
Indole alkaloid
Fungicidal activity
Synthesis
Structureeactivity relationships
1. Introduction
called streptochlorin, is a natural product with a structure similar to
that of pimprinine, and it has been reported to show broad fungi-
Natural products are well known as one of the most important
sources for lead discovery in medicinal and agricultural chemistry,
because their novel scaffolds can afford an opportunity to discover
novel candidates with different action modes from the existing
agents. Pimprinine 1 is an indole alkaloid produced by many
species of Streptomyces, first isolated from the filtrates of Strepto-
myces pimprina cultures in 1963 [1], and belonging to the class of
naturally occurring 5-(3-indolyl)oxazoles. Members of this family,
as shown in Fig. 1, display a range of biological activities. For
example, pimprinine itself is a monoamine oxidase (MAO) inhibitor
and is reported to have anti-epileptic effects [2,3]. Screening con-
ducted at Syngenta showed that pimprinine is active against the
phytopathogenic fungi Aureobasidium pullulans, Botrytis cinerea,
Magnaporthe grisea and Septoria tritici when tested in liquid culture
assays (unpublished data). WS-30581 A 4 and WS-30581 B 5 have
potent inhibitory effects on platelet aggregation, labradorin 1 6 and
labradorin 2 7 were found to be potent inhibitors of the growth
of human cancer cells [4,5], martefragin A 8 was reported to be
a very potent inhibitor of lipid peroxidation [6,7], and the complex
marine natural product diazonamide A 9 exhibited pronounced
cytotoxic activities [8e10]. 4-Chloro -5-(3-indolyl)oxazole 10,
cidal activity against Pythium, Botrytis cinerea, S. tritici, Pyricularia
oryzae, Fusarium culmorum and Rhizoctonia solani [11e14].
However, its potency is too low to be used as agricultural fungicide.
As a continuation of our extensive research program to discover
novel bioactive lead compounds, pimprinine was used as the
parent structure to carry out structural optimization with the aim
of discovering synthetic analogues with simpler chemical struc-
tures and improved fungicidal activity. We describe structuree
activity relationships around pimprinine, including analogues in
which the indole nitrogen has been derivatised.
2. Materials and methods
2.1. Chemistry
The reagents were all analytically pure. All solvents and liquid
reagents were dried by standard methods in advance and distilled
before use. p-Toluene-sulfonylmethyl isocyanide (TosMIC) and
AmbersepÒ 900(OH) ion exchange resin were bought from the Alfa
Aesar Company (Tianjin, China). Yields were not optimized. 1H
NMR spectra were recorded on a VARIAN Mercury-Plus 600 or
Mercury-Plus 400 spectrometer in CDCl3 or DMSO-d6 with TMS as
the internal reference. High resolution mass spectra (HRMS) were
acquired in positive mode on a WATERS MALDI SYNAPT G2 HDMS
* Corresponding author. Tel.: þ86 27 67867800; fax: þ86 27 67867141.
** Corresponding author.
E-mail address: gfyang@mail.ccnu.edu.cn (G.-F. Yang).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.04.012

284
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 53 (2012) 283e291
H
1
O
N
N
R
N
O
N
N
O
N
O
N
H
HOOC
Cl
O
OH
O
Cl
N
H
NH
N
N
O
H
H
1
Pimprinine (1)
Pimprinethine (2)
(R =CH )
3
N
Martefragin A (8)
1
Cl
(R =CH CH )
2
3
Diazonamide A (9)
O
1
Pimprinaphine (3)
WS-30581 A (4)
WS-30581 B (5)
Labradorins 1 (6)
Labradorins 2 (7)
(R =CH Ph)
2
1
(R =CH CH CH )
2
2
3
1
(R =CH CH CH CH )
2
2
2
3
N
1
(R =iso-butyl)
H
1
(R =n-pentyl)
Streptochlorin (10)
Fig. 1. Chemical structure of pimprinine and its analogues.
(MA, USA) or an Agilent 6520 Accurate-Mass Q-TOF liquid chro-
matography/mass spectrometry (LC/MS) (USA). FTIR was recorded
on a Thermo Nicolet Avatar 360 FTIR Spectrometer, and melting
points were taken on a Büchi B-545 melting point apparatus and
are uncorrected. Microwave syntheses were carried out on a Smith
synthesizer.
PhSO2Cl (24.00 mmol, 4.24 g) in anhydrous THF was added drop-
wise. When TLC monitoring showed that the starting material 13
had disappeared, the reaction mixture was evaporated under
reduced pressure to remove the solvent, the residue was quenched
by slowly adding cold water and neutralized to pH ¼ 7 by the
addition of dilute hydrochloric acid, and then extracted with 60 mL
CH2Cl2. The extracts were dried over Na2SO4, evaporated under
reduced pressure to remove the solvent, and the crude product was
purified by flash column chromatography using 15e25% acetone/
petroleum ether (60e90 ꢀC) as eluent to give the desired inter-
mediate compound 14 in a yield of 69%, mp 147e149 ꢀC 1H NMR
2.1.1. Preparation of 1-(phenylsulfonyl)-3-indolecarboxaldehyde 12
NaH (60% dispersion in mineral oil, 40.00 mmol, 0.96 g) was
added portionwise to a stirred solution of indole-3-carboxaldehyde
11 (20.00 mmol, 2.90 g) in anhydrous THF (50 mL) cooled in an ice
bath, then slowly allowed to warm to r.t. After stirring for 30 min
PhSO2Cl (24.00 mmol, 4.24 g) in anhydrous THF was added drop-
wise. When TLC monitoring showed that the starting material 11
had disappeared, the reaction mixture was evaporated under
reduced pressure to remove the solvent and then diluted with ice
water (300 mL). Solid products were filtrated off and recrystallized
from acetone/petroleum ether (60e90 ꢀC) to give the desired
intermediate 12 in a yield of 97%, mp 151e153 ꢀC 1H NMR
(600 MHz, CDCl3):
d
: 7.36 (t, J ¼ 7.2 Hz, 1H), 7.39e7.44 (m, 2H), 7.47
(t, J ¼ 7.2 Hz, 2H), 7.57 (t, J ¼ 6.6 Hz, 1H), 7.78 (d, J ¼ 7.8 Hz, 1H), 7.94
(d, J ¼ 6.6 Hz, 3H), 7.97 (s, 1H), 8.06 (d, J ¼ 8.4 Hz, 1H). 13C NMR
(600 MHz, CDCl3): d: 102.1, 111.0, 119.6, 120.5, 121.7, 124.1, 125.4,
126.5, 126.9, 127.6, 128.5, 128.8, 129.5, 133.5, 135.5, 138.1, 150.6.
HRMS (MALDI): m/z 325.0635. Calcd. for C17H12N2O3S: 325.0647
[M þ H]þ.
2.1.4. Preparation of 4-halogen-5-(1-(phenylsulfonyl)-1H-indol-3-yl)
oxazole 15 and 16
(600 MHz, CDCl3):
d
: 7.37 (t, J ¼ 7.2 Hz, 1H), 7.42 (dd, J ¼ 11.4, 4.2 Hz,
1H), 7.52 (t, J ¼ 7.8 Hz, 2H), 7.62 (t, J ¼ 7.2 Hz, 1H), 7.97 (t, J ¼ 7.8 Hz,
3H), 8.20e8.31 (m, 2H), 10.11 (s, 1H). HRMS (MALDI): m/z 286.0515.
Calcd. C15H11NO3S: 286.0538 [M þ H]þ.
To a stirred solution of 14 (1.33 g, 4.10 mmol) in THFeCCl4
(50 mL, 1:1) was added NCS/NBS (4.51 mmol) and the resulting
mixture was heated at 50 ꢀC for 8 h and then allowed to cool. The
solvent was removed under reduced pressure and the crude
product was purified by flash column chromatography using
15e25% acetone/petroleum ether (60e90 ꢀC) as eluent to give the
desired intermediate compounds 15 and 16 in yields of 88% and
75%, respectively.
2.1.2. Preparation of 5-(3-indolyl)oxazole 13
A
solution of 1-(phenylsulfonyl)-3-indole- carboxaldehyde
(8.76 mmol, 2.50 g) and p-toluene-sulfonylmethyl isocyanide
(TosMIC) (9.64 mmol, 1.88 g) in 1:1 DME/MeOH (100 mL, both
anhydrous) was refluxed with AmbersepÒ 900(OH) ion exchange
resin (17.5 g, exchange capacity 1.18 meq/mL) for 2 h. The reaction
mixture was filtered, the resin was washed (MeOH, 3 ꢁ 20 mL), and
the combined filtrates were concentrated to give the crude product,
which was purified by flash column chromatography using 20e30%
acetone/petroleum ether (60e90 ꢀC) as eluent to give the pure
product 13 in a yield of 66%, mp 167e169 ꢀC 1H NMR (600 MHz,
Data for 15: mp, 155e157 ꢀC. IR (KBr) cmꢂ1: IR (KBr) cmꢂ1: 621
(CeCl), 1135 (CeOeC), 1372 (eSO2e), 1643 (C]N), 3124 (AreCH),
3442 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 7.34 (t,
J ¼ 7.8 Hz, 1H), 7.42 (t, J ¼ 7.8 Hz, 1H), 7.48 (t, J ¼ 7.8 Hz, 2H), 7.57 (t,
J ¼ 7.8 Hz, 1H), 7.91 (s, 1H), 7.95 (d, J ¼ 7.8 Hz, 2H), 8.01 (d, J ¼ 8.4 Hz,
1H), 8.05 (d, J ¼ 8.4 Hz, 1H), 8.16 (s, 1H). 13C NMR (400 MHz, CDCl3):
d: 102.0, 111.0, 119.6, 120.5, 121.7, 124.3, 125.5, 125.8, 126.9, 127.6,
DMSO-d6):
(m, 2H), 7.82 (s, 1H), 7.87 (d, J ¼ 7.8 Hz, 1H), 8.34 (s, 1H), 11.60 (s, 1H).
13C NMR (600 MHz, CDCl3):
: 105.6, 111.6, 119.5, 119.9, 121.0, 122.1,
123.1, 124.0, 136.2, 147.9, 148.2. HRMS (MALDI): m/z 185.0753.
Calcd. for C11H8N2O: 185.0715 [M þ H]þ.
d
: 7.16 (t, J ¼ 7.2 Hz, 1H), 7.22 (t, J ¼ 7.2 Hz, 1H), 7.41e7.54
128.5, 128.6, 128.9, 129.5, 135.5, 138.2, 150.7. HRMS (MALDI): m/z
359.0241. Calcd. for C17H11ClN2O3S: 359.0257 [M þ H]þ.
d
Data for 16: mp, 160e162 ꢀC. IR (KBr) cmꢂ1: 593 (CeBr), 1134
(CeOeC), 1373 (eSO2e), 1617 (C]N), 3124 (AreCH), 3443 (Pyrrolyl-
CH). 1H NMR (600 MHz, CDCl3):
d
: 7.34 (t, J ¼ 7.6 Hz, 1H), 7.41 (t,
J ¼ 7.8 Hz, 1H), 7.48 (t, J ¼ 7.9 Hz, 2H), 7.57 (t, J ¼ 7.5 Hz, 1H),
2.1.3. Preparation of 5-(1-(phenylsulfonyl)-1H-indol-3-yl)oxazole 14
NaH (60% dispersion in mineral oil, 40.00 mmol, 0.96 g) was
added portionwise to a stirred solution of 5-(3-indolyl)oxazole 13
(20.00 mmol, 3.68 g) in anhydrous THF (50 mL), cooled in an ice
bath, then slowly allowed to warm to r.t. After 30 min of stirring,
7.92e7.98 (m, 3H), 8.00 (d, J ¼ 7.9 Hz, 1H), 8.05 (d, J ¼ 8.3 Hz, 1H),
8.27 (s, 1H). 13C NMR (400 MHz, CDCl3):
d: 102.3, 109.5, 111.4,
113.6, 121.6, 124.2, 124.3, 125.7, 126.9, 127.3, 128.5, 129.5, 134.3,
134.5, 137.6, 143.4, 149.6. HRMS (MALDI): m/z 424.9922. Calcd. for
C17H11BrN2O3S: 424.9571 [M þ Na]þ.

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 53 (2012) 283e291
285
2.1.5. Preparation of 4-halogen-5-(3-indolyl)oxazoles 10 and 17
To a stirred solution of 15 or 16 (4.00 mmol) in EtOHeH2O
(50 mL, 1:1) was added NaOH (20.00 mmol) and the resulting
mixture was heated under reflux for 2 h, then allowed to cool. The
solvent was removed under reduced pressure and the crude
product was purified by flash column chromatography using
15e25% acetone/petroleum ether (60e90 ꢀC) as eluent to give the
desired intermediate compounds 10 and 17 in yields of 64% and
56%, respectively. From 13. To a stirred solution of 13 (0.74 g,
4.00 mmol) in THFeCCl4 (30 mL, 1:1) was added NCS/NBS
(4.40 mmol) and the resulting mixture was heated for 8 h at 50 ꢀC,
cooled, The solvent was removed under reduced pressure and the
crude product was purified by flash column chromatography using
15e25% acetone/petroleum ether (60e90 ꢀC) as eluent to give the
desired intermediate compounds 10 and 17 in yields of 72% and
84%, respectively.
1H), 7.33 (t, J ¼ 7.8 Hz, 1H), 7.39 (d, J ¼ 8.4 Hz, 1H), 7.67 (s, 1H), 7.86
(s, 1H), 8.08 (d, J ¼ 7.8 Hz, 1H). 13C NMR (400 MHz, CDCl3):
d: 33.3,
102.1,109.7, 120.8, 120.9, 121.1, 122.8, 125.0, 127.6, 128.5, 136.6, 147.3.
HRMS (MALDI): m/z 233.0522. Calcd. for C12H9ClN2O: 233.0482
[M þ H]þ.
Data for 18b: Yield, 66%. mp, 42e44 ꢀC. IR (KBr) cmꢂ1: 642
(CeCl), 1108 (CeOeC), 1626 (C]N), 3129 (AreCH), 3446 (Pyrrolyl-
CH). 1H NMR (600 MHz, CDCl3):
d
: 1.51 (t, J ¼ 7.2 Hz, 3H), 4.22 (q,
J ¼ 7.2 Hz, 2H), 7.24 (dd, J ¼ 9.6, 5.4 Hz, 1H), 7.29e7.32 (t, J ¼ 7.2 Hz,
1H), 7.31e7.32 (m, J ¼ 8.4 Hz, 1H), 7.71 (s, 1H), 7.83 (s, 1H), 8.06 (d,
J ¼ 8.4 Hz, 1H). 13C NMR (400 MHz, CDCl3):
d: 15.3, 41.5, 103.4, 109.7,
119.9, 120.8, 121.0, 121.3, 122.7, 125.0, 125.9, 139.0, 147.3. HRMS
(MALDI): m/z 247.0686. Calcd. for C13H11ClN2O: 247.0638 [M þ H]þ.
Data for 18c: Yield, 99%. mp, 72e74 ꢀC. IR (KBr) cmꢂ1: 642
(CeCl), 993 (C]C),1102 (CeOeC),1624 (C]N), 3127 (AreCH), 3450
(Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 4.81 (d, J ¼ 5.4 Hz, 2H),
Data for 10: Yield, 66%. mp, 167e169 ꢀC. IR (KBr) cmꢂ1: 641
(CeCl),1127 (CeOeC),1629 (C]N), 3045 (AreCH), 3206 (NH), 3443
5.16 (d, J ¼ 16.8 Hz, 1H), 5.24e5.35 (m, 1H), 6.03 (m, 1H), 7.24 (d,
J ¼ 7.2 Hz, 1H), 7.31 (t, J ¼ 7.8 Hz, 1H), 7.38 (d, J ¼ 8.4 Hz, 1H),
7.87 (s, 1H), 7.71 (s, 1H), 8.09 (d, J ¼ 7.8 Hz, 1H). 13C NMR
(Pyrrolyl-CH). 1H NMR (600 MHz, DMSO-d6):
d
: 7.17 (t, J ¼ 7.5 Hz,
1H), 7.23 (t, J ¼ 7.5 Hz, 1H), 7.51 (d, J ¼ 8.0 Hz, 1H), 7.92 (d, J ¼ 7.7 Hz,
2H), 8.50 (s, 1H), 11.81 (s, 1H). 13C NMR (600 MHz, CDCl3):
: 103.7,
(400 MHz, CDCl3): d: 49.1, 102.5, 110.0, 118.0, 120.9, 121.0, 122.8,
d
125.1, 126.6, 128.5, 132.5, 135.9, 143.1, 147.4. HRMS(ESI): m/z
111.5, 120.8, 121.2, 121.6, 123.2, 123.3, 124.4, 135.6, 143.2, 147.6.
HRMS (MALDI): m/z 219.0364. Calcd. for C11H7ClN2O: 219.0325
[M þ H]þ.
259.0617. Calcd. for C14H11ClN2O: 259.0638 [M þ H]þ.
Data for 18d: Yield, 39%. mp, 83e85 ꢀC. IR (KBr) cmꢂ1: 642
(CeCl), 1110 (CeOeC), 1620 (C]N), 3117 (AreCH), 3446 (Pyrrolyl-
Data for 17: Yield, 47%. mp, 147e149 ꢀC. IR (KBr) cmꢂ1: 639
(CeBr), 1123 (CeOeC),1607 (C]N), 3045 (AreCH), 3129 (NH), 3454
CH). 1H NMR (600 MHz, CDCl3):
d
: 4.93e4.92 (d, J ¼ 6.6 Hz, 1H),
6.09e6.07 (t, J ¼ 6.6 Hz, 1H), 7.38e7.26 (t, J ¼ 7.8 Hz, 1H),
7.38e7.34 (m, 2H), 7.69 (s, 1H), 7.87 (s, 1H), 8.09 (d, J ¼ 7.8 Hz,
(Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d
: 7.25e7.26 (t, J ¼ 7.2 Hz,
1H), 7.32 (t, J ¼ 7.2 Hz, 1H), 7.45e7.47 (d, J ¼ 8.4 Hz, 1H), 7.94 (s,1H),
2H). 13C NMR (600 MHz, CDCl3):
d: 45.3, 103.2, 109.6, 121.2, 121.3,
7.95 (s, 1H), 8.09e8.11 (d, J ¼ 8.4 Hz, 1H), 8.51 (bs, 1H). 13C NMR
121.6, 123.3, 124.4, 124.5, 125.2, 126.0, 135.6, 142.7, 147.5. HRMS
(MALDI): m/z 326.9835. Calcd. for C14H9Cl3N2O: 326.9859
[M þ H]þ.
(600 MHz, CDCl3): d: 103.8, 107.9, 111.5, 120.8, 121.2, 123.3, 123.6,
124.5, 135.6, 145.7, 148.6. HRMS (MALDI): m/z 262.9766. Calcd. for
C11H7BrN2O: 262.9820 [M þ H]þ.
Data for 18e: Yield, 76%. mp, 158e160 ꢀC. IR (KBr) cmꢂ1: 642
(CeCl), 1113 (CeOeC), 1620 (C]N), 1720 (C]O), 3111 (AreCH),
2.1.6. General procedure for the synthesis of target compounds 18
and 19
3444 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 2.73 (s, 3H),
7.40 (t, J ¼ 7.8 Hz, 1H), 7.46 (d, J ¼ 8.4 Hz, 1H), 7.96 (s, 1H), 8.01 (s,
NaH (60% dispersion in mineral oil, 4.00 mmol) was added
portionwise to a stirred solution of 10 or 17 (2.00 mmol) in anhy-
drous THF (50 mL). At first, the mixture was cooled in an ice bath,
but it was then allowed to warm and was stirred at r.t. for 30 min.
The appropriate electrophile (2.40 mmol) as a solution in anhy-
drous THF was then added dropwise. When TLC monitoring
showed that the starting material 11 had disappeared, the reaction
mixture was evaporated under reduced pressure to remove the
solvent and was then diluted with ice water (300 mL). The solid
products were filtered off and recrystallized from acetone/petroleum
ether (60e90 ꢀC) to give the target compounds 18 and 19.
1H), 8.07 (d, J ¼ 7.2 Hz, 1H), 8.52 (d, J ¼ 8.4 Hz, 1H). 13C NMR
(400 MHz, CDCl3): d: 24.0, 109.1, 116.7, 120.9, 123.0, 124.4, 126.3,
126.8, 135.4, 140.8, 141.2, 148.6, 168.5. HRMS (MALDI): m/z
261.0390. Calcd. for C13H9ClN2O2: 261.0431 [M þ H]þ.
Data for 18f: Yield, 65%. mp, 120e122 ꢀC. IR (KBr) cmꢂ1: 619
(CeCl), 1118 (CeOeC), 1615 (C]N), 1695 (C]O), 3127 (AreCH),
3443 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 1.39 (t,
J ¼ 7.2 Hz, 3H), 3.05 (q, J ¼ 7.2 Hz, 2H), 7.39 (t, J ¼ 7.2 Hz, 1H), 7.46 (t,
J ¼ 8.4 Hz, 1H), 7.95 (s, 1H), 8.06 (m, 2H), 8.54 (d, J ¼ 9.0 Hz, 1H). 13C
NMR (600 MHz, CDCl3): d: 8.5, 29.2, 108.8, 116.6, 120.8, 122.2, 124.3,
124.4, 126.1, 126.6, 135.4, 141.3, 148.5, 172.0. HRMS (ESI): m/z
275.0599. Calcd. for C14H11ClN2O2: 275.0587 [M þ H]þ.
2.1.7. Microwave-assisted synthesis of compounds 18r and 19o
NaH (60% dispersion in mineral oil, 0.40 mmol) was added
dropwise into a stirred solution of 10 (0.20 mmol) in anhydrous THF
(5 mL) for 30 min, cyclopropylmethyl bromide (0.24 mmol) was
then added dropwise. The mixture was sealed in a microwave tube,
synthesized, and irradiated at 90 ꢀC for 15 min. The resulted
mixture was cooled and diluted with 10 mL of ice water, and
neutralized to pH ¼ 7 by the addition of dilute hydrochloric acid,
and then extracted with 10 mL CH2Cl2. The extracts were dried over
Na2SO4, evaporated under reduced pressure to remove the solvent,
and the crude product was purified by flash column chromatog-
raphy using 15e25% acetone/petroleum ether (60e90 ꢀC) as eluent
to give the desired intermediate compound 18r in a yield of 87%. For
19o: From compound 17, as described for the synthesis of
compound 18r.
Data for 18g: Yield, 63%. mp, 113e115 ꢀC. IR (KBr) cmꢂ1: 614
(CeCl), 1136 (CeOeC), 1364 (eSO2e), 1570 (C]N), 3141 (AreCH),
3443 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 1.28 (t,
J ¼ 7.2 Hz, 3H), 3.40 (q, J ¼ 7.2 Hz, 2H), 7.42 (t, J ¼ 7.2 Hz, 1H), 7.46 (t,
J ¼ 7.8 Hz, 1H), 7.92e8.00 (m, 2H), 8.03 (s, 1H), 8.11 (d, J ¼ 7.8 Hz,
1H). 13C NMR (600 MHz, DMSO-d6):
d: 7.8, 48.5, 107.0, 113.3,
119.8, 121.2, 124.1, 124.7, 125.8, 126.2, 134.4, 139.8, 151.1. HRMS
(MALDI): m/z 311.0238. Calcd. C13H11ClN2O3S: 311.0257 [M þ H]þ.
Data for 18h: Yield, 62%. mp, 157e159 ꢀC. IR (KBr) cmꢂ1: 614
(CeCl), 1121 (CeOeC), 1570 (C]N), 1713 (C]O), 3130 (AreCH),
3444 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 4.66 (s, 2H),
7.44 (t, J ¼ 7.2 Hz,1H), 7.50 (t, J ¼ 7.2 Hz,1H), 7.97 (s, 1H), 8.03 (s,1H),
8.08 (d, J ¼ 8.4 Hz, 1H), 8.51 (d, J ¼ 8.4 Hz, 1H). 13C NMR (600 MHz,
CDCl3): d: 42.3, 102.1, 111.0, 119.6, 120.5, 121.3, 121.9, 124.1, 125.3,
126.8, 127.6, 135.5, 164.1. HRMS (MALDI): m/z 295.0115. Calcd.
Data for 18a: Yield, 96%. mp, 117e119 ꢀC. IR (KBr) cmꢂ1: 642
(CeCl), 1111 (CeOeC), 1623 (C]N), 3124 (AreCH), 3443 (Pyrrolyl-
C13H8Cl2N2O2: 295.0041 [M þ H]þ.
Data for 18i: Yield, 59%. mp, 129e131 ꢀC. IR (KBr) cmꢂ1: 621
(CeCl), 1126 (CeOeC), 1571 (C]N), 1726 (C]O), 3139 (AreCH),
CH). 1H NMR (600 MHz, CDCl3):
d: 3.88 (s, 3H), 7.25 (d, J ¼ 7.8 Hz,

286
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 53 (2012) 283e291
3456 (Pyrrolyl-CH). 1H NMR (600 MHz, DMSO-d6):
J ¼ 7.2 Hz, 1H), 7.56 (t, J ¼ 7.2 Hz, 1H), 8.02 (t, J ¼ 4.2 Hz, 2H),
8.43e8.45 (m, 2H), 8.71 (s, 1H). 13C NMR (400 MHz, CDCl3):
: 65.6,
d
: 7.50 (t,
164.5. HRMS (MALDI): m/z 345.0569. Calcd. for C18H11ClF2N2O:
345.0606 [M þ H]þ.
d
Data for 18q: Yield, 61%. mp, 85e87 ꢀC. IR (KBr) cmꢂ1: 616
(CeCl), 1122 (CeOeC), 1570 (C]N), 3131 (AreCH), 3452 (Pyrrolyl-
102.1, 110.9, 117.1, 121.3, 122.0, 125.7, 126.7, 127.1, 135.9, 140.6, 149.0,
160.7. HRMS (MALDI): m/z 328.9620. Calcd. C13H7Cl3N2O2:
328.9651 [M þ H]þ.
CH). 1H NMR (600 MHz, CDCl3):
d
: 2.52 (t, J ¼ 4.2 Hz, 1H), 2.86 (t,
J ¼ 4.2 Hz,1H), 3.34 (m,1H), 4.55e4.23 (dd, J ¼ 15.0, 5.4 Hz, 2H), 7.27
(t, J ¼ 9.0 Hz, 1H), 7.34 (t, J ¼ 7.2 Hz, 1H), 7.45 (d, J ¼ 8.4 Hz, 1H), 7.75
(s, 1H), 7.87 (s, 1H), 8.09 (d, J ¼ 8.4 Hz, 1H). 13C NMR (400 MHz,
Data for 18j: Yield, 54%. mp, 155e157 ꢀC. IR (KBr) cmꢂ1: 623
(CeCl), 1120 (CeOeC), 1570 (C]N), 1719 (C]O), 3135 (AreCH),
3446 (Pyrrolyl-CH). 1H NMR (600 MHz, DMSO-d6):
d: 7.57 (t,
CDCl3): d: 45.2, 48.2, 50.6, 109.8, 121.1, 121.2, 121.7, 123.2, 124.1,
J ¼ 7.2 Hz, 1H), 7.63 (t, J ¼ 7.2 Hz, 1H), 8.08 (d, J ¼ 8.4 Hz, 1H), 8.43 (d,
127.0, 127.6, 128.3, 135.5, 147.5. HRMS (MALDI): m/z 275.0603.
J ¼ 8.4 Hz, 1H), 8.58 (s, 1H), 8.75 (s, 1H). 13C NMR (600 MHz, DMSO-
Calcd. for C14H11ClN2O2: 275.0587 [M þ H]þ.
d6):
d
: 79.7, 101.8, 112.7, 120.2, 120.4, 120.9, 122.9, 124.4, 125.1, 127.2,
Data for 18r: Yield, 87%. mp, 91e93 ꢀC. IR (KBr) cmꢂ1: 634
(CeCl), 1117 (CeOeC), 1571 (C]N), 3138 (AreCH), 3444 (Pyrrolyl-
136.3, 143.2, 149.9. HRMS(ESI): m/z 362.9283. Calcd. C13H6Cl4N2O2:
362.9262 [M þ H]þ.
CH). 1H NMR (600 MHz, CDCl3):
d
: 0.43 (d, J ¼ 4.8 Hz, 2H), 0.69 (d,
Data for 18k: Yield, 60%. mp, 137e139 ꢀC. IR (KBr) cmꢂ1: 617
(CeCl), 1125 (CeOeC), 1571 (C]N), 1705 (C]O), 3127 (AreCH),
J ¼ 7.8 Hz, 2H),1.34 (m,1H), 4.05 (d, J ¼ 6.6 Hz, 2H), 7.24 (m,1H), 7.31
(t, J ¼ 7.8 Hz, 1H), 7.42 (d, J ¼ 8.4 Hz, 1H), 7.88 (s, 1H), 7.94 (s, 1H),
3446 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d:
1.91 (d,
8.08 (d, J ¼ 7.8 Hz, 1H). 13C NMR (400 MHz, CDCl3):
d: 4.2, 11.1, 51.0,
J ¼ 6.6 Hz, 3H), 5.11 (q, J ¼ 6.6 Hz, 1H), 7.43 (t, J ¼ 8.4 Hz, 1H), 7.49 (t,
102.2, 107.5, 109.9, 120.8, 121.0, 122.7, 125.2, 126.6, 137.6, 136.0,
148.3. HRMS (MALDI): m/z 273.0819. Calcd. for C15H13ClN2O:
273.0795 [M þ H]þ.
J ¼ 7.2 Hz, 1H), 7.97 (s, 1H), 8.06 (d, J ¼ 8.4 Hz, 1H), 8.16 (s, 1H), 8.55
(d, J ¼ 9.0 Hz,1H). 13C NMR (400 MHz, DMSO-d6):
d: 20.1, 51.8,108.2,
116.4, 120.8, 124.4, 124.9, 126.4, 126.6, 127.6, 135.1, 139.9, 151.4,
168.0. HRMS (MALDI): m/z 309.0170. Calcd. C14H10Cl2N2O2:
309.0198 [M þ H]þ.
Data for 19a: Yield, 99%. mp, 131e133 ꢀC. IR (KBr) cmꢂ1: 540
(CeBr), 1110 (CeOeC), 1571 (C]N), 3122(AreCH), 3454 (Pyrrolyl-
CH). 1H NMR (600 MHz, CDCl3):
d
: 3.88 (s, 3H), 7.24 (t, J ¼ 7.8 Hz,
Data for 18l: Yield, 65%. mp, 114e116 ꢀC. IR (KBr) cmꢂ1: 614
(CeCl), 1119 (CeOeC), 1571 (C]N), 1744 (eCO2e), 3126 (AreCH),
1H), 7.33 (t, J ¼ 7.8 Hz, 1H), 7.38 (d, J ¼ 8.4 Hz, 1H), 7.78 (s, 1H), 7.89
(s, 1H), 8.08 (d, J ¼ 8.4 Hz, 1H). 13C NMR (400 MHz, CDCl3):
d: 33.2,
3447 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 4.14 (s, 3H),
102.2, 107.4, 109.6, 120.8, 120.9, 122.8, 125.1, 127.8, 136.5, 147.3,
148.3. HRMS (MALDI): m/z 276.9927. Calcd. for C12H9BrN2O:
276.9976 [M þ H]þ.
7.33 (t, J ¼ 7.2 Hz,1H), 7.37e7.44 (t, J ¼ 7.2 Hz,1H), 7.52 (d, J ¼ 7.8 Hz,
1H), 8.01 (s, 1H), 8.03 (s, 1H), 8.13 (d, J ¼ 9.0 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6):
d: 54.8, 106.4, 115.5, 119.2, 124.2, 124.4,
Data for 19b: Yield, 99%. mp, 68e70 ꢀC. IR (KBr) cmꢂ1: 539
(CeBr), 1122 (CeOeC), 1572 (C]N), 3135 (AreCH), 3450 (Pyrrolyl-
125.6, 125.7, 127.7, 134.4, 137.1, 150.0, 153.3. HRMS (MALDI): m/z
314.9988. Calcd. C13H9ClN2O3: 314.9939 [M þ K]þ.
CH). 1H NMR (600 MHz, CDCl3):
d
: 1.54 (t, J ¼ 7.2 Hz, 3H), 4.25 (q,
Data for 18m: Yield, 50%. mp, 103e105 ꢀC. IR (KBr) cmꢂ1: 642
(CeCl), 1127 (CeOeC), 1571 (C]N), 1719 (C]O), 3108 (AreCH),
J ¼ 7.2 Hz, 2H), 7.24 (t, J ¼ 7.8 Hz, 1H), 7.31 (t, J ¼ 7.8 Hz, 1H), 7.41 (d,
J ¼ 7.8 Hz, 1H), 7.84 (s, 1H), 7.89 (s, 1H), 8.08 (d, J ¼ 7.8 Hz, 1H). 13C
3443 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 3.58 (s, 3H),
NMR (400 MHz, CDCl3): d: 15.3, 41.5, 102.5, 106.8, 109.7, 120.8, 121.1,
4.65 (s, 2H), 7.40e7.42 (t, J ¼ 7.8 Hz,1H), 7.46e7.48 (t, J ¼ 7.8 Hz,1H),
122.7, 126.2, 127.5, 136.7, 147.6, 148.3. HRMS (MALDI): m/z 291.0088.
7.95 (s, 1H), 8.05 (d, J ¼ 8.4 Hz, 1H), 8.11 (s, 1H), 8.52 (d, J ¼ 8.4 Hz,
Calcd. for C13H11BrN2O: 291.0133 [M þ H]þ.
1H). 13C NMR (600 MHz, DMSO-d6):
d
: 59.7, 72.4, 109.7, 116.5, 116.7,
Data for 19c: Yield, 47%. mp, 65e67 ꢀC. IR (KBr) cmꢂ1: 538
(CeBr), 993 (C]C), 1101 (CeOeC), 1573 (C]N), 3130 (AreCH),
121.1, 121.6, 124.7, 126.3, 135.4, 141.0, 147.5, 148.8, 167.7. HRMS
(MALDI): m/z 291.0515. Calcd. C14H11ClN2O3: 291.0536 [M þ H]þ.
Data for 18n: Yield, 40%. mp, 60e62 ꢀC. IR (KBr) cmꢂ1: 617
(CeCl), 1121 (CeOeC), 1571 (C]N), 1747 (C]O), 3134 (AreCH),
3444 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 4.81 (d,
J ¼ 4.2 Hz, 2H), 5.16 (d, J ¼ 16.2 Hz, 1H), 5.28 (d, J ¼ 9.6 Hz, 1H),
6.17e5.90 (m, 1H), 7.24 (t, J ¼ 7.8 Hz, 1H), 7.32 (t, J ¼ 7.2 Hz, 1H), 7.38
(d, J ¼ 7.8 Hz, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 8.09 (d, J ¼ 7.8 Hz,1H). 13C
3446 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 1.27 (t,
J ¼ 7.2 Hz, 3H), 4.23 (q, J ¼ 7.2 Hz, 2H), 4.89 (s, 2H), 7.25 (dd, J ¼ 13.2,
NMR (400 MHz, CDCl3): d: 49.1,102.5,107.6,110.0,117.9,120.9,121.0,
5.4 Hz, 2H), 7.30e7.37 (m, 1H), 7.71 (s, 1H), 7.85 (s, 1H), 8.08 (d,
122.8, 125.2, 126.8, 132.4, 135.9, 145.5, 148.3. HRMS (ESI): m/z
J ¼ 7.8 Hz, 1H). 13C NMR (400 MHz, CDCl3):
d: 14.1, 48.0, 62.0,
303.0149. Calcd. for C14H12BrN2O: 303.0133 [M þ H]þ.
103.5, 109.4, 121.2, 121.3, 123.4, 125.0, 127.2, 127.6, 136.3, 142.9,
127.6, 167.8. HRMS: m/z 305.0678. Calcd. for C15H13ClN2O3:
305.0693 [M þ H]þ.
Data for 19d: Yield, 43%. mp, 95e97 ꢀC. IR (KBr) cmꢂ1: 539
(CeBr), 1123 (CeOeC), 1571 (C]N), 3110 (AreCH), 3441 (Pyrrolyl-
CH). 1H NMR (600 MHz, CDCl3):
d
: 4.94e4.93 (d, J ¼ 6.0 Hz, 1H),
Data for 18o: Yield, 56%. mp, 111e113 ꢀC. IR (KBr) cmꢂ1: 616
(CeCl), 1122 (CeOeC), 1570 (C]N), 1746 (COCO), 3125 (AreCH),
6.11e6.08 (t, J ¼ 6.6 Hz, 1H), 7.28e7.30 (t, J ¼ 6.6 Hz, 1H),
7.35e7.39 (m, 2H), 7.81 (s, 1H), 7.90 (s, 1H), 8.08e8.10 (d,
3445 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d
: 1.50e1.53 (t,
J ¼ 8.4 Hz, 2H). 13C NMR (400 MHz, CDCl3):
d: 45.4, 103.4, 108.1,
J ¼ 7.2 Hz, 3H), 4.54e4.58 (q, J ¼ 7.2 Hz, 2H), 7.44e7.47 (t,
J ¼ 7.8 Hz, 1H), 7.48e7.51 (t, J ¼ 7.8 Hz, 1H), 7.96 (d, J ¼ 7.8 Hz,
1H), 8.08 (d, J ¼ 7.8 Hz, 1H), 8.31 (s, 1H), 8.50 (s, 1H). 13C NMR
109.7, 121.2, 121.3, 123.4, 124.5, 125.4, 126.4, 132.4, 135.7, 145.2,
148.5. HRMS (MALDI): m/z 370.9328. Calcd. for C14H9BrCl2N2O:
370.9354 [M þ H]þ.
(400 MHz, DMSO-d6):
d: 14.0, 63.7, 111.1, 116.9, 121.3, 123.3, 125.5,
Data for 19e: Yield, 99%. mp, 150e152 ꢀC. IR (KBr) cmꢂ1: 540
(CeBr), 1109 (CeOeC), 1570 (C]N), 1719 (C]O), 3105 (AreCH),
126.7, 127.2, 128.5, 135.4, 140.7, 148.9, 157.0, 159.6. HRMS (MALDI):
m/z 319.0634. Calcd. C15H11ClN2O4: 319.0486 [M þ H]þ.
3445 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 2.73 (s, 3H),
Data for 18p: Yield, 92%. mp, 102e104 ꢀC. IR (KBr) cmꢂ1: 642
(CeCl),1113 (CeOeC), 1140 (CeF), 1604 (C]N), 3128 (AreCH), 3444
7.40 (t, J ¼ 7.8 Hz, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.97 (s, 1H), 8.06 (d,
J ¼ 7.8 Hz, 1H), 8.14 (s, 1H), 8.51 (d, J ¼ 8.4 Hz, 1H). 13C NMR
(Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d
: 5.40 (s, 2H), 6.78 (t,
(400 MHz, DMSO-d6): d: 23.9, 107.4, 110.9, 116.2, 120.6, 124.2, 125.2,
J ¼ 7.8 Hz, 1H), 6.88 (t, J ¼ 9.0 Hz, 1H), 6.90e6.98 (m, 1H), 7.27 (t,
J ¼ 7.8 Hz, 2H), 7.30 (t, J ¼ 7.8 Hz, 1H), 7.36 (d, J ¼ 8.4 Hz, 1H),
7.77 (s, 1H), 7.88 (s, 1H), 8.10 (d, J ¼ 7.8 Hz, 1H). 13C NMR
125.8, 126.5, 134.7, 142.6, 152.0, 169.6. HRMS (MALDI): m/z
304.9926. Calcd. C13H9BrN2O2: 304.9926 [M þ H]þ.
Data for 19f: Yield, 84%. mp, 135e137 ꢀC. IR (KBr) cmꢂ1: 538
(CeBr), 1114 (CeOeC), 1573 (C]N), 1709 (C]O), 3124 (AreCH),
(400 MHz, CDCl3): d: 43.8, 104.0, 104.2, 104.5, 109.9, 111.7, 111.9,
121.1, 121.2, 123.3, 125.2, 124.1, 126.8, 129.8, 135.9, 147.5, 160.8,
3445 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 1.38e1.41

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 53 (2012) 283e291
287
(t, J ¼ 7.2 Hz, 3H), 3.02e3.06 (q, J ¼ 7.2 Hz, 2H), 7.38e7.40 (t,
J ¼ 7.8 Hz, 1H), 7.96 (s, 1H), 8.04e8.05 (d, J ¼ 7.8 Hz, 1H), 8.17 (s,
2H), 8.53e8.54 (d, J ¼ 8.4 Hz, 1H). 13C NMR (400 MHz, DMSO-d6):
Data for 19n: Yield, 97%. mp, 101e103 ꢀC. IR (KBr) cmꢂ1: 539
(CeBr), 1119 (CeOeC), 1572 (C]N), 3129 (AreCH), 3442 (Pyrrolyl-
CH). 1H NMR (600 MHz, CDCl3):
d: 2.51 (s, 1H), 2.85 (s, 1H), 3.34 (s,
d: 8.3, 28.4, 107.4, 110.6, 116.1, 120.5, 124.2, 125.8, 126.3, 128.5,
1H), 4.19e4.22 (dd, J ¼ 15.0, 3.6 Hz, 1H), 4.54 (d, J ¼ 15.0 Hz, 1H),
7.26 (t, J ¼ 7.8 Hz, 1H), 7.33 (t, J ¼ 7.2 Hz, 1H), 7.45 (d, J ¼ 7.8 Hz,
1H), 7.85 (s, 1H), 7.88 (s, 1H), 8.08 (d, J ¼ 7.8 Hz, 1H). 13C NMR
134.8, 142.6, 151.8, 172.6. HRMS (MALDI): m/z 319.0063. Calcd.
C14H11BrN2O2: 319.0082 [M þ H]þ.
Data for 19g: Yield, 54%. mp, 132e135 ꢀC. IR (KBr) cmꢂ1: 545
(CeBr), 1118 (CeOeC), 1363 (eSO2e), 1572 (C]N), 3140 (AreCH),
(400 MHz, DMSO-d6): d: 45.1, 48.0, 50.6, 103.1, 107.9, 109.8, 121.0,
121.2, 123.1, 125.2, 127.3, 128.5, 136.2, 148.5. HRMS (MALDI): m/z
3446 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 1.28 (t,
319.0320. Calcd. for C14H11BrN2O2: 319.0289 [M þ H]þ.
J ¼ 7.2 Hz, 3H), 3.40 (q, J ¼ 7.2 Hz, 2H), 7.40e7.43 (t, J ¼ 7.2 Hz, 1H),
Data for 19o: Yield, 87%. mp, 78e80 ꢀC. IR (KBr) cmꢂ1: 539
(CeBr), 1109 (CeOeC), 1572 (C]N), 3111 (AreCH), 3454 (Pyrrolyl-
7.45e7.47 (t, J ¼ 7.2 Hz, 1H), 7.97e7.98 (m, 2H), 8.11 (d, J ¼ 7.8 Hz,
1H), 8.14 (s, 1H). 13C NMR (400 MHz, DMSO-d6):
d: 7.8, 48.5, 107.3,
CH). 1H NMR (600 MHz, CDCl3):
d
: 0.43 (d, J ¼ 7.2 Hz, 2H), 0.69 (d,
111.1, 113.3, 121.3, 124.1, 124.9, 125.8, 126.4, 134.3, 142.2, 152.0.
HRMS (MALDI): m/z 354.9735. Calcd. C13H11BrN2O3S: 354.9752
[M þ H]þ.
J ¼ 7.2 Hz, 2H), 1.34 (m, 1H), 4.05 (d, J ¼ 6.6 Hz, 2H), 7.24 (t,
J ¼ 6.6 Hz, 1H), 7.31 (t, J ¼ 7.2 Hz, 1H), 7.43 (d, J ¼ 7.2 Hz, 1H), 7.89 (s,
1H), 7.95 (s, 1H), 8.08 (d, J ¼ 7.2 Hz, 1H). 13C NMR (400 MHz, CDCl3):
Data for 19h: Yield, 62%. mp, 98e100 ꢀC. IR (KBr) cmꢂ1: 539
(CeBr), 1125 (CeOeC), 1571 (C]N), 1731 (C]O), 3138 (AreCH),
d: 4.0, 4.1, 11.0, 51.0, 102.5, 107.8, 109.8, 120.8, 121.0, 122.7, 125.7,
126.6, 136.2, 148.3, 150.4. HRMS (MALDI): m/z 317.0249. Calcd.
3444 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 4.66 (s, 2H),
C15H13BrN2O: 317.0289 [M þ H]þ.
7.44 (t, J ¼ 7.2 Hz, 1H), 7.50 (t, J ¼ 7.2 Hz, 1H), 8.00 (s, 1H), 8.07 (d,
J ¼ 7.8 Hz, 1H), 8.18 (s, 1H), 8.51 (d, J ¼ 8.4 Hz, 1H). 13C NMR
2.2. X-ray diffraction analysis
(400 MHz, DMSO-d6): d: 42.3, 107.5, 110.6, 111.9, 116.8, 121.2, 122.2,
125.2, 126.8, 128.5, 135.5, 149.8, 164.1. HRMS (ESI): m/z 338.9558.
Colourless crystals of compound 10 (0.26 mm ꢁ 0.20 mm ꢁ
0.10 mm) were mounted on a quartz fibre with protection oil. Cell
dimensions and intensities were measured at 299 K on a Bruker
SMART CCD area detector diffractometer with graphite mono-
Calcd. C13H8BrClN2O2: 338.9536 [M þ H]þ.
Data for 19i: Yield, 41%. mp, 114e116 ꢀC. IR (KBr) cmꢂ1: 540
(CeBr), 1147 (CeOeC), 1571 (C]N), 1724 (C]O), 3141 (AreCH),
3442 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d
: 6.61 (s, 1H),
chromated Mo Ka radiation (
l
¼ 0.71073 Å); qmax ¼ 20.30; 3172
7.46e7.47 (t, J ¼ 7.8 Hz, 1H), 7.50e7.51 (t, J ¼ 7.8 Hz, 1H), 7.91e7.92
measured reflections; 1809 independent reflections (Rint ¼ 0.0275)
of which 557 had [I > 2s(I)]. The structure was solved by direct
methods using SHELXS-97; all other calculations were performed
with Bruker SAINT System and Bruker SMART programs. Full-
matrix least-squares refinement based on F2 using the weight of
(d, J ¼ 7.8 Hz, 1H), 8.01 (s, 1H), 8.07e8.08 (d, J ¼ 7.8 Hz, 1H), 8.49 (s,
1H). 13C NMR (400 MHz, DMSO-d6):
d: 65.7, 111.1, 112.3, 117.0, 121.3,
122.4, 125.7, 126.9, 127.1, 128.6, 135.8, 149.9, 160.7. HRMS (MALDI):
m/z 372.9133. Calcd. for C13H7BrCl2N2O2: 372.9146 [M þ H]þ.
Data for 19j: Yield, 55%. mp, 143e145 ꢀC. IR (KBr) cmꢂ1: 554
(CeBr), 1123 (CeOeC), 1572 (C]N), 1704 (C]O), 3124 (AreCH),
u
¼ 1/[
s
2(Fo2) þ (0.0659P)2 þ 0.0500P] gave final values of
R ¼ 0.0644,
u
R ¼ 0.1363, and GOF(F) ¼ 1.065 for 139 restraints and
3444 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d:
1.91 (d,
1174 parameters reflections. Maximum shift/error ¼ 0.000(3), max/
min residual electron density ¼ 0.270/ꢂ0.195 eÅꢂ3. Hydrogen
atoms were observed and refined with a fixed value of their
isotropic displacement parameter. In compound 10, C11H7ClN2O,
the benzene and pyrrole rings are almost coplanar [dihedral
angle ¼ 0.8 (0)ꢀ]. The dihedral angle between the indole and oxa-
zole rings is 18.7 (1)ꢀ. The crystal structure is stabilized by NeH.N
J ¼ 6.6 Hz, 3H), 5.10 (q, J ¼ 6.6 Hz, 1H), 7.43 (t, J ¼ 7.2 Hz, 1H),
7.48e7.52 (t, J ¼ 7.2 Hz, 1H), 7.99 (s, 1H), 8.06 (d, J ¼ 8.4 Hz, 1H), 8.30
(s, 1H), 8.54 (d, J ¼ 8.4 Hz, 1H). 13C NMR (400 MHz, DMSO-d6):
d:
20.1, 51.8, 108.5, 111.5, 120.8, 121.1, 124.9, 126.4, 126.7, 128.4, 135.1,
142.2, 152.3, 167.9. HRMS (MALDI): m/z 352.9699. Calcd. for
C14H10BrClN2O2: 352.9692 [M þ H]þ.
Data for 19k: Yield, 72%. mp, 149e151 ꢀC. IR (KBr) cmꢂ1: 539
(CeBr), 1113 (CeOeC), 1571 (C]N), 1740 (CO2-), 3127 (AreCH),
hydrogen bonds and there are also pep stacking interactions.
Colourless crystals of compound 18o (0.16 mm ꢁ 0.12 mm ꢁ
0.10 mm) were mounted on a quartz fibre with protection oil. Cell
dimensions and intensities were measured at 297 K on a Bruker
SMART CCD area detector diffractometer with graphite mono-
3445 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 4.11 (s, 3H),
7.37 (t, J ¼ 7.8 Hz, 1H), 7.44 (t, J ¼ 7.8 Hz, 1H), 7.95 (s, 1H), 8.05 (d,
J ¼ 7.2 Hz, 1H), 8.26 (d, J ¼ 8.4 Hz, 1H), 8.29 (s, 1H). 13C NMR
(400 MHz, DMSO-d6):
d: 54.6, 107.4, 110.7, 114.9, 120.8, 123.2, 123.8,
chromated Mo K
a
radiation (
l
¼ 0.71073 Å); qmax ¼ 23.48; 8953
125.6, 126.2, 134.3, 142.5, 151.7, 161.1. HRMS (MALDI): m/z 320.9850.
measured reflections; 5043 independent reflections (Rint ¼ 0.0349)
Calcd. for C13H9BrN2O3: 320.9875 [M þ H]þ.
of which 2235 had [I > 2s(I)]. Data were corrected for Lorentz and
Data for 19l: Yield, 63%. mp, 101e103 ꢀC. IR (KBr) cmꢂ1: 540
(CeBr), 1126 (CeOeC), 1572 (C]N), 1717 (C]O), 3128 (AreCH),
polarization effects and for absorption (Tmin
¼
0.9551;
Tmax ¼ 0.9716). The structure was solved by direct methods using
SHELXS-97; all other calculations were performed with Bruker
SAINT System and Bruker SMART programs. Full-matrix least-
3443 (Pyrrolyl-CH). 1H NMR (600 MHz, CDCl3):
d: 3.58 (s, 3H),
4.66 (s, 2H), 7.44 (t, J ¼ 7.2 Hz, 1H), 7.47 (t, J ¼ 7.2, 1H), 7.98 (s, 1H),
8.05e8.06 (d, J ¼ 7.8 Hz, 1H), 8.27 (s, 1H), 8.54 (d, J ¼ 8.4 Hz, 1H). 13C
squares refinement based on F2 using the weight of
u
¼ 1/
NMR (400 MHz, DMSO-d6):
d
: 58.8, 71.1, 112.2, 116.1, 119.9, 120.5,
[
u
s
2(Fo2) þ (0.0633P)2 þ 0.4557P] gave final values of R ¼ 0.0615,
120.7, 122.5, 123.7, 124.5, 124.8, 126.1, 150.4, 169.0. HRMS
(MALDI): m/z 335.0038. Calcd. C14H11BrN2O3: 335.0031 [M þ H]þ.
Data for 19m: Yield, 74%. mp, 116e118 ꢀC. IR (KBr) cmꢂ1: 541
(CeBr), 1115 (CeOeC), 1572 (C]N), 1703 (COCO), 3127 (AreCH),
R ¼ 0.1387, and GOF(F) ¼ 1.105 for 200 restraints and 2131
parameters reflections. Maximum shift/error ¼ 0.000(3), max/min
residual electron density ¼ 0.261/ꢂ0.163 eÅꢂ3. Hydrogen atoms
were observed and refined with a fixed value of their isotropic
displacement parameter. In compound 18o, C15H11ClN2O4, the
benzene and pyrrole rings are almost coplanar [dihedral
angle ¼ 0.2 (5)ꢀ]. The dihedral angle between the indole and oxa-
zole rings is 6.8 (2)ꢀ. The crystal structure is stabilized by Van der
Waals forces and there are also pep stacking interactions.
The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre with the deposition No.
3444 (Pyrrolyl-CH). 1H NMR (600 MHz, DMSO-d6):
d: 1.37e1.40
(t, J ¼ 7.2 Hz, 3H), 4.44e4.47 (q, J ¼ 7.2 Hz, 2H), 7.51e7.55 (m,
2H), 8.04e8.05 (s, 1H), 8.40 (s, 1H), 8.53 (s, 1H), 8.69e8.70 (d,
J ¼ 7.8 Hz,,1H). 13C NMR (400 MHz, DMSO-d6):
d: 13.8, 63.4, 109.3,
111.4, 116.2, 121.0, 125.5, 126.4, 126.6, 128.5, 134.9, 142.0, 152.0,
156.5, 158.7. HRMS (MALDI): m/z 362.9973. Calcd. for
C15H11BrN2O4: 362.9980 [M þ H]þ.

288
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 53 (2012) 283e291
Table 1
Table 3
Details of the primary-level leaf-piece assays.
Assessment criteria for the biological assays.
Pathogen
Host
Chemical
ratesa
Replicatesb
2
Spore ratesc
150,000
Scoring band
Well condition
0
0e49% control of disease or pathogen
50e80% control of disease or pathogen
81e100% control of disease or pathogen
Not captured (too phytotoxic)
Phytophthora
infestans
Septoria tritici
Uromyces viciae-fabae
Tomato
200, 60
55
99
NCH
NC
Wheat
Field bean
100
100
3
2
1,000,000
0.3c
Not captured (test failure)
a
Rates are given as parts per million a.i. in the formulated sample applied to the
leaf-piece.
b
c
3. Results and discussion
Number of replicates per rate.
Spore rates are sporangia per ml for P. infestans, conidia per ml for S. tritici, and
mg per ml for U. viciae-fabae.
3.1. Synthetic chemistry
The synthetic route to the target compounds 18 and 19 is shown
in Scheme 1. The commercially available indole-3-carboxaldehyde
11 was used as the starting material. Following protection of the
indole nitrogen with a phenylsulfonyl group [15,16], reaction with
p-toluene-sulfonylmethyl isocyanide (TosMIC) in the presence of
the ion exchange resin of AmbersepÒ 900(OH) in a mixture of DME
and methanol (v/v, 1:1) as solvent afforded 5-(1H-indol-3-yl)oxa-
zole 13 in a yield of 66%. Compared to the previous method,
cyclization protocol used herein shortened the reaction time from
8 h to 2 h, and meanwhile N-deprotection occurred as well that
would be very convenient for the subsequent substitution to the
NH group [17,18]. Originally, we were concerned that the free NH
group would interfere with the subsequent halogenation of the
oxazole ring, so we reprotected compound 13 to give the inter-
mediate 14, which was chlorinated or brominated with NCS or NBS,
respectively, and then deprotected under basic conditions to afford
the key intermediates 10 and 17 (Route 1) [15,19]. In fact, this
transformation of compound 13 into compound 10 involves three
steps and the overall yield was very low. In order to prepare
sufficient intermediate 10 to continue with the sequence, we then
made the improvement that compound 13 could be converted
directly into 10 or 17 without N-protection (Route 2). After opti-
mization, we found that intermediate 13 can be treated directly
with NBS/NCS (1.1 equivalents) in a mixture of THF and CCl4 at 50 ꢀC
to afford 17/10 in a good yield of 84% and 72%, respectively. In
addition, this new synthetic route would complete within 8 h and
afford about 46% yield, whereas the three-step route (Protection-
Halogenation-Deprotection) usually require more than 48 h and
lead to lower yield (25%). Finally, the target compounds 18 and 19
were easily prepared by the reaction between the intermediate 10/
17 and various electrophiles. The reaction conditions and yields for
the target compounds 18 and 19 are listed in Table 4.
CCDC-835955 (compound 10) and 835956 (compound 18o). Copies
of the data can be obtained free of charge via http://www.ccdc.cam.
ac.uk/.
2.3. Biological assays
2.3.1. Leaf-piece assays
200e300 ml water agar per well was dispensed into the 96-well
assay plates, and 6 mm diameter leaf pieces (6 mm length for
wheat) were cut and placed on the surface of the agar. Compounds
to be tested were formulated to the appropriate rate, and 10
samples were dispensed onto the leaf pieces.
ml
The plates were inoculated with spore suspensions of the
appropriate pathogen at a set rate (Table 1), using a handheld spray
gun. The plates were covered with lids and placed in controlled
environment cabinets for between 5 and 14 days, depending on the
species being tested.
2.3.2. Artificial media assays
Spore suspensions were prepared from stock plates of the target
pathogens (Table 2) for all species apart from Pythium dissimile, for
which a suspension of fragmented mycelia was used. These
suspensions were made into a 3% agar, and dispensed into 96-well
plates containing formulated samples of the compounds to be
tested (10
ml formulated sample and 90 ml spore suspension, to give
the chemical rates detailed in Table 2).
The plates were then stored in controlled environments set to
appropriate conditions, until assessment between 5 and 14 days
later, depending on the species.
2.3.3. Assessment of biological assays
The structures of all the intermediates and final target
compounds were confirmed by 1H NMR and HRMS spectral data. In
addition, the crystal structures of the intermediate 10 and the
target compound 18o were determined by X-ray diffraction anal-
ysis, as shown in Fig. 2.
Assessment for all assays was carried out by eye, with each
individual well scored on a three-band pattern with additional
result types for assay failure and phytotoxic activity on the leaf
piece (Table 3). The resulting data were collated for each
compound, and averages across replicates were used to make
a judgement of the overall activity level of the compound.
3.2. Fungicidal activity and the structureeactivity relationships
Table 2
The results of the biological testing against sevenphytopathogenic
fungi are given in Table 5. For the purposes of the structureeactivity
relationship analysis, compound 13, compounds (10, 18aer) and
compounds (17, 19aeo) were defined as indole-oxazole, 4-
chloroindole-oxazole derivatives and 4-bromoindole-oxazole deriv-
atives, respectively. It is noticeable that any activity present is mainly
in the artificial media assays, and rarely extends to those pathogens
tested on leaf pieces. It is also noticeable that the fungicidal activity
lacks potency, rarely extending to the lower rates tested.
Details of the primary-level assays conducted in artificial media.
Pathogen
Chemical
ratesa
Replicatesb
Spore
ratec
0.5c
20,000
15,000
10,000
Pythium dissimile
Alternaria solani
Botryotinia fuckeliana (Botrytis cinerea)
Gibberella zeae (Fusarium graminearum)
20, 2
20, 2
20, 2
20, 2
2
2
2
2
a
Rates are given as parts per million a.i. in the final artificial media mixture.
Number of replicates per rate.
Spore rates are given in spores per ml, with the exception of P. dissimile which is
b
c
Although it is difficult to extract clear structureeactivity rela-
tionships from the biological data, the first conclusion that can be
given as an optical density reading at 425 nm.

M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 53 (2012) 283e291
289
Scheme 1. Synthetic route to the compounds 18 and 19.
drawn is that the spectrum of fungicidal activity is improved by
substituting a halogen onto the 4-position of the oxazole ring. For
example, compared with compound 13, compounds 10 and 17
displayed a broader spectrum of activity in the artificial media
assays and some moderate activity on the leaf-piece assays.
Compound 10 was also the only analogue to show clear activity
at a low rate, in this case against Alternaria solani. However,
when derivatives with equivalent substitutions are compared it
is not possible to determine a consistent difference in biological
activity between the 4-chloroindoleoxazoles and the 4-
bromoindoleoxazoles. This may in part be due to limitations
inherent in the test method and it is possible that biological assays
with a greater number of rates and species and a more nuanced
scoring system would detect a difference.
Substitution on the nitrogen of the indole ring was also found to
clearly affect fungicidal activity. Compounds with alkyl substituents
(18a, 18b, 19a, 19b) had dramatically reduced activity compared to
the unsubstituted equivalents, and compounds with acetyl or
propionyl substituents at this position (18e, 18f, 19e, 19f) were
completely inactive. Substitutions with aromatic groups also ten-
ded to reduce fungicidal activity (e.g. 18p, 18q). By contrast, certain
N-acyl derivatives showed activity similar to that of the unsub-
stituted compounds on the artificial media assays, and the 4-
bromoindoxazole with a chloro-acetyl substituent (19h) matched
Table 4
Conditions and yields for the synthesis of compounds of 18 and 19.
Entry
R1
Timea (h)
Yieldb (%)
96
Entry
R1
Timea (h)
0.25c
Yieldb (%)
87
18a
CH3
3
18r
18b
18c
18d
18e
18f
18g
18h
18i
18j
18k
18l
18m
18n
CH3CH2
3
6
3
3
6
3
3
6
6
3
3
3
6
66
99
39
76
65
63
62
59
54
60
65
50
40
19a
19b
19c
19d
19e
19f
19g
19h
19i
CH3
CH3CH2
3
3
6
3
3
6
6
6
6
3
6
3
3
99
99
47
43
99
84
54
62
41
55
72
63
74
CH2:CHCH2
CCl2:CHCH2
CH3CO
CH3CH2CO
CH3CH2SO2
ClCH2CO
Cl2CHCO
CCl3CO
CH3CHClCO
CH3OCO
CH3OCH2CO
CH3CH2OCOCH2
CH2:CHCH2
CCl2:CHCH2
CH3CO
CH3CH2CO
CH3CH2SO2
ClCH2CO
Cl2CHCO
CH3ClCHCO
CH3OCO
19j
19k
19l
CH3OCH2CO
CH3CH2OCOCO
19m
18o
18p
CH3CH2OCOCO
2,4-di-F-C6H3CH2
O
3
56
19n
19o
3
59
87
O
3
3
92
61
0.25c
18q
a
Time to finish the reaction monitored by TLC.
Isolated yields.
Microwave-assisted synthesis was employed.
b
c

290
M.-Z. Zhang et al. / European Journal of Medicinal Chemistry 53 (2012) 283e291
Fig. 2. Crystal structures of compounds 10 and 18o.
or even slightly improved upon the activity of the equivalent
unsubstituted compound (17) on the leaf-piece assays, although
the 4-chloroindoxazole with a similar substitution lacked this
activity (18h).
4. Conclusion
In summary, we have synthesized a series of pimprinine
analogues and measured their fungicidal activities. Biological
testing showed that some of the analogues exhibited broad-
spectrum fungicidal activity against plant pathogens growing in
artificial media. The seven most active compounds 10, 17, 18h, 18o,
19h, 19i and 19l were identified as the most promising candidates
for further study. Further structural optimization of pimprinine
analogues is well under way, alongside more detailed biological
testing of the most active compounds, in order to better define their
levels of fungicidal activity.
Table 5
Fungicidal activities of pimprinine analogues. Data are presented as means of the
assessment scores (Table 4) across two replicates unless otherwise stated.
No. Species
Rate (ppm) 200/60 100
PHYa
SEPa,b URO a PYTa
ALTa
20/2
BOTa GIBa
100
20/2
20/2
20/2
10
13
17
0/49
0/0
49/0
0/0
0/0
0/0
ec
36
0
0
0
0
55
0
77
77
99
99
e
99/0
99/0
99/0
0/0
55/0
0/0
99/99 99/0
99/0
0/0
99/0
0/0
0/0
0/0
e
77/0
99/0
0/0
0/0
0/0
0/0
99/0
0/0
0/0
0/0
e
Acknowledgements
18a
18b
18c
18d
18e
18f
18g
18h
18i
0
e
We thank the Biology Team at Syngenta for their kind help in
screening the compounds for biological activity.
e
e
0/0
0/0
0/0
27/0
0/0
0/0
0/0
0/0
0/0
49/0
0/0
0/49
0/0
49/0
49/0
0/0
49/0
0/0
0/0
0/0
0/0
99/0
0/0
0/0
0/0
0/0
ec
0
0
0
0
0
0
0
0
0
0
33
0
0
33
0
0
18
0
0
0
0
18
0
0
0
0
e
e
0
0
0
0/0
0/0
0/0
0/0
0/0
0/0
0/0
0/0
99/0
99/0
99/0
0/0
e/e
77/0
0/0
99/0
0/0
0/0
0/0
0/0
0/0
27/0
0/0
0/0
0/0
0/0
0/0
0/0
0/0
99/0
99/0
99/0
0/0
0/0
0/0
0/0
99/0
0/0
0/0
0/0
0/0
0/49
0/0
0/0
0/0
0/0
0/0
99/0
99/0
0/0
0/0
99/0
e
55
49
0
55
55
0
55
0
0
27
77
55
55
99
49
0
0
0
0
49
27
27
0
77
e
27/0
99/0
99/0
99/0
0/0
0/0
55/0
0/0
77/0
0/0
0/0
99/0
0/0
55/49 55/0
0/0
0/0
0/0
0/0
0/0
99/0
77/0
0/0
0/0
77/0
e
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55/0
99/0
99/0
55/0
0/0
99/0
0/0
99/0
0/0
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PHY, Phytophthora infestans (on tomato leaf pieces); SEP, Septoria tritici (on
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