Synthesis of pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates via the Hurd-Mori reaction. Investigating the effect of the N-protecting group on the cyclization

Article abstract of DOI:10.3390/10020367

A route to methyl pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates as potential plant activators and inducers of systemic acquired resistance (SAR) is reported. A synthetic strategy based on cyclization of the thiadiazole ring system utilizing thionyl chloride via the Hurd-Mori protocol as key step was developed. Success of the ring closure reaction turned out to be highly dependent on the nature of the N-protecting group of the pyrrolidine precursor. While electron donors such as alkyl gave only poor conversion to the required 1,2,3-thiadiazoles, an electron withdrawing substituent such as methyl carbamate gave superior yields.

Full text of DOI:10.3390/10020367

Molecules 2005, 10, 367-375
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates
via the Hurd-Mori Reaction. Investigating the Effect of the
N-Protecting Group on the Cyclization.
Peter Stanetty,* Martin Turner, and Marko D. Mihovilovic
Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC,
A-1060 Vienna, Austria
* Author to whom correspondence should be addressed; Email: peter.stanetty@tuwien.ac.at
Received: 23 November 2004 / Accepted: 16 December 2004 / Published: 28 February 2005
Abstract: A route to methyl pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates as potential
plant activators and inducers of systemic acquired resistance (SAR) is reported. A synthetic
strategy based on cyclization of the thiadiazole ring system utilizing thionyl chloride via the
Hurd-Mori protocol as key step was developed. Success of the ring closure reaction turned
out to be highly dependent on the nature of the N-protecting group of the pyrrolidine
precursor. While electron donors such as alkyl gave only poor conversion to the required
1,2,3-thiadiazoles, an electron withdrawing substituent such as methyl carbamate gave
superior yields.
Keywords: Hurd-Mori reaction; 1,2,3-thiadiazoles; thionyl chloride; plant activators;
systemic acquired resistance.
Introduction
Systemic acquired resistance (SAR) represents a novel concept in plant protection chemistry. This
approach takes advantage of the plant's own defense mechanisms. In previous studies it was
demonstrated that the local infection of a plant may result in developing a resistance to subsequent
challenges by a variety of pathogens throughout the whole organism. While on the molecular level this
response is linked to the expression of PR-proteins, the complete mechanism is not fully understood,
so far, and intensive scientific research is currently under way to elucidate this intricate effect [1].

Molecules 2005, 10
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In addition to the “traditional” mode of infection with a pathogen, the stimulation of this effect can
also be induced by several non-natural compounds. Such agents became known as plant activators, and
heterocyclic molecules like 2,6-dichloroisonicotinic acid 1, various 1,2,3-benzothiadiazole-7-
carboxylic acid derivatives such as 2, [2] or thiophene fused thiadiazoles 3 [3,4] are capable to trigger
the same biochemical cascade subsequently resulting in an immunization of the plant (Scheme 1).
Previously, Bion® 2 became the first commercialized product with this novel mode of action.
Scheme 1.
COOH
COSMe
COOMe
R
COOMe
S
S
N
N
S
N
N
N
N
S
N
Cl
N
1
Cl
R'
2
3
4
Acibenzolar-S-methyl; Bion®
R = H, Me, Hal
R' = H, alkyl, acyl
Recent efforts to find new heterocyclic systems based on the lead structure 2 [5,6] suggested the
1,2,3-thiadiazole system [7] as an integral motif for biological activity. Consequently, we became
interested in modifying the benzo-part of Bion® 2, a strategy successfully applied in the development
of biologically active thieno compounds 3. In the present paper we present a synthetic route to pyrrolo-
fused analogs 4. Based on structure activity relationships the position of the ester group adjacent to the
annelation site is an important structural feature for the activity as an inducer of systemic acquired
resistance, narrowing the number of first choice candidates in the pyrrolo series.
In our quest to develop an optimized approach to the corresponding thieno targets 3 [3] we became
interested in the Hurd-Mori cyclization [8] as a most simple and versatile protocol for the generation
of 1,2,3-thiadiazoles.[9] In the particular case of 3, the reaction with thionyl chloride gave a fully
aromatized product, which was an especially intriguing aspect to us. We have suggested a mechanistic
rational for our observations in the thieno series, previously. [3,10] For the construction of the
analogous pyrrolo products we envisioned a similar approach.
Results and Discussion
Synthesis of alkyl substituted pyrrolo-thiadiazoles 4a (R = Bn) and 4b (R = Me) started from
itaconic acid or its dimethylester (Scheme 2). Cyclization towards the pyrrolidine system 5a/b was
optimized based on a protocol by Feldkamp and coworker [11].
From our previous experiences in the thieno-series we had already expected that efficient
conversion to the hydrazone precursor for the Hurd-Mori reaction required formation of a thiocarbonyl
species. Consequently, lactams 5a/b were transformed into the corresponding thiolactams 6a/b using
Lawesson’s reagent.[12] As work-up conditions for reactions involving this reagent are troublesome,
sometimes, we found Kugelrohr distillation as a most convenient form to purify the products.
Thiolactams 6a/b gave clean conversion to the corresponding hydrazono cyclization precursors
7a/b by treatment with ethyl carbazate upon refluxing in THF in the presence of Hg(OAc)2. In the

Molecules 2005, 10
369
absence of this reagent, the reaction progress was significantly decreased. In addition, equilibrium
concentrations are shifted by precipitation of HgS.
Scheme 2.
COOMe
5a-b
COOMe
COOR'
i) or ii)
iii)
R'OOC
O
S
N
R
N
R
R' = H, Me
6a-b
iv)
a: R = Bn
b: R = Me
COOMe
4a-b
COOMe
S
N
v)
N
EtOOCNHN
N
R
N
R
7a-b
i) R’ = H: BnNH2, 130°C; then MeOH, H2SO4, 88% (5a); ii) R’ = Me:
MeNH2/H2O, MeOH, 95% (5b); iii) Lawesson’s reagent, THF, 98% (6a), 87%
(6b); iv) EtOOCNHNH2, Hg(OAc)2, THF, 75% (7a), 81% (7b); v) SOCl2, CHCl3,
25% (4a), 15% (4b).
The actual Hurd-Mori cyclization towards the alkyl-thiadiazoles gave fully aromatized products
4a/b with both precursors. However, it turned out to be disappointing with yields of 25% (4a) and 15%
(4b), respectively, even under optimized reaction conditions. The pyrrolidino-precursors required
significantly harsher conditions (chloroform at reflux) to display reasonable conversion rates. However,
at such temperatures the stability of the starting material and/or of intermediate products becomes a
limiting factor. In all optimization experiments significant decomposition was observed by darkening
of the reaction mixtures and/or precipitation of insoluble material.
Although we could demonstrate access to N-alkyl-pyrrolo-thiadiazole-carboxylates 4a and 4b in
principal, the chosen strategy did not seem suitable for scale-up in order to provide larger quantities
for derivatization studies. We attribute the limited stability to the presence of a relatively electron rich
nitrogen species in all cyclization precursors and intermediates. Consequently, another option to
overcome the poor cyclization yields could be by changing the protecting group at the pyrrolidine
system to an electron withdrawing substituent.
In order to confirm this hypothesis, we started a second series from 5-oxopyrrolidin-3-carboxylate
methylester (Scheme 3).[13,14] Conversion to the thiolactam 8 was again accomplished in excellent
yields using Lawesson’s reagent. Introduction of the carbamate protecting group gave compound 6c in
only moderate yields, as complete conversion could not be achieved. Based on consumed starting
material almost quantitative transformation can be accomplished. Reaction with ethyl carbazate did not
require presence of a mercury additive and produced compound 7c in excellent yield.

Molecules 2005, 10
370
Scheme 3.
COOMe
COOMe
COOMe
i)
ii)
O
S
S
N
N
H
N
H
COOMe
8
6c
iii)
COOMe
COOMe
COOMe
S
N
S
N
v)
iv)
N
N
H
N
EtOOCNHN
N
N
COOMe
COOMe
4d
4c
7c
i) Lawesson’s reagent, THF, 99%; ii) MeOOCCl, TEA, DMAP, CH2Cl2, 30%; iii)
EtOOCNHNH2, CH2Cl2, 98%; iv) SOCl2, CH2Cl2, 94%; v) SiO2, MeOH, 99%.
In contrast to the alkyl precursors, Hurd-Mori reaction with 7c required cooling and progressed
smoothly to fully aromatized thiadiazole 4c. No significant side products were observed and
compound 4c was isolated after simple recrystallization in 94% yield. Final deprotection of the pyrrolo
nitrogen was accomplished by treatment of a methanolic solution of 4c with silica gel to afford 4d
quantitatively.
Conclusions
Basicity of the ring nitrogen atom in precursors for the Hurd-Mori reaction has a major effect on
the success of the transformation. Presence of an electron withdrawing protecting group at the nitrogen
plays a significant role for a successful cyclization. We have successfully established a synthetic route
to pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylates via this versatile cyclization protocol. Best results
were observed for electron withdrawing protecting groups at the pyrrolo nitrogen. In all cases, fully
aromatized target compounds were obtained. Further optimization efforts for the synthetic steps
towards the cyclization precursors are currently underway in our laboratory.
Experimental
General
Unless otherwise noted, chemicals were purchased from commercial suppliers and used without
further purification. All solvents were distilled prior to use. Flash column chromatography was
performed on silica gel 60 from Merck (40-63µm). Melting points were determined using a Kofler-
type Leica Galen III micro hot stage microscope and are uncorrected. NMR-spectra were recorded
from CDCl3 or DMSO-d6 solutions on a Bruker AC 200 (200 MHz) spectrometer and chemical shifts
are reported in ppm using TMS as internal standard. Combustion analysis was carried out in the
Microanalytic Laboratory, University of Vienna.

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1-Benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester (5a).
Itaconic acid (36.11 g, 0.28 mol) and benzylamine (29.74 g, 0.28 mol) were heated in substance to
130°C and the water formed was distilled off during 3 hours. Crystals of crude 1-benzyl-5-
oxopyrrolidine-3-carboxylic acid (55.13 g, 0.25 mol, 90 %) were collected by filtration after treatment
of the reaction mixture with ice/water and dried in vacuo. This material was dissolved in methanol
(200 mL) and treated with conc. sulfuric acid (28.66 g, 0.27 mol) at reflux for 3 hours. The reaction
solution was concentrated to approx. half volume, subsequently neutralized with 10N NaOH, 2N
NaOH, and satd. NaHCO3-solution, and repeatedly extracted with dichloromethane. The combined
organic layers were washed with water, dried over sodium sulfate, and concentrated to give 56.92g
(88% overall) of 5a [11] as colorless crystals; m.p. 71-73°C; 1H-NMR (CDCl3): 2.90-3.10 (m, 2H, H-
4), 3.18-3.37 (m, 1H, H-3), 3.58 (d, J=8Hz, 2H, H-2), 3.69 (s, 3H, OCH3), 4.45-4.50 (m, 2H, PhCH2),
7.14-7.38 (m, 5H, arom. H); 13C-NMR (DMSO-d6): 33.4 (t, C-4), 35.1 (d, C-3), 45.3 (t, PhCH2), 48.1
(t, C-2), 52.0 (q, OCH3), 127.3 (d, C-4`), 127.6 (d, C-3`+ C-5`), 128.5 (d, C-2`+ C-6`), 136.6 (s, C-1`),
171.7 (s, COOCH3), 173.4 (s, C-5).
1-Methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester (5b).
Dimethyl itaconate (30g, 0.19mol) was added to aqueous methylamine solution (17.2 mL, 15.53 g,
40% solution, 0.2 mol) at 5-10°C and maintained at this temperature for another hour. Afterwards, the
mixture was warmed to room temperature and stirred for 16 hours, concentrated and distilled in vacuo
to give 29.0 g (95%) of 5b [11] as a colorless liquid; b.p. 160-161°C/24mbar; 1H-NMR (CDCl3): 2.60-
2.75 (m, 2H, H-4), 2.86 (s, 3H, NCH3), 3.16-3.38 (m, 1H, H-3), 3.40 (d, J=8Hz, 2H, H-2), 3.66 (s, 3H,
OCH3); 13C-NMR (CDCl3): 28.0 (q, NCH3), 32.5 (t, C-4), 34.4 (d, C-3), 49.8 (t, C-2), 51.0 (q, OCH3),
171.0 (s, COOCH3), 172.2 (s, C-5).
1-Benzyl-5-thioxopyrrolidine-3-carboxylic acid methyl ester (6a).
Lactam 5a (56.9 g, 0.244 mol) and Lawesson’s reagent (49.35 g, 0.15 mol) were stirred at room
temperature for 30 min in dry THF (400 mL). The solvent was removed in vacuo and the crude
material was Kugelrohr distilled to give 59.6 g (98%) of 6a as beige oil; b.p. 155-165°C/0.001-
1
0.005mbar; nD20=1.5880; H-NMR (CDCl3): 3.11-3.40 (m, 3H, H-3, H-4), 3.69 (s, 3H, OCH3), 3.61-
3.91 (m, 2H, H-2), 4.90-5.00 (m, 2H, PhCH2), 7.20-7.40 (m, 5H, arom. H); 13C-NMR (CDCl3): 37.0 (d,
C-3), 47.1 (t, C-4), 51.0 (t, PhCH2), 52.1 (q, OCH3), 55.3 (t, C-2), 127.8 (d, C-4`), 127.9 (d, C-3`+ C-
5`), 128.5 (d, C-2`+C-6`), 134.2 (s, C-1`), 172.1 (s, COOCH3), 198.7 (s, C-5); Anal. for C13H15NO2S
(249.33): calc.: C 62.63%, H 6.06%, N 5.62%; found.: C 62.75%, H 6.30%, N 5.57%.

Molecules 2005, 10
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1-Methyl-5-thioxopyrrolidine-3-carboxylic acid methyl ester (6b).
Lactam 5b (29.0 g, 0.18 mol) and Lawesson’s reagent (60.0 g, 0.18 mol) were stirred at room
temperature for 30 min in dry THF (400 mL). The solvent was removed in vacuo and the crude
material was Kugelrohr distilled to give 26.0 g (87%) of 6b as beige oil; b.p. 100°C/0.01-0.02mbar;
1H-NMR (CDCl3): 3.28 (s, 3H, NCH3), 3.20-3.50 (m, 3H, H-3, H-4), 3.76 (s, 3H, OCH3), 3.86-4.12 (m,
2H, H-2); 13C-NMR (CDCl3): 33.9 (d, C-3), 35.9 (q, NCH3), 46.0 (t, C-4), 51.2 (q, OCH3), 57.3 (t, C-
2), 171.4 (s, COOCH3), 196.8 (s, C-5); Anal. for C7H11NO2S (173.23): calc.: C 48.53%, H 6.40%, N
8.09%; found.: C 48.56%, H 6.32%, N 8.06%.
5-Thioxopyrrolidine-3-carboxylic acid methyl ester (8).
Methyl 5-oxopyrrolidine-3-carboxylate (5.0 g, 34.9 mmol) and Lawesson’s reagent (14.1 g, 34.9
mmol) were stirred at room temperature for 2 hours in dry THF (50 mL). The solvent was removed in
vacuo and the residue was purified by flash column chromatography (triethylamine impregnated silica
gel, LP/EtOAc = 3:2), followed by recrystallization from toluene to give 5.51g (99%) of 8 as colorless
crystals; m.p. 106-109°C; 1H-NMR (CDCl3): 3.10-3.30 (m, 2H, H-4), 3.40-3.55 (m, 1H, H-3), 3.75 (s,
3H, OMe), 3.83 (dd, J=11.3Hz, 5.5Hz, 1H, H-2), 3.96 (dd, J=11.3Hz, 6.5Hz, 1H, H-2), 8.85 (bs, 1H,
NH); 13C-NMR (CDCl3): 40.7 (t, C-4), 45.8 (d, C-3), 51.5 (q, OCH3), 52.6 (t, C-2), 172.4 (s,
COOCH3), 203.0 (s, C-5); Anal. for C6H9NO2S (159.21): calc.: C 45.27%, H 5.70%, N 8.80%; found.:
C 45.33%, H 5.71%, N 8.67%.
5-Thioxopyrrolidine-1,3-dicarboxylic acid dimethyl ester (6c).
Thiolactam 8 (4.50 g, 28.3 mmol), triethylamine (2.86 g, 28.3 mmol), and DMAP (3.45 g, 28.3
mmol) were dissolved in dry dichloromethane (100 mL) and treated with methyl chloroformate (5.34 g,
56.5 mmol) in dry dichloromethane (20 mL) at -60 to -70°C. After complete addition the reaction
mixture was warmed to room temperature, stirred for 12 hours, and subsequently concentrated in
vacuo. Flash column chromatography (silica gel, LP/EtOAc = 1:1) gave 3.13 g of recovered starting
1
material 8 and 1.80 g (30 %, 96% based on consumed 8) of 6c as beige crystals; m.p. 89-91°C; H-
NMR (CDCl3): 3.20-3.41 (m, 3H, H-3, H-4), 3.76 (s, 3H, C-3-COOCH3), 3.89 (s, 3H, N1-COOCH3),
4.24-4.44 (m, 2H, H-2); 13C-NMR (CDCl3): 37.4 (d, C-3), 50.4 (t, C-4), 52.5 (q, C3-COOCH3), 53.6 (q,
N1-COOCH3), 54.8 (t, C-2), 151.6 (s, N1-COOCH3), 171.7 (s, C3-COOCH3), 204.0 (s, C-5); Anal. for
C8H11NO4S (217.24): calc.: C 44.23%, H 5.10%, N 6.45%; found.: C 44.45%, H 4.92%, N 6.35%.
1-Benzyl-5-(2-ethoxycarbonyl-2-hydrazinyl-1-yliden)-pyrrolidine-3-carboxylic acid methyl ester (7a).
Thiolactam 6a (59.6 g, 0.24 mol) and ethyl carbazate (24.9 g, 0.24 mol) were dissolved in dry THF
(100 mL) and treated with Hg(OAc)2 (76.2 g, 0.24 mol). The mixture was stirred at room temperature
for 16 hours, then charcoal was added and the suspension was filtered through a pad of Celite®. The
resulting solution was concentrated and the residue was recrystallized from diisopropyl ether to give
1
57.5 g (75%) of 7a as colorless crystals; m.p. 103-107°C; H-NMR (CDCl3): 1.29 (t, J=7Hz, 3H,

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OCH2CH3), 2.90-3.25 (m, 3H, H-3, H-4), 3.43 (d, J=8Hz, 2H, H-2), 3.69 (s, 3H, OCH3), 4.19 (q,
J=7Hz, 2H, OCH2CH3), 4.45-4.55 (m, 2H, PhCH2), 6.78 (bs, 1H, NH), 7.20-7.40 (m, 5H, arom. H);
13C-NMR (CDCl3): 14.7 (q, OCH2CH3), 30.0 (t, C-4), 37.0 (d, C-3), 47.2 (t, PhCH2), 50.7 (t, C-2),
52.0 (q, OCH3), 59.5 (t, OCH2CH3), 127.0 (d, C-4`), 127.8 (d, C-3`+ C-5`), 128.3 (d, C-2`+ C-6`),
137.2 (s, C-1`), 154.7 (s, COOEt), 162.6 (s, C-5), 173.1 (s, COOMe); Anal. for C16H21N3O4 (319.36):
calc.: C 60.18%, H 6.63%, N 13.16%; found.: C 59.92%, H 6.48%, N 13.03%.
1-Methyl-5-(2-ethoxycarbonyl-2-hydrazinyl-1-yliden)-pyrrolidine-3-carboxylic acid methyl ester (7b).
Thiolactam 6b (11.0 g, 63 mmol) and ethyl carbazate (6.6 g, 63 mmol) were dissolved in dry THF
(100 mL) and treated with Hg(OAc)2 (20.24 g, 63 mmol). The mixture was stirred at room temperature
for 16 hours, then charcoal was added and the suspension was filtered through a pad of Celite®. The
resulting solution was concentrated to give 12.35 g (81%) of 7b as orange, highly viscous oil, which is
sufficiently pure for the subsequent cyclization. Additional chromatographic purification (silica gel,
1
LP/EtOAc = 1:1) gives beige crystals of m.p. 95-96°C; H-NMR (CDCl3): 1.25 (t, J=7Hz, 3H,
OCH2CH3), 2.88 (s, 3H, NCH3), 2.90-3.20 (m, 3H, H-3, H-4), 3.55 (d, J=8Hz, 2H, H-2), 3.72 (s, 3H,
13
OCH3), 4.16 (q, J=7Hz, 2H, OCH2CH3), 6.58 (bs, 1H, NH); C-NMR (CDCl3): 14.2 (q, OCH2CH3),
29.9 (t, C-4), 31.0 (q, NCH3), 37.2 (d, C-3), 51.8 (q, OCH3), 52.5 (t, C-2), 60.4 (t, OCH2CH3), 155.4 (s,
COOEt), 165.2 (s, C-5), 172.6 (s, COOMe); Anal. for C10H17N3O4 (243.26): calc.: C 49.38%, H 7.04%,
N 17.27%; found.: C 49.63%, H 7.05%, N 17.22%.
5-(Ethoxycarbonyl-2-hydrazinyl-1-yliden)-pyrrolidine-1,3-dicarboxylic acid dimethyl ester (7c).
Thiolactam 6c (1.42 g, 6.54 mmol) and ethyl carbazate (0.68 g, 6.54 mmol) were refluxed in dry
dichloromethane (30 mL) for 21 hours. The mixture was concentrated in vacuo and the oily residue
was dissolved in hot EtOAc. Pure 7c crystallizes upon storage at -35°C for 48 hours, yielding 1.85 g
(99%) as colorless crystals; m.p. 90-92°C; 1H-NMR (CDCl3): 1.30 (t, J=7Hz, 3H, OCH2CH3), 2.61 (bs,
1H, NH), 2.95-3.25 (m, 3H, H-3, H-4), 3.74 (s, 3H, C3-COOCH3), 3.83 (s, 3H, N1-COOCH3), 3.95
(dd, J=18.5Hz, J=6.6 Hz, 1H, H-2), 4.03 (dd, J=18.5Hz, J=8.1Hz, 1H, H-2), 4.21 (q, J=7Hz, 2H,
OCH2CH3); 13C-NMR (CDCl3): 14.4 (q, OCH2CH3), 29.8 (t, C-4), 36.9 (d, C-3), 49.8 (t, C-2), 52.5 (q,
C3-COOCH3), 53.3 (q, N1-COOCH3), 61.7 (t, OCH2CH3), 151.8 (s, N1-COOCH3), 154.6 (s,
COOCH2CH3), 171.9 (s, C3-COOCH3).
4-Benzyl-pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylic acid methyl ester (4a).
Compound 7a (1.0 g, 3.13 mmol) was dissolved in dry chloroform (10 mL) and added to a
refluxing mixture of thionyl chloride (2.6 g, 21.9 mmol) and dry chloroform (10 mL). After complete
addition, refluxing was continued for another 16 hours. The mixture was concentrated in vacuo and the
residue was taken up with dichloromethane. The organic layer was washed with satd. NaHCO3-
solution and water, dried over sodium sulfate, and concentrated. Pure 4a (0.21 g, 25%) was obtained
after flash column chromatography (silica gel, LP/EtOAc = 10:1) and subsequent recrystallization
1
from diisopropyl ether as colorless crystals; m.p. 150-151°C; H-NMR (CDCl3): 3.89 (s, 3H, OCH3),

Molecules 2005, 10
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13
5.60 (s, 2H, PhCH2), 7.30-7.40 (m, 5H, arom. H), 7.85 (s, 1H, H-5); C-NMR (CDCl3): 51.8 (q,
OCH3), 52.3 (t, PhCH2), 107.0 (s, C-6), 128.2, 128.8, 129.1 (3 d, C-2’, C-6’, C-3’, C-5’, C-4’), 130.8
(s, C-6a), 134.7 (s, C-1’), 135.8 (d, C-5), 161.0, 163.0 (2 s, CO, C-3a); Anal. for C13H11N3O2S
(273.31): calc.: C 57.13%, H 4.06%, N 15.37%; found.: C 57.27%, H 4.03%, N 15.42%.
4-Methyl-pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylic acid methyl ester (4b).
Compound 7b (0.5 g, 2.06 mmol) was dissolved in dry chloroform (10 mL) and added to a
refluxing mixture of thionyl chloride (2.6 g, 21.9 mmol) and dry chloroform (10 mL). After complete
addition, refluxing was continued for another 16 hours. The mixture was concentrated in vacuo and the
residue was taken up with dichloromethane. The organic layer was washed with satd. NaHCO3-
solution and water, dried over sodium sulfate, and concentrated. Pure 4b (0.06 g, 15%) was obtained
after flash column chromatography (silica gel, LP/EtOAc = 10:1) and subsequent recrystallization
1
from diisopropyl ether as colorless crystals; m.p. 161-165°C; H-NMR (CDCl3): 3.90 (s, 3H, OCH3),
13
4.17 (s, 3H, NCH3), 7.82 (s, 1H, H-5); C-NMR (CDCl3): 34.9 (q, NCH3), 51.9 (q, OCH3), 106.6 (s,
C-6), 130.7 (s, C-6a), 137.1 (s, C-5), 161.4, 163.1 (2 s, CO, C-3a); Anal. for C7H7N3O2S (197.22):
calc.: C 42.63%, H 3.58%, N 21.31%; found.: C 41.88%, H 3.44%, N 20.78%.
Pyrrolo[2,3-d][1,2,3]thiadiazole-4,6-dicarboxylic acid dimethyl ester (4c).
Compound 7c (1.7 g, 5.9 mmol) was dissolved in dry dichloromethane (20 mL) and added to a
cooled mixture (-10 to -5°C) of thionyl chloride (4.9 g, 41.4 mmol) and dry dichloromethane (70 mL)
over a period of 60 min. After complete addition, the mixture was warmed to room temperature and
stirred overnight. The mixture was concentrated in vacuo and the residue was taken up with
dichloromethane, treated with an excess of triethylamine and concentrated again. The residue was
taken up with dichloromethane and washed with water. The organic layer was dried over sodium
sulfate and concentrated. Recrystallization from EtOAc gave 1.34 g (94%) of pure 4c as colorless
1
crystals; m.p. 152-154°C; H-NMR (CDCl3): 3.95 (s, 3H, C6-COOCH3), 4.24 (s, 3H, N1-COOCH3),
13
8.38 (s, 1H, H-5); C-NMR (CDCl3): 52.4 (q, C6-COOCH3), 55.6 (q, N1-COOCH3), 110.8 (s, C-6),
133.8 (d, C-5), 134.2 (s, C-6a), 148.6 (s, N1-CO), 157.9 (s, C-3a), 161.8 (s, COO); Anal. for
C8H7N3O4S (241.23): calc.: C 39.83%, H 2.92%, N 17.42%; found.: C 39.91%, H 3.01%, N 17.27%.
Pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylic acid methyl ester (4d).
A suspension of product 4c (0.40 g, 1.66 mmol) and silica gel (5 g) in dry methanol (20 mL) was
stirred at room temperature for 3 days. The silica gel was removed by filtration and the obtained
solution was concentrated in vacuo. Pure 4d (0.30 g, 99%) was obtained without further purification as
1
colorless crystals; m.p. 218-220°C; H-NMR (CDCl3 + 10% DMSO-d6): 3.90 (s, 3H, OCH3), 7.99 (s,
13
1H, H-5), 8.78 (bs, 1H, H-4); C-NMR (CDCl3 + 10% DMSO-d6): 51.2 (q, OCH3), 106.5 (s, C-6),
130.2 (s, C-6a), 134.4 (d, C-5), 160.9 (s, C-3a), 163.0 (s, COO); Anal. for C6H5N3O2S (183.19): calc.:
C 39.34%, H 2.75%, N 22.94%; found.: C 39.63%, H 2.65%, N 22.67%.

Molecules 2005, 10
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References and Notes
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Kessmann, H.; Staub, T.; Hofmann, C.; Maetzke, T.; Herzog, J. Annu. Rev. Phytopathol. 1994,
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Fischer Verlag: Jena, 1995; p. 543.
[2] Schurter, R. Eur. Pat. Appl. EP 347377 A2, 1989; [Chem. Abstr., 1990, 113, 172020z].
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Arvanitis, E.; Motevalli, M.; Wyatt, P. B. Tetrahedron Lett. 1996, 24, 4277; (c) Tsuge, O.;
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[14] For an optimized access to this starting material: Stanetty, P.; Turner, M.; Mihovilovic, M.D. in
preparation.
Sample Availability: Available from the authors.
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