Investigation of the regioselectivity of the Hurde-Mori reaction for the formation of bicyclic1,2,3-thiadiazoles

Article abstract of DOI:10.1016/j.tet.2010.05.017

A series of new pyrrolo[d][1,2,3]thiadiazole carboxylates and 5,6-dihydro-4H-cyclopenta[d][1,2,3]thia-diazoles has been synthesized via the HurdeMori reaction.The regioselectivity of the cyclization has been studied and trends were established to predict the cyclization direction to afford bicyclic 1,2,3-thiadiazoles.Effects promoting and disfavoring the reaction have also been investigated to guide the synthesis of scaffolds of this type.

Full text of DOI:10.1016/j.tet.2010.05.017

Tetrahedron 66 (2010) 5472e5478
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Investigation of the regioselectivity of the HurdeMori reaction
for the formation of bicyclic 1,2,3-thiadiazoles
*
Martin Turner, Thomas Linder, Michael Schnürch, Marko D. Mihovilovic , Peter Stanetty
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new pyrrolo[d][1,2,3]thiadiazole carboxylates and 5,6-dihydro-4H-cyclopenta[d][1,2,3]thia-
diazoles has been synthesized via the HurdeMori reaction. The regioselectivity of the cyclization has
been studied and trends were established to predict the cyclization direction to afford bicyclic 1,2,3-
thiadiazoles. Effects promoting and disfavoring the reaction have also been investigated to guide the
synthesis of scaffolds of this type.
Received 8 April 2010
Received in revised form
5 May 2010
Accepted 6 May 2010
Available online 11 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
This work is dedicated to Professor Saverio
Florio on the occasion of his 70th birthday
Keywords:
Annelated heterocycle
Cyclization
Protecting group
Regioselectivity
Systemic acquired resistance
1. Introduction
organism, such as a crop, to develop an otherwise not observed
immune response when confronted with pathogens. This phe-
Structures containing a 1,2,3-thiadiazole are promising targets
in medicinal and agrochemical applications.1 Most notably, interest
in the aryl- or heteroaryl-fused bicyclic thiadiazole motif arose
when benzo[d][1,2,3]thiadiazole-7-carboxylic acid and its methyl
carbothioatedthe latter being commercialized as ActigardÒ
(BIONÒ)dwere identified as a class of compounds known as plant
activators.2,3 These substances are capable of stimulating a higher
nomenon is commonly referred to as ‘systemic acquired re-
sistance’.4 Previously, we could show that various methyl thieno
[2,3-d][1,2,3]-thiadiazole-6-carboxylates act as active bioisosters of
ActigardÒ (Fig. 1).5
Access to 1,2,3-thiadiazoles in general can be gained via a variety
of methods, and the topic has been extensively reviewed.6 Among
these pathways are the cycloaddition of diazoalkanes to thio-
carbonyl compounds (PechmanneNold synthesis7) and the cyclo-
addition of
a
-diazo thiocarbonyl precursors (Wolff synthesis8).
However, the most versatile route to enable the synthesis of fused
thiadiazoles of the general structure III starts from the corre-
sponding monocyclic carbonyl or thiocarbonyl materials I. The bi-
cyclic system is then formed by incorporating both nitrogen atoms
from a hydrazine-derived reagent (such as ethyl hydrazinecarbox-
ylate or tosylhydrazide) and the sulfur atom from an electrophile
(in many cases thionyl chloride) used in excess. This method is
known as the HurdeMori cyclization (Scheme 1).9 Despite its quite
universal applicability, including a recent solid-phase adaptation,10
the success of the transformation crucially depends on the func-
tional decoration of the starting compounds. In particular, the
regioselectivity of the ring-closing step is heavily influenced by
both electronic and steric factors.
Figure 1. Systemic acquired resistance-inducing bicyclic 1,2,3-thiadizoles.
* Corresponding author. Tel.: þ43 1 58801 15420; fax: þ43 1 58801 15499; e-mail
address: marko.mihovilovic@tuwien.ac.at (M.D. Mihovilovic).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.017

M. Turner et al. / Tetrahedron 66 (2010) 5472e5478
5473
(ꢀ5 to ꢀ20 ꢁC). Our earlier results18 showed that the efficiency of
the cyclization was dramatically affected by the electronic proper-
ties of the 2-hydrazonopyrrolidine substrate species (Scheme 2).
Excellent yield of 95% was observed in the case where the strongly
electron withdrawing methoxycarbonyl group at the pyrrolidine
nitrogen was present (IIb), and poor amounts of isolated material in
the case of N-substituents such as benzyl or the even donating
methyl group (IIc: 25% and IId: 15%).18
We now found that if Boc is used as the N-protecting group 2 in
place of MeCO2, a comparable yield of 82% of the thiadiazole 3 was
obtainable (Scheme 3). In agreement with the aforementioned ef-
fect we also observed that retaining the N-methoxycarbonyl group
but removing the ester from the 4-position instead, as in compound
6, led to lower yields also, thereby giving the N-methoxycarbonyl-
protected parent compound 4H-pyrrolo[2,3-d][1,2,3]thiadiazole 7
in moderate 29% yield. These results make it clear already that
substituent-induced electron deficiency promotes successful
HurdeMori cyclization. It shall also be pointed out that the choice
of the N-protecting group is not trivial, as the Boc-group can be
removed more smoothly but, when placed on different regioiso-
Scheme 1. HurdeMori retrosynthetic analysis.
These effects, exerted by the various structural elements, may
oppose each other and questions arise as to which aspect will dom-
inate. The reaction involves nucleophilic attack of the a-carbon of
hydrazone II to the electron deficient sulfur moiety and subsequent
cyclization toward formation of a 1,2,3-thiadiazolin-1-one as key
intermediate (Scheme 2).11 Therefore, the ease of enolization under
the applied reaction conditions is the most important directing factor
for substrates where enolization can occur in two different di-
rections.12 However, theelectronicinfluenceofsucha substituentcan
be overruled if a neighboring group is sterically demanding.13 In
contrast to this, the E/Z ratio of the hydrazone at equilibrium was
found to be unimportant andthe nature of the leaving group had only
a minor, albeit noticeable, effect on the cyclization direction.14,15
Scheme 2. Route to reported 1,2,3-thiadiazole target structures and proposed mechanistic rationale for aromatization, giving rise to fused 1,2,3-thiadiazoles.
In an earlier contribution we demonstrated the use of the
method in the synthesis of IIIa from hydrazinecarboxylate IIa di-
rectly, i.e., with complete aromatization occurring concomitantly
with ring closure (Scheme 2).16 Our findings indicated that a more
complex process than simple oxidation of a dihydro intermediate is
involved, which allowed us to suggest a mechanism for this
transformation to account for the complete aromatization of the
product species as well as for a halogenated side product formed
under certain reaction conditions.16,17
meric substrates, did not withstand the acidic conditions of the
HurdeMori step in every case even though the temperature con-
ditions were milder than in the synthesis of 3 (i.e., in case of 16:
addition at ꢀ20 ꢁC and subsequent reaction at ꢀ16 ꢁC, Scheme 5).
The biological activity found in these compounds then led us to
pursue this strategy in a follow-up approach to the analogous pyr-
rolo[2,3-d][1,2,3]thiadiazole-6-carboxylates (IIIbed).18 We were
thus prompted to a systematic investigation to allow for selectivity
and efficiency predictions of target structures of this type and con-
tinued to study the scope and limitations of the method in the quest
for potential biologically active analogs. Therefore, we present the
synthesis of hitherto unreported pyrrolo[d][1,2,3]thiadiazole car-
boxylates and 5,6-dihydro-4H-cyclopenta[d][1,2,3]thiadiazoles, in
which case it was possible to draw conclusions as to the applicability
of the HurdeMori route for the desired targets and compare it to the
synthesis of similar compounds that we had established previously.
Scheme 3. Reagents and conditions: (i) EtCO2NHNH2, CH2Cl2, reflux, 21 h; (ii) SOCl2,
CH2Cl2, ꢀ10 to ꢀ5 ꢁC, dropwise addition 1 h; to rt, overnight; (iii) CF3CO2H, CH2Cl2,
reflux 5 h; (iv) EtCO2NHNH2, CH2Cl2, rt, 72 h; (v) KOH, MeOH, reflux, 16 h.
2. Results and discussion
The regioisomer 11 (Scheme 4) with the ester group adjacent to
the pyrrolo-N could be synthesized starting from thiolactam 9. The
carbazate 10 formed with ethyl hydrazinecarboxylate could be used
for the HurdeMori cyclization without purification of this
The general reaction conditions involved dropwise addition of
the precursors II to 7 equiv of SOCl2 in CH2Cl2 at low temperature

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M. Turner et al. / Tetrahedron 66 (2010) 5472e5478
intermediate. In the presence of an electron withdrawing group,
significantly more amount of the desired material (53%) was obtained
compared to the preparation of 7. The use of Boc proved to be pref-
erable to MeCO2 protection because of its more facile introduction
(catalyzed by DMAP/Et3N) prior to the key step of the reaction se-
quence and the milder conditions sufficient for its removal.
(40 h with DDQ in refluxing dioxane, making use of a known pro-
cedure20), indicating that compound 16 is very stable and therefore
not converted further under HurdeMori conditions.
Scheme 4. Reagents and conditions: (i) EtCO2NHNH2, CH2Cl2, reflux, 72 h; (ii) SOCl2,
CH2Cl2, ꢀ10 to ꢀ5 ꢁC, dropwise addition 1 h; to rt, overnight; (iii) CF3CO2H, CH2Cl2,
reflux, 5 h.
As already reported,18 lactams needed to be converted into the
corresponding thio compounds (with Lawesson’s reagent) to allow
for efficient reaction with ethyl hydrazine. This step was not re-
quired for keto-substrate 13 (in place of the amides corresponding
to 1, 5, and 9), obtained from the related alcohol via Collins oxi-
dation, as starting material (Scheme 5). As in the sequences before,
conversion with tosylhydrazide was immediately followed by
treatment with SOCl2 to effect thiadiazole formation. Since
HurdeMori cyclization of precursor 13 can occur at both sides of
Figure 2. Related structures for shift comparison. 1H NMR shifts (ppm) are indicated.
Incidentally, 16 is a 1,2,3-thiadiazole-fused (and therefore very
rigid) proline derivative with its acid and amine functionalities
protected, and scaffolds of this sort have received much attention in
peptide and therapeutic research,21 as well as in organocatalysis.22
Its structure could be determined by comparison of the chemical
shifts of the diastereotopic (het-)aryl-adjacent methylene group as
well as the methine protons to data from analogous materials: 16
displayed congruent 1H NMR characteristics with 21a, which was
formed unambiguously in a different HurdeMori cyclization (de-
scribed below), as well as tocompounds such as 20.23 In contrast,15a
would display proton shifts similar to 23 from one of our previous
studies,17 as well as 22.24 The clear shift difference of approximately
1 ppm strongly supports our structure assignment (Scheme 5).
As mentioned before, the protecting group has to be chosen
carefully. Removing the MeCO2 from the pyrrolo-N gave an un-
satisfactory yield of 42%, calling for an alternative. Therefore, the
whole synthesis was attempted employing the Boc group for N-
protection instead, but using otherwise identical reaction condi-
tions. In this case we could identify only small amounts of N-Boc-
deprotected products corresponding to 17 and 15b (3% and 5%,
respectively), along with traces of the expected HurdeMori product
in analogy to 16. Additionally, major amounts of unidentified de-
composition products were formed. This suggests that the pro-
tecting group is cleaved prior to the cyclization. Obviously, the
deprotected substrate does not undergo the HurdeMori reaction
efficiently but is prone to decomposition under the applied reaction
conditions.
the sp2-carbon after hydrazone formation,
a
mixture of
regioisomers had to be expected. Surprisingly, this cyclization gave
only products 16 and 17 with sulfur incorporation at the distal site
relative to the pyrrolidine nitrogen. However, in contrast to pre-
vious examples only a very small amount (3%) of the fully aroma-
tized product 17 was obtained. Instead, the HurdeMori reaction
gave compound 16 (61%, 20:1 ratio of 16 and 17), predominantly.
When compared to the other pyrrolo[d][1,2,3]thiadiazole carbox-
ylates, it is evident that aromatization to 17 requires oxidation of
two non-adjacent ring carbon atoms. It is known that similar
structures such as benzo-fused pyrrole 19 (isoindole) are ortho-
quinoid, but non-aromatic systems (Fig. 2).19 Hence, it appears that
the aromaticity of the 1,2,3-thiadiazole ring in 16 has to be dis-
rupted as well in order to be transformed to 17. Conversely, there is
less gain in aromatization energy as the formation of 17 occurs,
unlike in the case of 3, 7, and 11. This also becomes apparent as the
oxidation of 16, although proceeding with 92% yield, is very slow
At this point, the results obtained from the pyrrolo series can be
compared to analogous compounds that lack the ring nitrogen.
Structure 28 is a known compound prepared from the tosylhy-
drazone of cyclopentanone under HurdeMori conditions (neat
SOCl2, rt, 22%).25 Repetition of this synthesis using milder condi-
tions (SOCl2, CH2Cl2, ꢀ10 ꢁC, 28%) was comparable with our find-
ings in the case of 7. Placing an electron withdrawing group
(methoxycarbonyl on 24 or cyano on 26) at the carbon which is 1,3-
related to the carbonyl group has the same effect of increasing the
efficiency of the transformation (25: 46% and 27: 45%; Scheme 6).
Moreover, this comparison gives some more insight into the effects
governing the regiochemistry of the ring formation: no isomeric
products 29 were found. Consequently, ring closure is strongly di-
rected away from the substituent. However, this behavior can be
completely reversed by introducing the carbamate group into the
starting material, as indicated by the exclusive formation of 16,
starting from 14. Aromatization of the newly formed ring cannot
occur in bicyclic systems such as 25, 27, and 28, and only the
HurdeMori reaction itself takes place.
Scheme 5. Reagents and conditions: (i) TsNHNH2, EtOH, rt, 16 h; (ii) SOCl2, CH2Cl2,
ꢀ20 ꢁC, dropwise addition; then ꢀ16 ꢁC, 4 h and rt, 5 h; (iii) DDQ, 1,4-dioxane, reflux,
40 h; (iv) aq HCl, reflux, 8 d; then acid removal (CHCl3 azeotrope); then HCl/satd
MeOH, 25 ꢁC, 5 h and reflux, 2 h. 1H NMR shifts (ppm) are indicated.

M. Turner et al. / Tetrahedron 66 (2010) 5472e5478
5475
3. Conclusions
The results obtained within this study underline the importance
of systematic exploration of the HurdeMori reaction for the for-
mation of bicyclic 1,2,3-thiadiazoles, because they show how sev-
eral interrelated constitutional elements of the pre-existing ring
determine the reaction product in a way that could not have been
predicted a priori. From the various examples presented, it can be
concluded that an electron withdrawing (methyl ester or cyano)
group on the existing ring strongly increases the conversion effi-
ciency to the fused thiadiazole product. This effect is observed even
when the substituent is in a remote position relative to the reactive
centers. While promoting product formation, such an exocyclic
group directs ring closure away from itself, as does an acylated ring
nitrogen. The latter was found to dictate the regioselectivity com-
pletely when the two moieties adopt competitive positions. We can
infer from these results that the operative process leading to ring
closure is very susceptible to steric demand, even to the point
where a methoxycarbonyl group at nitrogendpositioned in the
plane of the ring due to conjugationddominates in steric repulsion
over an angular methoxycarbonyl group at a tetrahedral carbon
atom, allowing attack of the sulfur moiety from the opposite side.
We would like to emphasize that the current mechanistic ra-
tionale is still a hypothesis and requires additional refinement.
However, the present contributions to obtaining a better un-
derstanding of the concept provide a good basis for predictions for
the chemical behavior of novel reaction precursors.
Scheme 6. Reagents and conditions: (i) TsNHNH2, EtOH, rt, overnight; then solvent
removal and SOCl2, CH2Cl2, ꢀ10 ꢁC, dropwise addition; to rt, 4 h; (ii) TsNHNH2, CH2Cl2, rt,
overnight; then solvent removal and SOCl2, CH2Cl2, ꢀ10 ꢁC, dropwise addition; to rt, 5 h.
It was therefore intriguing to study the course of the cyclization
if the carbonyl group and the carbon atom bearing the methoxy-
carbonyl substituent are 1,2-related as in 30, i.e., whether a stabi-
lized enol would result in CeS bond-formation into the position of
the carbon bearing the most acidic proton. However, ring closure
proceeded neatly into the opposite direction (31, 56%), again with
complete regioselectivity (Scheme 7). Notably, this is not only the
kinetically favored isomer, but the angular ester group would also
prevent aromatization in the thiadiazole ring. Consequently, it was
not surprising that this transformation was hampered when the
cyclization was forced in this manner to proceed toward a sterically
demanding Boc-protected ring-nitrogen, as exemplified by the
unfavorable conversion of 32 into 33 (yielding 27%). In accordance
with the mechanism depicted in Scheme 2, no fully aromatized
system was obtained, because this would require the elimination of
a proton in 33 from the position where actually the NBoc group is in
place.
While the overall yields are moderate, it should be pointed out
that this facile route accomplishes to produce these five-membered
and strained bicyclic systems from commercially available or
readily prepared starting materials. In particular, when a one-pot
protocol is used, the synthesis is short and exclusive regioselectivity
is observed, even when the governing forces of this selectivity are
opposed to each other.
4. Experimental
4.1. General
Scheme 7. Reagents and conditions: (i) TsNHNH2, EtOH, rt, 16 h; then solvent removal
and SOCl2, CH2Cl2, ꢀ10 ꢁC, dropwise addition; then 0 ꢁC, 64 h; (ii) TsNHNH2, EtOH, rt,
16 h; then solvent removal and SOCl2, CH2Cl2, ꢀ20 ꢁC, dropwise addition; then ꢀ16 ꢁC,
4 h and rt, 5 h; (iii) CF3CO2H, CH2Cl2, reflux 5 h.
Solvents were dried and distilled prior to use. Flash column
chromatography was performed on silica gel 60 (40e63 mm),
obtained from Merck. Melting points were determined using
a Kofler type Leica Galen III micro hot stage microscope and are
uncorrected. NMR spectra were recorded on a Bruker AC 200
spectrometer and chemical shifts are reported in parts per million,
using TMS as internal standard. Combustion analysis was carried
out at the Microanalytic Laboratory, University of Vienna.
Finally, we aimed for the synthesis of compound 21 from the
appropriate precursors 36. Hydrazone formation to 37 proceeded
smoothly, but attempts to convert these intermediates into the
corresponding thiadiazoles under conditions successful in the
case of 16 and 33 produced only traces (1%) of the expected
products of type 21 with either protecting group, accompanied by
elementary sulfur precipitating from the reaction mixture and
a small amount of oxidation product 38 (3%, Scheme 8). We be-
lieve that the direction of the enamine formation is preferred
toward the ester group because the so formed double bond is in
conjugation with the carbonyl C]O and cyclization to a thiadia-
zole product cannot take place. However, the isolation of 21a
helped to establish the structure of 16 as the regiochemistry of
21a is unambiguous.
4.2. Compounds
4.2.1. 1-tert-Butyl 3-methyl 5-thioxopyrrolidine-1,3-dicarboxylate 1.
Methyl 5-thioxopyrrolidine-3-carboxylate (2.13 g, 13.4 mmol,
1.00 equiv), DMAP (1.63 g, 13.4 mmol, 1.00 equiv), and Et3N
(1.35 g, 13.4 mmol, 1.00 equiv) were combined with anhydrous
CH2Cl2 (100 mL) and Boc2O (2.92 g, 13.4 mmol, 1.00 equiv) in
CH2Cl2 (50 mL) was added dropwise at ꢀ70 to ꢀ60 ꢁC. The solu-
tion was stirred for 48 h, thereby warming it slowly to rt; then the
solvent and Et3N were removed in vacuo and the residue was
redissolved in CH2Cl2. Silica gel (5 g) was added and the crude
product was adsorbed by solvent evaporation. Purification via
flash column chromatography (petrol ether/EtOAc, 5:1) afforded 1
(2.56 g, 9.87 mmol, 74%); mp 121e124 ꢁC. 1H NMR (200 MHz,
CDCl3):
6.9 Hz, 2H). 13C NMR (50.3 MHz, CDCl3):
(t), 52.5 (q), 55.0 (t), 84.4 (s), 149.8 (s), 165.1 (s), 172.0 (s), 203.9 (s).
d
1.56 (s, 9H), 3.18e3.38 (m, 3H), 3.76 (s, 3H), 4.28 (d, J
d
27.9 (q), 37.4 (d), 50.8
Scheme 8. Reagents and conditions: (i) TsNHNH2, EtOH, rt, 16 h; (ii) SOCl2, CH2Cl2,
ꢀ20 ꢁC, dropwise addition; then ꢀ16 ꢁC, 4 h and rt, 5 h.

5476
M. Turner et al. / Tetrahedron 66 (2010) 5472e5478
Anal. Calcd for C11H17NO4S: C, 50.95; H, 6.61; N, 5.40. Found: C,
51.19; H, 6.67; N, 5.35.
(50.3 MHz, CDCl3): d 14.3 (q), 19.2 (t), 26.7 (t), 48.1 (t), 53.0 (q), 61.5
(t), 152.2 (s), 154.6 (s); C2 gives no signal.
4.2.2. 1-tert-Butyl 3-methyl 5-[2-(ethoxycarbonyl)hydrazono]pyrro-
4.2.7. Methyl 4H-pyrrolo[2,3-d][1,2,3]thiadiazole-4-carboxylate 7.
Compound 6 (10.00 g, 54.0 mmol, 1.00 equiv), dissolved in anhy-
drous CH2Cl2 (50 mL), was added dropwise over 1 h to a solution of
SOCl2 (29.6 mL, 378 mmol, 7.00 equiv) in CH2Cl2 (150 mL) at ꢀ10 to
ꢀ5 ꢁC and allowed to warm to rt while stirring overnight. The
mixture was concentrated in vacuo, redissolved in CH2Cl2, washed
with satd aq NaHCO3 and H2O, dried with Na2SO4, filtered, and the
solvent removed. Purification via flash column chromatography
and recrystallization from DIPE afforded 7 (2.90 g, 15.8 mmol, 29%);
lidine-1,3-dicarboxylate 2. Compound
1
(1.70 g, 6.55 mmol,
1.00 equiv) and ethyl hydrazinecarboxylate (0.68 g, 6.55 mmol,
1.00 equiv) were combined with anhydrous CH2Cl2 (25 mL) and
refluxed for 21 h. Concentration in vacuo gave a viscous oil, to
which sufficient EtOAc was added at elevated temperature to
achieve complete dissolution. Storage at ꢀ35 ꢁC for 48 h and fil-
tration of the precipitate afforded 2 (2.11 g, 6.40 mmol, 98%); mp
123e125 ꢁC. 1H NMR (200 MHz, CDCl3):
d 1.31 (t, J 7.1 Hz, 3H), 1.54
(s, 9H), 2.97e3.27 (m, 3H), 3.74 (s, 3H), 3.89 (dd, J 10.6 Hz, 6.9 Hz,
mp 108e111 ꢁC. 1H NMR (200 MHz, CDCl3):
d 4.19 (s, 3H), 6.71 (d, J
1H), 3.98 (dd, J 10.6 Hz, 8.0 Hz, 1H), 4.22 (q, J 7.0 Hz, 2H). 13C NMR
3.7 Hz, 1H), 7.83 (d, J 3.7 Hz, 1H). 13C NMR (50.3 MHz, CDCl3):
d 54.9
(50.3 MHz, CDCl3):
d
14.4 (q), 28.0 (q), 29.9 (t), 36.9 (d), 49.8 (t),
(q), 102.7 (d), 130.6 (d), 136.2 (s), 149.1 (s), 158.4 (s).
52.4 (q), 61.6 (t), 82.2 (s), 145.0 (s), 156.0 (s), 172.0 (s); C5 gives no
signal.
4.2.8. 4H-Pyrrolo[2,3-d][1,2,3]thiadiazole 8. Compound 7 (0.50 g,
2.70 mmol, 1.00 equiv) was added to anhydrous MeOH (10 mL),
combined with excess KOH (7.5 g) dissolved in MeOH, and the so-
lution refluxed for 16 h. It was neutralized with CF3CO2H (15.3 g),
concentrated, and dried in vacuo, then repeatedly heated in DIPE
and filtered to extract the crude product from the inorganic residue.
The filtrated fractions were combined and the solvent was evapo-
rated to afford 8 (0.27 g, 2.16 mmol, 79%) by recrystallization from
4.2.3. 4-tert-Butyl 6-methyl 4H-pyrrolo[2,3-d][1,2,3]thiadiazole-4,6-
dicarboxylate 3. Compound 2 (0.35 g, 1.06 mmol, 1.00 equiv) dis-
solved in anhydrous CH2Cl2 was added dropwise over 1 h to a so-
lution of SOCl2 (0.58 mL, 7.4 mmol, 7.00 equiv) in CH2Cl2 at ꢀ10 to
ꢀ5 ꢁC and allowed to warm to rt while stirring overnight. The
mixture was concentrated in vacuo and redissolved in CH2Cl2. Then
Et3N was added, concentration and redissolution were repeated
and the solution was washed with H2O, dried with Na2SO4, filtered,
and the solvent removed; recrystallization from EtOAc afforded 3
(0.246 g, 0.87 mmol, 82%); mp (decomp.) 120e123 ꢁC. 1H NMR
EtOAc; mp 87e88 ꢁC. 1H NMR (200 MHz, DMSO-d6):
3.0 Hz, 1H), 7.68 (d, J 3.0 Hz, 1H), 8.63 (br s, 1H). 13C NMR (50.3 MHz,
DMSO-d6): 98.6 (d), 130.8 (s), 131.8 (d), 161.6 (s).
d 6.59 (d, J
d
(200 MHz, CDCl3):
(50.3 MHz, CDCl3):
d
1.74 (s, 9H), 3.94 (s, 3H), 8.33 (s, 1H). 13C NMR
27.9 (q), 52.3 (q), 87.3 (s), 110.0 (s), 133.9 (s)
4.2.9. 1-tert-Butyl 2-methyl 5-thioxopyrrolidine-1,2-dicarboxylate
9. Methyl 5-thioxopyrrolidine-2-carboxylate (4.41 g, 27.7 mmol,
1.00 equiv), DMAP (3.37 g, 27.7 mmol, 1.00 equiv), and Et3N (2.80 g,
27.7 mmol, 1.00 equiv) were combined with anhydrous CH2Cl2
(200 mL); Boc2O (6.04 g, 27.7 mmol, 1.00 equiv) in CH2Cl2 (80 mL)
was added dropwise at ꢀ70 to ꢀ60 ꢁC. The solution was stirred for
48 h, thereby warming it slowly to rt; then the solvent and Et3N
were removed in vacuo and the residue redissolved in CH2Cl2. Silica
gel (10 g) was added and the crude product then adsorbed by sol-
vent evaporation. Purification via flash column chromatography
afforded 9 (5.61 g, 21.63 mmol, 78%); mp 114e116 ꢁC. 1H NMR
d
and (d) isochronous, 146.3 (s), 158.4 (s), 162.2 (s). Anal. Calcd for
C11H13N3O4S: C, 46.64; H, 4.62; N, 14.83. Found: C, 46.83; H, 4.45; N,
14.89.
4.2.4. Methyl 4H-pyrrolo[2,3-d][1,2,3]thiadiazole-6-carboxylate 4.
Compound 3 (0.20 g, 0.71 mmol, 1.00 equiv) and CF3CO2H (0.02 g,
25 mol%) were dissolved in anhydrous CH2Cl2 (15 mL) and refluxed
for 5 h. Concentration in vacuo and recrystallization from EtOAc
afforded 4 (0.125 g, 0.69 mmol, 98%); mp 218e220 (change in
crystal morphology at 195 ꢁC). All characterization data in accor-
dance with Ref. 18.
(200 MHz, CDCl3):
2H), 3.81 (s, 3H), 4.95 (dd, J 9.5 Hz, 2.9 Hz, 1H). 13C NMR (50.3 MHz,
CDCl3): 24.0 (t), 27.6 (q), 46.8 (t), 52.4 (s), 65.6 (d), 84.4 (s), 149.3
d 1.51 (s, 9H), 2.02e2.54 (m, 2H), 3.03e3.18 (m,
d
4.2.5. Methyl 2-thioxopyrrolidine-1-carboxylate 5. Pyrrolidine-2-
thione (10.0 g, 98.8 mmol, 1.00 equiv), DMAP (12.1 g, 98.8 mmol,
1.00 equiv), and Et3N (10.0 g, 98.8 mmol, 1.00 equiv) were com-
bined with anhydrous CH2Cl2 (200 mL) and methyl chloroformate
(18.7 g, 197 mmol, 2.00 equiv) in CH2Cl2 was added dropwise at
ꢀ70 to ꢀ60 ꢁC. The solution was stirred for 12 h and thereby it
warmed slowly to rt; then the solvent, Et3N, and residual methyl
chloroformate were evaporated in vacuo, DMAP and Et3NHCl were
removed via flash column chromatography (petrol ether/EtOAc,
1:1) and the crude product recrystallized from EtOAc to afford 5
(15.3 g, 96.1 mmol, 97%); mp 40e42 ꢁC. 1H NMR (200 MHz, CDCl3):
(s), 170.8 (s), 206.7 (s). Anal. Calcd for C11H17NO4S: C, 50.95; H, 6.61;
N, 5.40. Found: C, 51.19; H, 6.55; N, 5.35.
4.2.10. 4-tert-Butyl 5-methyl 4H-pyrrolo[2,3-d][1,2,3]thiadiazole-
4,5-dicarboxylate 11. Compound 9 (0.61 g, 2.35 mmol, 1.00 equiv),
ethyl hydrazinecarboxylate (0.24 g, 2.35 mmol, 1.00 equiv), and
anhydrous CH2Cl2 were combined and refluxed for 72 h (until H2S
ceased to evolve). The mixture was concentrated to dryness,
redissolved in anhydrous CH2Cl2 and then added dropwise over 1 h
to a solution of SOCl2 (1.29 mL, 16.5 mmol, 7.00 equiv) in CH2Cl2 at
ꢀ10 to ꢀ5 ꢁC and allowed to warm to rt while stirring overnight.
The mixture was concentrated in vacuo and redissolved in CH2Cl2.
Then Et3N was added, concentration, and redissolution were re-
peated and the solution was washed with H2O, dried with Na2SO4,
filtered, and the solvent removed; purification via flash column
chromatography afforded 11 (0.351 g, 1.24 mmol, 53%); mp
d
2.02 (quin, J 7.5 Hz, 2H), 3.00 (t, J 7.8 Hz, 2H), 3.80 (s, 3H), 4.05 (t, J
7.2 Hz, 2H). 13C NMR (50.3 MHz, CDCl3):
53.2 (t), 151.7 (s), 207.6 (s).
d 19.8 (t), 48.3 (t), 53.1 (q),
4.2.6. Methyl
2-[2-(ethoxycarbonyl)hydrazono]pyrrolidine-1-car-
boxylate 6. Compound 5 (15.0 g, 94.2 mmol, 1.00 equiv) and ethyl
hydrazinecarboxylate (9.8 g, 94.2 mmol, 1.00 equiv) were com-
bined with anhydrous CH2Cl2 (80 mL) and stirred for 72 h at rt.
Concentration in vacuo, redissolution in CHCl3, storage at ꢀ35 ꢁC
for 48 h, and filtration of the precipitate afforded 6 (16.5 g,
(decomp.) 105e108 ꢁC. 1H NMR (200 MHz, CDCl3):
d
1.58 (s, 9H),
27.3 (q), 52.5
3.85 (s, 3H), 7.02 (s, 1H). 13C NMR (50.3 MHz, CDCl3):
d
(q), 86.3 (s), 106.9 (d), 132.2 (s), 133.9 (s), 146.0 (s), 160.2 (s) and (d)
isochronous. Anal. Calcd for C11H13N3O4S: C, 46.64; H, 4.62; N,
14.83. Found: C, 46.55; H, 4.45; N, 14.77.
89.1 mmol, 95%); mp 82e84 ꢁC. 1H NMR (200 MHz, CDCl3):
d 1.31 (t,
J 7.1 Hz, 3H), 2.00 (quin, J 7.5 Hz, 2H), 2.73 (t, J 7.8 Hz, 2H), 2.84 (br s,
4.2.11. Methyl 4H-pyrrolo[2,3-d][1,2,3]thiadiazole-5-carboxylate 12.
Compound 11 (0.20 g, 0.71 mmol, 1.00 equiv) and CF3CO2H (0.02 g,
1H), 3.78 (t, J 7.2 Hz, 2H), 3.82 (s, 3H), 4.22 (q, J 7.1 Hz, 2H). 13C NMR

M. Turner et al. / Tetrahedron 66 (2010) 5472e5478
5477
25 mol %) were dissolved in anhydrous CH2Cl2 (10 mL) and refluxed
for 5 h. Concentration in vacuo and recrystallization from EtOAc
afforded 12 (0.112 g, 6.88 mmol, 97%); mp 186e188 ꢁC (sublimes at
distillation afforded 25 (0.827 g, 4.49 mmol, 46%); bp 125e130 ꢁC/
0.01 mbar. 1H NMR (200 MHz, CDCl3):
3.36e3.54 (m, 4H), 3.78 (s,
3H), 3.93e4.15 (m, 1H). 13C NMR (50.3 MHz, CDCl3):
28.1 (t), 28.7 (t),
48.0 (d), 51.9 (q), 152.9 (s), 169.1 (s), 173.2 (s). Anal. Calcd for
C7H8N2O2S: C, 45.64; H, 4.38; N,15.21. Found:C, 45.74; H, 4.33; N,15.07.
d
d
150e160 ꢁC). 1H NMR (200 MHz, DMSO-d6):
d
3.91 (s, 3H), 7.22 (d, J
1.9 Hz, 1H; becomes singlet on DeH exchange), 7.60 (br s, 1H). 13C
NMR (50.3 MHz, DMSO-d6): 52.3 (q), 103.8 (d), 123.0 (s), 132.5 (s),
d
161.1 (s), 161.6 (s). Anal. Calcd for C6H5N3O2S: C, 39.34; H, 2.75; N,
22.94. Found: C, 39.57; H, 2.70; N, 22.73.
4.2.16. 5,6-Dihydro-4H-cyclopenta[d][1,2,3]thiadiazole-5-carbo-
nitrile 27. Compound 26 (0.66 g, 6.00 mmol, 1.00 equiv), tosylhy-
drazide (1.13 g, 6.00 mmol,1.00 equiv), and anhydrous CH2Cl2 (30 mL)
were combined and stirred overnight at rt (a white precipitate could
be observed after 3 h). The mixture was concentrated to dryness,
redissolved in anhydrous CH2Cl2 (10 mL), then added dropwise to
a solution of SOCl2 (3.3 mL, 42 mmol, 7.00 equiv) in CH2Cl2 (10 mL) at
ꢀ10 ꢁC and allowed to warm to rt over 5 h. The mixture was concen-
trated in vacuo and redissolved in CH2Cl2. Then excess Et3N was added
and the solution repeatedly washed with brine, dried with Na2SO4,
and filtered. Silica gel (2 g) was added and the crude product adsorbed
by solvent evaporation. Purification via flash column chromatography
and Kugelrohr distillation afforded 27 (0.406 g, 2.69 mmol, 45%); bp
4.2.12. Dimethyl
4H-pyrrolo[3,4-d][1,2,3]thiadiazole-5,6(6H)-di-
carboxylate 16. Compound 13 (5.11 g, 25.4 mmol, 1.00 equiv), tosyl-
hydrazide (4.73 g, 25.4 mmol, 1.00 equiv), and anhydrous EtOH
(50 mL) were combined and stirred for 16 h at rt. The mixture was
concentrated to dryness, redissolved in anhydrous CH2Cl2 (50 mL)
and then added dropwise to a solution of SOCl2 (13.9 mL, 178 mmol,
7 equiv)inCH2Cl2 (300 mL) atꢀ20 ꢁC.Thenitwasstirredatꢀ16 ꢁCfor
4 h and subsequently at rt for 5 h. The mixture was concentrated in
vacuo, redissolvedinCH2Cl2, repeatedlywashedwithsatdaqNaHCO3,
dried with Na2SO4, filtered, and concentrated. Purification via flash
column chromatography with concomitant removal of byproduct 17
and recrystallization from EtOAc afforded 16 (3.77 g,15.5 mmol, 61%);
110e115 ꢁC/0.01 mbar. 1H NMR (200 MHz, CDCl3):
4H), 3.97e4.15 (m, 1H). 13C NMR (50.3 MHz, CDCl3):
d
3.33e3.75 (m,
d
29.9 (t), 30.7 (t),
mp 87e88 ꢁC. 1H NMR (200 MHz, CDCl3):
3.82 (s, 3H), 4.97e5.08 (m, 2H), 5.77 and 5.83 (2dd, J 3.0 Hz, J 3.2 Hz,
S1H). 13C NMR (50.3 MHz, CDCl3):
46.6 and 46.9 (2t), 53.3 and 53.5
d
3.80 and 3.86 (2s, S3H),
32.4 (d),120.3 (s),151.9 (s),168.1 (s). Anal. Calcd for C6H5N3S: C, 47.67;
H, 3.33; N, 27.79. Found: C, 47.89; H, 3.44; N, 27.85.
d
(2q), 60.8 and 60.9 (2d), 146.6 and 146.8 (2s), 154.2 and 154.9 (2s),
165.1 and165.4 (2s),167.3and167.5 (2s). Anal. CalcdforC8H9N3O4S:C,
39.50; H, 3.73; N, 17.27. Found: C, 39.80; H, 3.69; N, 17.29.
4.2.17. Methyl 5,6-dihydro-4H-cyclopenta[d][1,2,3]thiadiazole-4-
carboxylate 31. Compound 30 (6.90 g, 48.5 mmol, 1.00 equiv),
tosylhydrazide (9.03 g, 48.5 mmol, 1.00 equiv), and anhydrous EtOH
(100 mL) were combined and stirred for 16 h at rt. The mixture was
concentrated to dryness, suspended in anhydrous CH2Cl2 (100 mL),
then added dropwise to a solution of SOCl2 (26.7 mL, 340 mmol,
7.00 equiv) in CH2Cl2 (150 mL) at ꢀ10 ꢁC and stirred at 0 ꢁC for 64 h.
The mixture was concentrated in vacuo and redissolved in CH2Cl2.
Then, excess Et3N wasaddedandthesolutionwasrepeatedlywashed
with H2O, dried with Na2SO4, filtered, and the solvent removed. Pu-
rification via flash column chromatographyand Kugelrohrdistillation
afforded 31 (5.04 g, 27.4 mmol, 56%); bp 125e130 ꢁC/0.01 mbar. 1H
4.2.13. Dimethyl 5H-pyrrolo[3,4-d][1,2,3]thiadiazole-5,6-dicarbox-
ylate 17.20 Compound 16 (2.03 g, 8.35 mmol, 1.00 equiv) and DDQ
(1.89 g, 8.35 mmol, 1.00 equiv) were combined with 1,4-dioxane
(25 mL) and refluxed for 40 h. The solvent was removed in vacuo and
the residue redissolved in CH2Cl2; silica gel (3 g) was added to adsorb
the crude product by solvent evaporation. Purification via flash col-
umn chromatography afforded 17 (1.85 g, 7.67 mmol, 92%); mp
116e118 ꢁC.1H NMR (200 MHz, CDCl3):
(s,1H).13C NMR (50.3 MHz, CDCl3):
52.3 (q), 55.4 (q),110.1 (d),128.0
d 3.96 (s, 3H), 4.11 (s, 3H), 7.58
d
NMR (200 MHz, CDCl3):
d
2.97e3.32 (m, 4H), 3.76 (s, 3H), 4.27e4.39
24.5 (t), 34.8 (t), 42.2 (d), 51.9
(s), 129.3 (s), 133.2 (s), 155.2 (s), 159.3 (s). Anal. Calcd for C8H7N3O4S:
C, 39.83; H, 2.92; N, 17.42. Found: C, 39.89; H, 3.00; N, 17.39.
(m, 1H). 13C NMR (50.3 MHz, CDCl3):
d
(q),156.9(s),168.1(s),171.6(s). Anal.CalcdforC7H8N2O2S:C, 45.64;H,
4.38; N, 15.21. Found: C, 45.94; H, 4.28; N, 15.35.
4.2.14. Methyl
5H-pyrrolo[3,4-d][1,2,3]thiadiazole-6-carboxylate
18. Compound 17 (0.50 g, 2.07 mmol, 1.00 equiv) was suspended in
aq HCl (37.5 g, 8 mol Lꢀ1) and refluxed for 8 days. The mixture was
concentrated in vacuo and residual H2O removed by repeated
azeotropic distillation with CHCl3. The crystalline intermediate was
dissolved in HCl/satd anhydrous MeOH (10 mL) at 25 ꢁC and stirred
for 5 h, then more HCl/satd MeOH (5 mL) was added and the so-
lution refluxed for 2 h. Solvent evaporation and recrystallization
from EtOAc afforded 18 (0.158 g, 0.86 mmol, 42%); mp (decomp.)
4.2.18. 4-tert-Butyl 6-methyl 4H-pyrrolo[3,2-d][1,2,3]thiadiazole-
4,6-dicarboxylate 33. Compound 32 (6.75 g, 27.9 mmol, 1.00 equiv),
tosylhydrazide (5.12 g, 27.9 mmol, 1.00 equiv), and anhydrous EtOH
(100 mL) were combined and stirred for 16 h at rt. The mixture was
concentrated to dryness, suspendedinanhydrousCH2Cl2 (70 mL) and
then added dropwise to a solution of SOCl2 (15.3 mL, 195 mmol,
7.00 equiv) in CH2Cl2 (150 mL) at ꢀ20 ꢁC. Then, it was stirred at
ꢀ16 ꢁC for 4 h and subsequently at rt for 5 h. The mixture was con-
centrated in vacuo, redissolved in CH2Cl2, repeatedly washed with
satdaqNaHCO3, dried with Na2SO4, filtered, and thesolventremoved.
Purification via flash column chromatography and recrystallization
from EtOAc afforded 33 (2.15 g, 7.54 mmol, 27%); mp 129e131 ꢁC. 1H
197e201 ꢁC. 1H NMR (200 MHz, DMSO-d6):
1H), 8.37 (d, J 3.7 Hz, 1H; becomes singlet on DeH exchange). 13C
NMR (50.3 MHz, DMSO-d6): 51.9 (q), 108.3 (s), 115.1 (d), 129.8 (s),
d 3.86 (s, 3H), 7.38 (br s,
d
159.4 (s), 159.6 (s). Anal. Calcd for C6H5N3O2S: C, 39.34; H, 2.75; N,
22.94. Found: C, 39.60; H, 2.79; N, 22.71.
NMR (200 MHz, CDCl3):
NMR (50.3 MHz, CDCl3):
d
1.72 (s, 9H), 4.01 (s, 3H), 8.21 (s, 1H). 13
27.6 (q), 52.1 (q), 87.9 (s),110.6 (s),133.2 (d),
C
d
4.2.15. Methyl
5,6-dihydro-4H-cyclopenta[d][1,2,3]thiadiazole-5-
141.2 (s), 146.3 (s), 155.7 (s), 161.9 (s). Anal. Calcd for C11H15N3O4S: C,
46.64; H, 4.63; N, 14.83. Found: C, 46.91; H, 4.51; N, 14.80.
carboxylate 25. Compound 24 (1.40 g, 9.85 mmol, 1.00 equiv), tosyl-
hydrazide (1.83 g, 9.85 mmol, 1.00 equiv), and anhydrous EtOH
(50 mL) were combined and stirred overnight at rt. The mixture was
concentrated to dryness, suspended in anhydrous CH2Cl2 (50 mL),
then added dropwise to a solution of SOCl2 (5.4 mL, 69 mmol,
7.00 equiv) in CH2Cl2 (150 mL) at ꢀ10 ꢁC and allowed to warm to rt
over 4 h. The mixture was concentrated in vacuo and redissolved in
CH2Cl2. Then excess Et3N was added and the solution repeatedly
washed with brine, dried with Na2SO4, filtered, and the solvent re-
moved. Purification via flash column chromatography and Kugelrohr
4.2.19. Methyl
4H-pyrrolo[3,2-d][1,2,3]thiadiazole-6-carboxylate
34. Compound 33 (0.70 g, 2.47 mmol, 1.00 equiv) and CF3CO2H
(0.07 g, 25 mol %) were dissolved in anhydrous CH2Cl2 (20 mL) and
refluxed for 5 h. Concentration in vacuo and recrystallization from
EtOAc afforded 34 (0.435 g, 2.37 mmol, 96%); mp (decomp.)
195e205 ꢁC. 1H NMR (200 MHz, CDCl3/DMSO-d6, 3:20):
d
3.85 (s,
3H), 8.10 (s, 1H), 8.91 (br s, 1H). 13C NMR (50.3 MHz, CDCl3/DMSO-
d6, 3:20): 51.3 (q), 105.0 (s), 136.4 (d), 141.8 (s), 156.0 (s), 162.5 (s).
d

5478
M. Turner et al. / Tetrahedron 66 (2010) 5472e5478
7. Pechmann, H.; Nold, A. Chem. Ber. 1986, 28, 2588; Martin, D.; Mucke, W. Liebigs
Ann. Chem. 1965, 6823, 90.
8. Wolff, L. Liebigs Ann. Chem. 1902, 325, 129; Wolff, L. Liebigs Ann. Chem. 1904, 333,
Anal. Calcd for C6H5N3O2S: C, 39.34; H, 2.75; N, 22.94. Found: C,
39.58; H, 2.77; N, 22.69.
1.
9. Seminal publication: Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359; See
also: Demaree, P.; Doria, M. C.; Muchowsky, J. M. Can. J. Chem. 1977, 55, 243;
Bellesia, F.; Grandi, R.; Pagnoni, U.; Treve, R. Gazz. Chim. Ital. 1981, 11, 289;
Stanetty, P.; Turner, M.; Mihovilovic, M. D. In Targets in Heterocyclic Systems;
Attanasi, O. A., Spinelli, D., Eds.; Società Chimica Italiana: Rome, 1999; Vol. 3,
pp 265e299.
10. Liu, Z.; Mu, Y.; Lin, J.; Chen, Y. Synth. Commun. 2008, 38, 4407.
11. Fujita, M.; Nimura, K.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1995, 41,
2413.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.05.017. These data include
MOL file and InChiKeys of the most important compounds de-
scribed in this article.
12. Fujita, M.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1993, 36, 33.
13. L’abbé, G.; Vossen, P.; Dehaen, W.; Toppet, S. J. Chem. Soc., Perkin Trans. 1 1995,
2079.
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