Poorly reactive 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines rendered as valid substrates for Groebke-Blackburn type multi-component reaction with aldehydes and isocyanides using TMSCl as a promoter

Article abstract of DOI:10.1016/j.tetlet.2008.06.113

N-Substituted 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines that fail to undergo Groebke-Blackburn type MCR with aldehydes and isocyanides provide fair to good yields of the respective 2-piperazin-1-ylimidazo[2,1-b][1,3,4]thiadiazoles when such reaction is promoted by an equimolar quantity of trimethylsilyl chloride in aprotic medium. These findings further extend the utility of TMSCl as the isocyanide-based MCR promoter, and also demonstrate that this silicon Lewis acid is the actual promoter of the reaction.

Full text of DOI:10.1016/j.tetlet.2008.06.113

Tetrahedron Letters 49 (2008) 5241–5243
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Tetrahedron Letters
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Poorly reactive 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines rendered
as valid substrates for Groebke–Blackburn type multi-component reaction
with aldehydes and isocyanides using TMSCl as a promoter
a
a
c
Mikhail Krasavin a,b, , Sergey Tsirulnikov , Mikhail Nikulnikov , Volodymyr Kysil ,
*
Alexandre Ivachtchenko c
a Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg., 141400, Russia
b Department of Organic and Biological Chemistry, L. N. Tolstoy State Pedagogical University, 125 Lenin Av., Tula 300026, Russia
c ChemDiv, Inc., 6605 Nancy Ridge Dr., San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Substituted 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines that fail to undergo Groebke–Blackburn type
MCR with aldehydes and isocyanides provide fair to good yields of the respective 2-piperazin-1-ylimi-
dazo[2,1-b][1,3,4]thiadiazoles when such reaction is promoted by an equimolar quantity of trimethylsilyl
chloride in aprotic medium. These findings further extend the utility of TMSCl as the isocyanide-based
MCR promoter, and also demonstrate that this silicon Lewis acid is the actual promoter of the reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 3 June 2008
Revised 17 June 2008
Accepted 26 June 2008
Available online 1 July 2008
Keywords:
Isocyanide-based multi-component
reactions
Groebke–Blackburn type reactions
2-Aminoazoles
Trimethylchlorosilane
Lewis acid promoted MCR
A novel reactivity pattern of 2-aminoazines in multi-component
reactions (MCRs) with aldehydes and isocyanides leading to drug-
like fused imidazo[1,2-a]azines was first reported simultaneously
by the Groebke1 and Blackburn2 groups in 1998. Shortly after-
wards, the same strategy was broadened by Rhone-Poulenc
researchers3 to include 2-aminoazoles as substrates. These pio-
neering works have led to numerous publications on new types
of MCR.4 In these transformations, the aminoheterocycle compo-
nent plays a dual role by providing both the amino group and
the intercepting nucleophile (the ring nitrogen atom) for the
incoming isocyanide. Thus, the two components of the traditional
isocyanide-based Ugi MCR—the amine and the carboxylate compo-
nents—are replaced in the Groebke–Blackburn variant with a single
bifunctional reagent, leading to a ring-forming process (Scheme 1).
Among various 2-aminoazoles studied in these reactions to
date, only one example3 of a 1,3,4-thiadiazol-2-amine was shown
to provide the respective imidazo[2,1-b][1,3,4]thiadiazole in a
MCR with benzaldehyde and tert-butyl isocyanide (Scheme 2). In
our research aimed at utilizing known isocyanide-based MCRs for
creating larger compound libraries in a combinatorial fashion,5,6
R1
R3
N
H2N
3
1
N+
C
R2
R2
R
R
CHO
+
+
N
N
N
H
Scheme 1. Reaction of 2-aminoazines and -azoles with aldehydes and isonitriles
(Groebke–Blackburn reaction).
as well as for developing novel MCRs,7,8 we envisioned that readily
available N-substituted 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines
1 could serve as substrates for Groebke–Blackburn type MCRs.
These compounds have already been used9,10 as starting materials
for combinatorial development of various heterocyclic compound
libraries (Fig. 1). Their preparation, as described in the literature9
and modified by us, is outlined in Scheme 3.
Our initial attempts to run the Groebke–Blackburn reaction
with a representative starting material 1 (R = Bn), tert-butyl isocy-
anide and m-fluorobenzaldehyde proved to be somewhat discour-
aging. Simple mixing of the three components in methanol and
adding a methanolic solution of a mineral acid (catalytic to equi-
molar quantity of either HCl, HClO4 or H2SO4) resulted in complex
reaction mixtures with a target material content of less than 10%,
as estimated by LCMS analyses. This was in contrast with the
* Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780.
E-mail address: myk@chemdiv.com (M. Krasavin).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.113

5242
M. Krasavin et al. / Tetrahedron Letters 49 (2008) 5241–5243
HN
HClO4
N
N
O
N+
C
+
+
N
N
CF3CH2OH
rt, 18 h
NH2
S
N
S
76%
Scheme 2. An example3 of 1,3,4-thiadiazol-2-amine as a partner in a Groebke–Blackburn type reaction.
OR'
N
O
O
O
OR'
N
N
N
N
N
N
O
N
NH2
S
N
N
N
N
S
S
R
N
N
R
R
1
B
A
O
N
N
R'
N
N
S
N
R
C
Figure 1. N-Substituted 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines (1) and examples (A,8 B–C9) of compound libraries incorporating them as part of the core structure.
N
N
N N
N
N
N
N
a
c
b
N
NH2
N
NH2
N
NH2
Br
NH2
O
S
S
S
S
N
HN
N
R
O
1
Scheme 3. Preparation of various N-substituted 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines (1). Reagents and conditions: (a) N-Boc-piperazine (1.1 equiv), Et3N (1.2 equiv),
EtOH reflux, 3 h, 80%; (b) HCl/dioxane, rt, 1 h, quant. yield; (c) R = alkyl: RCHO/NaBH(OAc)3 or RHal/DMF, R = acyl: R0COCl/pyridine, R = carbamoyl: R0NCO/DCM.
unsubstituted 1,3,4-thiadiazol-2-amine example reported.3 We
therefore decided to attempt the desired Groebke–Blackburn reac-
tion using a Lewis acid as promoter instead. After screening a small
set of Lewis acids, we found that a catalytic (0.2 equiv.) or even
equimolar amount of metal triflates such as Yb(OTf)3 or Sc(OTf)3
(as initially used by Blackburn2) led to better yields of the target
material (25–30%, as judged by LCMS analyses of the reaction mix-
tures). However, isolation of the target was complicated by the
presence of several unidentified by-products. A similar degree of
conversion (ꢀ25%) was achieved when trimethylsilyl chloride
(TMSCl) was used as the promoter under the same reaction condi-
tions (1 equiv TMSCl, MeOH, rt, 18 h) as those recently employed
by us to promote the MCR of ethylenediamine with carbonyl com-
pounds and isocyanides.7 Despite the low conversion, the TMSCl-
promoted reaction offered a clear advantage over other methods
tested as it gave virtually no by-products. After some additional
experimentation that involved changing the reaction medium
(EtOH, AcOH, MeCN) as well as the order of mixing the reactants,
we arrived at an optimized reaction protocol that allowed prepara-
tion and easy purification of various 2-piperazin-1-ylimidazo-
[2,1-b][1,3,4]thiadiazoles 2 as summarized in Table 1.
twice). The residue was then suspended in anhydrous MeCN and
treated with a solution of an equimolar amount of TMSCl in anhy-
drous DCM. The mixture was stirred at ambient temperature for
30 min (in most cases the suspension cleared), and then treated
with a solution of isocyanide (1 equiv) in MeCN and heated at
70 °C overnight. At this stage, all of the reactions described herein
were complete by LCMS analyses (as judged by the disappearance
of 1). In a number of cases the products isolated by filtration were
at least 90% pure as judged from LCMS and 1H NMR data. In some
cases, chromatographic isolation of the products was required (sil-
ica gel, eluted by appropriate gradients of 0?10% methanol in
dichloromethane). All of the synthesized compounds were charac-
terized by 1H and 13C NMR, LCMS and elemental analyses.12
The use of aprotic solvents as the reaction medium is worthy of
note. In our previous work,7 TMSCl was used as a promoter for iso-
cyanide-based MCRs in methanol, and thus there was some room
for arguing that a low concentration of HCl resulting from reaction
of TMSCl with methanol could be the actual catalyst for the reac-
tion. This possibility was partly ruled out by using a HCl solution
in dioxane, which provided inferior results compared to those of
TMSCl. The present work, in our opinion, could be considered as
further proof of the silicon-based Lewis acid being the effective
reaction promoter, as presumably no HCl is generated in aprotic
anhydrous solvents.
The optimized protocol involved mixing equimolar amounts of
the starting amine 1 and an aldehyde in anhydrous MeCN and
heating the resulting solution at reflux for 2 h to ensure complete
formation of the respective imine intermediate.11 The reaction
mixture was then cooled to room temperature and evaporated to
dryness. The solid residue was further dried by addition of toluene
and concentration of the resulting suspension in vacuo (repeated
In conclusion, we have developed a robust synthetic protocol
for the Groebke–Blackburn MCR using TMSCl as a promoter. This
protocol allows the use of N-substituted 5-piperazin-1-yl-1,3,4-
thiadiazol-2-amines as substrates for this reaction, a process that

M. Krasavin et al. / Tetrahedron Letters 49 (2008) 5241–5243
5243
Table 1
TMSCl-promoted MCRs of N-substituted 5-piperazin-1-yl-1,3,4-thiadiazol-2-amines 1, aldehydes and isonitriles
R3
H
i. 1 eq. R2CHO, MeCN, reflux, 2 h
N
ii. TMSCl (1 eq.), MeCN/DCM, 30 min
N
N
S
iii. R3NC
N
N
R1
N
N
R1
N
R2
N
S
N
NH2
1
2
Entry
R1
R2
R3
Yield (%)
a
b
c
2-PyCH2
Allyl
3-MeOC6H4CH2
Bn
4-EtC6H4
4-MeC6H4
4-FC6H4
3-FC6H4
Cyclopentyl
cyclopentyl
tert-Butyl
78a
72a
84a
92a
d
tert-Butyl
O
e
Ph
tert-Butyl
56a
N
*
f
g
3-ClC6H4CH2
4-NCC6H4CH2
Ph
Ph
tert-Butyl
tert-Butyl
75a
88a
O
h
i
4-EtC6H4
tert-Butyl
67b
*
O
3-MeC6H4
tert-Butyl
48b
*
j
k
4-FC6H4CO
tert-BuNHCO
3-MeC6H4
4-EtC6H4
tert-Butyl
Cyclopentyl
78b
92b
O
O
l
4-FC6H4
Cyclopentyl
69b
N
H
*
a
Yield after chromatography.
Yield after product isolation by simple filtration (total yield may be higher).
b
9. (a) Herrling, S. German Patent DE 2755615, 1977; Chem. Abstr. 1977, 91,
91655.; (b) Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P. Farmaco Ed.
Sci. 1986, 41, 737–746.
10. Compound libraries B–C are part of the ChemDiv (www.chemdiv.com)
screening compound collection.
11. We have observed that the complete formation of the imine intermediate prior
to the addition of other reactants and the promoter is essential: it suppresses
by-product formation and also ensures an unambiguous regiochemical course
of the Groebke–Blackburn MCRs. Simple mixing of all the reaction components
and an acid catalyst in a polar solvent can lead (as was observed for various 2-
aminoazines by us5 and others4e) to concomitant formation of the undesired
regioisomer. For a thorough insight into possible regiochemical outcomes of
the Groebke–Blackburn reaction, see: Mandair, G. S.; Light, M.; Russell, A.;
Hursthouse, M.; Bradley, M. Tetrahedron Lett. 2002, 43, 4267–4269.
we found to be inefficient under the standard reaction conditions
reported in the literature. These findings further extend the appli-
cability of trimethylchlorosilane as an efficient equimolar pro-
moter of isocyanide-based MCRs and reagent, which often
appears to be the only workable metal-free Lewis acid alternative
to traditional Brønsted acid catalysts. We are currently in the pro-
cess of extending these findings to other 2-aminoazole substrates.
The results of these studies will be reported in due course.
References and notes
12. Representative characterization data for the synthesized compounds: Compound
2d—grey solid, mp = 186 °C (decomp.); 1H NMR (300 MHz, DMSO-d6) d 7.85–
7.97 (m, 2H), 7.23–7.39 (m, 6H), 6.90–6.70 (m, 1H), 4.20 (br s, 1H), 3.56 (s, 2H),
3.40–3.49 (m, 4H), 2.52–2.57 (m, 4H), 1.10 (s, 9H); 13C NMR (75 Hz, DMSO-d6)
d 161.9 (d, JC–F = 260.3 Hz), 161.2, 158.9, 138.5, 133.9 (two lines), 129.5 (d,
JC–F = 6.8 Hz), 128.8, 128.3, 127.4, 121.5 (two lines), 112.0 (d, JC–F = 29.0 Hz),
110.5 (d, JC–F = 28.5 Hz), 95.4, 61.8, 54.9, 51.4, 48.1, 30.1; LCMS (M+H) 465;
Anal. Calcd for C25H29FN6S: C, 64.63; H, 6.29; N, 18.09. Found: C, 64.70; H, 6.33;
N, 18.17. Compound 2j—off-white solid, mp = 172–176 °C; 1H NMR (300 MHz,
DMSO-d6) d 7.95 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.49–7.57 (m, 2H), 7.26–7.34
(m, 2H), 7.16–7.22 (m, 1H), 6.96 (d, J = 7.4 Hz, 1H), 4.17 (br s, 1H), 3.43–3.71 (br
m, 8H), 2.30 (s, 3H), 1.08 (s, 9H); 13C NMR (75 Hz, DMSO-d6) d 168.5, 163.1,
162.6 (d, JC–F = 245.1 Hz), 136.6, 136.2, 134.7, 131.9, 129.7 (d, JC–F = 8.6 Hz),
127.7, 126.7, 126.4, 122.9, 115.5 (d, JC–F = 21.7 Hz), 95.5, 54.8, 47.9, 30.2, 21.2;
LCMS (M+H) 493; Anal. Calcd for C26H29FN6OS: C, 63.39; H, 5.93; N, 17.06.
Found: C, 63.43; H, 6.00; N, 17.12. Compound 2l—grey solid, mp = 154–156 °C;
1H NMR (300 MHz, DMSO-d6) d 8.01–8.08 (m, 2H), 7.11–7.19 (m, 2H), 6.71 (br
t, J = 5.1 Hz, 1H), 4.42 (br d, J = 4.3 Hz, 1H), 3.77–3.85 (m, 1H), 3.32–3.50 (m,
10H), 3.24 (s, 3H), 3.15–3.23 (m, 2H), 1.42–1.73 (m, 8H); 13C NMR (75 Hz,
DMSO-d6) d 163.8, 160.4 (d, JC–F = 241.1 Hz), 157.2, 135.8, 131.8, 131.1, 128.5,
126.6 (d, JC–F = 7.4 Hz), 114.8 (d, JC–F = 21.1 Hz), 95.5, 71.3, 66.4, 57.9, 47.8, 42.5,
32.5, 23.4; LCMS (M+H) 488; Anal. Calcd for C23H30FN7O2S: C, 56.66; H, 6.20; N,
20.11. Found: C, 56.71; H, 6.25; N, 20.16.
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