Synthesis of enantiopure bis-heterocycles derived from (S)- prolinehydrazides

Article abstract of DOI:10.1080/10426507.2012.738737

A convenient synthesis of new enantiomerically pure bis-heterocycles containing a (S)-proline moiety starting from (S)-N-benzylprolinehydrazide (1) is described. The reactions of 1b with isothiocyanates in refluxing MeOH led to the thiosemicarbazide 3 with a N-benzylprolinoyl residue. Thiosemicarbazide 3 underwent cyclization reactions under basic (NaOH) and acidic (H2SO4) conditions to yield (S)-prolinyl-substituted 1,2,4-triazole-3-thione 4 and 1,3,4-thiadiazole-2-amine 5, respectively.

Full text of DOI:10.1080/10426507.2012.738737

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Enantiopure Bis-
Heterocycles Derived from (S)-
Prolinehydrazides
a
Adam M. Pieczonka a & Grzegorz Mlostoń
a Department of Organic and Applied Chemistry, University of Łódź ,
Łódź , Poland
Accepted author version posted online: 25 Oct 2012.Published
online: 29 May 2013.
To cite this article: Adam M. Pieczonka & Grzegorz Mlostoń (2013) Synthesis of Enantiopure Bis-
Heterocycles Derived from (S)-Prolinehydrazides, Phosphorus, Sulfur, and Silicon and the Related
Elements, 188:4, 493-495, DOI: 10.1080/10426507.2012.738737
To link to this article: http://dx.doi.org/10.1080/10426507.2012.738737
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Phosphorus, Sulfur, and Silicon, 188:493–495, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.738737
SYNTHESIS OF ENANTIOPURE BIS-HETEROCYCLES
DERIVED FROM (S)-PROLINEHYDRAZIDES
Adam M. Pieczonka and Grzegorz Mloston´
Department of Organic and Applied Chemistry, University of Ło´dz´, Ło´dz´, Poland
GRAPHICAL ABSTRACT
Abstract A convenient synthesis of new enantiomerically pure bis-heterocycles containing
a (S)-proline moiety starting from (S)-N-benzylprolinehydrazide (1) is described. The reac-
tions of 1b with isothiocyanates in refluxing MeOH led to the thiosemicarbazide 3 with a
N-benzylprolinoyl residue. Thiosemicarbazide 3 underwent cyclization reactions under basic
(NaOH) and acidic (H2SO4) conditions to yield (S)-prolinyl-substituted 1,2,4-triazole-3-thione
4 and 1,3,4-thiadiazole-2-amine 5, respectively.
Keywords Bis-heterocycles; enantiomerically pure; proline
INTRODUCTION
It is well documented that enantiopure (S)-proline and its derivatives belong to the
group of “privileged catalysts” widely applied in the field of asymmetric synthesis and
organocatalysis.1 The preparation of diverse compounds via functionalization of proline is
of current interest. On the other hand, carbohydrazides are important building blocks for the
preparation of N,O,S-heterocycles2 with diverse size, which are of potential importance for
practical applications as agrochemicals and pharmaceuticals.3 In our recent publications,
the preparation of prolinehydrazides 1 was described.4 The nonprotected prolinehydrazide
(1a), as well as N-benzylprolinehydrazide, (1b) was shown to react with aromatic aldehydes
and cycloaliphatic ketones at r.t. to give the corresponding hydrazones of type 2 in good
yields (Scheme 1). Therefore, for the present study aimed at the preparation of new bis-
heterocycles derived from (S)-proline, the N-benzylprolinehydrazide (1b) was selected as
the key substrate.
Received 30 September 2012; accepted 8 October 2012.
The presented results summarize our recent efforts in the synthesis of enantiomerically pure bis-heterocycles
containing (S)-proline moiety. Adam M. Pieczonka thanks for financial support within the project co-funded by
the European Union under the European Social Fund “HUMAN – BEST INVESTMENT!.”
Address correspondence to Adam M. Pieczonka, Department of Organic and Applied Chemistry, University
of Ło´dz´, Tamka 12, PL-91-403 Ło´dz´, Poland. E-mail: adam.pieczonka@gmail.com
493

´
494
A. M. PIECZONKA AND G. MLOSTON
Scheme 1 Synthesis of (S)-prolinehydrazide hydrazones 2: a) MeOH, r.t., 16 h.
RESULTS
Our project was aimed at the development of simple and efficient procedures for
the synthesis of enantiopure (S)-prolinehydrazides 1. We demonstrated, that carbohy-
drazides react smoothly with isothiocyanates yielding thiosemicarbazides 3.4,5 The ob-
tained thiosemicarbazides 3 with a N-benzylprolinoyl residue were treated with 5% aqueous
NaOH under reflux conditions, and the corresponding 1,2,4-triazole-3-thione derivatives
4a–4c were obtained as crystalline products (Scheme 2).4b An alternative cyclization of
thiosemicarbazides 3 was observed under acidic conditions. Thus, the reactions of 3a–3c
in concentrated H2SO4 at r.t. furnished 1,3,4-thiadiazol-2-amines 5a–5c in fair yields
(Scheme 2, Table 1).4b
The triazole-3-thiones 4 and thiadiazol-2-amines 5 are optically active com-
1
pounds and the enantiomeric purity was tested by recording the H-NMR spectrum
in the presence of equimolar amounts of the chiral solvating agent (–)-(SP)-(tert-
1
butyl)(phenyl)phosphinothioic acid (MOD reagent).6 The H-NMR spectrum of racemic
bis-heterocycles obtained, starting with racemic N-benzylprolinehydrazide, was also
recorded in the presence of MOD reagent. The registered spectra with diagnostic AB
systems of the PhCH2 groups for racemic compounds showed two well-separated sets of
AB signals (eight lines).4b On the other hand, the spectrum of optically active compounds,
prepared from (S)-1b, showed only four lines typical for the AB system. Thus, the obtained
results evidenced that the cyclization of (S)-3 under basic or acidic conditions gave the
enantiomerically pure products, i.e., occurred without racemization.
Table 1 Data of bis-heterocycles containing (S)-proline moiety
R1
Yield,%
M. p., ◦C
α20
3a
3b
3c
3d
4a
4b
4c
5a
5b
5c
Me
Ph
n-Bu
tert-Bu
Me
Ph
n-Bu
Me
p-SO3H-C6H4
n-Bu
90
92
93
97
80
85
67
88
34
56
Oil
Oil
Oil
154–156
130–132
129–131
135–136
128–130
262–264
99–100
−79
−59
−68
−63
−42
−55
−126
−99
−89
−92

SYNTHESIS OF ENANTIOPURE BIS-HETEROCYCLES
495
Scheme 2 Synthesis of bis-heterocycles containing (S)-proline moiety: a) isothiocyanates (1 eq.), MeOH, reflux,
2 h; b) 2% NaOHaq, reflux, 2h; and c) H2SO4, r.t., 24 h.
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