Improved erlenmeyer synthesis with 5-thiazolone and catalytic Mn(II) acetate. Crystal structure confirmation of the reaction stereochemistry

Article abstract of DOI:10.1002/jhet.1921

2-Phenylthiazolin-5-one (5, a thioazlactone) condenses with various aldehydes in the presence of the mild base Mn(II) acetate as catalyst in CH ₂Cl₂ solution. This leads to the corresponding Erlenmeyer reaction products (6) in excell

Full text of DOI:10.1002/jhet.1921

E172
Improved Erlenmeyer Synthesis with 5-Thiazolone and Catalytic Mn(II)
Vol 51
Acetate. Crystal Structure Confirmation of the Reaction Stereochemistry
*
Sosale Chandrasekhar and V. Mohana Rao
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
*
E-mail: sosale@orgchem.iisc.ernet.in
Received September 10, 2012
DOI 10.1002/jhet.1921
Published online 18 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
2-Phenylthiazolin-5-one (5, a thioazlactone) condenses with various aldehydes in the presence of the mild
base Mn(II) acetate as catalyst in CH2Cl2 solution. This leads to the corresponding Erlenmeyer reaction
products (6) in excellent yields in the case of aromatic aldehydes and moderate yields in others. The mildness
of the reaction conditions is apparently enabled by the aromaticity of the (putative) intermediate thiazolone
anion. The structure and stereochemistry (Z) of the product derived from i-BuCHO was confirmed by single
crystal X-ray diffraction. This study overcomes key limitations of the classical Erlenmeyer synthesis and also
introduces the relatively nontoxic Mn(II) acetate as a reagent in heterocyclic chemistry.
J. Heterocyclic Chem., 51, E172 (2014).
INTRODUCTION
was used as the catalytic base was a serious drawback.
Herein, we report that the reaction can be performed
with the relatively nontoxic manganese diacetate as
catalytic base.
Over a century after their initial discovery by Plöchl
and by Erlenmeyer, azlactones continue to find diverse
applications in synthesis [1]. The classical azlactone
synthesis involved the reaction of the precursor, hippuric
acid (1a), with an aromatic aldehyde in the presence of
acetate ion as base (Scheme 1) [2]. This furnished the
4-arylidene azlactone (3) in one step, via in situ
formation of the azlactone (2), its deprotonation to the
anion I and subsequent condensation with aldehyde
(ArCHO). However, harsh conditions (refluxing acetic
anhydride) and limitations with nonaromatic aldehydes
were serious drawbacks. (Several improved versions
have evolved over the decades, as may be gleaned from
the many excellent reviews covering the Erlenmeyer
reaction [2–4]).
In view of the fact that the Erlenmeyer azlactone
products can be transformed to a-amino acids (4)—of great
value in both chemistry and biology—we have been inter-
ested in developing improved versions of the original
synthesis [5]. In particular, we have proposed that the
Erlenmeyer synthesis is facilitated by the aromaticity of
the intermediate azlactone anion I [5(b)] and also showed
that the thioazlactone analogs, whose derived anions would
possess enhanced aromaticity, react readily [6].
RESULTS AND DISCUSSION
2-Phenylthiazolin-5-one (5) was prepared from thiohip-
puric acid (1b) and dicyclohexylcarbodiimide (DCC) in
CH2Cl2 solution at RT, and condensed in situ with various
aromatic and nonaromatic aldehydes. The reaction was
catalyzed by manganese diacetate, and the expected 4-
arylidene or 4-alkylidene products (6) were formed in
fair-to-excellent yields (Scheme 2 and Table 1). The yields
are clearly better in the case of the aromatic aldehydes,
although it is noteworthy that the original synthesis was
largely confined to these [2–4].
A plausible mechanism is also shown in Scheme 2.
This involves the initial coordination of the thiazolone
carbonyl oxygen atom with Mn(II), followed by a
concerted a-deprotonation by an internal acetoxy group
(as shown in II). This leads to the Mn(II) enolate species
and a molecule of acetic acid, shown in III. This is
followed by electrophilic attack upon the enolate by the
aldehyde (presumably aided by a molecule of acetic acid),
as shown in IV. This leads to the alcohol adduct V, which
is dehydrated to 6 along with release of Mn(OAc)2
(possibly under acid catalysis, but this is not shown).
Thus, 2-phenylthiazolin-5-one (5, Scheme 2) reacts with
various aldehydes under exceedingly mild conditions [6].
However, the fact that the relatively toxic lead diacetate
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August 2014
Improved Erlenmeyer Synthesis with 5-Thiazolone and Catalytic Mn(II) Acetate
E173
Table 1
The key feature of the present method is the use of the
relatively nontoxic and mild base, manganese diacetate
[7]. This is presumably facilitated by the enhanced
aromatic stability of the putative thioazlactone anion
intermediate (cf. III) [5(a),6]. This is apparently not only
one of the mildest and least toxic versions of the
Erlenmeyer azlactone synthesis known to date, but also
one that applies to nonaromatic aldehydes.
The choice of manganous acetate as catalyst was
suggested by the previous success of the synthesis with
plumbous acetate [6]. Thus, we sought a stable, low
valent metal salt without interfering redox equilibria
(that could possibly affect the sulfur center in 5). Mn(II)
Percentage yields of thiazolone product 6 formed from 1b (Scheme 2).
6
Ar/R
% Yield (h)a
a
b
c
d
e
f
g
h
Ph
78 (1)
86 (1)
74 (1)
89 (1)
81 (1)
58 (2)
59 (2)
49 (2)
4-(MeO)-C6H4-
Naphth-2-yl
Cinnamyl
Furan-2-yl
Et
i-Bu
Cyclohexyl
aReaction time in hours in parenthesis.
is the most stable oxidation state of manganese (although
it suffers oxidation to Mn(III) in aqueous base). Several
Mn(II) salts are known [7,8], the acetate but finding only
brief mention in the earlier literature for its technical
applications [8(b)]. (It is used as a “siccative” in paints
and varnishes; its reputed plant-growth stimulant action
attests to its nontoxicity.)
Scheme 1
Manganese (a group VII metal) is considerably electro-
positive, and Mn(II) is also believed to be a hard acid [7].
This indicates possible coordination of the Mn(II) center
with the carbonyl oxygen atom of 5, thus facilitating
proton abstraction as indicated in II. Mn(II) acetate is
expected to be a weaker base than the alkali and alkaline
earth acetates. Interestingly, however, there are hardly
any reports of applications of Mn(II) acetate in organic
synthesis, and this work thus serves to introduce it as a
synthetic reagent.
Interestingly, the continuing interest in the Erlenmeyer
synthesis is evidenced by several recent improvements
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E174
S. Chandrasekhar and V. Mohana Rao
Vol 51
and modifications. In particular, the role of the base has
been the subject of a detailed study [1(c)], which
apparently indicated that organic bases could be superior
under some conditions. Although several bases have been
employed for the Erlenmeyer synthesis, the “ideal base”
seems to depend on both the aldehyde and the reaction
conditions. (A heavy metal derivative, lead acetate, was
apparently first introduced into the Erlenmeyer synthesis
by Baltazzi and Robinson in 1954 [4(b)], and this was
carried over into later work [6].)
CONCLUSIONS
We have described a vastly improved thioazlactone
analog of the classical Erlenmeyer synthesis. Because of
its enhanced aromaticity, the putative thioazlactone anion
can be generated by manganous acetate, a relatively weak
and nontoxic base. The synthesis applies to both aromatic
and aliphatic aldehydes, noting that the original method
was largely limited to the former. The Z stereochemistry
originally assigned to the Erlenmeyer products has been
confirmed by the crystal structure in one case.
We have also determined the crystal structure of the
iso-butylidene derivative (6g) via single crystal X-ray
diffraction, thus confirming both the structural and stereo-
chemical assignments (Figure 1 and Table 2) [9]. The
arylidene azlactone products of the Erlenmeyer synthesis
have historically been assigned the Z stereochemistry at
the newly formed exocyclic double bond [2–4] (although
the E form can predominate under certain reaction
conditions [3]). However, we are not aware of previous
crystallographic confirmation of the assignment.
EXPERIMENTAL
General.
The following instruments were employed:
JASCO 410 (JASCO International Co. Ltd., Tokyo, Japan;
FTIR); Bruker AV-400 (Bruker Corporation, Billerica, MA;
NMR); Micromass Q-TOF AMPS MAX 10/6A (Waters
Corporation, Milford, MA; HRMS); Stuart SMP10 (Dynalab
Corp., Rochester, NY; melting point); and Büchi Rotavapor
R-200 (BUCHI Labortechnik AG, Flawil, Switzerland; rotary
evaporator). Melting points (mp) are uncorrected. IR spectra
were recorded neat, and the values (nmax) are quoted in
reciprocal centimeters. NMR spectra were recorded in CDCl3
solution with TMS as internal standard at either 300MHz (dH)
or 75 MHz (dC); the coupling constants (J ) are in Hertz. The
NMR assignments indicate only the atom connectivity,
hydrogen atoms and substituents being generally omitted; the
hydrogen or carbon atom pertinent to the observed resonance is
italicized; the numbering refers to the thiazolone ring atoms,
unless otherwise mentioned. Derivatives of 6 other than the
naphthyl (6c), furanyl (6e), and cyclohexyl (6h) were reported
previously [6], and their spectral details are not repeated herein.
Mn(OAc)2.4H2O, and other reagents and solvents employed,
were of reagent grade; thiohippuric acid (1b) was prepared as
reported [6]. Upon aqueous work-up and extraction, extracts
were generally dried with MgSO4 prior to evaporation of
solvent in vacuo in a rotary evaporator.
4-Alkylidene and 4-arylidene thiazolin-5-ones (6). A stirred
solution of N-(thiobenzoyl)glycine (1b; 195mg, 1 mmol) in dry
CH2Cl2 (3.0 mL) was treated dropwise with DCC (247 mg,
1.2 mmol) in CH2Cl2 (2.0mL) under dry nitrogen at 25ꢀC. The
reaction mixture was stirred for 10 min, and the resulting
suspension was treated with Mn(OAc)2.4H2O (24 mg, 0.1mmol),
followed by the aldehyde (1.2mmol). Reaction was continued for
the indicated time (Table 1) when the mixture was filtered through
a plug of Na2SO4; this was washed with CH2Cl2, and the
combined filtrate concentrated in vacuo. The resulting residue was
column-chromatographed over silica to obtain the pure alkylidene
or arylidene thioazlactones (6). These were identified spectrally as
described later. (The inclusion of molecular sieves in the
aforementioned procedure did not improve the yields of 6.)
(Z)-4-Benzylidene-2-phenylthiazol-5(4H)-one (6a). Yellow
solid, mp 131–132ꢀC (lit. [6] 130–131ꢀC).
Figure 1. Crystallographic ORTEP (Oak Ridge Thermal Ellipsoid Plot)
diagram of iso-butylidene derivative 6g [9]. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com].
Table 2
Key crystallographic data of iso-butyl derivative 6g (Figure 1 and Table 1)
[9].
Property
Data
(Z)-4-(4-Methoxybenzylidene)-2-phenylthiazol-5(4H)-one
(6b). Yellow solid, mp 158–159ꢀC (lit. [6] 158–159ꢀC).
(Z)-4-(Naphth-2-ylidene)-2-phenylthiazol-5(4H)-one
(6c). Yellow solid, mp 136–138ꢀC; nmax 3056 (CH), 1704 (CO),
1605 (C═C), 1592 (C═C), 1253, 1137, 997; dH 8.62–8.59 (1H,
dd, J= 1.8 and 8.7, ArH), 8.54 (1H, s, ArH/naphthyl C1), 8.08–8.05
Crystal system
Space group
Volume of unit cell (Ǻ)3
Rall, Robs
Monoclinic
P 21/n
1344.4 (8)
0.085, 0.054
1.049
G.o.F.
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Improved Erlenmeyer Synthesis with 5-Thiazolone and Catalytic Mn(II) Acetate
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(2H, m, ArH), 7.94–7.91 (2H, m, ArH), 7.87–7.84 (1H, m, ArH),
7.60–7.50 (5H, m, ArH), 7.40 (1H, s, C4═CH); dC 194.66 (C═O),
166.53 (C2), 146.31 (C4), 135.19 (C═C4), 134.53 (CAr), 133.48
(CAr), 133.18 (CAr), 132.64 (CAr), 131.55 (CAr), 131.42 (CAr),
129.20 (CAr), 128.99 (CAr), 128.61 (CAr), 128.36 (CAr), 128.24
(CAr), 128.20 (CAr), 127.79 (CAr), 126.66 (CAr); HRMS: m/z Calcd
for C20H13NOS +Na: 338.0616. Found: 338.0606.
(Z)-2-Phenyl-4-[(E)-3-phenylallylidene]thiazol-5(4H)-one
(6d). Yellow solid, mp 132–133ꢀC (lit. [6] 132–133ꢀC).
(Z)-4-(Furan-2-ylmethylene)-2-phenylthiazol-5(4H)-one
(6e). Pale yellow solid, mp 162–164ꢀC; nmax 2924 (CH), 1691
(CO), 1593 (C═C), 1254, 1153, 991; dH 8.03–7.99 (2H, m, ArH),
7.72–7.68 (2H, m, ArH), 7.59–7.49 (3H, m, ArH), 7.21 (1H, s,
C4═CH), 6.69–6.67 (1H, m, ArH/furanyl C4); dC 193.30 (C═O),
166.18 (C2), 151.25 (CAr/furanyl C5), 147.14 (CAr), 143.48 (C4),
133.47 (C═C4), 132.54 (CAr), 128.95 (CAr), 128.14 (CAr), 120.94
(CAr), 118.00 (CAr/furanyl C2), 114.05 (CAr/furanyl C4); HRMS:
m/z Calcd for C14H9NO2S + Na: 278.0252. Found: 278.0258.
(Z)-2-Phenyl-4-propylidenethiazol-5(4H)-one (6f). Colorless
solid, mp 51–52ꢀC (lit. [6] 51–52ꢀC).
Acknowledgment. We are grateful to CSIR (New Delhi) for
generous fellowship support to V. M. R.
REFERENCES AND NOTES
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[5] (a) Chandrasekhar, S.; Karri, P. Tetrahedron Lett 2006, 47,
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[9] Chandrasekhar, S.; Mohana Rao, V.; Naik, S. K.; Guru Row,
T. N. Unpublished results 2011. Full details of the crystallographic
study have been deposited in the Cambridge Crystallographic Data
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Cambridge CB2 1EZ, (U. K.), (e-mail: deposit@ccdc.cam.ac.uk), and
can be obtained by quoting the no. 844384.
(Z)-4-(3-Methylbutylidene)-2-phenylthiazol-5(4H)-one
(6g). Pale yellow solid, mp 57–58ꢀC (lit. [6] 55–57ꢀC).
(Z)-4-(Cyclohexylmethylene)-2-phenylthiazol-5(4H)-
one (6h). Colorless solid, mp 62–64ꢀC; nmax 2927 (CH), 2851
(CH), 1705 (CO), 1626 (C═N), 1597 (C═C), 1447, 1255, 959; dH
7.95–7.93 (2H, m, ArH), 7.53–7.45 (3H, m, ArH), 6.56–6.53
(1H, d, J=9.9, C4═CH), 3.21–3.10 (1H, m, cyclohexyl C1H),
1.84–1.71 (4H, m, cyclohexyl C2H+C6H), 1.48–1.21 (6H, m,
cyclohexyl C3H+C4H+C5H); dC 193.96 (C═O), 164.91 (C2),
148.25 (C4), 144.09 (CAr), 133.39 (C═C4), 132.29 (CAr), 128.80
(CAr), 127.95 (CAr), 38.66 (cyclohexyl C1), 31.91 (cyclohexyl
C2 +C6), 25.71 (cyclohexyl C3 +C5), 25.24 (cyclohexyl C4);
HRMS: m/z Calcd for C16H17NOS +Na: 294.0929. Found: 294.0926.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet