Simultaneous assembly of the β-lactam and thiazole moiety by a new multicomponent reaction

Article abstract of DOI:10.1016/S0040-4039(02)01621-0

A novel multicomponent reaction of β-aminothiocarboxylic acids, aldehydes, and 3-dimethylamino-2-isocyanoacylate is described. During the course of this reaction two heterocyclic moieties, a thiazole and a β-lactam ring, are formed simultaneously and under mild conditions. The increase in molecular complexity here is dramatic as 2 C-N, 2 C-S and 1 C-C bonds are formed in a new 'one-pot' multicomponent reaction.

Full text of DOI:10.1016/S0040-4039(02)01621-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6897–6901
Simultaneous assembly of the b-lactam and thiazole moiety by a
new multicomponent reaction
Ju¨rgen Kolb,a Barbara Beckb and Alexander Do¨mlingb,*
aTechnische Universita¨t Mu¨nchen, Lichtenbergstr. 4, 85747 Garching, Germany
bMorphochem AG, Gmunder Str. 37-37a, 81379 Mu¨nchen, Germany
Received 22 July 2002; revised 2 August 2002; accepted 3 August 2002
Abstract—A novel multicomponent reaction of b-aminothiocarboxylic acids, aldehydes, and 3-dimethylamino-2-isocyanoacylate is
described. During the course of this reaction two heterocyclic moieties, a thiazole and a b-lactam ring, are formed simultaneously
and under mild conditions. The increase in molecular complexity here is dramatic as 2 CꢀN, 2 CꢀS and 1 CꢀC bonds are formed
in a new ‘one-pot’ multicomponent reaction. © 2002 Published by Elsevier Science Ltd.
A major challenge of modern drug discovery is the
design of highly efficient chemical reaction sequences
which provide a maximum of structural complexity and
diversity with just a minimum number of synthetic steps
to assemble compounds with interesting properties.1
According to Corey molecular size, element and func-
tional group content, cyclic connectivity, stereocenter
content, chemical reactivity, and structural instability
all contribute to molecular complexity.2
area of MCRs new reactions leading to novel scaffolds
are described frequently. The immense possibilities of
synthetic variations make it likely to find starting mate-
rials and conditions suitable for the discovery of new
MCRs.8
Continuing our interest in the discovery of new MCRs,9
we herein disclose the hitherto unknown three compo-
nent reaction, which, starting from acyclic precursors
and under mild conditions, affords a product consti-
tuted of a highly strained b-lactam ring with an
appended heteroaromatic thiazole moiety. Recently, we
discovered that thiocarboxylic acids, aldehydes, pri-
mary amines, and isocyanides react in a Ugi-type reac-
tion highly regioselectively to afford the corresponding
a-aminoacyl thioacylamides rather than a mixture of
the a-aminoacyl thioacylamides and the a-
aminothioacyl acylamides.10 Using a special class of
isocyanides, the 3-dimethylamino-2-isocyanoacrylates,
we then found that the intermediate a-aminoacyl
thioacylamides cyclize to the heteroaromatic thia-
zoles.11 Thus, highly substituted thiazoles are syntheti-
cally accessible employing this four component
reaction. Significantly, when the same isocyanide or a
derivative thereof, is reacted with aldehydes in the
presence of bifunctional b-aminothiocarboxylic acids,
1-thiazole-2-yl-methyl-azetidin-2-ones are smoothly
formed (Scheme 1).12 A plausible mechanism based on
existing knowledge regarding MCRs can be proposed:
during the course of the reaction the b-aminothiocar-
boxylic acid, the 3-dimethylamino-2-isocyanoacrylates,
and the aldehyde react to form a seven-membered
intermediate I. The secondary amine is then intramolec-
ularly acylated, resulting in a ring contraction. The
Recently multicomponent reactions (MCRs) have
emerged as a highly valuable synthetic tool in the
context of modern drug discovery. The atom economi-
cal and convergent character, the simplicity of a one-
pot procedure, the possible structural variations, the
accessible complexity of the molecules, as well as the
very large number of accessible compounds are among
the described advantages of MCRs.3 Thus, they are
perfectly amenable to automation for combinatorial
synthesis.4 Amongst the known multicomponent reac-
tions, isocyanide based MCRs are especially valuable.5
Many different scaffolds are accessible, each with very
many examples.6 Thus they are prototypic complexity
and diversity generating reactions.
But is it possible to discover new MCRs that may also
lead to novel scaffolds?
In the classical chemistry of two component reactions,
few reactions are discovered anymore.7 However in the
* Corresponding author. Tel.: ++4989780050; fax: ++498978005555;
e-mail: alexander.doemling@morphochem.de
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01621-0

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J. Kolb et al. / Tetrahedron Letters 43 (2002) 6897–6901
Scheme 1. Proposed reaction mechanism.
sulfur atom of the intermediate II adds to the acrylic
acid moiety in a Michael-type manner. Finally the
thiazole ring is formed by elimination of dimethyl-
amine. The special reactivity of this isocyanide, first
described by Scho¨llkopf et al.13 is based upon three
inherent properties: the isocyano reactivity, paired with
the Michael acceptor character, and the built-in leaving
group ability of dimethylamine. On employing unsym-
metrical oxocomponents and another chiral component
(e.g. isocyanide or b-aminothiocarboxylic acid), rather
b-aminothiocarboxylic acids with gaseous H2S (Scheme
2, Table 2). The third starting material, the b-dimethyl-
aminoisocyano acrylic acid derivatives, are accessible in
some variety from monosubstituted methylisocyanides
analogously to the described procedure (Scheme 3).16
In conclusion a new three component reaction of b-
aminothiocarboxylic acids, b-dimethylamino-2-iso-
cyanoacrylates, and aldehydes yielding substituted
1-thiazole-2-ylmethyl-azetidin-2-ones has been devel-
oped. This new MCR is particularly noteworthy
because under mild conditions, and starting from
acyclic precursors, products containing two heterocy-
cles are formed in good yields. In contrast, classical
thiazole syntheses require much harsher conditions and
typically the strained b-lactam ring system is also not
easily formed.17 In addition, the products emanating
from this MCR are variable at three positions. More-
over, the corresponding starting materials are easily
accessible from their available precursors. Compounds
of this class, namely substituted 1-thiazole-2-ylmethyl-
azetidin-2-ones, are potentially useful as protease
inhibitors, as antibiotics, or as cholesterol absorption
modifiers.18 Further efforts in our laboratory are
then
symmetrical
ketones
or
formaldehyde,
diastereomers are formed. Not unexpectedly, the dias-
teromeric excess is poor, as it generally is true for
MCRs of isocyanides. The reaction demonstrably
works well with a number of starting materials in
acceptable to good yields. Typical examples are shown
in Table 1.
The thus-far relatively unknown b-aminothiocarboxylic
acids are synthetically accessible via
a two-step
sequence.14 After much experimentation, we have devel-
oped a new and expedient synthetic route for their
preparation. We treated Z-protected b-amino acids
with PBr3 yielding the homo-Leuchs’ anhydrides.15
These sensitive compounds are then converted to the

J. Kolb et al. / Tetrahedron Letters 43 (2002) 6897–6901
6899
Table 1. Structures and yields of some prepared thiazole-
b-lactams according to the new one-pot procedure
Table 2. Synthesized b-aminothiocarboxylic acids accord-
ing to Scheme 2
Scheme 3. Synthesis of 2-dimethylamino-1-(4-pyridyl)-1-
ethenylisocyanide.
Acknowledgements
Dedicated to the 72nd birthday of Professor Ivar Ugi.
We thank Robert Eckl for measurement of the NMR
spectra and Sepp Achatz for his support in isocyanide
chemistry.
directed towards solid-phase variations of this reaction,
the synthetic utility of such reactive compounds and an
in-depth biological evaluation of this interesting class of
compounds. This reaction is yet another example of
how highly convergent MCRs can function as a supe-
rior tool for diversity-oriented and complexity-generat-
ing synthesis.19
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Scheme 2. Synthesis scheme for b-aminothiocarboxylic acid.

6900
J. Kolb et al. / Tetrahedron Letters 43 (2002) 6897–6901
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mL/min, 32 min, gradient from 90% H2O to 10% H2O
(0.5% CH3COOH versus CH3CN) tR (minor)=6.167
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MHz): l=0.81–0.83 (m, 6H, CHCH(CH3)2); 1.13–1.15
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(m, 6H, CHCH(CH3 2
CH3); 1.34–1.36 (m, 6H, b-lactam CH3); 2.48–2.55 (m,
2H, b-lactam CH2); 2.64–2.70 (m, 1H, CHCH(CH3)2);
2.78–2.87 (m, 1H, CHCH(CH3)2); 2.96–3.06 (m, 1H, b-
lactam CH2); 3.64–3.71 (m, 2H, b-lactam CH); 3.95 (s,
6H, -OCH3); 4.26 (d, 1H, N-CHCH(CH3)2); 4.46 (d,
1H, N-CHCH(CH3)2); 8.17 (s, 1H, thiazole-H); 8.20 (s,
1H, thiazole-H). 13C NMR (CDCl3, 100 MHz): l=
17.68 (b-lactam CH3); 18.67 (CHCH(CH3)2); 18.76 (b-
lactam CH3); 18.79 (CHCH(CH3)2); 19.21 (CHCH-
(CH3)2); 19.49 (CHCH(CH3)2); 30.27 (CHCH(CH3)2);
31.29 (CHCH(CH3)2); 42.47 (b-lactam CH2); 42.75
6 ) ); 1.27–1.28 (m, 3H, b-lactam
6
6
6
6. Actual examples of new MCRs: (a) Hulme, C.; Ma, L.;
Romano, J. J.; Morton, G.; Tang, S.-Y.; Cherrier, M.
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12. Procedure for 2-[2-methyl-1-(2-methyl-4-oxo-azetidin-1-
yl)-propyl]-thiazole-4-carbonic-acid methylester 1 as a
diastereomeric mixture: under a dry nitrogen atmo-
sphere, a solution of 5 mmol (0.596 g) b-aminothiopro-
pionic acid and 0.5 g MgSO4 in dry methanol (10 mL)
was stirred and cooled to −15°C. Isobutyric aldehyde (5
mmol, 0.361 g) in methanol (5 mL) was slowly added
to the solution and was stirred for a further hour. 3-
Dimethylamino-2-isocyanoacrylicacid methylester (5
mmol, 0.77 g) was added. The mixture was allowed to
reach 20°C and was stirred for an additional 24 h.
After evaporation of the solvent, the residue was dis-
solved in 40 ml of DCM, extracted three times each
with 10 ml of 1% phosphoric acid, 10 ml of saturated
sodium hydrogencarbonate solution and 10 ml of dis-
tilled water. The organic phase was dried over Na2SO4,
and the solvent was evaporated. The resulting oil was
purified with chromatography on SiO2 to give 0.98 g
(69%) of a foam, as a mixture of diastereomers (de=
0.84). Characterization of compound 1: MW
(C13H18N2O3S)=282.36; HPLC-MS spectra (Hewlett–
6
6
6
6
6
6
6
(b-lactam CH2); 46.18 (b-lactam CH); 48.37 (b-
lactam CH); 51.34 (-OCH3); 51.39 (-OCH3); 61.47
(-C6 HCH(CH3)2); 61.96 (-C6 HCH(CH3)2); 127.40 (thiazole-
C-5); 127.98 (thiazole-C-5); 144.59 (thiazole-C-4); 145.08
(thiazole-C-4); 159.57 (thiazole-C-2); 160.60 (thiazole-
C-2); 165.17 (-CH2C
6
O); 165.43 (-CH2C
6 O); 168.45
(-COOCH3); 169.59 (-C
6
6 OOCH3).
13. Scho¨llkopf, U.; Porsch, H.; Lau, H. H. Ann. Chem.
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14. Surprisingly only one b-aminothiocarboxylic acid has
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15. General procedure for the preparation of N-carboxy-b-
aminobutyric acid anhydride 12: 50 mmol of the N-
benzyloxycarbonyl
protected
b-amino
acid
(2-aminopropanic acid) was suspended in 400 mL
DCM. Under a N2 atmosphere 30 mmol phosphortri-
bromid (8.121 g or 2.85 mL) was added via a septum.
After 24 h the slurry was filtered under a N2 atmo-
sphere. The solvent was distilled of until it again starts
to precipitates. Dry hexane was added. The precipitate
was filtered under dry conditions to yield 4.38 g (68%)
of the product. MW (C5H7NO3)=129.11; 1H NMR:
3
(CDCl3, 400 MHz): l=1.36 (d, 3H, J=6.4 Hz, -CH3
6
);
-); 2.87
-); 3.77 (m, 1H,
-). 13C NMR (CDCl3, 100
); 36.2 (-CH2-); 42.9 (-CH(CH3)-);
ONH-); 164.4 (-CH2CO-).
16. Procedure for the preparation of 2-dimethylamino-1-(4-
pyridyl)-1-ethenylisocyanide 13: 5.9 4-iso-
2.53 (dd, 1H, 2J=16.2 Hz, 3J=9.3 Hz, -CH2
6
2
3
(dd, 1H, J=16.2 Hz, J=4.3 Hz, -CH2
-CH(CH3)); 6.74 (b, 1H, -NH
MHz): l=20.8 (-CH3
150.2 (-C
6
6
6
6
6
6
6
6
g
cyanomethylpyridin (Scho¨llkopf, U.; Eilers, E.; Hantke,
K. Liebigs Ann. Chem. 1976, 969) (50 mmol) and 7.35
g dimethylformamiddiethylacetal (50 mmol) were dis-
solved in 10 mL ethanol and stirred for 16 h at 20°C.
The solvent was evaporated at reduced pressure and the
residue was purified by chromatography on silica gel.
Yield 2.4 g (28%) as a violet solid. 1H NMR (CDCl3,
400 MHz): l=2.49 (s, 6H, 2×N-CH3); 5.97 (s, 1H,
ꢁCH); 6.37 (d, 2H, Pyr); 7.66 (d, 2H, Pyr); 13C NMR
Packard HP1100; YMC column, 2×50 mm,
2 mm
ODSA, 220 and 254 nm; 0.6 mL/min, 4 min, gradient
from 90% H2O to 10% H2O (0.5% CH3COOH versus
CH3CN) coupled with a MSD mass spectrometer using
(CDCl3, 100 MHz): l=42.47 (N(C
(ꢁCHN(CH3)2); 138.97 (Pyr-C-3); 142.70 (Pyr-C-4);
149.38 (Pyr-C-2); 167.41 (-NC). These isocyanides are
commercially available at: http://www.priaton.de/.
6 H3)2); 115.46
6
6
electronspray ionization (ESI)): tR,
nm=3.348 min;
254
m/z=305 [M+Na]+, 283 [M+H]+, 241 [M−CON]+.

J. Kolb et al. / Tetrahedron Letters 43 (2002) 6897–6901
6901
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18. Structurally similar compounds have been described in