Solid-phase synthesis of 3-aryl-3-oxo-propan amides by reaction of lithium enolates with 4-nitrophenyl carbamate resin or polymer-bound isocyanate

Article abstract of DOI:10.1016/S0040-4039(03)00757-3

Two synthetic procedures to enable a straightforward and efficient solid-phase synthesis of 3-aryl-3-oxo-propan amides (β-keto amides) are described and compared. Lithium enolates, which can be obtained by deprotonation of methyl ketones with LiHMDS, are added to either an immobilized isocyanate or activated carbamate. After cleavage of the products from the solid support, various 3-aryl-3-oxo-propan amides are released in high yield and purity. The advantage of this method is that many of the commercially available methyl ketone building blocks can be used. The immobilized 3-aryl-3-oxo-propan amides generated may serve as intermediates for the preparation of structurally diverse libraries.

Full text of DOI:10.1016/S0040-4039(03)00757-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3939–3942
Solid-phase synthesis of 3-aryl-3-oxo-propan amides by reaction
of lithium enolates with 4-nitrophenyl carbamate resin or
polymer-bound isocyanate
Alexander G. Groß,a,* Holger Deppeb and Andreas Schobera
aInstitute for Physical High Technologies, Micro Systems Division, POB 100239, D-07702 Jena, Germany
bMerck KGaA, Preclinical Research, Medicinal Chemistry CVS, D-64271 Darmstadt, Germany
Received 2 September 2002; revised 28 January 2003; accepted 25 March 2003
Abstract—Two synthetic procedures to enable a straightforward and efficient solid-phase synthesis of 3-aryl-3-oxo-propan amides
(b-keto amides) are described and compared. Lithium enolates, which can be obtained by deprotonation of methyl ketones with
LiHMDS, are added to either an immobilized isocyanate or activated carbamate. After cleavage of the products from the solid
support, various 3-aryl-3-oxo-propan amides are released in high yield and purity. The advantage of this method is that many of
the commercially available methyl ketone building blocks can be used. The immobilized 3-aryl-3-oxo-propan amides generated
may serve as intermediates for the preparation of structurally diverse libraries. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
resin.3 The second method describes the reaction of
immobilized amino acid derivatives with acylated Mel-
drum’s acids;2 the latter have to be prepared in separate
steps beforehand.
3-Aryl-3-oxo-propan amides (b-keto amides) can serve
as useful intermediates for the preparation of struc-
turally diverse libraries.1,2 Therefore, a straightforward
synthetic method which allows the variation of the
b-substituent would be of great benefit in this area.
Recent solid-phase literature contains only two meth-
ods for the preparation of immobilized b-keto amides.
The first enables the preparation of 3-oxo-butanamide
by a reaction of diketene, diketene acetone adduct and
N-hydroxy-succinimidylacetoacetate with Rink amide
In addition, attempts have been made to link the
chemically related b-keto esters to a solid support.
Reported methods describe either the reactions of
diketene4 and acylated Meldrum’s acids5 with immobi-
lized HO-groups or the transesterfication of appropri-
ate b-keto esters to HO-resins.5,6 These protocols also
require diverse b-keto esters or acylated Meldrum’s
Scheme 1. Reagents and conditions: (i) 4-NO2PhOCOCl, DIEA, THF/DCM (1:1 v/v), 0°C to >25°C, 3 h; (ii) (OCCl3)2CO, DIEA,
THF, cat. DMAP, 80°C, 12 h; (iii) NEt3, THF/DCM (1:1 v/v), 60°C, 16 h; (iv) 3, THF, 0°C to >25°C, 12–48 h.
Keywords: b-keto amide; 3-oxo-propan amide; 3-hydroxy acrylamide; solid-phase; NanoSynTest; multiple core.
* Corresponding author. E-mail: grossalexander@gmx.net
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00757-3

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A. G. Groß et al. / Tetrahedron Letters 44 (2003) 3939–3942
acids. The b-keto esters are first immobilized, and the
subsequent reaction steps can lead to the production of
different structures, which are linked to the solid-phase
by a carboxylic group. Under acidic cleavage condi-
tions, the decarboxylation of the generated products
appears to be possible.7 Moreover, immobilized b-keto
esters can be cleaved off the solid support if drastic
nucleophilic reaction conditions are used.8 Appropriate
b-keto amides are much more stable against nucle-
ophilic attack and the released amide motif can further
be used for modifications after cleavage.9 With these
properties in mind, we developed two simple and
efficient synthetic protocols for b-keto amides on a
solid support and assessed them.
reaction of aryl methyl ketones with LiHMDS at 0°C in
THF. The isocyanate resin 1 was treated with 10 equiv.
of the cooled lithium enolate solution 3 and shaken
over night at ambient temperature. After washing and
cleavage, the expected b-keto amides 5 were obtained in
high yield and purity (see Table 1).
An alternative method was also investigated, in which
the 4-nitrophenol moiety in the activated carbamate 2
was substituted by the lithium enolates 3 (Scheme 1,
steps i, iv). To obtain the activated carbamate 2, a
previously published procedure was performed.13 After
a reaction of 10 equiv. of the lithium enolates with the
carbamate resin 2, followed by washing and cleavage,
the corresponding b-keto amides 5 were also obtained
(see Table 1). Under these conditions, two chemical
mechanisms are conceivable: the direct addition of the
enolate 3 to the activated carbamate 2 to yield product
4; or alternatively, the conversion of 2 to isocyanate 1
by elimination of the 4-nitrophenol moiety with subse-
quent addition of another equivalent enolate 3 to yield
product 4. However, in the thoroughly analyzed case of
5c we could not prove that the elimination addition
mechanism took place. This observation is based on the
findings that resin 2, which was not completely
converted to 4, did not show the characteristic
IR-absorption for the NCO-group, but the 4-nitro-
phenyl-carbamat could be observed by LC-MS
2. Results and discussion
A classic solution-phase approach for the synthesis of
substituted b-keto amides is the addition of lithium
enolates to isocyanates.10 The adaptation of this
method to solid-phase chemistry, as outlined in Scheme
1 (steps ii, iv), requires the preparation of immobilized
isocyanate 1. This reaction was accomplished by treat-
ing Rink-amide resin11 with triphosgene under standard
conditions.12 The resulting resin 1 shows a characteris-
tic strong isocyanate IR-absorption at 2245 cm−1. Cor-
responding lithium enolates
3 were prepared by
Table 1. Compounds prepared on the solid support

A. G. Groß et al. / Tetrahedron Letters 44 (2003) 3939–3942
3941
analysis after cleavage. Nevertheless, it is still possible
to convert the 4-nitrophenyl-carbamate resin 2 into the
isocyanate resin 1, but this reaction has to be carried
out in the presence of NEt3 for 16 h at 60°C (Scheme 1,
step iii).
equiv.) was added dropwise within 10 min. The cooled
solution was added to a suspension of Rink-amide
resin15 (1 g, 0.7 mmol, 1 equiv.) in 20 ml dry THF/
DCM (1:1 v/v). This batch was allowed to reach ambi-
ent temperature within 3 h under shaking. The liquid
was removed and the polymer washed three times with
dry THF.
A set of different aryl methyl ketones 3a–n (see Table 1)
were used with both methods. To prevent isomeric
products, we chose only aryl methyl ketones without
another nucleophilic position. Cleavage from the solid
support leads, in the majority of cases, to the expected
tautomeric mixture of 5a and 5b in different ratios
(Scheme 2). For the tautomeric mixture of 5c a ratio of
1:2 between the 3-oxo-propionamide 5a,c and 3-
Preparation of the immobilized isocyanate 3: Triphos-
gene (0.207 g, 0.7 mmol, 1 equiv.) was dissolved in 40
ml dry THF/DCM (1:1 v/v), cooled to 0°C and DIEA
(1.1 ml, 4.3 mmol, 6.1 equiv.) was added dropwise
within 10 min. The cooled solution was added to a
suspension of Rink-amide resin15 (1 g, 0.7 mmol, 1
equiv.) in 20 ml dry THF/DCM (1:1 v/v). A catalytic
amount of DMAP (approx. 5 mg) was added and the
reaction vial was closed immediately. Caution toxic
phosgene gas formation. The corresponding suspension
was heated under shaking to 80°C over night. After
cooling to ambient temperature, the liquid was removed
and the polymer washed three times with 50 ml dry
THF. The corresponding resin exhibits the expected
characteristic IR-absorption at 2245 cm−1.
1
hydroxy-acrylamide 5b,c was estimated in the H NMR
spectrum ([D-6]-acetone). We observed that both reac-
tions show nearly the same kinetic behavior. Donor
substituted aryl compounds like 3,c,i react much faster
than acceptor substituted ones like 3e,f,j. Most of the
compounds required at least 12 h to complete the
reaction. There is one exception, however, the acceptor
substituted aryl compounds 3g,l needs about 48 h reac-
tion time and only the 4-nitrophenyl- and 4-pyridyl-
methyl enolates 3h,m, although did not react under
these conditions (see Table 1). This may be due to the
poor nucleophilicity or solubility of the corresponding
enolates.
Addition of lithium enolates: 4-Methoxy-acetophenone
(1.051 g, 7 mmol, 10 equiv.) was dissolved in 15 ml dry
THF. After cooling to 0°C, LiHMDS solution (7 ml, 1
M in THF, 10 equiv.) was added dropwise over 10 min.
The solution was allowed to reach room temperature
under stirring within 1 h. After recooling to 0°C, the
whole of this cooled solution was added in one portion
to the corresponding polymer 1 or 2. The resulting
suspension was gently shaken at ambient temperature
over night and after removing the solution, the polymer
was washed successively with THF, THF/AcOH (95:1
3. Conclusion
In summary, the two protocols presented allow the
straightforward and efficient preparation of structurally
divers b-keto amides. In terms of reaction time, the
substitution protocol (Scheme 1, steps i, iv) is more
advantageous than the isocyanate addition one (Scheme
1, steps ii, iv). The preparation of the activated carba-
mate 2 needs 3 h, whereas the formation of the isocya-
nate 2 requires at least 12 h reaction time. The obtained
b-keto amides 4 open up a wide range of subsequent
possible reactions and may prove to be useful as inter-
mediates for the preparation of multiple core structure
libraries.1,14
i
v/v), THF, DCM/iPrOH and finally with PrOH. After
which, the resin was dried in vacuo.
Cleavage from solid support: The resin-bound product
4c (100 mg) was suspended in 2 ml TFA/DCM (1:1 v/v)
for 1 h. The resin was then filtered and washed with 2
ml DCM. The collected filtrates were evaporated and
the residue redissolved in DCM/CH3OH (1:1 v/v).
Evaporation of the solvent leads to the expected tau-
tomeric mixture 5a,c/5b,c: (18 mg, 95%), HPLC (220
1
Typical experimental procedures and data for representa-
tive examples
nm): 97%, DAD-UV: 282 nm, 221, 208. H NMR (500
MHz, [D6]-acetone): tautomeric mixture of 3-(4-
methoxyphenyl)-3-oxo-propionamide
5a,c/3-(4-
Each of the following worksteps, with the exception of
the cleavage step, was carried out under N2.
methoxy-phenyl)-3-hydroxy-acrylamide 5b,c, rate 1:2. l
(ppm): 3.82 (s, 5b,c OCH3, 3H); 3.83 (s, 5a,c C(2)H2,
2H); 3.86 (s, 5a,c OCH3, 3H); 5.62 (s, 5b,c C(2)H, 1H);
5.78, 6.47, 6.92 (s, br, CONH2); 6.97 (d, 9.0 Hz, 5b,c
C(2%, 6% o. 3%, 5%)H, 1H); 7.01 (d, 8.9 Hz, 5a,c C(2%, 6% o.
3%, 5%)H, 1H); 7.71 (d, 9.0 Hz, 5b,c C(2%, 6% o. 3%, 5%)H,
1H); 7.95 (d, 8.9 Hz, 5a,c C(2%, 6% o. 3%, 5%)H, 1H); 14.81
Preparation of the immobilized 4-nitrophenyl carbamate
2: 4-Nitrophenylchloroformiate (0.705 g, 3.5 mmol, 5
equiv.) was dissolved in 40 ml dry THF/DCM (1:1 v/v),
cooled to 0°C and DIEA (0.61 ml, 3.57 mmol, 5.1
Scheme 2. Reagents and conditions: (i) TFA/DCM (1:1 v/v), 1 h.

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A. G. Groß et al. / Tetrahedron Letters 44 (2003) 3939–3942
(s, br, 5b,c C(3)OH). EI-MS: 193 (M+, 30%); 177
(-NH3, 5%); 135 (MeO-Ph-CO+, 100%); 107 (MeO-Ph+,
10%); 77 (Ph+, 35%). HR-MS: C10H11NO3, exp.:
193.0739, obs.: 193.0739. IR (KBr): 3405s w(N–H);
3190m w(O–H); 1668s w(CꢀO); 1663s w(CꢀC).
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1999, 1, 184–187.
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Lett. 1998, 39, 2207–2210; (b) Kim, D. Y.; Suh, K. H.
Synth. Commun. 1999, 29, 1271–1275.
Acknowledgements
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The authors thank Dr. H. Wurziger for helpful discus-
sion and technical support. The present work was sup-
ported by grants from the BMBF (FKZ 0311766) and
Merck KGaA (FKZ 0311767) during the NanoSyn-
Test™ project.
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