Solid phase synthesis of aminopropenones and aminopropenoates; efficient and versatile synthons for combinatorial synthesis of heterocycles

Article abstract of DOI:10.1055/s-2003-39156

Simple and fast solid phase methods for the synthesis of heterocycles will be described. Two different three-step methods are presented. The first method includes esterifications of N-protected glycine derivatives to a solid support (Merrifield resin), formation of aminopropenoates and subsequent reaction with dinucleophiles. The second method includes methylamination of a Merrifield resin, formation of aminopropenones via in-situ formation of an active intermediate in a three-component reaction and finally treatment with dinucleophiles to form heterocycles. These procedures lead not only to the formation of heterocycles but also to simultaneous intramolecular cleavage of the products from the resin giving the product in pure form in the solution. In addition, the use of microwave dielectric heating enhanced the velocity of all reaction steps and was found to be a very efficient complement to the solid phase synthesis.

Full text of DOI:10.1055/s-2003-39156

PAPER
1025
Solid Phase Synthesis of Aminopropenones and Aminopropenoates; Efficient
and Versatile Synthons for Combinatorial Synthesis of Heterocycles
Solid
P
has
a
e
Synthesis
c
of
A
minop
o
ropenones
a
b
nd Aminopropeno
W
tes estman,*a Ronny Lundinb
a
Actar AB, Franzéngatan 6, 112 51 Stockholm, Sweden
Fax +46(8)54560806; E-mail: jacob.westman@actar.se
b
Personal Chemistry AB, Kungsgatan 76, 753 18 Uppsala, Sweden
Fax +46(18)4899200
Received 20 12 2002; revised 30 01 2003
good leaving group, have been used in many applications
using conventional heating methods, probably most ex-
tensively described by Stanovnik et al.2 The intermediates
could then be reacted with dinucleophiles to form differ-
Abstract: Simple and fast solid phase methods for the synthesis of
heterocycles will be described. Two different three-step methods
are presented. The first method includes esterifications of N-pro-
tected glycine derivatives to a solid support (Merrifield resin), for-
mation of aminopropenoates and subsequent reaction with ent heterocycles. We have recently reported efficient mi-
dinucleophiles. The second method includes methylamination of a
crowave assisted one-pot methods for the synthesis of a
number of small libraries in solution3 based on alkylami-
Merrifield resin, formation of aminopropenones via in-situ forma-
tion of an active intermediate in a three-component reaction and fi-
nopropenones or alkylaminopropenoates.
nally treatment with dinucleophiles to form heterocycles. These
When producing a large number of substances in solution,
the subsequent purifications will be time-consuming, and
thereby diminish the advantage given by the short reaction
times found by the use of microwave heating.
procedures lead not only to the formation of heterocycles but also to
simultaneous intramolecular cleavage of the products from the resin
giving the product in pure form in the solution. In addition, the use
of microwave dielectric heating enhanced the velocity of all reac-
tion steps and was found to be a very efficient complement to the
solid phase synthesis.
In order to overcome cumbersome purification we found
it reasonable to try a solid phase synthesis approach to
those reactions. It is well known that the solid phase tech-
nique besides allowing for easy automation also could
eliminate certain time-consuming purification steps. For
example, a large excess of reagent could be used in a re-
action with a resin bound substrate and thus drive the re-
action to completion. The redundant amount of reagent
could then be removed by a simple filtration. On the other
hand, one well-known disadvantage of solid phase synthe-
sis is that longer reaction times usually are required com-
pared to reactions performed in a homogeneous solution
system. We have however found that also the reaction
times in heterogeneous systems could be substantially
shortened by the use of microwave heating.4
Key words: solid-phase synthesis, microwave irradiation, combi-
natorial chemistry, heterocycles
Highly functionalized heterocycles of various ring sizes,
with different heteroatoms and substitution patterns are of
major interest in the pharmaceutical and agricultural in-
dustry due to the their many intrinsic biological proper-
ties.
In medicinal chemistry in general, and combinatorial
chemistry in particular, the use of versatile synthons or
versatile scaffolds which are available after just a few re-
action steps are of great interest. One reagent producing
such synthons is N,N-dimethylformamide diethyl acetal
(DMFDEA).1 Condensation reactions between an activat-
ed methyl or methylene group adjacent to a keto or ester
functionality and DMFDEA form alkylaminopropenones
or alkylaminopropenoates (see Scheme 1). These inter-
mediates, in which the dimethylamino moiety acts as a
The analysis of the degree of incorporation of a certain
compound into the resin is usually performed by cleavage
of the compound from the resin and then analyzing the
cleavage mixture,5 by quantitative colorizing methods6 or
by elemental analysis. We chose to adopt a recently devel-
Scheme 1 Examples of the formation of dimethylaminopropenoates (A) and dimethylaminopropenones (B) from dimethylformamide
diethylacetal.
Synthesis 2003, No. 7, Print: 20 05 2003.
Art Id.1437-210X,E;2003,0,07,1025,1030,ftx,en;C00102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1026
J. Westman, R. Lundin
PAPER
1
oped NMR-technique, Magic angle spinning H NMR group (PhCH2OCO) the yield could be determined as
(MAS-NMR) analysis. The technology was developed shown in Figure 1. For the two last steps we applied the
some years ago7,8 and has shown to work well with resins same protocols as was developed for solution phase3 with
such as TentaGel and Merrifield resin. We herein describe minor modifications. Formation of an ester linkage be-
the efficient combination of microwave heating and solid tween a carboxylic acid substrate and a solid phase resin
phase synthesis for reducing both the reaction time and is a common reaction in the area of peptide synthesis and
the purification time.
combinatorial chemistry and is well described in the liter-
ature.5,9 Merrifield resin was treated with 5 equivalents of
N-benzoylated glycine 1 together with cesium carbonate
in 2 mL of DMF at 200 °C for 10 min10 giving 2. The anal-
ysis (MAS-NMR and elemental analysis) showed a load-
ing of approximately 1 mmol/g (80% yield) (Figure 1),
which is in the same range as described in the literature,
but approximately within a 100-fold shorter reaction time.
After washing, the resin was treated with 5 equivalents
DMFDEA in 2.5 ml DMF at 180 °C for 10 min to form the
dimethylamino propenoates intermediate 4.
Dialkylamino propenoates react with dinucleophiles in a
two-step reaction where substitution of the dimethylami-
no group is followed by a nucleophilic attack on the ester
functionality, which cleaves the ester. Dialkylamino pro-
penones also reacts with dinucleophiles. In this case the
reactions proceed differently since a condensation reac-
tion with the keto function is followed by the substitution
of the dialkylamino group. Based on the two different re-
action pathways, two different solid phase intermediates
were proposed as described in Scheme 2. Since the pro-
posed procedures form the heterocycles by an intramolec-
ular cyclization mechanism that simultaneously cleaves
the products from the resin it will give the products in pure
form in the solution and thus, any reaction step for cleav-
age from the resin is not needed. Since the heterocycles
from dialkylpropenoates are formed after cleavage of the
ester (approach 1) the chosen approach was therefore to
form the ester bond to the solid phase. For the formation
of heterocycles from propenones (approach 2) the chosen
approach was to bind the leaving group (the dialkylamino
group) to the solid phase.
Scheme 3 Synthesis of 3-(benzoyl)amino-4H-pyrido[1,2-a]pyrimi-
din-4-one. Reaction conditions: (i) Hippuric acid (5 equiv), CsCO3 (5
equiv), DMF, 200 °C, 10 min. (ii) DMFDEA (5 equiv) in DMF, 180
°C, 10 min (iii) 2-aminopyridine (0.5 equiv) in HOAc, 180 °C, 10
min.
Scheme 2 Approaches 1 and 2.
Synthesis of Heterocycles from Solid Phase Bound
Dialkylaminopropenoates
Formation of heterocycles where one of the substrates is
bound to the resin was performed in a 3 step reaction as
described in Scheme 3. Magic angle spinning NMR
(MAS-NMR) analysis7,8 was used for the protocol devel-
opment. NMR analysis of Merrifield resin gives, howev-
er, a poorer resolution with respect to line width and
spectral purity compared to resins like Tentagel.8 Merri-
field resin was used due to its high loading capacity and
high thermal stability. By comparing the peak area from
the methylene group in the resin handle (PhCH2Cl) and
the peak area from the solid phase benzylester methylene
Figure 1 By comparing the peak area of the benzylic methylene
group the yield could be determined.
The resin was washed, dried and then swelled in 0.5 mL
of HOAc. In order to minimize the amount of unreacted
dinucleophiles in the final reaction solution we only added
0.5–0.7 equivalents of dinucleophiles (5, 15, 16) to the re-
action mixtures, based on an assumed 1 mmol/g loading
of the intermediate. The reaction mixtures were heated for
an additional 10 min at 180 °C. After filtration and wash-
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Synthesis of Aminopropenones and Aminopropenoates
1027
ing of the resin, evaporation of the solvent was performed reaction steps needed to form the reagent. This strategy
and the products (6, 17, 18) were found in high purity was therefore not adopted. Meerwein et al. have also de-
(>90%) and in yields between 77–95% (see Table 1).
scribed that when a dialkylamine was reacted with
DMFDEA an amine exchange occurs in-situ giving the di-
alkylformamide diethylacetal. Unfortunately, when trying
this method, benzyl methylformamide was formed as the
only product. Bienaymé14 reported recently the formation
of substituted isonitriles by treatment of a dialkyl amine,
Synthesis of Heterocycles from Solid Phase Bound
Dialkylaminopropenones
Approach 2 (Scheme 2) where dialkyl formamide diethyl imidazole diethylacetal and methyl isocyanoacetate,
acetal is bound to the solid phase and where the cleavage which form dialkylamino propenoates by a three-compo-
from the resin occurs when the dialkyl amino group is nent cascade reaction15 mechanism (Scheme 5). Since this
cleaved by a nucleophile was not as straightforward as ap- multi-component approach forms the reagent in-situ it
proach 1. The idea was to form the dialkylformamide di- also reduces the number of reaction steps needed for the
ethyl acetal on solid phase starting from methylaminated formation of the reactive intermediate.
Merrifield resin (benzylchloride handle) and consequent-
ly we used benzyl methylamine (7) as a model substance
in order to develop a protocol in solution which then could
be transferred into solid phase conditions (Scheme 4).
Benzyl methylamine was treated with 9 equivalents of tri-
ethyl orthoformate (8) in 2.0 mL of DMF at 200 °C for 5
Scheme 5 Formation of amino propenoates in a multicomponent
min. to form benzyl methylformamide diethylacetal (9)
approach via amine exchange.
according to a method described by Gmeiner et al.11 How-
ever, we only found benzyl methylformamide as the prod-
uct 10. On the other hand we found, in accordance with
We therefore decided to try this approach to our model
synthesis and we found that when reacting benzylmethyl-
amine with DMFDEA and acetophenone in 2.0 mL of
the reference, that imidazole 11 forms the imidazolium di-
ethylacetal (12) after treatment with triethyl-
orthoformate12 in 2.0 mL of DMF at 200 °C for 5 min.
DMF at 180 °C for 5 min the desired propenone was
formed in good yield based on LC/MS analysis. The out-
come of the reaction indicated that this procedure could be
successfully applied to our planned strategy with the solid
phase linked N-methyl benzylamine The following proce-
dure was therefore performed: Merrifield resin was react-
ed with 2.0 mL methylamine in water at 150 °C for 10 min
to form the solid supported benzylmethylamine (13) in
high yield (86% yield, 1.08 mmol/g based on elemental
analysis). The MAS-NMR analysis was in this case diffi-
cult to interpret and therefore not used.16 The resin was,
after washing, treated with 5 equivalents DMFDEA to-
gether with 5 equivalents of 4-phenoxyacetophenone at
180 °C for 10 min in 2.0 mL of DMF to form the solid sup-
ported benzyl methyl aminopropenones 14. MAS-NMR
showed that products were formed but the spectra was not
resolved well enough to make a good interpretation.
Scheme 4 Synthesis of benzyl methylformamide. Reaction conditi-
ons: DMF, 200 °C, 5 min.
Our plan was then to follow the procedure describe by
Meerwein et al.13 for the synthesis of DMFDEA from
DMF. The solid supported benzylmethyl amine could be
treated with triethyloxonium tetrafluoroborate to afford a
tetrafluoroborate salt. Treatment of the salt with sodium
ethoxide should then give the diethylacetal compound.
The major drawback with this procedure is the number of
After washing, the resin was finally treated (the resin
bound intermediate in excess) at 180°C for 10 min in 2.0
mL EtOH, DMF, or HOAc with 0.5 equivalents of the
dinucleophiles to form the heterocycles in pure form. In
Scheme 6 Example of a solid phase synthesis of 1-Phenyl-5-(4-phenoxyphenyl)-pyrazole. Reaction conditions: (i) MeNH2 in H2O, 150 °C,
10 min (ii) DMF, 150 °C, 10 min (iii) HOAc, 150 °C, 10 min.
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

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J. Westman, R. Lundin
PAPER
Table 1 Synthesis of Heterocycles via Propenoatesa
Substrates
Products
Yields
77%
Purity
96%
92%
95%
95%
98%
a Reaction conditions: 100–200 mg of solid supported propenoates were reacted with 0.5 equiv. of substrate 5, 15, 16 in HOAc at 180 °C for
10 min.
The microwave-assisted reactions were performed in a SmithSyn-
thesizerTM, a single mode microwave cavity, from Personal Chem-
istry. NMR spectra were recorded in CDCl3 or DMSO-d6 at 25 °C,
using a Bruker at 300 MHz (1H)/75 MHz (13C) or a Varian 600 MHz
instrument with a nano probe for the MAS-NMR analysis. All NMR
order to verify the developed methods described above,
we performed a number of syntheses of heterocycles
where both approaches 1 and 2 were performed
(Scheme 6, Table 2).
In conclusion, we have described two ways to form acti- spectra recorded were in agreement with the postulated structures
and only selected data are reported. HPLC-MS chromatograms and
vated aminopropenones and aminopropenoates on solid
spectra were obtained with an Agilent 1100 system with a diode ar-
phase which in turn could be used in combinatorial syn-
ray detector and a Agilent MSD. The analytical HPLC column was
a HiChrome ACE AQ-5mm, C18. A gradient elution of 10% MeCN
in H2O by an increase to 95% MeCN in 2.5 min was used unless oth-
theses of a large number of different heterocycles with an
overall reaction time of approximately 30 min to give
products of high purity in good to excellent yields. The
major benefit with this approach is that purification is not
needed. Our belief is that this approach could be extended
further, to construct high libraries with high purity and
large degree of diversity.
erwise specified. Retention time for LC/MS is reported with % area
of the peak. Elemental analyses were performed by Mikrokemi AB,
Uppsala, Sweden. All starting reagents were of the best grade avail-
able (Aldrich or Lancaster) and were used without purification.
CAUTION: These reactions are not recommended to be carried
out in a multimode domestic microwave oven due to non-uni-
Table 2 Synthesis of Heterocycles via Propenonesa
Substrates
Products
Yields
81%
Purity
85%
’’
81%
92%
93%
91%
’’
94%
88%
a Reaction conditions: 100–200 mg of solid supported propenones were reacted with 0.5 equiv of substrate 20–22 at 180 °C for 10 min.
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Synthesis of Aminopropenones and Aminopropenoates
3-(Benzoyl)amino-1-cyano-4H-quinolizin-4-one (17)18
1029
form irradiation and no temperature control (risk of explosion
and thermal runaway). Also observe that the reactions are run in
a closed vessel and that in several cases the pressure during the re-
action is between 5 and 20 bar overpressure.
Solid supported compound 4 (100 mg) was added to 2-pyridyl-ace-
tonitrile (15) (5.6 µL , 0.05 mmol) in HOAc (0.5 mL). The soln was
exposed to microwaves at 180 °C for 10 min and then cooled to r.t.
The HOAc was evaporated. The residue was dissolved in CH2Cl2
and filtered through a plug of silica. Crude analysis showed a LC/
MS purity of 95%. Evaporation of the solvent gave the product 17
(13.3 mg), a total yield of 92%. The structure was confirmed by
NMR.
1H NMR (300 MHz, CDCl3): δ = 7.02 (ddd, 1 H, ArH), 7.32–7.42
(m, 4 H, ArH), 7.77 (m, 2 H, ArH), 7.81 (dt, 1 H, ArH), 8.88 (s, 1
H, NH), 8.92 (dt, 1 H, ArH), 9.11 (s, 1 H, quinolizin-4-one). The
structure was in accordance with the already published data.
Coupling of N-Benzoyl Glycine to Merrifield Resin (2)
Merrifield resin (200 mg, 1.25 mmol/g loading capacity) was
swelled in DMF (2.5 mL, 1.25 mmol, 5 equiv). N-Benzoyl glycine
(Hippuric acid) (1), Cs2CO3 (1.25 mmol) were added and the reac-
tion mixture was heated at 200 °C for 10 min. The reaction mixture
was then cooled down to r.t. by pressurized air. The residue was
washed several times with DMF, H2O, and CH2Cl2. The resin was
dried under reduce pressure in a desiccator. MAS-NMR analysis in-
dicate compound 2 in a yield of 80% (approx. 1.0 mmol/g loading).
1H NMR (CDCl3): δ = 4.24 (COCH2NCO), 5.11 (PhCH2CO), 7.30–
7.40 (4 H, Ar), 7.80 (1 H, Ar).
3-(Benzoyl)amino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-2H-1-
benzopyran-2-one (18)19
Solid supported compound 4 (100 mg) were added to 5,5 dimethyl-
1,3-cyclohexanedione (16) (7.0 mg) in HOAc (0.5 mL). The soln
was exposed to microwaves at 180 °C for 10 min. and then cooled
to r.t. The HOAc was evaporated giving product 18 (14.8 mg), a to-
tal yield of 95% and 98% purity based on LC/MS analysis. The
structure was confirmed by NMR.
1H NMR (300 MHz, CDCl3): δ = 1.2 (s, 6 H, CH3) 2.48 (s, 2 H,
CH2), 2.78 (s, 2 H, CH2), 7.5–7.7 (m, 3 H, ArH), 7.92 (m, 2 H, ArH),
8.59 (s, 1 H, NH), 8.83 (s, 1 H, CH). The structure was in accor-
dance with the already published data.
Elemental analysis: 1.35 weight % giving 0.96 mmol/g loading
Methylamination of Merrifield Resin (13)
Merrifield resin (200 mg, 1.25 mmol/g loading capacity) was treat-
ed with methylamine (2.0 mL) in H2O (40% w/w) (excess) at 150
°C for 5 min. The reaction mixture was then cooled to r.t. by pres-
surized air. The residue was washed several times with H2O,
CH2Cl2 and MeOH to give compound 13. Elemental analysis gave
1.52-weight% giving ca. 1.08 mmol/g loading.
Dimethyl Amino Propenoates from N-Benzoyl Glycine on Solid
Support (4)
(4-Phenoxy)phenylisoxazole (23)
Solid supported N-Benzoyl glycine benzyl ester 2 (250 mg, ca. 0.25
mmol) was swelled in DMF (2.5 mL), DMFDEA (1.57 mmol) was
added and the reaction mixture was heated at 180 °C for 10 min. The
reaction mixture was then cooled to r.t. by pressurized air. The res-
idue was washed several times with DMF, H2O, and CH2Cl2. The
resin was dried under reduce pressure in a desiccator. MAS-NMR
analysis indicate compound 4 but no yield was determined due to
low resolution.
Solid supported compound 14 (200 mg) was mixed with hydroxy-
lamine hydrochloride (0.5 equiv, 0.1 mmol) (20) and EtOH (2 mL).
The mixture was exposed to microwaves at 180 °C for 10 min and
then cooled to r.t. The solvent was evaporated. The product 23 was
isolated in 81% yield and 85% purity based on LC/MS analysis.
HPLC: tR 2.32 min (85%).
1H NMR (300 MHz, CDCl3): δ = 6.44 (d, 1 H, J = 1.9 Hz, isox-
azole), 7.04 (m, 4 H, ArH), 7.17 (dt, 1 H, ArH), 7.38 (m, 2 H, ArH),
7.76 (m, 2 H, ArH), 8.25 (d, 1 H, J = 1.9 Hz, isoxazole).
Benzyl Methyl Amino Propenones from 4-Phenoxy Acetophe-
none on Solid Support (14)
MS (APCI): m/z = 238.1 [M + H]+.
Benzyl methylamine (200 mg) on solid support 13 (ca. 0.2 mmol)
was swelled in DMF (2.0 mL), DMFDEA (214 µL), 4-phenoxy
acetophenone (155 µL) were added and the reaction mixture was
heated at 180 °C for 10 min. The reaction mixture was then cooled
down to r.t. by pressurized air. The residue was washed several
times with DMF, H2O, and CH2Cl2. The resin was dried under re-
duce pressure in a desiccator. MAS-NMR analysis indicated com-
pound 14 but no yield was determined due to low resolution.
1-Phenyl-5-(4-phenoxyphenyl)-pyrazole (24)
Solid supported compound 14 (200 mg) was mixed with phenylhy-
drazine (21) (0.5 equiv, 0.1 mmol) and HOAc (2 mL). The mixture
was exposed to microwaves at 180 °C for 10 min and then cooled to
r.t. The solvent was evaporated.The product 24 was isolated in 81%
yield and 93% purity.
HPLC: tR 2.48 min (93%).
1H NMR (300 MHz, CDCl3): δ = 6.48 (d, 1 H, J = 1.9 Hz, pyra-
zole), 6.91 (dd, 2 H, ArH), 7.03 (m, 2 H, ArH), 7.18 (dd, 2 H, ArH),
7.3–7.4 (m, 8 H, ArH), 7.71 (d, 1 H, J = 1.9 Hz, pyrazole).
Benzyl Methyl Amino Propenones from Ethyl 4-nitrobenzo-
ylacetate on Solid Support (19)
Benzyl methylamine (200 mg) on solid support 13 was treated with
ethyl 4-nitrobenzoylacetate as describe above for the synthesis of
compound 19. MAS-NMR analysis indicated compound 19 but no
yield was determined due to low resolution.
MS (APCI): m/z = 313.0 [M + H]+.
Ethyl 1-Phenyl-3-(4-nitrophenyl)-pyrazole-4-carboxylate (25)
Solid supported compound 19 (200 mg) was treated as described for
compound 24 using EtOH as solvent. The EtOH was evaporated
giving product 25 (31.0 mg) in 92% yield and 91% purity. The
structure was confirmed by NMR.
3-(Benzoyl)amino-4H-pyrido[1,2-a]pyrimidin-4-one (6)17
Solid supported compound 4 (100 mg) were added to 2-aminopyri-
dine (5) (6.6 mg, 0.07 mmol) in HOAc (0.5 mL). The soln was ex-
posed to microwaves at 180 °C for 10 min and then cooled to r.t.
The HOAc was evaporated giving product 6 (14.2 mg), a total yield
of 77% and 96% purity based on LC/MS analysis. The structure was
confirmed by NMR.
1H NMR (300 MHz, CDCl3): δ = 7.16 (dt, 1 H, ArH), 7.45–7.65 (m,
4 H, ArH), 7,75 (dd, 1 H, ArH), 7.95 (dd, 2 H, ArH), 8.84 (s, 1 H,
NH), 8.95 (dd, 1 H, ArH), 9.75 (s, 1 H, pyrimidin-H). The structure
was in accordance with the already published data.
HPLC: tR 2.28 min (91%).
1H NMR (300 MHz, CDCl3): δ =1.28 (t, 3 H, CH3CH2), 4.25 (q, 2
H, CH2CH3), 7.20 (m, 2 H, ArH), 7.35 (m, 3 H, ArH), 7.51(d, 2 H,
ArH), 8.21 (d, 2 H, ArH), 8.23(s, 1 H, pyrazole).
MS (APCI): m/z = 338.0 [M + H]+.
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

1030
J. Westman, R. Lundin
PAPER
(6) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I.
Ethyl 2-Phenyl-4-(4-nitrophenyl)-pyrimidine-5-carboxylate
(26)
Anal. Biochem. 1970, 34, 595.
Solid supported compound 19 (200 mg) in DMF (2 mL) was treated
with 4-amidinobenzene hydrochloride (22) (0.1 mmol, ca. 0.5
equiv) and KOH (0.15 mmol), exposed to microwaves at 180 °C for
10 min and then cooled to r.t. The solvent was evaporated. The
product (26) was isolated in 94% (32.7 mg) in 88% purity.
(7) (a) Anderson, R. C.; Stokes, J. P.; Shapiro, M. J.
Tetrahedron Lett. 1995, 36, 5311. (b) Fitch, W. L.; Detre,
G.; Holmes, C. P.; Shoolery, J. N.; Keifer, P. A. J. Org.
Chem. 1994, 59, 7955.
(8) Wehler, T.; Westman, J. Tetrahedron Lett. 1996, 37, 4771.
(9) (a) Früchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 17. (b) Thompson, L. A.; Ellman, J. A. Chem. Rev.
1996, 96, 555. (c) Balkenhohl, F.; Bussche-Hünnefeld, C.;
Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996,
35, 2289.
HPLC: tR 2.51 min (88%).
1H NMR (300 MHz, CDCl3): δ = 1.22 (t, 3 H, CH3CH2), 4.28 (q, 2
H, CH2CH3), 7.54 (m, 3 H, ArH), 7.85 (m, 2 H, ArH), 8.35 (dd, 2
H, NO2-phenyl), 8.56 (dd, 2 H, NO2-phenyl), 9.31 (s, 1 H, pyrimi-
dine).
(10) In this project SmithSynthesizerTM available from Personal
Chemistry AB was used. This instrument is fully automated
equipped with temperature and pressure control and can run
up to 120 unattended reactions sequentially the process vial
is cooled actively by pressurized air after the irradiation.
(11) Gmeiner, P.; Kraxner, J.; Bollinger, B. Synthesis 1996, 1196.
(12) Results not shown.
MS (APCI): m/z = 350.0 [M + H]+.
Acknowledgment
We thank Dr. Thomas Wehler at Biovitrum AB, Sweden for the as-
sistance with MAS-NMR analysis.
(13) Meerwein, H.; Borner, P.; Fuchs, O.; Sasse, H. J.; Schrodt,
H.; Spille, J. Chem. Ber. 1956, 89, 2060.
(14) Bienaymé, H. Tetrahedron Lett. 1998, 39, 4255.
(15) Tietze, L. F. Chem. Rev. 1996, 115.
References
(16) To our surprise we could not form the solid supported
benzylmethylamine from methylamine in MeOH under the
same conditions.
(17) (a) Tsuge, O.; Noguchi, M. Heterocycles 1981, 16, 2149.
(b) Hermecz, I.; Horvath, A.; Vasvari-Debreczy, L.;
Meszaros, Z. Synthesis 1984, 152.
(18) Smodis, J.; Stanovnik, B.; Tisler, M. J. Heterocycl. Chem.
1994, 31, 125.
(19) Kocevar, M.; Polanc, S.; Tisler, M.; Vercek, B. Synth.
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(1) Abdulla, R. F.; Brinkmeyer, R. V. Tetrahedron 1979, 35,
1675.
(2) Stanovnik, B.; Svete, J. Synlett 2000, 1077; and references
cited therein.
(3) Westman, J.; Lundin, R.; Stålberg, J.; Östbye, M.; Franzén,
Hurynowics.A. Combin. Chem. High Throughput Screen
2002, 57, 565.
(4) Westman, J. Org. Lett. 2001, 3, 3745.
(5) (a) Gisin, B. F. Helv. Chim. Acta 1973, 56, 1476.
(b) Monahan, M. W.; Gilon, C. Biopolymers 1973, 12, 2513.
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
1025
Solid Phase Synthesis of Aminopropenones and Aminopropenoates; Efficient
and Versatile Synthons for Combinatorial Synthesis of Heterocycles
Solid
P
has
a
e
Synthesis
c
of
A
minop
o
ropenones
a
b
nd Aminopropeno
W
tes estman,*a Ronny Lundinb
a
Actar AB, Franzéngatan 6, 112 51 Stockholm, Sweden
Fax +46(8)54560806; E-mail: jacob.westman@actar.se
b
Personal Chemistry AB, Kungsgatan 76, 753 18 Uppsala, Sweden
Fax +46(18)4899200
Received 20 12 2002; revised 30 01 2003
good leaving group, have been used in many applications
using conventional heating methods, probably most ex-
tensively described by Stanovnik et al.2 The intermediates
could then be reacted with dinucleophiles to form differ-
Abstract: Simple and fast solid phase methods for the synthesis of
heterocycles will be described. Two different three-step methods
are presented. The first method includes esterifications of N-pro-
tected glycine derivatives to a solid support (Merrifield resin), for-
mation of aminopropenoates and subsequent reaction with ent heterocycles. We have recently reported efficient mi-
dinucleophiles. The second method includes methylamination of a
crowave assisted one-pot methods for the synthesis of a
number of small libraries in solution3 based on alkylami-
Merrifield resin, formation of aminopropenones via in-situ forma-
tion of an active intermediate in a three-component reaction and fi-
nopropenones or alkylaminopropenoates.
nally treatment with dinucleophiles to form heterocycles. These
When producing a large number of substances in solution,
the subsequent purifications will be time-consuming, and
thereby diminish the advantage given by the short reaction
times found by the use of microwave heating.
procedures lead not only to the formation of heterocycles but also to
simultaneous intramolecular cleavage of the products from the resin
giving the product in pure form in the solution. In addition, the use
of microwave dielectric heating enhanced the velocity of all reac-
tion steps and was found to be a very efficient complement to the
solid phase synthesis.
In order to overcome cumbersome purification we found
it reasonable to try a solid phase synthesis approach to
those reactions. It is well known that the solid phase tech-
nique besides allowing for easy automation also could
eliminate certain time-consuming purification steps. For
example, a large excess of reagent could be used in a re-
action with a resin bound substrate and thus drive the re-
action to completion. The redundant amount of reagent
could then be removed by a simple filtration. On the other
hand, one well-known disadvantage of solid phase synthe-
sis is that longer reaction times usually are required com-
pared to reactions performed in a homogeneous solution
system. We have however found that also the reaction
times in heterogeneous systems could be substantially
shortened by the use of microwave heating.4
Key words: solid-phase synthesis, microwave irradiation, combi-
natorial chemistry, heterocycles
Highly functionalized heterocycles of various ring sizes,
with different heteroatoms and substitution patterns are of
major interest in the pharmaceutical and agricultural in-
dustry due to the their many intrinsic biological proper-
ties.
In medicinal chemistry in general, and combinatorial
chemistry in particular, the use of versatile synthons or
versatile scaffolds which are available after just a few re-
action steps are of great interest. One reagent producing
such synthons is N,N-dimethylformamide diethyl acetal
(DMFDEA).1 Condensation reactions between an activat-
ed methyl or methylene group adjacent to a keto or ester
functionality and DMFDEA form alkylaminopropenones
or alkylaminopropenoates (see Scheme 1). These inter-
mediates, in which the dimethylamino moiety acts as a
The analysis of the degree of incorporation of a certain
compound into the resin is usually performed by cleavage
of the compound from the resin and then analyzing the
cleavage mixture,5 by quantitative colorizing methods6 or
by elemental analysis. We chose to adopt a recently devel-
Scheme 1 Examples of the formation of dimethylaminopropenoates (A) and dimethylaminopropenones (B) from dimethylformamide
diethylacetal.
Synthesis 2003, No. 7, Print: 20 05 2003.
Art Id.1437-210X,E;2003,0,07,1025,1030,ftx,en;C00102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1026
J. Westman, R. Lundin
PAPER
1
oped NMR-technique, Magic angle spinning H NMR group (PhCH2OCO) the yield could be determined as
(MAS-NMR) analysis. The technology was developed shown in Figure 1. For the two last steps we applied the
some years ago7,8 and has shown to work well with resins same protocols as was developed for solution phase3 with
such as TentaGel and Merrifield resin. We herein describe minor modifications. Formation of an ester linkage be-
the efficient combination of microwave heating and solid tween a carboxylic acid substrate and a solid phase resin
phase synthesis for reducing both the reaction time and is a common reaction in the area of peptide synthesis and
the purification time.
combinatorial chemistry and is well described in the liter-
ature.5,9 Merrifield resin was treated with 5 equivalents of
N-benzoylated glycine 1 together with cesium carbonate
in 2 mL of DMF at 200 °C for 10 min10 giving 2. The anal-
ysis (MAS-NMR and elemental analysis) showed a load-
ing of approximately 1 mmol/g (80% yield) (Figure 1),
which is in the same range as described in the literature,
but approximately within a 100-fold shorter reaction time.
After washing, the resin was treated with 5 equivalents
DMFDEA in 2.5 ml DMF at 180 °C for 10 min to form the
dimethylamino propenoates intermediate 4.
Dialkylamino propenoates react with dinucleophiles in a
two-step reaction where substitution of the dimethylami-
no group is followed by a nucleophilic attack on the ester
functionality, which cleaves the ester. Dialkylamino pro-
penones also reacts with dinucleophiles. In this case the
reactions proceed differently since a condensation reac-
tion with the keto function is followed by the substitution
of the dialkylamino group. Based on the two different re-
action pathways, two different solid phase intermediates
were proposed as described in Scheme 2. Since the pro-
posed procedures form the heterocycles by an intramolec-
ular cyclization mechanism that simultaneously cleaves
the products from the resin it will give the products in pure
form in the solution and thus, any reaction step for cleav-
age from the resin is not needed. Since the heterocycles
from dialkylpropenoates are formed after cleavage of the
ester (approach 1) the chosen approach was therefore to
form the ester bond to the solid phase. For the formation
of heterocycles from propenones (approach 2) the chosen
approach was to bind the leaving group (the dialkylamino
group) to the solid phase.
Scheme 3 Synthesis of 3-(benzoyl)amino-4H-pyrido[1,2-a]pyrimi-
din-4-one. Reaction conditions: (i) Hippuric acid (5 equiv), CsCO3 (5
equiv), DMF, 200 °C, 10 min. (ii) DMFDEA (5 equiv) in DMF, 180
°C, 10 min (iii) 2-aminopyridine (0.5 equiv) in HOAc, 180 °C, 10
min.
Scheme 2 Approaches 1 and 2.
Synthesis of Heterocycles from Solid Phase Bound
Dialkylaminopropenoates
Formation of heterocycles where one of the substrates is
bound to the resin was performed in a 3 step reaction as
described in Scheme 3. Magic angle spinning NMR
(MAS-NMR) analysis7,8 was used for the protocol devel-
opment. NMR analysis of Merrifield resin gives, howev-
er, a poorer resolution with respect to line width and
spectral purity compared to resins like Tentagel.8 Merri-
field resin was used due to its high loading capacity and
high thermal stability. By comparing the peak area from
the methylene group in the resin handle (PhCH2Cl) and
the peak area from the solid phase benzylester methylene
Figure 1 By comparing the peak area of the benzylic methylene
group the yield could be determined.
The resin was washed, dried and then swelled in 0.5 mL
of HOAc. In order to minimize the amount of unreacted
dinucleophiles in the final reaction solution we only added
0.5–0.7 equivalents of dinucleophiles (5, 15, 16) to the re-
action mixtures, based on an assumed 1 mmol/g loading
of the intermediate. The reaction mixtures were heated for
an additional 10 min at 180 °C. After filtration and wash-
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Synthesis of Aminopropenones and Aminopropenoates
1027
ing of the resin, evaporation of the solvent was performed reaction steps needed to form the reagent. This strategy
and the products (6, 17, 18) were found in high purity was therefore not adopted. Meerwein et al. have also de-
(>90%) and in yields between 77–95% (see Table 1).
scribed that when a dialkylamine was reacted with
DMFDEA an amine exchange occurs in-situ giving the di-
alkylformamide diethylacetal. Unfortunately, when trying
this method, benzyl methylformamide was formed as the
only product. Bienaymé14 reported recently the formation
of substituted isonitriles by treatment of a dialkyl amine,
Synthesis of Heterocycles from Solid Phase Bound
Dialkylaminopropenones
Approach 2 (Scheme 2) where dialkyl formamide diethyl imidazole diethylacetal and methyl isocyanoacetate,
acetal is bound to the solid phase and where the cleavage which form dialkylamino propenoates by a three-compo-
from the resin occurs when the dialkyl amino group is nent cascade reaction15 mechanism (Scheme 5). Since this
cleaved by a nucleophile was not as straightforward as ap- multi-component approach forms the reagent in-situ it
proach 1. The idea was to form the dialkylformamide di- also reduces the number of reaction steps needed for the
ethyl acetal on solid phase starting from methylaminated formation of the reactive intermediate.
Merrifield resin (benzylchloride handle) and consequent-
ly we used benzyl methylamine (7) as a model substance
in order to develop a protocol in solution which then could
be transferred into solid phase conditions (Scheme 4).
Benzyl methylamine was treated with 9 equivalents of tri-
ethyl orthoformate (8) in 2.0 mL of DMF at 200 °C for 5
Scheme 5 Formation of amino propenoates in a multicomponent
min. to form benzyl methylformamide diethylacetal (9)
approach via amine exchange.
according to a method described by Gmeiner et al.11 How-
ever, we only found benzyl methylformamide as the prod-
uct 10. On the other hand we found, in accordance with
We therefore decided to try this approach to our model
synthesis and we found that when reacting benzylmethyl-
amine with DMFDEA and acetophenone in 2.0 mL of
the reference, that imidazole 11 forms the imidazolium di-
ethylacetal (12) after treatment with triethyl-
orthoformate12 in 2.0 mL of DMF at 200 °C for 5 min.
DMF at 180 °C for 5 min the desired propenone was
formed in good yield based on LC/MS analysis. The out-
come of the reaction indicated that this procedure could be
successfully applied to our planned strategy with the solid
phase linked N-methyl benzylamine The following proce-
dure was therefore performed: Merrifield resin was react-
ed with 2.0 mL methylamine in water at 150 °C for 10 min
to form the solid supported benzylmethylamine (13) in
high yield (86% yield, 1.08 mmol/g based on elemental
analysis). The MAS-NMR analysis was in this case diffi-
cult to interpret and therefore not used.16 The resin was,
after washing, treated with 5 equivalents DMFDEA to-
gether with 5 equivalents of 4-phenoxyacetophenone at
180 °C for 10 min in 2.0 mL of DMF to form the solid sup-
ported benzyl methyl aminopropenones 14. MAS-NMR
showed that products were formed but the spectra was not
resolved well enough to make a good interpretation.
Scheme 4 Synthesis of benzyl methylformamide. Reaction conditi-
ons: DMF, 200 °C, 5 min.
Our plan was then to follow the procedure describe by
Meerwein et al.13 for the synthesis of DMFDEA from
DMF. The solid supported benzylmethyl amine could be
treated with triethyloxonium tetrafluoroborate to afford a
tetrafluoroborate salt. Treatment of the salt with sodium
ethoxide should then give the diethylacetal compound.
The major drawback with this procedure is the number of
After washing, the resin was finally treated (the resin
bound intermediate in excess) at 180°C for 10 min in 2.0
mL EtOH, DMF, or HOAc with 0.5 equivalents of the
dinucleophiles to form the heterocycles in pure form. In
Scheme 6 Example of a solid phase synthesis of 1-Phenyl-5-(4-phenoxyphenyl)-pyrazole. Reaction conditions: (i) MeNH2 in H2O, 150 °C,
10 min (ii) DMF, 150 °C, 10 min (iii) HOAc, 150 °C, 10 min.
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

1028
J. Westman, R. Lundin
PAPER
Table 1 Synthesis of Heterocycles via Propenoatesa
Substrates
Products
Yields
77%
Purity
96%
92%
95%
95%
98%
a Reaction conditions: 100–200 mg of solid supported propenoates were reacted with 0.5 equiv. of substrate 5, 15, 16 in HOAc at 180 °C for
10 min.
The microwave-assisted reactions were performed in a SmithSyn-
thesizerTM, a single mode microwave cavity, from Personal Chem-
istry. NMR spectra were recorded in CDCl3 or DMSO-d6 at 25 °C,
using a Bruker at 300 MHz (1H)/75 MHz (13C) or a Varian 600 MHz
instrument with a nano probe for the MAS-NMR analysis. All NMR
order to verify the developed methods described above,
we performed a number of syntheses of heterocycles
where both approaches 1 and 2 were performed
(Scheme 6, Table 2).
In conclusion, we have described two ways to form acti- spectra recorded were in agreement with the postulated structures
and only selected data are reported. HPLC-MS chromatograms and
vated aminopropenones and aminopropenoates on solid
spectra were obtained with an Agilent 1100 system with a diode ar-
phase which in turn could be used in combinatorial syn-
ray detector and a Agilent MSD. The analytical HPLC column was
a HiChrome ACE AQ-5mm, C18. A gradient elution of 10% MeCN
in H2O by an increase to 95% MeCN in 2.5 min was used unless oth-
theses of a large number of different heterocycles with an
overall reaction time of approximately 30 min to give
products of high purity in good to excellent yields. The
major benefit with this approach is that purification is not
needed. Our belief is that this approach could be extended
further, to construct high libraries with high purity and
large degree of diversity.
erwise specified. Retention time for LC/MS is reported with % area
of the peak. Elemental analyses were performed by Mikrokemi AB,
Uppsala, Sweden. All starting reagents were of the best grade avail-
able (Aldrich or Lancaster) and were used without purification.
CAUTION: These reactions are not recommended to be carried
out in a multimode domestic microwave oven due to non-uni-
Table 2 Synthesis of Heterocycles via Propenonesa
Substrates
Products
Yields
81%
Purity
85%
’’
81%
92%
93%
91%
’’
94%
88%
a Reaction conditions: 100–200 mg of solid supported propenones were reacted with 0.5 equiv of substrate 20–22 at 180 °C for 10 min.
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Synthesis of Aminopropenones and Aminopropenoates
3-(Benzoyl)amino-1-cyano-4H-quinolizin-4-one (17)18
1029
form irradiation and no temperature control (risk of explosion
and thermal runaway). Also observe that the reactions are run in
a closed vessel and that in several cases the pressure during the re-
action is between 5 and 20 bar overpressure.
Solid supported compound 4 (100 mg) was added to 2-pyridyl-ace-
tonitrile (15) (5.6 µL , 0.05 mmol) in HOAc (0.5 mL). The soln was
exposed to microwaves at 180 °C for 10 min and then cooled to r.t.
The HOAc was evaporated. The residue was dissolved in CH2Cl2
and filtered through a plug of silica. Crude analysis showed a LC/
MS purity of 95%. Evaporation of the solvent gave the product 17
(13.3 mg), a total yield of 92%. The structure was confirmed by
NMR.
1H NMR (300 MHz, CDCl3): δ = 7.02 (ddd, 1 H, ArH), 7.32–7.42
(m, 4 H, ArH), 7.77 (m, 2 H, ArH), 7.81 (dt, 1 H, ArH), 8.88 (s, 1
H, NH), 8.92 (dt, 1 H, ArH), 9.11 (s, 1 H, quinolizin-4-one). The
structure was in accordance with the already published data.
Coupling of N-Benzoyl Glycine to Merrifield Resin (2)
Merrifield resin (200 mg, 1.25 mmol/g loading capacity) was
swelled in DMF (2.5 mL, 1.25 mmol, 5 equiv). N-Benzoyl glycine
(Hippuric acid) (1), Cs2CO3 (1.25 mmol) were added and the reac-
tion mixture was heated at 200 °C for 10 min. The reaction mixture
was then cooled down to r.t. by pressurized air. The residue was
washed several times with DMF, H2O, and CH2Cl2. The resin was
dried under reduce pressure in a desiccator. MAS-NMR analysis in-
dicate compound 2 in a yield of 80% (approx. 1.0 mmol/g loading).
1H NMR (CDCl3): δ = 4.24 (COCH2NCO), 5.11 (PhCH2CO), 7.30–
7.40 (4 H, Ar), 7.80 (1 H, Ar).
3-(Benzoyl)amino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-2H-1-
benzopyran-2-one (18)19
Solid supported compound 4 (100 mg) were added to 5,5 dimethyl-
1,3-cyclohexanedione (16) (7.0 mg) in HOAc (0.5 mL). The soln
was exposed to microwaves at 180 °C for 10 min. and then cooled
to r.t. The HOAc was evaporated giving product 18 (14.8 mg), a to-
tal yield of 95% and 98% purity based on LC/MS analysis. The
structure was confirmed by NMR.
1H NMR (300 MHz, CDCl3): δ = 1.2 (s, 6 H, CH3) 2.48 (s, 2 H,
CH2), 2.78 (s, 2 H, CH2), 7.5–7.7 (m, 3 H, ArH), 7.92 (m, 2 H, ArH),
8.59 (s, 1 H, NH), 8.83 (s, 1 H, CH). The structure was in accor-
dance with the already published data.
Elemental analysis: 1.35 weight % giving 0.96 mmol/g loading
Methylamination of Merrifield Resin (13)
Merrifield resin (200 mg, 1.25 mmol/g loading capacity) was treat-
ed with methylamine (2.0 mL) in H2O (40% w/w) (excess) at 150
°C for 5 min. The reaction mixture was then cooled to r.t. by pres-
surized air. The residue was washed several times with H2O,
CH2Cl2 and MeOH to give compound 13. Elemental analysis gave
1.52-weight% giving ca. 1.08 mmol/g loading.
Dimethyl Amino Propenoates from N-Benzoyl Glycine on Solid
Support (4)
(4-Phenoxy)phenylisoxazole (23)
Solid supported N-Benzoyl glycine benzyl ester 2 (250 mg, ca. 0.25
mmol) was swelled in DMF (2.5 mL), DMFDEA (1.57 mmol) was
added and the reaction mixture was heated at 180 °C for 10 min. The
reaction mixture was then cooled to r.t. by pressurized air. The res-
idue was washed several times with DMF, H2O, and CH2Cl2. The
resin was dried under reduce pressure in a desiccator. MAS-NMR
analysis indicate compound 4 but no yield was determined due to
low resolution.
Solid supported compound 14 (200 mg) was mixed with hydroxy-
lamine hydrochloride (0.5 equiv, 0.1 mmol) (20) and EtOH (2 mL).
The mixture was exposed to microwaves at 180 °C for 10 min and
then cooled to r.t. The solvent was evaporated. The product 23 was
isolated in 81% yield and 85% purity based on LC/MS analysis.
HPLC: tR 2.32 min (85%).
1H NMR (300 MHz, CDCl3): δ = 6.44 (d, 1 H, J = 1.9 Hz, isox-
azole), 7.04 (m, 4 H, ArH), 7.17 (dt, 1 H, ArH), 7.38 (m, 2 H, ArH),
7.76 (m, 2 H, ArH), 8.25 (d, 1 H, J = 1.9 Hz, isoxazole).
Benzyl Methyl Amino Propenones from 4-Phenoxy Acetophe-
none on Solid Support (14)
MS (APCI): m/z = 238.1 [M + H]+.
Benzyl methylamine (200 mg) on solid support 13 (ca. 0.2 mmol)
was swelled in DMF (2.0 mL), DMFDEA (214 µL), 4-phenoxy
acetophenone (155 µL) were added and the reaction mixture was
heated at 180 °C for 10 min. The reaction mixture was then cooled
down to r.t. by pressurized air. The residue was washed several
times with DMF, H2O, and CH2Cl2. The resin was dried under re-
duce pressure in a desiccator. MAS-NMR analysis indicated com-
pound 14 but no yield was determined due to low resolution.
1-Phenyl-5-(4-phenoxyphenyl)-pyrazole (24)
Solid supported compound 14 (200 mg) was mixed with phenylhy-
drazine (21) (0.5 equiv, 0.1 mmol) and HOAc (2 mL). The mixture
was exposed to microwaves at 180 °C for 10 min and then cooled to
r.t. The solvent was evaporated.The product 24 was isolated in 81%
yield and 93% purity.
HPLC: tR 2.48 min (93%).
1H NMR (300 MHz, CDCl3): δ = 6.48 (d, 1 H, J = 1.9 Hz, pyra-
zole), 6.91 (dd, 2 H, ArH), 7.03 (m, 2 H, ArH), 7.18 (dd, 2 H, ArH),
7.3–7.4 (m, 8 H, ArH), 7.71 (d, 1 H, J = 1.9 Hz, pyrazole).
Benzyl Methyl Amino Propenones from Ethyl 4-nitrobenzo-
ylacetate on Solid Support (19)
Benzyl methylamine (200 mg) on solid support 13 was treated with
ethyl 4-nitrobenzoylacetate as describe above for the synthesis of
compound 19. MAS-NMR analysis indicated compound 19 but no
yield was determined due to low resolution.
MS (APCI): m/z = 313.0 [M + H]+.
Ethyl 1-Phenyl-3-(4-nitrophenyl)-pyrazole-4-carboxylate (25)
Solid supported compound 19 (200 mg) was treated as described for
compound 24 using EtOH as solvent. The EtOH was evaporated
giving product 25 (31.0 mg) in 92% yield and 91% purity. The
structure was confirmed by NMR.
3-(Benzoyl)amino-4H-pyrido[1,2-a]pyrimidin-4-one (6)17
Solid supported compound 4 (100 mg) were added to 2-aminopyri-
dine (5) (6.6 mg, 0.07 mmol) in HOAc (0.5 mL). The soln was ex-
posed to microwaves at 180 °C for 10 min and then cooled to r.t.
The HOAc was evaporated giving product 6 (14.2 mg), a total yield
of 77% and 96% purity based on LC/MS analysis. The structure was
confirmed by NMR.
1H NMR (300 MHz, CDCl3): δ = 7.16 (dt, 1 H, ArH), 7.45–7.65 (m,
4 H, ArH), 7,75 (dd, 1 H, ArH), 7.95 (dd, 2 H, ArH), 8.84 (s, 1 H,
NH), 8.95 (dd, 1 H, ArH), 9.75 (s, 1 H, pyrimidin-H). The structure
was in accordance with the already published data.
HPLC: tR 2.28 min (91%).
1H NMR (300 MHz, CDCl3): δ =1.28 (t, 3 H, CH3CH2), 4.25 (q, 2
H, CH2CH3), 7.20 (m, 2 H, ArH), 7.35 (m, 3 H, ArH), 7.51(d, 2 H,
ArH), 8.21 (d, 2 H, ArH), 8.23(s, 1 H, pyrazole).
MS (APCI): m/z = 338.0 [M + H]+.
Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York

1030
J. Westman, R. Lundin
PAPER
(6) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I.
Ethyl 2-Phenyl-4-(4-nitrophenyl)-pyrimidine-5-carboxylate
(26)
Anal. Biochem. 1970, 34, 595.
Solid supported compound 19 (200 mg) in DMF (2 mL) was treated
with 4-amidinobenzene hydrochloride (22) (0.1 mmol, ca. 0.5
equiv) and KOH (0.15 mmol), exposed to microwaves at 180 °C for
10 min and then cooled to r.t. The solvent was evaporated. The
product (26) was isolated in 94% (32.7 mg) in 88% purity.
(7) (a) Anderson, R. C.; Stokes, J. P.; Shapiro, M. J.
Tetrahedron Lett. 1995, 36, 5311. (b) Fitch, W. L.; Detre,
G.; Holmes, C. P.; Shoolery, J. N.; Keifer, P. A. J. Org.
Chem. 1994, 59, 7955.
(8) Wehler, T.; Westman, J. Tetrahedron Lett. 1996, 37, 4771.
(9) (a) Früchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. Engl.
1996, 35, 17. (b) Thompson, L. A.; Ellman, J. A. Chem. Rev.
1996, 96, 555. (c) Balkenhohl, F.; Bussche-Hünnefeld, C.;
Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996,
35, 2289.
HPLC: tR 2.51 min (88%).
1H NMR (300 MHz, CDCl3): δ = 1.22 (t, 3 H, CH3CH2), 4.28 (q, 2
H, CH2CH3), 7.54 (m, 3 H, ArH), 7.85 (m, 2 H, ArH), 8.35 (dd, 2
H, NO2-phenyl), 8.56 (dd, 2 H, NO2-phenyl), 9.31 (s, 1 H, pyrimi-
dine).
(10) In this project SmithSynthesizerTM available from Personal
Chemistry AB was used. This instrument is fully automated
equipped with temperature and pressure control and can run
up to 120 unattended reactions sequentially the process vial
is cooled actively by pressurized air after the irradiation.
(11) Gmeiner, P.; Kraxner, J.; Bollinger, B. Synthesis 1996, 1196.
(12) Results not shown.
MS (APCI): m/z = 350.0 [M + H]+.
Acknowledgment
We thank Dr. Thomas Wehler at Biovitrum AB, Sweden for the as-
sistance with MAS-NMR analysis.
(13) Meerwein, H.; Borner, P.; Fuchs, O.; Sasse, H. J.; Schrodt,
H.; Spille, J. Chem. Ber. 1956, 89, 2060.
(14) Bienaymé, H. Tetrahedron Lett. 1998, 39, 4255.
(15) Tietze, L. F. Chem. Rev. 1996, 115.
References
(16) To our surprise we could not form the solid supported
benzylmethylamine from methylamine in MeOH under the
same conditions.
(17) (a) Tsuge, O.; Noguchi, M. Heterocycles 1981, 16, 2149.
(b) Hermecz, I.; Horvath, A.; Vasvari-Debreczy, L.;
Meszaros, Z. Synthesis 1984, 152.
(18) Smodis, J.; Stanovnik, B.; Tisler, M. J. Heterocycl. Chem.
1994, 31, 125.
(19) Kocevar, M.; Polanc, S.; Tisler, M.; Vercek, B. Synth.
Commun. 1989, 19, 1713.
(1) Abdulla, R. F.; Brinkmeyer, R. V. Tetrahedron 1979, 35,
1675.
(2) Stanovnik, B.; Svete, J. Synlett 2000, 1077; and references
cited therein.
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Synthesis 2003, No. 7, 1025–1030 ISSN 0039-7881 © Thieme Stuttgart · New York