The effect of microwave irradiation on carbodiimide-mediated esterifications on solid support

Article abstract of DOI:10.1016/S0040-4020(01)00260-5

The esterification of a polymer-supported alcohol (PS Wang resin) with benzoic acid was investigated using microwave irradiation. Activation of the carboxylic acid was carried out using diisopropylcarbodiimide, either via the O-acylisourea or symmetrical anhydride protocols. In the microwave-assisted solid-phase coupling using the O-acylisourea method the main product of the reaction was 1-benzoyl-1,3-diisopropylurea, formed by rearrangement of the thermolabile isourea intermediate. On the other hand, significant rate enhancements were observed for the coupling of benzoic anhydride to Wang resin using microwave flash heating in 1-methyl-2-pyrrolidone as solvent. Reaction times were reduced from 2 to 3 days using conventional conditions, to 10 min by microwave dielectric heating.

Full text of DOI:10.1016/S0040-4020(01)00260-5

TETRAHEDRON
Pergamon
Tetrahedron 57 '2001) 3915±3920
The effect of microwave irradiation on carbodiimide-mediated
esteri®cations on solid support
Alexander Stadler and C. Oliver Kappep
Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Received 25 January 2001; accepted 22 February 2001
AbstractÐThe esteri®cation of a polymer-supported alcohol 'PS Wang resin) with benzoic acid was investigated using microwave
irradiation. Activation of the carboxylic acid was carried out using diisopropylcarbodiimide, either via the O-acylisourea or symmetrical
anhydride protocols. In the microwave-assisted solid-phase coupling using the O-acylisourea method the main product of the reaction was
1-benzoyl-1,3-diisopropylurea, formed by rearrangement of the thermolabile isourea intermediate. On the other hand, signi®cant rate
enhancements were observed for the coupling of benzoic anhydride to Wang resin using microwave ¯ash heating in 1-methyl-2-pyrrolidone
as solvent. Reaction times were reduced from 2 to 3 days using conventional conditions, to 10 min by microwave dielectric heating. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
bound alcohols '®rst residue attachment),5 the activation of
carboxylic acids by carbodiimides still constitutes the most
frequently used method.1±5
One of the most common transformations in solid-phase
organic synthesis involves the construction of an ester link-
age between a solid-supported hydroxy or halogen function-
ality and a carboxylic acid derivative.1±5 While different
strategies to generate suchan ester linkage on solid support
are available, one especially convenient and straightforward
method involves the direct esteri®cation of a polymer-
bound alcohol with a carboxylic acid using suitable
coupling protocols.1±5 Although many different reagent
combinations, e.g. of the aminium or phosphonium type,
have been reported in the recent literature, in particular in
the context of attaching protected amino acids to polymer-
Depending on the speci®c reaction conditions, such an acti-
vation proceeds either via an O-acylisourea '1 equiv. acid
used), or via a symmetrical anhydride '2 equiv. acids) as
reactive species 'Scheme 1).6±8 In the latter case, the carbo-
diimide is ®rst treated withthe carboxylic acid in a separate
reaction vessel, before the polymer-bound alcohol is added
to the preformed anhydride.5 Alternatively, in situ activation
of the carboxylic acid as, for example, a reactive benzo-
triazole ester 'R1CO2Bt) is also possible employing
1-hydroxy-1H-benzotriazole 'HOBt) as additive in the
Scheme 1.
Keywords: combinatorial chemistry; solid-phase synthesis; microwave-enhanced chemistry; O-acylisourea; anhydrides.
Corresponding author. Tel.: 143-316-3805352; fax: 143-316-3809840; e-mail: oliver.kappe@uni-graz.at
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'01)00260-5

3916
A. Stadler, C. O. Kappe / Tetrahedron 57 +2001) 3915±3920
one-pot sequence.5 Although most of the transformations
shown in Scheme 1 have been optimized to proceed under
mild reaction conditions for a variety of carboxylic acids
and polymer supports, long reaction times and non-quanti-
tative loadings have nevertheless been known to create
problems in these solid-phase esteri®cation reactions.1±5
limited solubility of some of the anhydrides used in other
solvents, particularly in DCM.1±5,19±21
For the present model studies involving benzoic acid we
have generally employed a DCM/DMF 9:1 mixture for the
isourea method, since this solvent combination is found
most frequently in the literature. All anhydride reactions
were carried out in 1-methyl-2-pyrrolidone 'NMP) instead
of the more commonly used DMF because of our previous
encouraging experience withthis solvent in microwave-
assisted solid-phase synthesis 'see below).18 For an initial
evaluation of bothmethods two series of kinetic experi-
ments coupling benzoic acid to polystyrene Wang resin
'2.3 mequiv. OH/g) were carried out. In the ®rst series,
the acid was coupled via the one-pot isourea method
'3.5 equiv. DIC, 5 equiv. PhCO2H) witheth above-
mentioned DCM/DMF solvent mixture and small amounts
of DMAP as catalyst. These are essentially the conditions
used, e.g., by Ley et al.21 for closely related coupling proto-
cols. Similarly, benzoic anhydride couplings '5 equiv.) were
carried out in NMP in the presence of catalytic amounts of
DMAP.22 These experiments were conveniently conducted
in a manual synthesizer in Te¯on frits at room temperature
'see Section 3). In all experiments the loading of the resins
In recent years, the concept of speeding up resin-bound
chemistry by microwave activation has created a lot of
interest, bothfrom teh academic and industrial com-
munities.9±18 In a number of publications signi®cant rate-
accelerations and very high loadings for several solid-phase
protocols including, e.g., peptide,9 Suzuki,10 Ugi,11 and
Knoevenagel reactions,12 have been reported, with reaction
times being reduced in some cases from hours to a few
minutes.9±17 Despite these initial reports, the bene®ts asso-
ciated with this new technology have not been rigorously
established, since in many cases domestic household micro-
wave ovens have been employed that do not allow the moni-
toring of temperature or pressure pro®les during the
irradiation experiments. In a recent study using dedicated
microwave reactors we have demonstrated that microwave
¯ash heating, i.e. the very rapid heating of the reaction
mixture, in combination withhighreaction temperatures,
may be responsible for the observed rate enhancements
using this non-conventional heating method.18 We now
report on the effect of microwave irradiation on the ester
coupling processes outlined in Scheme 1, speci®cally on the
carbodiimide-mediated attachment of benzoic acid to Wang
resin.
is estimated by on-bead FTIR analysis 'nCvOˆ1720 cm21
,
KBr pellet, cf. Fig. 1)23 and also determined accurately by
cleavage of all the loaded resins with 50% tri¯uoroacetic
acid 'TFA) in DCM 'Fig. 2). As can be seen from inspection
of the data in Fig. 2, both coupling protocols provide
rather similar results in terms of reaction rates. Under the
relatively concentrated reaction conditions used here
2. Results and discussion
As a suitable model reaction for the transformations shown
in Scheme 1 we have chosen the diisopropylcarbodiimide
'DIC)-mediated coupling of benzoic acid to Wang resin. As
a solid-support standard polystyrene Wang resins '1% DVB
cross linked) were employed. In the literature such DIC-
promoted acid couplings have not only been described for
loading N-protected amino acids to solid supports,5 but also
have been used to attach aromatic,19 aliphatic,20 and acrylic
acids21 onto resin. Therefore, a number of different experi-
mental procedures are available for either the so-called
O-acylisourea method, or the symmetrical anhydride proto-
col.1±5,19±21 In general, when the reaction is conducted in
one pot, i.e. by adding bothDIC and the corresponding acid
to the hydroxy functionalized resin in the presence of a
suitable catalyst suchas DMAP, an O-acylisourea deriva-
tive is implicated as an intermediate.7 On the other hand,
many procedures allow for the initial preparation and iso-
lation of the corresponding symmetrical anhydride by treat-
ment of DIC with2 equiv. of acid, followed by addition of
the anhydride to the hydroxy resin and DMAP.5 Naturally, it
is dif®cult to differentiate strictly between the isourea and
anhydride reaction pathways if the one-pot method is
chosen, in particular when non-equal amounts of carbodi-
imide and acid are employed, as is frequently the case. The
choice of solvent in these processes is also critical. In most
literature procedures, mixtures of dichloromethane 'DCM)
and dimethylformamide 'DMF) are employed for the
isourea coupling method, whereas DMF is the solvent of
choice for the anhydride reaction, due to the apparently
Figure 1. FTIR-monitoring of benzoic acid coupling to Wang resin
'nCvOˆ1720 cm21, KBr pellet).
Figure 2. Kinetics of O-acylisourea versus symmetrical anhydride coupling
'ACT PLS 4£6 synthesizer).

A. Stadler, C. O. Kappe / Tetrahedron 57 +2001) 3915±3920
3917
measurements 'Fig. 1), which demonstrated the increasing
intensity of the ester carbonyl absorption at 1720 cm21. By
subsequent cleavage the exact yields were determined for
reaction times of 18 h'66%), 48 h'87%), and 72 h'99%).
Complete conversion under these conditions at room
temperature '258C) therefore requires ca. 2±3 days. A simi-
lar set of experiments was then conducted at elevated, i.e.
re¯ux temperature. As one would expect the speed of this
coupling process is signi®cantly enhanced by performing
the solid-phase process at re¯ux temperature, i.e. 448C for
the DCM/DMF 9:1 mixture. Here, a complete loading of the
resin was achievable within 3 h 'loadings after:
15 minˆ32%; 30 minˆ59%; 45 minˆ82%; 60 min 93%;
180 min 99%). Using the identical set of Pyrex glassware
the same experiments were carried out in a microwave
reactor having a re¯ux condenser ®tted through the roof
of the cavity 'see Section 3). Here, a very similar conversion
rate was observed at the identical temperature of 448C.
Although superheating of solvents at atmospheric pressure
is a common phenomenon when dealing with microwave
heating of organic solvents,24,25 we have discovered that
with the instrument and setup used in the experiments
reported herein, magnetic stirring of the reaction mixture
effectively eliminates this phenomenon as demonstrated
for suchcommon solvents, suchas ethanol and acetone
'Fig. 3). Therefore, the nearly identical conversion rates in
the microwave-irradiation experiment as compared to the
conventional heating are not surprising. A non-thermal
microwave effect could evidently not have been observed.
Figure 3. Heating pro®les 'superheating effects) for ethanol, acetone, and
DCM/DMF 9:1. Sample volume 25 mL, 500 W output power '300 W for
acetone), ¯uoroptic temperature measurement. Magnetic stirring on after
3 min 'A), stirring off after 4 min 'B), microwave power off after 5 min.
Temperatures for ethanol: 898C 'superheating), 788C 'withstirring); for
acetone: 628C 'superheating), 568C 'withstirring); for DCM/DMF 9:1:
518C 'superheating); 448C 'withstirring).
'0.46 mol/L of acid or anhydride, respectively) both pro-
cedures led to a more or less quantitative coupling in ca.
3 h, with a slight preference for the anhydride method.
While a direct kinetic comparison between the two pro-
cedures is not feasible because of the different relative
amounts of reagents and different solvents used, the above
experiments nevertheless suggest that a priori both methods
may be suitable for potential rate enhancements by micro-
wave irradiation.
With this information in hand we have conducted a series of
experiments at elevated temperature using bothconven-
tional and microwave dielectric heating under atmospheric
and sealed vessel conditions. These irradiation experiments
were either carried out at a ®xed microwave output power
'e.g. 100 W), or at a preselected maximum temperature. In
the latter case, the software algorithm of the microwave
reactor adjusts the output power so that the selected
temperature pro®le is maintained. Because we wanted to
observe and evaluate potential rate-enhancement effects
more easily, we have chosen to use more dilute reaction
conditions for all subsequent experiments. This was also
necessitated by the microwave reactor and ¯uoroptic
temperature measurement design, which would not allow
such small volumes to be used as in the above synthesizer
experiments 'ca. 5 mL). Towards this end we have designed
a new series of experiments for the isourea coupling proto-
col using Wang resin and the previously employed reagent
and solvent mix '3.5 equiv. DIC, 5 equiv. PhCO2H, DCM/
DMF 9:1) in conventional glassware. Due to the now larger
volume of solvent the effective concentration of benzoic
acid was reduced to ca. 0.13 mol/L 'see Section 3). The
coupling reaction was conveniently monitored by FTIR-
Since we wanted to further decrease the reaction time by
microwave activation we decided to repeat the above
irradiation experiments in a closed vessel system under
pressure. For this purpose the reaction mixture 'identical
to the experiments carried out under atmospheric pressure)
was placed inside a Te¯on-based sealed vessel speci®cally
designed for microwave-irradiation experiments that allows
on-line temperature and pressure monitoring 'see Section
3).18,26 This setup was initially irradiated at 100 W which
led to a coupling in 73% yield after 15 min. Surprisingly,
this seemed to be the maximum achievable conversion.
Further increase of the irradiation power, leading to higher
reaction temperatures, diminished the conversion rates,
rather than increasing them 'Table 1). Equally unsuccessful
were attempts to change the reaction times 'data not shown).
Analysis of the reaction mixture after ®ltration from the
resin indicated in all cases the formation of 1-benzoyl-1,3-
diisopropylurea in substantial molar ratios. The reason for
this unsatisfactory result is clearly the rearrangement of the
DIC-activated acid 'i.e. the O-acylisourea) under the
relatively drastic reaction conditions used to the thermo-
dynamically more stable N-acylurea 'Scheme 2).6±8
Table 1. Effects of microwave power on the conversion in the O-acylisourea-mediated coupling of benzoic acid to Wang resin
Microwave power 'W)
Temperature '8C)
Pressure 'bar)
Conversion '%)
50
68
89
132
153
1.4
2.7
8.8
10.1
48
73
53
50
100
200
400
Sealed vessel conditions, 15 min reaction time, 3.5 equiv. DIC, 5 equiv. PhCO2H, solvent: DCM/DMF 9:1; catalyst: DMAP. Yields given in % as determined
after cleavage; see Section 3.

3918
A. Stadler, C. O. Kappe / Tetrahedron 57 +2001) 3915±3920
Scheme 2.
Apparently, at higher temperatures, such isourea derivatives
preferably undergo rearrangement rather then the desired
coupling to the corresponding polymer bound benzylic
alcohol 'Scheme 1), in particular in the presence of basic
catalysts. The situation is further complicated however, by
the fact that some of the isourea intermediate can also be
expected to be converted into a symmetrical anhydride by
the excess of acid present in the reaction medium 'Scheme
1).6±8 This makes the reaction system a rather complex one,
not allowing for any detailed kinetic analysis of the
individual reaction pathways.
synthesizer experiments initially described in Fig. 2. In
the event, Wang resin was treated with 5 equiv. of inde-
pendently prepared 'PhCO)2O in 12 mL of NMP 'effective
anhydride concentration ca. 0.13 mol/L). Similar to the
experiments in the isourea-mediated coupling procedure a
reaction time of 2±3 days was necessary to completely load
the resin with benzoic anhydride at room temperature 'load-
ings after 18 h, 76%, 48 h, 95%, 72 h, .99%). Since NMP
'bp 202±2048C) was selected as solvent, all microwave
irradiation experiments could be conveniently carried out
in standard glassware inside the microwave cavity, making
it unnecessary to carry out reactions in specialized sealed
vessels under elevated pressure.18 In contrast to the results
obtained by the isourea method 'Tables 1 and 2), here a
signi®cant increase in the reaction rates was observed
'Table 3). Near quantitative loadings, for example, were
achieved at 1508C within 20 min, or at 2008C using only
10 min of microwave irradiation. Considering the fact
that these solid-phase couplings were carried out under
relatively diluteÐand therefore unfavorable conditionsÐ
it is reasonable to assume that even shorter reaction times
can in principle be achieved using the more commonly
employed higher reagent concentrations 'Scheme 3).
In independent experiments involving DIC and benzoic acid
in the DCM/DMF 9:1 solvent mixture 'in the absence of
polymer-bound alcohol) we have found that at elevated
reaction temperatures however, the formation of N-acylurea
2 does not require the presence of DMAP. Even in the
absence of the catalyst the formation of this product can
be observed. It is formed, i.e. in 58% isolated yield within
60 min at 908C '3 bar, 100 W, see Section 3).
Interestingly, we have discovered that by modifying the
solvent mixture in the isourea coupling process, i.e. by
elimination of DMF, this unwanted side reaction can be
suppressed and a decent loading of the resin with benzoic
acid can after all be achieved. Employing pure DCM as a
solvent led to 84% loading after irradiation for 3 hunder
pressure, a mixture of DCM/THF 9:1 even provides 95%
yield after only 1 hof irradiation at 89 8C 'Table 2). Using
these solvent mixtures the formation of urea 2 could not be
observed. Nevertheless, it is quite evident from the experi-
ments described above that the one-pot O-acylisourea
coupling protocol is probably not suited for any practical
rate-enhancements by microwave irradiation, due to the
inherent unfavorable effects of the higher temperatures on
the thermally labile isourea 1.
In conclusion, we have demonstrated that microwave
irradiation can be effectively employed to couple carboxylic
acids to hydroxymethyl polystyrene resins, provided that the
symmetrical anhydride protocol is used, and not the three-
component O-acylisourea activation method. For the model
Table 3. Effect of reaction temperature on the microwave-assisted ester-
i®cation of Wang resin withbenzoic anhydride
Temperature '8C)
Time 'min) Equiv. 'PhCO)2O Conversion '%)
50
80
10
10
10
10
20
20
5
10
5
10
3
3
3
3
3
5
3
3
5
5
27
39
48
53
77
98
67
74
75
99
120
150
150
150
200
200
200
200
We have therefore focused our attention on the symmetrical
anhydride procedure. As with the isourea protocols
illustrated above, we have used considerably more dilute
reaction conditions for the microwave runs than in the
Table 2. Solvent effects on the conversion in the O-acylisourea-mediated
coupling of benzoic acid to Wang resin
Solvent: NMP, atmospheric pressure. Yields given in % as determined after
cleavage; see Section 3.
Reaction time 'min)
Solvent:DCM
Solvent DCM/THF 9:1
15
30
45
60
180
29
57
68
73
84
53
77
89
95
n.d.
100 W microwave power '898C, 2.9 bar), sealed vessel. Yields given in %
as determined after cleavage; see Section 3.
Scheme 3.

A. Stadler, C. O. Kappe / Tetrahedron 57 +2001) 3915±3920
3919
system investigated, reaction times could be reduced from
days using conventional coupling conditions at room
temperature to only minutes using microwave irradiation.
As in our previously reported study on the concept of micro-
wave-assisted solid-phase synthesis,18 we believe that the
reason for the observed rate enhancements is the direct
and rapid `in core' heating of the solvent by microwave
energy, and not a speci®c 'so-called non-thermal) micro-
wave effect. The application of the microwave coupling
reactions reported herein towards more complex systems
'i.e. peptides couplings) is currently under investigation.
1.61 mmol, 203 mg), benzoic acid '5 equiv., 2.3 mmol,
281 mg) dissolved in NMP '2 mL), and a catalytic amount
of DMAP '0.1 equiv., 0.03 mmol, 4 mg) dissolved in NMP
'1 mL) was added and the mixture was shaken at rt for the
times speci®ed in Fig. 2. After the respective reaction cycles
were completed the resin was ®ltered, washed with DMF
'2£), MeOH '3£), DCM '3£) and MeOH '3£), and dried by
suction for approximately 20 min. For cleavage TFA/DCM
1:1 '3 mL) was added and the mixture was shaken for
another 30 min at rt. The solution was ®ltered and washed
with DCM '3 mL). Concentration to dryness furnished the
recovered acid in the yields indicated in Fig. 2.
3. Experimental
'B) Symmetrical anhydride method. The procedure was
carried out in an analogous fashion as described above,
using 5 equiv. benzoic anhydride '2.3 mmol, 520 mg)
dissolved in NMP '2 mL) as reagent. Cleavage was carried
out as described above.
1H and 13C NMR spectra were obtained on a Bruker AMX
360 instrument at 360 and 90 MHz, respectively. FTIR
spectra of resins were recorded on a Mattson Instruments
Unicam FTIR 7000 spectrophotometer using the KBr pellet
method. Micro-analyses were obtained on a Fisons Mod.
EA 1108 elemental analyzer.
3.4. Benzoic acid coupling experiments &Pyrex
glassware)
3.1. Materials
'A) Room temperature conditions. PS Wang resin '250 mg,
1.0 mequiv. OH/g) was placed in a 25 mL two-necked ¯ask
and was allowed to swell in DCM/DMF 9:1 '10 mL) for
10 min. DIC '3.5 equiv., 0.875 mmol, 110 mg), benzoic
acid '5 equiv., 1.25 mmol, 153 mg) in DCM/DMF '2 mL)
and a catalytic amount of DMAP was added, and the
mixture was allowed to stirr at rt for several hours '18, 48,
or 72 h). After the reaction the resin was ®ltered, washed
withMeOH '3 £), DCM '3£), MeOH '3£) and dried over-
night '408C, 10 mbar, FTIR analysis see Fig. 1). For
cleavage the resin was treated with TFA/DCM 1:1 '3 mL)
for 30 min at rt. The solution was ®ltered and the resin
washed with DCM '3 mL). Evaporation of the solvent
yielded the recovered benzoic acid.
The following polymer supports were used: Polystyrene
Wang resin '1.0 mequiv. OH/g, 1% DVB, 200±400 mesh,
Fluka 13611; 1.62 mequiv. OH/g, 1% DVB, 100±200 mesh,
Novabiochem 01-64-0174; 2.3 mequiv. OH/g, 1% DVB,
100±200 mesh, Advanced Chemtech SA5110). Benzoic
acid, DIC, DMAP, TFA, and anhydrous NMP were
purchased from Aldrich and used as received.
3.2. Microwave irradiation experiments
Milestone MLS ETHOS 1600 Reactor: The multimode
microwave reactor has a twin magnetron '2£800 W,
2455 MHz) witha maximum delivered power of 1000 W
in 10 W increments 'pulsed irradiation). A rotating micro-
wave diffuser ensures homogeneous microwave distribution
throughout the plasma coated PTFE cavity '35 cm£
35 cm£35 cm). For normal pressure operations standard
glassware '25 mL two-necked Pyrex round-bottomed
¯ask) witha water-cooled re¯ux condenser ®tted on top
of the cavity was used. For experiments carried out in sealed
vessels a 100 mL PFA reaction vessel contained in a single
high-pressure HPR1000 rotor block segment was employed.
Built-in magnetic stirring 'Te¯on-coated stirring bar) was
used in bothnormal pressure and sealed vessel operation.
During experiments, time, temperature, pressure, and power
was monitored/controlled withteh `easy wave' software
package 'Ver. 3.2.). Temperature was monitored withthe
aid of a ¯uoroptic probe 'ATC-FO) and/or witha shielded
thermocouple 'ATC-300) inserted directly into the corre-
sponding reaction container. For experiments in sealed
vessels a pressure sensor 'APC-55) was additionally
employed.
'B) Thermal re¯ux conditions. The procedure was carried
out in an analogous fashion as described above, by heating
the DCM/DMF mixture in a conventional oil bath to re¯ux
'448C). Work-up etc. was performed as described under 'A).
'C) Microwave heating conditions 'atmospheric pressure).
The procedure was carried out in an analogous fashion as
described above, by heating the DCM/DMF mixture in the
cavity of the ETHOS microwave oven at 100 W with
magnetic stirring 'Tˆ448C). Work-up etc. was performed
as described under 'A).
'D) Microwave heating conditions 'sealed vessel). Poly-
styrene Wang resin '250 mg, 1.0 mequiv. OH/g) was placed
in a 100 mL PFA sealed reactor vessel and allowed to swell
in DCM or DCM/THF 9:1 '10 mL) 'see Table 2) for 10 min.
DIC '3.5 equiv., 0.875 mmol, 110 mg), benzoic acid
'5 equiv., 1.25 mmol, 153 mg) dissolved in solvent '2 mL)
and a catalytic amount of DMAP was added and the mixture
was subsequently irradiated in the microwave cavity at
100 W, leading to a temperature of ca. 908C and a pressure
of ca. 3.0 bar independent of the solvent used. After cooling
the mixture to rt using an ice bath, the resin was ®ltered,
washed with MeOH '3£), DCM '3£), MeOH '3£) and dried
overnight '408C, 10 mbar). Cleavage is carried out in the
same way as described above.
3.3. Benzoic acid coupling experiments &PLS 4£6
synthesizer, Advanced Chemtech
'A) O-Acylisourea-method. PS Wang resin '200 mg,
2.3 mequiv. OH/g) was placed in a Te¯on frit and allowed
to swell in dry NMP '2 mL) for 10 min. DIC '3.5 equiv.,

3920
A. Stadler, C. O. Kappe / Tetrahedron 57 +2001) 3915±3920
3.4.1. 1-Benzoyl-1,3-diisopropylurea &2). 3.5 equiv. DIC
and a catalytic amount of DMAP was added to a solution
of 5 equiv. of benzoic acid in DCM/DMF 9:1 '10 mL). The
mixture was transferred into a 100 mL PFA sealed reactor
vessel and irradiated at 100 W for 60 min '3.0 bar, 908C).
After cooling to rt the solvent was evaporated and the
remainder puri®ed by ¯ash chromatography, using petro-
leum ether/ethyl acetate 1:1 as an eluent. After evaporation
of the solvent N-acylurea 2 was isolated in 58% yield as a
white powder, mp 1148C; IR 'KBr): 3300, 2970, 1687, and
References
È
1. Zaragoza Dorwald, F. Organic Synthesis on Solid Phase;
Wiley/VCH: Weinheim, 2000.
2. Solid-Phase Organic Synthesis; Burgess, K., Ed.; Wiley/
Interscience: New York, 2000.
3. Obrecht, D.; Villalgordo, J. M. Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound-
Libraries; Pergamon: Oxford, 1998.
4. Bunin, B. A. The Combinatorial Index; Academic: San Diego,
1998.
1642 cm21 1H NMR 'CDCl3) d 1.00 and 1.45 '2d,
;
Jˆ7.0 Hz, CH'CH3)2, 2£6H), 3.80 and 4.35 '2m,
Jˆ7.0 Hz, CH'CH3)2, 2£1H), 6.65 'brs, NH, 1H), 8.32±
8.50 'm, ArH, 5H); 13C NMR 'CDCl3): d 20.9, 22.3, 42.7,
50.4, 126.4, 128.7, 130.6, 137.3, 154.2, 172.5 ppm; calcd for
C14H20N2O2: C, 67.72; H, 8.12; N, 11.27. Found: C 67.61;
H, 8.17; N, 10.88.
5. Fmoc Solid Phase Peptide Synthesis; Chan, W. C., White,
P. D., Eds.; Oxford University: Oxford, 2000.
6. Slebioda, M. Tetrahedron 1995, 51, 7829±7834.
7. Mathias, L. J. Synthesis 1979, 561±576.
8. Kurzer, F.; Douraghi-Zadeh, K. Chem. Rev. 1967, 67, 107±
143.
9. Yu, H.-M.; Chen, S.-T.; Wang, K.-T. J. Org. Chem. 1992, 57,
4781±4784.
3.5. Benzoic anhydride coupling experiments &Pyrex
glassware)
10. Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett.
1996, 37, 8219±8222.
11. Hoel, A. M. L.; Nielsen, J. Tetrahedron Lett. 1999, 40, 3941±
3944.
'A) At room temperature. To a solution of benzoic acid
'10 equiv. relative to resin loading, 3.24 mmol, 396 mg) in
NMP '10 mL) DIC '5 equiv. relative to resin loading,
1.62 mmol, 204 mg) was added. The ¯ask was ®tted with
a CaCl2-tube and the mixture was cooled down to 08C with
an ice bath. The formation of benzoic anhydride was moni-
tored during the reaction by TLC. After 30 min, when no
more starting material was detected, the ice bath was
removed and PS Wang resin '200 mg, 1.62 mequiv., OH/
g), preswollen in NMP '2 mL) was added. Under slight
stirring the mixture was allowed to react at room tempera-
ture for several hours '18, 48, and 72 h). The resin was
®ltered and washed with MeOH '3£), DCM '3£) and
MeOH '3£) and dried overnight '408C, 10 mbar). For
cleavage the resin was treated with 50% TFA in DCM
'3 mL) for 30 min at rt. The solution is ®ltered and washed
with3 mL DCM. Concentration to dryness furnished the
recovered acid in the yields indicated in the text.
12. Kuster, G.; Scheeren, H. W. Tetrahedron Lett. 2000, 41, 515±
519.
13. Yu, A.-M.; Zhang, Z.-P.; Yang, H.-Z.; Thang, C.-Y.; Liu, Z.
Synth. Commun. 1999, 29, 1595±1599.
14. Chandrasekhar, S.; Padmaja, M. B.; Raza, A. Synlett 1999,
1597±1599.
15. Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623±1626.
16. Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984±
7989.
17. Scharn, D.; Wenschuh, H.; Reineke, U.; Schneider-Mergener,
J.; Germeroth, L. J. Combust. Chem. 2000, 2, 361±369.
18. Stadler, A.; Kappe, C. O.; Eur J. Org. Chem. 2001, 919±925.
19. Kiselyov, A. S.; Armstrong, R. W. Tetrahedron Lett. 1997, 35,
6163±6166.
20. Li, W.; Yan, B. J. Org. Chem. 1998, 63, 4092±4097.
21. Ley, S. V.; Mynett, D. M.; Koot, W.-J. Synlett 1995, 1017±
1020.
'B) Microwave ¯ashehating. PS Wang resin '200 mg,
1.62 mequiv. OH/g) was placed in a 25 mL two-necked
¯ask and allowed to swell in dry NMP '10 mL) for
22. Ref. 5, p. 46.
23. Yan, B. Acc. Chem. Res. 1998, 31, 621±630.
24. Baghurst, D. R.; Mingos, D. M. P. J. Chem. Soc., Chem.
Commun. 1992, 674±677.
10 min. Next,
3
or 5 equiv. benzoic anhydride
'0.97 mmol, 220 mg; or 1.62 mmol, 366 mg, respectively),
dissolved in NMP '2 mL) and a catalytic amount of DMAP
was added and the mixture was irradiated in the microwave
cavity at 700 W withpreselected temperatures between 50
and 2008C 'Table 3). After cooling to rt using a water bath,
the resin was ®ltered, washed with MeOH '3£), DCM '3£),
MeOH '3£) and dried over night '408C, 10 mbar). Cleavage
was carried out as described above.
25. Saillard, R.; Poux, M.; Berlan, J.; Audhuy-Peaudecerf, M.
Tetrahedron 1995, 51, 4033±4042.
26. Stadler, A.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 2 2000,
1363±1368.
Acknowledgements
This work was supported by the Austrian Science Fund
'FWF, Project P-11994-CHE).