Polymer-supported triazenes as smart reagents for the alkylation of carboxylic acids

Article abstract of DOI:10.1002/chem.200204739

Starting from polystyrene, a simple four-step synthesis of polymer-supported alkyltriazenes (alkyl = Me, Et, benzyl) is described. With this synthesis, a loading capacity of 2.2 mmol g^-1 can be reached. The most prominent application of these polymer-supported reagents is the rapid, highly selective and high-yielding esterification of carboxylic acids, which involves a simple mix and filter off procedure at room temperature. If stored in a refrigerator, these reagents are stable for many months and they can be recycled several times.

Full text of DOI:10.1002/chem.200204739

FULL PAPER
Polymer-Supported Triazenes as Smart Reagents for the Alkylation of
Carboxylic Acids
Bernhard Erb,[a] Jean-Philippe Kucma,[b] Sandrine Mourey,[c] and Fritz Struber*[a]
Abstract: Starting from polystyrene, a
simple four-step synthesis of polymer-
supported alkyltriazenes (alkyl ˆ Me,
Et, benzyl) is described. With this syn-
thesis, a loading capacity of 2.2 mmolgÀ1
can be reached. The most prominent
application of these polymer-supported
reagents is the rapid, highly selective
and high-yielding esterification of car-
boxylic acids, which involves a simple
™mix and filter off∫ procedure at room
temperature. If stored in a refrigerator,
these reagents are stable for many
months and they can be recycled several
times.
Keywords: alkylation ¥ combinato-
rial chemistry ¥ diazo compounds ¥
polymers ¥ solid-phase synthesis
diazomethane in many methylation reactions.[2] Polymer-
supported reagents have become state-of-the-art tools in
organic synthesis because of their easy handling, easy work-up
and their increased safety compared with classical reagents.[3]
In the polymer-supported triazenes (PSTs) the advantages of
triazenes[4] and polymer-supported reagents are unified. The
synthesis of methyl esters directly from carboxylic acids by
using polymer-supported O-methylisourea has recently
been described by Linclau.[5] Rademann×s group[6] have found
PSTs to be excellent reagents for this purpose, which react
well at room temperature and which are commercially
available.[7] PSTs have also been used by Br‰se et al. for the
synthesis of alkyl halides and esters,[8] as well as for alkyl
sulfonates.[9] Furthermore, PSTs have been used as cleavable
supports for solid-phase synthesis.[10, 11] We describe here
further examples of the synthetic scope of PSTs as alkylating
agents, and in particular we describe an improved procedure
for their preparation. It involves an efficient four-step syn-
thesis starting from simple polystyrene rather than from the
more expensive chloromethyl polystyrene used by Rademann
and Br‰se. This new methodology was optimized with
ecological and safety criteria, as well as the economical aspect
in mind.
Introduction
Alkylating agents are among the classes of reagents most
commonly used in organic synthesis. In addition to the known
reagents (e.g. alkyl halides, alkyl triflates, Meerwein salts and
diazoalkanes) there is still a demand for less toxic, more
stable, more selective, easier to handle and recyclable
alkylating agents. 3-Alkyl-1-aryltriazenes[1] are known for
the low-temperature alkylation of acidic substances (carbox-
ylic acids, phenols, enols) under mild conditions, but so far
they have not reached widespread application in synthesis.
3-Methyl-1-p-tolyltriazene 1 is a commercially available but
toxic solid that can replace the far more toxic and explosive
[a] Dr. F. Struber, Dr. B. Erb
Novartis Pharma, Chemical & Analytical Development
4002 Basel (Switzerland)
Results and Discussion
Fax : (‡41)61-3241519
E-mail: fritz.struber@pharma.novartis.com
Synthesis of polymer-supported triazenes: Starting from
commercially available polystyrene 1% cross-linked with
divinylbenzene, the PSTs were synthesized in four simple
steps (Scheme 1).
The nitration of polystyrene to poly(p-nitrostyrene) 2 was
best performed with 94% HNO3 at 08C, under which
conditions elemental analysis indicated 100% nitration.[12]
[b] J.-P. Kucma
¬
Trainee from the Ecole Nationale Superieure de Chimie
Clermont-Ferrand (France)
at Novartis Basel 1999
[c] S. Mourey
¬
Trainee from the Ecole Nationale Superieure de Chimie
Clermont-Ferrand (France)
at Novartis Basel 2000
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¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200204739
Chem. Eur. J. 2003, 9, 2582 2588

2582 2588
Scheme 1. Synthesis of polymer-supported triazenes (PSTs) 5a d from polystyrene and their application in the esterification of carboxylic acids at room
temperature.
Nitration was also possible with a mixture of 65% HNO3 and
H2SO4, however the product was agglutinated and could not
be reduced fully in the next step. The reduction of 2 to the
poly(p-aminostyrene) 3 was successful with pure phenyl
hydrazine at 1608C.[13] The use of xylene as a cosolvent led
to incompletely reduced material. However pure phenyl
hydrazine showed a strong exothermic decomposition above
1608C according to differential scanning calorimetry. At
1208C the reduction was still effective, and the safety risk
could thus be minimized, but for the routine use of this
procedure on a larger scale more detailed calorimetric
measurements have to be carried out. The reaction was
monitored by IR spectroscopy and elemental analysis. Other
reducing agents (Na2S2O4/H2O[14] at 708C, Na2S/S/H2O[15] at
1508C and 6 bar or SnCl2 ¥ 2H2O/EtOH[16] at 708C) were
ineffective according to elemental analysis. Classical aqueous
diazotation[14] with HCl/NaNO2 led successfully to the poly-
mer-bound diazonium salt 4, whilst diazotation with tert-
6.2 mmolgÀ1. One explanation for the lower loading could
be the intramolecular coupling of two equivalents of the
diazonium salt with the amine to yield pentazenes.
The preparation described above is a simple approach to
the desired functionalized reagents. The synthesis shows
economical merits in comparison with the existing syntheses
of PSTs on Merrifield resin and was done on larger scale
starting from 750 g polystyrene.
Applications of polymer-supported triazenes: The outstand-
ing feature of PSTs was shown to be the esterification of
carboxylic acids, which can be done in a simple ™mix and filter
off∫ procedure at room temperature. In order to study the
scope and limitations of the PSTs, 20 acids with different
structural and electronic features were alkylated, mainly with
Me-PST 5a (Table 1). As seen from the table, phenyl groups,
double bonds, asymmetric centres, amino groups, aliphatic
and aromatic hydroxy groups were not affected. In most cases
stirring the carboxylic acid solution with 1.2 equivalents of
PST for 1to 24 h is sufficient for complete esterification. After
filtration of the resin and evaporation of the solvent, the pure
ester was obtained. Although N-protected a-amino acids
(entry 23) worked well, unprotected amino acids failed to
react. Et-PST 5b (entry 2) and Bn-PST 5d (entry 3) were
tested only with benzoic acid, and also showed a clean and
high-yielding conversion. A broad range of solvents like
CH2Cl2, DME, MeCN, THF or DMF was successful for
esterification with PSTs, but CH2Cl2 was the solvent of choice
due to reaction speed and ease of product isolation.
butylnitrite/BF3 ¥ Et2O[11, 17] or NOBF4 in organic solvents
[18]
was less successful. The diazotation reaction was best
monitored by quenching samples of 4 with amine and
checking the activity of the resulting PST 5. The amination
of 4 to the desired poly(p-alkyltriazenestyrenes) 5a 5d was
best performed with aqueous solutions of the corresponding
amine. The tert-butyl derivative 5c decomposed during
isolation or use as reagent, with the release of 2-methyl-
prop-1-ene, presumably in a reaction initiated by the proton-
ation of the triazene moiety involving the tert-butyl cation.[19]
The loading of the PSTs was easily determined by esterifica-
tion of an excess of benzoic acid in CDCl3; after an aliquot
had been decanted, an NMR spectra was taken. From the
extent of conversion to the corresponding benzoate ester, the
loadings were calculated as follows: 1.7 2.2 mmolgÀ1 for
Me-PST 5a, 0.9 mmolgÀ1 for Et-PST 5b and 0.8 mmolgÀ1 for
Bn-PST 5d (Bn ˆ benzyl). It has to be mentioned that the
maximum loading for noncopolymerized 5a should be
As indicated above, the reaction is initiated with the
protonation of the triazene moiety, and therefore the pKa
value of the acid greatly influences the reaction time. Whereas
treatment of benzoic acid 6 (pKa ˆ 4.2)[20] in DME with
1.2 equiv of 5a for 1h gave a conversion of 35%, 4-nitro-
benzoic acid 7 (pKa ˆ 3.4)[20] gave a conversion of 94%
according to HPLC. The high selectivity of PSTs for
Chem. Eur. J. 2003, 9, 2582 2588
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F. Struber et al.
FULL PAPER
Table 1Alkylation of carboxylic acids with Me-PST 5a, Et-PST 5b or Bn-PST 5d at room temperature.
Acid
Product
Conditions
Purity (GC)
98.9%
Isolated
Yield
1.2 equiv 5a
CH2Cl2, 3 h
83%
79%
99%
97%
100%
1
2
3
4
5
6
6a
1.2 equiv 5b
CH2Cl2, 4 h
99.3%
89.3%
99.2%
98.9%
6
6
6b
6d
2 equiv 5d
CH2Cl2, 6 h
1.5 equiv 5a
DME, 16 h
7
8
7a
8a
2 equiv 5a
DME, 4 d
2 equiv 5a
DME, 22 h
96.0%
99.4%
98.1%
87%
93%
89%
6
7
8
9
9a
1.2 equiv 5a
DME, 21h
10
10a
1.2 equiv 5a
DME, 22 h
11
12
11a
12a
1.2 equiv 5a
DME, 4 d
98.3%
100%
9
2.4 equiv 5a
DMF, 5 d
100%
99.9%
66%
86%
10
11
13
13a
1.2 equiv 5a
CH2Cl2, 24 h
14
15
14a
15a
1.2 equiv 5a
MeCN, 6 h
99.5%
91%
12
2.4 equiv 5a
DME, 1h
95.4%
96.1%
81%
85%
13
14
16
16a
2.4 equiv 5a
DME, 1.5 h
17
17a
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Chem. Eur. J. 2003, 9, 2582 2588
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Polymer-Supported Triazenes
2582 2588
Table 1(continued).
Acid
Product
Conditions
Purity (GC)
98.4%
Isolated
Yield
1.2 equiv 5a
CH2Cl2, 3 h
42%
15
18
18a
4 equiv 5a
DME, 17 h
98.0%
80.0%
93%
16
19
19a
1.2 equiv 5a
CH2Cl2, 1 h
55%
88%
17
20
20a
1.2 equiv 5a
CH2Cl2, 2 h
95.6%
18
21
21a
22a
1.2 equiv 5a
DME, 3 h
99.0%
96.6%
34%
94%
19
22
2 equiv 5a
CH2Cl2, 24 h
20
23
23a
1.2 equiv 5a
CH2Cl2, 20 h
98.9%
94%
21
22
24
24a
1.2 equiv 5a
H2O or 1m
HCl/THF (1:1)
no significant
reaction
25
2 equiv 5a
CH2Cl2, 3 h
98.8%
92%
23
26
26a
carboxylic hydroxy groups is a result of this fact. Other less
acidic hydroxy groups like phenols, alcohols or enolizable
carbonyl functions are barely affected in the presence of a
carboxylic acid. However phenols also react with PSTs and, as
expected, the pKa is a crucial
Acetophenone (pKa ˆ 19.1)[21] in CDCl3 stirred for 3 h with
2 equivalents of 5a showed no enolether formation accord-
ing to NMR spectra. Aliphatic alcohols did not react with
PSTs.
parameter. Phenol 27 (pKa ˆ
Table 2 Alkylation of phenols with Me-PST 5a at room temperature.
10.0)[21] treated with 2 equiv of
Me-PST in CH2Cl2 showed 8%
conversion to anisole 27a after
1d (Table 2, entry 1), whereas
4-nitrophenol 28 (pKa ˆ 7.2)[21]
was converted with 74% to
the corresponding ether 28a
after only 7 h (Table 2, entry 2).
Interestingly, addition of HCl
or an acidic ion exchanger did
not reduce the reaction time.
For the synthesis of 28a, DME
was the solvent of choice be-
cause of the higher product
solubility (Table 2, entry 3).
Phenol
Product
Conditions
Conversion
(HPLC)
Isolated
yield
2 equiv 5a
1d: 8%
CH2Cl2
3 d: 21 %
1 4 d: 44%
77 d: 57%
1
27
27a
2 equiv 5a
CH2Cl2
1h: 46%
4 h: 60%
7 h: 74%
2
3
28
28a
28
28a
2 equiv 5a
1h: 83%
1d: 98%
3 d: 99%
DME
94%
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F. Struber et al.
FULL PAPER
Table 3 Decrease of loading from Me-PST 5a, Et-PST 5b and Bn-PST 5d at various temperatures in relation to time.
Me-PST 5a
Et-PST 5b
Bn-PST 5d
T
‡ 48C
RT
‡ 408C
‡ 48C
RT
‡ 408C
‡ 48C
RT
‡ 408C
Initial loading
[mmolgÀ1
]
1.7
1.7
1.7
0.9
0.9
0.9
0.8
0.8
0.8
4 weeks
8 weeks
12 weeks
2 years
1.6
1.5
1.5
1.2
1.5
1.5
1.4
0.7
1.3
1.2
1.1
0.9
0.9
0.9
0.7
0.8
0.8
0.7
0.3
0.7
0.6
0.6
0.8
0.8
0.8
0.4
0.7
0.7
0.6
0.1
0.6
0.4
0.3
Stability of polymer-supported triazenes: 3-Alkyl-1-aryltria-
zenes are known to decompose when treated with acids[1, 22, 23]
or metal ions.[24] As stated above tBu-PST 5c decomposed
during isolation or use at room temperature. Me-, Et- and Bn-
PST (5a,5b,5d ) are only moderately stable at elevated
temperatures (Table 3). This is in agreement with the differ-
ential scanning calorimetry.[25] Me-PST 5a begins to decom-
pose exothermically at 558C (Figure 1), whereas decomposi-
tion of the monomolecular 3-methyl-1-p-tolyltriazene 1 starts
after melting at 858C (Figure 2). Et-PST 5b starts to decom-
pose at 708C and Bn-PST 5d at 608C. PSTs suffer minimal
loss of activity when stored in the dark at ‡48C, however Bn-
PST 5d is more temperature sensitive than 5a or 5b. These
data are insufficient to assess the safety of storing large
amounts of PSTs, and a detailed thermal analysis of the
decomposition is necessary.
Recycling of polymer-supported triazenes: The recyclability
of Me-PST 5a was examined. After reaction with a large
excess of benzoic acid, the resulting poly(p-aminostyrene) 2
was diazotized, aminated again, and the activity was checked
by NMR spectroscopy. Me-PST 5a with an initial loading of
2.0 mmolgÀ1 was treated in this manner six times (Table 4).
With a relative loss of 10 20% loading per cycle, the reagent
can be reasonably recycled several times.
Table 4 Decrease of loading from Me-PST 5a after several recycling steps.
No. of recycling steps
Loading (mmolgÀ1
0
12
3
4
5
6
)
2.0
1.7
1.5
1.2
0.8
0.8
0.7
Conclusion
In the present paper we describe a new, simple four-step
synthesis of polymer-supported triazenes (PSTs) applicable to
larger scale preparation. Starting from polystyrene beads, this
synthesis is economically superior to the synthesis of PSTs on
Merrifield resin. The outstanding feature of PSTs 5a,5b and
5d was demonstrated to be the esterification of carboxylic
acids, which can be done in a simple ™mix and filter off∫
procedure at room temperature. Twenty acids with different
structural features were esterified with high yield and purity in
most cases. Phenols were alkylated much more slowly with
Me-PST 5a. PSTs are only moderately stable at room
temperature, but can be stored in a refrigerator for many
months. Furthermore it was shown that Me-PST 5a can be
reasonably recycled several times. PSTs are thus attractive
reagents whenever an easy, safe, clean and high-yielding
esterification of an carboxylic acid is required in a research
lab, for the derivatization of analytical samples or for high
throughput synthesis.
Figure 1. Differential scanning calorimetry thermogram of Me-PST 5a
(loading: 1.6 mmolgÀ1). Gold-plated steel crucible sealed under argon;
test: 4.76 mg, dynamic.
Experimental Section
General
Starting materials and reagents: Polystyrene beads 100 200 mesh (75
150 mm), cross-linked with 1% divinylbenzene, were purchased from
Purolite (IP 1130). These and all other chemicals were used as received.
Products obtained from alkylations with PSTs were compared with
commercially available samples with a purity mostly >98% according
GC, 1H NMR, melting point or refractive index.
Figure 2. Differential scanning calorimetry thermogram of 3-methyl-1-p-
tolyltriazene 1. Gold-plated steel crucible sealed under argon; test: 4.12 mg,
dynamic.
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Polymer-Supported Triazenes
2582 2588
Equipment: IR: Midac FTIR M-series, Spectacle software, KBr pellets.
1H NMR: Varian Gemini200 (200 MHz for 1H); d in ppm downfield from
TMS (d ˆ 0). Capillary gas chromatography (CGC): Hewlett Packard
HP6890 series, FID detector; column: Macherey Nagel 726821Optima-1;
carrier gas: H2; oven: initial temperature 508C for 3 min, final temperature
2508C (rate 108C minÀ1). HPLC: Hewlett Packard series 1050 with a
detector HP series II 1040M (210 nm); column: Macherey Nagel CC125/
4 Nucleosil 100 5C8, temperature 358C; eluent: 50% phase A (MeCN/
H2O 1:9 with phosphate buffer solution, pH 5.1), 50% phase B (MeCN/
H2O 9:1) for 15 min and after 100% B with a flow of 1 mLminÀ1. Elemental
analysis: ECO800 system. Melting points: open glass capillaries, B¸chi 535
(Tottoli apparatus), uncorrected. Refractive index: ABBE Mark II, digital
refractometer (Reichert Jung) at 208C. [a]D at 208C on Perkin Elmer 241
polarimeter. TLC: sheets from Merck (1.05719; silica gel 60 F254). Differ-
ential scanning calorimetry (DSC): Mettler Toledo STAR with STAR5.12
software and DSC-821cells.
73%) with a loading of 0.9 mmolgÀ1. Et-PST 5b is best stored in the dark at
‡48C. IR (KBr): 2919, 1518, 1440, 1399, 1341, 1236, 1175, 828; elemental
analysis calcd (%) for C10H13N3 (175.23): C 68.54, H 7.48, N 23.98; found: C
70.0, H 6.4, N 15.2, O 7.8, H2O 0.96.
Poly(p-benzyltriazenestyrene),5d (Bn-PST)
: Poly(p-aminostyrene) 3
(60 g, 0.50 mol) was diazotized as described for 5a. The resulting
polymer-bound diazonium salt 4 was transferred into ice water (1.7 L).
Then BnNH2 (720 mL, 6.45 mol) was added at 08C over 15 min. The
reaction mixture was stirred at 08C for 12 h and for 1 h at room
temperature. After filtration the polymer was washed with H2O (3 L)
and stirred in EtOH (2 L) for 1h, filtered again and washed with EtOH
(2 L) and CH2Cl2 (2 L) until the washing solution became colourless. The
product was dried in vacuo at 258C for 4 d to yield brown beads of Bn-PST
5d (81g, 0.34 mol, 68%) with a loading of 0.8 mmolg À1. Bn-PST 5d is best
stored in the dark at ‡48C. IR (KBr): 2911, 1514, 1449, 1391, 1341, 1163,
692; elemental analysis calcd (%) for C15H15N3 (237.31): C 75.92, H 6.37, N
17.71; found: C 75.0, H 6.2, N 13.7, O 4.7, H2O 0.78.
Activity checks of PSTs with NMR: Benzoic acid (100 mg, 0.819 mmol)
was added to Me-PST 5a (50.0 mg) in CDCl3 (8 mL) in a round-bottom
flask equipped with a magnetic stirrer. The mixture was stirred overnight at
room temperature, after which a 1H NMR spectrum of the decanted and
clear solution was taken. Integration then established the extent of
conversion of benzoic acid to methyl benzoate. Thus from a conversion
of 13% the loading of Me-PST 5a could be calculated as 2.1mmolg À1. The
activity checks of Et-PST 5b and Bn-PST 5d were performed in the same
manner.
Alkylation of Carboxylic Acids:
Methyl benzoate (6a): Me-PST 5a (2.90 g, loading 1.7 mmolgÀ1
,
4.93 mmol) was added to a solution of benzoic acid 6 (500 mg, 4.09 mmol)
in CH2Cl2 (13 mL), and the reaction mixture was stirred at room
temperature for 3 h. Then the polymer was filtered off on a sintered glass
funnel and washed with CH2Cl2. Evaporation under vacuum afforded 6a
(457 mg, 3.38 mmol, 83%) with a purity of 98.9% (GC and 1H NMR). nD
1.5131 (1.5170[26]).
ˆ
Poly(p-nitrostyrene) (2): Nitric acid (94%, 10 L) was chilled to 08C before
polystyrene beads (750 g, 7.21mol) were added portion-wise with stirring.
First the polymer turned black, then orange. The slurry was stirred at 08C
for 3 h. Then the resin was filtered on a sintered glass funnel, poured into
ice water (10 L), filtered again and washed with EtOH (3 Â 2 L) and TBME
(2 Â 2 L). The product was dried in vacuo at 508C overnight to yield
yellowish beads (1110 g, 7.45 mol, 103%). IR (KBr): 2926, 1595, 1518, 1344,
855; elemental analysis calcd (%) for C8H7NO2 (149.15): C 64.42, H 4.73, N
9.39, O 21.45; found: C 62.13, H 5.08, N 9.58, O 23.45.
Ethyl benzoate (6b): Benzoic acid 6 (200 mg, 1.64 mmol) in CH2Cl2
(10 mL) was treated with Et-PST 5b (2.20 g, loading 0.9 mmolgÀ1
,
1.98 mmol) for 4 h as described for 6a to afford 6b (194 mg, 1.29 mmol,
1
79%) with a purity of 99.3% (GC and H NMR). nD ˆ 1.5028 (1.5050[26]).
Benzyl benzoate (6d): Benzoic acid 6 (214 mg, 1.75 mmol) in CH2Cl2
(10 mL) was treated with Bn-PST 5d (4.38 g, loading 0.8 mmolgÀ1
,
3.50 mmol) for 6 h as described for 6a to afford 6d (369 mg, 1.74 mmol,
1
99%) with a purity of 89.3% (GC and H NMR). nD ˆ 1.5635 (1.5680[26]).
Methyl 4-nitrobenzoate (7a): 4-Nitrobenzoic acid 7 (512 mg, 3.06 mmol) in
Poly(p-aminostyrene) 3: Poly(p-nitrostyrene) 2 (1100 g, 7.38 mol) was
added to phenylhydrazine (22 L), and the mixture was stirred at 1208C
internal temperature for 18 h. The product was filtered and washed with
water (10 L). Then the polymer was stirred in EtOH (25 L) at 408C for
15 min, filtered and washed with EtOH (3 Â 25 L). The product was dried
in vacuo at 508C for 3 d to yield dark brown beads (867 g, 7.29 mol, 99%).
IR (KBr): 3354, 2914, 1618, 1510, 1518, 1340, 1263; elemental analysis calcd
(%) for C8H9N (119.17): C 80.63, H 7.61, N 11.76; found: C 75.7, H 6.8, N
11.6, O 5.8, H2O 1.06.
DME (14 mL) was treated with Me-PST 5a (2.70 g, loading 1.7 mmolgÀ1
,
4.59 mmol) for 16 h as described for 6a to afford 7a (540 mg, 2.98 mmol,
97%) with a purity of 99.2% (GC and 1H NMR). M.p. 94.5 95.28C (94
968C[26]).
Methyl 4-aminobenzoate (8a): 4-Aminobenzoic acid 8 (107 mg, 0.78 mmol)
in DME (5 mL) was treated with Me-PST 5a (0.92 g, loading 1.7 mmolgÀ1
,
1.56 mmol) for 4 d as described for 6a to afford 8a (118 mg, 0.78 mmol,
100%) with a purity of 98.9% (GC and 1H NMR). M.p. 110.0 110.68C
(111 1138C[26]).
Poly(p-methyltriazenestyrene),5a (Me-PST)
: Poly(p-aminostyrene) 3
Methyl anthranilate (9a): Anthranilic acid 9 (1018 mg, 7.42 mmol) in DME
(550 g, 4.61mol) was added to a chilled solution of NaNO 2 (830 g,
12.0 mol) in H2O (10 L). The mixture was stirred at À58C while 37% aq.
HCl (1L, 12.0 mol) was added in portions over 30 min. Then the slurry was
stirred at 08C for a further 2 h, filtered and washed with chilled water
(40 L). The resulting polymer-bound diazonium salt 4 was transferred into
ice water (5 L). Then 40% aq. MeNH2 (5 L, 59 mol) was added in portions
at 08C over 30 min. The reaction mixture was stirred at 08C for 12 h and for
1h at room temperature. After filtration, the polymer was washed with
H2O (10 L) and stirred in EtOH (6 L) for 1 h, filtered again and washed
with EtOH (8 L) and CH2Cl2 (8 L) until the washing solution became
colourless. The product was dried in vacuo at 308C for 4 d to yield brown
(50 mL) was treated with Me-PST 5a (9.89 g, loading 1.5 mmolgÀ1
,
14.8 mmol) for 22 h as described for 6a to afford 9a (980 mg, 6.48 mmol,
1
87%) with a purity of 96.0% (GC and H NMR). nD ˆ 1.5735 (1.5830[26]).
Methyl 4-chlorobenzoate (10a): 4-Chlorobenzoic acid 10 (1023 mg,
6.53 mmol) in DME (50 mL) was treated with Me-PST 5a (5.22 g, loading
1.5 mmolgÀ1, 7.83 mmol) for 21h as described for 6a to afford 10a
(1037 mg, 6.08 mmol, 93%) with a purity of 99.4% (GC and 1H NMR).
M.p. 35.5 36.48C (42 448C[26]).
Methyl salicylate (11a): Salicylic acid 11 (1018 mg, 7.37 mmol) in DME
(50 mL) was treated with Me-PST 5a (5.90 g, loading 1.5 mmolgÀ1
,
beads of Me-PST 5a (605 g, 3.76 mol, 82%) with a loading of 1.7 mmolgÀ1
.
8.85 mmol) for 22 h as described for 6a to afford 11a (1002 mg, 6.59 mmol,
89%) with a purity of 98.1% (GC and 1H NMR). nD ˆ 1.5307 (1.5360[26]).
Methyl diphenylacetate (12a): Diphenylacetic acid 12 (202 mg, 0.95 mmol)
in DME (10 mL) was treated with Me-PST 5a (765 mg, loading
1.5 mmolgÀ1, 1.15 mmol) for 4 d as described for 6a to afford 12a (215 mg,
0.95 mmol, 100%) as an oil with a purity of 98.3% (GC and 1H NMR).
This procedure was repeated several times also on smaller scale, when
loadings up to 2.2 mmolgÀ1 were typical. Me-PST 5a is best stored in the
dark at ‡48C. IR (KBr): 2915, 1518, 1433, 1379, 1341, 1240, 1175, 828;
elemental analysis calcd (%) for C9H11N3 (161.21): C 67.06, H 6.88, N 26.07;
found: C 67.7, H 6.3, N 18.5, O 6.6, H2O 0.75.
Poly(p-ethyltriazenestyrene),5b (Et-PST) : Poly(p-aminostyrene) 3 (80 g,
0.67 mol) was diazotized as described for 5a. The resulting polymer-bound
diazonium salt 4 was transferred into ice water (1L). Then 70% aq. EtNH 2
(690 mL, 8.60 mol) was added in portions at 08C over 30 min. The reaction
mixture was stirred at 08C for 12 h and for 1 h at room temperature. After
filtration the polymer was washed with H2O (2 L) and stirred in EtOH
(2 L) for 1h, filtered again and washed with EtOH (2 L) and CH 2Cl2 (2 L)
until the washing solution became colourless. The product was dried in
vacuo at 308C for 4 d to yield brown beads of Et-PST 5b (86 g, 0.49 mol,
Dimethyl terephthalate (13a): Me-PST 5a (4.84 g, loading 1.5 mmolgÀ1
,
7.26 mmol) was added to a solution of terephthalic acid 13 (502 mg,
3.02 mmol) in DMF (25 mL), and the reaction mixture was stirred at room
temperature for 5 d. Then the polymer was filtered off on a sintered glass
funnel and washed with DMF. H2O (25 mL) was added to the filtrate, and
the mixture was kept in the refrigerator for 2 h. After the precipitate was
collected and evaporated under vacuum to afford 13a (385 mg, 1.98 mmol,
66%) with a purity of 100% (GC and 1H NMR). M.p. 139.8 140.78C
(140 1428C[26]).
Chem. Eur. J. 2003, 9, 2582 2588
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2587

F. Struber et al.
FULL PAPER
Methyl cinnamate (14a): Cinnamic acid 14 (107 mg, 0.72 mmol) in CH2Cl2
resulting poly(p-aminostyrene) 3 was diazotized and aminated as described
for 5a. An activity check with 50 mg of this recycled material showed a
loading of 1.7 mmolgÀ1. The alkylation of benzoic acid and recycling was
repeated five times with the following decrease of loading: 1.5 mmolgÀ1
(2nd cycle), 1.2 mmolgÀ1 (3rd cycle), 0.8 mmolgÀ1 (4th cycle), 0.8 mmolgÀ1
(5th cycle), 0.7 mmolgÀ1 (6th cycle).
(5 mL) was treated with Me-PST 5a (554 mg, loading 1.6 mmolgÀ1
,
0.88 mmol) for 24 h as described for 6a to afford 14a (100 mg, 0.62 mmol,
86%) with a purity of 99.9% (GC and 1H NMR). M.p. 34.4 34.98C (36
388C[26]).
Methyl (R)-(À)-mandelate (15a): (R)-(À)-Mandelic acid 15 (203 mg,
1.34 mmol) in MeCN (10 mL) was treated with Me-PST 5a (1.07 g, loading
1.5 mmolgÀ1, 1.60 mmol) for 6 h as described for 6a to afford 15a (202 mg,
1.22 mmol, 91 %) with a purity of 99.5% (GC and 1H NMR). M.p. 53.3
53.98C (56 588C[26]); [a]D at 208C ˆ À138.6 (c ˆ 1in MeOH) ( À144.0[26]).
Acknowledgement
The authors would like to thank Dr. Gottfried Sedelmeier, Novartis
Pharma AG, for private communications. Dr. Anthony C. O×Sullivan,
Syngenta Crop Protection AG, and Dr. Christoph Heuberger, Safety
Laboratory at Novartis Pharma AG, are gratefully acknowledged for
careful proof-reading of this manuscript and helpful discussions.
Dimethyl maleate (16a): Maleic acid 16 (509 mg, 4.39 mmol) in DME
(25 mL) was treated with Me-PST 5a (7.05 g, loading 1.5 mmolgÀ1
,
10.57 mmol) for exactly 1 h as described for 6a to afford 16a (510 mg,
3.54 mmol, 81%) with a purity of 95.4% (GC and 1H NMR). If the reaction
mixture was stirred for longer than 1h, a partial isomerization to dimethyl
fumarate 17a occurred, which reached 2.3% (4 h), 18% (21 h), 47% (4 d)
or 62% (11 d) according HPLC and NMR. nD ˆ 1.4326 (1.4410[26]).
Dimethyl fumarate (17a): Fumaric acid 16 (501mg, 4.32 mmol) in DME
[1] E. H. White, H. Scherrer, Tetrahedron Lett. 1961, 21, 758 762.
[2] E. H. White, R. W. Darbeau in Encyclopedia of Reagents for Organic
Synthesis, Vol. 5 (Ed.: L. A. Paquette), Wiley, Chichester, 1995,
pp. 3609 3611.
[3] a) S. J. Shuttleworth, S. M. Allin, R. D. Wilson, D. Nasturica, Synthesis
1997, 1035 1074; b) D. H. Drewry, D. M. Coe, S. Poon, Med. Res. Rev.
1999, 19, 97 148; c) D. C. Sherrington, Chem. Commun. 1998, 2275
2286.
[4] D. B. Kimball, M. M. Haley, Angew. Chem. 2002, 114, 3484 3498;
Angew. Chem. Int. Ed. 2002, 41, 3338 3351.
[5] B. Linclau, S. Crosignani, P. D. White, Org. Lett. 2002, 4, 1035 1037.
[6] J. Rademann, J. Smerdka, G. Jung, P. Grosche, D. Schmid, Angew.
Chem. 2001, 113, 390 393; Angew. Chem. Int. Ed. 2001, 40, 381 385.
[7] http://www.novabiochem.com
À1
(40 mL) was treated with Me-PST 5a (6.91g, loading 1.5 mmolg
,
10.37 mmol) for 1.5 h as described for 6a to afford 17a (526 mg, 3.65 mmol,
85%) with a purity of 96.1% (GC and 1H NMR). M.p. 100.1 101.38C
(103 1048C[26]).
Methyl valerate (18a): Valeric acid 18 (1043 mg, 10.21 mmol) in CH2Cl2
(50 mL) was treated with Me-PST 5a (8.16 g, loading 1.5 mmolgÀ1
,
12.24 mmol) for 3 h as described for 6a to afford 18a (495 mg, 4.27 mmol,
1
42%) with a purity of 98.4% (GC and H NMR). nD ˆ 1.3981 (1.3970[26]).
Dimethyl adipate (19a): Adipic acid 19 (202 mg, 1.38 mmol) in DME
(10 mL) was treated with Me-PST 5a (3.70 g, loading 1.5 mmolgÀ1
,
5.55 mmol) for 17 h as described for 6a to afford 19a (223 mg, 1.28 mmol,
1
93%) with a purity of 98.0% (GC and H NMR). nD ˆ 1.4257 (1.4280[26]).
Methyl 2-oxopentanoate (20a): Freshly distilled 2-oxopentanoic acid 20
(209 mg, 1.80 mmol) in CH2Cl2 (10 mL) was treated with Me-PST 5a
(1.44 g, loading 1.5 mmolgÀ1, 2.16 mmol) for 1 h as described for 6a to
afford 20a (129 mg, 0.99 mmol, 55%) with a purity of 80.0% (GC). The
1H NMR spectrum corresponded to the literature.[27]
[8] C. Pilot, S. Dahmen, F. Lauterwasser, S. Br‰se, Tetrahedron Lett. 2001,
42, 9179 9181.
[9] N. Vignola, S. Dahmen, D. Enders, S. Br‰se, Tetrahedron Lett. 2001, 42,
7833 7836.
[10] J. K. Young, J. C. Nelson, J. S. Moore, J. Am. Chem. Soc. 1994, 116,
10841 10842.
[11] S. Br‰se, J. Kˆbberling, D. Enders, R. Lazny, M. Wang, S. Brandtner,
Tetrahedron Lett. 1999, 40, 2105 2108.
[12] G. B. Bachman, H. Hellman, K. R. Robinson, R. W. Finholt, E. J.
Kahler, L. J. Filar, L. V. Heisey, L. L. Lewis, D. D. Micucci, J. Org.
Chem. 1947, 12, 108 121.
[13] I. J. Roh, W. S. Ha, J. Kim, J. Korean Fiber Soc. 1996, 33, 947 954.
[14] V. L. Covolan, L. H. Innocentini Mei, C. L. Rossi, Polym. Adv. Tech.
1997, 8, 44 50.
Methyl levulinate (21a): Levulinic acid 21 (109 mg, 0.94 mmol) in CH2Cl2
(5 mL) was treated with Me-PST 5a (660 mg, loading 1.7 mmolgÀ1
,
1.12 mmol) for 2 h as described for 6a to afford 21a (108 mg, 0.83 mmol,
88%) with a purity of 95.6% (GC and 1H NMR). nD ˆ 1.4230 (1.422[28]).
Methyl glycolate (22a): Glycolic acid 22 (212 mg, 2.79 mmol) in DME
(10 mL) was treated with Me-PST 5a (2.23 g, loading 1.5 mmolgÀ1
,
3.35 mmol) for 3 h as described for 6a to afford 22a (85 mg, 0.94 mmol,
1
34%) with a purity of 99.0% (GC and H NMR). nD ˆ 1.4136 (1.4170[26]).
Methyl linoleate (23a): Linoleic acid 23 (216 mg, 0.77 mmol) in CH2Cl2
[15] P. Schneider, Methoden Org. Chem. (Houben-Weyl) 4th ed. 1963, 14/2,
696 697.
(10 mL) was treated with Me-PST 5a (1.03 g, loading 1.5 mmolgÀ1
,
1.55 mmol) for 24 h as described for 6a to afford 23a (213 mg, 0.72 mmol,
[16] F. D. Bellamy, K. Ou, Tetrahedron Lett. 1984, 25, 839 842.
[17] M. P. Doyle, W. J. Bryker, J. Org. Chem. 1979, 44, 1572 1574.
[18] U. Wannagat, G. Hohlstein, Chem. Ber. 1955, 88, 1839 1846.
[19] A. A. R. Laila, Gazz. Chim. Ital. 1989, 119, 453 456.
[20] CRC Handbook of Chemistry and Physics, 78th ed. (Ed.: D. R. Lide),
CRC Press, Boca Raton, 1997, pp. 8 51 .
1
94%) with a purity of 96.6% (GC and H NMR). nD ˆ 1.4625 (1.4620[26]).
Methyl 1-adamantaneoate (24a): 1-Adamantanecarboxylic acid 24
(102 mg, 0.57 mmol) in CH2Cl2 (5 mL) was treated with Me-PST 5a
(400 mg, loading 1.7 mmolgÀ1, 0.68 mmol) for 20 h as described for 6a to
afford 24a (103 mg, 0.53 mmol, 94%) with a purity of 98.9% (GC). The
1H NMR spectrum corresponded to the literature.[29]
[21] M. B. Smith, Organic Synthesis, McGraw-Hill, Singapore, 1994,
pp. 101 and 858.
N-(tert-Butyloxycarbonyl)-l-alanine methylester (26a): N-(tert-Butyloxy-
carbonyl)-l-alanine 26 (208 mg, 1.10 mmol) in CH2Cl2 (10 mL) was treated
with Me-PST 5a (1.41 g, loading 1.5 mmolgÀ1, 2.11 mmol) for 3 h as
described for 6a to afford 26a (206 mg, 1.01 mmol, 92%) with a purity of
[22] H. Goldschmidt, J. Holm, Ber. Dtsch. Chem. Ges. 1888, 21, 1016 1026.
[23] N. S. Isaacs, E. Rannala, J. Chem. Soc. Perkin Trans. 2 1974, 899 902.
[24] J. Iley, R. Moreira, E. Rosa, J. Chem. Soc. Perkin Trans. 2 1991, 81 86.
[25] Polymer-bound diazonium salts were thermochemically investigated:
S. Br‰se, S. Dahmen, C. Popescu, M. Schroen, F. J. Wortmann, Polym.
Degrad. Stab. 2002, 75, 329 335.
[26] Aldrich, Handbook of Fine Chemicals and Laboratory Equipment
2003 2004.
[27] H. Ahlbrecht, H. Simon, Synthesis 1983, 58 60.
[28] Fluka, Scientific Research 2003/2004.
1
98.8% (GC and H NMR).
Alkylation of phenols
4-Nitroanisole (28a): 4-Nitrophenol 28 (110 mg, 0.79 mmol) in DME
(5 mL) was treated with Me-PST 5a (940 mg, loading 1.7 mmolgÀ1
,
1.60 mmol) for 3 d as described for 6a to afford 28a (113 mg, 0.74 mmol,
94%) with a purity of 96.0% (GC and 1H NMR). M.p. 49.3 50.68C
(548C[30]).
[29] A. K. Chakraborti, A. Basak, V. Grover, J. Org. Chem. 1999, 64,
8014 8017.
Recycling of Me-PST 5a: Me-PST 5a (6.3 g, loading 2.0 mmolgÀ1
,
12.6 mmol) was added to a solution of excess benzoic acid 6 (7.1g,
58.2 mmol) in CH2Cl2 (70 mL), and the reaction mixture was stirred at
room temperature until the gas evolution finished. Then the polymer was
filtered off on a sintered glass funnel, washed with CH2Cl2 and dried. The
[30] The Merck Index, 13th ed., Merck & Co., Whitehouse Station, NJ,
2001, p. 6619.
Received: January 16, 2003 [F4739]
2588
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2582 2588