Polymer-bound diazonium salts for the synthesis of diazoacetic esters

Article abstract of DOI:10.1016/j.tet.2005.09.145

Starting from Merrifield resin, various polymer-bound diazonium salts were prepared. Upon treatment with amino acid esters, resulting the appropriate triazenes, the corresponding diazoacetic esters were formed by basic cleavage. Scope and limitation of th

Full text of DOI:10.1016/j.tet.2005.09.145

Tetrahedron 61 (2005) 12186–12192
Polymer-bound diazonium salts for the synthesis
of diazoacetic esters
*
¨
Maarten Schroen and Stefan Brase
¨
¨
Institut fur Organische Chemie, Universitat Karlsruhe (TH), Fritz-Haber-Weg 6, D-76131 Karlsruhe, Germany
Received 5 August 2005; revised 13 September 2005; accepted 13 September 2005
Available online 2 November 2005
Abstract—Starting from Merrifield resin, various polymer-bound diazonium salts were prepared. Upon treatment with amino acid esters,
resulting the appropriate triazenes, the corresponding diazoacetic esters were formed by basic cleavage. Scope and limitation of this
transformation were investigated.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
described the use of polymer-bound triazenes based on the
T2* linker in the synthesis of alkyl sulfonates 6 (XZRSO3)
starting from the corresponding sulfonic acid and in extension
from sodium sulfonates.9 Extension to phosphonates 6
(XZ(RO)2PO2) and phosphinates 6 (XZRPHO2) was also
possible (Scheme 1).10 In a related context, the ability of
polymer-bound triazene linkers as alkylating agents was
demonstrated in the synthesis of various carboxylic esters
starting from the corresponding acids.11
Polymer-bound reagents are versatile tools for the modern
high-throughput synthesis of medium- to large-sized
compound collections. Although many reagents have been
developed in the past,1 an azo-transfer reagent to transform
amines into diazo compounds is not available to our
knowledge.2
In several reports,3 we and others4 demonstrated the use of
triazenes 3 as linker moieties in solid-phase organic synthesis
to detach amines,5 guanidines,6 ureas and amides7 from solid
supports. In addition, we have demonstrated that immobilized
primary triazenes derived from an aromatic diazonium ion
and primary amines are suitable for the alkylation of acids
and for the synthesis of alkyl halides 6 (XZHal) (Path A,
Scheme 1).8 In a preceding communication, we have
In all these cases, the triazene moiety serves as a capped
diazoalkane equivalent, delivering the alkyl group upon
protonation.12 Earlier, we proposed8c that polymer-bound
triazenes might also deliver diazoalkanes upon cleavage,
however, this transformation remained elusive (Path B,
Scheme 1).
Diazonium ions were synthesized previously on cellu-
lose13,14 and macroporous supports.15 They were used for
16
the immobilization of enzymes.15 Benes et al. showed,
ˇ
R1
Path A
H+
+
HN
N
R1
R2
+
N
that (p-aminophenylsulfonyl)ethyl modified cellulose could
be diazotized to give a diazonium salt, which is, according
to the authors, unstable. This can be coupled with
b-naphthol to the corresponding azo dye. Lipophilic
supports are being used in a sequence consisting of
diazotation and subsequent reduction for the synthesis of
hydrazines.17 The diazotation of aliphatic amines in the
presence of halide ions is a convenient method and has been
used for the synthesis of Merrifield-type resins on a
Multipin-supporte.18
N
N
N
HN
3
R2
R1
R2
4
1
H2N
Path B:
basic
cleavage
X-
-H+
2
R1
R2
R1
R2
-
+
HX
N
N
X
5
6
Scheme 1. Cleavage of polymer-bound disubstituted triazenes.
We have synthesized diazonium ions with different
substitution pattern, determined their thermophysical pro-
perties19 and used them for the synthesis of triazenes.9,10,20,21
Keywords: Diazonium salts; Diazoacetic esters; Merrifield resin.
*
Corresponding author. e-mail: braese@ioc.uka.de
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.145

¨
M. Schroen, S. Brase / Tetrahedron 61 (2005) 12186–12192
12187
Rademann et al. used the T2-para resin for the synthesis of
O
OH
OH NO2
OH
triazenes,11while Struber et al. developed solid-phase bound
triazenes based on nitration and further functionalization of
polystyrene and investigated their chemical and thermophy-
sical properties.22
OH
NO2
Cl
O
O
O
NO2
Cl
NH2
NH2
8c
NH2
8b
NH2
8d
8a
2. Synthesis of a-diazoacetic esters from polymeric
diazonium ions
Figure 1. Building blocks for resin synthesis (all commercial available).
Piperazine (10) was used as spacer for a better coupling of
the anthranilic acids to the Merrifield resin (9, approx.
1 mmol/g, 1–2% cross-linked). The former method of
coupling benzoic acids or phenols with Cs2CO3 or NaH to
Merrifield resin,19b gave, in the cases of electron-poor
anthranilic acids, only low yields. Coupling of the benzoic
acids with DIC (without protecting the amino function) to
the resin 11, which is commercially available, resulted in a
complete loading of the resin (Scheme 3). The loadings of
the resins 12a–d were determined by CHN analysis.
Diazoacetic esters are very reactive building blocks for
organic syntheses. They can be used for cyclopropanation
reactions,23 [1,3]-dipolar cycloaddition (‘Huisgen reaction’)24
and N–H, O–H and S–H insertion reactions.25,26 These esters
have been synthesized by nitroxylation,27 alkylation28 or
diazotransfer.26,29
To the best of our knowledge, no practical approach for a
one-step conversion of amines into diazo compounds has
yet been reported. Herein, we present in detail, the
development of this methodology and further extensions.
HN
+
Cl
N
NH
NH
The goal of this project was to prepare a-diazoacetic esters
from the corresponding a-aminoacid esters with a poly-
meric diazonium ion as nitrogen donor. Reaction of an
aromatic diazonium ion with a primary amine results in a
triazene.12 First discovered by Baumgarten, the basic
cleavage of triazenes derived from glycine being substituted
with a para-nitroaryl group gave diazoacetic ester and left
an amine function at the original diazonium position.30 It is
known that triazenes based on amino acids having a
free carboxylic moiety are only relatively stable.31 Only
triazenes of proline and cysteine were reported so far.
However, when the carboxylic terminus of these amino
acids are esterificated, triazenes derived from the latter are
stable to be isolated.
9
11
10
O
NH2
HO
O2N
O2N
N
N
8a
NH2
DIC, DMF
24 h, RT
O
12a
O2N
N
BuONO, BF3·Et2O
N
-
N2+BF4
O
13a
1,3-Substituted triazenes exist in two tautomeric forms32,33
(allyl isomers) (Scheme 2).
Scheme 3. Preparation and diazotation of the T2*-like piperazine aryl
amino resin 12a.
H
The subsequent diazotation reaction of these amino resins
with tert-butyl nitrite (tBuONO) and bortrifluoride etherate
(BF3$Et2O) in THF between 0 and K10 8C led to polymer-
bound diazonium ions 13a–d. In analogy to the electron-
poor resins synthesized and characterized before,19b they
display a high temperature stability and can be stored at
room temperature for several days or even weeks.
H
N
N
N
N
R
N
N
R
X
X
7a
7b
Scheme 2. Tautomerism of triazenes. XZNO2, OMe, Hal.
For the attachment to these resins, amino acid esters were
liberated from their hydrochloride salts with KOH in water
and extracted with diethylether and added directly to the
diazonium resins 13. After 1 h, an excess of triethylamine
was added. Shaking this mixture for 2 h gave a new UV
active spot on the TLC. Filtration of the solution, and
chromatographically workup of the filtrate gave the desired
diazo acetic ester, but only in a very low yield of 5%.
In case of electron-withdrawing groups at the aromatic ring
(XZNO2), the dominant form is the one where the double
bond is not conjugated with the phenyl ring (b). For the base
induced preparation of diazoacetic esters, we used electron-
poor triazenes prepared before.19b However, basic cleavage
of amino acids attached to these resins did not lead to any
product with the exception of a nitro substituted resin which
gave small amounts of the diazoacetic esters (vide infra).
Therefore we synthesized a few new T2* like diazonium-
ions having electron-withdrawing groups based on the
building blocks 8a–d (Fig. 1). A series of new polymer-
bound resins were designed to take the influence of
substituents into account.
Another method to prepare the triazenes is to liberate the
aminoacidesterfromitshydrochloridewithsodiumcarbonate
in a mixture of water/methylene chloride at 0 8C, and addition
of the diazonium resin to this mixture. In this case, we could

¨
M. Schroen, S. Brase / Tetrahedron 61 (2005) 12186–12192
12188
isolate and analyze the triazene resin. This resin was cleaved
with triethylamine in THF and gave the diazoacetic ester 16a
(R1ZPh, XR2ZOEt), after filtrating the solution over a small
amount of silica gel in excellent purities and in an overall
yield of 38% based on the loading of the resin. This
transformation worked also with substituted phenylalanine
ester (R1Zp-ClC6H4, XR2ZOEt). Remarkably, azotransfer
proceeded also well with the dipeptide HLeuLeuOMe (R1Z
iPr, XR2ZLeuOMe) and thus gave access to labeled peptides
such a 16d (Scheme 4).
The resins 13a–d were tested on their diazo-transfer-
capability (Table 1). Therefore, we used phenylalanine
ethylester as the reference reagent. All resins form the
desired triazene 15{a,a–d}. Only 15{c,a} gave no product
after cleavage with triethylamine. Resins 15{a,a} and
15{b,a} gave a good yield of of 2-diazo-3-phenyl-propionic
acid ethyl ester (16a). This is a nice evidence for our
assumption, that the nitrogen transfer happens with electron
withdrawing groups regarding the triazene function. Resin
15{d,a} gave also the desired a-diazo ester, but in a very
low yield (2.5%).
However, extension to glycine ethyl ester failed. Although
being attachable to the resin, basic cleavage gave no
detectable product. IR-stretches and elemental analysis
indicated that a new product is formed on the resin. It
appears that a Dimroth cyclization34 took place to give
triazoles 17,35,36 which are not detached from the resin
under these conditions (Fig. 2). Apparently, a smaller
substituent favors cyclization rather than cleavage. On the
other hand, the benzyl ester of glycine 14c does not undergo
this cyclization on the resin. After cleavage, it gives the azo-
acetic ester benzyl ester 16c in a good yield. Amides did not
undergo this cyclization. Therefore, peptides ought to be
substrates of choice.
-
+
1)
BF4
N2
N
R1
R1
N
XR2
XR2
13a
NO2
O
2) Et3N
H2N
N2
O
O
up to 39%
14a-d
16a-d
R1
O2N
N
N
XR2
N
N
N
H
O
O
15{a,a-d}
a: R1 = CH2Ph, XR2 = OEt
O2N
OH
b: R1 = p-ClC6H4CH2, XR2 = OEt
c: R1 = H, XR2 = OBn
N
N
N
R1
d: R1 = CH2iPr, XR2 = LeuOMe
N
O
N
Scheme 4. Synthesis of diazoesters 16.
17
Figure 2. Viable product formed by cyclization prior cleavage.
In conclusion, we synthesized novel and bench-stable
electron-poor diazonium salts and used them for the first
azo-transfer to amino acids mediated by polymer-bound
reagents. Although this transformation is not fully explored,
this method should enable the synthesis of labeled amino
acids and peptides. Since diazoacetic esters are valuable
building blocks for the synthesis of heterocycles37
and cyclopropanes38 and can be used in combinatorial
chemistry, we are directing efforts in our group toward
applications of these important synthons.
Table 1. Yields (regarding the loadings of the amine resins 12a–d) of the
nitrogentransfer from different diazonium resins (13a–d) to phenylalanine
ethylester
Entry
Yield (%) of 2-diazo-3-phenyl-
propionic acid ethyl ester (16a)
N
R
R
N
13a
31
37
O
N2BF4
O2N
O
13b
13c
3. Experimental
3.1. General
NO2
N2BF4
0
O
1H NMR: Bruker DP 300 (300 MHz), Bruker DP 400
(400 MHz); dZ2.50 ppm for [D5] dimethylsulfoxide,
3.31 ppm for [D3] methanol, 7.24 ppm for CHCl3.
Description of signals: sZsinglet, bsZbroad singlet,
dZdoublet, tZtriplet, qZquartet, mZmultiplet, mcZ
centered multiplet, ddZdoublet of doublet, dddZdoublet
of dd, dtZdoublet of triplets, dqZdoublet of quartets,
ttZtriplet of triplets, caZcomplex area. The spectra were
analyzed according to first order. All couplings constants
are absolute values. Abbreviations for signals: Ar-HZAr.
13C NMR: Bruker DP 300 (75 MHz), Bruker DP 400
N2BF4
NO2
13d
2.5
O
Cl
N2BF4
Cl

¨
M. Schroen, S. Brase / Tetrahedron 61 (2005) 12186–12192
12189
(100 MHz); dZ39.52 ppm for perdeuterodimethylsulfoxide,
77.20 ppm for deuterochloroform, 49.00 for perdeutero-
methanol. The signal structure was analyzed by DEPT and
describedasfollows:CZprimaryortertiaryC-atom(positive
signal), KZsecondary C-atom (negative signal),) and qZ
quaternary C-atom (no signal). IR (infrared-spectroscopy):
Perkin Elmer FT-IR 1750. The substances were dissolved
in distilled dichloromethane. The resins were measured as
KBr pellets on a Bruker IFS88 IR. psZpolystyrene. -MS
(mass spectroscopy): EI-HRMS (electronic ionization-high
resolution mass spectroscopy): Kratos MS 50 (70 eV) and
Thermo Quest Finnigan MAT 95 XL (70 eV). GC (gas
chromatography) analytical: Hewlett–Packard HP 5890
Series II 12 m!0.25 mm capillary column HP I (carrier
gas N2). TLC (Thin layer chromatography): Silica gel
coated aluminium plates (Merck, silica gel 60, F254).
Detection under UV-light at 254 nm, displayed with
molybdato phosphate (5% phosphor molybdic acid in
ethanol, dipping solution), and potassium permanganate
(0.45 g potassium permanganate and 2.35 g of sodium
carbonate in 90 ml of water, dipping solution). Elemental
analysis: elementar vario EL at the Mikroanalytisches
(1074 g/mol) calcd C 89.50, H 7.90, N 2.60, found C 88.69, H
7.78, N 3.07; loading: quant.
3.2. General procedure for the attachment of amino
benzoic acids with electron withdrawing group
to the piperazine resin
In a 500 ml round bottom flask, 80 mmol of the amino
benzoic acid was dissolved in 200 ml of DMF. Then, 20 g
(ca. 20 mmol) of the piperazine resin 11 (approx. 1 mmol/g)
were added and the mixture was shaken at room
temperature. During the shaking, 10.1 g (80 mmol) of DIC
were slowly added with a syringe. After 48 h, the resin was
filtered off, washed with DMF, THF and methanol, and
dried under vacuum.
3.3. General procedure for the preparation
of diazoacetic acids
In a 50 ml round bottom flask, 0.138 g (1.3 mmol) of
Na2CO3 was solved in 3 ml of water. Then, 8 ml of
methylene chloride were added and the mixture was cooled
in an ice bath. At 0 8C, 2.5 mmol of the amino acid ester
were added carefully. After 10 min stirring, the diazonium
resin was added and the mixture was shaken for 2 h. Then,
the resin was filtered off, and washed with water, methylene
chloride and THF, and finally dried under vacuum.
¨
Labor of the Institute for Organic Chemistry, Universitat
Karlsruhe (TH). Descriptions without nominated tempera-
ture were done at room temperature (rt). Solid materials,
except resins, were powdered. All Chemicals, solvents,
and reagents were purchased from Acros, Aldrich, Fluka,
Janssen, or Merck. The Merrifield resin (1–2% cross-
linked, 200–400 mesh) was obtained from Polymer-
Laboratories with loadingZ1.06 g molK1. All resins were
washed sequentially by using a vacuum reservoir
connected to a sintered glass frit. Cleavage was conducted
either using Teflon tubes with a frit connected to a
vacuum line, with a glass pipette filled with glass wool, or
simply paper-filtered. Evaporation of the solvent was
achieved using a rota-vapor and/or under a high vacuum
(ca. 0.1 mbar). All solvents were dried by conventional
methods and distilled under argon. General washing
procedure: (methanol, THF, pentane, dichloromethane)
three times; (methanol, DMF, pentane, THF) once and
(pentane, dichloromethane, pentane) two times.
This triazene resin was given into 10 ml of THF and while
shaking, 1 ml of triethylamine was added. After 12 h, the
resin was filtered off and the filtrate was rotavaporated and
the remaining product (yellow oil) was dried under high
vacuum.
3.3.1. (3-Amino-6-nitrophenyl)-N-carboxypiperazinyl-
N0-methylpolystyrene (12a).
O
NH2
N
N
O2N
All resins were characterized by IR spectroscopy, loading
and conversions were valued by CHN combustion analysis.
Experimental examined loading of the resins can be
correlated very well with the results from CHN-combustion
analysis.
According to the general procedure, the reaction starting
from 5.70 g (31.3 mmol) of 2-nitro-5-amino benzoic acid
(8a), 8.4 g (7.8 mmol) of piperazine resin and 4.0 g
(31.7 mmol) of DIC in ca. 100 ml DMF (abs.) at rt
for 24 h yields a black/brown resin. IR (neat): nZ3477
[s, nas(N–H)], 3341 [s, ns(N–H)], 3227 (s), 2801
[m, n(CH2)], 2767 (m), 1688 [s, n(C]O)], 1642 [s,
nAr(C]C)], 1567 (m), 1526 (m), 1402 [m, d(C–H)], 1233
[m, ns(N]O)], 1133 (m), 996 (m), 857 (m). C87H88N4O3
(1244 g/mol) calcd C 84.45, H 7.18, N 4.51, found C 83.80,
H 7.41, N 4.09; loading: 90%.
Typical loadings of the used chloromethylpolystyrene were
between 0.6 and 1.4 mmol g-1. All new compounds were
characterized completely or compared to known substances.
3.1.1. Procedureforthepreparationofpiperazineresin11.
In a 250 ml three-necked round bottom flask equipped with a
mechanical stirrer, 17.2 g (200 mmol) of piperazine were
suspended in 100 ml of DMF and dissolved at 60 8C. Then,
8 ml of triethylamine (60 mmol) and 20 g of Merrifield resin
(approx. 1 mmol/g) were added. The mixture was stirred for
48 h at 60 8C. The hot resin was filtered off and washed along
the general washing procedure and dried under high vacuum.
IR (neat): nZ3340 [m, ns(N–H)], 2802 [s, n(CH2)], 2759 (s),
1688 [s, n(C]O)], 1134 (m), 1009 (m), 808 (m). C80H84N2
3.3.2. (4-Amino-3-nitrophenyl)-N-carboxypiperazinyl-
N0-methylpolystyrene (12b). Similarly, the reaction
starting from 2.73 g (15 mmol) of 4-amino-3-nitro benzoic
acid (8b), 5.00 g (4.66 mmol) piperazine resin and 1.89 g
(15 mmol) of DIC in ca. 100 ml DMF (abs.) at rt for 24 h
yields a brown resin. IR (KBr): nZ3473 [s, nas(N–H)], 3384
(s), 3325 [s, ns(N–H)], 3185 (s), 2801 [m, n(CH2)], 2766
(m), 1689 [s, n(C]O)], 1641 [s, nAr(C]C)], 1561 (s), 1525

¨
M. Schroen, S. Brase / Tetrahedron 61 (2005) 12186–12192
12190
(s), 1408 [m, d(C–H)], 1229 [m, ns(N]O)], 1133 (m), 996
(w), 858 (m). C87H88N4O3 (1244 g/mol) calcd C 84.45, H
7.18, N 4.51, found C 85.62, H 7.31, N 3.54; loading: 75%.
3.3.6. Resin 15{b,a}. Similarly, the reaction starting from
0.50 g of amino resin 12b (0.30 mmol), 0.4 ml (3.0 mmol)
of BF3$OEt2 and 0.40 ml (3.2 mmol) of tert-BuONO in
10 ml of THF at rt for 1.5 h yields the brown diazonium
resin. To an ice-cooled mixture of 0.138 g (1.3 mmol) of
Na2CO3 dissolved in 3 ml of water and 8 ml of methylene
chloride, were slowly added 0.575 g (2.5 mmol) of
phenylalanine ethylester hydrochloride, and stirred for
10 min. Then, at 0 8C the diazonium resin 13b was added
and shaken for 2 h. The resulting triazene resin was filtered
off and washed with water, CH2Cl2, THF. IR (neat): nZ
3322 [s, nas(N–H)], 2985 (w), 2802 [s, n(CH2)], 2766 (s),
1738 [s, n(C]O)], 1688 s, n(C]O)], 1643 [s, nAr(C]C)],
1566 (m), 1530 (m), 1406 [m, d(C–H)], 1222 [s, ns(N]O)],
1132 (m), 997 (w), 859 (w). C98H100N6O5 (1442 g/mol):
calcd C 81.66, H 7.01, N 5.81, found C 83.95, H 7.53, N
3.88;
3.3.3. (3-Amino-5-nitrophenyl)-N-carboxypiperazinyl-
N0-methylpolystyrene (12c). Similarly, the reaction
starting from 2.73 g (15 mmol) of 3-amino-5-nitro benzoic
acid (8c), 5.00 g (4.66 mmol) of piperazine resin 11 and
1.89 g (15 mmol) of DIC in ca. 100 ml DMF (abs.) at rt for
24 h yields a green resin. IR (neat): nZ3474 [s, nas(N–H)],
3350 [s, ns(N–H)], 3233 (s), 2802 [m, n(CH2)], 2767 (m),
1688 [s, n(C]O)], 1640 [s, nAr(C]C)], 1530 (s), 1399 [m,
d(C–H)], 1229 [m, ns(N]O)], 1135 (m), 996 (m), 857
(m). C87H88N4O3 (1244 g/mol) calcd C 84.45, H 7.18, N
4.51, found C 86.04, H 7.22, N 3.30; loading: 70%.
3.3.4. (3-Amino-2,5-dichlorophenyl)-N-carboxypiperazi-
nyl-N0-methylpolystyrene (12d).
3.3.7. Resin 15c. Similarly, the reaction starting from 0.50 g
of amino resin 12c, 0.40 ml (3.0 mmol) of BF3$OEt2 and
0.4 ml (3.2 mmol) of tert-BuONO in 10 ml THF at rt for
1.5 h yields the yellow diazonium resin. To an ice-cooled
mixture of 0.138 g (1.3 mmol) of Na2CO3 dissolved in 3 ml
of water and 8 ml of methylene chloride, were slowly
added 0.575 g (2.5 mmol) of phenylalanine ethylester
hydrochloride, and stirred for 10 min. Then, at 0 8C the
diazonium resin 13c was added and shaken for 2 h. The
resulting triazene resin was filtered off and washed with
water, CH2Cl2, THF. IR (neat): nZ3257 [s, nas(N–H)], 2985
(w), 2802 [s, n(CH2)], 2766 (s), 1749 [s, n(C]O)], 1689 s,
n(C]O)], 1644 [s, nAr(C]C)], 1562 (m), 1530 (m), 1407
[m, d(C–H)], 1225 [s, ns(N]O)], 1134 (m), 996 (w), 859
(w). C98H100N6O5 (1442 g/mol): calcd C 81.66, H 7.01, N
5.81, found C 83.07, H 7.38, N 3.94;
O
Cl
NH2
N
N
Cl
Similarly, the reaction starting from 3.09 g (15 mmol)
3-amino-2,5-dichloro benzoic acid (8d), 5.00 g (4.66 mmol)
of piperazine resin 11 and 1.89 g (15 mmol) DIC in ca.
100 ml DMF (abs.) at rt for 24 h yields a light beige resin.
IR(neat): nZ3483 [s, nas(N–H)], 3346 [s, ns(N–H)], 3221
(s), 2803 [m, n(CH2)], 2767 (m), 1688 [s, n(C]O)], 1641 [s,
nAr(C]C)], 1567 (m), 1470 (w), 1399 [m, d(C–H)], 1133
(m), 997 (m), 855 (m), C87H87N3OCl2 (1262 g/mol) calcd C
82.86, H 6.97, N 3.32, found C 84.73, H 6.84, N 2.57;
loading: 74%.
3.3.8. Resin 15{d,a}.
3.3.5. Resin 15{a,a}.
O
Cl
Cl
O
H
N
N
N
O
O
H
N
N
O
N
N
N
N
N
O
O2N
Similarly, the reaction starting from 0.50 g of amino resin
12a (0.36 mmol), 0.40 ml (3.0 mmol) of BF3$OEt2 and
0.40 ml (3.2 mmol) of tert-BuONO in 10 ml of THF at rt for
1.5 h yields a brown diazonium resin 13a. To an ice-cooled
mixture of 0.138 g (1.3 mmol) of Na2CO3 dissolved in 3 ml
of water and 8 ml of methylene chloride, were slowly added
0.575 g (2.5 mmol) of phenylalanine ethylester hydrochlo-
ride, and stirred for 10 min. Then, at 0 8C the diazonium
resin 13a was added and shaken for 2 h. The resulting
triazene resin was filtered off and washed with water,
CH2Cl2, THF. IR (neat): nZ3316 [s, nas(N–H)], 2985 (w),
2802 [s, n(CH2)], 2767 (s), 1737 [s, n(C]O)], 1688 s,
n(C]O)], 1642 [s, nAr(C]C)], 1568 (m), 1528 (m), 1404
[m, d(C–H)], 1231 [s, ns(N]O)], 1133 (m), 996 (m), 858
(m). C98H100N6O5 (1442 g/mol): calcd C 81.66, H 7.01, N
5.81, found C 80.97, H 7.10, N 4.76;
Similarly, the reaction starting from 0.50 g (0.29 mmol) of
amino resin 12b, 0.40 ml (3.0 mmol) of BF3$OEt2 and
0.40 ml (3.2 mmol) of tert-BuONO in 10 ml THF at rt for
1.5 h yields the yellow diazonium resin. To an ice-cooled
mixture of 0.138 g (1.3 mmol) of Na2CO3 dissolved in 3 ml
of water and 8 ml of methylene chloride, were slowly added
0.575 g (2.5 mmol) of phenylalanine ethylester hydrochlo-
ride, and stirred for 10 min. Then, at 0 8C the diazonium
resin 13d was added and shaken for 2 h. The resulting
triazene resin was filtered off and washed with water,
CH2Cl2, THF. IR (neat): nZ3261 [s, nas(N–H)], 2985 (w),
2802 [s, n(CH2)], 2767 (s), 1738 [s, n(C]O)], 1689 s,
n(C]O)], 1642 [s, nAr(C]C)], 1562 (m), 1523 (m), 1404
[m, d(C–H)], 1226, 1133 (m), 996 (w), 864 (m).
C98H99N5O3Cl2 (1466 g/mol): calcd C80.34, H 6.82, N
4.76, found C 82.82, H 7.39, N 3.25;

¨
M. Schroen, S. Brase / Tetrahedron 61 (2005) 12186–12192
12191
3.3.9. 2-Diazo-3-phenyl-propionic acid ethyl ester (16a).
Acknowledgements
Financial supports to this work from German Science
Foundation (BR 1730) and Fonds der Chemischen Industrie
are gratefully acknowledged.
O
N2
O
References and notes
The triazene resin 15{a-d,a} was added into 10 ml of THF
and 0.5 ml of triethylamine was also added. The mixture
was shaken for 4 h. The resin was filtered off and the filtrate
was liberated from the solvent by rotavaporation and
yielded 22.3 mg (0.11 mmol, 31%) of 2-diazo-3-phenyl-
propionic acid ethyl ester; 1H NMR (250 MHz, CDCl3) dZ
7.15–7.32 (m, 5 H), 4.18 (q, 2 H, JZ7.15 Hz), 3.56 (s, 2 H),
1.19 (t, 3 H, JZ7.15 Hz); 13C NMR (100 MHz, CDCl3) dZ
167.0, 136.3, 128.4, 127.8, 127.3, 126.1, 60.0, 28.3,
13.5 ppm; EI-MS m/z (relative intensity): 204.1 (15), 176
(14), 148 (17), 103 (100), 91 (89); HRMS (m/z) calculated
for C11H12N2O2 204.089878 found 204.0896.
1. Novabiochem Catalogue 2004.
2. (a) Baxendal, I. R.; Ley, S. V.; Piutti, C. Angew. Chem., Int.
Ed. 2002, 41, 2194–2197. (b) Angew. Chem. 2002, 114,
2298–2301. (c) Handbook of Combinatorial Chemistry;
Nicolaou, K. C., Hanko, R., Hartwig, W., Eds.; Wiley-VCH:
Weinheim, 2002.
¨
3. For an account: Brase, S. Acc. Chem. Res. 2004, 37, 805–815.
¨
4. Enders, D.; Rijksen, C.; Bremus-Kobberling, E.; Gillner, A.;
¨
Kobberling, J. Tetrahedron Lett. 2004, 45, 2839–2841.
5. Bra¨se, S.; Ko¨bberling, J.; Enders, D.; Wang, M.; Lazny, R.;
Brandtner, S. Tetrahedron Lett. 1999, 40, 2105–2108.
¨
6. Dahmen, S.; Brase, S. Org. Lett. 2000, 2, 3563–3565.
3.3.10. 3-(4-Chloro-phenyl)-2-diazo-propionic acid ethyl
ester (16b).
¨
7. Brase, S.; Dahmen, S.; Pfefferkorn, M. J. Comb. Chem. 2000,
2, 710–717.
8. (a) Pilot, C. Matrise de Chimie, RWTH Aachen 1999. (b)
¨ ¨
Brase, S. Chim. Oggi 2000, 18, 14–19. (c) Brase, S.; Dahmen,
Cl
S. Chem. Eur. J. 2000, 6, 1899–1905.
9. Vignola, N.; Dahmen, S.; Enders, D.; Brase, S. Tetrahedron
¨
O
N2
Lett. 2001, 42, 7833–7836.
10. Vignola, N.; Dahmen, S.; Enders, D.; Brase, S. J. Comb.
Chem. 2003, 5, 138–144.
¨
O
11. (a) Rademann, J.; Smerdka, J.; Jung, G.; Grosche, P.; Schmid,
D. Angew. Chem. 2001, 113, 390–394. (b) Angew. Chem., Int.
Ed. 2001, 40, 381–385.
Similarly, the modificated triazene resin 15{a,b} was added
into 10 ml of THF and 0.5 ml of triethylamine was also
added. This mixture was shaken for 12 h. The resin was
filtered off and the filtrate was liberated from the solvent by
rotavaporation and yielded 12.7 mg of 3-(4-chloro-phenyl)-
2-diazo-propionic acid ethyl ester (15%); 1H NMR
(250 MHz, CDCl3) dZ7.09–7.24 (m, 4 H), 4.16 (q, 2 H,
JZ7.15 Hz), 3.53 (s, 2 H), 1.21 (t, 3 H, JZ7.15 Hz); 13C
NMR (100 MHz, CDCl3) dZ167.0, 135.9, 132.4, 130.7,
128.9, 61.0, 28.9, 14.5 ppm.
12. Zollinger, H. Diazo Chemistry 1, Aromatic and Heteroaro-
matic Compounds; VCH: Weinheim, 1994.
13. Fontanel, M. L.; Bazin, H.; Teoule, R. Bioconj. Chem. 1993, 4,
380–385.
14. Docolomansky, P.; Breier, A.; Gmeiner, P.; Ziegelhoffer, A.
Anal. Lett. 1995, 28, 2585–2594.
15. Tao, G. L.; Furusaki, S. Polym. J. 1995, 27, 111–121.
ˇ
16. (a) Benes, M. J.; Lenfeld, J.; Pradova, O. J. Mol. Recog. 1996,
ˇ
9, 701–705. (b) Lenfeld, J.; Benes, M. J.; Fraga, A. N. React.
Polym. 1994, 22, 127–130.
3.3.11. 2-Diazo-acetic acid benzyl ester (16c).
17. Semenov, A. N.; Gordeev, K. Y.; Int, J. Peptide Protein Res.
1995, 45, 303–304.
18. Bui, C. T.; Maeji, N. J.; Rasoul, F.; Bray, A. M. Tetrahedron
Lett. 1999, 40, 5383–5386.
¨
19. (a) Brase, S.; Dahmen, S.; Popescu, C.; Schroen, M.;
O
N2
O
Wortmann, F.-J. Polym. Deg. Stab. 2002, 75, 325–335. (b)
¨
Brase, S.; Dahmen, S.; Popescu, C.; Schroen, M.; Wortmann,
Similarly, the modificated triazene resin 15a00 (instead of the
phenylglycine ethyl ester, there is a glycine benzyl ester
bound as a triazene) was added into 10 ml of THF and
0.5 ml of triethylamine was also added. This mixture was
shaken for 12 h. The resin was filtered off and the filtrate
was liberated from the solvent by rotavaporation and
yielded 25 mg of 2-diazo-acetic acid benzyl ester (39%);
1H NMR (250 MHz, CDCl3) dZ7.21–7.35 (m, 5 H), 5.12 (s,
2 H), 4.72 (s, 1 H); 13C NMR (100 MHz, C6D6) dZ166.0,
142.0, 136.6, 127.4, 127.0, 66.3 ppm; 16d.
F.-J. Chem. Eur. J. 2004, 10, 5285–5296.
¨
20. Brase, S.; Dahmen, S.; Lormann, M. In Methods in
Enzymology, 369; Morales, G., Bunin, B., Eds.; Academic
Press, 2003; pp 127–150.
¨
21. Pilot, C.; Dahmen, S.; Lauterwasser, F.; Brase, S. Tetrahedron
Lett. 2001, 42, 9179–9181.
22. Erb, B.; Kucma, J. P.; Mourey, S.; Struber, F. Chem. Eur. J.
2003, 9, 2582–2588.
23. Barrett, A. G. M.; Braddock, D. C.; Lenoir, I.; Tone, H. J. Org.
Chem. 2001, 66, 8260–8263.

¨
M. Schroen, S. Brase / Tetrahedron 61 (2005) 12186–12192
12192
24. Eichenauer, U.; Huisgen, R.; Mitra, A.; Moran, J. R.
Heterocycles 1987, 25, 129–132.
33. Hadzi, D.; Jan J. Spectrosc. Lett. 1968, 1, 139–143.
34. (a) Wamhoff, H.; Wambach, W. Chemiker-Ztg. 1989, 113,
¨
11–15 and references therein. (b) See also, review: Brase, S.;
Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed.
25. Bachmann, S.; Fielenbach, D.; Jørgensen, K. A. Org. Biomol.
Chem. 2004, 3044–3049.
26. Taber, D. F.; Sheth, R. B.; Joshi, P. V. J. Org. Chem. 2005, 70,
2851–2854.
2005, 44, 5188–5240. (c)
5320–5374.
Angew. Chem. 2005, 117,
27. Takamura, N.; Mizoguchi, T.; Koga, K.; Yamada, S.
Tetrahedron Lett. 1971, 8, 4495–4498.
35. Zaragoza, F.; Petersen, S. V. Tetrahedron 1996, 52,
10823–10826.
¨
28. Schollkopf, U.; Rieber, N. Angew. Chem., Int. Ed. 1967, 6, 261.
29. Charette, A. B.; Wurz, R. P.; Ollevier, T. Helv. Chim. Acta
2002, 85, 4468–4484.
36. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057–3064.
37. Lee, Y. R.; Hwang, J. C. Eur. J. Org. Chem. 2005, 1568–1577.
38. (a) Boverie, S.; Simal, F.; Demonceau, A.; Noels, A. F.;
Eremenko, I. L.; Sidorov, A. A.; Nefedov, S. E. Tetrahedron
Lett. 1997, 38, 7543–7546. (b) Caballero, A.; Diaz-Requejo,
M. M.; Trofimenko, S.; Belderrain, T. R.; Perez, P. J. J. Org.
Chem. 2005, 70, 6101–6104.
30. Baumgarten, R. J. J. Org. Chem. 1967, 32, 484–485.
31. Zahn, H.; Wollemann, B.; Waschka, O. Hoppe-Seyler’s
Zeitschrift Physiol. Chem. Chem. 1954, 294, 100–107.
32. (a) Mitsuhashi, T.; Simumara, O. Chem. Ind. 1964, 5, 578. (b)
Weckherlin, S.; Lu¨ttke, W. Tetrahedron Lett. 1964, 5, 1711.