Synthesis of orthogonally protected pyrrole tricarboxylic acid derivatives: Versatile building blocks for pyrrole-containing compounds

Article abstract of DOI:10.1055/s-2005-918435

The large-scale synthesis of three new orthogonally protected pyrrole tricarboxylates 1-3 is described. Using different cleavage conditions, each of the three carboxylates can be set free selectively without affecting the others, making these pyrrole derivatives versatile synthetic building blocks for a wide range of applications in natural product or supramolecular chemistry. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918435

PAPER
89
Synthesis of Orthogonally Protected Pyrrole Tricarboxylic Acid Derivatives:
Versatile Building Blocks for Pyrrole-Containing Compounds
New
P
yrrole Tric
a
arboxylate
r
Building
s
Blocks ten Schmuck,* Daniel Rupprecht, Christian Urban, Nicholas Walden
University of Würzburg, Institute of Organic Chemistry, Am Hubland, 97074 Würzburg, Germany
Fax +49(931)8884625; E-mail: schmuck@chemie.uni-wuerzburg.de
Received 11 May 2005; revised 23 June 2005
Dedicated to Prof. Albrecht Berkessel on the occasion of his 50th birthday
We chose the corresponding tert-butyl, benzyl and meth-
Abstract: The large-scale synthesis of three new orthogonally pro-
tected pyrrole tricarboxylates 1–3 is described. Using different
cleavage conditions, each of the three carboxylates can be set free
selectively without affecting the others, making these pyrrole deriv-
yl/ethyl esters as orthogonal protecting groups.6 Whereas
the tert-butyl ester can be cleaved easily under acidic con-
ditions (e.g. TFA in CH2Cl2), the benzyl ester can be re-
atives versatile synthetic building blocks for a wide range of appli- moved by hydrogenolysis (H2/Pd) and the methyl/ethyl
cations in natural product or supramolecular chemistry.
ester by basic hydrolysis (LiOH in MeOH). Choosing the
correct substitution pattern of the three carboxyl groups as
in 1, 2 or 3 each of the carboxylates can be set free subse-
quently without affecting the remaining esters in the mol-
ecule. These three derivatives therefore allow for
maximum synthetic flexibility in any further desired
transformation of these useful synthetic building blocks.
Key words: pyrroles, carboxylic acids, protecting groups, trans-
esterifications, oxidations
Substituted pyrroles are versatile synthetic building
blocks for a variety of applications ranging from natural
products to pharmaceutical agents and supramolecular
chemistry.1 For our own specific purposes, the design of
artificial receptors for biologically relevant substrates2 or
self-assembling zwitterions3 we were interested in pyrrole
tricarboxylic acids of the general structure shown in
Figure 1. The two carboxyl groups in position 2 and 5 of
the pyrrole ring are needed for further attachment of spe-
cific binding sites such as a guanidino or an amide group
whereas the side-chain carboxyl group serves as a handle
to attach the resulting guanidiniocarbonyl pyrrole binding
motif to either a solid support or for linking two or more
of these recognition motifs into a multivalent display. For
this purpose, however, a sequential and selective transfor-
mation of the three carboxylic acid groups is necessary.
Whereas in principle the side-chain carboxylate is more
reactive than the two pyrrole carboxylates and can be re-
acted at least with some selectivity, a distinction between
the latter two is not possible based on their intrinsic reac-
tivity. Even the selective transformation of the side-chain
carboxylate, for example its hydrolysis into the corre-
sponding acid, requires a careful control of the reaction
conditions to avoid mixtures of products.4 The use of or-
thogonal protecting groups offers a solution to this prob-
lem. We were therefore interested in developing a
versatile approach, which allows the large-scale synthesis
of a variety of new pyrrole triesters with varying substitu-
tion patterns at the three ester groups. The corresponding
target compounds 1–3 are summarized in Figure 1. All tri-
esters are new compounds that have not been described in
the literature so far.5
R2
t-Bu
Me
Bn
R3
Bn
R5
Et
O
OR3
1
2
3
R5O
OR2
t-Bu
Me
Bn
t-Bu
N
H
O
O
Figure 1 Triply orthogonally protected pyrrole tricarboxylates.
The general synthetic procedure is described in Scheme 1.
The triesters can be traced back to the a-methyl pyrrole
from which they can be synthesized by selective a-oxida-
tion and subsequent esterification in position R2. The a-
methyl pyrroles can be prepared by Knorr-type cycliza-
tion of a b-diketone (e. g. the R3-4-acetyl-5-oxohex-
anoate) with an a-amino-b-dicarbonyl compound, which
can be obtained by reduction from the corresponding
oxime.7 Due to the frequent instability of many of these
aminocarbonyl compounds the reduction of the oxime to
the amine is in general performed in situ in the presence
of the second carbonyl compound to start the Knorr reac-
tion immediately after release of the amine.8
Our first target compound was triester 1 (Scheme 2). The
preparation started from the pyrrole diester 4 synthesized
according to methods described in the literature.8b,9 The
carboxylic acid 5 was obtained by treatment of 4 with
NaOH in EtOH and water at 60 °C.10 To avoid the trans-
esterification to the methyl ester we chose EtOH as a sol-
vent even though the solubility of 4 in EtOH is rather
limited compared to MeOH. Selective hydrolysis of the
side-chain ethyl ester was thus achieved and the desired
product was obtained in 80% yield. In the next step the
free side-chain carboxylic acid group of 5 was trans-
formed into the benzyl ester by reaction with benzyl chlo-
SYNTHESIS 2006, No. 1, pp 0089–0096
x
x
.
x
x
.2
0
0
5
Advanced online publication: 25.10.2005
DOI: 10.1055/s-2005-918435; Art ID: T05905SS
© Georg Thieme Verlag Stuttgart · New York

90
C. Schmuck et al.
PAPER
O
O
reaction times especially under acidic conditions or even
during work up, pyrrole carboxylic acids tend to decar-
boxylate which very often significantly reduces the yields
of isolated product in this oxidation step. Good yields are
often found for products, which easily crystallize and are
thereby removed from the aggressive reaction mixture.
OR3
OR3
R5O
OR2
R5O
N
N
H
H
O
O
O
O
O
O
O
O
OR3
R5O
X
(b)
(a)
N
OH
R5O
X = OR5, Me
O
OR3
N
H
O
Scheme 1 Retrosynthetic analysis of the tricarboxylates.
O
O
OR3
Cl
OR3
ride in DMF–Et3N to give the diester 6 in 90% yield.11
Attempts to directly transform the starting diester 4 into 6
by transesterification with benzylate failed due to signifi-
cant amounts of dibenzyl derivative in the product mix-
ture. Even the transesterification of the ethyl ester
derivative of 15 (Scheme 6, R3 = Et instead of Me) with
NaOBn in refluxing toluene led to transesterification at
both ester positions, although position R5 is derived from
a rather unreactive electron-rich pyrrole carboxylate and
tert-butyl esters in general are assumed to be inert towards
basic transesterification.
R5O
R5O
Cl
Cl
N
N
H
H
Cl
Cl
R2OH
O
O
H2O
O
O
OR3
OR3
Ox.
O
O
R5O
H
R5O
OR2
OR3
OBn
N
N
H
H
4: R3 = Et
O
O
O
O
(i)
5: R3 = H
Scheme 3 Threefold a-chlorination followed by hydrolysis or alco-
holysis (a, right part) or twofold a-chlorination, hydrolysis and subse-
quent oxidation (b, left part) to obtain pyrrole tricarboxylates.
(ii)
EtO
EtO
N
N
H
H
O
O
6
O
For the hitherto unknown compound 7, we first chose a
standard procedure.14 The a-methyl group in 6 was oxi-
dized by treatment with sulfuryl chloride in AcOH fol-
lowed by aqueous workup at 0 °C. Fast precipitation
avoided decomposition of the resulting carboxylic acid 7,
otherwise quite sensitive to acidic conditions. After addi-
tion of water to the reaction mixture (which led to libera-
tion of HCl from the hydrolysis of the trichloride and by
decomposition of unreacted SO2Cl2) a change in the color
of the reaction mixture from slightly yellow to brown in-
dicated the beginning of decomposition during workup,
but fortunately in this case the product precipitated imme-
diately after pouring into ice-water, thereby removing it
from the aggressive reaction medium and giving a yield of
92%. In contrast to this, for example, the direct oxidation
of the diethyl ester 4 only gave trace amount of acid under
the same conditions, because the product does not crystal-
lize as easily as 7. Compound 7 was then transformed into
the corresponding acyl chloride using oxalyl chloride in
CH2Cl2 with a catalytic amount of DMF. Finally, the new
pyrrole triester 1 was obtained by reaction of this acyl
chloride with t-BuOK in tert-BuOH in 50% yield.
OBn
OR2
(iii)
EtO
7:
1: R2 = t-Bu
R
2 = H
(iv)
N
H
O
O
Scheme 2 Reagents and conditions: (i) NaOH, H2O, EtOH, 60 °C,
3.5 h, 80%. (ii) BnCl, DMF–Et3N (2:1), r.t., 24 h, 90%. (iii) SO2Cl2,
AcOH, 0 °C, 5 h; H2O, 0–4 °C, 1.5 h, 92%. (iv) Oxalyl chloride,
CH2Cl2, DMF (cat.), r.t., 1 h; t-BuOK, t-BuOH, 40 °C, 2 h, 50%.
The next step required the oxidation of the a-methyl group
to introduce the third carboxylic acid group. For methyl
pyrroles in general a wide range of procedures and reac-
tion conditions are described for this transformation in the
literature. The most common one is the radical chlorina-
tion with subsequent hydrolysis (Scheme 3, route a).12
This oxidation can be carried out with or without basic
quenching of the liberated hydrochloric acid. The yields
reported vary from < 30–99%, significantly depending
also on other functionalities present in the molecule. The
problem of this reaction step is mainly the instability of
the resulting pyrrole carboxylic acids.13 Upon prolonged
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New Pyrrole Tricarboxylate Building Blocks
91
The three carboxylic acid groups in this triester 1 or the tion of 4 to the corresponding benzyl ester (R2 = Bn) by
free acid 7 can be released in nearly any desired sequence quenching the reaction mixture with benzyl alcohol in-
except for one limitation: The cleavage of the benzylic es- stead of water (see Scheme 3, route a). After flash chro-
1
ter in the side-chain has to occur prior to the hydrolysis of matography the H NMR indicated a mixture of the
the ethyl ester in position 5. Therefore, triester 1 does not benzylic ester and some unwanted by-products (according
allow to further react both carboxylates attached to the to NMR the aldehyde resulting from incomplete oxidation
pyrrole ring before the side-chain carboxylate is trans- of the methyl group even in the presence of excess sulfu-
formed. To circumvent this problem, we were interested ryl chloride). We could not separate this mixture either by
in triester 2, in which the side-chain carboxylate is now column chromatography or by crystallization.
protected as the tert-butyl ester and the a-positions of the
We finally succeeded in preparing 10 in acceptable yields
pyrrole as benzyl and methyl esters, respectively. This tri-
by performing the oxidation in two subsequent steps
ester 2 together with the corresponding free acid 10 allows
any of the three carboxylates to react in any order.
(Scheme 3, route b). First, chlorination of 9 with 2 equiv-
alents of sulfuryl chloride in Et2O at 0 °C followed by
aqueous workup gave the corresponding aldehyde, which
O
O
was then oxidized without further purification in situ by
treatment with KMnO4 in acetone–water at room temper-
ature. This provided the hitherto unknown pyrrole deriva-
tive 10 in 42% overall yield. The oxidation of the
intermediate pyrrole aldehyde (which was identified via
NMR in the reaction mixture) with KMnO4 represents ob-
viously much milder conditions than the direct oxidation
using excess sulfuryl chloride preventing the decomposi-
tion of the resulting free carboxylic acid. Hence, route b is
an alternative for highly sensitive compounds. Compound
10 was then reacted with MeI in DMF in the presence of
K2CO3 to obtain the triester 2 in a yield of 45%. Triester 2
or the free acid 10 now allow to further transform both
carboxylic acid groups attached to the pyrrole before the
side-chain ester.
OH
Ot-Bu
5:
8:
R
R
5 = Et
(i)
5 = Bn
R5O
BnO
(ii)
N
N
H
H
O
O
9
O
Ot-Bu
OR2
(iii)
10: R2 = H
2:
2 = Me
BnO
O
(iv)
N
R
H
O
Scheme 4 Reagents and conditions: (i) NaOBn, BnOH, 10–20
mbar, 100 °C, 6 h, 64%. (ii) Oxalyl chloride, CH2Cl2, DMF (cat.), r.t.,
2 h, t-BuOK, t-BuOH, 40 °C, 6 h, 72%. (iii) SO2Cl2 (2 equiv), K2CO3
(4 equiv), Et2O, 0 °C, 2 h; H2O, r.t., 0.5 h, then KMnO4 (1 equiv), ace-
tone–H2O (1:1), r.t., 2 h, 42%. (iv) DMF, MeI (1 equiv), K2CO3, 1 d,
45%.
The two triesters 1 and 2, synthesized here for the first
time, now offer a broad flexibility for the introduction of
other functionalities into this pyrrole skeleton via their es-
ter groups. Furthermore, besides hydrolysis and subse-
quent ester or amide formation via the free acid, the ester
groups could also be transformed into other even more
versatile functionalities via the corresponding aldehydes
or alcohols. For example, in a first experiment we were
able to obtain the side-chain aldehyde 11 by reaction of 4
with DIBAL-H at –78 °C in toluene (Scheme 5).17 Hence,
the side-chain ester can be selectively reduced while keep-
ing the pyrrole ester intact. The aldehyde functionality of-
fers additional synthetic flexibility, for example via imine
formation or reductive amination. However, in this first
experiment substantial amounts (15%) of the correspond-
ing alcohol were also formed, although TLC still indicat-
ed a trace of unreacted starting material. Further
optimization would be required to find the best reaction
conditions for aldehyde formation. For example, protec-
tion of the pyrrole nitrogen could be beneficial18 or the use
of LiHAl(Ot-Bu)3 instead of DIBAL-H.19 However, we
have not yet investigated this approach any further.
The synthesis of 2 also started from the carboxylic acid 5
(Scheme 4). The remaining ethyl ester group in position 5
was exchanged for a benyzl ester by treatment with sodi-
um benzylate in benzyl alcohol at 100 °C over a period of
6 hours under reduced pressure (10–20 mbar) to remove
the liberated EtOH to give 8 in 64% yield. These condi-
tions proved to be mild enough to avoid decomposition.
The same reaction at atmospheric pressure and a temper-
ature of 140 °C, conditions similar to those found in the
literature for related systems,12c,15 resulted only in very
low yields (< 16%) when applied to 5. Compound 8 was
then esterified via the acyl chloride (obtained from its re-
action with oxalyl chloride) and subsequent treatment
with t-BuOK in tert-BuOH at 40 °C to give 9 in 72%
yield. In analogy to the synthesis of 7, direct oxidation of
the a-methyl group to the carboxylic acid using sulfuryl
chloride was attempted in various solvents, but even un-
der very mild and slightly basic conditions only decompo-
sition of the product was observed. Only trace amounts of
the desired carboxylic acid 10 could by isolated.
The two new pyrrole derivatives 1 and 2 can be prepared
on multi gram scales via the synthesis described above,
but the total sequences are still rather time-consuming and
require extensive purification by flash chromatography.
Furthermore, the starting material 4 is not commercially
available and has also to be synthesized (two steps with a
total yield of 59%). We therefore developed an even sim-
Another approach to avoid decarboxylation of the free
carboxylic acid is to use an alcohol instead of water for
hydrolysis of the intermediate trichloride to directly ob-
tain the corresponding ester.16 We tried this for the oxida-
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92
C. Schmuck et al.
PAPER
(see above), but also because of the acid-sensitive tert-bu-
tyl ester which is otherwise cleaved. The free acid 16 can
then easily be converted into triester 3 with benzyl bro-
mide and K2CO3 in DMF in quantitative yield. Aqueous
workup followed by column chromatography gave the tri-
ester 3 in 98% yield. Hence, triester 3 was synthesized
from commercially available starting materials on a multi
gram scale in only four steps without any intermediate
chromatographic purification needed in between in 14%
overall yield in excellent purity.
O
HO
(i)
4
+
EtO
EtO
N
N
H
O
H
O
11
12
Scheme 5 Reagents and conditions: (i) toluene, –78 °C, 1 M
DIBAL-H in toluene (stepwise 2.5 equiv), 4 h, 46%.
In conclusion, we present here the versatile and large-
scale synthesis of three new triply orthogonally protected
pyrrole tricarboxylates 1–3. Even though their synthesis
followed the same general approach (Scheme 1), each
compound required a careful optimization of the reaction
conditions especially for the oxidation of the a-methyl
group. This step was crucial for the total yield. With the
procedures developed here multi-gram quantities of these
versatile synthetic building blocks can now easily be pre-
pared.
pler approach to another not yet described pyrrole triester
3, which also offers maximum flexibility with regard to
further transformations of the carboxylates. Its synthesis
however requires only four steps starting from the readily
available and inexpensive starting material 13 and 14
(Scheme 6). Furthermore, the intermediate products,
mainly the acid 16, can be easily purified simply by crys-
tallization. No flash chromatography is required to purify
any of the intermediates.
Reaction solvents were dried and distilled under Ar before use. All
other reagents were used as obtained from either Aldrich or Fluka.
1H and 13C NMR spectra were measured on a Bruker Avance 400 or
AC 250 and the chemical shifts are reported relative to the deuter-
ated solvents. Peak assignments are based on either DEPT, 2D
NMR studies and/or comparison with literature data. Melting points
were measured on a Büchi SMP-20 apparatus and are not corrected.
IR spectra were collected on a Perkin-Elmer FT-IR 1600 instru-
ment. MS data were measured on a Bruker Daltonic mikro TOF or
a Finnigan MAT 8200 spectrometer.
O
OMe
O
O
O
O
(i)
Ot-Bu
O
t-BuO
14
13
N
H
O
OMe
O
15
OMe
4-(2-Carboxyethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicAcid
Ethyl Ester (5)
(ii)
A suspension of 4 (14.0 g, 52.4 mmol) in EtOH (56 mL), 1 N etha-
nolic NaOH (150 mL) and water (15 mL) was stirred for 3.5 h at 60
°C. The solvent was then removed under reduced pressure, and the
remaining solid was dissolved in water and precipitated with diluted
sulfuric acid. The precipitate was filtered off and washed with water
(3 × 50 mL). Compound 5 (9.90 g, 41.4 mmol, 79%) was obtained
as colorless crystals; mp 194 °C.
t-BuO
OR2
16: R2 = H
3: R2 = Bn
(iii)
N
H
O
O
Scheme 6 Reagents and conditions: (i) NaNO2, AcOH–H2O, 0 °C,
12 h, then 13, Zn, 65 °C, 12 h, 32%. (ii) Et2O, SO2Cl2 (3.2 equiv),
K2CO3, –20 °C to reflux, 8 h, 49%. (iii) BnBr, DMF, K2CO3, 98%.
IR (KBr): 3290 (s), 2911 (m), 1708 (s), 1670 (s), 1457 (m), 1281 (s),
1258 (s), 1103 (m), 940 (m), 773 (s), 623 (w) cm–1.
The acetoacetate 13 could be easily prepared in a one-pot
synthesis from methyl acrylate and pentane-2,4-dione in
88% yield after distillation according to a known literature
procedure.8a,20 Commercially available 14 was reacted
with sodium nitrite in AcOH to give the corresponding
oxime which was reduced in situ with zinc in the presence
of 13 to give the pyrrole 15 in a 32% yield after crystalli-
zation from hexane–isopropanol.21 For the oxidation of
the methyl group in 15 we found the complete chlorina-
tion using sulfuryl chloride in Et2O in the presence of
K2CO3 to be the best method.12e,22 The trichlorinated prod-
uct could easily be separated from the excess K2CO3 by
filtration and was then directly hydrolyzed without further
isolation with NaOAc in 50% water in dioxane to give the
free acid 16 in a good yield of 49% after crystallization.
The basic in situ quenching of the liberated HCl with car-
bonate is crucial for the yield. Not only to avoid decarbox-
ylation of the pyrrole carboxylic acid once it is formed
1H NMR (400 MHz, DMSO-d6): d = 1.26 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 2.13 (s, 3 H, pyrrole-CH3), 2.17 (s, 3 H, pyrrole-
CH3), 2.27 (t, J = 7.6 Hz, 2 H, pyrrole-CH2CH2), 2.55 (t, J = 7.6 Hz,
2 H, pyrrole-CH2), 4.18 (q, J = 7.1, 2 H, CO2CH2CH3), 11.0 (s, 1 H,
NH), 12.0 (s, 1 H, CO2H).
13C NMR (100 MHz, DMSO-d6): d = 10.4, 10.8 (pyrrole-CH3), 14.6
(CO2CH2CH3), 19.3 (pyrrole-CH2), 34.9 (pyrrole-CH2CH2), 58.7
(CO2CH2CH3), 115.9, 119.5, 125.8, 130.5 (pyrrole-Cq), 160.8
(CO2Et), 174.0 (CO2H).
MS (EI, 70 eV): m/z (%) = 239 (28) [M]+, 180 (60), 134 (101).
4-(2-Benzyloxycarbonylethyl)-3,5-dimethyl-1H-pyrrole-2-car-
boxylic Acid Ethyl Ester (6)
A solution of 5 (9.90 g, 41.4 mmol) in anhyd DMF (250 mL), Et3N
(120 mL) and benzyl chloride (70.0 mL, 60.9 mmol) was stirred for
24 h at r.t. The solvent was then removed at 75 °C under reduced
pressure. The remaining solid was dissolved in CH2Cl2 (200 mL),
extracted with a sat. solution of NaHCO3 (3 × 100 mL) and water
(3 × 100 mL) and the organic phase was concentrated to dryness.
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New Pyrrole Tricarboxylate Building Blocks
93
The remaining red oil was treated with hexane (15 mL), filtered off
and washed with small amounts of hexane. After drying, 6 (12.2 g,
36.9 mmol, 90%) was obtained as colorless crystals; mp 75 °C.
IR (nujol mull): 3446 (w), 1712 (s), 1457 (s), 1376 (s), 1281 (m),
1159 (m), 725 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.36 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.55 [s, 9 H, C(CH3)3], 2.26 (s, 3 H, pyrrole-CH3),
2.56 (t, J = 8.0 Hz, 2 H, pyrrole-CH2CH2), 3.02 (t, J = 8.0 Hz, 2 H,
pyrrole-CH2), 4.33 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 5.11 (s, 2 H,
benzyl-CH2), 7.31–7.35 (m, 5 H, aryl-H), 9.36 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 10.1 (pyrrole-CH3), 14.5
(CO2CH2CH3), 20.4 (pyrrole-CH2), 28.8 [C(CH3)3], 35.2 (pyrrole-
CH2CH2), 60.7 (CO2CH2CH3), 66.3 (benzyl-CH2), 82.2 [C(CH3)3],
121.5, 123.1, 126.9, 136.2 (pyrrole-Cq), 128.3, 128.4, 128.6, 128.7
(aryl-Cq), 160.3 (CO2Et), 161.1 (CO2t-Bu), 172.9 (CO2Bn).
IR (KBr): 3317 (s), 3283 (s), 2988 (s), 2955 (m), 1730 (s), 1659 (s),
1441 (s), 1267 (s), 1148 (s), 1092 (s), 1026 (m), 955 (m), 773 (s),
748 (s), 698 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 2.17 (s, 3 H, pyrrole-CH3), 2.27 (s, 3 H, pyrrole-
CH3), 2.48 (t, J = 7.7 Hz, 2 H, pyrrole-CH2CH2), 2.72 (t, J = 7.7 Hz,
2 H, pyrrole-CH2), 4.29 (q, J = 7.20 Hz, 2 H, CO2CH2CH3), 5.10 (s,
2 H, benzyl-CH2), 7.32 (m, 5 H, aryl-H), 8.58 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 10.7, 11.6 (pyrrole-CH3), 14.7
(CO2CH2CH3), 19.8 (pyrrole-CH2), 35.2 (pyrrole-CH2CH2), 59.8
(CO2CH2CH3), 66.3 (benzyl-CH2), 117.2, 120.1, 129.8, 136.1 (pyr-
role-Cq), 128.3, 128.3, 128.7 (aryl-Cq), 161.8 (CO2Et), 173.1
(CO2Bn).
MS (EI, 70 eV): m/z (%) = 415 (12) [M]+, 359 (26), 268 (100), 250
(98), 160 (23), 91 (81), 57 (18).
+
HRMS (ESI): m/z [M + Na]+ calcd for C23H29NNaO6 : 438.1887;
found: 438.1878.
MS (EI, 70 eV): m/z (%) = 329 (58) [M]+, 284 (12), 238 (100), 167
(15), 134 (70), 91 (67), 41 (18).
4-(2-Carboxyethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylicAcid
Benzyl Ester (8)
3-(2-Benzyloxycarbonylethyl)-4-methyl-1H-pyrrole-2,5-dicar-
boxylic Acid 5-Ethyl Ester (7)
A solution of 5 (3.78 g, 15.8 mmol) in benzyl alcohol (100 mL) was
added to a solution of sodium (726 mg, 31.6 mmol) in benzyl alco-
hol (50 mL). The reaction mixture was heated to reflux at 10–20
mbar and 100 °C for 6 h. The solvent was removed under reduced
pressure, and the remaining solid was dissolved in water (100 mL)
and extracted with CH2Cl2 (2 × 50 mL). The organic phase was ex-
tracted with a sat. solution of NaHCO3 (3 × 100 mL). The combined
aqueous phases were acidified with concd sulfuric acid to pH = 3
and stored at 4 °C for 2 h. The precipitate was filtered off and
washed with water (2 × 30 mL) and hexane (2 × 30 mL). Compound
8 (3.03 g, 10.1 mmol, 64%) was obtained as a reddish, crystalline
solid; mp 127 °C.
A solution of sulfuryl chloride (2.13 mL, 26.5 mmol) in glacial
AcOH (20 mL) was added dropwise over a period of 1 h to a solu-
tion of 6 (2.50 g, 7.59 mmol) in glacial AcOH (40 mL). The result-
ing solution was stirred for 4 h at r.t. Water (8 mL) was added and
the solution was stirred for another 30 min. The solution was poured
into ice-water (200 mL) and stored for 1 h at 4 °C. The precipitate
was filtered off and 7 (2.18 g, 6.07 mmol, 80%) was obtained as a
white solid; mp 75 °C.
IR (KBr): 3299 (s), 3938 (m), 1736 (s), 1702 (s), 1559 (m), 1471
(m), 1446 (m), 1269 (s), 1152 (s), 757 (m), 1015 (m), 957 (m), 699
(m), 620 (m), 496 (m) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.29 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 2.18 (s, 3 H, pyrrole-CH3), 2.53 (t, J = 7.8 Hz, 2 H,
pyrrole-CH2CH2), 2.95 (t, J = 7.8 Hz, 2 H, pyrrole-CH2), 4.23 (q,
J = 7.1 Hz, 2 H, CO2CH2CH3), 5.06 (s, 2 H, benzyl-CH2), 7.29–7.35
(m, 5 H, aryl-H), 11.50 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 9.7 (pyrrole-CH3), 14.2
(CO2CH2CH3), 19.8 (pyrrole-CH2), 34.4 (pyrrole-CH2CH2), 59.8
(CO2CH2CH3), 65.3 (benzyl-CH2), 121.4, 122.6, 125.7, 136.2 (pyr-
role-Cq), 127.8, 127.9, 128.4, 128.5 (aryl-Cq), 160.4 (CO2H), 161.6
(CO2Et), 172.2 (CO2Bn).
IR (KBr): 2918 (s), 1721 (m), 1673 (s), 1455 (s), 1270 (s), 1219 (m),
1162 (s), 1091 (s), 933 (m), 696 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.13 (s, 3 H, pyrrole-CH3),
2.17 (s, 3 H, pyrrole-CH3), 2.27 (t, J = 7.7 Hz, 2 H, pyrrole-
CH2CH2), 2.54 (t, J = 7.6 Hz, 2 H, pyrrole-CH2), 5.24 (s, 2 H, ben-
zyl-CH2), 7.31–7.41 (m, 5 H, aryl-H), 11.1 (s, 1 H, NH), 12.0 (s, 1
H, CO2H).
13C NMR (100 MHz, DMSO-d6): d = 10.4, 10.8 (pyrrole-CH3), 19.2
(pyrrole-CH2), 34.8 (pyrrole-CH2CH2), 64.2 (benzyl-CH2), 115.4,
119.7, 126.4, 131.0 (pyrrole-Cq), 127.6, 127.7, 128.4, 137.1 (aryl-
Cq), 160.5 (CO2Bn), 173.9 (CO2H).
MS (EI, 70 eV): m/z (%) = 343 (15) [M – O]+, 268 (11), 210 (82),
MS (EI, 70 eV): m/z (%) = 301 (16) [M]+, 242 (18), 134 (20), 91
164 (30), 91 (81).
(100).
+
+
HRMS (ESI): m/z [M + Na]+ calcd for C19H21NNaO6 : 382.1261;
HRMS (EI): m/z [M]+ calcd for C17H19NO4 : 301.1305; found:
found: 382.1264.
301.1307.
3-(2-Benzyloxycarbonylethyl)-4-methyl-1H-pyrrole-2,5-dicar-
boxylic Acid 2-tert-Butyl Ester 5-Ethyl Ester (1)
4-(2-tert-Butoxycarbonylethyl)-3,5-dimethyl-1H-pyrrole-2-car-
boxylic Acid Benzyl Ester (9)
A solution of oxalyl chloride (1.21 mL, 14.1 mmol) in anhyd
CH2Cl2 (10 mL) was added to a solution of 7 (1.69 g, 4.71 mmol) in
anhyd CH2Cl2 (70 mL) with catalytic amounts of anhyd DMF
stirred for 1 h at r.t. The solution was concentrated to dryness under
reduced pressure and the remaining brown oil was dissolved in an-
hyd t-BuOH (40 mL). The reaction mixture was heated to 40 °C and
t-BuOK (1.05 g, 9.42 mmol) was added in small portions. After 2 h
of stirring at 40 °C the solvent was removed under reduced pressure
and the remaining brown oil was dissolved in CH2Cl2 (100 mL).
This solution was washed with 1 M NaHSO4 (50 mL), a sat. solution
of NaHCO3 (3 × 50 mL) and water (2 × 50 mL). The organic phase
was concentrated to dryness under reduced pressure and the remain-
ing brown oil was purified by flash chromatography (SiO2, hexane–
EtOAc, 5:1). Compound 1 (980 mg, 2.36 mmol, 50%) was obtained
as a yellow oil; Rf 0.36.
A solution of oxalyl chloride (853 mL, 9.90 mmol) in anhyd CH2Cl2
(10 mL) was added dropwise to a solution of 8 (1.00 g, 3.32 mmol)
in anhyd CH2Cl2 (20 mL) with catalytic amounts of anhyd DMF and
stirred for 2 h at r.t. The solution was concentrated to dryness under
reduced pressure and the remaining solid was dissolved in t-BuOH
(40 mL). The solution was heated to 40 °C and t-BuOK (747 mg,
6.65 mmol) was added in small portions. The reaction mixture was
stirred at 40 °C for 2 h. The solvent was removed under reduced
pressure, and the remaining brown oil was dissolved in CH2Cl2 (30
mL) and washed with a 1 M NaHSO4 (2 × 25 mL), a sat. solution of
NaHCO3 (2 × 25 mL) and water (25 mL). The organic phase was
concentrated to dryness under reduced pressure and the remaining
solid was washed with hexane (25 mL). Compound 9 (960 mg, 2.67
mmol, 80%) was obtained as a pink, crystalline solid; mp 93 °C.
Synthesis 2006, No. 1, 89–96 © Thieme Stuttgart · New York

94
C. Schmuck et al.
PAPER
IR (KBr): 2983 (m), 2927 (m), 1729 (s), 1657 (s), 1454 (s), 1367
(m), 1268 (s), 1150 (s), 1092 (s), 769 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.42 [s, 9 H, C(CH3)3], 2.20 (s, 3
H, pyrrole-CH3), 2.29 (s, 3 H, pyrrole-CH3), 2.32 (t, J = 8.0 Hz, 2
H, pyrrole-CH2CH2), 2.65 (t, J = 8.0 Hz, 2 H, pyrrole-CH2), 5.29 (s,
2 H, benzyl-CH2), 7.32–7.42 (m, 5 H, aryl-H), 8.56 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 10.0 (pyrrole-CH3), 19.0 (pyr-
role-CH2), 28.2 [C(CH3)3], 36.6 (pyrrole-CH2CH2), 66.8 (benzyl-
CH2), 81.0 [C(CH3)3], 124.3, 127.3, 130.2, 132.6 (pyrrole-Cq),
128.6, 128.7, 128.9, 135.6 (benzyl-Cq), 160.7 (CO2Bn), 171.7
(CO2t-Bu), 179.9 (CHO).
MS (EI, 70 eV): m/z (%) = 371 (1) [M]+, 315 (21), 91 (100), 57 (28).
+
13C NMR (100 MHz, CDCl3): d = 10.8, 11.7 (pyrrole-CH3), 19.8
(pyrrole-CH2), 28.2 [C(CH3)3], 36.4 (pyrrole-CH2CH2), 65.6 (ben-
zyl-CH2), 80.3 [C(CH3)3], 116.7, 120.7, 130.2, 136.8 (pyrrole-Cq),
128.2, 128.2, 128.7 (benzyl-Cq), 161.4 (CO2Bn), 172.7 (CO2t-Bu).
MS (EI, 70 eV): m/z (%) = 357 (23) [M]+, 301 (26), 242 (44), 166
(70), 91 (100), 57 (97).
HRMS (EI): m/z [M]+ calcd for C17H25NO5 : 371.1723; found:
371.1725.
3-(2-tert-Butoxycarbonylethyl)-4-methyl-1H-pyrrole-2,5-dicar-
boxylic Acid 2-Methyl Ester 5-Benzyl Ester (2)
A solution of 10 (100 mg, 258 mmol), MeI (16.2 mL, 260 mmol) and
K2CO3 (74.0 mg, 535 mmol) in anhyd DMF (15 mL) was stirred at
0 °C for 10 min and at r.t. for 1 d. Water (10 mL) was added and the
stirring was continued for 10 min. After dilution with Et2O (30 mL),
the organic layer was washed with water (3 × 15 mL), dried over
MgSO4 and concentrated to dryness in vacuo. Compound 2 (47.0
mg, 117 mmol, 45%) was obtained as a pale yellow solid; mp 84 °C.
HRMS (EI): m/z [M]+ calcd for C21H27NO4 : 357.1933; found:
+
357.1934.
3-(2-tert-Butoxycarbonylethyl)-4-methyl-1H-pyrrole-2,5-dicar-
boxylic Acid 5-Benzyl Ester (10)
A solution of sulfuryl chloride (3.66 mL, 45.5 mmol) in anhyd Et2O
was added dropwise to a solution of 9 (5.40 g, 15.2 mmol) in anhyd
Et2O (200 mL) with K2CO3 (13.5 g, 114 mmol) at 0 °C and it was
stirred for 2 h at 0 °C. Water (10 mL) was added to the reaction mix-
ture and it was stirred for 30 min at r.t. The solvent was removed un-
der reduced pressure and the remaining solid was dissolved in
acetone (150 mL). A solution of KMnO4 (5.57 g, 14.0 mmol) in ac-
etone–water (1:1, 100 mL) was added dropwise over the period of
1 h and the resulting mixture was stirred for 1 h at r.t. Na2S2O4 was
added until the purple color disappeared. The precipitating MnO2
was filtered off and the colorless solution was extracted with EtOAc
(3 × 50 mL). The organic phase was washed with water (3 × 30 mL)
and concentrated to dryness under reduced pressure. Compound 10
(2.45 g, 6.32 mmol, 42%) was obtained as an off-white solid; mp
134 °C.
1H NMR (400 MHz, CDCl3): d = 1.43 [s, 9 H, C(CH3)3], 2.31 (s, 3
H, pyrrole-CH3), 2.40 (t, J = 8.0 Hz, 2 H, pyrrole-CH2CH2), 3.00 (t,
J = 8.0 Hz, 2 H, pyrrole-CH2), 3.87 (s, 3 H, CO2CH3), 5.33 (s, 2 H,
benzyl-CH2), 7.35–7.44 (m, 5 H, aryl-H), 9.40 (s, 1 H, NH).
13C NMR (63 MHz, CDCl3): d = 10.3 (pyrrole-CH3), 20.3 (pyrrole-
CH2), 28.3 [C(CH3)3], 36.1 (pyrrole-CH2CH2), 51.9 (CO2CH3), 66.5
(benzyl-CH2), 80.3 [C(CH3)3], 121.7, 127.4, 130.4, 135.9 (pyrrole-
Cq), 128.5, 128.6, 128.8 (benzyl-Cq), 160.8 (CO2CH3), 161.1
(CO2Bn), 171.7 (CO2t-Bu).
MS (EI, 70 eV): m/z (%) = 401 (1) [M]+, 345 (17), 299 (17), 91
(100), 57 (21).
+
HRMS (ESI): m/z [M + Na]+ calcd for C22H27NNaO6 : 424.1731;
found: 424.1736.
IR (KBr): 2967 (w), 2932 (w), 1708 (m), 1670 (s), 1355 (m), 1262
(s), 1147 (s), 821 (m) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.35 [s, 9 H, C(CH3)3], 2.20 (s,
3 H, pyrrole-CH3), 2.33 (t, J = 7.8 Hz, 2 H, pyrrole-CH2CH2), 2.88
(t, J = 7.8 Hz, 2 H, pyrrole-CH2), 5.28 (s, 2 H, benzyl-CH2), 7.33–
7.47 (m, 5 H, aryl-H), 11.59 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 9.88 (pyrrole-CH3), 19.8 (pyr-
role-CH2), 27.7 [C(CH3)3], 35.5 (pyrrole-CH2CH2), 65.3 (benzyl-
CH2), 79.5 [C(CH3)3], 121.0, 123.0, 126.2, 128.6 (pyrrole-Cq),
127.9, 128.4, 136.4 (benzyl-Cq), 160.2 (CO2H), 161.6 (CO2Bn),
171.7 (CO2t-Bu).
4-(2-Methoxycarbonylethyl)-3,5-dimethyl-1H-pyrrole-2-car-
boxylic Acid tert-Butyl Ester (15)
tert-Butyl acetoacetate 14 (64.8 g, 410 mmol) was dissolved in
AcOH (115 mL) and cooled down to 5 °C. A solution of sodium ni-
trite (27.5 g, 399 mmol) in water (95 mL) was added slowly via an
addition funnel and the resulting solution was stirred overnight at 5
°C. To assure complete conversion the disappearance of 14 was ob-
tained by TLC monitoring (deactivated SiO2, cyclohexane–EtOAc,
4:1; Rf 0.29). The resulting solution was added to a suspension of 13
(75.5 g, 405 mmol), NaOAc (82.5 g, 1.01 mol) and zinc (82.5 g,
1.26 mol) in AcOH (90 mL). Further zinc (82.5 g, 1.26 mol) was
added slowly in small portions and the resulting mixture was stirred
overnight at 65 °C. The reaction was cooled down to r.t. and poured
into an ice-water dispersion (1.5 L). The precipitate was filtered off,
washed with water and dried in vacuo. The solid was dissolved in
EtOH and the zinc residue was removed by filtration. After evapo-
ration of the solvent, crystallization from hexane–i-PrOH led to 15
(36.2 g, 129 mmol, 32%) as a white solid; mp 96 °C.
MS (EI, 70 eV): m/z (%) = 331 (11) [M – C4H8]+, 91 (100), 57 (33).
+
HRMS (EI): m/z [M – C4H8]+ calcd for C17H17NO6 : 331.1048;
found: 331.1050.
Dichloride Intermediate
1H NMR (400 MHz, DMSO-d6): d = 1.41 [s, 9 H, C(CH3)3], 2.27 (s,
3 H, pyrrole-CH3), 2.38 (t, J = 7.3 Hz, 2 H, pyrrole-CH2CH2), 2.72
(t, J = 7.3 Hz, 2 H, pyrrole-CH2), 5.34 (s, 2 H, benzyl-CH2), 7.05 (s,
1 H, CHCl2), 7.30–7.45 (m, 5 H, aryl-H), 9.10 (s, 1 H, NH).
IR (KBr): 2974 (m), 2951 (w), 2924 (m), 1738 (s), 1666 (s), 1449
(m), 1435 (m), 1364 (m), 1281 (m), 1163 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.49 [s, 9 H, C(CH3)3], 2.11 (s,
3 H, pyrrole-CH3), 2.13 (s, 3 H, pyrrole-CH3), 2.35 (t, J = 7.4 Hz, 2
H, pyrrole-CH2CH2), 2.56 (t, J = 7.4 Hz, 2 H, pyrrole-CH2), 3.56 (s,
3 H, CO2CH3), 10.81 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 10.3, 10.7 (pyrrole-CH3), 19.2
(pyrrole-CH2), 28.2 [C(CH3)3], 34.5 (pyrrole-CH2CH2), 51.2
(CO2CH3), 78.8 [C(CH3)3], 117.3, 118.8, 124.8, 129.7 (pyrrole-Cq),
160.5 (CO2t-Bu), 172.8 (CO2Me).
Aldehyde Intermediate
Mp 96 °C.
IR (KBr): 2975 (m), 2923 (m), 1724 (s), 1657 (s), 1471 (m), 1370
(m), 1250 (m), 1161 (s), 1082 (m), 731 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40 [s, 9 H, C(CH3)3], 2.31 (s, 3
H, pyrrole-CH3), 2.46 (t, J = 7.5 Hz, 2 H, pyrrole-CH2CH2), 3.00 (t,
J = 7.5 Hz, 2 H, pyrrole-CH2), 5.33 (s, 2 H, benzyl-CH2), 7.38–7.47
(m, 5 H, aryl-H), 9.46 (s, 1 H, NH), 9.81 (s, 1 H, CHO).
MS (EI, 70 eV): m/z (%) = 281 (16) [M]+, 225 (40), 208 (19), 152
(100), 134 (45), 41 (5).
Synthesis 2006, No. 1, 89–96 © Thieme Stuttgart · New York

PAPER
New Pyrrole Tricarboxylate Building Blocks
95
3-(2-Methoxycarbonylethyl)-4-methyl-1H-pyrrole-2,5-dicar-
boxylic Acid 5-tert-Butyl Ester (16)
3,5-Dimethyl-4-(3-oxopropyl)-1H-pyrrole-2-carboxylic Acid
Ethyl Ester (11)
Compound 15 (3.29 g, 11.7 mmol) and K2CO3 (6.43 g, 46.6 mmol)
were suspended under Ar in anhyd Et2O (100 mL) and cooled down
to –20 °C. A solution of sulfuryl chloride (3.50 mL, 37.4 mmol) in
anhyd Et2O (50 mL) was added slowly via an addition funnel. The
mixture was warmed slowly to r.t. and heated to reflux for 7 h. The
solvent was reduced to a few mL in vacuo without heating and the
oily residue was stirred for 2 h in a solution of NaOAc (10.0 g, 122
mmol) in water–dioxane (1:1, 200 mL) at 110 °C. The solution was
cooled down to 0 °C and adjusted carefully to pH = 2 with hydro-
chloric acid and extracted with Et2O (3 × 100 mL). The combined
organic phases were extracted with sat. NaHCO3–water (1:1, 3 ×
250 mL) and the combined aqueous solutions were cooled down to
0 °C. This aqueous solution was then acidified slowly and under
vigorous stirring with concentrated hydrochloric acid to pH = 1–2.
The precipitate was filtered off, washed with cold water (150 mL)
and recrystallized from MeOH–water to give 16 (1.77 g, 5.69
mmol, 49%) as white needles; mp 169 °C.
Compound 4 (441 mg, 1.65 mmol) was dissolved under Ar atmo-
sphere in anhyd toluene (10 mL) and cooled down to –78 °C.
DIBAL-H (1 M) in toluene (1.75 mL, 1.75 mmol) was added and
after stirring for 1 h further DIBAL-H (1 M, 2.50 mL, 2.50 mmol)
was added in 0.5 mL steps under TLC monitoring until the starting
material nearly disappeared. After 4 h the reaction was quenched
with 0.1 M HCl (4 mL) and warmed to r.t. After dilution with
EtOAc (200 mL), sat. NaCl (200 mL) and water (until the precipi-
tate was dissolved) were added. Then the organic phase was sepa-
rated, washed with sat. NaHCO3 (150 mL) and sat. NaCl (200 mL),
dried with Na2SO4 and the solvent was removed in vacuo. Flash
chromatography (SiO2, cyclohexane–EtOAc, 4:1) yielded 11 (175
mg, 785 mmol, 46%) as a white solid; Rf 0.26; mp 98 °C.
IR (KBr): 2924 (m), 2855 (m), 2725 (w), 1720 (s), 1654 (s), 1445
(m), 1270 (m), 1101 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 7.0 Hz, 3 H,
CO2CH2CH3), 2.22 (s, 3 H, pyrrole-CH3), 2.27 (s, 3 H, pyrrole-
CH3), 2.60–2.56 (m, 2 H, pyrrole-CH2CH2), 2.70 (t, J = 7.7 Hz, 2 H,
pyrrole-CH2), 4.29 (q, J = 7.0 Hz, 2 H, CO2CH2CH3), 8.55 (s, 1 H,
NH), 9.79 (t, J = 1.5 Hz, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 10.5, 11.5 (pyrrole-CH3), 14.5
(CO2CH2CH3), 16.7 (pyrrole-CH2), 44.6 (pyrrole-CH2CH2), 59.7
(CO2CH2CH3), 117.1, 119.8, 126.7, 129.4 (pyrrole-Cq), 161.5
(CO2Et), 202.0 (CHO).
IR (KBr): 3473 (m), 3340 (s), 2977 (m), 2952 (w), 1737 (s), 1716
(s), 1695 (s), 1674 (s), 1469 (m), 1278 (s), 1154 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.52 [s, 9 H, C(CH3)3], 2.17 (s,
3 H, pyrrole-CH3), 2.44 (t, J = 8.1 Hz, 2 H, pyrrole-CH2CH2), 2.90
(t, J = 8.1 Hz, 2 H, pyrrole-CH2), 3.57 (s, 3 H, CO2CH3), 11.26 (s,
1 H, NH), 12.81 (br s, 1 H, CO2H).
13C NMR (100 MHz, DMSO-d6): d = 9.68 (pyrrole-CH3), 19.7 (pyr-
role-CH2), 30.0 [C(CH3)3], 34.3 (pyrrole-CH2CH2), 51.2 (CO2CH3),
80.6 [C(CH3)3], 122.0, 122.7, 125.0 128.5 (pyrrole-Cq), 159.9
(CO2H), 161.7 (CO2t-Bu), 172.7 (CO2Me).
MS (EI, 70 eV): m/z (%) = 223 (24) [M]+, 180 (21), 167 (50), 134
(100), 65 (17), 39 (11).
+
HRMS (EI): m/z [M]+ calcd for C12H17NO3 : 223.1203; found:
MS (EI, 70 eV): m/z (%) = 311 (17) [M]+, 280 (4), 255 (7), 238 (12),
211 (27), 195 (100), 164 (23), 138 (15).
223.1206.
+
HRMS (EI): m/z [M]+ calcd for C15H21NO6 : 311.1363; found:
311.1365.
4-(3-Hydroxypropyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic
Acid Ethyl Ester (12)
1H NMR (400 MHz, CDCl3): d = 1.34 (t, J = 7.0 Hz, 3 H,
CO2CH2CH3), 1.74–1.67 (m, 2 H, pyrrole-CH2CH2), 2.21 (s, 3 H,
pyrrole-CH3), 2.27 (s, 3 H, pyrrole-CH3), 2.46 (t, J = 7.7 Hz, 2 H,
CH2OH), 3.64 (t, J = 6.4 Hz, 2 H, pyrrole-CH2), 4.29 (q, J = 7.0 Hz,
2 H, CO2CH2CH3), 8.61 (s, 1 H, NH).
3-(2-Methoxycarbonylethyl)-4-methyl-1H-pyrrole-2,5-dicar-
boxylic Acid 2-Benzyl Ester 5-tert-Butyl Ester (3)
Compound 16 (262 mg, 842 mmol), benzyl bromide (89.0 mL, 749
mmol) and K2CO3 (164 mg, 1.19 mmol) were suspended under Ar
in anhyd DMF (15 mL) and stirred overnight. The reaction mixture
was diluted with EtOAc (150 mL) and washed subsequently with
sat. NaHCO3 (100 mL), sat. NaCl (100 mL), sat. NH4Cl (100 mL)
and again sat. NaCl (100 mL). The organic phase was dried with
Na2SO4 and the solvent was removed in vacuo. After flash column
chromatography (deactivated SiO2, cyclohexane–EtOAc, 2:1) 3
(295 mg, 734 mmol, 98%) was obtained as a slightly yellow oil; Rf
0.63.
Acknowledgment
Financial support from the Fonds der Chemischen Industrie (Ke-
kulé-Fellowship for D.R.) and the Deutsche Forschungsgemein-
schaft is gratefully acknowledged.
References
IR (KBr): 3458 (bw), 2977 (w), 2952 (w), 1738 (s), 1707 (s), 1561
(w), 1369 (w), 1282 (s), 1159 (s) cm–1.
(1) (a) Vogel, E.; Michels, M.; Zander, L.; Lex, J.; Tuzun, N. S.;
Houk, K. N. Angew. Chem. 2003, 115, 2964. (b) Sessler, J.
L.; Salvatore, C.; Gale, P. A. Coord. Chem. Rev. 2003, 240,
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Comprehensive Heterocyclic Chemistry, Vol. 2; Pergamon:
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Chapman, C. P.; Light, M. E.; Coles, S. J.; Hursthouse, M.
B. J. Org. Chem. 2001, 66, 7849. (e) Hoffmann, H.; Lindel,
T. Synthesis 2003, 1753. (f) Guernion, N. J. L.; Hayes, W.
Curr. Org. Chem. 2004, 8, 637.
1H NMR (400 MHz, CDCl3): d = 1.57 [s, 9 H, C(CH3)3], 2.25 (s, 3
H, pyrrole-CH3), 2.48 (t, J = 7.8 Hz, 2 H, pyrrole-CH2CH2), 3.03 (t,
J = 8.2 Hz, 2 H, pyrrole-CH2), 3.63 (s, 3 H, CO2CH3), 5.32 (s, 2 H,
benzyl-CH2), 7.42–7.33 (m, 5 H, aryl-H), 9.35 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 10.1 (pyrrole-CH3), 20.3 (pyr-
role-CH2), 28.5 [C(CH3)3], 34.8 (pyrrole-CH2CH2), 51.7 (CO2CH3),
66.6 (benzyl-CH2), 82.0 [C(CH3)3], 120.8, 123.6, 128.1 (aryl-Cq),
128.6, 128.8 (aryl-CH), 130.3, 135.8 (aryl-Cq), 160.5 (CO2Bn,
CO2t-Bu), 173.5 (CO2Me).
(2) (a) Schmuck, C.; Schwegmann, M. J. Am. Chem. Soc. 2005,
127, 3373. (b) Schmuck, C.; Geiger, L. J. Am. Chem. Soc.
2004, 126, 8898. (c) Schmuck, C.; Bickert, V. Org. Lett.
2003, 5, 4579. (d) Schmuck, C.; Geiger, L. Curr. Org.
Chem. 2003, 7, 1485. (e) Schmuck, C. Chem. Eur. J. 2000,
6, 709.
MS (EI, 70 eV): m/z (%) = 401 (11) [M]+, 328 (7), 310 (4), 254 (36),
222 (100), 194 (9).
HRMS (EI): m/z [M]+ calcd for C22H27NO6 : 401.1833; found:
+
401.1832.
(3) (a) Schmuck, C.; Wienand, W. J. Am. Chem. Soc. 2003, 125,
452. (b) Schmuck, C. Eur. J. Org. Chem. 1999, 2397.
Synthesis 2006, No. 1, 89–96 © Thieme Stuttgart · New York

96
C. Schmuck et al.
PAPER
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Synthesis 2006, No. 1, 89–96 © Thieme Stuttgart · New York