Traceless linking of pyrroles: General methology and solid phase supported functionalizations

Article abstract of DOI:10.1055/s-2002-19813

Transacetalization reaction of the diethoxymethyl (DEM) protected pyrroles 2a-f with the diol functionalized resin 3 resulted in the formation of the immobilized pyrroles 4a-f. Regioselective transformations including Pd-catalyzed coupling reactions and reductive aminations on solid phase were demonstrated.

Full text of DOI:10.1055/s-2002-19813

2
74
PAPER
Traceless Linking of Pyrroles: General Methology and Solid Phase Supported
Functionalizations
T
M
raceless Linking of
P
a
yrroles rkus Bergauer, Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstr. 19, 91052 Erlangen, Germany
Fax +49(9131)8522585; E-mail: gmeiner@pharmazie.uni-erlangen.de
Received 2 November 2001; revised 24 November 2001
9
subsequent acidic hydrolysis. In fact, transacetalization
was observed in the presence of p-toluenesulfonic acid.
Using 1,4-dioxane as a solvent, the polymer bound diox-
oselective transformations including Pd-catalyzed coupling reac- olanes 4a and 4b were monitored by FTIR analysis of the
Abstract: Transacetalization reaction of the diethoxymethyl
(DEM) protected pyrroles 2a–f with the diol functionalized resin 3
resulted in the formation of the immobilized pyrroles 4a–f. Regi-
tions and reductive aminations on solid phase were demonstrated.
carefully washed resin beads. Investigation of the level of
immobilization by combustion analysis showed loadings
Key words: solid-phase synthesis, traceless linker, pyrroles, palla-
dium, DEM-protection
–1
of 1.08 and 0.68 mmolg , respectively (Table). To dem-
onstrate the reversibility of the process, hydrolysis of the
acetal linkage was attempted by treatment of the immobi-
lized pyrroles 4a,b with trifluoroacetic acid (TFA) in ace-
tonitrile and 1,4-dioxane (3:1) followed by 2 N sodium
hydroxide. This afforded 0.63 mmolg–1 and 0.46
Solid phase chemistry has proven to be a powerful tool in
accelerating drug discovery and lead structure optimiza-
1
tion processes. Numerous efforts were made addressing
–
1
mmolg of the starting materials 1a and 1b, respectively,
both in >95% purity. In order to investigate the scope and
limitations of the immobilization reaction, linking the car-
bonitrile 2c with the carbaldehydes 2d and 2e, which are
of potential utility for a parallel synthesis of pyrrole de-
rived bioactive libraries, was elaborated. As expected, for-
mation of the resin bound pyrrole carbonitrile 4c
occurred, starting from the carbonitrile 2c. When immobi-
immobilization and parallel modifications of pharmaco-
2
logically important heterocycles. Since the pyrrole moi-
ety is known to act as a pharmacophoric element in many
bioactive compounds, its chemoselective transformation
3
has drawn considerable interest.
In earlier studies, we showed that diethoxymethyl (DEM)-
protected indoles act as useful building blocks for solid
phase organic synthesis on diol functionalized Merrifield
lizing the carbaldehydes 2d and 2e, a C=O absorption at
4
resin. Very recently, we described the DEM protection of
–1
1
720 cm was noticed in the IR spectrum besides the
acceptor-substituted pyrroles and their chemo- and regi-
–1
main C=O band for the 2-formyl substituent at 1670 cm
indicating the N-formyl substituted side products 5a,b.
Obviously, this is due to a partial hydrolysis of the DEM
group to give a N-formyl functionality which leads to a
decrease of deactivation of the carbaldehyde function in
position 2 through the nitrogen of the pyrrole nucleus. Ac-
cordingly, immobilization of the unprotected 4-iodopyr-
role derivative 1e via the carbaldehyde functionality was
5
oselective transformations. As a continuation of our stud-
ies, we herein describe our results towards the
immobilization of DEM-protected pyrroles via transace-
6
talization of the polymer bound glycerol derivative 3. Re-
gioselective transformations on solid phase including Pd-
catalyzed coupling and reductive amination reactions are
also presented.
According to our recently described protocol, we synthe- not possible. When treating the resin with 2 N sodium hy-
sized the mono- and di-functionalized DEM-pyrroles 2a– droxide in 1,4-dioxane for 24 hours at room temperature,
–1
e from their precursors 1a–e in neat triethyl orthofor- the band at 1720 cm completely disappeared indicating
5
mate. The hitherto unknown 4-bromo- and 4-iodopyrrole hydrolytic cleavage of the N-formyl group. Complete re-
carboxylates 1a,b were prepared by site-selective bromi- gioselectivity can be achieved by employing the masked
7
nation of ethyl pyrrole-2-carboxylate and alcoholysis of pyrrole derivative 2f. Thus, transacetalization and subse-
8
2
-trichloroacetyl-4-iodopyrrole, respectively. Knoevena- quent retro-Knoevenagel reaction in the presence of
gel reaction of the DEM-protected pyrrole carbaldehyde NaOH resulted in the formation of the pure resin bound
e with malononitrile gave access to the dicyanovinyl pyrrole carbaldehyde 4e through the dicyanovinyl pro-
substituted pyrrole 2f.
tected intermediate 4f.
We first attempted to attach the building blocks 2a and 2b Based on our currently investigated lead structures in the
2
10
to the 1,3-diol linker of the Leznoff resin 3, which was field of selective dopamine D4 receptor ligands, parallel
readily available by reacting Merrifield resin with the so- synthesis of aminomethyl, alkynyl and aryl substituted
dium salt of 2,2-dimethyl-1,3-dioxolane-4-methanol and pyrrole derivatives are of special interest for us. There-
fore, reductive aminations and palladium-catalyzed coup-
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
437-210X,E;2002,0,02,0274,0278,ftx,en;Z11801SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
ling reactions were chosen for one- and two-dimensional
functionalizations.
1
©

PAPER
Traceless Linking of Pyrroles
275
Table Immobilization of DEM-Pyrroles
4-iodo aldehyde 4e and phenylboronic acid as a represen-
tative example. Our initial attempts using Pd(PPh ) re-
3
4
sulted in incomplete conversion of the iodide 4e. Further
improvements were possible employing a Pd(OAc)2
based system. Finally we used Pd (dba) /P(t-Bu) , previ-
2
3
3
1
1
ously introduced by Littke and Fu, for reacting aryl chlo-
rides in various coupling procedures, which promoted
complete conversion of the iodo derivative 4e to give the
phenylpyrrole 9a. Hydrolytic cleavage furnished pure 9b
in 82% yield. In order to investigate the possibilities for
two-dimensional library syntheses with increased diversi-
ty, we further functionalized the resin bound aldehyde 8a
via reductive amination. This was done by treating 8a
with phenylpiperazine and sodium triacetoxyborohydride
for 22 hours at room temperature. Finally, hydrolytic
cleavage of the amination product gave the potential
dopamine D4 receptor ligand 10b in 45% yield and 78%
purity, containing 8b as a side product, which is obviously
due to a minor immobilization through the 2-carbalde-
hyde function.
Reagents and conditions: (a) HC(OEt) , reflux; (b) TsOH, 1,4-diox-
ane, r.t.
3
DEM Protected X
Pyrrole
EWG
Resin Bound Loading via
Pyrrole
CHN
mmolg )
–1
(
2a
2b
2c
2d
2e
2f
Br
I
CO Et
4a
4b
4c
4d
4e
1.08
0.68
0.76
0.98a
0.80b
0.67
2
CO Et
2
H
H
I
CN
CHO
CHO
c
I
CHC(CN)2 4f
a
b
c
Including 5a as a minor side product.
Including 5b as a minor side product.
Malononitrile, piperidine, MeOH, r.t., 30 min (70%).
In practice, we treated the resin bound aldehyde 4d with
phenylpiperazine and sodium triacetoxyborohydride ob-
serving the disappearance of the C=O stretching frequen-
–
1
cy (1666 cm ) within 22 hours. Subsequent hydrolysis
gave the piperazine 6b in moderate yield (Scheme). To
functionalize the immobilized iodopyrroles 4b and 4e, we NaOH, r.t., 3 h (6b: 29%, 10b: 46%; 80% purity); (c) 4b, e: phenyla-
Scheme (a) phenylpiperazine, NaBH(OAc) , 1,2-dichloroethane,
r.t., 22 h; (b) 1. 1,4-dioxane–MeCN–TFA (2:6:1), 60 °C, 48 h; 2. 2 N
3
employed Sonogashira’s Pd-catalyzed coupling method cetylene, 15% PdCl
(PPh
) , 30% CuI, Et N–1,4-dioxane (1:2), r.t.,
2
3 2 3
2
4 h; 4e: phenylboronic acid, 15% Pd (dba) , P(t-Bu) , Cs CO , 1,4-
using PdCl (PPh ) as a catalyst and triethylamine as a
2
3
3
2
3
2
3 2
dioxane, 80 °C, 24 h; (d) 8a: phenylpiperazine, NaBH(OAc) , 1,2-di-
chloroethane, r.t., 22 h; (e) 1. 1,4-dioxane–MeCN–TFA (1:3:0.1),
3
base - a system that showed excellent reactivity with
DEM-pyrroles in solution. Concerning the solid phase
procedures, the resin bound hetaryl bromide 4a and phe-
nylacetylene failed to give the coupling product 7a. How-
ever, starting from the 4-iodo derivatives 4b and 4e
formation of the 4-phenylethinyl derivatives 7a and 8a
was accomplished within 24 h. Subsequent hydrolysis
gave the desired products 7b and 8b in 83 and 80% yield
6
>
0 °C, 48 h; 2. 2 N NaOH, r.t., 30 min (7b: 80%, 8b: 80%, 9b: 75%;
95% purity)
In conclusion, the first traceless linking method for pyr-
roles was demonstrated. Reductive amination and Pd-cat-
alyzed coupling reactions were investigated as flexible
tools that are expected to facilitate the introduction of a
broad variety of substituents into the pyrrole moiety. Due
to the pharmacophoric properties of the pyrrole moiety,
bioactive compound libraries can be accessed.
1
and >95% purity as indicated by H NMR spectroscopy.
With ethynyltrimethylsilane as a coupling partner, de-
composition during the release reaction was observed. We
also tried to establish a Suzuki-protocol using resin bound
Synthesis 2002, No. 2, 274–278 ISSN 0039-7881 © Thieme Stuttgart · New York

2
76
M. Bergauer, P. Gmeiner
PAPER
1
1
,4-Dioxane was distilled from Na immediately before use. All liq-
H NMR (CDCl , 360 MHz):
= 1.22 [t, 6 H, J = 7.1 Hz,
3
uid reagents were purified by distillation. Light petroleum used had
bp 45–65 °C. Unless otherwise noted reactions were conducted un-
CH(OCH CH ) ], 1.34 (t, 3 H, J = 7.1 Hz, CO CH CH ), 3.57 [dq,
2 3 2 2 2 3
2 H, J = 9.4, 7.1 Hz, CH(OCH CH ) ], 3.66 [dq, 2 H, J = 9.4, 7.1
2
3 2
der dry N . Evaporations of final product solutions were done under
Hz, CH(OCH CH ) ], 4.28 (q, 2 H, J = 7.1 Hz, CO CH CH ), 6.95
2
2 3 2 2 2 3
vacuum with a rotatory evaporator. Flash chromatography was car-
ried out with 230–400 mesh silica gel. Melting points: Büchi melt-
ing point apparatus, uncorrected. IR spectra: Jasco FT/IR 410
spectrometer. Mass spectra: Finnigan MAT TSQ 70 instrument.
(d, 1 H, J = 1.8 Hz, pyrrole H-3), 6.97 [s, 1 H, CH(OCH CH ) ],
2 3 2
7.31 (d, J = 1.8 Hz, 1 H, pyrrole H-5).
13
C NMR (CDCl , 90 MHz):
= 14.3 (CO CH CH ), 14.8
2 2 3
3
[
CH(OCH CH ) ], 60.4 (CO CH CH ), 62.6 [CH(OCH CH ) ],
1
2 3 2 2 2 3 2 3 2
High resolution mass spectrometry: Finnigan MAT 8200. H NMR
9
6.9 (pyrrole C-4), 101.5 [CH(OCH CH ) ], 120.4, 123.8 (pyrrole
2 3 2
and 13C NMR spectra: Bruker AM 360 spectrometer at 360 MHz
C-3, 5), 122.6 (pyrrole C-2), 160.2 (C=O).
and 90 MHz. Spectra were measured in CDCl using TMS as inter-
3
+
79
+ 81
EI-MS: m/z = 319 [M ( Br)], 321 [M ( Br)].
nal standard. Elemental analysis were performed by the Organic
Chemistry Department of the Friedrich-Alexander University Er-
langen-Nürnberg.
Anal. Calcd for C H BrNO (320.2): C, 45.02; H, 5.62; N, 4.37.
1
2
18
4
Found: C, 45.29; H, 5.27; N, 4.35.
4
-Bromo-1H-pyrrole-2-carboxylic Acid Ethyl Ester (1a)
1
-Diethoxymethyl-4-iodo-2-carboxylic Acid Ethyl Ester (2b)
7
1H-Pyrrole-2-carboxylic acid ethyl ester (139 mg, 1.00 mmol) was
Pyrrole 1b (1.00 g, 3.77 mmol) and triethyl orthoformate (6.3 mL,
37.7 mmol) were reacted (16 h) and worked up (light petroleum–
EtOAc, 95:5) as described for 2a to give 2b (1.028 g, 74%) as a col-
orless oil.
dissolved in CCl (5 mL) and cooled to –15 °C. Then, a solution of
Br (57 L, 1.10 mmol) in CCl (10 mL) was added dropwise and
the mixture was stirred for 1 h. After warming to r.t., aq 2 N NaOH
4
2
4
(10 mL) was added. The separated organic layer was dried
–
1
IR (film): 3135, 1704, 1076 cm .
1H NMR (CDCl
, 360 MHz):
CH(OCH CH ], 1.34 (t, 3 H, J = 7.1 Hz, CO
2 H, J = 9.5, 7.1 Hz, CH(OCH CH ], 3.66 [dq, 2 H, J = 9.5, 7.1
Hz, CH(OCH CH ], 4.28 (q, 2 H, J = 7.1 Hz, CO
(
MgSO ), filtered and evaporated under reduced pressure. The res-
4
idue was purified by flash chromatography (light petroleum–
EtOAc, 9:1) to give 1a (117 mg, 54%) as a colorless solid; mp 55
3
= 1.22 [t, 6 H, J = 7.1 Hz,
CH CH ), 3.57 [dq,
)
2
3
2
2
2
3
°C.
2
3 2
)
–
1
2
3
)
2
2
CH
2
CH
3
), 7.05
IR (KBr): 3282, 1685 cm .
(
d, 1 H, J = 2.1 Hz, pyrrole H-3), 6.96 [s, 1 H, CH(OCH CH ) ],
2 3 2
1
H NMR (CDCl , 360 MHz):
= 1.35 (t, 3 H, J = 7.1 Hz,
3
7.38 (d, 1 H, J = 2.1 Hz, pyrrole H-5).
13
(CO CH CH ), 4.32 (q, 2 H, J = 7.1 Hz, (CO CH CH ), 6.89 (dd, 1
2
2
3
2
2
3
C NMR (CDCl , 90 MHz):
= 14.3 (CO CH CH ), 14.8
2 2 3
3
H, J = 3.0, 1.6 Hz, pyrrole H-3), 6.93 (dd, 1 H, J = 3.0, 1.6 Hz, pyr-
role H-5), 9.28 (s, 1 H, NH).
[CH(OCH CH ) ], 60.4 (CO CH CH ), 60.8 (pyrrole C-4), 62.6
2 3 2 2 2 3
[CH(OCH CH ) ], 101.5 [CH(OCH CH ) ], 123.9 (pyrrole C-2),
2
3
2
2
3 2
1
3
C NMR (CDCl , 90 MHz):
= 14.3 (CO CH CH ), 60.8
2 2 3
3
125.3, 128.8 (pyrrole C-3,5), 160.0 (C=O).
EI-MS: m/z = 367 (M+).
(CO CH CH ), 97.8 (pyrrole C-4), 116.8, 122.6 (pyrrole C-3, -C-5),
2 2 3
1
23.3 (pyrrole C-2), 160.5 (C=O).
+
79
+ 81
Anal. Calcd for C12
Found: C, 39.62; H, 5.07; N, 3.85.
H18INO (367.2): C, 39.25; H, 4.94; N, 3.81.
4
EI-MS: m/z = 217 [M ( Br)], 219 [M ( Br)].
Anal. Calcd for C H BrNO (218.1): C, 38.56; H, 3.70; N, 6.42.
7
8
2
Found: C, 38.59; H, 3.68; N, 6.25.
2
-(1-Diethoxymethyl-4-iodo-1H-pyrrole-2-ylmethylene)malo-
nonitrile (2f)
4
2
-Iodo-1H-pyrrole-2-carboxylic Acid Ethyl Ester (1b)
-Trichloroacetyl-4-iodo-1H-pyrrole (500 mg, 1.48 mmol) and
5
Compound 2e (362 mg, 1.120 mmol) and malononitrile (81 mg,
.23 mmol) were dissolved in MeOH (2 mL). Two drops of piperi-
8
1
K CO (256 mg, 1.85 mmol) were dissolved in EtOH (5 mL) and
stirred for 45 min at 70 °C. Then the mixture was cooled to r.t. and
Et O (100 mL) was added. After filtration and extraction with brine
2
3
dine were added and the mixture was stirred at r.t. for 30 min. The
precipitate was filtered and washed with cold MeOH. The filtrate
was evaporated and dissolved in a small amount of cold MeOH. The
remaining product was precipitated by careful addition of H O and
filtered. After drying in high vacuum, pure 2f (293 mg, 70%) was
isolated as a yellow solid; mp 91 °C.
2
(
2 20 mL), the separated organic layer was dried (MgSO ), filtered
4
2
and evaporated under reduced pressure to give pure 1b (384 mg,
8%) as a colorless solid; mp 64 °C.
9
–
1
IR (KBr): 3278, 1683, 1313, 1234, 910 cm .
IR (KBr): 3135, 2977, 2217, 1577, 1106, 1079 cm–1.
1
H NMR (CDCl , 360 MHz):
= 1.35 (t, 3 H, J = 7.1 Hz,
1
3
H NMR (CDCl , 360 MHz):
= 1.25 [t, 6 H, J = 7.1 Hz,
3
CO CH CH ), 4.32 (q, 2 H, J = 7.1 Hz, CO CH CH ), 7.0 (m, 2 H,
pyrrole H-2,5), 9.41 (s, 1 H, NH).
2
2
3
2
2
3
CH(OCH CH ) ], 3.54 [dq, 2 H, J = 9.1, 7.1 Hz, CH(OCH CH ) ],
2
3
2
2
3
2
3
.61 [dq, 2 H, J = 9.1, 7.1 Hz, CH(OCH CH ) ], 6.01 [s, 1 H,
2 3 2
1
3
CH(OCH CH ) ], 7.33 (d, 1 H, J = 1.7 Hz, pyrrole H-3), 7.76 (dd,
C NMR (CDCl , 90 MHz):
= 14.3 (CO CH CH ), 60.8
2 3 2
3
2
2
3
1
H, J = 1.7 Hz, pyrrole H-5), 7.95 [s, 1 H, CH=C(CN)2].
(CO CH CH ), 61.6 (pyrrole C-4), 121.6, 127.4 (pyrrole C-3,5),
2 2 3
1
24.7 (pyrrole C-2), 160.1 (C=O).
13
C NMR (CDCl , 90 MHz): = 14.6 [CH(OCH CH ) ], 62.3
3
2
3 2
EI-MS: m/z = 265 (M+).
[CH(OCH CH ) ], 64.2 (pyrrole C-4), 74.6 [ArHCC(CN) ], 103.1
2
3
2
2
[
CH(OCH CH ) ], 113.8, 114.7 [ArHCC(CN) ], 126.9 (pyrrole C-
2 3 2 2
Anal. Calcd for C H INO (265.1): C, 31.72; H, 3.04; N, 5.28.
7
8
2
2
), 127.3, 132.9 (pyrrole C-3,5), 143.8 [ArHCC(CN)2].
Found: C, 31.80; H, 2.98; N, 5.20.
EI-MS: m/z = 371 (M+).
4
- Bromo-1-diethoxymethyl-1H-pyrrole-2-carboxylic Acid
Anal. Calcd for C H IN O (371.2): C, 42.07; H, 3.80; N, 11.32.
Found: C, 41.93; H, 3.82; N, 11.22.
1
3
14
3
2
Ethyl Ester (2a); Typical Procedure
A mixture of 1a (804 mg, 3.69 mmol) and triethyl orthoformate (6.1
mL, 36.9 mmol) was refluxed for 86 h, concentrated under reduced
pressure and purified by flash chromatography (light petroleum–
EtOAc, 9:1) to give 2a (707 mg, 60%) as a colorless oil.
Immobilization of DEM-Pyrroles 2a–f
DEM-Pyrrole (3–4 mmol), resin 3 (1 mmol) and TsOH (1 mmol)
were dissolved in 1,4-dioxane (15 mL/mmol resin) and stirred for 4
h at r.t. (2f: 50 °C). The progress of the reaction was monitored by
9
–
1
IR (film): 3125, 2981, 2896, 1708, 1160, 1072 cm .
Synthesis 2002, No. 2, 274–278 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Traceless Linking of Pyrroles
277
IR according to the characteristic stretching frequencies of the func-
tional groups. The resin was washed with 1,4-dioxane, 1,4-diox-
ane–H O (1:1), EtOH and Et O (50 mL each) and vacuum dried to
give the immobilized compounds 4a–f with a loading, determined
by combustion analysis (Table 1).
7b
–
1
IR (KBr): 3289, 2217, 1685 cm .
2
2
1
H NMR (CDCl , 360 MHz):
= 1.36 (t, 3 H, J = 7.1 Hz,
3
(CO CH CH ), 4.33 (q, 2 H, J = 7.1 Hz, (CO CH CH ), 7.04 (dd, 1
2 2 3 2 2 3
H, J = 2.5, 1.5 Hz, pyrrole H-3), 7.17 (dd, 1 H, J = 3.0, 1.5 Hz, pyr-
IR (KBr): 1708 (4a); 1704 (4b); 2217 (4c); 1720 (5a), 1666 (4d);
role H-5), 7.2–7.6 (m, 5 H, C H ), 9.17 (s, 1 H, NH).
6
5
–
1
1
718 (5b), 1670 (4e); 2221 cm (4f).
13
C NMR (CDCl , 90 MHz):
= 14.3 (CO CH CH ), 60.7
2 2 3
3
(
1
1
CO CH CH ), 83.3 (C C), 88.4 (C C), 106.9, 117.8, 123.2, 123.6,
25.9, 127.8 (pyrrole C, C H C-1,4), 131.4, 128.3 (C H C-2,3),
6 5 6 5
60.7 (C=O).
2 2 3
Cleavage of the Immobilized Pyrroles; General Procedure
The resin (150 mg) was swollen with MeCN (3 mL) and 1,4-diox-
ane (1 mL). TFA (0.1 mL, 1.30 mmol) was added and the mixture
was stirred for 48 h at 60 °C. After cooling to r.t., aq 2 N NaOH (1.5
mL, 3.0 mmol) was added and stirring at r.t. was continued for an
EI-MS: m/z = 239 (M+).
Anal. Calcd for C H NO (239.3): C, 75.30; H, 5.48; N, 5.85.
Found: C, 75.09; H, 5.45; N, 5.54.
1
5
13
2
additional 30 min. The resin was filtered and washed with Et O (20
2
mL). The filtrate was washed with H O (10 mL) and the organic
2
layer was dried (MgSO ), filtered and evaporated to give the free
4
–
4-Phenylethynyl-1H-pyrrole-2-carbaldehyde (8b)
First, resin 8a was prepared as described for the resin 7a using 4e
1
–1
–1
pyrrole (1a: 0.46 mmolg ; 1b: 0.63 mmolg ; 1e: 0.52 mmolg ; pu-
1
rity >95% for all compounds as indicated by H NMR spectrosco-
(
154 mg, 0.123 mmol) to give 8a (135 mg).
py).
8
a
1
-Phenyl-4-(1H-pyrrole-2-yl-methyl)piperazine (6b); Typical
–1
IR (KBr): 2213, 1670 cm .
Procedure
For hydrolysis, the resin 8a (135 mg, 0.108 mmol) was subjected to
the above described cleavage procedure to give 8b [11 mg, 0.42
mmolg , 80% (based on 0.52 mmolg cleavable 1e), purity >95%
Resin 4d (300 mg, 0.294 mmol) was swollen in 1,2-dichloroethane
(7 mL). Phenylpiperazine (0.23 mL, 1.53 mmol) and sodium triac-
–
1
–1
etoxyborohydride (324 mg, 1.53 mmol) were added. The mixture
was stirred for 22 h at r.t. Then, aq 3 N HCl (3 mL) was added and
stirred for an additional 15 min. The product resin was filtered and
washed with 1,4-dioxane, 1,4-dioxane–H O (1:1), EtOH and Et O
1
as indicated by H NMR spectroscopy]; mp 170 °C.
8
b
2
2
–1
IR (KBr): 3255, 2217, 1646 cm .
(20 mL each) to give 6a (311 mg).
1
H NMR (CDCl , 360 MHz): = 7.11 (dd, 1 H, J = 2.5, 1.4 Hz, pyr-
3
For hydrolysis, the resin 6a (200 mg, 0.196 mmol) was swollen with
MeCN (3 mL) and 1,4-dioxane (1 mL). TFA (0.5 mL, 6.5 mmol)
was added and the mixture was stirred for 48 h at 60 °C. After cool-
role H-3), 7.5 (m, 1 H, pyrrole H-5), 7.3–7.6 (m, 5 H, C H ), 9.52
6
5
(
s, 1 H, CHO), 9.82 (s, 1 H, NH).
13C NMR (CDCl
, 90 MHz): = 82.4, 89.0 (C C), 107.9, 122.7,
ing to r.t., the resin was filtered and washed with Et O (20 mL). The
3
2
filtrate was washed with aq 2 N NaOH (10 mL) and the organic lay-
122.8, 123.3, 128.1, 128.3, 128.7, 131.4 (C H C, pyrrole C), 179.2
6 5
er was dried (MgSO ), filtered and evaporated to give 6b (14 mg,
(CHO).
EI-MS: m/z = 195 (M+).
4
–
1
0
.29 mmolg , 29%, purity 80%). Identity was confirmed by com-
1
10
paring the H NMR data of previously prepared 6b; mp 91 °C.
Anal. Calcd for C H NO (195.2): C, 79.98; H, 4.65; N, 7.17.
Found: C, 80.20; H, 4.64; N, 6.91.
1
3
9
IR (KBr): 3418, 3093, 2937, 2879, 2819, 1599, 1502, 1453, 1238
–
1
cm .
1
H NMR (CDCl , 360 MHz):
= 2.56–2.61 [m, 4 H,
4-Phenyl-1H-pyrrole-2-carbaldehyde (9b)
3
N(CH CH ) N], 3.16–3.21 [m, 4 H, N(CH CH ) N)], 3.55 (s, 2 H,
Resin 4e (600 mg, 0.480 mmol) was swollen in 1,4-dioxane (12
2
2
2
2
2 2
ArCH N), 6.04–6.07 (m, 1 H, pyrrole H-3), 6.13 (dd, 1 H, J = 5.6,
mL). Phenylboronic acid (240 mg, 1.968 mmol), Cs
0.590 mmol), P(t-Bu) (24 mg, 0.118 mmol) and Pd
2
CO
(dba)
3
(192 mg,
(45 mg,
3
2
2
.8 Hz, pyrrole H-4), 6.74–6.77 (m, 1 H, pyrrole H-5), 6.82–6.87
3
2
(
8
m, 1 H, C H ), 6.89–6.94 (m, 2 H, C H ), 7.22–7.28 (m, 2 H, C H ),
.52 (s, 1 H, NH).
0.049 mmol) were added and the mixture was stirred at 80 °C for 24
h. Then, the resin was filtered and washed with 1,4-dioxane, 1,4-di-
6
5
6
5
6
5
EI-MS: m/z = 241 (M+).
oxane–H
2
O (1:1), EtOH and Et O (20 mL each) to give the resin 9a
2
(
555 mg).
Anal. Calcd for C H N (241.3): C, 74.65; H, 7.94; N, 17.41.
1
5
19
3
Found: C, 74.13; H, 8.02; N, 17.68.
9
a
–
1
IR (KBr): 1667 cm .
4
-Phenylethynyl-1H-pyrrole-2-carboxylic Acid Ethyl Ester (7b)
For hydrolysis, resin 9a (150 mg, 0.120 mmol) was subjected to the
above cleavage procedure to give 9b (10 mg, 0.39 mmolg , 75%
Resin 4b (200 mg, 0.136 mmol) was swollen in 1,4-dioxane (3 mL),
–
1
and Et N (1.5 mL), phenylacetylene (90 L, 0.816 mmol),
3
–1
(
based on 0.52 mmolg cleavable 1e), purity >95% as indicated by
PdCl (PPh ) (16 mg, 0.020 mmol) and CuI (8 mg, 0.041 mmol)
2
3 2
1
H NMR spectroscopy); mp 210 °C (dec.).
were added. The mixture was stirred for 21 h at r.t. Then, the resin
was filtered and washed with 1,4-dioxane, 1,4-dioxane–H O (1:1),
2
9
b
EtOH and Et O (20 mL each) to give resin 7a (162 mg).
2
–1
IR (KBr): 3156, 1643 cm .
7
a
1
H NMR (CDCl , 360 MHz): = 7.2 (m, 1 H, C H H-4), 7.3–7.4
3
6
5
–
1
IR (KBr): 2217, 1704 cm .
(
m, 2 H, C H H-3,5), 7.40 (m, 1 H, pyrrole H-3), 7.6–7.7 (m, 2 H,
6 5
C H H-2,6), 7.73 (m, 1 H, pyrrole H-5), 9.52 (s, 1 H, CHO), 12.28
For hydrolysis, the resin 7a (162 mg, 0.110 mmol) was subjected to
6
5
(
s, 1 H, NH).
the above described typical cleavage procedure, for the formation of
–
1
6
b from 6a, to give 7b (15 mg, 0.39 mmolg , 80% (based on 0.48
EI-MS: m/z = 171 (M+).
–
1
1
mmolg cleavable 1b), purity >95% as indicated by H NMR spec-
+
HRMS: m/z calcd for C H NO (M ): 171.06842. Found:
1
1
9
troscopy; mp 66 °C.
1
71.06841.
Synthesis 2002, No. 2, 274–278 ISSN 0039-7881 © Thieme Stuttgart · New York

2
78
M. Bergauer, P. Gmeiner
PAPER
1
-(4-Phenylethynyl-1H-pyrrol-2-yl-methyl)-4-phenylpipera-
References
zine (10b)
(
1) For reviews, see: (a) Brown, R. C. D. J. Chem. Soc., Perkin
Trans. 1 1998, 3293. (b) Blackburn, C.; Albericio, F.; Kates,
S. A. Drugs of the Future 1997, 22, 1007. (c) Früchtel, J.
S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17.
(d) Balkenhohl, F.; Von dem Bussche-Hünnefeld, C.;
Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996,
First, resin 10a was prepared as described for resin 8a and 6a using
4
e (300 mg, 0.240 mmol) to give 10a (257 mg). For hydrolysis, res-
in 10a (224 mg, 0.195 mmol) was treated as described above for res-
–
1
in 6a to give 10b (18 mg, 0.24 mmolg , 46% (based on 0.52
mmolg–1 cleavable 1e), purity 80% as indicated by H NMR).
1
–
1
IR (film): 3413, 2823, 2210, 1596, 1496, 1234, 1126 cm .
35, 2288. (e) Hermkens, P. H.; Ottenheijm, H. C. J.; Rees, D.
1
H NMR (CDCl , 360 MHz):
= 2.60 (t, 4 H, J = 5.0 Hz,
Tetrahedron 1996, 52, 4527.
3
NCH CH N), 3.18 (t, 4 H, J = 5.0 Hz, NCH CH N), 3.52 [s, 2 H,
(2) James, I. W. Tetrahedron 1999, 55, 4855.
(3) Liu, J.-H.; Chan, H.-W.; Wong, H. N. C. J. Org. Chem.
2000, 65, 3274; and references cited therein.
(4) (a) Hübner, H.; Kraxner, J.; Gmeiner, P. J. Med. Chem.
2000, 43, 4563. (b) Kraxner, J.; Arlt, M.; Gmeiner, P.
Synlett 2000, 125.
2
2
2
2
CH N(CH CH ) NPh], 6.23 (dd, 1 H, J = 2.6, 1.7 Hz, pyrrole H-3),
2
2
2 2
7
.02 (dd, 1 H, J = 2.6, 1.7 Hz, pyrrole H-5), 6.8–6.9 (m, 1 H, NC H
6 5
H-4), 6.9–7.0 (m, 2 H, NC H H-2,6), 7.2–7.4 (m, 5 H, NC H H-3/
6
5
6
5
5
, C H H-3/5, H-4), 7.5 (m, 2 H, C H H-2), 8.62 (s, 1 H, NH).
6 5 6 5
1
3
C NMR (CDCl , 90 MHz): = 49.08 [N(CH CH ) N], 53.02
3
2
2 2
(
(
5) Bergauer, M.; Gmeiner, P. Synthesis 2001, 2281.
6) For earlier investigations on the solid phase synthesis of
pyrroles, see: (a) Wurtz, N. R.; Turner, J. M.; Baird, E. E.;
Dervan, P. B. Org. Lett. 2001, 3, 1201. (b) Trautwein, A.
W.; Süßmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett.
[
N(CH CH ) N], 55.04 (pyrrole–CH N), 85.00, 87.59 (C C),
2 2 2 2
1
1
1
1
04.11 (pyrrole C-4), 111.05 (pyrrole C-3), 116.04 (NC H C-2/6),
6 5
19.79 (NC H C4), 122.04 (pyrrole C-5), 124.21 (C H C-1),
6
5
6
5
27.38 (pyrrole C-2), 128.19 (C H C-4), 128.67 (C H C-3/5),
6
5
6
5
29.11 (NC H C-3/5), 131.24 (C H C-2/6), 151.16 (NC H C-1).
6
5
6
5
6
5
1998, 8, 2381. (c) Trautwein, A. W.; Jung, G. Tetrahedron
EI-MS: m/z = 341 (M+).
Lett. 1998, 39, 8263. (d) Baird, E. E.; Dervan, P. B. J. Am.
Chem. Soc. 1996, 118, 6141. (e) Mjalli, A. M. M.; Sarshar,
S.; Baiga, T. J. Tetrahedron Lett. 1996, 37, 2943.
+
HRMS: m/z calcd for C H N (M ): 341.18921. Found:
2
3
23
3
3
41.18931.
(7) Signaigo, F. K.; Adkins, H. J. Am. Chem. Soc. 1936, 58,
1122.
Acknowledgment
(8) (a) Banwell, M. G.; Flynn, B. L.; Hockless, D. C. R.;
Longmore, R. W.; Rae, A. D. Aust. J. Chem. 1998, 52, 755.
The generous support of the Fonds der Chemische Industrie is gra-
tefully acknowledged.
(
b) Volz, H.; Holzbecher, M. Angew. Chem., Int. Ed. Engl.
997, 36, 1442.
9) (a) Leznoff, C. C.; Wong, J. Y. Can. J. Chem. 1973, 51,
756. (b) Xu, Z.-H.; McArthur, C. R.; Leznoff, C. C. Can. J.
Chem. 1983, 61, 1405.
1
(
3
(10) Haubmann, C.; Hübner, H.; Gmeiner, P. Bioorg. Med.
Chem. Lett. 1999, 9, 1969.
(
11) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37,
3387.
Synthesis 2002, No. 2, 274–278 ISSN 0039-7881 © Thieme Stuttgart · New York