Diethoxymethyl protected pyrroles: Synthesis and regioselective transformations

Article abstract of DOI:10.1055/s-2001-18445

Treatment of the acceptor-substituted pyrroles 1a-k with neat triethyl orthoformate gives access to the diethoxymethyl (DEM) protected derivatives 2a-k in high yield. Convenient and mild cleavage was achieved by subsequent treatment of the DEM-pyrroles 2a-k with trifluoroacetic acid in acetonitrile and aqueous NaOH at room temperature. DEM protection proved suitable for a variety of regioselective transformations involving directed orthometalation and iodine-magnesium exchange processes. Furthermore, electrophilic halogenations and Pd-catalyzed coupling reactions were also carried out.

Full text of DOI:10.1055/s-2001-18445

PAPER
2281
Diethoxymethyl Protected Pyrroles: Synthesis and Regioselective
Transformations
Diethoxymethyl
P
rotec
a
tedPyrrole
r
s
kus 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 28 June 2001; revised 25 August 2001
and 3-substituted pyrroles gave yields in a similar range.
If the electron density in the system is decreased by two
electron-withdrawing groups quantitative protection
without need for further purification was observed (see
Abstract: Treatment of the acceptor-substituted pyrroles 1a–k with
neat triethyl orthoformate gives access to the diethoxymethyl
(DEM) protected derivatives 2a–k in high yield. Convenient and
mild cleavage was achieved by subsequent treatment of the DEM-
pyrroles 2a–k with trifluoroacetic acid in acetonitrile and aqueous the synthesis of 2j). Deprotection was possible under mild
NaOH at room temperature. DEM protection proved suitable for a
variety of regioselective transformations involving directed ortho-
metalation and iodine–magnesium exchange processes. Further-
derivative 2k, which underwent a retro-Knoevenagel re-
more, electrophilic halogenations and Pd-catalyzed coupling reac-
tions were also carried out.
conditions, when the starting materials 1b–f were recov-
ered in 65–99% yield. An exception was the dicyanovinyl
action to give the carbaldehyde 2a.
Unfortunately, our efforts to protect pyrrole and donor
substituted pyrrole derivatives failed. Although we tried
various reaction conditions including the application of
more reactive orthoesters, we were not able to synthesize
DEM-protected 2-benzylpyrrole (5) by N-substitution of
610 (Scheme 1). Obviously, this is due to the thermal insta-
bility of electron rich pyrroles. Generally, DEM-pyrroles
can be synthesized from acceptor substituted precursors
as was demonstrated for the representative 5. Thus, the
benzylpyrrole 5 was readily available from the benzoyl
derivative 2e via the intermediates 3 and 4, by subse-
quent NaBH4 reduction and Barton–McCombie deoxy-
genation11 (Scheme 1).
Key words: protecting groups, pyrroles, metalations, Suzuki-cou-
pling, Sonogashira reaction, halogen–metal exchange
Chemo- and regioselective functionalization of N-protect-
ed pyrroles has generated considerable interest owing to
their ability to act as a pharmacophoric element in a num-
ber of bioactive compounds.1 In our investigation on the
synthesis of subtype-selective dopamine receptor agonists
and antagonists, we have shown that a diethoxymethyl
substituent (DEM) can be utilized for an efficient nitrogen
protection of amides, lactams and indoles.2 Formation by
simply heating in neat triethyl orthoformate, stability dur-
ing multi-step synthesis and smooth hydrolytic cleavage
have all been demonstrated.3 The DEM group can also be
used as a versatile building block and for a traceless link-
ing of indoles.4 As an extension of our studies, we herein
describe the DEM protection and cleavage of pyrroles and
its utility in a variety of reaction sequences.
Having in mind the advantage of acceptor substituents for
the preparation of DEM-indoles, our investigations were
initiated by attaching DEM onto pyrrole-2-carbaldehyde
(1a). In fact, N-protection was achieved in 86% yield by
heating in triethyl orthoformate. The best condition for
cleavage was found to be the treatment of the DEM-pyr-
role 2a with trifluoroacetic acid in acetonitrile followed
by aqueous 2 N NaOH at room temperature. To evaluate
the scope and limitations of the method, we reacted the
commercially available starting materials 1f and 1j, as
well as the 2- and 3-substituted pyrroles 1b–e, 1g–i, 1k,
readily prepared by standard procedures,5–9 under the con-
ditions indicated in Table 1.
Scheme 1 : (a) i-PrOH, NaBH4, reflux, 2.5 h (88%); (b) CS2, 50%
NaOH, Bu4NHSO4, MeI, r.t., 1.5 h (47%); (c) benzene, AIBN,
Bu3SnH, reflux, 28 h (83%)
The data in Table 1 clearly shows that acceptor substitut-
ed pyrroles can be efficiently DEM-protected and that 2-
Synthesis 2001, No. 15, 12 11 2001. Article Identifier:
1437-210X,E;2001,0,15,2281,2288,ftx,en;Z07101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2282
M. Bergauer, P. Gmeiner
PAPER
Table 1 Protection and Cleavage of the Pyrrole Derivatives 1a–k and 2a–k
Protection
t1 (h)
Cleavage
Pyrrole
1a/2a
1b/2b
1c/2c
1d/2d
1e/2e
1f/2f
EWG1
CHO
CO2Et
CO2Me
COMe
COPh
CN
EWG2
H
EWG3
Yield (%)a
t2 (h)
0.25
2
t3 (h)
0.25
0.5
Yield (%)b
H
47
144
92
86
70
83
82
73
79
92
79
74
99b
80
70
79
77
65
92
83
72
68
99
90
23c
H
H
H
H
0.5
0.5
0.75
2
0.5
H
H
23
0.5
H
H
72
0.5
H
H
144
24
0.25
0.5
1g/2g
1h/2h
1i/2i
H
CHO
COMe
COPh
CO2Et
H
H
1
H
H
30
0.5
0.75
15
0.5
H
H
41
0.5
1j/2j
H
CO2Et
H
17
0.5
1k/2k
CH=C(CN)2
21
0.75
0.75
a Isolated yield after flash chromatography.
b Isolated yield without further purification. Purity >95% as indicated by NMR spectroscopy.
c Compound 2a was isolated as the product.
The ability of DEM to serve as a N-directed ortho-meta- NIS gave a starting material/product mixture that was dif-
lation group for pyrroles was investigated starting from ficult to purify, we elaborated a reversed reaction se-
the building blocks 2b and 2f (Table 2). Lithiation of the quence through the intermediate 1113 affording the iodide
pyrrole carboxylate 2b by LDA at –50 °C and subsequent 12. We next subjected 12 to representative Pd-catalyzed
trapping with trimethylsilyl chloride resulted in regiose- coupling procedures. Employing Pd(PPh3)4 as a catalyst
lective formation of the 2,5-disubstituted heterocycle 7. and aq 2 M Na2CO3 as a base, a Suzuki reaction with phe-
Starting from the carbonitrile 2f, silylation in position 5 nylboronic acid gave the arylation product 13a in 66%
was best accomplished at 0 °C, affording the silylation yield. Sonogashira reaction of 12 with trimethylsilylacet-
product 8 in 41% yield. Alternative treatment with tribu-
tyltin chloride furnished the respective stannane 9, which
has the potential to be further transformed by Stille cou-
pling reactions.
Table 2 Modification of 2b and 2f Through Directed ortho-Metala-
tion
We next investigated halogenation reactions of DEM-pro-
tected pyrroles to make the 4-position chemically accessi-
ble for reactions involving halogen–metal exchange or
Pd-insertion. According to previous findings, pyrroles
with electron-withdrawing substituents in position 2 are
preferentially attacked by electrophiles in position 4.12
Starting EWG1
Material
Conditions
RX
Product Yield
(%)
In fact, treatment of the DEM-protected pyrrole-2-carbal-
dehyde 2a with NBS in THF resulted in regioselective
bromination to give the aryl bromide 10 in 70% yield
(Scheme 2). However, the value of 10 as a synthetic inter-
mediate was limited by the low yield of the subsequent
coupling reactions. Thus, the iodide 12 was approached as
a more reactive alternative. Since iodination of 2a with
2b
2f
2f
CO2Et
LDA, Et2O,
–50 °C, 1 h
Me3SiCl
Me3SiCl
Bu3SnCl
7
8
9
41
41
47
CN
LDA, THF,
0 °C, 15 min
CN
LDA, THF,
r.t., 15 min
Synthesis 2001, No. 15, 2281–2288 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diethoxymethyl Protected Pyrroles
2283
ylene promoted by CuI and PdCl2(PPh3)2 provided the ex-
pected 4-alkynyl substituted pyrrole 13b in 85% yield.
Table 3 Synthesis and Modification of the Iodide 15 through Halo-
gen-Metal Exchange
(a) HC(OEt)3, reflux, 19 h (79%);
(b) 1. i-PrMgCl, THF, –40 °C, 1 h; 2. electrophile, –40 °C, 2 h
Electrophile
H2O
R
Product Yield(%)
H
2f
82a
66
76
75
66
Scheme 2 (a) NBS, THF, –20 °C to r.t. 20 h (70%); (b) Pd(PPh3)4,
phenylboronic acid, toluene, Na2CO3, 80 °C, 25 h (13a: 7%); (c)
HC(OEt)3, reflux, 22 h (77%); (d) 13a: Pd(PPh3)4, phenylboronic
acid, toluene, Na2CO3, 80 °C, 2 h (66%); 13b: TMSC CH,
Pd(PPh3)2Cl2, CuI, dioxane/Et3N, r.t., 1 h (85%)
PhCHO
CH(OH)Ph
CH(OH)Et
CHO
16a
16b
16c
16d
EtCHO
DMF
2,2´-dithio dipyridine
Very recently, Knochel and coworkers have demonstrated
that an iodine–magnesium exchange allows an elegant
and smooth preparation of polyfunctional aryl- or het-
eroarylmagnesium halides that can be exploited for a va-
riety of structural manipulations.14 Thus, as a valuable
complement to the above described palladium promoted
methodology, iodine–magnesium exchange reactions was
evaluated (Table 3). The cyano moiety was selected as an
electron-withdrawing functional group tolerating iodine–
magnesium exchange under mild conditions. In detail, the
iodine in the DEM protected iodopyrrole 15, which was
readily prepared from the precursor 14,15 was exchanged
for magnesium by reacting with i-PrMgCl at –40 °C in
THF as a solvent. After 1 h, the intermediate was
quenched with water, in order to estimate whether the ex-
change process was complete. We could isolate the proto-
nated product 2f in 82% yield without further purification.
1H NMR clearly showed an exchange rate greater than
95%. Nucleophilic attack of the Grignard reagent at the
carbonitrile function was not observed. Using the iodine-
magnesium exchange conditions described above, the or-
ganomagnesium intermediate was reacted with benzalde-
hyde, propionaldehyde, DMF, 2,2´-dithiodipyridine and
tributyltin chloride to provide the 2,4-difunctional pyr-
roles 16a–e in 45–76% yield.
Bu3SnCl
SnBu3
16e
45
a Isolated without further purification. 1H NMR indicated
an exchange rate of >95%.
solution was done under vacuum with a rotatory evaporator. Flash
chromatography was carried out with 230–400 mesh silica gel.
Melting points: Büchi melting point apparatus, uncorrected. IR
spectra: Jasco FT/IR 410 spectrometer. Mass spectra: Finnigan
MAT TSQ 70 instrument. High resolution mass spectrometry:
Finnigan MAT 8200. 1H NMR and 13C NMR spectra: Bruker AM
360 spectrometer at 360 MHz and 90 MHz. Spectra were measured
in CDCl3 using TMS as internal standard. Elemental analyses were
performed by the Organic Chemistry Department of the Friedrich-
Alexander University Erlangen-Nürnberg.
1-Diethoxymethyl-1H-pyrrole-2-carbaldehyde (2a); Typical
Procedure
A mixture of 1a (951 mg, 10.0 mmol) and triethyl orthoformate
(16.6 mL, 100 mmol) was refluxed for 47 h, concentrated under re-
duced pressure and purified by flash chromatography (light petro-
leum/Et2O, 8:2) to give 2a (1.69 g, 86%) as a colorless oil.
IR (film): 1667, 1182, 1065 cm–1.
1H NMR (CDCl3, 360 MHz):
C(OCH2CH3)2], 3.57 [dq, 2 H, J = 9.5, 7.0 Hz, CH(OCH2CH3)2],
3.69 [dq, 2 H, J = 9.5, 7.0 Hz, CH(OCH2CH3)2], 6.29 (dd, 1 H,
J = 4.0, 3.0 Hz, H-4), 6.98 [s, 1 H, CH(OCH2CH3)2], 6.98 (dd, 1 H,
J = 4.0, 1.5 Hz, H-3), 7.48 (dd, 1 H, J = 3.0, 1.5 Hz, H-5), 9.57 (s, 1
H, CHO).
13C NMR (CDCl3, 90 MHz): = 14.8 [CH(OCH2CH3)2], 62.6
[CH(OCH2CH3)2], 101.6 [CH(OCH2CH3)2], 110.5 (C-4), 125.6 (C-
3), 126.9 (C-5), 131.5 (C-2), 179.6 (CHO).
= 1.22 [t, 6 H, J = 7.0 Hz,
In conclusion, it has been demonstrated that the di-
ethoxymethyl group is a suitable and highly practical pro-
tecting group for pyrroles. Further experiments using
DEM-protected pyrroles for the solid phase supported
synthesis of bioactive receptor ligands are currently under
investigation.
EI-MS: m/z = 197 (M+).
Et2O, THF, 1,4-dioxane and toluene were distilled from Na imme-
diately before use. All liquid reagents were purified by distillation.
Light petroleum used had bp 45 60 °C. Unless otherwise noted re-
actions were conducted under dry N2. Evaporation of final product
Anal. Calcd for C10H15NO3 (197.2): C, 60.90; H, 7.67; N, 7.10.
Found: C, 61.26; H, 7.97; N, 7.10.
Synthesis 2001, No. 15, 2281–2288 ISSN 0039-7881 © Thieme Stuttgart · New York

2284
M. Bergauer, P. Gmeiner
PAPER
Ethyl 1-Diethoxymethyl-1H-pyrrole-2-carboxylate (2b)
Pyrrole 1b5 (806 mg, 5.79 mmol) and triethyl orthoformate (9.60
mL, 57.9 mmol) were reacted (6 d) and worked up (light petroleum/
EtOAc, 9:1) as described for 2a to give 2b (984 mg, 70%) as a col-
orless oil.
EtOAc, 8:2) as described for 2a to give 2e (169 mg, 73%) as a col-
orless oil.
IR (film): 1630, 1104, 1068 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.25 [t, 6 H, J = 7.0 Hz,
CH(OCH2CH3)2], 3.64 [dq, 2 H, J = 9.4, 7.0 Hz, CH(OCH2CH3)2],
3.76 [dq, 2 H, J = 9.4, 7.0 Hz, CH(OCH2CH3)2], 6.24 (dd, 1 H,
J = 3.7, 2.8 Hz, H-4), 6.77 (dd, 1 H, J = 3.7, 1.8 Hz, H-3), 7.13 [s, 1
H, CH(OCH2CH3)2], 7.5–7.6 (m, 1 H, H-5), 7.4–7.9 (m, 5 H, C6H5).
13C NMR (CDCl3, 90 MHz): = 14.9 [CH(OCH2CH3)2], 62.8
[CH(OCH2CH3)2], 102.0 [CH(OCH2CH3)2], 109.2 (C-4), 124.5,
126.1 (C-5,3), 128.1, 129.2 (C6H5 C-2,3), 130.1 (C-2), 131.6 (C6H5
C-4), 186.3 (C=O).
IR (film): 1703, 1095 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.22 [t, 6 H, J = 7.1 Hz,
CH(OCH2CH3)2], 1.35 (t, 3 H, J = 7.1 Hz, CO2CH2CH3), 3.56 [dq,
2 H, J = 9.5, 7.1 Hz, CH(OCH2CH3)2], 3.67 [dq, 2 H, J = 9.5, 7.1
Hz, CH(OCH2CH3)2], 4.28 (q, 4 H, J = 7.1 Hz, CO2CH2CH3), 6.19
(dd, 1 H, J = 3.8, 2.7 Hz, H-4), 6.98 (dd, 1 H, J = 3.8, 2.0 Hz, H-3),
7.02 [s, 1 H, CH(OCH2CH3)2], 7.35 (dd, 1 H, J = 2.7, 2.0 Hz, H-5).
13C NMR (CDCl3, 90 MHz):
= 14.4 (CO2CH2CH3), 14.8
EI-MS: m/z = 273 (M+).
[CH(OCH2CH3)2], 60.0 (CO2CH2CH3), 62.4 [CH(OCH2CH3)2],
101.5 [CH(OCH2CH3)2], 108.8 (C-4), 118.9 (C-3), 122.1 (C-2),
124.2 (C-5), 161.2 (C=O).
Anal. Calcd for C16H19NO3 (273.3): C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.04; H, 7.12; N, 5.20.
EI-MS: m/z = 241 (M+).
1-Diethoxymethyl-1H-pyrrole-2-carbonitrile (2f)
Method A: Pyrrole 1f (960 mg, 10.42 mmol) and triethyl orthofor-
mate (17.2 mL, 104 mmol) were reacted (6 d) and worked up (light
petroleum/EtOAc, 9:1) as described for 2a to give 2f (1.60 g, 79%)
as a colorless oil.
Anal. Calcd for C12H19NO4 (241.3): C, 59.73; H, 7.94; N, 5.80.
Found: C, 59.64; H, 8.04; N, 5.79.
Methyl 1-Diethoxymethyl-1H-pyrrole-2-carboxylate (2c)
Pyrrole 1c6 (250 mg, 2.0 mmol) and triethyl orthoformate (3.3 mL,
20 mmol) were reacted (92 h) and worked up (light petroleum/
EtOAc, 9:1) as described for 2a to give 2c (377 mg, 83%) as a col-
orless oil.
IR (film): 1707, 1096 cm–1.
1H NMR (CDCl3, 360 MHz):
CH(OCH2CH3)2], 3.55 [dq, 2 H, J = 9.4, 7.1 Hz, CH(OCH2CH3)2],
3.67 [dq, 2 H, J = 9.4, 7.1 Hz, CH(OCH2CH3)2], 3.82 (s, 3 H,
CO2CH3), 6.19 (dd, 1 H, J = 3.8, 2.7 Hz, H-4), 6.98 (dd, 1 H,
J = 3.8, 1.7 Hz, H-3), 7.01 [s, 1 H, CH(OCH2CH3)2], 7.36 (dd, 1 H,
J = 2.7, 1.7 Hz, H-5).
13C NMR (CDCl3, 90 MHz):
(CO2CH3), 62.4 [CH(OCH2CH3)2], 101.5 [CH(OCH2CH3)2], 108.9
Method B: Pyrrole 15 (86 mg, 0.269 mmol) was dissolved in THF
(5 mL) and cooled to –40 °C. Then isopropylmagnesium chloride
(0.14 mL, 0.282 mmol) was added and the mixture was stirred for 1
h. After adding H2O (2 mL), the mixture was allowed to come to r.t.
Sat. aq NH4Cl solution (5 mL) was added and the mixture was ex-
tracted with Et2O (10 mL). The organic layer was dried (MgSO4)
and evaporated under reduced pressure to give 2f (43 mg, 82%) as
a colorless oil.
= 1.22 [t, 6 H, J = 7.1 Hz,
IR (film): 2219, 1102, 1039 cm–1.
1H NMR (CDCl3, 360 MHz): = 1.26 [t, 6 H, J = 7.2 Hz,
CH(OCH2CH3)2], 3.5–3.7 [m, 4 H, CH(OCH2CH3)2], 6.12 [s, 1 H,
CH(OCH2CH3)29, 6.22 (dd, 1 H, J = 3.8, 2.7 Hz, H-4), 6.85 (dd, 1
H, J = 3.8, 1.7 Hz, H-3), 7.18 (dd, 1 H, J = 2.7, 1.7 Hz, H-5).
= 14.8 [CH(OCH2CH3)2], 51.1
(C-4), 119.1 (C-3), 121.7 (C-2), 124.3 (C-5), 161.6 (C=O).
EI-MS: m/z = 227 (M+).
13C NMR (CDCl3, 90 MHz): = 14.6 [CH(OCH2CH3)2], 62.2
[CH(OCH2CH3)2], 101.9 (C-2), 102.3 [CH(OCH2CH3)2], 109.8 (C-
4), 113.3 (CN), 121.2 (C-3), 123.3 (C-5).
Anal. Calcd for C11H17NO4 (227.3): C, 58.14; H, 7.54; N, 6.16.
Found: C, 58.07; H, 7.77; N, 6.15.
EI-MS: m/z = 194 (M+).
Anal. Calcd for C10H14N2O2 (194.2): C, 61.84; H, 7.27; N, 14.42.
Found: C, 61.69; H, 6.99; N, 14.55.
1-(1-Diethoxymethyl-1H-pyrrole-2-yl)ethanone (2d)
Pyrrole 1d7 (218 mg, 2.0 mmol) and triethyl orthoformate (5.0 mL,
30 mmol) were reacted (23 h) and worked up (light petroleum/
EtOAc, 8:2) as described for 2a to give 2d (347 mg, 82%) as a col-
orless oil.
1-Diethoxymethyl-1H-pyrrole-3-carbaldehyde (2g)
Pyrrole 1g8 (285 mg, 3.0 mmol) and triethyl orthoformate (5.0 mL,
30 mmol) were reacted (24 h) and worked up (light petroleum/
EtOAc, 7:3) as described for 2a to give 2g (547 mg, 92%) as a col-
orless oil.
IR (film): 1653, 1110, 1069 cm–1.
1H NMR (CDCl3, 360 MHz):
CH(OCH2CH3)2], 2.45 (s, 3 H, COCH3), 3.57 [dq, 2 H, J = 9.5, 7.1
Hz, CH(OCH2CH3)2], 3.68 [dq, H, J = 9.5, 7.1 Hz,
= 1.22 [t, 6 H, J = 7.2 Hz,
IR (film): 1674, 1106, 1068 cm–1.
2
1H NMR (CDCl3; 360 MHz):
= 1.25 [t, 6 H, J = 7.1 Hz,
CH(OCH2CH3)2], 6.21 (dd, 1 H, J = 3.8, 2.8 Hz, H-4), 7.00 (dd, 1
H, J = 3.8, 1.7 Hz, H-3), 7.11 [s, 1 H, CH(OCH2CH3)2], 7.43 (dd, 1
H, J = 2.8, 1.7 Hz, H-5).
CH(OCH2CH3)2], 3.59 [q, 4 H, J = 7.1 Hz, CH(OCH2CH3)2], 5.97
[s, 1 H, CH(OCH2CH3)2], 6.66 (dd, 1 H, J = 3.1, 1.7 Hz, H-4), 6.91
(dd, 1 H, J = 3.1, 2.0 Hz, H-5), 7.54 (dd, 1 H, J = 2.0, 1.7 Hz, H-2),
9.78 (s, 1 H, CHO).
13C NMR (CDCl3, 90 MHz):
= 14.8 [CH(OCH2CH3)2], 27.4
(COCH3), 62.7 [CH(OCH2CH3)2], 101.9 [CH(OCH2CH3)2], 109.1
(C-4), 121.3 (C-3), 125.5 (C-5), 130.5 (C-2), 188.6 (C=O).
EI-MS: m/z = 211 (M+).
13C NMR (CDCl3, 90 MHz): = 14.7 [CH(OCH2CH3)2], 61.1
[CH(OCH2CH3)2], 102.6 [CH(OCH2CH3)2], 108.1 (C-4), 120.5 (C-
5), 126.7 (C-2,3), 185.8 (CHO).
Anal. Calcd for C11H17NO3 (211.3): C, 62.54; H, 8.11; N, 6.63.
Found: C, 62.29; H, 8.25; N, 6.73.
EI-MS: m/z = 197 (M+).
Anal. Calcd. for C10H15NO3 (197.2): C, 60.90; H, 7.67; N, 7.10.
Found: C, 60.59; H, 7.70; N, 7.23.
1-(1-Diethoxymethyl-1H-pyrrole-2-yl)phenylmethanone (2e)
Pyrrole 1e7 (144 mg, 0.841 mmol) and triethyl orthoformate (5.0
mL, 30 mmol) were reacted (72 h) and worked up (light petroleum/
Synthesis 2001, No. 15, 2281–2288 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diethoxymethyl Protected Pyrroles
2285
1-(1-Diethoxymethyl-1H-pyrrole-3-yl)ethanone (2h)
Pyrole 1h7 (218 mg, 2.0 mmol) and triethyl orthoformate (5.0 mL,
30 mmol) were reacted (30 h) and worked up (light petroleum/
EtOAc, 7:3) as described for 2a to give 2h (333 mg, 79%) as a col-
orless oil.
IR (KBr): 2219,1104, 1093, 1066, 1038 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.24 [t, 6 H, J = 7.0 Hz,
CH(OCH2CH3)2], 3.52 [dq, 2 H, J = 9.5, 7.0 Hz, CH(OCH2CH3)2],
3.61 [dq, 2 H, J = 9.5, 7.0 Hz, CH(OCH2CH3)2], 6.39 (dd, 1 H,
J = 4.1, 2.7 Hz, H-4), 6.03 [s, 1 H, CH(OCH2CH3)2], 7.29 (dd, 1 H,
J = 2.7, 1.2 Hz, H-5), 7.72 (dd, 1 H, J = 4.1, 1.2 Hz, H-3), 8.07 [s, 1
H, CH=C(CN)2].
13C NMR (CDCl3, 90 MHz): = 14.6 [CH(OCH2CH3)2], 62.2
[CH(OCH2CH3)2], 72.5 [ArCH=C(CN)2], 103.5 [CH(OCH2CH3)2],
112.0 (C-4), 114.4, 115.3 [ArCH=C(CN)2], 121.9 (C-3), 125.4 (C-
2), 129.0 (C-5), 145.4 [ArCH=C(CN)2].
IR (film): 1664, 1184, 1095 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.25 [t, 6 H, J = 7.0 Hz,
CH(OCH2CH3)2], 2.41 (s, 3 H, COCH3), 3.5–3.7 [m, 4 H,
CH(OCH2CH3)2], 5.94 [s, 1 H, CH(OCH2CH3)2], 6.62 (dd, 1 H,
J = 3.1, 1.7 Hz, H-4), 6.86 (dd, 1 H, J = 3.1, 2.0 Hz, H-5), 7.52 (dd,
1 H, J = 2.0, 1.7 Hz, H-2).
13C NMR (CDCl3, 90 MHz):
= 14.7 [CH(OCH2CH3)2], 27.1
EI-MS: m/z = 245 (M+).
(COCH3), 61.1 [CH(OCH2CH3)2], 102.7 [CH(OCH2CH3)2], 109.3
(C-4), 119.4 (C-5), 123.1 (C-2), 126.3 (C-3), 193.7 (C=O).
EI-MS: m/z = 211 (M+).
Anal. Calcd for C13H15N3O2 (245.3): C, 63.66; H, 6.16; N, 17.13.
Found: C, 63.99; H, 6.33; N, 17.01.
Deprotection of 2a–k; General Procedure
Anal. Calcd for C11H17NO3 (211.3): C, 62.54; H, 8.11; N, 6.63.
Found: C, 62.34; H, 7.91; N, 6.79.
A mixture of 2a–k (0.50 mmol), TFA (77 L, 114 mg, 1.0 mmol)
and MeCN (5 mL) was stirred for t2 h (Table 1) at r.t. Then aq 2 N
NaOH (1 mL) was added and the mixture was stirred for an addi-
tional t3 h (Table 1). Then, H2O (20 mL) was added and extracted
with Et2O (3 10 mL). The combined organic layers were dried
1-(1-Diethoxymethyl-1H-pyrrole-3-yl)phenylmethanone (2i)
Pyrrole 1i7 (514 mg, 3.0 mmol) and triethyl orthoformate (5.0 mL,
30 mmol) were reacted (41 h) and worked up (light petroleum/
EtOAc, 7:3) as described for 2a to give 2i (609 mg, 74%) as a col-
orless oil.
1
(MgSO4) an evaporated to give pure (>95% as indicated by H
NMR) 1a–j and 2a (Table 1).
IR (film): 1636, 1106, 1068 cm–1.
1H NMR (CDCl3, 360 MHz):
CH(OCH2CH3)2], 3.5–3.7 [m, 4 H, CH(OCH2CH3)2], 5.96 [s, 1 H,
CH(OCH2CH3)2], 6.73 (dd, 1 H, J = 3.1, 1.7 Hz, H-4), 6.93 (dd, 1
H, J = 3.1, 2.0 Hz, H-5), 7.4–7.6 (m, 1 H, H-2), 7.4–7.9 (m, 5 H,
C6H5).
13C NMR (CDCl3, 90 MHz):
[CH(OCH2CH3)2], 102.8 [CH(OCH2CH3)2], 111.0 (C-4), 119.3 (C-
5), 124.7 (C-3), 125.2 (C-2), 128.1, 128.9 (C6H5 C-2,3), 131.4
(C6H5 C-4), 190.8 (C=O).
(1-Diethoxymethyl-1H-pyrrole-2-yl)phenylmethanol (3)
Pyrrole 2e (542 mg, 1.98 mmol) was dissolved in propan-2-ol (20
mL). NaBH4 (299 mg, 7.92 mmol) was added and the mixture was
refluxed for 2.5 h. After cooling to r.t., H2O (20 mL) was added
carefully. The mixture was stirred at 50 °C for 30 min and extracted
with CH2Cl2 (3 15 mL) after cooling to r.t. The combined organic
layers were dried (MgSO4) and the solvent evaporated to give pure
3 (479 mg, 88%) as a colorless oil.
= 1.25 [t, 6 H, J = 7.0 Hz,
= 14.7 [CH(OCH2CH3)2], 61.2
IR (film): 3455, 1100, 1063 cm–1.
1H NMR (CDCl3; 360 MHz):
= 1.16 [t, 3 H, J = 7.0 Hz,
EI-MS: m/z = 273 (M+).
CH(OCH2CH3)2], 1.23 [t, 3 H, J = 7.0 Hz, CH(OCH2CH3)2], 3.23
(d, 1 H, J = 4.1 Hz, OH), 3.3–3.7 [m, 4 H, CH(OCH2CH3)2], 5.81
(dd, 1 H, J = 3.5, 2.5 Hz, H-4), 5.97 (s, 1 H, CHOH), 6.10 [s, 1 H,
CH(OCH2CH3)2], 6.10 (m, 1 H, H-3), 6.95 (dd, 1 H, J = 2.5, 1.9 Hz,
H-5), 7.3–7.9 (m, 5 H, C6H5).
13C NMR (CDCl3, 90 MHz): = 14.6, 14.7 [CH(OCH2CH3)2], 61.8,
62.0 [CH(OCH2CH3)2], 68.6 (PhCHOH), 102.5 [CH(OCH2CH3)2],
107.1, 111.2 (C-3,4), 120.0 (C-5), 126.5, 127.3, 128.1 (C6H5 C-
2,3,4), 134.2 (C-2), 141.9 (C6H5 C-1).
Anal. Calcd for C16H19NO3 (273.3): C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.16; H, 7.17; N, 5.22.
Diethyl 1-Diethoxymethyl-1H-pyrrole-3,4-dicarboxylate (2j)
Pyrrole 1j (422 mg, 2.0 mmol) and triethyl orthoformate (5.0 mL,
30 mmol) were reacted (17 h) and worked up as described for 2a
without flash chromatographic purification to give 2j (622 mg,
99%) as a colorless oil.
EI-MS: m/z = 275 (M+).
IR (film): 1738, 1183, 1065 cm–1.
1H NMR (CDCl3; 360 MHz):
CO2CH2CH3) 1.34 [t, 6 H, J = 7.2 Hz, CH(OCH2CH3)2], 4.30 (q, 4
H, J = 7.1 Hz, CO2CH2CH3), 3.5–3.7 [m, 4 H, CH(OCH2CH3)2],
5.91 [s, 1 H, CH(OCH2CH3)2], 7.43 (s, 2 H, H-2,5).
13C NMR (CDCl3, 90 MHz):
[CH(OCH2CH3)2], 60.3 (CO2CH2CH3), 61.1 [CH(OCH2CH3)2],
102.5 [CH(OCH2CH3)2], 116.5 (C-3,4), 124.7 (C-2,5), 163.6
(C=O).
= 1.24 [t, 6 H, J = 7.1 Hz,
Anal. Calcd for C16H21NO3 (275.4): C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.60; H, 7.48; N, 5.10.
Dithiocarbonic Acid O-[(1-Diethoxymethyl-1H-pyrrole-2-
yl)phenylmethyl]ester S-Methyl Ester (4)
= 14.3 (CO2CH2CH3), 14.7
To a solution of 3 (61 mg, 0.221 mol) in CS2 (2 mL) were added tet-
rabutylammonium hydrogensulfate (8 mg, 0.023 mmol), MeI (15
L, 0.243 mmol) and NaOH (2 mL, 50% in H2O) and the mixture
was stirred for 1.5 h at r.t. Then H2O (10 mL) and CS2 (20 mL) were
added. The separated organic layer was dried (MgSO4) and the sol-
vent evaporated. The residue was purified by flash chromatography
(light petroleum/EtOAc, 95:5) to give 4 (38 mg, 47%) as a yellow
oil.
EI-MS: m/z = 313 (M+).
Anal. Calcd for C15H23NO6 (313.3): C, 57.50; H, 7.40; N, 4.47.
Found: C, 57.82; H, 7.66; N, 4.54.
IR (film): 2977, 2929, 1644, 1282, 1101, 1064 cm–1.
2-(1-Diethoxymethyl-1H-pyrrole-2-yl)methylenecarbodinitrile
(2k)
1H NMR (CDCl3, 360 MHz):
= 1.11 [t, 3 H, J = 7.1 Hz,
Pyrrole 1k9 (286 mg, 2.0 mmol) and triethyl orthoformate (5.0 mL,
30 mmol) were reacted (21 h) and worked up (light petroleum/
EtOAc, 7:3) as described for 2a to give 2k (392 mg, 80%) as a
brown solid; mp 55 °C.
CH(OCH2CH3)2], 1.18 [t, 3 H, J = 7.1 Hz, CH(OCH2CH3)2], 2.40
(s, 3 H, SCH3), 3.44 [dq, 2 H, J = 7.1, 9.5 Hz, CH(OCH2CH3)2],
3.57 [dq, 2 H, J = 7.1, 9.5 Hz, CH(OCH2CH3)2], 5.92 [s, 1 H,
CH(OCH2CH3)2], 6.08 (dd, 1 H, J = 3.2, 2.8 Hz, H-4), 6.13 (dd, 1
Synthesis 2001, No. 15, 2281–2288 ISSN 0039-7881 © Thieme Stuttgart · New York

2286
M. Bergauer, P. Gmeiner
PAPER
H, J = 3.2, 1.8 Hz, H-3), 6.28 (s, 1 H, CHOCS2CH3), 6.94 (dd, 1 H,
J = 2.8, 1.8 Hz, H-5), 7.2–7.4 (m, 5 H, C6H5).
15 min. After that trimethylsilyl chloride (47 L, 0.370 mmol) was
added. After another 30 min in the ice bath, the mixture was treated
with aq NaHCO3 solution (20 mL) and extracted with Et2O (3 10
mL). The combined organic layers were dried (MgSO4), filtered and
evaporated under reduced pressure. The residue was purified by
flash chromatography (light petroleum/EtOAc, 9:1) to give 8 (27
mg, 41%) as a colorless oil.
13C NMR (CDCl3, 90 MHz):
= 14.6 [CH(OCH2CH3)2], 45.6
(SCH3), 61.1, 61.8 [CHOCS2CH3, CH(OCH2CH3)2], 101.7
[CH(OCH2CH3)2], 107.5, 111.5 (C-3,4), 119.4 (C-5), 127.5, 128.2,
128.3 (C6H5 C-2,3,4), 129.0 (C-2), 139.9 (C6H5 C-1), 188.4 (C=S).
EI-MS: m/z = 365 (M+).
IR (film): = 2214, 1105, 1075 cm–1.
Anal. Calcd for C18H23NO3S2 (365.5): C, 59.15; H, 6.34; N, 3.83; S,
17.54. Found: C, 59.24; H, 6.51; N, 3.77; S, 17.26.
1H NMR (CDCl3, 360 MHz): = 0.31 [s, 9 H, Si(CH3)3], 1.26 [t, 6
H, J = 7.0 Hz, CH(OCH2CH3)2], 3.52 [dq, 2 H, J = 9.4, 7.0 Hz,
CH(OCH2CH3)2], 3.70 [dq, 2 H, J = 9.4, 7.0 Hz, CH(OCH2CH3)2],
6.15 [s, 1 H, CH(OCH2CH3)2], 6.41 (d, 1 H, J = 3.5 Hz, H-4), 6.83
(d, 1 H, J = 3.5 Hz, H-3).
2-Benzyl-1-diethoxymethyl-1H-pyrrole (5)
Pyrrole 4 (22 mg, 0.060 mmol), AIBN (2 mg, 0.012 mmol) and
tributyl tinhydride (48 L, 0.180 mmol) were dissolved in anhyd
benzene (5 mL) and refluxed for 28 h. After cooling to r.t., the sol-
vent was evaporated and the residue was purified by flash chroma-
tography (light petroleum/EtOAc, 95:5) to give 5 (13 mg, 83%) as
a colorless oil.
13C NMR (CDCl3, 90 MHz):
[CH(OCH2CH3)2], 62.6
= 0.70 [Si(CH3)3], 14.6
[CH(OCH2CH3)2], 103.5
[CH(OCH2CH3)2], 106.2 (C-2), 113.8 (CN), 120.7 (C-3,4), 139.3
(C-5).
IR (film): 3061, 3026, 2976, 2915, 1282, 1101, 1064 cm–1.
EI-MS: m/z = 266 (M+).
1H NMR (CDCl3, 360 MHz): = 1.10 [m, 6 H, CH(OCH2CH3)2],
3.3–3.5 [m, 4 H, CH(OCH2CH3)2], 5.99 [s, 1 H, CH(OCH2CH3)2],
6.11 (dd,1 H, J = 3.5, 2.8 Hz, H-4), 6.27 (dd, 1 H, J = 3.5, 1.8 Hz,
H-3), 6.92 (dd, 1 H, J = 2.8, 1.8 Hz, H-5), 7.2–7.4 (m, 5 H, C6H5).
Anal. Calcd for C13H22N2O2Si (266.4): C, 58.61; H, 8.32; N, 10.51.
Found: C, 58.70; H, 8.09; N, 10.61.
5-Tributylstannyl-1-diethoxymethyl-1H-pyrrole-2-carbonitrile
(9)
13C NMR (CDCl3, 90 MHz):
= 14.6 [CH(OCH2CH3)2], 47.4
To a stirred solution of 2f (153 mg, 0.788 mmol) in THF (2 mL) was
added an ice cold solution of LDA in THF (5.48 mL, 0.867 mmol)
and the mixture was stirred for additional 15 min. After cooling the
mixture to –78 °C, tributyltin chloride (0.42 mL, 1.567 mmol) was
added. After another 30 min at –78 °C, the mixture was warmed to
r.t., treated with aq NaHCO3 solution (10 mL) and extracted with
Et2O (1 30 mL, 2 10 mL). The combined organic layers were
dried (MgSO4), filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography (light petroleum/
EtOAc, 95:5) to give 9 (179 mg, 47%) as a colorless oil.
(CH2), 61.1, 61.6 [CH(OCH2CH3)2], 101.7 [CH(OCH2CH3)2],
107.3, 110.7 (C-3,4), 119.0 (C-5), 127.1 (C6H5 C-4), 128.4, 128.7
(C6H5 C-2,3), 130.6 (C-2), 140.4 (C6H5 C-1).
EI-MS: m/z = 259 (M+).
HRMS: m/z calcd for C16H21NO2 (M+): 259.15723. Found:
259.15721.
Ethyl 1-Diethoxymethyl-5-trimethylsilyl-1H-pyrrole-2-
carboxylate (7)
IR (film): 2211, 1101, 1068 cm–1.
1H NMR (CDCl3, 360 MHz):
Sn(CH2CH2CH2CH3)3), 1.0–1.1 [m, 6 H, Sn(CH2CH2CH2CH3)3],
1.24 [t, 6 H, J = 7.1 Hz, CH(OCH2CH3)2], 1.3–1.4 [m, 6 H,
Sn(CH2CH2CH2CH3)3), 1.5–1.6 [m, 6 H, Sn(CH2CH2CH2CH3)3],
3.51 [dq, 2 H, J = 9.5, 7.1 Hz, CH(OCH2CH3)2], 3.67 [dq, 2 H,
J = 9.5, 7.1 Hz, CH(OCH2CH3)2], 6.12 [s, 1 H, CH(OCH2CH3)2],
6.31 (d, 1 H, J = 3.5 Hz, H-4), 6.87 (d, 1 H, J = 3.5 Hz, H-3).
Pyrrole 2b (58 mg, 0.240 mmol) was dissolved in Et2O (2 mL) and
cooled to –50 °C. Then an ice cold solution of LDA in Et2O (1.52
mL, 0.240 mmol) was added and the mixture was stirred for addi-
tional 60 min. MeSiCl (61 L, 0.480 mmol) was then added. After
another 3 h at –50 °C, H2O (3 mL) was added and the mixture was
warmed to r.t., treated with aq NaHCO3 solution (10 mL) and ex-
tracted with Et2O (3 10 mL). The separated organic layer was
dried (MgSO4), filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography (light petroleum/
Et2O, 95:5) to give 7 (31 mg, 41%) as a colorless oil.
= 0.89 [t, 9 H, J = 7.2 Hz,
13C NMR (CDCl3, 90 MHz): = 11.1 [Sn(CH2CH2CH2CH3)3], 13.6
[Sn(CH2CH2CH2CH3)3],
14.5
[(CH(OCH2CH3)2],
27.3
IR (film): 1700, 1101, 1066 cm–1.
[Sn(CH2CH2CH2CH3)3], 28.9 [Sn(CH2CH2CH2CH3)3], 62.7
[CH(OCH2CH3)2] 103.3 [CH(OCH2CH3)2], 105.8 (C-2), 114.0
(CN), 120.7, 120.8 (C-3,4), 138.9 (C-5).
EI-MS: m/z = 483 (M+).
1H NMR (CDCl3, 360 MHz): = 0.30 [s, 9 H, Si(CH3)3], 1.21 [t, 6
H, J = 7.1 Hz, CH(OCH2CH3)2], 1.34 (t, 3 H, J = 7.1 Hz,
(CO2CH2CH3), 3.51 [dq, 2 H, J = 9.8, 7.1 Hz, CH(OCH2CH3)2],
3.68 [dq, 2 H, J = 9.8, 7.1 Hz, CH(OCH2CH3)2], 4.27 (q, 2 H,
J = 7.1 Hz, CO2CH2CH3), 6.44 (d, 1 H, J = 3.8 Hz, H-4), 6.97 (d, 1
H, J = 3.8 Hz, H-3), 7.30 [s, 1 H, CH(OCH2CH3)2].
Anal. Calcd for C22H40N2O2Sn (483.3): C, 54.68; H, 8.34; N, 5.80.
Found: C, 54.72; H, 8.35; N, 5.73.
13C NMR (CDCl3, 90 MHz):
(CO2CH2CH3), 14.7 [CH(OCH2CH3)2], 60.0 (CO2CH2CH3), 62.4
[CH(OCH2CH3)2], 101.8 [CH(OCH2CH3)2], 118.5, 120.6 (C-4,3),
126.5 (C-2), 140.5 (C-5), 161.4 (C=O).
= 0.73 [Si(CH3)3], 14.4
4-Bromo-1-diethoxymethyl-1H-pyrrole-2-carbaldehyde (10)
Pyrrole 2a (567 mg, 2.87 mmol) was dissolved in THF (10 mL) and
cooled to –20 °C. Then NBS (612 mg, 3.44 mmol) was added and
the mixture was stirred for 3 h at –20 °C and an additional 17 h at
r.t. The mixture was cooled in an ice bath and hexane (15 mL) was
added. The solution was filtered and evaporated under reduced
pressure. The residue was purified by flash chromatography (light
petroleum/EtOAc, 9:1) to give 10 (551 mg, 70%) as a colorless oil.
EI-MS: m/z = 313 (M+).
Anal. Calcd for C15H27NO4Si (313.5): C, 57.47; H, 8.68; N, 4.47.
Found: C, 57.62; H, 8.39; N, 4.51.
IR (film): 1670, 1105, 1070 cm–1.
1H NMR (CDCl3, 360 MHz):
CH(OCH2CH3)2], 3.58 [dq, 2 H, J = 9.4, 7.0 Hz, CH(OCH2CH3)2],
3.68 [dq, 2 H, J = 9.4, 7.0 Hz, CH(OCH2CH3)2], 6.90 [s, 1 H,
1-Diethoxymethyl-5-trimethylsilyl-1H-pyrrole-2-carbonitrile
(8)
Pyrrole 2f (48 mg, 0.247 mmol) was dissolved in THF (3 mL) and
cooled to 0 °C. Then an ice cold solution of LDA in THF (1.65 mL,
0.296 mmol) was added and the solution was stirred for additional
= 1.23 [t, 6 H, J = 7.0 Hz,
Synthesis 2001, No. 15, 2281–2288 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Diethoxymethyl Protected Pyrroles
2287
CH(OCH2CH3)2], 6.95 (d, 1 H, J = 2.1 Hz, H-3), 7.43 (d, 1 H,
J = 2.1 Hz, H-5).
1-Diethoxymethyl-4-trimethylsilylethinyl-1H-pyrrole-2-carbal-
dehyde (13b)
To a solution of 12 (200 mg, 0.619 mmol) in 1,4-dioxane (5 mL)
and Et3N (2.5 mL) were subsequently added PdCl2(PPh3)2 (49 mg,
0.062 mmol), CuI (24 mg, 0.126 mmol) and trimethylsilylacetylene
(105 L, 0.743 mmol). After stirring for 1 h at r.t., aq sat. NaHCO3
solution (20 mL) was added and extracted with Et2O (3 10 mL).
The combine organic layers were dried (MgSO4) and evaporated
under reduced pressure and the residue was purified by flash chro-
matography (light petroleum/Et2O, 8:2) to give 13b (154 mg, 85%).
13C NMR (CDCl3, 90 MHz):
[CH(OCH2CH3)2], 98.3 (C-4), 101.7 [CH(OCH2CH3)2], 126.1 (C-
3), 126.4 (C-5), 131.6 (C-2), 179.1 (CHO).
EI-MS: m/z = 274 [M+ (79Br)], 276 [M+ (81Br)].
= 14.7 [CH(OCH2CH3)2], 62.8
Anal. Calcd for C10H14BrNO3 (276.1): C, 43.50; H, 5.11; N, 5.07.
Found: C, 43.63; H, 5.26; N, 5.18.
IR (film): 1672, 1106, 1072 cm–1.
1-Diethoxymethyl-4-iodo-1H-pyrrole-2-carbaldehyde (12)
Compound 1113 (4.00 g, 18.1 mmol) and triethyl orthoformate (30
mL, 181 mmol) were reacted (22 h) and worked up (light petroleum/
EtOAc, 9:1) as described for 2a to give 12 (4.92 g, 77%) as a white
solid; mp 41–42 °C.
1H NMR (CDCl3, 360 MHz): = 0.23 [s, 9 H, Si(CH3)3], 1.21 [t, 6
H, J = 7.1 Hz, CH(OCH2CH3)2], 3.56 [dq, 2 H, J = 9.5, 7.1 Hz,
CH(OCH2CH3)2], 3.65 (dq, 2 H, J = 9.5, 7.1 Hz, CH(OCH2CH3)2],
6.90 [s, 1 H, CH(OCH2CH3)2], 7.04 (d, 1 H, J = 1.7 Hz, H-3), 7.61
(d, 1 H, J = 1.7 Hz, H-5), 9.51 (s, 1 H, CHO).
IR (film): 1670, 1105, 1070 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.23 [t, 6 H, J = 7.0 Hz,
13C NMR (CDCl3, 90 MHz):
= 0.0 [(CH3)3Si], 14.7
CH(OCH2CH3)2], 3.58 [dq, 2 H, J = 9.5, 7.0 Hz, CH(OCH2CH3)2],
3.68 [dq, 2 H, J = 9.5, 7.0 Hz, CH(OCH2CH3)2], 6.08 [s, 1 H,
CH(OCH2CH3)2], 7.05 (d, 1 H, J = 1.6 Hz, H-3), 7.49 (dd, 1 H,
J = 1.6 Hz, H-5), 9.51 (s, 1 H, CHO).
13C NMR (CDCl3, 90 MHz): = 14.7 [CH(OCH2CH3)2], 62.1 (C-
4), 62.8 [CH(OCH2CH3)2], 101.6 [CH(OCH2CH3)2], 131.2, 131.3
(C-3,5), 133.0 (C-2), 178.8 (CHO).
[CH(OCH2CH3)2], 62.6 [CH(OCH2CH3)2], 94.1, 98.0 (C C), 101.7
[CH(OCH2CH3)2], 106.7 (C-4), 127.8, 130.5 (C-3,5), 130.9 (C-2),
179.5 (CHO).
EI-MS: m/z = 293 (M+).
Anal. Calcd for C15H23NO3Si (293.4): C, 61.40; H, 7.90; N, 4.77.
Found: C, 61.19; H, 8.02; N, 4.76.
EI-MS: m/z = 323 (M+).
1-Diethoxymethyl-4-iodo-1H-pyrrole-2-carbonitrile (15)
Compound 1415 (2.00 g, 9.17 mmol) and triethyl orthoformate
(15.25 mL, 91.7 mmol) were reacted (19 h) and worked up (light pe-
troleum/EtOAc, 9:1) as described for 2a to give 15 (2.34 g, 79%) as
a colorless oil.
Anal. Calcd for C10H14INO3 (323.13): C, 37.10; H, 4.37; N, 4.33.
Found: C, 37.22; H, 4.27; N, 4.21.
1-Diethoxymethyl-4-phenyl-1H-pyrrole-2-carbaldehyde (13a)
Method A: Compound 10 (123 mg, 0.445 mmol) and Pd(PPh3)4 (26
mg, 0.022 mmol) were dissolved in toluene (10 mL) and stirred at
r.t. for 10 min. Then phenylboronic acid (81 mg, 0.667 mmol) in
EtOH (2 mL) and aq 2 M Na2CO3 solution (2 mL) were added and
stirred at 80 °C for 4 h. After adding again Pd(PPh3)4 (26 mg, 0.022
mmol), the mixture was stirred for an additional 23 h. The mixture
was treated with H2O (20 mL) and extracted with Et2O (3 20 mL).
The combined organic layers were dried (MgSO4) and evaporated
under reduced pressure and the residue was purified by flash chro-
matography (light petroleum/EtOAc, 9:1) to give 13a (9 mg, 7%; 59
mg, 48% of 10 was recovered).
IR (film): 2221, 1079, 917 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.27 [t, 6 H, J = 7.1 Hz,
CH(OCH2CH3)2], 3.60 (dq, 2 H, J = 9.5, 7.1 Hz, CH(OCH2CH3)2],
3.66 (dq, 2 H, J = 9.5, 7.1 Hz, CH(OCH2CH3)2], 6.08 [s, 1 H,
CH(OCH2CH3)2], 6.91 (d, 1 H, J = 1.8 Hz, H-3), 7.23 (dd, 1 H,
J = 1.8 Hz, H-5).
13C NMR (CDCl3, 90 MHz): = 14.6 [CH(OCH2CH3)2], 60.6 (C-
4), 62.3 [CH(OCH2CH3)2], 102.3 [CH(OCH2CH3)2], 103.8 (C-2),
111.6 (CN), 127.3, 128.2 (C-3,5).
EI-MS: m/z = 320 (M+).
Method B: Compound 12 (205 mg, 0.634 mmol) and Pd(PPh3)4 (37
mg, 0.032 mmol) were dissolved in toluene (10 mL) and stirred at
r.t. for 10 min. Then phenylboronic acid (116 mg, 0.951 mmol) in
EtOH (2 mL) and aq 2 M Na2CO3 solution (2 mL) were added and
stirred at 80 °C for 2 h. The mixture was treated with H2O (20 mL)
and extracted with Et2O (3 20 mL). The combined organic layers
were dried (MgSO4) and evaporated under reduced pressure and the
residue was purified by flash chromatography (light petroleum/
EtOAc, 9:1) to give 13a (114 mg, 66%).
Anal. Calcd for C10H13IN2O2 (320.1): C, 37.52; H, 4.09; N, 8.75.
Found: C, 37.23; H, 3.84; N, 8.67.
1-Diethoxymethyl-4-(hydroxymethylphenyl)-1H-pyrrole-2-
carbonitrile (16a); Typical Procedure
To a solution of 15 (53 mg, 0.165 mmol) in THF (5 mL) was added
isopropylmagnesium chloride (87 L, 0.173 mmol) at –40 °C. After
stirring for 1 h, benzaldehyde (21 L, 0.198 mmol) was added and
stirring was continued for further 2 h. After adding aq sat. NH4Cl
solution (5 mL), the mixture was allowed to warm to r.t. and extract-
ed with Et2O (10 mL). The organic layer was dried (MgSO4) and
evaporated under reduced pressure. The residue was purified by
flash chromatography (light petroleum/EtOAc, 7:3) to give 16a (33
mg, 66%) as a colorless oil.
IR (film): 1665, 1104, 1076 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.25 [t, 6 H, J = 7.1 Hz,
CH(OCH2CH3)2], 3.61 [dq, 2 H, J = 9.5, 7.1 Hz, CH(OCH2CH3)2],
3.73 [dq, 2H, J = 9.5, 7.1 Hz, CH(OCH2CH3)2], 7.00 [s, 1 H,
CH(OCH2CH3)2], 7.25 (d, 1 H, J = 2.0 Hz, H-3), 7.2–7.7 (m, 5 H,
C6H5), 7.76 (d, 1 H, J = 2.0 Hz, H-5).
IR (film): 3436, 2218, 1130, 1099 cm–1.
13C NMR (CDCl3, 90 MHz):
= 14.8 [CH(OCH2CH3)2], 62.8
1H NMR (CDCl3; 360 MHz):
= 1.25 [t, 6 H, J = 7.1 Hz,
[CH(OCH2CH3)2], 101.8 [CH(OCH2CH3)2], 122.2, 123.4, 125.3,
126.6, 126.7, 128.9, 132.1, 133.6 (pyrrole-C, phenyl-C), 178.8
(CHO).
EI-MS: m/z = 273 (M+).
CH(OCH2CH3)2], 2.17 (s, 1 H, OH), 3.58 [dq, 2 H, J = 9.2, 7.1 Hz,
CH(OCH2CH3)2], 3.65 [dq, 2 H, J = 9.2, 7.1 Hz, CH(OCH2CH3)2],
5.75 (s, 1 H, CHOH), 6.05 [s, 1 H, CH(OCH2CH3)2], 6.73 (d, 1 H,
J = 1.4 Hz, H-3), 7.08 (d, 1 H, J = 1.4 Hz, H-5), 7.2–7.5 (m, 5 H,
ArH).
13C NMR (CDCl3, 90 MHz): = 14.6 [CH(OCH2CH3)2], 62.3
[CH(OCH2CH3)2], 70.5 (CHOH), 102.2 (C-2), 102.4
Anal. Calcd for C16H19NO3 (273.3): C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.12; H, 7.30; N, 4.91.
Synthesis 2001, No. 15, 2281–2288 ISSN 0039-7881 © Thieme Stuttgart · New York

2288
M. Bergauer, P. Gmeiner
PAPER
[CH(OCH2CH3)2), 113.0 (CN), 119.6, 121.1 (C-3,5), 126.3, 127.9,
128.4 (C6H5 C-2,3,4), 128.8 (C-4), 143.2 (C6H5 C-1).
4-Tributylstannyl-1-diethoxymethyl-1H-pyrrole-2-carbonitrile
(16e)
Compound 16e was prepared from 15 (86 mg, 0.269 mmol) and
tributyltin chloride (0.14 mL, 0.538 mmol) using the procedure de-
scribed for 16a to give 58 mg (45%) as a colorless oil.
IR (film): 2217, 1168, 1099 cm–1.
EI-MS: m/z = 300 (M+).
Anal. Calcd for C17H20N2O3 (300.4): C, 67.98; H, 6.71; N, 9.33.
Found: C, 68.27; H, 6.65; N, 9.11
1-Diethoxymethyl-4-(1-hydroxypropyl)-1H-pyrrole-2-carbo-
nitrile (16b)
Compound 16b was prepared from 15 (100 mg, 0.312 mmol) and
propionaldehyde (50 L, 0.686 mmol) using the procedure de-
scribed for 16a to give 60 mg (76%) as a colorless oil.
1H NMR (CDCl3; 360 MHz):
= 0.88 [t, 9 H, J = 7.3 Hz,
Sn(CH2CH2CH2CH3)3], 0.9–1.1 [m, 6 H, Sn(CH2CH2CH2CH3)3],
1.2–1.4 [m, 6 H, Sn(CH2CH2CH2CH3)3], 1.26 [t, 6 H, J = 7.1 Hz,
CH(OCH2CH3)2], 1.5–1.6 (m, 6 H, Sn(CH2CH2CH2CH3)3], 3.57
[dq, 2 H, J = 9.4, 7.1 Hz, CH(OCH2CH3)2], 3.67 [dq, 2 H, J = 9.4,
7.1 Hz, CH(OCH2CH3)2], 6.12 [s, 1 H, CH(OCH2CH3)2], 6.86 (d, 1
H, J = 1.4 Hz, H-3), 7.07 (d, 1 H, J = 1.4 Hz, H-5).
IR (film): 3440, 2217, 1137, 1076 cm–1.
1H NMR (CDCl3, 360 MHz): = 0.94 (t, 3 H, J = 7.4 Hz, CH3CH2),
1.27 [t, 6 H, J = 7.0 Hz, CH(OCH2CH3)2], 1.67 (s, 1 H, OH), 1.7–
1.8 (m, 2 H, CH3CH2), 3.59 [dq, 2 H, J = 9.3, 7.0 Hz,
CH(OCH2CH3)2], 3.66 (dq, 2 H, J = 9.3, 7.0 Hz, CH(OCH2CH3)2],
4.5–4.6 (m, 1 H, CHOH), 6.08 [s, 1 H, CH(OCH2CH3)2], 6.83 (d, 1
H, J = 1.8 Hz, H-3), 7.15 (d, 1 H, J = 1.8 Hz, H-5).
13C NMR (CDCl3, 90 MHz): = 9.9 [Sn(CH2CH2CH2CH3)3], 11.7
[Sn(CH2CH2CH2CH3)3],
14.7
[CH(OCH2CH3)2],
26.9
[Sn(CH2CH2CH2CH3)3], 29.1 [Sn(CH2CH2CH2CH3)3], 62.2
[CH(OCH2CH3)2], 102.3 [CH(OCH2CH3)2], 103.2 (C-2), 113.7
(CN), 116.5 (C-4), 128.4, 128.8 (C-3,5).
EI-MS: m/z = 483 (M+).
13C NMR (CDCl3, 90 MHz):
= 10.0 (CH3), 14.6
[CH(OCH2CH3)2], 31.2 (CH2), 62.2 [CH(OCH2CH3)2], 69.5
(CHOH), 102.0 (C-2), 102.3 [CH(OCH2CH3)2], 113.1 (CN), 118.9,
120.5 (C-3,5), 129.1 (C-4).
Anal. Calcd for C22H40N2O2Sn (483.3): C, 54.68; H, 8.34; N, 5.80.
Found: C, 54.42; H, 8.67; N, 5.67.
EI-MS: m/z = 252 (M+).
HRMS: m/z calcd for C13H20N2O3 (M+): 252.14740. Found:
Acknowledgment
The generous support of the Fonds der Chemische Industrie is gra-
tefully acknowledged.
252.14722.
1-Diethoxymethyl-4-formyl-1H-pyrrole-2-carbonitrile (16c)
Compound 16c was prepared from 15 (255 mg, 0.796 mmol) and
DMF (92 L, 1.194 mmol) using the procedure described for 16a to
give 133 mg (75%) as a colorless oil.
References
(1) Liu, J.-H.; Chan, H.-W.; Wong, H. N. C. J. Org. Chem.
2000, 65, 3274; and references cited therein.
(2) (a) Gmeiner, P.; Bollinger, B. Synthesis 1995, 168.
(b) Gmeiner, P.; Kraxner, J.; Bollinger, B. Synthesis 1996,
1196.
(3) (a) Gmeiner, P.; Bollinger, B. Tetrahedron Lett. 1991, 32,
5927. (b) Gmeiner, P.; Bollinger, B.; Lotter, H. J.
Heterocycl. Chem. 1996, 33, 481.
IR (film): 2229, 1685, 1118, 1099 cm–1.
1H NMR (CDCl3, 360 MHz):
= 1.30 (t, 6 H, J = 7.1 Hz,
CH(OCH2CH3)2], 3.68 [q, 4 H, J = 7.1 Hz, CH(OCH2CH3)2], 6.17
[s, 1 H, CH(OCH2CH3)2], 7.29 (d, 1 H, J = 1.8 Hz, H-3), 7.77 (d, 1
H, J = 1.8 Hz, H-5), 9.80 (s, 1 H, CHO).
13C NMR (CDCl3, 90 MHz):
= 14.6 [CH(OCH2CH3)2], 62.4
(4) (a) Kraxner, J.; Gmeiner, P. Synthesis 2000, 1081.
(b) Kraxner, J.; Arlt, M.; Gmeiner, P. Synlett 2000, 125.
(5) Signaigo, F. K.; Adkins, H. J. Am. Chem. Soc. 1936, 58,
1122.
(6) Hong, F.; Zaidi, J.; Pang, Y.-P.; Cusack, B.; Richelson, E. J.
Chem. Soc., Perkin Trans. 1 1997, 2997.
(7) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org.
Chem. 1983, 48, 3214.
(8) Carson, J. R.; Davis, N. M. J. Org. Chem. 1981, 46, 839.
(9) Gazit, A.; Yaish, P.; Gilon, C.; Levitzki, A. J. Med. Chem.
1989, 32, 2344.
[CH(OCH2CH3)2], 102.4 [CH(OCH2CH3)2], 104.5 (C-2), 111.7
(CN), 120.2 (C-3), 125.9 (C-4), 128.7 (C-5), 184.4 (CHO).
Anal. Calcd for C11H14N2O3 (222.3): C, 59.45; H, 6.30; N, 12.60.
Found: C, 59.48; H, 5.99; N, 12.67.
1-Diethoxymethyl-4-(pyridine-2-ylsulfanyl)-1H-pyrrole-2-car-
bonitrile (16d)
Compound 16d was prepared from 15 (67 mg, 0.209 mmol) and
2,2´-dithiodipyridine (92 mg, 0.418 mmol) using the procedure de-
scribed for 16a to give 42 mg (66%) as a colorless oil.
IR (film): 2225, 1573, 1450, 1419, 1303, 1091 cm–1.
(10) Greenhouse, R.; Ramirez, C.; Muchowski, J. M. J. Org.
Chem. 1985, 50, 2961.
(11) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
1H NMR (CDCl3, 360 MHz):
= 1.29 [t, 6 H, J = 7.1 Hz,
CH(OCH2CH3)2], 3.6–3.8 [m, 4 H, CH(OCH2CH3)2], 6.16 [s, 1 H,
CH(OCH2CH3)2], 6.90 (ddd, 1 H, J = 8.0, 0.9, 0.9 Hz, pyridine H-
3], 7.00 (ddd, 1 H, J = 7.4, 4.9, 0.9 Hz, pyridine H-5], 7.01 (d, 1 H,
J = 1.8 Hz, pyrrole H-3), 7.41 (d, 1 H, J = 1.8 Hz, pyrrole H-5), 7.48
(ddd, J = 8.0, 7.4, 2.0 Hz, pyridine H-4), 8.39 (ddd, J = 4.9, 2.0, 0.9
Hz, pyridine H-6).
(12) Anderson, H. J.; Loader, C. E. Synthesis 1985, 353.
(13) Farnier, M.; Fournari, P. Bull. Soc. Chim. Fr. 1973, 351.
(14) (a) Bérillon, L.; Leprêtre, A.; Turck, A.; Plé, N.; Quéguiner,
G.; Cahiez, G.; Knochel, P. Synlett 1998, 1359.
(b) Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 1701. (c) Dehmel, F.;
Abarbri, M.; Knochel, P. Synlett 2000, 345. (d) Abarbri,
M.; Thibonnet, J.; Bérillon, L.; Dehmel, F.; Rottländer, M.;
Knochel, P. J. Org. Chem. 2000, 65, 4618. (e) Rottländer,
M.; Boymond, L.; Bérillon, L.; Leprêtre, A.; Varchi, G.;
Avolio, S.; Laaziri, H.; Quéguiner, G.; Ricci, A.; Cahiez, G.;
Knochel, P. Chem.–Eur. J. 2000, 6, 767.
13C NMR (CDCl3, 90 MHz):
= 14.6 [CH(OCH2CH3)2], 62.3
8CH(OCH2CH3)2], 102.5 [CH(OCH2CH3)2], 103.5 (pyrrole C-2),
109.9 (pyrrole C-4), 112.2 (CN), 119.8, 120.0, 126.8, 129.2, 136.7,
149.5 (pyrrole C, pyridine C), 161.3 (pyridine C-2).
EI-MS: m/z = 303 (M+).
Anal. Calcd for C15H17N3O2S (303.4): C, 59.39; H, 5.65; N, 13.85;
S, 10.57. Found: C, 59.50; H, 5.76; N, 13.52; S 10.19.
(15) Demopoulos, B. J.; Anderson, H. J.; Loader, C. E.; Faber, K.
Can. J. Chem. 1983, 61, 2415.
Synthesis 2001, No. 15, 2281–2288 ISSN 0039-7881 © Thieme Stuttgart · New York