A short and efficient synthesis of 3,4-dialkoxypyrroles

Article abstract of DOI:10.1055/s-1999-3687

3,4-Dialkoxypyrroles are obtained in four steps from commercially available 2,5-dimethoxy-2,5-dihydrofuran (1). The dihydrofuran 1 is first oxidized by KMnO₄ to the diol 2 which is bis-alkylated to 3a-d. Reaction of the in situ generated dialdehydes with a primary amine affords the N- substituted dialkoxypyrroles 4a-m. N-Benzyl-3,4-dialkoxypyrroles and N- allyl-dialkoxypyrroles are cleaved by sodium in liquid ammonia affording N- unsubstituted dialkoxypyrroles 5a-c in good overall yield.

Full text of DOI:10.1055/s-1999-3687

9
4
PAPER
A Short and Efficient Synthesis of 3,4-Dialkoxypyrroles
Andreas Merz,* Thomas Meyer
Institut fŸr Organische Chemie der UniversitŠt Regensburg, D-93040 Regensburg, Germany
Fax: +49(941)9434121; E-mail: Andreas.Merz@chemie.uni-regensburg.de
Received 11 May 1998; revised 24 June 1998
Abstract: 3,4-Dialkoxypyrroles are obtained in four steps from
commercially available 2,5-dimethoxy-2,5-dihydrofuran (1). The
dihydrofuran 1 is first oxidized by KMnO to the diol 2 which is bis-
4
alkylated to 3aÐd. Reaction of the in situ generated dialdehydes
with a primary amine affords the N-substituted dialkoxypyrroles
4
aÐm. N-Benzyl-3,4-dialkoxypyrroles and N-allyl-dialkoxypyr-
roles are cleaved by sodium in liquid ammonia affording N-unsub-
stituted dialkoxypyrroles 5aÐc in good overall yield.
Key words: dihydroxydihydrofuran, tetraalkoxyfurans, O,N-ex-
change, N-benzyl cleavage, N-allyl cleavage
The most simple synthesis of porphyrins is the condensa-
tion of symmetric 2,5-unsubstituted pyrroles with an alde-
hyde and subsequent or concommitant dehydrogenation,1
however, the preparation of suitable precursors, e.g. 3,4-
diethylpyrrole, require several steps and only few estab-
2
lished protocols exist. Another series of suitable symmet-
ric pyrrole precursors are 3,4-dialkoxypyrroles, the
synthesis of which has only recently been accom-
3
,4
4,5
plished. A variety of octaalkoxyporphyrins have been
6
obtained, including tetra-crowned porphyrins and also
liquid crystalline species with decyloxy side chains. Fur-
7
thermore, dialkoxypyrroles are electrochemically oxi-
dized to highly conducting polypyrroles linked uniformly
in 2,5 position.8
Although substantial quantities of 3,4-dimethoxypyrrole
(
5a) can be prepared in six straightforward steps with 22%
Reagents and conditions: (a) KMnO /H O; (b) RBr or R SO /NaOH
4
2
2
4
4
total yield, this is not generally true for higher homologs.
In this paper we describe a significantly shorter synthesis or TosOH/THF/H
of N-substituted 3,4-dialkoxypyrroles 4aÐm in three
steps, and N-unsubstituted pyrroles 5 in one additional
step (Scheme).
or ROSO Me/NaH in dioxane; (c) 1. 2 N HCl or H SO for 30 min
2
2
4
O, 70¡C for 2 h, 2. then buffer to pH 6 with
2
+
Ð
NaOAc; (d) R'NH3 Cl , 25¡C, 10 to 15 h; (e) 1.2 equiv Na in liq
NH , then H O/NH Cl
3
2
4
Scheme
9
Commercial 2,5-dimethoxy-2,5-dihydrofuran (1) is a
mixture of the achiral cis and racemic trans forms with
tures of 3,4-dialkoxy-2,5-dimethoxytetrahydrofurans 3aÐ
f the configuration of 2 was actually of no importance
since in the final step of the synthesis all stereocenters are
lost.
various compositions depending on the source, e.g.
7
0:30,10 or 54:46 in this work. The oxidation of 1 with
11
KMnO yields 2 in much the same diastereomeric ratio
4
While the reaction of 2,5-dimethoxytetrahydrofuran with
primary amines in acetic acid, known as ElmingÐClaus-
of the achiral ttc and chiral cct isomers, although under
10
certain conditions cis-1 is reported to react faster. In our
hands, higher boiling fractions of 2 from simple vacuum
distillation consist of almost pure ttc-2. A third isomer
with all cis arrangement of all four substituents obviously
1
2
sonÐKaas synthesis, gives moderate to good yields of N-
substituted pyrroles, the tetraalkoxytetrahydrofurans 3aÐf
do not react under these conditions. On the other hand, the
diastereomers of 2 and 3a have been successfully used as
precursors of tropinone structures in RobinsonÐSchšpf
1
0
has been never observed. Depending on the nature of the
alkylating agent different procedures have been devel-
oped for the alkyation step. Due to the generally high
yields in these procedures to give the diastereomeric mix-
1
3,14
syntheses.
In these cases the tetrahydrofuran deriva-
tives were first hydrolyzed in aqueous mineral acid to give
the corresponding free or methylated tartaric aldehydes
Synthesis 1999, No. 1, 94Ð99 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
A Short and Efficient Synthesis of 3,4-Dialkoxypyrroles
95
which were then reacted with methylamine hydrochloride Procedure B (for 3cÐe): A mixture of 1 (20 mmol), KOH
(
0.10 mol), the corresponding alkyl bromide and solvent (40 mL)
and acetonedicarboxylic acid in buffered aqueous solution.
A bisphenylhydrazone of 2,3-dimethoxytartaric aldehyde
was isolated proving the presence of the dialdehyde. Sim-
ilarly, in the course of this work, 4-methoxypyridazine (6)
was obtained by treating the solution with hydrazine hy-
drate. When methylamine hydrochloride alone was added
to the dialdehyde solution, 3,4-dimethoxy-N-methylpyrrole
was heated under stirring for 18 h. The product was isolated by frac-
tional distillation.
14
Procedure C (for 3f): To a mixture of 2 (5 mmol) in dioxane
(15 mL) was added NaH (240 mg, 10 mmol) and the mixture str-
irred at r.t. until gas evolution had ceased. The corresponding alkyl
mesylate (10 mmol) was added and the mixture stirred for 20 h.
H O (20 mL) was added and the product extracted with Et O and
2
2
was isolated in 20% yield. Further optimization of this re- distilled.
action finally showed that good to excellent isolated yields
The analyses and spectroscopic data of 3aÐf were obtained from the
diastereomeric cct/ttc mixtures, except for 3b.
of N-substituted dialkoxypyrroles 4aÐm are obtained in a
two-phase system with chloroform.
2
2
9
,3,4,5-Tetramethoxytetrahydrofuran (3a)
0.04 g (90%); colorless oil; bp 106Ð110¡C/13 Torr (Lit:13 bp
5¡C/12 Torr).
The desired direct formation of N-unsubstituted dialkoxy-
pyrroles 5 with ammonia instead of primary amines has
not yet been achieved. Therefore it was necessary to find
N-substituents which would be easily cleaved from the
IR (film): n = 2980, 2920, 2820, 1190, 1030, 980, 940 cmÐ1.
pyrrole nitrogen. In our previous preparation of dialkoxy- 1H NMR (CDCl
, 250 MHz): ttc: d = 3.44 (s, 3 H, OCH ), 3.47 (s,
3
3
5
3 H, OCH ), 3.84 (AAÕ, 2 H, H3/H4), 5.00 (BBÕ, 2 H, H2/H5); cct:
d = 3.40 (s, 3 H, OCH ), 3.49 (s, 3 H, OCH ), 3.50 (s, 3 H, OCH ),
3
1
pyrroles, the nitrogen atom of diethyl 3,4-dihydroxypyr-
3
3
3
3
role-2,5-dicarboxylate was protected with a benzyl group
which after dialkylation was cleaved by either catalytic
hydrogenolysis or solvolysis in CF CO H/H SO but nei-
.51 (s, 3 H, OCH ), 3.65 (m, 1 H, H3), 3.91 (m, 1 H, H4), 5.00 (m,
3
H, H2), 5.05 (m, 1 H, H5).
3
2
2
4
13
C NMR (CDCl ): d = 55.50, 55.58, 56.41, 58.49, 58.55, 59.06,
3
ther method was applicable for the debenzylation of pyr-
roles 4d,h,j,k,m. However, N-debenzylation by reductive
7
9.47, 81.44, 83.42, 102.45, 105.93, 107.06.
+
+
EI-MS, 70 eV: m/z (%) = 161 (1, M Ð OCH ), 132 (2, M Ð OCH
Ð CHO), 101 (100, M Ð 2 OCH Ð CHO), 45 (32, C H O ).
3
3
cleavage with sodium in liquid NH followed by quench-
3
+
+
1
5
3
2
5
ing with aqueous NH Cl smoothly proceededto give the
4
Anal. C H O (192.2): calcd C 50.00, H 8.39; found C 49.22, H 8.08.
NH-pyrroles 5aÐc. The same method is applicable for
N-allyl pyrroles as demonstrated with 4f as a substrate.
Since the O-benzyl and O-allyl substituents of 4i,j,k,l are
likewise cleaved under these conditions, N-unsubstituted
diallyloxy- and dibenzyloxy pyrroles are, at present, not
8
16
5
3
2
,4-Diethoxy-2,5-dimethoxytetrahydrofuran (ttcÐ3b)
3.03 g (80%); colorless oil; bp 110Ð113¡C /13 Torr.
IR (film): n = 2900, 2810, 1140, 1030, 970 cmÐ1.
accessible by this method. The allyl group is also removed 1H NMR (CDCl
, 250 MHz): d = 1.24 (t, J = 7.02 Hz, 6 H,
3
1
6
OCH CH ), 3,44 (s, 6 H, OCH ), 3.62 (m, 4 H, OCH ), 3.91 (AA',
2
with stoichiometric MeMgI under Ni catalysis, but
2
3
3
2
H, H3/H4), 4.99 (BB', 2 H, H2/H5).
again, O-allyl and O-benzyl substituents are attacked as
well. A further approach for N-deprotection was attempt- 13C NMR (CDCl
): d = 15.24, 55.56, 66.27, 81.88, 107.71.
3
+
+
ed via retro-Michael cleavage of 4e but this compound
was inert to various basic conditions.
EI-MS, 70 eV: m/z (%) = 189 (5, M Ð OCH ), 160 (6, M Ð OCH
Ð CHO), 129 (69 M Ð 2 OCH Ð CHO), 115 (100, M Ð OCH Ð
3 3
OC H Ð CHO), 87 (38).
3
3
+
+
2
5
In summary we have presented a straightforward route to
symmetrical 3,4-dialkoxypyrroles.
Anal. C H O (220.3): calcd C 54.53, H 9.15, found C 53.45, H 9.01.
10 20
5
2
5
,5-Dimethoxy-3,4-dipentoxytetrahydrofuran (3c)
.78 g (95%); colorless oil; bp 95Ð115¡C/0.005 Torr.
The following analytical instruments were used: Beckman Acculab
1
2
or 2 (IR), Hitachi U 2000 (UV/Vis), Bruker AW 80, Bruker WM
50 or Bruker ARX 400 ( H NMR and C NMR spectra; TMS as
1
13
IR (film): n = 2950, 2930, 2860, 1195, 1040, 995 cmÐ1.
internal standard in CDCl unless noted otherwise); Varian MAT
3
1
H NMR (CDCl , 250 MHz): ttc: d = 0.87Ð0.92 (m, 6 H, CH ),
3
3
1
12 S (EI-MS (70 eV)); BŸchi 510 apparatus (melting points, un-
1
.27Ð1.36 (m, 8 H, CH CH ), 1.58Ð1.69 (m, 4 H, CH ), 3.43 (s, 6
2
2
2
corrected). Elemental analyses were performed by the Analytical
Laboratory of the University of Regensburg. Solvents were purified
H, OCH ), 3.71 (m, 4 H, OCH ), 3.88 (AA', 2 H, H3/H4), 4.98 (BB',
2 H, H2/H5); cct: d = 0.87Ð0.92 (m, 6 H, CH
CH CH ), 1.58Ð1.69 (m, 4 H, CH ), 3.47 (m, 4 H, OCH ), 3.48 (s,
3
2
1
7
3
), 1.27Ð1.36 (m, 8 H,
according to recommended procedures. Compound 1 was ob-
tained from Fluka, the diastereomeric mixture of 2 was prepared ac-
cording to Ref. 12, 6-(methanesulfonyloxy)hexene was prepared by
2
2
2
2
3
H, OCH ), 3,70 (m, 1 H, H4), 3,93 (m, 1 H, H3), 3.97 (s, 3 H,
3
1
8
OCH ), 5.00 (m, 1 H, H5), 5.02 (m, 1 H, H2).
3
a general procedure and used without purification.
13
C NMR (CDCl ): ttc: d = 13.95, 22.47, 28.22, 29.47, 55.54, 71.08,
3
8
2.10, 107.74; cct: d = 13.94, 13.94, 22.46, 22.46, 28.16, 28.14, 29.35,
3
,4-Dialkoxy-2,5-dimethoxytetrahydrofurans 3aÐf;
29.32, 56.07, 55.57, 71.33, 71.58, 78.20, 80.17, 102.72, 106.81.
General Procedures
Procedure A (for 3a,b): A stirred mixture of 2 (0.13 mol) and pow-
dered KOH (0.82 mol) in THF (260 mL) was heated at reflux for
+
+
EI-MS, 70 eV: m/z (%) = 244 (1, M Ð OCH Ð CHO), 213 (54, M
Ð 2 OCH Ð CHO), 157 (100, M Ð 2 OCH Ð CHO Ð C H ), 87 (79,
M Ð 2 OCH Ð CHO Ð C H Ð C H ).
3
+
3
3
4
8
1
h. Within 3 h a solution of the corresponding dialkyl sulfate
+
3
4
9
5
10
(0.39 mol) in THF (150 mL) was added. Stirring and heating were
Anal. C H O (304.4): calcd C 63.12, H 10.59, found C 63.22, H
1
16
32
5
continued for 16 h and H O (100 mL) was added. After 1 h the mix-
2
0.10.
ture was diluted with H O (600 mL) and extracted with Et O
2
2
(
150 mL) and CH Cl (4 × 150 mL). The product was purified by
2 2
3
4
,4-Diallyloxy-2,5-dimethoxytetrahydrofuran (3d)
.54 g (93%); yellowish oil; bp 92¡C/0.06 Torr.
fractional distillation in vacuo.
Synthesis 1999, No. 1, 94–99 ISSN 0039-7881 © Thieme Stuttgart · New York

9
6
A. Merz, T. Meyer
PAPER
IR (film): n = 3080, 2920, 1645, 1195, 1030, 995 cmÐ1.
isolated.14 The solution of the dialdehyde thus obtained was com-
1
bined with a suspension of NaOAc¥3H O (1.0 g, 7.1 mmol) and the
2
H NMR (CDCl , 250 MHz): ttc: d = 3.43 (s, 6 H, OCH ), 3.96
3
3
hydrochloride of the corresponding primary amine (5 mmol) in
(
AA', 2 H, H3/H4), 4.12 (m, 4 H, OCH ), 5.03 (BB', 2 H, H2/H5),
2
CHCl (15 mL), and the mixture was stirred for 24 h. The CHCl3
3
5
.25 (m, 4 H, =CH ), 5.92 (m, 2 H, CH=); cct: d = 3.42 (s, 3 H,
2
phase was washed with aq satd NaHCO solution (10 mL), dried
3
OCH ), 3.43 (s, 1 H, H4), 3.45 (s, 3 H, OCH ), 3.96 (m, 1 H, H3),
3
3
(
MgSO ) and the residue purified by chromatography with Et O
4
2
4
5
.12 (m, 4 H, OCH ), 4.94 (m, 2 H, H2/H5), 5.25 (m, 4 H, =CH ),
.92 (m, 2 H, CH=).
2
2
over a short silica gel column.
1
3
Procedure B (for 4hÐm): The hydrolysis of water insoluble 3cÐf
C NMR (CDCl ): d = 55.53, 55.55, 56.20, 71.65, 71.90, 72.04,
3
(
1
1 mmol) was performed in a mixture of CF CO H (77 mL,
3 2
7
1
6.55, 76.96, 78.88, 81.31, 102.64, 106.66, 107.64, 117.38, 117.62,
17.71, 134.35, 134.60.
mmol), and H O (150 mL) for 50 to 90 min. CHCl (20 mL), solid
2 3
NaOAc¥3 H O (0.96 g, 7 mmol) and the amine (5.0 mmol) were
2
+
EI-MS, 70 eV: m/z (%) = 153 (10, M Ð 2 OCH Ð CHO), 127 (23,
M Ð OCH Ð CHO Ð C H O), 112 (8, M Ð 2 OCH Ð CHO Ð C H ),
9
3
added subsequently and the mixture was stirred for 24 h at r.t. The
product was isolated and purified by column chromatography on
silica gel.
+
+
3
3
5
3
3
5
+
+
7 (16, M Ð 2 OCH Ð CHO Ð C H O + H), 85 (1, M Ð 2 OCH Ð
3 3 5 3
+
C H O Ð C H ), 41 (100, C H ).
3
5
3
6
3
5
Anal. C H O (244.3): calcd C 59.00, H 8.25, found C 56.92, H
3,4-Dimethoxy-1-methylpyrrole (4a)
Pale yellow oil; 74 mg (79%) from a 127 mg 3a, spectroscopic data
as given in Ref. 3.
1
2
20
5
7
.98.
3
,4-Dibenzyloxy-2,5-dimethoxytetrahydrofuran (3e)
5
.88 g (85%); bp 160Ð162¡C/0.01 Torr.
3,4-Dimethoxy-1-propylpyrrole (4b)
IR (film): n = 3090 vw, 3060, 3030, 2912, 1199, 992 cmÐ1.
Pale yellow oil; 327 mg (74%) from 500 mg 3a.
IR (Film): n = 3160, 3120, 2990, 1590, 1570, 1560 cmÐ1.
1
H NMR (CDCl , 250 MHz): ttc: d = 3.40 (s, 6 H, OCH ), 3.99
3
3
1
(
AA', 2 H, H3/H4), 4.59 (d, J = 12.14 Hz, 2 H, PhCH ), 4.64 (d, J
H NMR (CDCl , 250 MHz): d = 0.89 (t, 3 H, CH , J = 7.38 Hz,),
A
3
3
=
12.4 Hz, 2 H, PhCH ), 5.04 (BB', 2 H, H2/H5), 7.24Ð7.42 (m, 10
1.72 (m, 2 H NCH CH CH ), 3.62 (t, 2 H, NCH , J = 7.03 Hz), 3.73
B
2 2 3 2
H, Ph); cct: d = 3.30 (s, 3 H, OCH ), 3.51 (s, 3 H, OCH ), 3.73 (m,
(s, 6 H, OCH ), 6.09 (s, 2H, 2,5-Pyrrole-H).
3
3
3
1
4
H, H3), 3.95 (m, 1 H, H4), 4.57 (d, J = 12.19 Hz, 1 H, PhCHA),
+
+
EI-MS, 70 eV: m/z (%) = 169 (100, M ), 154 (33,M Ð CH ), 140
3
.64 (d, J = 12.19 Hz, 1 H, PhCH ), 4.66 (d, J = 12.53 Hz, 1 H, Ph-
+
+
B
(
32, M Ð C H ), 126 (31, M Ð C H ).
2 5 3 7
CH ), 4.71 (d, J = 12.53 Hz, 1 H, PhCH ), 4.95 (m, 1 H, H2), 4.99
C
D
Anal. C H NO (169.2): calcd C 63.88, H 8.93, N 8.28, found C
(m, 1 H, H5), 7.24Ð7.42 (m, 10 H, Ph).
9
15
2
6
1.91, H 8.93, N 7.45.
EI-MS, 70 eV: m/z (%) = 106 (45, PhCHO), 105 (43, PhCO), 91
+
+
(
100, C H ), 77 (53, C H ).
7 7 6 5
1
-(tert-Butyl)-3,4-dimethoxypyrrole (4c)
Anal. C H O (344.4): calcd C 69.75, H 7.02, found C 70.09, H
2
0
24
5
413 mg (87%) from 500 mg 3a; mp 74¡C.
IR (KBr): n = 3160, 3120, 2990, 1575, 1508 cmÐ1.
6
.94.
1
H NMR (CDCl , 250 MHz): d = 1.45 (s, 9 H, CH ), 3.74 (s, 6 H,
3
1
,4-Bis(hex-1-en-6-oxy)-2,5-dimethoxytetrahydrofuran (3f)
.42 g (87%); bp 100Ð110¡C/ 0.04 Torr.
3
3
OCH ), 6.25 (2 H, 2,5-Pyrrole-H).
3
13
IR (film): n = 3075, 2925, 1647, 1145, 995 cmÐ1.
C NMR (CDCl ): d = 30.10, 54.40, 58.62, 99.58, 137.18.
3
+
+
1
EI-MS, 70 eV: m/z (%) = 183 (60, M ), 168 (18, (M Ð CH ), 127
3
(
H NMR (CDCl , 250 MHz): ttc: d = 1.39Ð1.68 (m, 8 H, CH CH ),
3
2
2
+
+
89, M Ð C H ), 112 (100, M Ð C H , Ð CH ).
2
.02Ð2.12 (m, 4 H, CH CH=CH ), 3.43 (s, 6 H, OCH ), 3.54 (dd, J
4 8 4 8 3
2
2
3
1
=
6.48 Hz, J = 0.91 Hz, 4 H, OCH ), 3.87 (AA', 2 H, H3/H4), 4.97
2 2
Anal. C H NO (183.3): calcd C 65.54, H 9.35, N 7.64, found C
10 17 2
64.84, H 8.99, N 7.37.
(BB', 2 H, H2/H5), 4.91Ð5.04 (m, 4 H, =CH ), 5.80 (ddt, J = 16.97
2 1
Hz, J = 10.16 Hz, J = 6.96 Hz, 2 H, CH=CH ); cct: d = 1.39Ð1.68
2
3
2
(m, 8 H, CH CH ), 2.02Ð2.12 (m, 4 H, CH CH=), 3.42 (s, 3 H,
2
2
2
1-Benzyl-3,4-dimethoxypyrrole (4d)
Colorless oil; 484 mg (73%) from 585 mg 3a.
IR (film): n = 3170, 3140, 3100, 3060, 3030, 2980, 1590, 1560 cmÐ1.
OCH ), 3.45 (s, 3 H, OCH ), 3.50Ð3.64 (m, 4 H, OCH ), 3.68Ð3.71
3
3
2
(
m, 1 H, H4), 3.90Ð3.93 (m, 1 H, H3), 4.91Ð4.96 (m, 4 H, =CH2),
.98Ð5.00 (m, 1 H, H5), 5.02Ð5.06 (m, 1 H, H2), 5.71Ð5.88 (m, 2 H,
CH=).
4
1
H NMR (CDCl , 250 MHz): d = 3.72 (s, 6 H, OCH ), 4.85 (s, 2 H,
2
3
3
13
CH Ph), 6.12 (s, 2 H, 2,5-Pyrrole-H), 7.08Ð77.12 (m, 2 H, Ph),
C NMR (CDCl ): d = 25.26, 25.31, 25.37, 29.08, 29.11, 29.24,
3
7
.23Ð7.36 (m, 3 H, Ph).
3
8
1
3.37, 33.40, 33.47, 55.36, 55.57, 55.80, 70.84, 71.14, 74.25, 80.20,
2.13, 82.99, 102.68, 107.71, 108.16, 109.77, 114.48, 114.77,
38.33, 138.66, 138.73.
1
3
C NMR (CDCl ): d = 54.10, 58.60, 103.08, 126.96, 127.60,
3
128.65, 137.85, 138.34.
+
+
+
+
MS-EI, 70 eV: m/z (%) = 297 (2, M ÐOCH ), 237 (18, M Ð2 OCH Ð
EI-MS, 70 eV, m/z (%) = 217 (26, M ), 202 (10, M Ð CH ), 91
3
3
+ Ð
3
+
Ð
+
CHO), 185 (14), 169 (64, M 2 OCH CHOÐC H ), 155 (3, M
OCH Ð CHO Ð C H ), 87 (81, M Ð 2 OCH Ð CHO Ð C H
2
Ð
(100, C H ).
3
Ð
5
8
7
7
+
3
6
10
3
6
10
Anal. C H NO (217.3): calcd C 71.87, H 6.96, N 6.45, found C
13
15
2
C H ), 54 (100).
5
8
7
1.64, H 7.06, N 6.42.
Anal. C H O (328.5): calcd C 65.28, H 9.82; found C 63.99, H
1
8
32
5
9
.42.
1
-(2-Cyanoethyl)-3,4-dimethoxypyrrole (4e)
Colorless oil; 296 mg (71%) from 443 mg 3a.
IR (film): n = 3150, 3110, 2940, 2250, 1580, 1510 cmÐ1.
N-substituted 3,4-Dialkoxypyrroles 4aÐm; General Procedures
Procedure A (for 4aÐg): The water soluble ether acetals 3aÐb
1H NMR (CDCl
, 250 MHz): d = 2.69 (t, 2 H, NCH
, J = 6.62 Hz),
2
(
1 mmol) were hydrolyzed with aq 2N HCl or H SO (0.34 mmol)
3
2
4
at 70¡C for 30 min. From an aliquot of the hydrolysis solution the
bisphenylhydrazone of dimethoxytartaric aldehyde, mp 124¡C was
3.73 (s, 6 H, OCH
H, 2,5-Pyrrole-H).
3
), 3.99 (t, 2 H, CH CN, J = 6.62 Hz), 6.13 (s, 2
2
Synthesis 1999, No. 1, 94–99 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Short and Efficient Synthesis of 3,4-Dialkoxypyrroles
97
1
3
C NMR (CDCl ): d = 20.40, 46.12, 58.57, 102.23, 117.27, 138.58. Hz, 1 H, NCH CH=CH ), 6.06 (ddt, J = 17.28 Hz, J = 10.31 Hz,
3
2
2
1
2
+
+
J
3
= 5.58 Hz, 2 H, OCH
2
CH=CH
), 6.10 (s, 2 H, 2,5-Pyrrole-H).
2
EI-MS, 70 eV: m/z (%) = 180 (87, M ), 165 (45, M Ð CH ), 140
(
3
+
+
13
100, M Ð CH CN), 125 (24, M Ð CH Ð CH CN).
C NMR (CDCl ): d = 52.77, 72.65, 104.16, 116.99, 117.24,
2
3
2
3
1
34.38, 134.40, 136.52.
Anal. C H N O (180.2) calcd C 60.00, H 6.71, N 15.55; found C
5
9
12
2
2
+
+
9.85; H 6.83; N 15.34.
EI-MS, 70 eV: m/z (%) = 219 (42, M ), 178 (87, M Ð C H ), 150
49, M Ð C H , Ð CO), 41 (100, C H ).
3
5
+
+
(
3 5 3 5
1
-Allyl-3,4-dimethoxypyrrole (4f)
Anal. C H NO (219.3) calcd C 71.21, H 7.81, N 6.39, found C
13
17
2
Colorless oil; 585 mg (65%) from 1.04 g of 3a.
IR (film): n = 3120, 3090, 3080, 2980, 1570, 1540 cmÐ1.
6
8.98, H 7.62, N 5.96.
1
1-Benzyl-3,4-diallyloxypyrrole (4j)
Pale yellow oil; 811 mg (74%) from 1.00 g of 3d.
IR (film): n = 3137, 3084, 3028, 2983, 1647, 1577, 1554 cmÐ1.
H NMR (CDCl , 250 MHz): d = 3.73 (s, 6 H, OCH ), 4.27 (ddd, 2 H,
3
3
NCH , J = 5.79 Hz, J = 1.56 Hz, J = 1.56 Hz), 5.14 (ddt, 1 H,
=
=
Hz, J = 10.23 Hz, J = 5.79 Hz, 1 H, NCH CH=CH ), 6.09 (s, 2 H, 2,5-
Pyrrole-H).
2
1
2
3
CHtrans, J = 16.89 Hz, J = 1.56 Hz, J = 1.56 Hz), 5.18 (ddt, 1 H,
1 2 3
CH , J = 1.43 Hz, J = 1.43 Hz, J = 10.23 Hz), 5.93 (ddt, J = 16.89
1
cis
2
3
1
1
H NMR (CDCl , 250 MHz): d = 4.42 (ddd, J = 5.65 Hz, J =
3
1
2
2
3
2
2
1
.47 Hz, J = 1.54 Hz, 4 H, OCH ), 4.83 (s, 2 H, CH Ph), 5.23 (ddt,
3 2 2
J = 10.44 Hz, J = 1.47 Hz, J = 1.52 Hz, 2 H, =CH ), 5.36 (ddt,
1
2
3
cis
13
C NMR (CDCl ): d = 52.84, 58.61, 102.55, 117.33, 134.42,
J = 17.44 Hz, J = 1.54 Hz, J = 1.52 Hz, 2 H, =CHtrans), 6.04 (ddt,
3
1 2 3
1
37.63.
J = 17.44 Hz, J = 10.44 Hz, J = 5.65 Hz, 2 H, CH CH=CH ), 6.13
1 2 3 2 2
+
+
(s, 2 H, 2,5-Pyrrole-H), 7.06Ð7.11 (m, 2 H, Ph), 7.24Ð7.37 (m, 3 H,
Ph).
MS-EI, 70 eV: m/z (%) = 167 (100, M ), 152 (83, M Ð CH ), 136
(
3
+
+
+
17, M Ð OCH ), 126 (12, M Ð C H ), 41 (97, C H ).
3 3 7 3 7
1
3
C NMR (CDCl ): d = 54.05, 72.62, 104.72, 117.10, 126.88,
3
Anal. C H NO (167.2) calcd C 64.65, H 7.84, N 8.38, found C
9
13
2
1
27.57, 128.62, 134.35, 136.75, 138.36.
6
4.39, H 7.68, N 8.36.
+
+
EI-MS, 70 eV, m/z (%) = 269 (6, M ), 228 (17, M Ð C H ), 200 (7,
3
5
+
+
1
-tert-Butyl-3,4-diethoxypyrrole (4g)
M Ð C
3 5 7 7
H , Ð CO), 91 (100, C H ).
Yellowish oil; 1.27 g (81%) from 1.63 g 3b.
IR (film): n = 3150, 2980, 1570, 1545 cmÐ1.
Anal. C H NO (269.3) calcd C 75.81, H 7.11 N 5.20, found C
74.96 H 6.98, N 4.94.
17
19
2
1
H NMR (CDCl , 250 MHz): d = 1.37 (t, 6 H, OCH CH , J = 7.00
3
2
3
1
-Benzyl-3,4-dibenzyloxypyrrole (4k)
Hz), 1.43 (s, 9 H, CH ), 3.93 (q, 2 H, OCH , J = 7.00 Hz,), 6.24 (s,
3
2
Colorless crystals; 395 mg (66%) from 559 mg 3f; mp 82Ð83¡C.
IR (KBr): n = 3135, 3087, 3062, 3030, 2922, 1575, 1553 cmÐ1.
2
H, 2,5-Pyrrole-H).
13
C NMR (CDCl ): d = 30.10, 54.29, 55.59, 66.95, 100.62, 136.22.
3
1H NMR (CDCl
H, OCH Ph), 6.09 (s, 2 H, 2,5- Pyrrole-H), 7.00Ð7.46 (m, 15 H, Ph).
, 250 MHz): d = 4.78 (s, 2 H, NCH Ph), 4.95 (s, 4
3 2
+
+
EI-MS, 70 eV: m/z (%) = 211 (100, M ), 196 (19, M Ð CH ), 182
3
+
+
+
2
(14, M Ð C H ), 155 (33, M Ð C H ), 126 (95, M Ð C H , Ð C H ).
2 5 4 8 4 8 2 5
1
3
C NMR (CDCl ): d = 54.01, 73.81, 105.29, 126.80, 127.53,
3
Anal. C H NO (211.3) calcd C 68.21, H 10.02, N 6.63, found C
1
2
21
2
1
27.66, 127.73, 128.30, 128.62, 136.93, 137.93, 138.34.
6
5.30; H 9.68; N 6.21.
+
+
EI-MS, 70 eV: m/z (%) = 369 (8, M ), 278 (29, M Ð C H ), 91 (100,
7
7
+
C H ).
1
-Benzyl-3,4-dipentoxypyrrole (4h)
7
7
Colorless oil; 350 mg (77%) from 321 mg 3c.
IR (film): n = 3140, 3090, 3064, 3030, 2950, 1580, 1555 cmÐ1.
Anal. C H NO (369.5) calcd C 81.27, H 6.27, N 3.79, found:
C 80.81, H 6.04, N 3.64.
25
23
2
1
H NMR (CDCl , 250 MHz): d = 0.92 (t, 6 H, CH , J = 7.01 Hz),
3
3
1
-Allyl-3,4-dibenzyloxypyrrole (4l)
1
.30Ð1.80 (m, 12 H, CH CH CH ), 3.83 (t, 4 H, OCH , J = 6.73
2 2 2 2
Yellow oil; 508 mg (38%) from 1.42 g of 3f.
IR (film): n= 3140, 3087, 3064, 3031, 2911, 1643, 1574, 1553 cmÐ1.
Hz), 4.83 (s, 2 H, CH Ph), 6.11 (s, 2 H, 2,5-Pyrrole-H), 7.08Ð7.12
2
(m, 2 H, Ph), 7.23Ð7.37 (m, 3 H, Ph).
1
3
1
C NMR (CDCl ): d = 14.00, 22.50, 28.22, 29.22, 53.37, 54.03,
H NMR (CDCl , 250 MHz): d = 4.20 (ddd, J = 5.68 Hz, J =
3
3
1
2
7
1.79, 104.33, 126.90, 127.51, 128.60, 137.20, 138.52.
1.68 Hz, J = 1.41 Hz, 2 H, NCH ), 4.96 (s, 4 H, OCH Ph), 5.05
3
2
2
+
+
(ddt, J
(ddt, J
ddt, J1 = 16.99 Hz, J2 = 10.19 Hz, J3 = 5.68 Hz, 1 H,
NCH CH=CH ), 6.0 (s, 2 H, 2,5-Pyrrole-H), 7.24Ð7.44 (m, 10 H,
1
= 16.99 Hz, J
= 10.19 Hz, J
2
= 1.39 Hz, J
3
= 1.68 Hz, 1 H, =CHtrans), 5.13
EI-MS, 70 eV: m/z (%) = 329 (5, M ), 258 (19, M Ð C H ), 189
5
11
+
+
1
2
= 1.39 Hz, J
3
= 1.41 Hz, 1H, =CHcis), 5.87
(
23, M Ð 2 × C H ), 91 (100, C H ).
5 10 7 7
(
Anal. C H NO (329.5) calcd C 76.55, H 9.48, N 4.25, found C
2
1
31
2
2
2
7
4.03, H 9.21, N 4.24.
Ph).
1
3
C NMR (CDCl ): d = 52.73, 73.88, 104.67, 117.22, 127.62,
3
1
-Allyl-3,4-diallyloxypyrrole (4i)
1
27.64, 128.29, 134.33, 136.81, 138.02.
Yellowish oil; 1.51 g (86%) from 1.96 g 3d.
IR (film): n = 3137, 3082, 3014, 2983, 1646, 1576, 1553 cmÐ1.
+
+
EI-MS, 70 eV: m/z (%) = 319 (13, M ), 228 (40, M Ð C H ), 200
7
7
+
+
(
29, M Ð C H Ð CO), 91 (100, C H ).
7 7 7 7
1
H NMR (CDCl , 250 MHz): d = 4.25 (ddd, J = 5.88 Hz, J =
3
1
2
Anal. C H NO (319.4) calcd C 78.97; H 6.63; N 4.39; found C
21
21
2
1
1
1
.51 Hz, J = 1.44 Hz, 2 H, NCH ), 4.41 (ddd, J = 5.58 Hz, J =
3 2 1 2
7
8.23, H 6.65, N 4.17.
.46 Hz, J = 1.52 Hz, 2 H, OCH ), 5.17 (ddt, J = 10.31 Hz, J =
3
2
1
2
.44 Hz, J = 1.19 Hz, 1 H, NCH CH=CH ), 5,21 (ddt, J = 10,54
3
2
cis
1
1
-Benzyl-3,4-bis(hex-1-en-5-oxy)pyrrole (4m)
Colorless oil; 234 mg (45%) from 486 mg 3e. IR (film): n = 3135,
074, 3030, 2935, 1640, 1579, 1553 cm .
Hz, J = 1.61 Hz, J = 1.46 Hz, 2 H, OCH CH=CH ) 5.31 (ddt, J
2
3
2
cis
1
=
16.78 Hz, J = 1.51 Hz, J = 1.19 Hz, 1 H, NCH CH=CHtrans),
2 3 2
Ð1
3
5
.35 (ddt, J1 = 17.28 Hz, J2 = 1.61 Hz, J3 = 1.52 Hz, 2 H,
1
OCH CH=CH ), 5.91 ddt, J = 16.78 Hz, J = 10.31 Hz, J = 5.88
H NMR (CDCl , 250 MHz): d = 1.54Ð2.09 (m, 12 H,
CH CH CH ), 3.84 (t, J = 6.55 Hz, 2 H, OCH ), 3.84 (s, 2 H,
2
trans
1
2
3
3
2
2
2
2
Synthesis 1999, No. 1, 94–99 ISSN 0039-7881 © Thieme Stuttgart · New York

9
8
A. Merz, T. Meyer
PAPER
CH Ph), 4.94 (ddt, J = 10.16 Hz, J = 2.13 Hz, J = 1.24 Hz, 2 H,
3,4-Dimethoxypyrrole (5a) by Ni-Catalyzed Deallylation of 4f
A solution of 4f (297 mg, 1.78 mmol) in anhyd benzene (2 mL) was
added to a suspension of bis(triphenylphosphine)nickel dichloride
(116 mg, 0.177 mmol) and 1.77 M ethereal MeMgI (1.27 mL,
2
1
2
3
=
=
CH ), 5.00 (ddt, J = 17.12 Hz, J = 2.13 Hz, J = 1.59 Hz, 2 H,
cis 1 2 3
CHtrans), 5.81 (ddt, J = 17.12 Hz, J = 10.16 Hz, J = 6.63 Hz, 2
1
2
3
H, CH=CH ), 6.11 (s, 2 H, 2,5-Pyrrole-H), 7.05Ð7.10, 2 H, Ph),
2
7
.23Ð7.35 (m, 3 H, Ph).
2.25 mmol) in anhyd benzene (2.5 mL) und anhyd Et O (3.5 mL)
2
1
3
and strirred for 20 h at reflux temperature. EtOH (1 mL) and H O
2
C NMR (CDCl ): d = 25.35, 28.98, 33.47, 54.04, 104.37, 114.46,
3
(
15 mL) were added and the product was extracted with Et O; yield:
2
1
26.91, 127.53, 128.60, 137.14, 138.44, 138.74.
1
19 mg (53%).
+
+
EI-MS, 70 eV: m/z (%) = 353 (8, M ), 270 (32, M Ð C H ), 242
(
6
11
+
+
+
10, M Ð C H , Ð CO), 189 (33, M Ð 2 C H ); 91 (100, C H ).
6 11 6 9 7 7
Multigram Preparation of 5a
A solution of 3a (9.72 g, 0.05 mmol) in 1 M H SO (8.14 mL) was
Anal. C H NO (353.5) calcd C 78.15, H 8.84, N 3.96; found: C
1
3
31
2
2
4
7
7.77; H 8.72; N 4.10.
heated at 85¡C for 30 min during which time a MeOH/ H O mixture
2
(
ca 2 mL) was distilled at maximum 85¡C head temperature. The
residue was cooled to r.t. and added to a well stirred suspension of
benzylammonium hydrochloride (35.6 g, 0.25 mol) in H O (15 mL)
3
,4-Dialkoxypyrroles 5aÐc by N-Debenzylation:
General Procedure
The pyrrole (5 mmol) in anhyd THF (5 mL) was added dropwise to
a solution of sodium (230 mg, 10 mmol) in liquid ammonia (ca.
2
and CHCl (300 mL) and stirred for 17 h. The CHCl phase was
3
3
washed with satd aq NaHCO solution (2 × 100 mL) and dried
3
(
MgSO ). After removal of the solvent the solid residue was puri-
5
0 mL) at Ð78¡C. When the blue colour had faded (1.5 to 2.5 h) aq
4
fied by sublimation (80¡C/0.01 Torr) to give 9.3 g (84%) of 4d. A
THF solution (50 mL) of 4d was slowly added to a solution of Na
NH Cl (535 mg in 30 mL H O) was carefully added. After evapo-
4
2
ration of NH the aquoeus phase was extracted with CH Cl . The
3
2
2
(
2.0 g) in liquid NH (300 mL). After 4h, workup as given above
pyrroles were purified by chromatography on a silica gel column
3
gave 5.0 g of 5a (94%) after sublimation.
using Et O as an eluent.
2
4
-Methoxypyridazine (6)
To the hydrolyzed and buffered solution (procedure A) from 3a
0.392 g, 2.04 mmol) was added hydrazine sulfate (1.33 g,
0.2 mmol) and the mixture heated at 95¡C for 36 h. Extraction
with Et O yielded 0.18 g oil (80 %) which crystallized on cooling;
3
,4-Dimethoxypyrrole (5a)
3
Colorless crystals; 125 mg (94%) from 285 mg 4d; mp 93¡C (Lit:
mp 93Ð94¡C) or 127 mg (78%) from 240 mg of 4f.
(
1
3
,4-Dipentoxypyrrole (5b)
Colorless crystals; 212 mg (94%) from 312 mg of 4h; mp 36¡C
pentane).
2
19
20
mp 40¡C (Lit. 42Ð44¡C, mp 32Ð36¡C ).
IR (KBr): n = 3090, 2980, 1580, 1380, 1310cmÐ1.
(
IR (KBr): n = 3403, 3140, 2960, 1587, 1547 cmÐ1.
1
H NMR: d = 3.93 (s, 3 H, OCH ), 6.88Ð6.92 (m, 1 H, H5), 8.92Ð
3
1
8.99 (m, 2 H, H3/H6).
H NMR (CDCl , 250 MHz): d = 0.88Ð0.94 (m, 6 H, CH ), 1.29Ð
3
3
+
1
.48 (m, 8 H, CH CH ), 1.64Ð1.88 (m, 4 H, OCH CH ), 3.86 (t, 4
EI-MS, 70 eV: m/z (%) = 116 (100, M ), 52 (42), 39 (65).
2
2
2
2
H, OCH , J = 6.74 Hz), 6.21 (d, J = 3.24 Hz, 2 H, 2,5-Pyrrole-H),
2
6
.97 (br, 1 H, NH).
Acknowledgement
13
C NMR (CDCl ): d = 13.97, 22.48, 28.20, 29.19, 71.74, 100.97,
3
1
37.72.
Financial support of this work by the Deutsche Forschungsgemein-
schaft and the Fonds der Chemischen Industrie are gratefully
acknowldeged.
+
+
EI-MS, 70 eV: m/z (%) = 239 (3, M ), 168 (6 M Ð C H ), 125 (8,
M Ð 2 C H ), 99 (100, M Ð 2 C H ).
5
11
+
+
4
9
5
9
Anal. C H NO (239.4) calcd C 70.25, H 10.53, N 5.85; found C
1
4
25
2
7
0.32, H 10.61, N 10.38.
References
(
1) Rothemund, P.J. J. Am. Chem. Soc. 1935, 57, 2010.
Fischer, H.; Gleim, W. Liebigs Ann. Chem. 1936, 521, 157.
Cheng, D.O.; LeGoff, E. Tetrahedron Lett. 1977, 17, 1769.
Lindsay, J.S.; Schreiman, I.C.; Hsu, H.C.; Kearney, P.C.;
Marguerettaz, A.M. J. Org. Chem. 1987, 52, 827.
3
,4-Bis(hex-1-en-5-oxy)pyrrole (5c)
Colorless oil; 100 mg (53%) from 255 mg 4j; mp 26¡C (pentane).
IR (film): n = 3392, 3180, 3147, 2942, 1641, 1586, 1548 cmÐ1.
1
H NMR (CDCl , 250 MHz): d = 1.48Ð1.60 (m, 4 H, CH ), 1.72Ð
3
2
Treibs A.; HŠberle N. Liebigs Ann. 1968, 178, 183.
1
.84 (m, 4 H, CH ), 2.06Ð2.15 (m, 4 H, CH ), 3.87 (t, 4 H, J = 6.59
2
2
(
(
(
2) Sessler, J. J.; Mozzafari, M. R. Org. Synth. 1992, 70, 68.
3) Merz, A.; Schwarz, R. Adv. Mater. 1992, 4, 409.
4) Merz, A.; Schropp, R.; Lex, J. Angew. Chem. 1993, 105, 296;
Angew. Chem., Int. Ed. Engl. 1993, 32, 291.
Hz, OCH ), 4.95 (ddt, J = 10,20 Hz, J = 2.14 Hz, J = 1.28 Hz, 2
H, =CH ), 5.01 (ddt, J = 17.16 Hz, J = 2.14 Hz, J = 1.56 Hz, 2
H, =CHtrans), 5,82 (ddt, J = 17.16 Hz, J = 10.19 Hz, J = 6.61 Hz,
2
2
1
2
3
cis
1
2
3
1
2
3
H, =CH), 6.21 (d, J = 3.18 Hz, 2 H, 2,5-Pyrrole-H), 6.99 (br, 1 H,
(
(
5) Merz, A.; Schropp, R.; Dštterl, E. Synthesis 1995, 795.
6) Dštterl E., Ph.D. Dissertation, University of Regensburg,
NH).
13
C NMR (CDCl ): d = 25.36, 28.96, 33.47, 71.51, 101.00, 114.48,
3
1
996.
1
37.65, 138.74.
Murashima, T.; Uchihara, Y.; Wakamori, N.; Uno, H.;
Ogawa, T.; Ono, N. Tetrahedron Lett. 1996, 37, 3133.
+
+
EI-MS, 70 eV: m/z (%) = 263 (26, M ), 180 (11, M Ð C H ), 152
6
11
+
+
(8, M Ð C H Ð CO), 99 (100, M Ð 2 × C H ).
(7) Murashima T.; Wakamori, N.; Uchihara Y.; Ogawa, T.; Uno,
H.; Ono, N. Mol. Cryst. Liq. Cryst. 1996, 278, 165.
Merz, A.; Dštterl, E.; Kronberger, J.; Meier, H.; Lex, J. In
XVIIth European Colloquium on Heterocyclic Chemistry,
Program and Poster Abstracts; (ISBN 3-931253-007): Re-
gensburg, 1996, p. 138.
6
11
6
9
Anal. C H NO (263.4) calcd C 72.97, H 9.57, N 5.32; found C
7
1
6
25
2
3.55, H 9.64, N 5.07.
Synthesis 1999, No. 1, 94–99 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Short and Efficient Synthesis of 3,4-Dialkoxypyrroles
99
(
8) Merz, A.; Graf, S. J. Electroanal. Chem. 1996, 412, 11.
Gassner, F.; Graf. S.; Merz, A. Synth. Metals 1997, 87, 75.
9) Clauson-Kass, N.; Limborg, F. Acta Chem. Scand. 1952, 6,
(13) Kebrle, J.; Karrer, P. Helv. Chim. Acta 1954, 37, 484;
(14) Zeile, K.; Heusner, A. Chem. Ber. 1954, 87, 439.
(15) Baroni, S.; Stradi, R. J. Heterocycl. Chem. 1980, 17, 1221.
(16) Wenkert, E.; Angell C.H.; Ferreira, V.F.; Michelotti E.L.;
Piettre, S.R.; Sheu, J.H.; Swindel, C.S. J. Org. Chem. 1986,
51, 2343.
(
5
51.
Clauson-Kaas, N.; Tyle Z. ibid. 1952, 6, 667.
Nielsen, J.T.; Elming, N.; Clauson-Kaas N., ibid. 1958, 12,
6
3.
(17) Perrin, D. D.; Amarego, W.C.F.; Perrin, D.R. Purification of
Laboratory Chemicals, Pergamon: Oxford, 1980.
(18) Merz, A.; Karl, A.; Futterer, T.; Stacherdinger, N.; Schneider,
O.; Lex, J.; Luboch, E.; Biernat, J. Liebigs Ann. Chem., 1994,
1199.
Burness, D.M. Org. Synth. 1972, Coll. Vol. 5, 403.
(
(
10) Hšnel, M.; Mosher, H.S. J. Org. Chem. 1985, 50, 4396.
11) Villacampa, M.; Martinez, M.; Gonz‡les-Triogo, G.; Sšllhu-
ber, M. M. J. Heterocyclic Chem. 1992, 29, 1541.
(
12) Elming, N.; Clauson-Kaas, N. Acta Chem. Scand. 1952, 6,
(19) Natsume, Y; Itai, T. Chem. Pharm. Bull. 1963, 11, 83.
(20) Katritzky, A.R.; Pojarlieff I. J. Chem. Soc. B 1968, 873.
8
70.
Synthesis 1999, No. 1, 94–99 ISSN 0039-7881 © Thieme Stuttgart · New York