An Improved Method for the Preparation of 1-Methyl-2-formyl-5-bromopyrrole

Article abstract of DOI:10.1039/a803388i

1-Methyl-2-formyl-5-bromopyrrole 1 was prepared in 48% total yield by initial bromination of the intermediate 1-methyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)pyrrole 5 with N-bromosuccinimide to give the intermediate 1-methyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)-5-bromopyrrole 6, which was finally hydrolyzed to the product 1.

Full text of DOI:10.1039/a803388i

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786 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 786±787$
An Improved Method for the Preparation of
1-Methyl-2-formyl-5-bromopyrrole$
Roderick Hai-Ying He and Xi-Kui Jiang*
Shanghai Institute of Organic Chemistry, Academia Sinica, 354 Feng-Lin Lu, Shanghai 200032,
China
1-Methyl-2-formyl-5-bromopyrrole 1 was prepared in 48% total yield by initial bromination of the intermediate
1-methyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)pyrrole 5 with N-bromosuccinimide to give the intermediate 1-methyl-2-
(5,5-dimethyl-1,3-dioxan-2-yl)-5-bromopyrrole 6, which was finally hydrolyzed to the product 1.
In our ®rst study of the correlation of UV spectra of
heterocyclic aromatic compounds, i.e. 1-methyl-2-formyl-5-
Y-substituted pyrroles,1,2 it was necessary for us to prepare
1-methyl-2-formyl-5-bromopyrrole 1. However, there are
few reports about the bromination of pyrrolecarbaldehyde,
although various types of brominating agents, i.e. molecular
bromine, the bromonium ion, and the bromine atom, have
been described.3
After careful repetition of the reported reaction, the melting
point of pure 3 obtained in our laboratory was again found
to be 50±51 8C. Therefore, the main pure product isolated
from the reaction of 2 and NBS was demonstrated as 3.
The close Rf value and boiling point of 1 (Rf = 0.94) and
4 (Rf = 0.90) made it impossible to separate them either
by common column chromatography or by vacuum distilla-
tion. Although pure 1 could be isolated by reducing the
relative amount of NBS, the yield (ca. 7%) was too low for
synthetic purposes.
An early report4 on the bromination of 2-formylpyrrole
involved the use of bromine in carbon tetrachloride (see
Scheme 1). it was found that the electron-withdrawing
formyl group provided a 4-directing e€ect. For example, the
bromination reaction at 0 8C, with equimolar 2-formyl-
pyrrole and bromine, gave 2-formyl-4-bromopyrrole and
2-formyl-5-bromopyrrole in 60.7% and only 2.1% yield,
respectively. Bromine attack is much less selective at the
boiling point of carbon tetrachloride, and the amount of
5-bromo product approached that of 4-bromo product
(yield: ca. 20%); 2-formyl-4,5-dibromopyrrole was formed
simultaneously, and this made it dicult to purify each
component of the product mixture by column chromatog-
raphy.
Scheme 2 aIsolated yield of pure product; byield evaluated
from 1H NMR spectrum
Since an electron-withdrawing group often directs the
substitution to the 4-position while an electron-releasing
group directs the substitution to the 5-position,7 it would be
interesting to ®nd out what would happen if the electron-
withdrawing formyl group were converted to the dioxanyl
group. This idea inspired us to look for a new method for
the preparation of 1 (see Scheme 3).
Scheme 1
Another report by Meakins5 on the bromination of
1-methyl-2-formylpyrrole 2 involved the use of bromine and
AlCl3. With equimolar 2 and Br2, only 1-methyl-2-formyl-4-
bromopyrrole 3 was formed.
Since the above-mentioned regioselectivity of bromination
was poor, we ®rst attempted the Vilsmeier formylation
of 1-methyl-2-bromopyrrole with POCl3±DMF (DMF ˆ
dimethylformamide).6 However, no detectable amount of
1-methyl-2-formyl-5-bromopyrrole 1 was formed. We then
attempted the direct bromination of 2 with N-bromosuccin-
imide (NBS) (see Scheme 2). With equimolar 2 and NBS,
the reaction gave one product which could be isolated pure
together with a mixture of 1 and 1-methyl-2-formyl-4,5-
Scheme 3
By azeotropic distillation of 2 with 2,2-dimethylpropane-
1,3-diol, 1-methyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)pyrrole 5
could be obtained in 75% yield. With equimolar 5 and
NBS, the reaction gave one product 6 in 71% yield. Mass
spectrometry clearly showed only one molecular ion peak
for the monobromo product and the 1H NMR spectrum
showed that the bromine atom was at the 5-position. Acid
hydrolysis of 6 could easily produce the original formyl
group and 1 was obtained in 90% yield. Thus, 1 could be
prepared with a 48% total yield based on 2 by the improved
bromination method.
1
dibromopyrrole 4 in 62 and 17% yield, respectively. The H
NMR spectrum of the above pure product was identical
with that of 3, but its melting point (50±51 8C) was di€erent
from the melting point (93±95 8C) reported by Meakins.
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1998 787
To a stirred solution ( 20 8C) of 5 (3.0 g, 15 mmol) in dry THF
(100 ml) was added NBS (2.7 g, 15 mmol). After stirring for 30 min,
the solution was allowed to stand in a freezer overnight. The solvent
was evaporated in vacuo and the residue was separated by column
chromatography (silica gel). Elution of the column with light
petroleum±EtOAc (4:1) gave colorless needles of 6 (2.9 g, 71%).
Rf ˆ 0.94, mp 107±108 8C. d(CDCl3) 6.17 (d, 1 H, 3-H, J3±4 4.0 Hz),
Experimental
1-Methylpyrrole was purchased from Tokyo Chemical Industry
Co., Ltd. and redistilled before use. Solvents were puri®ed and
dried by standard procedures. Light petroleum (bp 60±90 8C) was
used. Melting points were recorded on a Buchi-535 instrument and
are uncorrected. The IR, 1H NMR and mass spectra were recorded
on a Shimadzu IR-440, a Varian FX-90Q (Me4Si as internal stan-
dard) and an HP 5989A MS instrument respectively. All reactions
were carried out under nitrogen.
Repeated Bromination of 2 with Br2±AlCl3.ÐCompound 2 was
prepared by the known method, bp 63 8C at 6 Torr (lit.,8 76 8C
at 11 Torr). Pure 3 was produced in 50% yield according to
the method reported by Meakins.5 Its melting point (50±51 8C) is
di€erent from that reported (93±95 8C).
±
±
6.04 (d, 1 H, 4-H, J3±4 4.0 Hz), 5.31 (s, 1 H, O CH O), 3.69
(s, 3 H, NCH3), 3.67 (s, 4 H, acetal CH2), 1.27, 0.79 (s, each 3 H,
acetal CH3); m/z (%) 276 (14.0), 275 (100.0), 274 (M , 42.4), 273
(93.0), 272 (27.5), 194 (48.2).
‡
To a stirred solution of 6 (2.9 g, 10 mmol) in acetone (10 ml) was
added 1 M HCl (20 ml). The mixture was stirred at 50 8C for 2 h
and then cooled to room temperature. The mixture was extracted
with Et2O (4Â 50 ml) and dried (Na2SO4). The solvents were
evaporated in vacuo and the residue was separated by column
chromatography to a€ord only one product 1 (1.8 g, 90%).
Direct Bromination of
2 with NBS.ÐTo a stirred solution
( 20 8C) of (9.0 g, 82 mmol) in dry tetrahydrofuran (THF)
2
(200 ml) was added NBS (14.6 g, 82 mmol). After the NBS had dis-
solved, the solution was allowed to stand in a freezer for 24 h. The
solvent
was evaporated in vacuo and the residue was separated by column
chromatography (silica gel). Elution of the column with light
petroleum±EtOAc (4:1) gave colorless needles of 3 (9.3 g, 60%) and
a mixture of 1 and 4 (2.0 g, ca. 17%). The yields of 1 and 4 as
evaluated by 1H NMR spectroscopy were 5 and 12%, respectively.
Vacuum distillation (bp 78±83 8C/at 0.4 Torr) still gave the mixture
of 1 and 4.
We thank the National Natural Science Foundation
of China and China Postdoctoral Science Foundation for
®nancial support.
Received, 6th May 1998; Accepted, 10th August 1998
Paper E/8/03388I
The foregoing experiment was repeated with a di€erent molar
ratio of 2 and NBS. When the molar ratio of 2 to NBS was 1:0.8,
the reaction gave colorless needles at 1 and colourless needles of 3
in 7% and 71% yield, respectively. When the molar ratio of 2: NBS
was 1:1.5, the reaction gave colorless needles of 3 and colorless
needles of 4 in 18 and 48% yield, respectively (cf. Scheme 2).
References
1 (a) X. K. Jiang, Acc. Chem. Res., 1997, 30, 283; (b) X. K. Jiang,
G. Z. Ji and D. Z. R. Wang, J. Phys. Org. Chem., 1995, 8, 143;
(c) X. K. Jiang, G. Z. Ji, D. Z. R. Wang and J. R. Y. Xie,
J. Phys. Org. Chem., 1995, 8, 781.
2 R. H. Y. He and X. K. Jiang, J. Chem. Res., 1998, submitted.
3 P. B. De La Mare and J. H. Ridd, Aromatic Substitution,
Butterworths, London, 1959, ch. 8.
1
1, Rf ˆ 0.94, mp 63±64 8C. ꢀ/cm (KBr) 1654 (CO), 1465, 1421,
1359, 1031, 778, 763; d(CDCl3) 9.35 (s, 1 H, CHO), 6.83 (d, 1 H, 3-
H, J3±4 4.0 Hz), 6.27 (d, 1 H, 4-H, J3±4 4.0 Hz), 3.94 (s, 3 H,
NCH3); m/z (%) 190 (7.5), 189 (100), 188 (M , 92.0), 187 (90.4),
‡
186 (79.0) (Found: C, 38.36; H, 3.12; N, 7.33. C6H6NBrO requires
C, 38.22; H, 3.22; N, 7.45%).
4 H. J. Anderson and S. F. Lee, Can. J. Chem., 1965, 43, 409.
5 P. T. Kaye, R. Macrae, G. D. Meakins and C. H. Patterson,
J. Chem. Soc., Perkin Trans. 2, 1980, 1631.
6 (a) W. C. Anthony, J. Org. Chem., 1960, 25, 2049; (b) H. M.
Gilow and D. E. Burton, J. Org. Chem., 1981, 46, 2221.
7 A. H. Jackson, `Pyrroles', in Comprehensive Organic Chemistry,
ed. P. G. Sammes, Pergamon Press, London, 1979, vol. 4, p. 290.
8 R. M. Silverstein, E. E. Ryskiewicz, C. Willard and R. C.
Koehler, J. Org. Chem., 1955, 20, 668.
1
3, Rf ˆ 0.70, mp 50±51 8C. ꢀ/cm (KBr) 1661 (CO), 1386, 1366,
1180, 827, 782; d(CDCl3) 9.54 (s, 1 H, CHO), 6.91 (s, 2 H, 3-H and
5-H), 3.96 (s, 3 H, NCH3); m/z (%) 190 (7.3), 189 (96.3), 188 (M ,
100), 187 (90.3), 186 (86.8).
‡
4, Rf ˆ 0.90, mp 118±119 8C (lit.,5 118±120 8C). d(CDCl3) 9.30
(s, 1 H, CHO), 6.89 (s, 1 H, 3-H), 3.96 (s, 3 H, NCH3); m/z (%)
269 (43.6), 268 (61.5), 267 (M , 86.3), 266 (100.0), 265 (47.0), 264
(44.0).
‡
9 (a) C. E. Loader, G. H. Barnett and H. J. Anderson, Can. J.
Chem., 1982, 60, 383; (b) C. E. Loader and H. J. Anderson,
Synthesis, 1978, 295.
Improved Bromination of 2 with NBS.ÐCompound 5 was pre-
pared by the known method9 in 75% yield.