Efficient and flexible access to polysubstituted pyrroles

Article abstract of DOI:10.1055/s-2001-16790

A series of polysubstituted pyrroles 3 have been synthesized very efficiently in two or three steps starting from primary amines 1. The key-step of this process is the bromocyclisation of δ-enaminoesters 2. The chemoselectivity of the reaction could depend on the nature of the solvent.

Full text of DOI:10.1055/s-2001-16790

1440
LETTER
Efficient and Flexible Access to Polysubstituted Pyrroles
Claude Agami, Luc Dechoux,* Séverine Hebbe
Laboratoire de Synthèse Asymétrique associé au CNRS, Université Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France
Fax (33) 01 44 27 26 20; E-mail: dechoux@ccr.jussieu.fr
Received 5 June 2001
CO2Me
O
Abstract: A series of polysubstituted pyrroles 3 have been synthe-
sized very efficiently in two or three steps starting from primary
amines 1. The key-step of this process is the bromocyclisation of -
enaminoesters 2. The chemoselectivity of the reaction could depend
on the nature of the solvent.
MeOH, reflux, 72h
yields 50-60 %
MeO
R1
CO2Me
1
+
HN
H
Ph
Key words: pyrroles, -enaminoesters, -enaminoesters, bromocy-
2a R1 =H
clisation, amines
2b R1 = Me
Scheme 2
Pyrroles are heterocycles of great importance because of
their presence in numerous natural products such as heme,
chlorophyll, vitamin B12 or enzymes like the various cyto-
chromes.1 In addition, polysubstituted pyrroles are molec-
ular frameworks of many biologically active compounds
and have emerged as chemotherapeutic agents.2 Although
there is a number of potentially useful methods, (for ex-
ample the well known Knorr reaction),3 many synthetic
designs for these ring systems continue to be developed.4
Six examples of the conversion of -enaminoesters 2 to
various substituted pyrroles are listed in Table 1. The re-
actions were performed by adding NBS to a solution of
substrates 2 in dichloromethane at 0 °C.10 The reactions
were completed in 5 minutes, the solvent evaporated and
the residue purified by chromatography on silica gel.
This paper describes a facile and flexible regioselective
synthesis of 2,4-dicarbonylated substituted pyrroles 3 in
two or three steps, starting from primary amines 1
(Scheme 1). The key-step involves the bromocyclisation
of -enaminoesters 2 with N-bromosuccinimide (NBS).
Table 1 Reaction of -enaminoesters 2 with NBS (Scheme 1)
The preparation of derivatives 2 has been achieved by two
different procedures.5 The first one allowed, in a one-pot
procedure, the stereoselective synthesis of
enami-
noester 2a,b by refluxing amines 1 (R1 = H or Me) with
methyl propiolate in methanol (Scheme 2). The Z-config-
uration of the double bond to the nitrogen atom is as-
sumed on grounds of earlier work.6 The E-configuration
of the second double bond is based upon the coupling
(15.5 Hz) of the ethylenic hydrogen atoms.
The products were usually obtained as solids.11 This
method gives very good results when R2 is a methyl group
(Table 1, entries 3-6). In contrast, when R1 and R2 are hy-
drogen atoms, pyrrole 3a is formed in moderate yield (Ta-
ble 1, entry 1). Moreover, when R2 = H and when R1 = Me
as in substrate 2b only traces of pyrrole 3b could be ob-
served in the 1H NMR spectrum of the crude mixture (Ta-
ble 1, entry 2). In this case compound 5b was obtained in
good yield.12
The -enaminoester 2c-f were prepared stereoselectively
via a two-step procedure:7 i) condensation between
amines 1 and methyl acetoacetate or 2,4-pentanedione led
to -enaminoester 4c-e and -enaminoketone 4f respec-
tively ii) addition of methyl propiolate8 to these adducts
4c-f afforded -enaminoester 2c-f in a diastereomerically
pure form (Scheme 3).9
CO2Me
O
O
R3
R2
R1
R3
NBS/CH2Cl2
Ph
NH2
MeO2C
R2
N
HN
R1
Ph
R1
Ph
2
1
3
Scheme 1
Synlett 2001, No. 9, 1440–1442 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient and Flexible Access to Polysubstituted Pyrroles
1441
O
4c R1 = CH2OH R3 = OMe
O
O
R3
R1
MeOH, reflux, 12h
4d R1 = H R3 = OMe
4e R1 =Me R3 = OMe
4f R1 = H R3 = Me
+
1
R3
yields 100 %
HN
Me
Ph
CO2Me
O
R3
MeOH, reflux, 72h
yields 80-95 %
2c-f
4c-f
+
CO2Me
HN
Me
R1
Ph
Scheme 3
Br
CO2Me
CO2Me
O
O
O
R3
R2
NBS/CH2Cl2
R3
R1
R3
+
MeO2C
N
R2
HN
R2
HN
R1
Ph
R1
Ph
Ph
2
3
5
Scheme 4
Similar brominated products 5 were detected by 1H NMR A dramatic solvent effect has been observed. Product 5b
as by-products in the reaction of NBS in dichloromethane is formed chemoselectively in all solvents (Table 2, en-
with all others substrates 2a,c-f. These compounds 5 were tries 1-5) except in methanol (Table 2, entry 6) which pro-
not isolated and led slowly (3-24 h) to pyrroles 3a,c-f motes the exclusive formation of pyrrole 3b; a wet DMSO
(Scheme 4).13
medium (Table 2, entry 7) shows the same effect, albeit to
a lesser extent. These results are in agreement with a nu-
cleophilic external addition of the solvent on an interme-
diate imminium. The resulting -bromo- -aminoester
would then cyclize to furnish, after elimination of metha-
nol (Table 2, entry 6) or water (Table 2, entry 7), the ex-
pected pyrrole 3b. Research aimed at elucidating this
intriguing question is currently underway.
In order to enhance the yield of formation of pyrrole 2b,
we examined the influence of various solvents on the
chemoselectivity of this reaction (Table 2). For this pur-
pose, a solution of -enaminoester 2b in various solvents
was added at room temperature to 1.2 equivalent of NBS.
Reactions were completed within a period of 5 minutes.
The solvents were then evaporated and the ratio of the
products 3b / 5b were determined by 1H NMR of the crude In summary, it appears that this synthetic two- or three-
material.
step sequence starting from commercially avalaible pri-
mary amines is straightforward and flexible for the prepa-
ration of 2,4-dicarbonylated pyrroles. This procedure
does not require harsh reaction conditions or difficult to
handle reagents, offers high yields and can be easily
scaled up to the preparation of gram quantities of pyrroles.
Table 2 Solvent effect on the reaction of -enaminoester 2b with
NBS (Scheme 4)
We currently investigate the use of pyrroles 3b,c,e in
asymmetric synthesis in order to prepare polysubstituted
chiral non racemic pyrroles and pyrrolidines.
References and Notes
(1) Yates, F.S. In Comprehensive Heterocyclic Chemistry;
Boulton, A.J.; McKillop, A., Eds.; Pergamon: Oxford 1984; 2,
511. Jones, R.A. In Pyrroles, Part II, The Synthesis, Reactivity
and Physical Properties of Substituted Pyrroles; J. Wiley and
Sons, New York 1992.
a Combined yields determined by 1H NMR
Synlett 2001, No. 9, 1440–1442 ISSN 0936-5214 © Thieme Stuttgart · New York

1442
C. Agami et al.
LETTER
(2) Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Lampis, G.;
Deidda, D.; Pompei, R. Bioorg. Med. Chem. Lett. 1998, 6,
2931. Ragno, R.; Marshall, G.R.; Di Santo, R.; Costi, R.;
Massa, S.; Rompei, R.; Artico, M. Bioorg. Med. Chem. Lett.
2000, 8, 1423.
(3) Knorr, L. Justus Liebigs Ann. Chem. 1886, 236, 290.
(4) Shiraishi, H.; Nishitani, T.; Nishihara, S.; Sakaguchi, S.; Ishii,
Y. Tetrahedron. 1999, 55, 13957. Franc, C.; Denone, F.;
Cuisinier, C.; Ghosez, L. Tetrahedron Lett. 1999, 40, 4555.
Liu, J., Yang, Q.; Mak, T.C.; Wong, H.N.C. J. Org. Chem.
2000, 65, 3587. Katritzky, A.R.; Huang, T.; Voronkov, M.V.;
Wang, M.; Kolb, H. J. Org. Chem. 2000, 65, 8819. Dieter,
R.K.; Yu, H. Org. Lett. 2000, 2, 2283. Fejes, I.; Toke, L.;
Blasko, G.; Nyerges, M.; Pak, C. S. Tetrahedron. 2000, 56,
8545. Aelterman, W.; De Kimpe, N.; Tyvorskii, V.;
Kulinkovich, O. J. Org. Chem. 2001, 66, 53.
(5) Similar -enaminodiester have already been described with
addition of additives: a) Caballero, E.; Madrigal, B.; Medarde,
M.; Puebla, P.; Honores, Z. Ach. Mod. Chem. 1998, 135, 457.
b) Khan, M.A.; Adams, H. Tetrahedron Lett. 1999, 40, 5389.
(6) Stoit, A.R.; Pandit, U.K. Tetrahedron 1988, 44, 6187.
Compound 2a was already described. Lee, C-H.; Kohn, H.
J.Heterocycl.Chem. 1990, 2107.
(7) General Procedure for the Synthesis of -Enaminoesters 2c-e.
To a solution of amines 1 (10 mmol) in MeOH (50 mL) was
added methyl acetoacetate (12 mmol). The reaction was
refluxed for 6 h and then allowed to reach room temperature.
At this stage, methyl propiolate (20 mmol) was added and the
mixture refluxed for 2 days. After evaporation of the solvent,
the residue was recrystallized in MeOH. -Enaminoesters 2c-
e were obtained as white solids. Selected data for compound
2d. mp: 106 °C. 1H NMR (250 MHz, CDCl3) 2.26 (s, 3H),
3.73 (s, 3H), 3.78 (s, 3H), 4.57 (d, J = 6Hz, 2H), 6.10 (d,
J = 15.7Hz, 1H), 7.31 (m, 5H), 7.76 (d, J = 15.7Hz 1H), 10.9
(lt, NH). 13C NMR (63 MHz, CDCl3) 16.1, 47.8, 50.8, 50.9,
93.8, 110.1, 126.8, 127.8, 129.0, 137.0, 140.6, 166.4, 169.8,
170.8.
(8) The introduction of a methyl group on -enaminoester 2 was
not possible. Treatment of -enaminoester 4 with an excess of
ethyl butynoate left the starting material unchanged.
(9) The Z-configuration of the double bond in dichloromethane is
assumed on grounds of earlier work, see ref 6. Moreover, in a
solvent such as DMSO, which is known to break intramole-
cular hydrogen bonds, we have observed for -enaminoester
2b a mixture of the two Z- and E-diastereoisomers (ratio Z/
E = 77/23).
(10) General procedure for the synthesis of pyrroles 3a,c-f. To a
solution of -enaminoester 2a,c-f (1 mmol) in
dichloromethane (10 mL) at 0 °C was added portion wise N-
bromosuccinimide (1.2 mmol). After 15 min at this
temperature the solvent was evaporated and the crude mixture
purified by chromatography on silica gel.
(11) Selected data for compound 3d. 1H NMR (250 MHz, CDCl3)
2.52 (s, 3H), 3.77 (s, 3H), 3.82 (s, 3H), 5.67 (s, 2H), 6.94 (m,
2H), 7.28 (m, 3H), 7.45 (s, 1H). 13C NMR (63 MHz, CDCl3)
11.3, 48.1, 51.0, 51.2, 112.7, 119.7, 121.4, 125.8, 127.3,
128.7, 137.0, 142.4, 162.0, 165.6. mp: 97 °C. MS: m/e
(relative intensity) 287 (70%), 255 (26%), 196 (12%), 91
(100%). IR (chloroform) 1697, 1555, 1493 cm-1. Anal. Calcd.
For C16H17NO4 C, 66.89; H, 5.96; N, 4.88. Found C, 66.78; H,
6.10; N, 4.72.
(12) Selected data for compound 5b. mp: 83 °C. 1H NMR (250
MHz, CDCl3) 3.75 (s, 3H), 3.82 (s, 3H), 4.52 (d, J = 5.7Hz,
2H), 7.35 (m, 5H), 8.30 (s, 1H), 8.61 (d, J = 13.5Hz, 1H) 9.53
(m, NH). 13C NMR (63 MHz, CDCl3) 51.2, 53.0, 53.4, 92.6,
100.7, 127.5, 128.2, 129.0, 136.4, 137.4, 155.6, 164.5, 169.2.
(13) The ratio 3c-f/5c-f were determined by 1H NMR
measurements of the crude material. The ratios 3c-f/5c-f are
> 9/1. Compounds 5c-f were quantitatively transformed into
pyrroles 3c-f within 24 hours at room temperature in CDCl3.
Article Identifier:
1437-2096,E;2001,0,09,1440,1442,ftx,en;G10801ST.pdf
Synlett 2001, No. 9, 1440–1442 ISSN 0936-5214 © Thieme Stuttgart · New York