Sodium borohydride-iodine mediated reduction of γ-lactam carboxylic acids followed by DDQ mediated oxidative aromatisation: A facile entry to N-aryl-formylpyrroles

Article abstract of DOI:10.1016/j.tetlet.2004.12.107

A simple methodology for the conversion of substituted N-aryl-γ- lactam 2/3-carboxylic acids to substituted N-aryl-2/3-formyl-pyrroles has been developed. Several N-aryl-γ-lactam 2/3-carboxylic acids were reduced to substituted (N-aryl-pyrrolidine-2/3-yl)

Full text of DOI:10.1016/j.tetlet.2004.12.107

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1071–1074
Sodium borohydride–iodine mediated reduction of
c-lactam carboxylic acids followed by DDQ mediated oxidative
aromatisation: a facile entry to N-aryl-formylpyrroles
Pranab Haldar, Joyram Guin and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 30 September 2004; revised 14 December 2004; accepted 21 December 2004
Available online 11 January 2005
Abstract—A simple methodology for the conversion of substituted N-aryl-c-lactam 2/3-carboxylic acids to substituted N-aryl-
2/3-formyl-pyrroles has been developed. Several N-aryl-c-lactam 2/3-carboxylic acids were reduced to substituted (N-aryl-
pyrrolidine-2/3-yl)-methanols in good yields at room temperature using sodium borohydride–iodine. Controlled oxidation and
aromatisation of these alcohols using DDQ produced N-aryl-2/3-formyl-pyrroles.
Ó 2004 Elsevier Ltd. All rights reserved.
Some substituted pyrroles are highly biologically active
compounds, which constitute an important class of syn-
N
thetic pharmaceuticals1a and natural products with fun-
gicidal1b and insecticidal1c activities and which also
constitute the building blocks of the porphyrin ring sys-
tems present in chlorophyll, heme, vitamin B12 and the
bile pigments.2 Additionally, there are a number of pyr-
role-containing small molecules that exhibit interesting
biological activities.3a–d 3-Substituted N-aryl pyrroles
act as potent aldose reductase (AR) inhibitors.3e
OH
OH
H
N
N
N
O
O
O
NH
P3
N
CF3
I
NHCHOCH3
O
3-Substituted pyrroles are the most difficult to synthesise
since most electrophilic aromatic substitution reactions
as well as lithiation reactions of N-substituted pyrroles
occur at the 2-position4 and so functionalisation at the
3-position of pyrrole is a challenging goal in synthetic
research.
N
CHO
O
N
N
N
N
N
N
III
HIV-1 protease inhibitors with an N-aryl-pyrrole-con-
taining moiety in the P3 position I have excellent antivi-
ral potency,5 3-(1H-pyrrol-1-yl)-2-oxazolidinones II
show antimycobacterial activity,6 and N-phenyl-3-(ami-
nomethyl)-pyrroles III act as potential antipsychotic
agents.7 In all cases (Fig. 1) the key synthetic intermedi-
ate was 3-formyl-N-phenyl pyrrole IV.5–7
IV
II
Figure 1.
Encouraged by the above reports we aimed to develop a
novel and simple approach for the synthesis of N-aryl 3-
formyl-pyrroles whose ultimate utility might extend to
unexpected applications.
Related to our studies of bioactive N-aryl-c-lactams8,9
we set out to discover an efficient method for the conver-
sion of c-lactam carboxylic acids to the desired pyrrole
Keywords: Lactam; Pyrrole; Reduction; Oxidative-aromatisation.
*
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222
282252; e-mail: jkray@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.107

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P. Haldar et al. / Tetrahedron Letters 46 (2005) 1071–1074
Ar
O
O
Ar
Ar
N
N
O
O
N
DDQ
Ar NH2
+
O
dry Benzene,
80 oC
CHO
CH2OH
CO2H
1
3
2
Scheme 1.
Scheme 3.
derivatives, keeping in mind that modification of the
heterocyclic ring is crucial in determining the biological
activity of these derivatives.10
Table 2.
Pyrrolidin-
3-ylmethanol
Ar
3-Formylpyrrole Yield (%)
N-Aryl-2-oxo-pyrrolidine-3-carboxylic acids 1 were syn-
thesised by the reaction of substituted arylamines and
6,6-dimethyldioxaspiro2,5octane-4,8-dione11 at room
temperature (Scheme 1).
2a
2b
2c
2d
2e
4-CH3–C6H4
4-Br–C6H4
4-Cl–C6H4
3a
3b
3c
62
64
65
62
60
3,4-Cl,Cl–C6H3 3d
3-Cl,4-F–C6H3 3e
Lithium aluminium hydride could reduce both the lac-
tam carbonyl and carboxylic acid group of compound
1 but this reagent suffers from disadvantages of cost,
inflammability and often problematical work-ups. Thus
we turned our attention to other reducing agents and
(N-aryl-pyrrolidine-3-yl)-methanol 2 was easily synthes-
ised in very good yield (Table 1) by reaction of 1 with
The pleasing outcome of the above reactions prompted
us to extend this methodology to the synthesis of N-
aryl-2-formyl-3-aryl/heteroaryl-pyrroles (Scheme 4,
Tables 3 and 4) starting from N-aryl-5-oxo-3-aryl/hetero-
aryl-pyrrolidine-2-carboxylic acids 4.9,12a A recent study
showed that N-aryl-2-formylpyrroles can act as key
starting materials for the synthesis of isotactic-polyprop-
ylene (IPP) catalysts15 and certain pyrrole Mannich
bases that act as antipsychotic agents.16
12
NaBH4–I2 in dry THF at room temperature (Scheme
2). The reagent system is safe, simple and inexpensive.
(1-Substituted pyrrolidin-3-yl)methanols and their cor-
responding chlorides13 are useful intermediates for the
preparation of a number of physiologically active com-
pounds of therapeutic value.
All the compounds were characterised by the usual spec-
troscopic data.
We hoped that DDQ14 might bring about oxidative aro-
matisation of N-subsituted pyrrolidin-3-ylmethanols to
produce N-aryl-3-formylpyrroles and this proved to be
the case.
In conclusion we have shown that NaBH4–I2 can effec-
tively reduce both the lactam carbonyl and the carbox-
ylic acid groups of N-aryl-2-oxo-pyrrolidine-3-
carboxylic acids at room temperature and that DDQ
effects the oxidative aromatisation of N-arylpyrrolidin-3-
ylmethanols in good yields, providing a simple and no-
vel approach for the conversion of c-lactam carboxylic
acids into N-aryl-3-formylpyrroles. This methodology
has been successfully applied to the synthesis of a range
of N-aryl-2-formylpyrroles.
Controlled oxidation and aromatisation of 2 by DDQ
furnished the desired compound 3 in one step and in
good yield (Scheme 3, Table 2).
Table 1.
Typical experimental procedure:
2-Oxopyrrolidine- Ar
3-carboxylic acid
Pyrrolidin-
3-ylmethanol
Yield (%)
(a) Synthesis of N-arylpyrrolidin-3-ylmethanols 2.
To a stirred solution of NaBH4 (6 mmol) in dry THF
(20 mL) a solution of iodine (3 mmol) in dry THF
(5 mL) was added dropwise under argon at 0 °C over
45 min. Next, lactam-monoacid (2 mmol) 1 in dry
THF (8 mL) was added and the mixture was stirred at
rt (25 °C) for 2 h. The mixture was then cooled to 0 °C
and the excess hydride was carefully destroyed by drop-
wise addition of methanol (10 mL). The solvents were
removed under vacuum and the residue was taken up
in 30 mL of 20% aqueous KOH and the mixture was ex-
tracted 3times with ether (80 mL). The ether layer was
washed with sodium thiosulfate solution and then with
brine and dried over anhydrous Na2SO4. The solvent
was evaporated and the crude product was purified by
column chromatography [silica gel/petroleum ether
(60–80 °C)-ethyl acetate (40:1)].
1a
1b
1c
1d
1e
4-CH3–C6H4
4-Br–C6H4
4-Cl–C6H4
2a
2b
2c
76
81
82
80
78
3,4-Cl,Cl–C6H3 2d
3-Cl,4-F–C6H3
2e
Ar
Ar
N
N
NaBH4/I2
dry THF 0-25 oC
,
O
CH2OH
CO2H
2
1
Scheme 2.

P. Haldar et al. / Tetrahedron Letters 46 (2005) 1071–1074
1073
Ar
Ar
Ar
CH2OH
Ar'
CO2H
Ar'
CHO
Ar'
NaBH4/I2
DDQ
N
N
N
dry THF,
0-78 oC
dry Benzene,
80 oC
O
4
6
5
Scheme 4.
Table 3.
c-Lactam-carboxylic acid
Ar
4-Cl–C6H4
Ar0
Pyrrolidin-2-ylmethanol
Yield (%)
4a
4b
4c
4d
4e
2-Thienyl
Phenyl
Phenyl
Phenyl
Phenyl
5a
5b
5c
5d
5e
79
83
85
82
80
4-CH3–C6H4
4-Cl–C6H4
3,4-F,F–C6H3
3-Cl,4-F–C6H3
Table 4.
Pyrrolidin-2-ylmethanol
Ar
Ar0
2-Formylpyrrole
Yield (%)
5a
5b
5c
5d
5e
4-Cl–C6H4
4-CH3–C6H4
4-Cl–C6H4
2-Thienyl
6a
6b
6c
6d
6e
67
70
72
68
69
Phenyl
Phenyl
Phenyl
Phenyl
3,4-F,F–C6H3
3-Cl,4-F–C6H3
(b) Synthesis of N-aryl-3-formylpyrroles 3.
7.28 (m, 2H), 7.43–7.49 (m, 6H), 9.64 (s, 1H). 13C
NMR (50 MHz, CDCl3): d 111.56, 116.49, 121.13,
126.09, 127.53, 128.04, 128.23, 128.38, 128.58,
129.61, 130.01, 130.80, 133.23, 136.24, 140.80,
179.61. Anal. Calcd for C17H11NOFCl: C, 68.11;
H, 3.67; N, 4.67%. Found: C, 67.98; H, 3.75;
N, 4.73%. ESI-MS: for C17H11NOFCl [M],
[M + H]+ = 300.14 (100%) (35Cl), 302.14 (33%)
(37Cl).
Compound 2 (1.4 mmol) was refluxed with DDQ
(8 mmol) in dry benzene [Caution: carcinogenic]
(40 mL) for 8 h. After completion of the reaction, the or-
ganic layer was washed with aqueous NaHCO3 solution,
dried over anhydrous Na2SO4, the solvent evaporated
and the product aldehyde 3 was purified by column
chromatography [neutral alumina/petroleum ether (60–
80 °C)-ethyl acetate (60:1)].
Spectral data of representative compounds.
Acknowledgements
(a) [N-(4-Chlorophenyl)pyrrolidin3-yl]methanol 2c: 1H
NMR (CDCl3, 200 MHz): d 1.79–1.86 (m, 1H),
2.12–2.16 (m, 1H), 2.55–2.59 (m, 1H), 3.07–
3.13 (m, 1H), 3.25–3.39 (m, 3H), 3.42–3.63 (m,
2H), 6.44–6.52 (m, 2H), 7.14–7.25 (m, 2H).
13C NMR (50 MHz, CDCl3): d 27.87, 40.91,
47.26, 50.64, 65.08, 112.75, 120.50, 128.84, 146.40.
Anal. Calcd for C11H14NOCl: C, 62.41; H, 6.62;
N, 6.62%. Found: C, 62.53; H, 6.65; N, 6.56%.
ESI-MS: for C11H14NOCl [M], [M + H]+ =
212.07 (100%) (35Cl), 214.07 (33%) (37Cl).
Financial support from DST (New Delhi) and CSIR
(New Delhi) (for a fellowship to P.H.) is gratefully
acknowledged.
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