CHAPTER THREE

Paal–Knorr Reaction in the

Synthesis of Heterocyclic
Compounds
Soheila Khaghaninejad and Majid M. Heravi1
Department of Chemistry, School of Sciences, Alzahra University,Vanak, Tehran, Iran
1Corresponding author: E-mail: mmh1331@yahoo.com

Contents
1.  Introduction96
2.  Pyrrole Synthesis 96
3.  Furan Synthesis 116
4.  Thiophene Synthesis 119
5.  Natural Products and Macromolecules Synthesis 122
6.  Conclusion137
Acknowledgments 140
References 140

Abstract
A reaction in organic chemistry that creates either furans, pyrroles, or thiophenes from
1,4-dicarbonyl compounds is called Paal–Knorr synthesis. It is a synthetically valued
process for gaining substituted furans, pyrroles and thiophene, common structural
components of many and variety of biologically active natural products. It was origi-
nally described separately by German chemists Carl Paal and Ludwig Knorr in 1884 as
a method for the synthesis of furans, and then has been modified for the synthesis of
pyrroles and thiophenes.
The Paal–Knorr reaction is relatively versatile and multipurpose. In this reaction, almost
all dicarbonyls can be converted to their corresponding heterocycles.
The Paal–Knorr originally is considered limited by harsh reaction conditions, such
as prolonged heating in acid, which may degrade sensitive functionalities in many
potential precursors.
However, contemporary approaches allow for much milder conditions by avoiding,
heat altogether, including microwave irradiation along with use of environmentally
benign catalyst required for cyclizations.

Keywords: 1,4-dicarbonyl; Furan; Paal–Knorr; Pyrrole; Thiophene.

Advances in Heterocyclic Chemistry, Volume 111 © 2014 Elsevier Inc.

ISSN 0065-2725, http://dx.doi.org/10.1016/B978-0-12-420160-6.00003-3 All rights reserved. 95
96 Soheila Khaghaninejad and Majid M. Heravi

1.  INTRODUCTION
In 1884, the Paal–Knorr (P–K) reaction was initially reported inde-
pendently by German chemists Carl Paal and Ludwig Knorr as a method
for the synthesis of furans, and then has been adapted for the synthesis of
pyrroles and thiophenes (1884MI2756, 1884MI2863). Before these reports,
in 1883 Ludwig Knorr had synthesized a pyrazolone derivative with anal-
gesic potency which then was called antipyrin (05MI125). Antipyrin, which
is now called phenazone, was a commercial success. Antipyrin is one of the
first synthetic drugs and was extensively prescribed, before being replaced
by the most famous Bayer product, aspirin, in the early twentieth century.
The P–K reaction introduces one of the most significant and simple
methods for the synthesis of a variety of heterocyclic compounds, especially
pyrrole derivatives. Furan, thiophene, pyrrole, imidazole, thiazole and quin-
oline are well-known heteroaromatic compounds and are found naturally
in plants and also in animal cells. 1,4-Dicarbonyl derivatives are important
precursors for the preparation of cyclopentenones (75S379, 81CB58128)
and five-membered heterocycles such as pyrroles, furans and thiophenes
(96T8707, 97T11529).
In spite of the abundant and widespread applications of the P–K reac-
tion in synthesis of heterocyclic compounds, unfortunately this old and
useful reaction has been largely overlooked, and not been comprehensively
reviewed. Herein, we try to present a useful and comprehensive review with
the hope of it being useful and attractive for organic chemists.

2.  PYRROLE SYNTHESIS

Pyrroles have broad applications as pharmaceutical agents
(06BMC8162, 2003JA6870, 81JOC2570), conducting polymers
(97CSR247, 2000JA4992), molecular optics (92H(34)2003, 01TL1309,
07T4258, 06OL3681), electronics (98JOC6715) and gas sensors
(00SM181) for organic compounds (96OPP641). Many physiologically
interesting natural products such as alkaloids, synthetic materials, bio-
active molecules such as vitamin B12, heme and cytochromes (00SCI1,
06T7213, 04JNP2141, 03S1753, 00OL2583), and biologically active com-
pounds such as indolizidine, unsaturated γ-lactams and bicyclic lactams
(03AG3528, 00JOC3587, 95HCA1511, 05T8226, 01T1961) have pyr-
roles as building blocks (1977AHC1) in their structures. These bioactive
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 97

compounds have broad applications in drug development and are being

used as antibacterial, anti-inflammatory, antitumor, antimalarial, antibacte-
rial, antiviral agents (00MI1423) and can also be used as antioxidant agents
(99TL4555).
There are several methods for the synthesis of pyrroles (00MI1423)
including the classical Hantzsch procedure (92TL6155), 1,3-dipolar cyclo-
addition (94JOC4551), the aza-Wittig reaction (95JOC6637), reduc-
tive coupling (04OL2957), titanium catalyzed hydroamination of diynes
(04AGE6238), as well as other multistep operations (92JCE313, 05JOC1471,
03T2865, 03S859, 99JOC4204, 04OL2957, 04S918). In spite of this variety,
the most widely used method is still the P–K synthesis, which involves the
cyclocondensation of 1,4-dicarbonyl compounds 1 with primary amines to
produce substituted pyrroles 2 using catalysts with each method having its
own merits and drawbacks (Scheme 1).
The most common catalysts are HCl (03SL711), PTSA (68JHC757),
HOAc (89SC2101), H2SO4 (04JOC213), I2 (06TL5383, 06T10130), differ-
ent metal complexes (05TL2643, 06CL632, 04TL5873, 03TL3923, 95TL6205,
98SC1661, 86S409, 06JHC1231, 05SC1051, 08MI174, 06MC220, 08MI877,
06T10130), montmorillonite (06MI2191, 04JOC213, 01H(55)1019) and a
variety of acidic materials, such as zeolite (98SC1661, 89SC2101), Ti(OPr-
i)4 (95TL6205, 04JOC213), Al2O3 (86S409, 06JHC1231, 06TL5383),
KSF, Fe+3-montmorillonite (04JOC213, 06CL632), HCl, montmo-
rillonite K10 (01H(55)1019), Sc(OTf)3 (95TL6205), Bi(NO3)3.5H2O
(04TL3417, 12T1), RuCl3 (08MI174), Ru2(CO)4(PPh3)2Br4 (12JOM58),
Ru(PPh3)3(CO)H2 (09T8981), InCl3 (08MI34), SnCl2.2H2O (06CL632),
layered zirconium phosphate, sulfophenyl phosphonate (03TL3923,
97T7999, 68JNC317, 92MI315), cellulose sulfuric acid (CSA) (11MI80),
silica sulfuric acid (SSA) (10TL2109), silica-supported antimony(III) chlo-
ride (SbCl3/SiO2), zirconium chloride (07M77, 05S1449, 07TL8730,
07CCAOAC1615, 05MI415, 08MI33, 08MI115, 08MI129, 07MI779), ura-
nyl nitrate hexahydrate[UO2(NO3)2.6H2O] (11TL5142, 07TL1845), RuCl3

Scheme 1 
98 Soheila Khaghaninejad and Majid M. Heravi

(08MI174), cobalt(II) chloride (08HAC592), aqueous zinc tetrafluoroborate

(06MC220), Sc(OTf)3 (06TL5383, 2005JA8942, 05OL1113, 05JOC6537,
05TL8507, 06MI299, 05OL4729), 02CRV2227), ZrOCl2·8H2O (11MI585,
03TL3923, 00PAC1373, 04SL627, 07MI325, 06T672), NiCl2.6H2O
(12TL4145), macroporous strongly acidic styrol resin (D001) (10MI664),
ionic liquid (04TL3417) and many others (08HAC144, 99CRV2071,
01MI101, 00AG3772, 01MI2399, 00PAC1391, 03TL5037, 02CRV3667,
98SC1661, 11TL1667, 10SC370).
Despite its widespread and extensive use, the mechanism had not
been fully understood until it was revealed by Amarnath et al. in the1990s
(95JOC301).The mechanism of the pyrrole synthesis from a 4-­ketoaldehyde,
such as 4-oxohexanal 3, and a primary amine in organic solvents, suggests
that 3 readily gives the imine 5 and then it is decomposed to pyrrole 6. How-
ever, in fact, the hemiaminal 4 rather than the enamine 5 is the intermediate,
which undergoes cyclization (Scheme 2) (95MI234). Results d­ isclose that
the rate of pyrrole formation of 4-oxohexanal in the absence of a methyl
substituent at one of the carbonyls was two-fold larger than that of 2,5-hex-
anedione. The higher reactivity of ketoaldehydes relative to diketones was
found to have physiological importance. The higher rate of pyrrole forma-
tion may explain the increased rate of pyrrole-mediated cross-linking of
proteins caused by γ-ketoaldehydes in comparison with γ-diketones.

Scheme 2 
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 99

Density functional theory of B3LYP has been utilized to study the

mechanism of reactions. The reaction has two plausible mechanistic
pathways: hemiaminal cyclization and enamine cyclization. Potential
energy surfaces that have been calculated showed that in the gas phase
and in solution the hemiaminal cyclization (path a) is the preferred path-
way (Scheme 3). Results also indicated that in the P–K mechanism, the
hemiaminal intermediate undergoes cyclization in the rate-­determining
step. The favorite mechanism consists of hemiaminal formation, hemi-
aminal cyclization and a dehydration step to yield the pyrrole ring.
Water and hydrogen-bonding interactions play a key role to catalyze the
hydrogen-transfer steps. In the reaction of 2,5-hexanedione and methyl-
amine, a water molecule functions as a catalyst as well as a reactant.
Water bridges assist in the formation of TSs to cause proton transfer.
Comparison of density functional theory of B3LYP with experimen-
tal results indicates that the hemiaminal is the real key intermediate
(07JST97).
In 1991, Amarnath et al. found that the formation of pyrroles from d,l
diastereomers of 3,4-dimethyl- and 3,4-diethyl-2,5-hexanedione needed
aprotic solvents and aqueous solutions near neutrality and is 1.3–57 times
faster than when the corresponding meso diastereomers are used as a pre-
cursor (Scheme 4) (91JOC6924).
N-substituted pyrroles were synthesized from 2,5-dimethoxytetrahydro-
furan 7 with aryl/alkyl, sulfonyl, and acyl amines in water, and ­catalyzed
by iron(III) chloride (FeCl3) under relatively mild conditions. The reaction
was also carried out in an organic solvent such as CH2Cl2, THF, benzene,
MeCN, EtOH, and solvent-free conditions. H2O yielded more product
(95%) (Scheme 5) (09S2245).

Scheme 3 
100 Soheila Khaghaninejad and Majid M. Heravi

Scheme 4 

Scheme 5 

Oxindoles show significant biological activities and are extensively used

as intermediates for the preparation of alkaloids, drug candidates, and clini-
cal pharmaceuticals (03EJO2209, 2003JA6261, 00OL2583).
Shanthi and Perumal have reported the synthesis of 2-pyrrolo-3́-yl-
oxindoles 9 via a three-component reaction of 3-phenacylideneoxindole
8, a β-ketoester, and ammonium acetate in ethanol catalyzed by InCl3
(Scheme 6) (09TL3959).
Blay et al. reported a useful synthesis of highly substituted biheteroaryls
10.The two-step synthesis of 3-(heteroaryl) indoles involves a ­Friedel–Crafts
alkylation of indoles using (E)-1,4-diaryl-2-buten-1,4-­diones to afford the
corresponding indoles bearing a 1,4-dicarbonyl moiety and subsequent
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 101

Scheme 6 

Scheme 7 

Scheme 8 

cyclization of the diones under different conditions, which allows the prepa-
ration of indoles substituted at C3 with 3-furanyl, 3-­pyrrolyl- and 3-­thienyl
moieties. The overall sequence is an alternative to the c­ross-­ coupling
between two electron-rich heterocycles, which is limited in capability and
difficulty (Scheme 7) (09T9264).
Condensation of 4-hydroxyproline 12 with substituted isatins 11, using
an ionic liquid, 1-butyl-3-methylimidazoliumtetrafluoroborate ([Bmim]
BF4) under microwave irradiation gives N-substituted pyrroles such as
3-(1H-pyrrol-1-yl)indolin-2-ones 13 (Scheme 8) (10TL3477).
The substituted pyrroles were synthesized via a one-pot multicompo-
nent reaction between acylsilanes, unsaturated carbonyl compounds, and
102 Soheila Khaghaninejad and Majid M. Heravi

Scheme 9 

amines catalyzed by a thiazolium salt utilizing a Sila-Stetter/P–K sequence

(Scheme 9) (04OL2465).
A bismuth-catalyzed ring expansion of β-oxo esters 14 with primary
amines affords eight-membered ring lactams (06SL106). Further exten-
tion is the conversion of tetrahydrofuran, tetrahydrothiophene and pyr-
rolidine derivatives to oxazocanes, thiazocanes and diazocanes respectively
(09JOC5431). A benzo[c]azocane-1-one derivative, an eight-membered
ring lactam, in a bismuth-mediated ring expansion of 15 has been obtained
via reacting ethyl 1-oxo-indane-2-carboxylate with methylamine.The ester
function in the heterocyclic product can be saponified to the free corre-
sponding carboxylic acid, which is further amidated with p-bromoaniline.
A spirolactam and an indeno[1,2-b]pyrrole can also be obtained from the
same precursor. Indanone-derived 1,4-diketone without an ester func-
tion can be reacted with several primary amines in a bismuth catalyzed
(BiNO3.5H2O) P–K reaction to give indeno[1,2-b]pyrrole derivatives with
up to quantitative yields in many cases (Scheme 10) (11EJO4231).
2-Hydroxy-3-(4-methoxyphenyl)-1-phenylpentane-1,4-dione 17 was
prepared with 89% yield via an aldol reaction of 1-(4-methoxyphenyl)
propan-2-one 16 with phenylglyoxal monohydrate using a catalytic amount
of (1,4-diazabicyclo[2.2.2]octane) DABCO in water at ambient tempera-
ture (Scheme 11) (11KG1330).
γ,γ-Dialkyl-γ-amino α,β-unsaturated carbonyl compounds 18 undergo
a selective skeletal rearrangement, and 1,2-alkyl shift under the influence of
modified organoaluminum Lewis acid to give unsymmetrically substituted
pyrroles 19 under acidic hydrolysis conditions (Scheme 12) (04TL9315).
2,4- And 2,3,4-substituted pyrroles were obtained in two or three
steps, involving an iridium-catalyzed isomerization, conversion of O-allyl
oximes to O-vinyl oximes, along with facile [3,3] rearrangement to a 1,
4-imino aldehyde. Then, with the P–K intermediates undergoing cycliza-
tion to the corresponding pyrroles. Cyano-substituted O-allyloximes have
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 103

Scheme 10 

Scheme 11 

also been identified as substrates amenable to this reaction (Scheme 13)

(10OL2290).
Wang et al. have described the isomerization O-allyl oximes to O-vinyl
oximes along with the transformation to 2,3,4- or 2,3,5-trisubstituted pyr-
roles. Oxime tautomerization with substituent effects and suitable reaction
conditions controlled the regioselectivity of formation of the pyrrole. The
electron withdrawing substituents at the R-position of the oxime and the
104 Soheila Khaghaninejad and Majid M. Heravi

Scheme 12 

Scheme 13 

addition of DBU to the mixture assisted the enolization, a [3,3] rearrange-

ment of the O-vinyl oxime intermediate, and formation of 2,3,4-trisubsti-
tuted pyrroles. On the contrary, electron-donating or electronically neutral
substituents at the R-position of the oxime and the lack of an amine base
inhibit enolization, allowing a [1,3] rearrangement of the O-vinyl oxime
intermediate to occur prior to tautomerization, cyclization and elimination
to provide 2,3,5-trisubstituted pyrroles (Scheme 14) (11JOC3203).
The synthesis of substituted pyrroles using iodine-catalyzed adjusted P–K
methods has been accomplished in superior yields (Scheme 15) (04SL2642,
04JOC213).
2,5-Di- and 1,2,5-trisubstituted pyrrole derivatives have been syn-
thesized by Surya Prakash Rao and Jothilingam from (E)-1,4-diaryl-
2-butene-1,4-diones in a one-pot operation through domino-pathways via
a palladium promoted transfer and hydrogenation followed by a P–K reac-
tion using ammonium formate and its analogs. The maximum yield was
reported when the reaction was tested in PEG-200 or tetraethylene glycol
(Scheme 16) (01TL6595).
The synthesis of one-pot, three-step, four-component 1,2,3,5-tet-
rasubstituted pyrroles has been described using a coupling-isomerization-
Stetter reaction followed by a P–K sequence of an electron-poor (hetero)
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 105

Scheme 14 

Scheme 15 

Scheme 16 

aryl halide, a terminal propargyl alcohol, an aldehyde, and a primary amine

by Braun et al. (Scheme 17) (01OL3297).
The preparation of a new nano-organo catalyst (Scheme 18) using sup-
porting glutathione on magnetic nanoparticles showed excellent activity
for microwave-promoted P–K, aza-Michael reactions, and pyrrole synthesis
(Scheme 19) (10T1091).
The synthesis of 2,5-dimethyl-N-substituted pyrroles from substituted
anilines and 2,5-hexanedione catalyzed nano lead oxide were described by
Pasha et al. (11MI891). The aforementioned catalyst has also been used in a
one-pot synthesis of quinoxalines (06JICS267). Protonated alkyldipeptides
react with acetonylacetone in a Fourier transformation cyclotron resonance
(FT-ICR) mass spectrometer. It is believed that this biomolecular gas-phase
reaction is catalyzed by the peptide carbonyl groups, which promote the
protonation of the acetonylacetone carbonyl oxygen atoms, furnishing the
106 Soheila Khaghaninejad and Majid M. Heravi

Scheme 17 

Scheme 18 

Scheme 19 
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 107

Scheme 20 

Scheme 21 

acetonylacetone carbonyl group more susceptible to nucleophilic attack by

the peptide amino group.
Gur et al. has explored whether or not the gas-phase P–K reactions
can be used to derivatize protonated peptides. Results obtained from both
the previously studied bimolecular hydrogen deuterium exchange behav-
ior, and this aforementioned reaction, reveal that the bimolecular reactiv-
ity of protonated alkyldipeptides is proportional to the extent of mobility
of the proton within the reactive complex (Scheme 20) (97IJM135).
Ryzhkov et al. also reported the synthesis of N-alkylpyrrole 21 with a
chiral substituent at the nitrogen atom using chiral esters of various amino
acids 20 (Scheme 21) (11KG182).
Fu et al. reported bipyrrole-based natural products such as 1,2′-and 1,3′-
bipyrroles 23 and 24 from 2- and 3-nitropyrroles 22 in a one-pot reaction
following a sequential nitro group reduction (Scheme 22) (08TL3545).
Various N-substituted pyrroles such as 2,3-, 2,4-, 1,2,3-, 1,2,4-, 2,3,5-,
and 1,2,3,5-substituted monocyclic as well as a number of fused-ring
polycyclic derivatives were obtained in two steps involving an olefin oxi-
dative cleavage and P–K cyclization of enones or enals 25 with alkynes
(Scheme 23) (11OL3289).
108 Soheila Khaghaninejad and Majid M. Heravi

Scheme 22 

Scheme 23 

A substituent effect on the diastereoselectivity of the Mo(CO)6-medi-

ated allenic Pauson–Khand reaction demonstrates that amino acid alle-
nynes and aromatic side chains affords R-alkylidene cyclopentenone with
the opposite diastereoselectivity compared to those with an aliphatic side
chain, attributed to complexation of the metal mediator to the aromatic
ring. An isomerization of one of the diastereomers of the R-alkylidene
cyclopentenone led to eventual decomposition. The stable diastereomers
reacted, following the Stetter reaction strategy, leading to 1,4-diketones,
which were converted to pyrroles.The observation that the first generation
of 2-alkyl-substituted pyrroles were unstable led to a second generation of
2-carboxamide pyrroles with sufficient and required stability for biological
activity tests, which are in progress (Schemes 24 and 25) (05JOC1745).
The synthesis of new derivatives of 1H-pyrrole such as 1,2,3,5-tetra-
substituted 28 from enaminone 26 and α-haloketones 27, in solventless
system, has also been described (Scheme 26) (11MI1219).
The synthesis of piperidinyl pyrroles 38 from 4-amino-N-ben-
zylpiperidine 29 as a primary amine through a modified P–K ­reaction
and Sonogashira cross-coupling has been reported by Haubmann et al.
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 109

Scheme 24 

Scheme 25 

Scheme 26 

(Figure 1). 2,2-Dicyanovinyl derivatives 31 can be prepared from the

reaction of 30 with malononitrile via Knoevenagel condensation.
Cyclocondensation of the carbaldehyde 30 with tosylmethyl isocyanide
(TosMIC) affords 32. Compounds 34–35, carrying conjugated substitu-
ents in position 2 of the pyrrole, can be synthesized using the P–K prod-
uct 33. Thus, introduction of a formyl group under Vilsmeier conditions
yields, regioselectively, the pyrrole-2-carbaldehyde 34, which can be
110 Soheila Khaghaninejad and Majid M. Heravi

Figure 1  Piperidinyl pyrroles. (For color version of this figure, the reader is referred to
the online version of this book.)

Scheme 27 

converted to the oxazole 36 using the aforementioned reaction con-

ditions. The 2-iodopyrrole 37 was prepared by iodination of 33 using
NIS as an iodinating reagent. Sonogashira cross-coupling of 37 with the
appropriate alkynes afforded the corresponding piperidinyl pyrroles 38
(Scheme 27) (99BMC3143).
Nevolina et al. reported a one-pot synthesis of pyrrolo[1,2-d][1,4]
benzodiazepin-6-ones 40 based on acid-catalyzed recyclization of
N-[2-(5-alkyl-2-furyl)phenyl]-2-aminoacetamides 39 (Scheme 28)
(11S3547). This reaction is believed to proceed via furan ring opening
to afford the diketone moiety, followed by sequential reactions of the
free amino group with both carbonyl groups.
Iden and Lubell reported the coupling of β-amino ester 41 with N-Boc-
α-amino acid 42 using O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 111

Scheme 28 

Scheme 29 

tetrafluoroborate (TBTU) and N-hydroxybenzotriazole (HOBT) in dichlo-

romethane to yield α-aminoacyl-β-amino esters 43 (Scheme 29) (03MI1498,
06OL3425). Then 43 reacted with vinylmagnesium bromide in the pres-
ence of copper cyanide as a catalyst in THF to afford homoallylic ketones 44
(03OL4887). A route featuring nitrogen deprotection and reduction of the
112 Soheila Khaghaninejad and Majid M. Heravi

Scheme 30 

Scheme 31 

imine intermediate with sodiumtriacetoxyborohydride in dilute dichloro-

ethane converts 44 to diazepinones 45 (96JOC3849). Pyrrolodiazepinones
48 and 49 were prepared from the common homoallylic ketone inter-
mediate 44. From the oxidation of olefin 44, using either ozonolysis or
periodate/osmium tetraoxide, 4-keto aldehydes 46 and 1,4-diketones 47
were obtained. Pyrrolodiazepinones 48 and 49 were synthesized from 46
and 47 by nitrogen deprotection and a P–K condensation, respectively
(1885CB299, 1885CB367).
The synthesis of N-aryl 50 and N-aryl sulfonyl pyrroles via an uncata-
lyzed P–K condensation under MW irradiation in water was described by
Wilson et al. (Scheme 30) (09TL4807).
The synthesis of 2,2′-bipyrrole-based natural products 51 in three
steps from pyrrolyl keto alcohols by a sequential alcohol oxidation, fol-
lowed by a P–K reaction was described by Fu and Gribble (Scheme 31)
(08TL7352).
Ji et al. reported that acetonylacetone reacts with either thiourea,
aniline, glycine or glutamic acid to give 2,5-dimethyl pyrrole deriva-
tives. The acetonylacetone with thiourea affords 52 in low yield. That is
probably due to the special structure of thiourea, which has steady P-π
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 113

Scheme 32 

conjugated system, making it difficult to have an efficient P–K reaction.

Treatment of acetonylacetone with aniline in anhydrous ethanol gives a
pyrrole derivative 53. Next, 53 in the presence of formaldehyde, diethyl-
amine and acetic acid afforded the product 54. The key step is a Mannich
reaction involving, the nucleophilic addition of an amine to formal-
dehyde (94MI677), which furnished imine ions. Compound 55 was
obtained via the reaction of acetonylacetone with glycine in anhydrous
ethanol in 87% yield. Compound 55 then reacted with dichloromethane
solution of either phenethyl alcohol, phenylallylic alcohol or leaf alcohol
to afford ester derivatives 56, 57 and 58 respectively. Glutamic acid and
acetonylacetone react in anhydrous ethanol and acetic acid to give 59
(Scheme 32) (10MI919).
114 Soheila Khaghaninejad and Majid M. Heravi

Scheme 33 

Scheme 34 

A method for the solution-phase synthesis of pyrrole-amides 60 was

described by Bianchi et al. (2006JA491) (Scheme 33). The β-ketoesters
reacted with aldehydes along with oxidation with PCC to produce a
series of substituted 1,4-dicarbonyl compounds. Rapid cyclization using
the microwave enhanced P–K reaction provided 24 pyrrole esters, which
were further functionalized via a trimethylaluminum-mediated aminoly-
sis to produce 288 different pyrrole-3-amides. Tetrasubstituted pyrroles
are significant as antibacterial, antiviral, anti-inflammatory and antioxidant
agents.
The synthesis of pyrrole-based amino acids of 1–4 ketoesters derived
from the corresponding β-ketoester have been presented by Alongi et al.
The amino group, which was protected with the Cbz moiety, is present on
the side chain in position 1 or 2 and the carboxylic group is fixed in posi-
tion 3 (Scheme 34) (05TL7069).
The synthesis of 178 tricyclic pyrrole-2-carboxamides 61 from
three benzoyl-protected amino acid methyl esters in nine steps via the
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 115

Scheme 35 

Figure 2  Diarylpyrroles. (For color version of this figure, the reader is referred to the
online version of this book.)

Pauson–Khand, Stetter reactions and a microwave-promoted P–K reaction

as a key consequence was reported by Werner et al. (Scheme 35) (06MI368).
Further manipulation was introduced, using two glyoxaldehydes and 41
primary amines.
Khanna et al. synthesized a series of 1,2-diarylpyrroles using the P–K
reaction as inhibitors of the human cyclooxygenase-2 (COX-2) enzyme.
They claimed that diarylpyrroles (Figure 2) are biologically very potent
(COX-2, IC50 = 60 nm) and selective (97JMC1619).
The keto acids 62 and 63 reacted with hydrazine derivatives in etha-
nol (1968AHC121, 1979AHC363, 1990AHC385) to give 64 and 65
respectively. Then 64 and 65 were reacted with suitable 1,4-dicarbonyl
compounds, in acetic acid under the P–K pyrrole synthesis conditions to
obtain the aimed compounds 67 and 68 respectively (Schemes 36 and 37)
(04MI1089).
116 Soheila Khaghaninejad and Majid M. Heravi

Scheme 36 

Scheme 37 

3.  FURAN SYNTHESIS

The furan ring can be found in many natural products, and several
derivatives of furan have industrial applications. One of the most important
methods for the preparation of furans is the P–K synthesis. Although the
reaction has been known for more than a century, very little was known
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 117

Scheme 38 

and understood about the mechanism. In 1995 Amarnath reported an

experimental proof for the mechanism of the P–K reaction involving the
acid-catalyzed cyclization of an l,4-diketone to form a furan (95JOC301).
It involves the fast protonation of one of the carbonyl groups, followed
by the electrophilic attack on the protonated carbonyl by the enol being
generated at the other carbonyl group. This is proposed to explain the dif-
ference in reaction rates between the diastereomers of 3,4-disubstituted
2,5-hexanediones.
Sasikala et al. reported the synthesis of 2,3,5-trisubstituted furans 70
from α-formylaroylketene dithioacetals 69 that involves conversion
of 69 to ­vinylketene dithioacetals via a Wittig reaction and subse-
quent N-­bromosuccinimide-­mediated (NBS) cyclization to 70.Then 70 was
reacted with ethylamine in refluxing ethanol and under the reaction condi-
tions resulted in the amino derivatives 71 (08JOC7625).This method is highly
useful in pharmaceutical development and medicinal chemistry (Scheme 38)
(11TL1667).
Multisubstituted furans 74 were synthesized from various ketones with
vinyl bromides 72 catalyzed by CuI/3,4,7,8-tetramethyl-1,10-phenanthro-
line 73 (Scheme 39) (10TL3678).
The phosphonic furans 76 were synthesized from the key intermediates
such as phosphonic dicarbonylated 75. This method was reported by Truel
et al. (97SC1165) (Scheme 40).
Alkylation of tert-butyl acetoacetate with an α-haloketone and sub-
sequent treatment of the intermediate with trifluoroacetic acid (TFA)
produced substituted 2-hydroxy-3-acetylfurans. Further alkylation of
the intermediate with trifluoroacetic acid gives access to disubstituted
2-­methylfurans (Scheme 41) (00OL3535).
A synthesis of indolyl-furan 77 from 1,4-dicarbonyl compounds via
linear domino reactions has been researched by Yang et al. (Scheme 42)
(11TL5142). This protocol is very useful in synthetic and medicinal chem-
istry.
118 Soheila Khaghaninejad and Majid M. Heravi

Scheme 39 

Scheme 40 

Scheme 41 

Lapina et al. reported that aminomethyl derivatives of furancarbox-

ylic acids 78 can react with 1,4-dicarbonyl compounds under the P–K
conditions to form the corresponding pyrrole ring 79. The aminomethyl
derivatives of furancarboxylic acids react faster than their analogs. Due to
combination of both parts in one molecule, these compounds can be bio-
logically active (Scheme 43) (07MI923).
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 119

Scheme 42 

Scheme 43 

4.  THIOPHENE SYNTHESIS

Mishra et al. published a review on the synthesis, properties and bio-
logical activities of thiophenes (11MI38). Thiophene belongs to an impor-
tant class of heterocyclic compounds and it is a significant and important
heterocycle in drugs being used in clinic, pharmacology and therapeutic
(10MI215). Thiophene structure is found in certain natural products.
Many thiophene derivatives have been developed as chemotherapeutic
agents and have a broad range of applications. Thiophene nucleus is one of
the most important heterocycles with extraordinary pharmacological activi-
ties (Figure 3). Thiophene derivatives show different activities. For instance,
1-[1-(2, 5-dimethylthiophene-3-yl) ethyl]-1-hydroxyurea 80 shows anti-
inflammatory activity, while the maleate salt of 1-(2,5-dimethylthiophene-
3-yl)-3-(5-methyl-1H-imidazol-4-yl) propan-1-one 81 behaves as serotonin
antagonist and is prescribed for the treatment of alzheimer disease.The latter
120 Soheila Khaghaninejad and Majid M. Heravi

Figure 3  Thiophene nucleus. (For color version of this figure, the reader is referred to
the online version of this book.)

Scheme 44 

has also been applied in the formulation of various inks for the computer
printers by the Xerox Group (99USP5958119) and as starting material
for the production of certain herbicides and pesticides (98USP5807805).
2-Butylthiophene 82 has been used as a raw material for the preparation of
some anticancer agents and 2-octylthiophene 83 has its particular usage in
the synthesis of anti-atherosclerotic agents such as 84 (11MI38).
Synthetic protocols to thiophenes include: the Fiesselmann, ­Hinsberg,
Gewald aminothiophene synthesis and the P–K thiophene synthesis,
which is also known as Paal thiophene synthesis. In the latter, 1,4-dicar-
bony1 compounds react with a source of sulfur resulting in thiophenes
(Scheme 44) (97T11529, 2005MI1I). The standard procedure for the Paal
thiophene synthesis employs P2S5 as the sulfur atom source.
Treatment of a dicarbonyl compound with phosphorus pentasulfide is
a main route for the preparation of the alkyl substituted thiophenes. An
alternative procedure that has been used is the Friedel–Crafts acylation, fol-
lowed by Wolff–Kishner reduction.When the α-position has an alkyl group,
2-acyl-5-alkylthiophenes are synthesized and when both α-positions carry
alkyl groups, 3-acyl-2,5-dialkylthiophenes are the products (Figure 4).
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 121

Figure 4  3-Acyl-2,5-dialkylthiophenes. (For color version of this figure, the reader is

referred to the online version of this book.)

Figure 5  Bis(trimethylsilyl) sulfide.

Scheme 45 

A thiophene ring can be built from nonheterocyclic precursors by two

reaction pathways (07T2724). a) Substituted open chain precursors. This
method involves the introduction of sulfur into a starting material contain-
ing the complete carbon skeleton. b) The functionalization at the positions
α or/and β to the sulfur atom of the preconstructed thiophene nucleus.
This route involved the reaction of a mercaptoacetate with a 1,3-dicar-
bonyl compound or the reaction of a thiodiacetate with a 1,2-dicarbonyl
compound. Recently, Lawesson reagent (LR), bis(trimethylsilyl) sulfide
(Figure 5), has also been widely used as a sulfur source (94JOC3695).
Lawesson reagent was first synthesized in 1956, via the reaction of arenes
with P4S10 (1956JA5018).
In 1952, Campaigne et al. reported that the intermediate in Paal thio-
phene synthesis is a thione and not a furan. Comparison of both routes, as
follows, indicated that the diketones give a higher yield of the thiophene,
suggesting that the furan is not a potential intermediate in the reaction
pathway, but is only a secondary product (Scheme 45) (52JOC1405).
Based on these observations, the following mechanism can be postulated
(Scheme 46).
122 Soheila Khaghaninejad and Majid M. Heravi

Scheme 46 

5.  NATURAL PRODUCTS AND MACROMOLECULES

SYNTHESIS
The monomer (DPB) 88 was synthesized from 1,4-di(2-thienyl)-1,
4-butanedione 86 using a two-step process. In the first step, thiophene
reacts with succinyl chloride 85 in the presence of AlCl3 in CH2Cl2 to
give 1,4-di(2-thienyl)-1,4-butanedione 86.Then 86 reacted with 4-amino-
benzonitrile, and PTSA as a catalyst in toluene to provide 1-(benzonitryl)-
2,5-di(2-thienyl)-1H-pyrrole (BTP) 87, and at the final step the latter is
hydrolyzed to (2,5-di(2-thienyl)-1H-pyrrole-1-yl)-1-(p-benzoic acid)
(DPB) 88 (Scheme 47) (10SM413).
The synthesis of 1-(meso-phenyl-4,4-difluoro-4-bora-3a,4a-diaza-
s-indacene)-2,5-di-2-thienyl-1H-pyrrole (SNS-BODIPY) 91 was carried
out from 1,4-di(thiophen-2-yl)butane-1,4-dione 89 (00MI107) and an
amino boron-dipyrrin dye 90 (2001JA100) (08MI786) (Scheme 48).
Hwang et al. synthesized 1-(3-pyridinyl)-2,5-di(2-thienyl)-1H-pyrrole
(PTPy) 92 and 1-(1,10-phenanthrolinyl)-2,5-di(2-thienyl)-1H-pyrrole
(Phen TPy) DTPs 93 using a catalytic amount of p-toluenesufonic acid
(PTSA) in dry toluene (Scheme 49) (10MI1286).
A series of pyrrole/polycyclic aromatic unit (Figure 6) hybrid fluoro-
phores was obtained from a two-stage synthetic method.Their central cores
were built via a P–K reaction. End capping triflate on to the central pyrrole
core provides an opportunity for the core to attach with various polycy-
clic aromatic units. The Buchwald–Hartwig amination protocol and the
Suzuki–Miyaura cross-coupling strategy were taken up to incorporate the
triflate end-capping pyrrole with N-phenylnaphthalen-1-amine and vari-
ous polycyclic aromatic units to form the hybrid fluorophores. Conclusion
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 123

Scheme 47 

Scheme 48 

Scheme 49 
124 Soheila Khaghaninejad and Majid M. Heravi

Figure 6  Pyrrole/polycyclic aromatic unit. (For color version of this figure, the reader is
referred to the online version of this book.)

Scheme 50 

of this study demonstrates that the sterically induced fluorescence of

crowded pyrrole and the fluorescent polycyclic aromatic units dramatically
have a special effect in the emission properties of the hybrid fluorophores
(Scheme 50) (2010JA4004).
Zhang et al. synthesized polymeric amines 94 from various low
molecular weight aliphatic polyketones with different kinds of di-amines
(Scheme 51) (08JAPNAB262). In this reaction, two adjacent carbonyl
groups react with two amino groups in the P–K reaction manner, to
afford a pyrrole ring. Protonation or alkylation of the amino groups give
interesting aqueous solution properties to the resulting polymer. Approx-
imately 70–80% of carbonyl groups of the polyketones may be trans-
formed into pyrrole moities in the spine. These polymers can be used as
polymeric surfactants and polyelectrolytes.
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 125

Scheme 51 

Amaladass et al. reported a two-step synthesis of π-conjugated mono-

mer 2,5-di(selenophen-2-yl)pyrroles, (SeNSe) 96 and 2,5-difuranylpyr-
roles, (ONO) derivatives using the P–K reaction of a diketone intermediate
and a wide range of aliphatic and aromatic amines (11TL711). The precur-
sor for this conversion can be obtained from two different pathways. (1)
Double Friedel–Crafts acylation on selenazole. (2) The reaction of succinyl
chloride with methoxy methyl ammonium chloride to afford 95, followed
by the reaction of the latter with selenazole and n-BuLi/THF system, in
45% yield. Analysis on SeNSe and ONO derivatives show lower oxidation
potentials compared with those of their terselenophene and terthiophene
analogs (Scheme 52) (02JCS(P1)2403).
Dimers or trimers are block copolymers in chemical generations that
have two or more heteroaromatic rings derived from thiophenes, furans
and pyrroles (86POLLDG455, 89POLLDG1319). Ak et al. reported a
synthesis of a polythiophene derivative of 1,6-bis(2,5-di(thiophen-2-yl)-
1H-pyrrol-1-yl)hexane (TPH) 97 by electrochemical oxidative polymer-
ization.They also conducted a synthesis via a potentiostatic electrochemical
polymerization to synthesize the polymer P(TPH) and its copolymer with
3,4-ethylenedioxythiophene (P(TPH-co-EDOT)). This route is useful for
the preparation of trimeric thiophene-pyrrole-thiophene derivatives substi-
tuted at the N-atom of the pyrrole ring (Scheme 53) (08JEC55).
Yavuz et al. described a two-step synthesis of tetrakis(4-(2,5-di-
2-­thiophen-2-yl-pyrrol-1-yl)) substituted metal-free (H2Pc-SNS) and
zinc phthalocyanine (ZnPc-SNS) complexes 99 (10JEC116) (Scheme 54).
The first step involved combination of 1,4-di(2-thienyl)-1,4-butadione
126 Soheila Khaghaninejad and Majid M. Heravi

Scheme 52 

Scheme 53 

(91S462) and 4-aminophthalonitrile (76JCS(P1)42) via the P–K reaction

(02T3467), to obtain product SNS-PN 98. In the second-step, SNS-PN
was dissolved in n-hexanol under nitrogen in the presence of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU).
The synthesis of prophyrazines possessing peripheral 2,5-dimethylpyrrol-
1-yl has been claimed by Szczolko et al. (Scheme 55) (12TL2040). Diamino
malononitrile 100 reacts with 2,5-hexanedione in benzene in the presence
of oxalic acid to give malononitrile derivative 101 via the modified P–K
synthesis, namely Begland’s procedure (74JOC2341). Compound 101 was
then methylated with dimethyl sulfate in the presence of NaH/THF to give
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 127

Scheme 54 

Scheme 55 

derivative 102 (03JOC1665). Compound 102 was applied in the Linstead

macrocyclization with Mg(n-BuO)2 in n-butanol to afford porphyrazine
103, bearing an interchange system of peripheral substituents, in 25% total
yield (01MI473, 52JCS4839). Demetallation of 103 was carried out in tri-
fluoroacetic acid (TFA) (01MI473, 09POL2579), which led to free-base
porphyrazine 104 in 35% yield, and other demetallated side-products. Dif-
ficulties encountered in separation of 104 from the side-products prompted
the researchers to apply another macrocyclization method on 102. They
found macrocyclization of 102 in dimethylaminoethanol (DMAE) along
with the use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base to
be the procedure of choice mainly due to the short reaction time (2 h)
128 Soheila Khaghaninejad and Majid M. Heravi

Scheme 56 

and lack of side products (94JCS(CC)697, 99ICA80). Malononitrile 102

was also used in macrocyclization reactions in n-pentanol with DBU using
various metal salts such as Zn(OAc)2, MnCl2.4H2O, and CuCl2 to afford
metallated porphyrazines 105–107. Only in the macrocyclization reaction
leading to copper porphyrazine 107 an additional isomeric side-product
was detected (12TL2040).
The two-steps synthesis of 1-(4-fluorophenyl)-2,5-di(thiophen-
2-yl)-1H-pyrrole (FPTP) 108 was described by Arslan et al. The first step
involves synthesis of 1,4-di(2-thienyl)-butane-1,4-dione and the second
step is the dehydrative cyclization of diketone with an amine via the P–K
reaction (Scheme 56) (07MI410).
Two dithienylpyrrole compounds with anthraquinone units (SNS-1AQ)
109 and (SNS-2AQ) 110 were synthesized in three steps using the P–K
condensation (Scheme 57) (10MI6933).
Camurlu et al. reported that 4-(2,5-di-thiophen-2-yl-pyrrole-1-yl)-
N-(ferrocenyl methyl)-phenylamine (SNS-An-Fc) 112 can be obtained in
a three-step synthetic route (Scheme 58) (12MI245). The first step involves
synthesis of 1,4-di(2-thienly)-1,4-butanedione 111 through the reaction
of thiophene and 1,4-dichlorobutanedione in the presence of AlCl3, and
the second step includes a P–K reaction between 1,4-di(2-thienly)-1,4-­
butanedione and p-phenylenediamine in the presence of a catalytic amount
of propionic acid. In the final step, one-pot condensation of ferrocenecarb-
aldehyde with SNS-An, gave a Schiff base which was reduced by NaBH4.
Three double dithienylpyrroles derivatives di-(4-[2,5-di(2-thienyl)-
1H-1-pyrrolyl]benzene) (2SNS-BEN-BEN) 113, di-(4-[2,5-di(2-
thienyl)-1H-1-pyrrolyl]phenyl)ether (2SNS-BEN-O-BEN) 114 and
di-(4-[2,5-di(2-thienyl)-1H-1-pyrrolyl]phenyl)methane (2SNSBEN-CH2-
BEN) 115 were synthesized using the P–K strategy. Furthermore, their corre-
sponding polymer films, P2SNS-BEN-BEN (P1), P2SNS-BEN-O-BEN (P2)
and P2SNSBEN-CH2-BEN (P3), were prepared by electropolymerization.
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 129

Scheme 57 

Scheme 58 

Their spectroelectrochemical, electrochromical and fluorescent properties

were investigated and compared (Scheme 59) (11JEC351). They have been
prepared from 1,4-di(thiophen-2-yl) butane-1,4-dione and various aromatic
diamines. Their corresponding polymer films were also synthesized via elec-
tropolymerization (11MI6352).
1,4-Di(thiophen-2-yl)butane-1,4-dione reacted with the correspond-
ing amine derivatives in the presence of p-toluenesulfonic acid in toluene
130 Soheila Khaghaninejad and Majid M. Heravi

Scheme 59 

to provide N-substituted (R = 116, 117, 118, 119), 1-(1-naphthyl)-2,

5-di(thiophen-2-yl)-1H-pyrrole, 1-(2-naphthyl)-2,5-di(thiophen-2-yl)-
1H-pyrrole, 1-(9H-fluoren-2-yl)-2,5-di(thiophen-2-yl)-1H-pyrrole and
1-(benzo-15-crown-5)-2,5-di(thiophen-2-yl)-1H-pyrrole, respectively
(Scheme 60) (08MI665).
The monomer of 2,5-di(thiophen-2-yl)-1-p-tolyl-1H-pyrrole (DTTP)
120 was synthesized via the reaction of 1,4-di(2-thienyl)-1,4-butanedione,
p-toluidine and catalytic amount of p-toluenesulfonic acid (67RTC37) by
Yigitsoy et al. (Scheme 61) (07MI3898).
1-(2-Ethyl-hexyl)-2,5-di-thiophen-2-yl-2,3-dihydro-1H-pyrrole
(SNS-HE) 121 was synthesized by a two-step synthetic route, the first
step involves synthesis of 1,4-di(2-thienyl)-1,4-butanedione through the
reaction of thiophene and 1,4-dichlorobutanedione and the second step
includes a P–K reaction between 1,4-di(2-thienyl)-1,4-butanedione and
2-ethyl-1-hexylamine in toluene. Additionally, copolymers based on SNS-
HE and 3,4-ethylenedioxythiophene (EDOT) were electrochemically syn-
thesized and characterized (Scheme 62) (12MI50).
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 131

Scheme 60 

Scheme 61 

Scheme 62 

Morita and Kato reported the synthesis of poly(1-oxotrimethylene)

(ECO) (Figure 7), from copolymerization of ethylene and carbon mon-
oxide (Scheme 63) (06JAPNAB3358). Due to its planar zigzag confor-
mation and because of its small cross-sectional area in the crystalline
phase, it is expected to form a high strength and high elastic-modulus
fiber. Since the starting monomers, ethylene and carbon monoxide, are
easily available and inexpensive, it is worthy of being considered as a
novel industrial fiber material. ECO can be used in wet spinning. Over
132 Soheila Khaghaninejad and Majid M. Heravi

Figure 7 Poly(1-oxotrimethylene).

Scheme 63 

a certain heating duration, however, the strength of the ECO fibers

significantly decreased. A higher heating temperature diminished the
heating time at which the extreme decrease in the maximum tenacity
commenced. On the basis of UV measurements of the undrawn fibers,
heating ECO in the aqueous metal salt solution invoked the thermal
degradation of ECO because of aldol condensation or the P–K furan
synthesis.
Zhu et al. reported that the lipid oxidation product 4-oxo-2-nonenal
(ONE) can be prepared from peroxidation of polyunsaturated fatty acids
and is a highly reactive protein cross-linking reagent. The major classes
of cross-links includes conjugate addition of side chain nucleophiles, for
example, sulfhydryl or imidazole groups to the CdC of ONE to afford
either a 2- or 3-substituted 4-ketoaldehyde, which then experiences a P–K
reaction using a primary amine of protein lysine side chains. Trapping of
ONE by GSH or carnosine results in a 4-ketoaldehyde capable of modify-
ing protein-based lysines (Schemes 64 and 65) (09MI1050).
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 133

Scheme 64 

Scheme 65 
134 Soheila Khaghaninejad and Majid M. Heravi

Figure 8  Streptorubin B. (For color version of this figure, the reader is referred to the
online version of this book.)

Scheme 66 

The enantioselective total synthesis of the natural product streptorubin B

(Figure 8) with their highly strained pyrrolophane cores is described by Hu
et al.A credible route involves a one-pot enantioselective aldol cyclization/Wit-
tig reaction and an anionic Oxy-Cope rearrangement to make the 10-mem-
bered ring. Analysis of pyrrole 122 showed that the syn 123 atropisomer was
formed kinetically during the P–K condensation (Scheme 66) (2011JA1799).
Salamone and Dudley described the preparation of a cyclopentenone-
fused pyrrolophane as a tricyclic core of roseophilin (Figure 9). The syn-
thetic route involves a palladium-catalyzed annulation, followed by an
oxidative cleavage sequence that provides a macrocyclic ketoester 124 and
then the P–K method and Friedel–Crafts acylation completes the synthesis
of the pyrrolophane model system 125 (Scheme 67) (05OL4443).
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 135

Figure 9  Roseophilin. (For color version of this figure, the reader is referred to the online
version of this book.)

Scheme 67 

Okada et al. reported the stereoselective total synthesis of (−)funebrine

126, starting from 2-butyn-1-ol in 14 steps. In this route (4R)-amino lac-
tone reacted with a 1,4-diketone in the presence of Et3N (Scheme 68)
(11TL5744).
The total synthesis of (±) funebral 130 as a pyrrole alkaloid was accom-
plished by Yu and Le Quesne (Scheme 69) (95TL6205). Lactone 127 reacted
with (2,9-dimethyldeca-2,8-dien-4,7-dione) 128 and catalyzed by titanium
isopropoxide to provide pyrrolic lactone 129 in 53% yield. Compound 129
was then converted to 130 via a route shown in Scheme 69.
4-(1-(4-Fluorophenyl)-2-methyl-5-(4-(methylthio)phenyl)-
1H-(pyrrol-3-yl)methyl)thiomorpholine 135 has antitubercular activity and
its safety is comparable with the common antitubercular drugs streptomy-
cin and rifampin. Substituted benzaldehydes 131 reacted with methyl vinyl
ketone 132 in the presence of triethylamine to afford diketone 133.The latter
was then cyclized in the presence of an appropriate amine and p-toluenesul-
fonic acid as a catalyst to afford 1,5-diarylpyrroles 134. Finally, following the
Mannich reaction protocol, pyrrole 134 was reacted with thiomorpholine
and formaldehyde in a mixture of acetic acid and acetonitrile to provide the
target compound 135. The pathway is shown in (Scheme 70) (10MI8076).
Taghavi-Moghadam et al. have focused their research on the applica-
tion of microreaction technology in the science industry. For example, the
136 Soheila Khaghaninejad and Majid M. Heravi

Scheme 68 

Scheme 69 

reaction is similar in mixing, heat transfer, and residence time distribution.

Along with these activities, they reported the synthesis of a pyrrole via
application of the P–K reaction combined with this technology. Important
advantages mentioned are high operational safety and the possibility to
transfer the experimental results directly from laboratory to the production
of pilot-plant scales (01MI652). This first, kilogram quantity application of
Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds 137

Scheme 70 

the P–K method makes it a good candidate for the industrial synthesis of
various five-member heterocycles containing N, S and O atoms.
Sawant and Maier described a method for the preparation of atorvas-
tatin lactone 140 using a P–K synthesis of pyrrole (Scheme 71) (10T9738).
The condensation of diketone with 2-((4R,6S)-6-(2-(benzyloxy)ethyl)-
2,2-dimethyl-1,3-dioxan-4-yl)ethanamine 136 as primary amine provided
pyrrole 137. Its acidic form 138 gave amide 139 via amide formation, ben-
zylation, oxidation and lactonization, followed with several other required
steps to yield atorvastatin lactone 140.
Ha et al. worked on the initial structure–activity relationships of a series
of 1,5-biaryl pyrrole EP1 receptor antagonists (Figure 10). The results
showed that an isobutyl group is the effective substituent. Cyclopentyl-
methyl and cyclohexylmethyl are also reckoned to be efficient for replace-
ments of the benzyl group (06BMC3657).

6.  CONCLUSION
In general, the P–K reaction is an efficient method to prepare a
wide variety of pyrroles, furans and thiophenes using various catalysts.
These aforementioned five-membered heterocycles are very important
key heterocycles, and are widely found in pharmaceuticals, natural prod-
ucts and macromolecules. The mechanism of the P–K reaction involves
138 Soheila Khaghaninejad and Majid M. Heravi

Scheme 71 

Figure 10  1,5-Biaryl pyrrole EP1, receptor antagonists. (For color version of this figure,
the reader is referred to the online version of this book.)

the cyclocondensation of 1,4-dicarbonyl compounds with primary amines.

Our survey showed that this synthetic method is much more common and
more widespread for the synthesis of various derivatives of pyrroles and
furans relative to thiophene derivatives. Surveying the number of articles
from 1884 to 2012 shows that the highest numbers have been published in
2006 (Figure 11). All in all, the broad applications of the P–K reaction in
 Paal–Knorr Reaction in the Synthesis of Heterocyclic Compounds
Figure 11  Surveying the number of articles from 1884 to 2012. (For color version of this figure, the reader is referred to the online version of
this book.)

139
140 Soheila Khaghaninejad and Majid M. Heravi

drug development as antibacterial, anti-inflammatory, antitumor, antima-

larial, antibacterial, antiviral and antioxidant agents are every day.

ACKNOWLEDGMENTS
We are grateful to Professor. M. Tajbakhsh, Dr M. Shiri and Dr H. Dolatabadi for their
invaluable comments and suggestions. Our thanks are also extended to the Department of
Chemistry of Alzahra University for the supports and encouragements.
S. Khaghaninejad is thankful to Arak University for the given opportunity to further
her study.

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