Synthesis of 2,3-dicarbonylated pyrroles and furans via the three-component Hantzsch reaction

Article abstract of DOI:10.1016/j.tetlet.2012.04.022

Pyrroles containing a 2,3-dicarbonyl substitution pattern are synthesized in one step via a three-component Hantzsch procedure. The normally difficult-to-access substrates are readily obtained in short reaction times and in moderate to good yields, giving pharmaceutically attractive products containing multiple handles for further elaboration.

Full text of DOI:10.1016/j.tetlet.2012.04.022

Tetrahedron Letters 53 (2012) 3056–3060
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2,3-dicarbonylated pyrroles and furans via the three-component
Hantzsch reaction
⇑
Thomas A. Moss , Thorsten Nowak
AstraZeneca Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrroles containing a 2,3-dicarbonyl substitution pattern are synthesized in one step via a three-compo-
nent Hantzsch procedure. The normally difficult-to-access substrates are readily obtained in short reac-
tion times and in moderate to good yields, giving pharmaceutically attractive products containing
multiple handles for further elaboration.
Received 6 March 2012
Revised 30 March 2012
Accepted 4 April 2012
Available online 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hantzsch
Pyrrole
Three-component
Heterocycle
Pyrroles are an important class of simple heterocycles, being
found in a broad range of natural products1 and displaying a wide
spectrum of pharmacological activity.2 The pyrrole nucleus also
occupies a central role in nature, being a structural component of
both haem and chlorophyll, as well as finding use in materials
science.3 As such, a number of synthetic methods have been
reported for the synthesis of both undecorated, and polysubstituted
pyrroles.4 One of the oldest is the Hantzsch procedure, which
to widen the scope of the Hantzsch procedure have been reported,
such as the use of solid supports7 and supramolecular catalysis.8
During the course of our studies, we required 2-formylpyrrole-
3-carbonitrile (1) and ethyl 2-formylpyrrole-3-carboxylate (2), and
derivatives thereof. We were surprised to find that both were
poorly precedent in the literature, despite their simplicity and po-
tential use as synthetic building blocks. Although some routes are
disclosed for the synthesis of unsubstituted pyrroles bearing 2,3-
carbonyl groups,9 they are typically long and/or limited in scope.
In fact, in a recent review on the challenges of synthesizing highly
functionalized pyrroles, only one example was given with a substi-
tution pattern similar to 1 and 2.10 To the best of our knowledge,
only a single report on the synthesis of nitrile 1 is described in
the literature, via photochemical pyrolysis of pyridine N-oxides.11
Requiring a more general route allowing for substitution at the
4- and 5-positions, we initially began by looking to install the alde-
hyde moiety into a pre-formed pyrrole. Aldehydes (incorporated
for example by Vilsmeier–Haack formylation) provide an incredi-
bly versatile platform to access electron-rich heteroaromatic rings
via traditional ring synthesis/condensation reactions. However, in
the case of ethyl pyrrole-3-carboxylate, primarily the 5-formyl
compound is formed (Scheme 2). Oxidation of the known
ethyl 2-methylpyrrole-3-carboxylate (3) with CAN12 was also
attempted, but in our hands it failed to give any of the desired
aldehyde. There are reports that methyl groups at the 2-position
of pyrroles can be oxidized by chlorination with sulfuryl chloride,13
followed by hydrolysis to the aldehyde. However when this was
attempted on 3, a mixture of products were obtained which
included products of over-chlorination of the methyl and
chlorination of the pyrrole CH positions (Scheme 2).
involves the condensation of a b-enaminone and an a-halocarbonyl
(Scheme 1).5 The enaminone can be used directly (commonly
referred to as a two-component Hantzsch procedure), or can be
formed in situ from
a ketone and primary amine (three-
component). Despite its potential to introduce molecular complex-
ity in a single condensation step, the Hantzsch procedure has not
been used widely in the literature. Common problems include poor
yields and self-condensation reactions, leading to byproducts and
complex reaction mixtures. As such, other procedures such as the
Paal–Knorr synthesis are often preferred.6 However, some studies
R2
R1
CO2Et
R2
R1
X
EtO2C
+
O
H2N
N
H
-H2O, HX
X = Cl, Br
Scheme 1. Classical two-component Hantzsch procedure.
⇑
Corresponding author.
E-mail address: thomas.moss@astrazeneca.com (T.A. Moss).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.022

T. A. Moss, T. Nowak / Tetrahedron Letters 53 (2012) 3056–3060
3057
EtO2C
51% yield. It was in fact possible to access aldehyde 1 in similar
yield directly from acetonitrile and ethyl 2,2-diethoxyacetate in a
one-pot sequence by telescoping formation of intermediate 4 with
EtO2C
EtO2C
Desired
R
POCl3, DMF
CHO
N
H
N
H
the Hantzsch procedure. This constitutes
a four-component
OHC
N
H
sequential Hantzsch-type reaction, and should be useful in optimi-
zation studies and high throughput chemistry.
EtO2C
OHC
[O]
R = CN, CO2Et
In a typical reaction sequence, enolate 4 was initially stirred
with ammonium acetate in ethanol for 5 min at room temperature,
which should result in protonation of the enolate 4 to form the
unstable acidified keto-nitrile in situ. After 5 min, chloroacetylal-
dehyde was added and the reaction was warmed to 80 °C. Forma-
tion of enamine 6 was expected to occur (this can be isolated
directly as an 8:1 ratio of E/Z enamines when 4 is heated with
NH4OAc in ethanol), followed by alkylation to give an intermediate
such as 7. Intramolecular condensation and aromatization should
then occur, followed by hydrolysis of the acetal to give pyrrole 1
(Scheme 4). It should be noted that an alternative mechanism,
beginning with initial condensation of enamine 6 through nitrogen
onto the aldehyde, followed by intramolecular C–C bond formation
with displacement of chloride would also give the same product,
and cannot be ruled out.
With this preliminary result in hand, we explored the potential
scope of the reaction by reacting 4 with a range of chloro-carbonyl
compounds. We also screened selected alkyl amines to see if N-
protected pyrroles could be accessed though this method. Pleas-
ingly, the reaction was tolerant of a range of chloroaldehydes
and chloroketones as well as alkyl amines, allowing substitution
on any position of the pyrrole product (Table 1).
X
N
1
2
N
H
3
H
Scheme 2. Failed routes towards 1 and 2.
Observing that ethyl 2-methylpyrrole-3-carboxylate (3) can be
synthesized in moderate yields by the Hantzsch reaction of chloro-
acetylaldehyde and ethyl 3-oxobutanoate, we considered the use
of the Hantzsch procedure to access the desired compounds by
replacing the methyl with a masked aldehyde moiety. In order to
test this hypothesis, we synthesized 4,4-diethoxy-3-oxobutanenit-
rile from ethyl 2,2-diethoxyacetate and acetonitrile with sodium
hydride. We found it to be unstable and difficult to isolate in its
protonated form however, which was in agreement with the liter-
ature reports for this compound.14 In order to address the stability
issue of 4,4-diethoxy-3-oxobutanenitrile, it was isolated and used
directly from the reaction mixture as the sodium salt 4 (after puri-
fication by trituration). Treatment of 4 with chloroacetylaldehyde
and ammonium hydroxide at room temperature (as per the syn-
thesis of 3) resulted in a sluggish reaction. Heating 4 with ammo-
nium acetate in ethanol gave rapid conversion into two new
products. LC–MS analysis suggested these were primarily the pyr-
role-acetal 5, and a small amount of the desired product 1 (Scheme
3). As the acetal protected product showed a propensity towards
hydrolysis even during the condensation reaction, the crude reac-
tion mixture was fully hydrolysed to the desired product by
in situ addition of acetic acid/water to give 1 in an acceptable
The reaction worked for secondary chloroaldehydes (entry 2) to
introduce a methyl into the 4-position of the pyrrole product, and
for chloroacetone to introduce a methyl into the 5-position in 55%
yield (entry 3). Cyclic halo-ketones (entries 4 and 5) also reacted
efficiently to give the partially reduced indole and azaindole prod-
ucts in 50% and 66% yield, respectively (in the case of entry 5, the
i) NaH, MeCN, 80 o
ii) EtOH, NH4OAc,
C
O
EtO
EtO
OEt
2-chloroacetylaldehyde
OEt
One-potsequence
AcOH/H2O
RT, 30 min
NaH, MeCN
80 o
C
NC
NC
ONa
O
NH4OAc, EtOH
80 oC, 1 h
+
O
CN
Cl
EtO
EtO
+
N
H
N
H
H
OEt
H
4
1
5
Scheme 3. Synthesis of 1 via three-component and four-component sequential Hantzsch reactions.
NH2
ONa
O
NH4OAc
NH4OAc
80 o
EtO
CN
EtO
CN
EtO
CN
[8:1]
EtOH, RT
C
OEt
OEt
6
OEt
4
O
Cl
H
O
NC
NC
NH
aq. AcOH
EtO
EtO
O
-H2O
N
H
N
H
1
OEt CN
7
EtO
H
5
Scheme 4. Possible mechanism for the formation of pyrrole 1.

3058
T. A. Moss, T. Nowak / Tetrahedron Letters 53 (2012) 3056–3060
bromo-ketone was used simply on the basis of availability). These
are particularly useful as potential building blocks as they intro-
duce an element of three-dimensionality into the molecule, and
in the case of entry 5, an additional point of reactivity to diversify
the product of the reaction through the cyclic amine. Replacement
of ammonium acetate with primary amines/acetic acid (entries 6
and 7) gave the N-substituted pyrroles in comparable yields to
ammonia, circumventing the need for subsequent pyrrole N-
alkylation.
We next attempted the reaction using the ethyl ester analogue
of 4. During preparation, it was found to be difficult to isolate this
compound as its sodium salt; however the acidified form 8
Table 1
Scope of the Hantzsch reactiona
Entry
Enolate
Chloro-carbonyl
Amine
Product
NC
Yieldb (%)
51
ONa
O
Cl
EtO
CN
O
H
1
NH4OAc
N
H
OEt
4
H
NC
O
Cl
O
2
3
4
4
4
4
NH4OAc
NH4OAc
NH4OAc
45
55
50
H
N
H
H
NC
O
Cl
O
N
H
H
NC
O
Cl
O
N
H
H
O
NC
NBoc
Br
O
H
5
4
4
NH4OAc
66
N
H
N
13
Boc
O
NC
O
Cl
H
6
7
MeNH2/AcOH
BnNH2/AcOH
44
49
N
H
NC
O
Cl
O
H
4
N
Bn
H
O
O
O
EtO2C
O
Cl
EtO
OEt
H
8
9
NH4OAc
NH4OAc
46
44
O
O
OEt
8
H
EtO2C
O
Cl
8
8
O
H
O
H
Cl
EtO2C
10c
NH4OAc
56
O
N
H
H
ONa
O
NC
Cl
MeO
MeO
CN
O
H
11
NH4OAc
NH4OAc
0
N
H
OMe
12
HO
NC
O
Cl
12d
12
38
O
N
H
HO
a
b
c
Reaction conditions: enolate (1 equiv, 2.5 mmol), chloro-carbonyl (1.5 equiv), NH4OAc (3 equiv), EtOH (12 mL), 80 °C, 1 h, then 80% AcOH in H2O, rt.
Isolated yield after column chromatography.
Alternative reaction conditions were used: keto-ester (1 equiv, 2.5 mmol) was stirred with K2CO3 (1 5 equiv), TBAB (0.1 equiv) and chloroacetone (1.2 equiv) in MeCN
(12 mL) at 70 °C for 2 h, then NH4OAc (3 equiv) was added and heating was continued for 1 h. Acetal hydrolysis was then performed as normal with aq AcOH.
d
The reaction was stirred for 4 h. Orthoformate hydrolysis occurred during the reaction, 80% aq AcOH was not added.

T. A. Moss, T. Nowak / Tetrahedron Letters 53 (2012) 3056–3060
3059
OH
4 N HCl
EtO2C
EtO
EtO2C
O
O
NH2
O
Cl
NH4OAc
EtO
OEt
8
O
O
11
EtOH, 80 o
10 min
C
2 h
EtO
OEt
H
10
9
K2CO3,
TBAB (10 mol%),
chloroacetone
MeCN, 80 o
O
O
O
NH4OAc
then aq. AcOH
EtO2C
EtO
OEt
O
C
OEt
N
H
H
Scheme 5. Formation of furan 11 through a Feist–Bénary type reaction, and formation of the pyrrole through an alkylation/condensation sequence.
NC
NBoc
N
N
H
15
pyrrolidine
NaCNBH3
70%
NC
O
NC
NC
NaBH4,
MeOH
NBoc
NBoc
NBoc
NaClO2
79%
HO
O
96%
N
N
H
N
H
13
H
H
HO
14
16
NH2NH2
70%
NH2
N
NBoc
N
N
H
17
Scheme 6. Synthesis of fragment-like molecules from 13.
appeared to be perfectly stable. When subjected to the Hantzsch
conditions, some unexpected observations were made. Initially
the enamine 9 was quickly formed, which was stable and could
be readily isolated. On further heating with chloroacetylaldehyde,
a more polar product was obtained which was identified as the
4-hydroxydihydrofuran 10. This was found to be surprisingly sta-
ble to aromatization by elimination of water under mildly acidic
conditions. However, hydrolysis with 4 N aq HCl solution led to ra-
pid dehydration with concomitant unmasking of the aldehyde
moiety to give ethyl 2-formylfuran-3-carboxylate (11) in respect-
able yield (46%). It was initially thought that the presence of base
in 2 (as it is used as the sodium salt) may affect the nature of the
products formed, however initial treatment of 8 with 1 equiv of so-
dium hydride followed by the normal reaction conditions still re-
sulted in the furan product being isolated. Although the required
compound 2 was not available through this method, the synthesis
of the furan was notable as 2,3-dicarbonylated furans are as
equally unexplored as their pyrrole analogues in the literature. In
practice, ester substituted pyrrole 2 could be readily accessed from
1 by hydrolysis of the nitrile and then esterification of the acid. The
formation of intermediate 10 and subsequent aromatization to the
furan 11 are consistent with the mechanism of the Feist–Bénary
furan synthesis.15 This does not usually involve enamine forma-
tion, which would be expected to give the corresponding pyrrole
(Scheme 5). 2-Chloropropanal also gave the furan product (entry
9), although when chloroacetone was used only the enamine
intermediate 9 was obtained, which is presumably due to the
greater reactivity of the aldehyde compared with the ketone. Ester
analogue 8 and chloroacetone could however be transformed into
the pyrrole by a sequential alkylation with potassium carbonate
and catalytic TBAB in MeCN followed by treatment with ammo-
nium acetate in a one-pot procedure (entry 10).
Finally, the reaction was conducted with a masked carboxylic
acid moiety (compound 12, entries 11 and 12). This proved to be
a much less reactive nucleophilic component than 4, nonetheless
the carboxylic acid substituted pyrrole was obtained in a slightly re-
duced yield of 38% with chloroacetone (entry 12). In this case, the
orthoformate hydrolysed completely during the reaction, so subse-
quent treatment with aqueous acetic acid was not necessary. No
pyrrole products were obtained with chloroacetylaldehyde (entry
11), however the aldehyde products were readily oxidized to the
carboxylic acid if this oxidation state was required (see Scheme 6).
Having established the generality of the route to fully function-
alized pyrroles, we demonstrated their general utility as a platform
to pyrrole based fragment-like molecules. Treatment of 13 with so-
dium borohydride selectively reduced the aldehyde in near-quan-
titative yield, whilst treatment with pyrrolidine and sodium
cyanoborohydride smoothly gave the reductive amination product
15 in 70% yield. The aldehyde could be readily oxidized to the car-
boxylic acid 16 with sodium chlorite, whilst treatment with hydra-
zine resulted in
a simultaneous condensation/intramolecular
cyclization to give the tricycle 18 (Scheme 6). The Boc protecting

3060
T. A. Moss, T. Nowak / Tetrahedron Letters 53 (2012) 3056–3060
Prep. Proced. Int. 2001, 33, 411; (d) Sundberg, R. J In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Vol. 2; Pergamon:
Oxford, 1996; p p 119.
group in all of these products could be readily removed with HCl in
1,4-dioxane.
In conclusion, we have shown that a three-component, one-pot
Hantzsch approach can give pyrroles and furans bearing differen-
tially reactive carbonyl moieties at the 2- and 3-positions, a hith-
erto challenging substitution pattern to access.16 Keto-nitrile
compound 4 reacted with a range of halo-carbonyls to give bis-,
tri- and polysubstituted pyrroles in reasonable yields. Interest-
ingly, its ester analogue 8 formed the corresponding furan, proba-
bly through a Feist–Bénary type mechanism. As demonstrated, the
products contain several handles for further manipulation and
thus, this method should find use in total synthesis and medicinal
chemistry campaigns.
5. (a) Roomi, M. W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689; (b)Angew.
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16. Representative procedure for the synthesis of 1: Enolate 4 (485 mg, 2.5 mmol)
was stirred in EtOH (12 mL) with NH4OAc (578 mg, 7.5 mmol). After 5 min the
solids had fully dissolved. At this point, chloroacetylaldehyde (50% in H2O,
0.48 mL, 3.75 mmol) was added and the reaction was warmed to 80 °C for 1 h.
Following cooling to room temperature, AcOH–H2O (4:1, 10 mL) was added
and stirring was continued for 30 min. The volatiles were removed under
vacuum and the residue was dissolved in CH2Cl2 and washed with H2O. The
aqueous was extracted once with CH2Cl2, and the combined organics were
dried over Na2SO4 and concentrated. The dark residue was purified by silica gel
chromatography [heptane/EtOAc, 9:1–3:1] to give 2-formylpyrrole-3-
carbonitrile (1) as an off-white solid, 153.5 mg, 51%. Mp 146–148 °C; mmax
(cmÀ1) 2995 (w), 2235 (w), 1685 (s), 1410 (w), 1360 (s), 1185 (m); 1H NMR
(400 MHz, CDCl3] 6.68 (t, 1H, J = 2.7, CHPyrrole), 7.15 (td, 1H, J = 1.0, 2.8,
CHPyrrole), 9.81 (d, 1H, J = 1.0, CHAldehyde), 10.03 (br s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) 98.73 (CAr), 114.72 (CN), 115.09 (CHAr), 126.58 (CHAr),
135.36 (CAr), 177.99 (CHO); m/z (EI) 120 [(M+H)+, 100%)], 92 (45), 64 (25);
HRMS (EI) [M+H]+ 120.0392, C6H4N2O requires 120.0324.
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