Limitations of the Jacobs-Gould reaction using microwave irradiation

Article abstract of DOI:10.1080/00397911.2010.486515

Upon investigating the green synthesis of some antimicrobial quinolone compounds, some atypical ring-closing patterns were observed during the synthesis of various intermediates using the Jacobs-Gould reaction.

Full text of DOI:10.1080/00397911.2010.486515

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Limitations of the Jacobs–Gould Reaction
Using Microwave Irradiation
a
a
b
Robert B. Smith , Hajira Faki & Ray Leslie
a
Centre for Materials Science, University of Central Lancashire ,
Preston , UK
b
School of Science and Technology, Nottingham Trent University ,
Nottingham , UK
Published online: 30 Mar 2011.
To cite this article: Robert B. Smith , Hajira Faki & Ray Leslie (2011) Limitations of the
Jacobs–Gould Reaction Using Microwave Irradiation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:10, 1492-1499, DOI:
10.1080/00397911.2010.486515
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1
Synthetic Communications , 41: 1492–1499, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.486515
LIMITATIONS OF THE JACOBS–GOULD REACTION
USING MICROWAVE IRRADIATION
1
Robert B. Smith, Hajira Faki, and Ray Leslie
1
2
1
Centre for Materials Science, University of Central Lancashire, Preston, UK
School of Science and Technology, Nottingham Trent University,
Nottingham, UK
2
GRAPHICAL ABSTRACT
Abstract Upon investigating the green synthesis of some antimicrobial quinolone
compounds, some atypical ring-closing patterns were observed during the synthesis of
various intermediates using the Jacobs–Gould reaction.
Keywords Cyclization; Jacobs–Gould reaction; microwave synthesis; quinolones
INTRODUCTION
The quinolones, in particular the clinically used fluoroquinolones, are broad-
spectrum antibiotics that inhibit bacterial deoxyribonucleic acid (DNA) gyrase or
the topoisomerase IV enzyme; these are required for DNA replication and transcrip-
[
1–3]
tion.
floxacin (4), the antibacterial fluoroquinolone used in the treatment of urinary
Scheme 1 shows the synthesis of the second-generation antibacterial nor-
[
4]
[5]
tract infections. The key intermediate (2) in this synthesis is formed through a
[
heat-mediated Jacobs–Gould intramolecular cyclization reaction. Although the
cyclization step seems simplistic, problems do exist that often lead to poor yields
6]
Received February 17, 2010.
Address correspondence to Robert B. Smith, Centre for Materials Science, University of Central
Lancashire, Preston PR1 2HE, UK. E-mail: rbsmith@uclan.ac.uk
1
492

LIMITATIONS OF THE JACOBS–GOULD REACTION
1493
Scheme 1. Synthesis of the second-generation antibacterial norfloxacin.
(with the reactants still present) and=or a mixture of cyclized products. This is
highlighted in Scheme 2, using the cyclization of diethyl N-(6-methyl-2-pyridyl)-
aminomethylenemalonate (5) as an example. In both cases, purification is required
to isolate the intermediate, which can prove tedious because of the polar nature of
these compounds.
It was our aim to form novel derivatives of nalidixic acid using microwave-
enhanced synthesis, isolate the key intermediates in good yield, and limit purification
procedures. Although the compounds presented in this article are not novel, we
believe the green methodology used to make these compounds is. It allows an easy
and clean isolation of the key intermediates, which is something that has not pre-
viously been achieved. We thus present this work as a clean and novel way to prepare
these types of heterocyclic compounds. However, it was noticed that some atypical
ring closures were occurring, and we also report this herein.
Scheme 2. Formation of naphthyridone (6) and pyrimidinone (7).

1494
R. B. SMITH, H. FAKI, AND R. LESLIE
RESULTS AND DISCUSSION
The first stage proceeds initially via a conjugate (Michael) addition=elimination
reaction as outlined in Scheme 2. This enamine bond formation was achieved in
excellent yields by condensation of diethyl ethoxymethylenemalonate (DEEM) using
microwave synthesis. This reaction historically has been accomplished using tra-
[
7]
ditional wet synthetic methods such as refluxing in ethanol for 16 h or reacting
in the presence of a base such as potassium hydroxide. Performing this reaction using
microwave synthesis opens up a possible new avenue in protection group chemistry,
[
8]
as DEEM has been reported as a protecting group for amines. Using the afore-
mentioned microwave method we were able to prepare substituted aminomethyl-
enemalonates using four different isomers of 2-aminopicolene in good yields.
Recrystallization in ethanol for each of these intermediates gave pure products,
and these reactions are highlighted in Table 1.
The second stage in the synthesis displays an example of electrophilic aromatic
substitution, specifically the Jacobs–Gould reaction, to yield the cyclized product as
shown in Table 2.
The Jacobs–Gould reaction can be achieved using conventional synthetic
methods; however, this can only be successfully accomplished if high-temperature
[7]
reflux conditions are employed.
[9]
Strauss et al. demonstrated that with established methods using heat-transfer
oils, this reaction proceeded in high conversion, rapidly and controllably, at tem-
ꢀ
peratures near 400 C. He also noted that this reaction can be accomplished without
solvent in a stainless steel coil; the temperature for this reaction has to be maintained
ꢀ
at 380 C using a fused sand bath. Over a 2-h period, three compounds were pro-
duced in the following yields: naphthyridone (6) (79%), pyrimidone (7) (8%), and
other unknown compounds (5%). The pure product was isolated as a precipitate
using diethyl ether once the reaction mixture had cooled. Although this reaction is
green, it would not be considered economically favorable within an industrial
environment.
In our quest to form novel quinonolones, N-(6-methyl-2-pyridyl)aminomethy-
lenemalonate (see Table 2, reaction 2d) was irradiated by microwaves (MW) for
1
5 min in the presence of diphenyl ether as a solvent, and the formation of the
naphthyridone in 79% yield was observed. No other side products or starting
materials were present. This was confirmed by both 1D and 2D NMR spectroscopy.
It is important to note that a high dilution factor is essential for these reactions to be
successful in a CEM microwave.
This reaction was also attempted using MW irradiation on N-(3-methyl-2-
pyridyl)aminomethylenemalonate to confirm the lack of cyclization due to the
3
-methyl substituent acting as a blocking group. However, it was noted that another
type of intramolecular cyclization occurred though the pyridine nitrogen, resulting in
the formation of a pyrimidone in a yield of 77% (see Table 2, reaction 2a). The litera-
ture shows that pyrimidones form in preference to the naphthyridones at low tem-
peratures. Because of the superheating effect from the MW, the two other
derivatives (4-methyl and 5-methyl substituents) were investigated. In the case of
these reactions, conventional heating would take the lower energy path to produce
the kinetic product (i.e., the pyrimidones). Using MW-enhanced synthesis, it was

LIMITATIONS OF THE JACOBS–GOULD REACTION
1495
Table 1. Spectroscopic information for the aminomethylenemalonates
Starting
2-amino-picoline
Yield
(%)
1
13
H, C (ppm) and MS
Reaction
Product
1
1
1
H NMR (d-CDCl
.29–1.39 (t x2, 6H, CH
s, 3H, Ar-CH ), 4.19–4.35 (q
), 6.93 (t, 1H,
3
) d ppm:
1
3
), 2.31
(
3
x2, 4H, CH
2
J ¼ 6.1 Hz, Ar-H), 7.46 (d, 1H,
J ¼ 6.5 Hz, Ar-H), 8.18 (d, 1H,
J ¼ 6.2 Hz, Ar-H), 9.26 (d, 1H,
J ¼ 12.5 Hz, C=C-H), 11.32 (br
1a
1b
1c
81
76
87
1
3
d, 1H, J ¼ 12.3 Hz, N-H).
C
NMR (d-CDCl
3
) d ppm: 14.35,
1
9
1
1
4.48, 16.41, 60.12, 60.60,
5.66, 119.49, 120.21, 139.27,
46.07, 149.12, 149.98, 165.38,
69.32; MS (LCMS)
m=z ¼ 278
H NMR (d-CDCl
3
) d ppm:
), 2.25
), 4.14–4.29 (q
2
), 6.61 (s, 1H, Ar-
1
.21–1.34 (t x2, 6H, CH
3
(s, 3H, Ar-CH
x2, 4H, CH
3
H), 6.78 (d, 1H, J ¼ 5.0 Hz,
Ar-H), 8.12 (d, 1H, J ¼ 5.2 Hz,
Ar-H), 9.08 (d, 1H,
J ¼ 13.0 Hz, C=C-H), 10.98 (br
1
3
d, 1H, J ¼ 13.0 Hz, N-H).
C
NMR (d-CDCl
3
) d ppm: 14.28,
1
9
1
1
4.43, 21.01, 60.09, 60.49,
5.14, 112.45, 120.95, 148.27,
49.94, 150.08, 150.74, 165.38,
68.86; MS (LCMS)
m=z ¼ 278
H NMR (d-CDCl
3
) d ppm:
), 2.28
), 4.20–4.34 (q
2
), 6.76 (d, 1H,
1
.29–1.40 (t x2, 6H, CH
3
(s, 3H, Ar-CH
x2, 4H, CH
3
J ¼ 8.0 Hz, Ar-H), 7.45 (d, 1H,
J ¼ 6.2 Hz, Ar-H), 8.15 (s, 1H,
Ar-H), 9.12 (d, 1H,
J ¼ 13.0 Hz, C=C-H), 11.06 (br
1
3
d, 1H, J ¼ 13.0 Hz, N-H).
C
NMR (d-CDCl
3
) d ppm: 14.34,
1
9
1
1
4.49, 17.80, 60.12, 60.53,
4.80, 111.46, 130.05 139.25,
48.60 150.07, 165.49, 169.08,
69.12; MS (LCMS)
m=z ¼ 278
(
Continued )

1496
R. B. SMITH, H. FAKI, AND R. LESLIE
Table 1. Continued
Starting
2-amino-picoline
Yield
(%)
1 13
H, C (ppm) and MS
Reaction
Product
1
H NMR (d
1
6
-DMSO) d ppm:
.32–1.37 (t x2, 6H, CH
s, 3H, Ar-CH ), 4.24 (q, 2H,
3
), 2.47
(
3
J ¼ 6.3 Hz, CH
2
), 4.29 (q, 2H,
), 6.63 (d, 1H,
J ¼ 6.3 Hz, CH
2
J ¼ 8.0 Hz, Ar-H), 6.85 (d, 1H,
J ¼ 7.6 Hz, Ar-H), 7.50 (t, 1H,
J ¼ 7.8 Hz, Ar-H), 9.17 (d, 1H,
J ¼ 12.0 Hz, CH¼C), 11.03 (d,
1d
85
1
3
C
1
H, J ¼ 12.8 Hz, NH).
6
NMR (d -DMSO) d ppm:
1
5
1
1
4.23, 14.34, 24.02, 59.76,
9.96, 94.84, 109.73, 119.28,
39.40, 148.14, 149.89, 157.17,
65.13, 167.05; MS (LCMS)
m=z ¼ 278
considered that the thermodynamic product (which was expected to be the naphthyr-
idone) would be produced because of superheating.
Table 2 shows the results of the MW irradiation for a range of N-(n-methyl-2-
pyridyl)aminomethylenemalonates (n denotes position of the methyl group on the
pyridine ring), over a period of 15 min. It is interesting to note that for reactions
2
a–2c (Table 2), the pyrimidone was formed with no naphthyridone present.
Attempts at a solventless synthesis for this six-member cyclization were investigated,
which led to the decomposition of the starting material with no naphthyridone or
pyrimidone detected by thin-layer chromatography (TLC) and NMR spectroscopy.
In conclusion, the Jacobs–Gould reaction can be achieved using MW irra-
diation over a 15-min period. Complex purification procedures are not required as
the product precipitates from the reaction mixture upon the addition of hexane; this
also aids the removal of the solvent diphenyl ether. As the pyrimidone forms at low
temperatures (kinetic product), it postulated that the naphthyridone should form the
major product for each of the reactions in Table 2 (except for reaction 2a, because of
the methyl blocking group) as a result of superheating. However, as the results show,
this is not the case, and it can be assumed that the pyrimidone products from reac-
tions 2b and 2c are both kinetically and thermodynamically more stable, judging by
the high yields produced. It is assumed that the product from reaction 2d, which is
the naphtyridone, is indeed more thermodynamically stable.
EXPERIMENTAL
MW synthesis was preformed using a CEM Discover microwave reactor.
NMR spectra were measured on a Jeol ECX 400-MHz spectrometer. Chemical shifts
are reported in parts per million (ppm) downfield from tetramethylsilane (TMS).
Mass spectra were recorded on a Thermo Finnigan LCQ Advantage MAX mass

LIMITATIONS OF THE JACOBS–GOULD REACTION
1497
Table 2. Spectroscopic information for the Jacobs–Gould cyclization reactions
Yield
(%)
1 13
H, C (ppm) and MS
Reaction
Starting material
Product
1
1
1
1
H NMR (d
6
-DMSO): 1.29 (t,
H, J ¼ 7.1 Hz, CH ), 2.53 (s,
H, Ar-CH ), 4.24 (q, 2H,
), 7.44 (t, 1H,
3
3
3
3
J ¼ 7.2 Hz, CH
2
J ¼ 7.1 Hz, Ar-H), 8.05 (d, 1H,
J ¼ 6.9 Hz, Ar-H), 8.83 (s, 1H,
Ar-H), 9.01 (d, 1H, J ¼ 7.3 Hz,
2
a
77
1
3
6
Ar-H). C (d -DMSO) d ppm:
1
1
1
4.21, 17.43, 60.08, 103.68,
17.53, 126.53, 134.68, 139.30,
52.16, 154.06, 157.19, 164.16.
(
LCMS) m=z ¼ 232
H NMR (d
6
-DMSO) d ppm:
1
2
2
1
1
8
.28 (t, 3H, J ¼ 7.1 Hz, CH
3
),
.52 (s, 3H, Ar-CH
3
), 4.25 (q,
), 7.42 (d,
H, J ¼ 7.1 Hz, CH
2
H, J ¼ 8.8 Hz, Ar-H), 7.66 (s,
H, Ar-H) 8.81 (s, 1H, Ar-H),
.03 (d, 1H, J ¼ 7.2 Hz, Ar-H).
2b
81
1
3
6
C (d -DMSO) d ppm: 14.27,
2
1
1
0.94, 60.00, 102.97, 120.46,
24.63, 127.96, 152.61, 153.05,
53.92, 158.51, 164.12.
(
LCMS) m=z ¼ 232
H NMR (d -DMSO): 1.37 (t,
6
3
H, J ¼ 7.2 Hz, CH ), 2.51 (s,
H, Ar-CH ), 4.35 (q, 2H,
), 7.72 (d, 1H,
3
3
3
J ¼ 7.1 Hz, CH
2
J ¼ 8.9 Hz, Ar-H), 8.03 (d, 1H,
J ¼ 8.9 Hz, Ar-H), 8.91 (s, 1H,
2c
56
13
C
Ar-H), 9.06 (s, 1H, Ar-H).
(
MeOD) d ppm: 14.65, 18.32,
6
1
1
1.93, 105.08, 126.62, 127.62,
30.66, 144.41, 153.39, 156.30,
59.07, 165.92. (LCMS)
m=z ¼ 232
H NMR (d
3
6
-DMSO): 1.26 (t,
), 2.57 (s,
), 4.19 (q, 2H,
), 7.34 (d, 1H,
H, J ¼ 7.1 Hz, CH
3
3
H, Ar-CH
3
J ¼ 7.1 Hz, CH
2
J ¼ 8.1 Hz, Ar-H), 8.37 (d, 1H,
J ¼ 8.2 Hz, Ar-H), 8.45 (s, 1H,
2d
79
1
3
6
Ar-H). C (d -DMSO) d ppm:
1
1
1
4.23, 24.28, 59.71, 110.91,
19.66, 121.19, 135.48, 145.48,
49.44, 163.02, 164.23, 173.68.
(
LCMS) m=z ¼ 232

1498
R. B. SMITH, H. FAKI, AND R. LESLIE
spectrometer. All chemicals and solvents were bought from either Sigma Aldrich or
Alfa Aesar and used without further purification.
N-(3-Methyl-2-pyridyl)aminomethylenemalonates (Table 1,
Reaction A)
A mixture of 2-amino-3-picoline (1.08 g, 10 mmol) and diethyl (ethoxymethyle-
ne)malonate (2 ml, 10 mmol) was irradiated for 30 s in a CEM microwave at half
power. Ethanol (10 ml), was added to the reaction mixture and heated until a clear
solution was obtained, which was treated with activated charcoal, filtered, and
allowed to cool naturally. The solid was filtered under suction and dried under
vacuum to yield N-(3-methyl-2-pyridyl)aminomethylenemalonate (81%) as white
crystals.
1
H NMR (d-CDCl ) d ppm: 1.29–1.39 (t x2, 6H, CH ), 2.31 (s, 3H, Ar-CH ),
3
3
3
4
.19–4.35 (q x2, 4H, CH ), 6.93 (t, 1H, J ¼ 6.1 Hz, Ar-H), 7.46 (d, 1H, J ¼ 6.5 Hz,
2
Ar-H), 8.18 (d, 1H, J ¼ 6.2 Hz, Ar-H), 9.26 (d, 1H, J ¼ 12.5 Hz, C=C-H), 11.32
1
3
(
6
br d, 1H, J ¼ 12.3 Hz, N-H). C NMR (d-CDCl ) d ppm: 14.35, 14.48, 16.41,
3
0.12, 60.60, 95.66, 119.49, 120.21, 139.27, 146.07, 149.12, 149.98, 165.38, 169.32;
MS (LCMS) m=z ¼ 278.
Each of the reactions are based on the same quantities and procedures as the
cyclization of N-(3-methyl-2-pyridyl)aminomethylene malonate.
Ethyl-9-methyl-4-oxo-4H-Pyrido[1,2a]pyrimidine-3-carboxylate
(
Table 2, Reaction A)
mixture of N-(3-methyl-2-pyridyl)aminomethylene malonate (0.70 g,
.5 mmol) and diphenyl ether (10 ml) was irradiated for 15 min in a CEM microwave
at full power. The mixture was allowed to cool to room temperature, and hexane
50 ml) was added with stirring. The yellow solid produced was filtered under suction
A
2
(
and washed with additional hexane (50 ml). The solid was dried under vacuum to
yield ethyl-9-methyl-4-oxo-4H-pyrido[1,2a]pyrimidine-3-carboxylate (0.45 g, 77%)
as a white solid.
1
H NMR (d -DMSO) d ppm: 1.29 (t, 3H, J ¼ 7.1 Hz, CH ), 2.53 (s, 3H, Ar-
6
3
CH ), 4.24 (q, 2H, J ¼ 7.2 Hz, CH ), 7.44 (t, 1H, J ¼ 7.1 Hz, Ar-H), 8.05 (d, 1H,
3
2
1
3
J ¼ 6.9 Hz, Ar-H), 8.83 (s, 1H, Ar-H), 9.01 (d, 1H, J ¼ 7.3 Hz, Ar-H). C (d -
6
DMSO) d ppm: 14.21, 17.43, 60.08, 103.68, 117.53, 126.53, 134.68, 139.30, 152.16,
1
54.06, 157.19, 164.16.
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