Highly efficient thermal cyclization reactions of alkylidene esters in continuous flow to give aromatic/heteroaromatic derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.11.125

Intramolecular thermal cyclization and benzannulation reactions of the Gould-Jacobs and Conrad-Limpach types were performed in a designed continuous flow reactor system at temperatures in the range of 300-360°C and under high pressure conditions (100-160 bar) with very short residence times (0.45-4.5 min) in tetrahydrofuran as a low-boiling point solvent. Substituted heteroaromatic compounds including pyridopyrimidinones and hydroxyquinolines were synthesized in moderate to high yields. Application of the reaction conditions also allows the synthesis of naphthol and biphenyl derivatives. The procedure involves an easy work-up and the non-batchwise preparative synthesis method is suitable for automation.

Full text of DOI:10.1016/j.tetlet.2011.11.125

Tetrahedron Letters 53 (2012) 738–743
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient thermal cyclization reactions of alkylidene esters in
continuous flow to give aromatic/heteroaromatic derivatives
⇑
László Lengyel, Tibor Zs. Nagy, Gellért Sipos, Richard Jones, György Dormán , László Ürge, Ferenc Darvas
ThalesNano Inc., Záhony u. 7. H-1031 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular thermal cyclization and benzannulation reactions of the Gould–Jacobs and Conrad
–Limpach types were performed in a designed continuous flow reactor system at temperatures in the
range of 300–360 °C and under high pressure conditions (100–160 bar) with very short residence times
(0.45–4.5 min) in tetrahydrofuran as a low-boiling point solvent. Substituted heteroaromatic compounds
including pyridopyrimidinones and hydroxyquinolines were synthesized in moderate to high yields.
Application of the reaction conditions also allows the synthesis of naphthol and biphenyl derivatives.
The procedure involves an easy work-up and the non-batchwise preparative synthesis method is suitable
for automation.
Received 4 August 2011
Revised 17 November 2011
Accepted 25 November 2011
Available online 13 December 2011
Keywords:
Thermal cyclization
Gould–Jacobs reaction
Conrad–Limpach reaction
Flow chemistry
Microreactor
Ó 2011 Elsevier Ltd. All rights reserved.
Benzannulation
Quinolines
Pyridopyrimidinones
Biphenyls
Alkylidene b-diesters or analogous substructures derived from
condensation with Meldrum’s acid (1a), or electron-withdrawing
group containing esters (1b) (e.g. malonic ester or cyanoacetic acid
esters) readily undergo pericyclic annulation reactions at high
temperatures if they are located in a favorable position relative
to aromatic or unsaturated system (Schemes 1 and 2).
The cyclization normally requires high temperature (>350 °C)
and a short reaction time to avoid side-reactions. In practice high
boiling point solvents are used (e.g., diphenyl ether, DOW-
THERM™, tetraglyme etc.)1 or the reaction is carried out using neat
(solvent-free) conditions.4 In such cases the work-up can be diffi-
cult due to uncontrolled precipitation of either the high boiling
point solvent or the product. Microwave (MW) heating, which en-
ables rapid and focused heat generation, is often applied in such
reactions but it is not suitable for scale-up. Since the key step of
One of the oldest reactions of this type is the Gould–Jacobs reac-
tion1 which has the following mechanism: (1) condensation of an
aryl amine with an alkoxy methylenemalonic ester to yield the ani-
lido methylenemalonic ester; (2) cyclization to a 4-hydroxy-3
-carboalkoxy-quinoline. In variations of the Gould–Jacobs reaction
the alkoxy methylenemalonic ester can be replaced with the corre-
sponding condensation product of cyanoacetic acid esters, b-keto
esters (Scheme 2), or Meldrum’s acid (Scheme 1). Meldrum’s acid
as an example of a ring-embedded alkylidene b-diester2, is often
used as a ketene precursor for thermal cyclization. Under classical
flash vacuum pyrolysis conditions (FVP), Meldrum’s acid loses ace-
tone and CO2 forming first a methyleneketene (a kumulenone spe-
cies) that undergoes a 1,3-N–H shift forming an imidoylketene 3a3
in the case of aniline precursors. In all the other cases the electron-
withdrawing group (EW) is retained in the product, so cyclization
leads to bicycles, such as 4-hydroxyquinoline 10c and analogues
10a,b (Table 1, 10a–c, EW = CN, CO2Et).
O
C
C
O
O
1,3-N-H
shift
O
C
O
O
CH
N
H
N
N
H
3a
2a
5a
1a
O
O
N
OH
N
H
H-shift
N
H
6a
4a
⇑
Corresponding author.
E-mail address: gyorgy.dorman@thalesnano.com (G. Dormán).
Scheme 1. Mechanism of the thermal ring closure to 4-hydroxy-quinolines (6a).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.125

L. Lengyel et al. / Tetrahedron Letters 53 (2012) 738–743
739
OR
OR
O
H
O
EW
EW
C
EW
1,5-shift
O
-OR
C
X
X
X
X = CH2, NH
X = CH, N
X = CH, N
3b
1b
2b
O
OH
O
H
EW
EW
EW
H-shift
X
X
X
X = CH, N
X = CH2, NH
4b
5b
6b
Scheme 2. Mechanism of the thermal ring closure to 4-hydroxy-quinolines
substituted with eletronwithdrawing groups in position 3 (6b).
the thermal cyclization is a pericyclic reaction (e.g., 6p electrocyc-
lization, see Scheme 1) of the resulting ketene intermediate, flash
vacuum pyrolysis (FVP) can also be applied, although current com-
mercially available devices are not suitable for continuous and
scalable operation.
The regioselectivity of the Gould–Jacobs type reactions is an-
other important issue, which is normally governed by steric and
electronic factors and often leads to a mixture of products. For
example, 2-aminopyridine-derived alkylidene esters may be ap-
plied for the synthesis of various pyrido[1,2-a]pyrimidin-4-ones
and 1,8-naphthyridinones depending on the substituents on the
pyridine ring and the other substitutents.5 Morgentin et al. studied
the effect of the substituents in Meldrum’s acid mediated ring clo-
sure. Their study of the ring-closure to 6,7-disubstituted quinolones
showed that electron-donating groups favor ring-closure at the
para position while electron-withdrawing groups direct ring-clo-
sure at the ortho position. Normally the more nucleophilic position
(having higher electron density) is involved in the ring-closure. In
order to reverse the regioselectivity the authors temporarily
blocked the otherwise favoured positions with a halogen which
was reductively removed after cyclization.6 Generally, it has been
claimed that a higher temperature leads more or less exclusively
to the thermodynamically more stable product. On the other hand,
the reaction (residence) time could further influence the product
ratio: a short reaction (residence) time favors the kinetically con-
trolled product. Finally, high dilution could also have an impact
on regioselectivity and often alters the ratio of the isomers.
The major drawbacks of the available technologies are the use of
high-boiling point solvents, the often poor selectivity, and the lack
of simple, scalable technologies suitable for process intensification.
Gould–Jacobs type thermal cyclization reactions are used
extensively to synthesize either heterocyclic ketones (pyridopyri-
midinones, naphthyridinones) or aromatic hydroxy derivaties if
keto-enol tautomerism is permitted and/or such tautomers are
favored (e.g., hydroxyquinolines, phenols). These compounds are
important structural motifs in various biologically active com-
Figure 1. X-Cube Flash™ schematic view.
pounds (e.g., norfloxacin, nalidixic acid). The open chain precur-
sors, having a suitably substituted three carbon extension on the
nitrogen, can be easily synthesized by simple condensation reac-
tions. While such thermal cyclization reactions were successfully
applied for the synthesis of various heterocyclic compounds, only
a few examples are reported with aromatic or unsaturated hydro-
carbons alone. The need for more rigorous conditions meant that
mostly FVP batch procedures were applied.
Continuous flow reactors offer several advantages. They extend
the parameter space of chemical reactions significantly (up to
350 °C and 200 bar), increase reaction rates via enhanced heat/
mass transfer (flash heating), enhance reproducibility and speed-
up optimization of reaction parameters due to fast and accurate
R
R
COOEt
Y
R'
R'
Δ
COOEt
+
10a-c
EtO
X
7
NH2
X
N
H
Y
8
9
a: R=H, R'=H, X=N, Y=COOEt
b: R=H, R'=H, X=N, Y=CN
c: R=H, R'=H, X=CH, Y=CN
Scheme 3. Reaction sequence leading to thermal cyclization products 10a–c (see structures 10a–c in Table 1).

740
L. Lengyel et al. / Tetrahedron Letters 53 (2012) 738–743
R
X
R
X
O
O
O
O
R'
R'
Δ
EtO
OEt
OEt
O
O
O
+
+
10d-h
N
H
NH2
O
7
9
d: R=H, R'=H, X=N
e: R=H, R'=H, X=CH
f: R=F, R'=H, X=C(CH3)
g: R=H, R'=CN, X=CH
h: R=H, R'=OCH3, X=CH
Scheme 4. Reaction sequence leading to thermal cyclization products 10d–h (see structures 10d–h in Table 2).
COOEt
COOEt
COOEt
O
Δ
COOEt
+
COOEt
OH
7i
9i
10i
Scheme 5. Thermal cyclization route to ethyl 1-hydroxy-4-methylnaphthalene-2-carboxylate (10i).
OH
COOEt
COOEt
COOEt
O
Δ
COOEt
COOEt
+
9j
7j
10j
Scheme 6. Thermal cyclization route to ethyl 4-hydroxy(1,1’-biphenyl)-3-carboxylate (10j).
H
OH
N
COOEt
O
OEt
OEt
COOEt
Δ
+
NH2
N
9k
O
RouteB
1,7-shift
Route A
1,7-shift
O
7k
10k
9j
Scheme 8. Thermal Conrad–Limpach-type of cyclization route 2-methyl-4-
hydroxy-quinolines (10k).
H
O
H
O
OEt
OEt
OEt
OEt
the selectivity through fine tuning the residence time. Flow reac-
tors offer a viable alternative solution to microwave-assisted batch
chemistry, and in many cases novel synthetic pathways can also be
explored.7 A high pressure/high temperature continuous flow
‘loop’ reactor, X-Cube Flash™ (Figure 1) has been developed and
described8 as a viable alternative to MW chemistry.
O
O
H
In the present study we investigated various thermal cycliza-
tions of alkylidene b-diesters (Schemes 3, 5 and 6) or analogue sub-
structures (Schemes 3, 4 and 8) using a low boiling point solvent
(THF) at high temperature/high pressure (300–360 °C/100–
160 bar) in a flow microreactor with relatively high flow rates
(1.5–4 mL/min) and short residence times (0.5–5 min) in order to
prevent side-reactions or decomposition. FVP typically applies
>500 °C and <0.06 mbar, while microwave-assisted reactions are
carried out <300 °C and at maximum 50 bar (in a sealed system).
Most of the attempted reactions were previously performed in
batch using typical high boiling point solvents (Table 1, entry 3,
6, Table 2, entry 1 and 2, 4 and 6), and often carried out under
MW heating (Table 1, entry 3, 4), and in some cases flash vacuum
pyrolysis was also applied (Table 1, entry 1, 2, 4 and 5). Interest-
ingly, independent of the procedure, either the hydroxy or the keto
form was obtained. All the presently synthesized compounds were
investigated by standard analytical and separation techniques
(LC-MS, NMR) and compared with previously reported spectra,
which confirmed their structure and purity. Since product 10f9
O
C
OEt
OH
OEt
OEt
O
O
OH
OEt
O
OEt
O
O
10j
Scheme 7. Hypothetical mechanistic pathways to 4-hydroxy(1,1’-biphenyl)-3-
carboxylate (10j).
changing of temperature and pressure parameters, prevent by-
product formation by moving the reagents away from the reaction
zone right after they form the desired product, and allow control of

L. Lengyel et al. / Tetrahedron Letters 53 (2012) 738–743
741
has not been reported before, the NMR spectrum is listed in Ref. 9
(All the spectra are available in the Supplementary data).
9j, we obtained ethyl 4-hydroxy[1,1’-biphenyl]-3-carboxylate
(10j)12 as the major product. There are two possible routes: during
the course of the reaction an antarafacial 1,7-hydrogen shift of the
allylic terminal H atom to the ester carbonyl oxygen takes place as
the initial step, followed by electrocyclization of the intermediate
to a half acetal cyclic diene structure that can eliminate EtOH form-
ing directly the phenol (Scheme 7, Route A). Alternatively the inter-
mediate after the 1,7-hydrogen shift eliminates EtOH leading to a
ketene which first cyclizes to a dienone and then tautomerizes to
the phenol (salicylic acid ester) (Scheme 7, Route B). Related O-
or S-substituted salicylic acid derivatives were reported by Hormi
et al.13 applying high temperature ring closure. To the best of our
knowledge, this is the first report of this type of thermal cyclization
employed in the synthesis of biphenyl derivatives and therefore
opens new avenues for the synthesis of such important intermedi-
ates that are commonly used motifs in medicinal chemistry.
Finally, we also successfully applied the above described flow
technology in a related thermal cyclization (Conrad-Limpach14
reaction), that is, cyclization of Schiff’s base 9k derived from ani-
line and a b-ketoester and allows the synthesis of 4-hydroxyquin-
olines with different substituent patterns than those obtained via
Gould–Jacobs reactions (Scheme 8). The resulting, 4-hydroxy-2-
methylquinoline (10k) was obtained in excellent yield (92%).
The aminomethylene and Knoevenagel adducts (precursors for
thermal cyclization) were prepared through the adaptation of liter-
ature procedures described below (Tables 1 and 2):
A purpose-built version of X-Cube Flash™10 was preheated to
the set temperature, (300–370 °C) while 10 mL of THF was pumped
through the reactor with a 3 mL/min flow rate. In the meantime, a
0.05 or 0.1 M THF solution of the starting material was pumped
through the 1.5 or 4 mL loop. (During the reaction the flow rate
was adjusted to the previously optimized parameter between 1–
10 mL/min. This gives a calculated effective residence time of be-
tween 0.45–4.5 min for the attempted reactions). The pressure
was set between 100–160 bar. (Since the flow system allowed ra-
pid parameter optimization, all the reactions were optimized indi-
vidually by finding the best parameter set for their preparation—
see Tables 1 and 2). At the end of the reaction the resulting solution
was evaporated and the solid residue washed with diethyl ether
(10 mL). The filtrate was then dried under reduced pressure to re-
cover the products, which, in most cases, were pure crystals. The
structures of the products were confirmed by 1H NMR analysis.
Using the above described procedure various heterocylic ke-
tones (substituted pyridopyrimidinones: 10a,b, 10d) and hydroxy-
quinolines (10c, 10e–h, 10k) were synthesized in moderate to high
yield and high purity. During our investigation we attempted to ex-
tend our flow methodology for benzannulation leading to naph-
thols. We applied this thermal cyclization approach to typical
Knoevenagel adducts derived from the condensation of aralkyl
aldehydes and malonic ester. As a first attempt, thermal cyclization
of the 2-phenylpropionaldehyde malonic ester adduct (9i) led to
the corresponding ethyl 1-hydroxy-4-methylnaphthalene-2-car-
boxylate (10i)11 in a 67% yield (Scheme 5).
Procedure A:15,16 To an ethanolic solution of amine (2 g), diethyl
ethoxymethylenemalonate (1.1 equiv) was added and the resulting
solution refluxed for 2 h. After cooling the crude product crystal-
lized. The crystals were filtered, washed with ethanol, and dried.
Yield: 50–60%.
However, when we attempted the thermal cyclization of the
malonic ester adduct of the
a,b-unsaturated aldehyde precursor
Table 1
Thermal cyclization products
Entry
Product
Procedure to
Reaction conditions
Yield (%)
Conditions of reference reactions
9a–c, 9i–k
N
O
10a
N
N
T = 360 °C, P = 130 bar, loop = 4.5 mL,
flow = 4 mL/min, c = 0.1 M, tresidence = 1.13 min
COOEt
CN
1
A
70
530 °C , 0.01 Torr22
N
T= 300 °C, P= 100 bar, loop= 4.5 mL,
flow= 3 mL/min, c = 0.1 M, tresidence = 1.5 min
2
3
B2
B2
75
73
530 °C , 0.01 Torr (98%)22
O
10b
N
(a). In diphenyl ether, 2 h, 265 °C (66%);16 (b).
In diphenyl ether, 0.25 h, 175 °C ,
microwave irradiation (58%)23
T = 350 °C, P= 100 bar, loop= 1.5 mL,
flow= 2 mL/min, c = 0.1 M, tresidence = 0.75 min
CN
OH
10c
T = 350 °C, P = 100 bar, loop = 4.5 mL,
flow = 1 mL/min, c = 0.93 M, tresidence = 4.5 min
4
C
95
Multistep different route24
Multistep different route25
COOEt
OH
10i
COOEt
OH
T = 350 °C, P = 100 bar, loop = 4.5 mL,
flow = 10 mL/min, c = 0.05 M, tresidence = 10 min
5
6
C
96
92
10j
N
T = 360–370 °C, P = 130 bar, loop = 1.5 mL,
flow = 2 mL/min, c = 0.05 M, tresidence = 0.75 min
Oxo form: in diphenyl ether, 0.5 h, 255 °C (53%);21
Enol form: 0.5 h, 250 °C (20%)26
D
OH
10k

742
L. Lengyel et al. / Tetrahedron Letters 53 (2012) 738–743
Table 2
Thermal cyclization products
Entry Product
Procedure
to 9d–h
Reaction conditions
Yield
(%)
Conditions of reference reactions
N
N
T = 300 °C, P = 160 bar, loop = 4.5 mL,
flow = 3 mL/min, c = 0.1 M, tresidence = 1.5 min
1
B1
B1
89
60
In diphenyl ether, 10 min, 260 °C27
O
10d
N
T = 300 °C, P = 100 bar, loop = 4.5 mL,
flow = 3 mL/min, c = 0.05 M, tresidence = 1.5 min
2
In diphenyl ether, 250 °C28
OH
10e
N
T = 360–370 °C, P = 100 bar, loop = 1.5 mL,
flow = 1.5 mL/min, c = 0.05 M,
tresidence = 1.0 min
3
B1
62
Not reported
F
OH
10f
N
T = 350–360 °C, P = 130 bar, loop = 1.5 mL,
flow = 2 mL/min, c = 0.05 M,
tresidence = 0.75 min
(a) 5 min, 300 °C , microwave irradiation;29 (b) In biphenyl,
diphenyl ether, 1 h, 250 °C;30 (c) 1.25 h, 200–600 °C , 0.02 Torr31
4
5
B1
B1
43
60
NC
OH
N
10g
T = 300 °C, P = 100 bar, loop = 4.5 mL,
flow = 3 mL/min, c = 0.05 M, tresidence = 1.5 min
Oxo form: (a) in diphenyl ether, 0.25 h, heating (71%);18 (b) 0.83 h,
O
170–600 °C , 0.02 Torr;31 enol form: in iphenyl ether, 260 °C.32
OH
10h
Procedure B: To an ethanolic solution containing amine (2 g)
either Meldrum’s acid (1.1 equiv) and triethylorthoformate
(1.1 equiv) (Procedure B1)17,18 or cyanoacetic acid ethyl ester
(1.1 equiv) and triethylorthoformate (1.1 equiv) (Procedure B2)19
were added and the resulting solution refluxed for 2 h. After cool-
ing the crude product crystallized. The crystals were filtered,
washed with ethanol, and dried. Yield: 55–65% (Procedure B1),
45% (Procedure B2) (if necessary the compounds were purified by
column chromatography).
(0.45–4.5 min). This novel procedure leading to biphenyl deriva-
tives opens new avenues for the synthesis of these important inter-
mediates. We replaced the high boiling point solvent (diphenyl
ether) with a low boiling point solvent (THF) under high pressure.
The advantage of the continuous flow procedure in a common low
boiling point solvent is that it allows easy work-up, supports auto-
mation and the process is suitable for process development and
scale-up. Since the low boiling point solvent can be readily recy-
cled (thus, reduces waste), this procedure can be considered as a
greener alternative of presently available processes.
Procedure C:20 is a typical Knoevenagel protocol: To a stirred
solution of the corresponding aldehyde (1 equiv) in dry dichloro-
methane, diethyl malonate (1.1 equiv), piperidine (0.1 equiv), ace-
tic acid (0.1 equiv), and 4 Å molecular sieves were added. The
reaction mixture was stirred for 30 min at rt, another portion of
molecular sieves was added, and stirring was continued for 2 h.
The reaction mixture was filtered, the solvent removed on a rotary
evaporator at 25 °C and the resulting slurry diluted with diethyl
ether (30 mL). The solution was extracted with water. The com-
bined organic layers were washed with water, 1 N hydrochloric
acid, saturated sodium bicarbonate solution, water, and brine,
and finally dried over anhydrous sodium sulfate. Filtration and re-
moval of the solvent resulted in the crude Knoevenagel adduct
which was purified by column chromatography. Yield: 50–60%.
Procedure D:21 For the Conrad-Limpach precursor imine, aniline
(5 g) was dissolved in ethanol (20 mL), then ethyl acetoacetate
(1 equiv), glacial acetic acid (0.02 equiv), and MgSO4 (7 g) were
added. The resulting mixture was refluxed overnight. After cooling
to rt and filtering, the filtrate was evaporated to dryness and puri-
fied by column chromatography. Yield: 52%
Acknowledgments
We are grateful to Dr. Georg Frater for his continuing advice and
scientific support. We also thank Dr. Viktor Gyóllai for his contri-
bution during the preparation of this manuscript. This work was
partially supported by the National Development Agency KMOP
1.1.4 Grant (#KMOP-1.1.4-09-2010-0145).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.125.
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11. Ethyl 1-hydroxy-4-methylnaphthalene-2-carboxylate (10i): Yield: 95%. 1H NMR
(400 MHz, CDCl3): d 1.45 (t, 3H, J = 7.1 Hz), 2.57 (s, 3H), 4.45 (q, 2H, J = 7.1 Hz),
7.51–7.55 (m, 1H), 7.59 (s, 1H), 7.62–7.66 (m, 1H), 7.88 (d, 1H, J = 8.4 Hz), 8.45
(d, 1H, J = 8.2 Hz), 11.88 (s, 1H); 13C NMR (CDCl3): d 14.3, 18.7, 61.3, 105.2,
123.9, 124.0, 124.3, 125.0, 125.4, 129.2, 136.4, 160.0, 171.0. MS (CI) m/z
230 M+. Data corresponds to Ref. 24
12. Ethyl 2-hydroxy-5-phenylbenzoate (10j): Yield: 96%. 1H NMR (400 MHz, CDCl3):
d 1.45 (t, 3H, J = 7.1 Hz), 4.45 (q, 2H, J = 7.1 Hz), 7.07 (d, 1H, J = 8.6 Hz), 7.34 (t,
1H, J = 7.3 Hz), 7.44 (t, 2H, J = 7.6 Hz), 7.56 (d, 2H, J = 8.5 Hz), 7.70 (dd, 1 H,
J1 = 8.6 Hz, J2 = 2.4 Hz), 8.08 (d, 1H, J = 2.4 Hz), 10.87 (s, 1H). MS (CI) m/z
242 M+. Data corresponds to Ref. 25
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