One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

Article abstract of DOI:10.3762/bjoc.9.232

The Bohlmann-Rahtz pyridine synthesis and the Hantzsch dihydropyridine synthesis can be carried out in a microwave flow reactor or using a conductive heating flow platform for the continuous processing of material. In the Bohlmann-Rahtz reaction, the use of a Bronsted acid catalyst allows Michael addition and cyclodehydration to be carried out in a single step without isolation of intermediates to give the corresponding trisubstituted pyridine as a single regioisomer in good yield. Furthermore, 3-substituted propargyl aldehydes undergo Hantzsch dihydropyridine synthesis in preference to Bohlmann-Rahtz reaction in a very high yielding process that is readily transferred to continuous flow processing.

Full text of DOI:10.3762/bjoc.9.232

One-step synthesis of pyridines and dihydro-
pyridines in a continuous flow microwave reactor
Mark C. Bagley*1, Vincenzo Fusillo2, Robert L. Jenkins2,
M. Caterina Lubinu2 and Christopher Mason3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1957–1968.
1Department of Chemistry, School of Life Sciences, University of
Sussex, Falmer, Brighton, East Sussex, BN1 9QJ, UK, 2School of
Chemistry, Main Building, Cardiff University, Park Place, Cardiff,
CF10 3AT, UK and 3CEM Microwave Technology Ltd, 2 Middle Slade,
Buckingham, MK18 1WA, UK
doi:10.3762/bjoc.9.232
Received: 05 July 2013
Accepted: 11 September 2013
Published: 30 September 2013
Email:
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
Mark C. Bagley* - m.c.bagley@sussex.ac.uk
* Corresponding author
© 2013 Bagley et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Bohlmann–Rahtz; continuous flow processing; ethynyl ketones; flow
chemistry; Hantzsch dihydropyridine synthesis; heterocycles;
microwave synthesis; multicomponent reactions; pyridine synthesis
Abstract
The Bohlmann–Rahtz pyridine synthesis and the Hantzsch dihydropyridine synthesis can be carried out in a microwave flow
reactor or using a conductive heating flow platform for the continuous processing of material. In the Bohlmann–Rahtz reaction, the
use of a Brønsted acid catalyst allows Michael addition and cyclodehydration to be carried out in a single step without isolation of
intermediates to give the corresponding trisubstituted pyridine as a single regioisomer in good yield. Furthermore, 3-substituted
propargyl aldehydes undergo Hantzsch dihydropyridine synthesis in preference to Bohlmann–Rahtz reaction in a very high yielding
process that is readily transferred to continuous flow processing.
Introduction
Microwave-assisted synthesis has revolutionized many wide range of instrumentation [1], the scale up of microwave-
processes in recent years as a valuable alternative to the use of mediated reactions still poses a number of challenges, in par-
conductive heating for accelerating transformations in synthetic ticular as a result of a lack of uniform heating [9]. Scale-up
organic chemistry [1], colloidal science [2], natural product using batch methodologies in open reaction vessels can give
chemistry [3], medicinal chemistry [4-6], solid-phase peptide excellent yields but might not be appropriate for certain volatile
synthesis [7] and in the biosciences [8]. Despite the many or toxic reagents whereas continuous flow processing,
advantages of this heating method, and the introduction of a providing the reaction mixture is homogeneous, allows transfer
1957

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
from small-scale sealed vessel conditions to mesoscale produc- With all of these developments, it is becoming increasingly
tion often without any modification of reaction conditions or clear that flow chemistry, and to some degree microwave flow
loss in product yield [10]. The transfer from microwave batch chemistry, is realizing its potential towards the next evolu-
reaction to continuous flow processing can offer many advan- tionary step in synthetic chemistry [43].
tages for scale up, certainly in terms of process intensification
or in combination with reagent and scavenger cartridges for In 2005 we described a new continuous flow reactor design for
multi-step synthesis [11], and is possible using conventionally microwave-assisted synthesis that operates in the optimum
heated micro- or mesofluidic flow devices [12,13], but is also standing-wave cavity of a proprietary instrument [44]. The prin-
feasible under microwave dielectric heating. Strauss first cipal features exhibited by this reactor, charged with sand to
demonstrated in 1994 that by combining microwave-heating produce a series of microchannels, included improved perfor-
technology with continuous flow processing, problems with the mance over a Teflon coil reactor, heated using the same single-
limited penetration depth of microwave irradiation and the mode instrument, and direct measurement of the flow cell
physical restrictions of a standing wave cavity could be over- temperature using the instrument’s in-built IR sensor. In a
come [14]. A continuous flow reactor has the potential for rapid range of synthetic transformations (Scheme 1), including
optimization using minimal quantities of reagents, and for Bohlmann–Rahtz cyclodehydration of aminodienones 1 to the
‘scaling out’ – the spatial resolution of reactants and products corresponding pyridines 2 [44,45], Fischer indole synthesis of
can, in principle, sustain indefinite production [15]. Following tetrahydrocarbazole 5 from phenylhydrazine (3) and cyclohexa-
Strauss’s original report, a variety of transformations have been none (4) [44], and hydrolysis of 4-chloromethylthiazole (6) to
described using this unique combination of microwave heating give the corresponding alcohol 7 [44], the transfer from batch
and continuous flow or stop-flow processing [16,17]. Contin- reactor operation to continuous flow processing was efficient
uous flow microwave reactors have been used in transition and required little further optimization. Furthermore, we
metal-mediated cross-coupling reactions by Organ et al. in a showed that methodology developed using different reaction
Pd-coated capillary [18-20], over a solid-supported Pd catalyst platforms, including commercial microreactors and stainless
using a thin layer of gold as a selective heating element [21], or steel continuous flow instruments, transfer well to our de novo
in a Pd-supported silica monolith flow reactor by Haswell et al. microwave flow cell and from there can be scaled up using a
[22], using palladated Raschig rings in a PEEK [poly(ether commercial microwave flow reactor for mesoscale production
ether ketone)] reactor by Kirschning et al. [23], in a de novo [45]. The basic design of our microwave flow cell has been
glass coiled flow cell by researchers at Boehringer Ingelheim adapted by Kappe for the synthesis of dihydropyrimidinone 8 in
[24] and with an encapsulated palladium catalyst by Baxendale a 3-component Biginelli reaction and for the preparation of
and Ley, et al. [25], the latter to process multigram quantities in N3-substituted dihydropyrimidinone 10 by Dimroth rearrange-
a microwave-assisted Suzuki–Miyaura coupling. A comparison ment of 1,3-thiazine 9 [46]. In these studies, the 10 mL flow
on the use of palladium(0) nanoparticle catalysts on glass- cell was loaded with glass beads and irradiated at 120 or
polymer composite materials in batch and flow-through experi- 200 °C, respectively, to give the target heterocycle in yields that
ments by Kappe, Kunz and Kirschning revealed that contin- compared very favourably with microwave-heated batch experi-
uous flow processing gave better conversions and improved ments. For dihydropyrimidinone 8, a flow rate of 2 mL min–1
catalyst recycling, with no loss of activity [26]. A range of other delivered a very respectable processing rate of 25 g h–1.
applications have been explored, from a continuous flow
isothermal narrow channel microreactor for process intensifica- Following the success of this reactor design in delivering pyri-
tion of benzyl alcohol oxidation [27], the esterification of dine and pyrimidine heterocycles, albeit from very different
benzoic acid in a microwave tubular flow reactor [28], a contin- processes, and the recent advent of new technology for
uous flow recycle microwave reactor for homogeneous and mesoscale microwave-assisted continuous flow reactions [30],
heterogeneous processes [29], a mesoscale flow reactor utilizing we set out to establish if readily-available ethynyl carbonyl
Fe3O4 as a microwave absorbing packed reactor bed with precursors were capable of delivering diverse heterocyclic
internal fibre optic temperature measurement [30], to the targets under a continuous flow regime under microwave
continuous flow preparation of biodiesel on large scale [31], heating. Ley and Baxendale et al. [47] have demonstrated that
processing up to 7.2 L min–1, and waxy ester production on ethynyl ketones can be generated in flow by the palladium-
pilot scale using a continuous microwave dry-media reactor catalysed acylation of terminal alkynes and further transformed
[32]. The introduction of proprietary instruments capable of in a continuous process to pyrazoles by cyclocondensation with
carrying out microwave-assisted transformations under flow hydrazines using a commercially available conductive heating
processing have greatly expanded the range of chemistries modular flow reactor. Given that this cyclocondensation
scaled up and evaluated using this technology [1,9,16,33-42]. proceeds in a similar fashion and high efficiency under
1958

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
Scheme 1: Mesoscale production of heterocycles in a continuous flow microwave reactor [44-46].
microwave irradiation [48], and that we have previously established its facility under microwave irradiation and so it
demonstrated that pyridines and pyrimidines can both be provided a good comparison of different technology platforms.
formed rapidly and efficiently from ethynyl ketones using If the cyclodehydration could be incorporated into a multi-step
microwave dielectric heating, the transfer of synthetic pro- process and was spontaneous under the reaction conditions,
cedures to a continuous flow processing regime in a microwave following Michael addition to ethynyl ketones, then the contin-
flow reactor seemed highly feasible to access pyridine deriva- uous production of pyridines from readily-available materials
tives in a single step.
could be realized.
Results and Discussion
Synthesis of pyridines in a continuous flow
Introduction to the Bohlmann–Rahtz pyridine
synthesis
Bohlmann and Rahtz first reported the synthesis of trisubsti-
tuted pyridines from a stabilized enamine, such as ethyl
β-aminocrotonate (11), and an ethynyl carbonyl compound,
such as butynone (12a), in 1957 [49]. In its original form it was
a two step procedure involving Michael addition, isolation of
the corresponding aminodiene intermediate (e.g. 1a) and subse-
reactor
Many of our previous studies on the synthesis of pyridines in a
continuous flow reactor examined the cyclodehydration of
Bohlmann–Rahtz aminodienone intermediates in the presence
of a Brønsted acid catalyst [44,45]. This relatively simple
cyclization reaction was utilized previously as we had already
1959

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
Scheme 2: The original Bohlmann–Rahtz synthesis of pyridines [49].
quent cyclodehydration under high temperature conditions neat ture revealed if unreacted starting materials were present.
under vacuum to give a 2,3,6-trisubstituted pyridine (2a: Microwave irradiation of a 1:1 ratio of starting materials 11 and
Scheme 2) with total regiocontrol. In recent years there has 12b at 100 °C for 15 min (hold time) in PhMe–AcOH (5:1 v/v)
been renewed interest in this transformation for its application and spectroscopic analysis of the crude reaction mixture showed
in target synthesis [50], in the development of one-pot the two-step-in-one synthesis of pyridine 2b was a success
procedures for pyridine synthesis [50-58], and for incorpor- (Table 1, entry 1). Cyclodehydration was spontaneous under the
ation into domino processes [57-59]. Given our precedent reaction conditions as no aminodienone intermediate 1b
that microwave irradiation can facilitate the one-pot
Bohlmann–Rahtz synthesis of pyridines from ethynyl ketones
[58-60], this reaction was an ideal starting point to investigate
the synthesis of pyridines under a continuous flow regime, from
which a comparison to other methods could be drawn.
Bohlmann–Rahtz pyridine synthesis in batch and
flow
The reaction conditions, temperature and residence time were
optimized in batch mode under microwave irradiation for the
one pot synthesis of pyridine 2b (Scheme 3) using ethyl
β-aminocrotonate (11) and a readily available ethynyl ketone,
phenylpropynone 12b (R = Ph) [51], in the presence of acetic
acid as a Brønsted acid catalyst for transfer to flow processing.
A range of conditions were investigated (Table 1) and, in each
Scheme 3: Bohlmann–Rahtz synthesis of pyridine 2b.
case, 1H NMR spectroscopic analysis of the crude reaction mix-
Table 1: Batch and flow experiments for Bohlmann–Rahtz synthesis of pyridine 2b.
Entry
Process
Heating
Conditionsa
Resultsb
1
2
3
4
5
6
7
8
9
Batch
Batch
Batch
Batch
Flow
Microwavesc
Microwavesc
Microwavesc
Microwavesc
Microwavesc
Conductivee
Conductivee
Microwavesf
Microwavesf
PhMe–AcOH, 100 °C, 15 min
PhMe–AcOH, 100 °C, 20 min
PhMe–AcOH, 140 °C, 5 min
EtOH–AcOH, 120 °C, 5 min
EtOH–AcOH, 120 °C, 5 min
EtOH–AcOH, 120 °C, 5 min
EtOH–AcOH, 120 °C, 5 min
EtOH–AcOH, 120 °C, 5 min
EtOH–AcOH, 100 °C, 2.5 min
2b:12b ~13:1d
2b:12b >95:5d
2b (74%)
2b (86%)
2b (76%)
Flow
2b (86%)
Flow
2b (71%)
Batch
Batch
2bd (32%)
2bd (28%)
aReagents (0.3 mmol) were used in a molar ratio (11:12b) of 1:1 (entry 1) or 1.2:1 (entries 2–7) in PhMe–AcOH or EtOH–AcOH (5:1 v/v); tempera-
ture refers to vessel temperature, maintained by moderation of the initial microwave power (120 W for experiments in PhMe, 90 W for batch experi-
ments in EtOH and 100 W using the flow cell), as measured by the in-built IR sensor (entries 1–5); boutcome determined by 1H NMR spectroscopic
analysis of the crude reaction mixture; numbers in parentheses refer to the isolated yield of pyridine 2b; ccarried out using a commercial CEM single-
mode instrument; dunreacted starting materials were present; ecarried out using a commercial Uniqsis FlowSyn stainless steel coil reactor at a flow
rate of 1 mL min–1 (5 mL reactor; entry 6) [60] or 4 mL min–1 (20 mL reactor; entry 7); fthe scaled up microwave-assisted reaction was carried out in a
60 mL Teflon vessel in batch mode using a commercial Milestone multi-mode instrument in a molar ratio (1a:2b) of 1.3:1 (15 mmol).
1960

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
(R = Ph) was observed, although some unreacted propynone tography, pyridine 2b was isolated as a single regioisomer in
remained (2b:12b ~13:1). The use of a small excess of enamine 76% yield (Table 1, entry 5) and comparable purity to the
11 (1.3 equiv) and extending the reaction time to 20 min, im- successful batch experiments. By carrying out both Michael
proved the product ratio (Table 1, entry 2). At a higher reaction addition and cyclodehydration in one continuous flow process,
temperature, consumption of reactants was complete in 5 min pyridine synthesis is possible in a single step from readily avail-
on irradiation at 140 °C in PhMe–AcOH (5:1) (Table 1, entry 3) able materials, avoiding the need to isolate and purify
or at 120 °C in EtOH–AcOH (5:1) (Table 1, entry 4), to give Bohlmann-Rahtz intermediate 1b and overcoming issues of its
pyridine 2b in 74 or 86% isolated yield, respectively. The use of poor solubility, which in past reports have necessitated carrying
ethanol as a protic solvent appeared to improve the efficiency of out the flow process under high dilution conditions [44,45].
the process, a phenomenon that has also been observed for two-
step-in-one Bohlmann–Rahtz reactions [54], in the Michael With successful transfer of parameters to the microwave flow
addition of ethynyl ketones [51], both under conductive heating, reactor, flow experiments were investigated with a commercial
and in the tandem oxidation Bohlmann–Rahtz synthesis of conductive heating flow reactor (Table 1) using either a 5 mL
nicotinonitriles under microwave irradiation [59]. These batch [60] (Table 1, entry 6) or 20 mL (Table 1, entry 7) stainless
experiments now established that microwave heating could steel coil reactor. Both processes gave efficient conversion to
establish efficient conversion to nicotinoate 2b in 5 min using pyridine 2b with small variations noted depending upon the size
only a small excess of enamine 11 and so these parameters of the flow cell – the smaller reactor (5 mL) and slower flow
(Table 1, entry 4) were favoured for transfer to flow processing rates delivering the highest efficiency (Table 1, entry 6). The
over previously reported procedures [58].
isolated yield of the continuous flow process (86%) outper-
formed the traditional Bohlmann–Rahtz reaction [49] in terms
Following the success of the microwave batch reaction condi- of overall yield (81% over two steps) and step efficiency.
tions, the most efficient parameters were transferred to the Furthermore, the process was comparable in efficiency to previ-
microwave flow reactor for continuous processing (Figure 1). ously reported two-step-in-one Bohlmann–Rahtz methods under
The Pyrex tube was filled with sand, connected to a back-pres- conductive heating [51], such as heating at 50 °C for 6 h in
sure regulator (100 psi) and primed with solvent at a flow rate PhMe–AcOH (85% yield) or heating at reflux in PhMe for 5.5 h
of 0.6 mL min−1 (for 5 min residence time) using a HPLC in the presence of zinc(II) bromide (15 mol %) (86% yield), and
pump. Microwave irradiation under continuous flow processing provides improvements in reaction kinetics and processing rate.
was initiated at an initial power of 100 W, which was modu-
lated to maintain 120 °C vessel temperature as measured by the Finally the improved performance of flow processing in this
in-built IR sensor. Once the flow cell temperature stabilized, the transformation was validated by a larger scale (15 mmol)
solution of the reactants was introduced and the cell was irradi- microwave-assisted batch reaction in a 60 mL Teflon vessel
ated at 120 °C for 5 min. Once all of the reactants were using a commercial multi-mode instrument (Table 1, entries 8
processed, the flow cell was washed with further batches of and 9). Irradiation at 120 °C for 5 min (Table 1, entry 8), in this
solvent and the outflow was quenched in a solution of aqueous case as measured by thermocouple, gave multiple components
NaHCO3. After extraction and purification by column chroma- by tlc analysis and provided pyridine 2b in poor isolated yield
Figure 1: Microwave flow reactor for the Bohlmann–Rahtz synthesis of pyridine 2b.
1961

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
(32%) although did allow rapid access to gram quantities of ma- flow cell. Mechanistically, there was evidence to support the
terial. In case a lack of homogeneity in heating had caused addi- hypothesis that the 4-component Hantzsch reaction [64]
tional decomposition, the experiment was repeated over a proceeds in a similar course to the Bohlmann–Rahtz pyridine
shorter reaction time at a slightly lower temperature (Table 1, synthesis [50], by Michael addition followed by cyclodehydra-
entry 9) but this caused no improvement in outcome (28% tion, and so it was reasonable to assume that similar conditions
yield). Difficulties in scaling up a microwave-assisted batch should enable the flow processing of material, provided that
reaction had been noted previously for the Bohlmann–Rahtz reactants and products were homogeneous in the solvent of
cyclodehydration [45]; in that case the use of a 60 mL vessel choice, thus providing further comparative studies on the
(1.9 mmol of 1b) in a multi-mode instrument had proved highly transfer of parameters between different platforms.
efficient (96%) under similar conditions. However, transfer to a
100 mL vessel (7.7 mmol of 1b) had caused a considerable Hantzsch dihydropyridine synthesis in batch and
decrease in efficiency (65%). For the two-step-in-one flow
Bohlmann–Rahtz reaction these difficulties seemed to be even Previous methods for carrying out the microwave-assisted batch
more pronounced: given the poor yield of the two processes reaction were first consolidated by setting up a series of reac-
(Table 1, entries 8 and 9), these difficulties were attributed to tions that were purified in a consistent fashion. A solution
low efficiency in the initial Michael addition. For this multistep containing an excess of ethyl acetoacetate (13), aqueous
process, reaction parameters did not transfer well between ammonia as the ammonia source, and either benzaldehyde (14a)
single-mode 10 mL and multi-mode 60 mL reactors and this or propionaldehyde (14b) (Scheme 4) was irradiated at 140 °C
justified the use of continuous flow processing for efficient for 10 min in EtOH–H2O (1:1 v/v) in a modification of the
mesoscale production. It is evident that the reliability of scaling Leadbeater conditions [73] (Table 2, entries 1 and 2). The
a microwave batch reaction is highly dependent upon the nature outcome was compared with a repeat of our previously estab-
of the transformation and even small changes in the process in lished conditions [70], based upon Westman’s report [68], in
question can cause unexpected problems, which require further EtOH (Table 2, entries 3 and 4), in all cases purifying by flash
optimization of parameters to resolve. From these considera- chromatography on silica. For the synthesis of phenyl-15a (70%
tions, we conclude that the most reliable means to scale to gram yield) and ethyl-DHP 15b (87% yield) on 2.5 mmol scale these
production from mg scale in a microwave-assisted batch reac- experiments indicated that the ideal solvent for this process was
tion using 10 mL sealed vessels is through continuous flow EtOH rather than EtOH–H2O (1:1 v/v). Reducing the molar
processing, using either microwave dielectric heating or equivalents of acetoacetate 13 from 5 to 3.4 (the stoichiometry
conductive heating, which in this case gave comparable results. used by Leadbeater [73]) caused a significant reduction in the
Synthesis of dihydropyridines in a contin-
uous flow reactor
Introduction to Hantzsch dihydropyridines
The Hantzsch dihydropyridine (DHP) synthesis, first discov-
ered in 1881 [61,62], is a well-studied multicomponent reaction,
that provides structures with well-catalogued clinical properties
for the treatment of cardiovascular disease, thrombosis and
atherogenesis [63-66]. The 4-component process has been
carried out under high temperature conditions in an autoclave
[67] and under microwave irradiation [10,68-72]. Furthermore,
this reaction has been studied in a conductive heating Uniqsis
FlowSyn reactor [71,73] and its comparison with microwave
heating batch experiments showed that the energy efficiency of
these technology platforms vary with scale, but broadly are
comparable [73]. Furthermore, recently a bespoke microwave
reactor with a glass containment cell has been used under
continuous flow processing for 4-component Hantzsch DHP
synthesis in good yield [74]. Given this precedent and our own
previous studies on the use of microwave irradiation in a single-
mode instrument to promote 4-component DHP synthesis [70],
Scheme 4: Four-component synthesis of Hantzsch DHP 15a,b.
this reaction seemed ideal to expand the scope of the microwave
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Beilstein J. Org. Chem. 2013, 9, 1957–1968.
Table 2: Batch and flow experiments for 4-component Hantzsch DHP 15 synthesis.
Entry
Process Heating
Reagents and conditionsa
15
Yieldb
1
Batch
Batch
Batch
Batch
Batch
Batch
Batch
Batch
Flow
Microwavesc 14a (1 equiv), 13 (5 equiv), NH4OH (4 equiv.), EtOH–H2O, 140 °C, 10 min
Microwavesc 14b (1 equiv), 13 (5 equiv), NH4OH (4 equiv.), EtOH–H2O, 140 °C, 10 min
Microwavesc 14a (1 equiv), 13 (5 equiv), NH4OH (4 equiv.), EtOH, 140 °C, 10 min
Microwavesc 14b (1 equiv), 13 (5 equiv), NH4OH (4 equiv), EtOH, 140 °C, 10 min
Microwavesc 14a (1 equiv), 13 (3.4 equiv), NH4OH (4 equiv), EtOH–H2O, 140 °C, 10 min
Microwavesc 14b (1 equiv), 13 (3.4 equiv), NH4OH (4 equiv), EtOH–H2O, 140 °C, 10 min
Microwavesc 14a (1 equiv), 13 (2 equiv), NH4OAc (3 equiv), EtOH–AcOH, 140 °C, 10 min
15a 41%
15b 67%
15a 70%
15b 82%
15a 35%
15b 46%
15a 43%
2
3
4
5
6
7
8
Microwavesc 14b (1 equiv), 13 (3.4 equiv), NH4OAc (6 equiv), EtOH–AcOH, 140 °C, 10 min 15b 28%
9
Conductivee 14a (1 equiv), 13 (5 equiv), NH4OH (4 equiv), EtOH, 140 °C, 10 min [71]
Conductivee 14a (1 equiv), 13 (5 equiv), NH4OH (4 equiv), EtOH, 120 °C, 30 min
Conductivee 14b (1 equiv), 13 (5 equiv), NH4OH (4 equiv), EtOH, 120 °C, 30 min
Conductivee 14b (1 equiv), 13 (5 equiv), NH4OH (4 equiv), EtOH, 140 °C, 7.5 min
Conductivee 14b (1 equiv), 13 (5 equiv), NH4OH (4 equiv), EtOH, 140 °C, 10 min
15a 43%
15a 35%
15b 34%
15b 39%
15b 68%
10
11
12
13
Flow
Flow
Flow
Flow
aTemperature refers to vessel temperature, maintained by moderation of the initial microwave power, as measured by the in-built IR sensor (entries
1–5); bisolated yield of DHP 15 after purification by column chromatography on silica, eluting with EtOAc–light petroleum; ccarried out using a
commercial CEM single-mode instrument at an initial power of 150 W; dunreacted starting materials were present; ecarried out using a commercial
Uniqsis FlowSyn stainless steel coil reactor (5 mL) at a flow rate of 0.5 mL min–1.
yield for both reactions (Table 2, entries 5 and 6) and so did DHP 15b (68%) under flow processing. Comparing the
justify the use of such a considerable excess of this precursor. optimum conditions under continuous flow processing for this
Similar observations on the ideal reagent stoichiometry have reaction, i.e. NH4OH/EtOH/140 °C/10 min, with Leadbeater’s
been made by Öhberg and Westman [68] in sealed tube process [73] for this transformation (43% yield vs 53% conver-
microwave reactions and our yields were broadly comparable sion), it was apparent that the small reduction in efficiency we
although higher than our previous report which included an ad- had observed was reasonably well justified: the change in
ditional purification step [70] (e.g. 70% (Table 2, entry 3) vs solvent had prevented problems with in-line precipitation and so
84% [67] or 47% [70]). The use of NH4OAc as ammonia greatly simplified the processing protocol. However, the
source in EtOH–AcOH, under similar conditions to a 3-compo- transfer to a continuous flow regime had caused a significant
nent Bohlmann–Rahtz reaction [54], failed to improve the effi- reduction in yield with respect to our microwave batch reaction
ciency of the process (Table 2, entries 7 and 8) and so, given the (Table 2, entry 3; 70% yield) and was considerably lower than
high yield and short reaction times of the Westman conditions the batch microwave process reported by Leadbeater on 0.5 mol
(Table 2, entries 3 and 4), and the Leadbeater precedent [73], it scale under open vessel conditions, which delivered an
was felt that this process was suitable for direct transfer to outstanding yield of 15a (96%) [10], so further experiments to
continuous flow processing under conductive heating to improve the continuous flow processing of Hantzsch dihydro-
examine if this offered any improvement over Leadbeater’s pyridines were considered.
established flow chemistry protocol. Thus, a solution of
NH4OH, as the ammonia source, aldehyde 14a and aceto- In an effort to improve the flow process further, a 3-component
acetate 13 (5 equiv) in EtOH was heated at 140 °C in a 5 mL process was investigated. In this transformation, the use of an
stainless steel coil for a residence time of 10 min (Table 2, entry ammonia source was no longer necessary and instead aceto-
9); the outflow was quenched in H2O, extracted and purified acetate 13 was replaced with ethyl β-aminocrotonate (11)
using column chromatography [71]. Although the isolated yield (Scheme 5). Removing the need to generate the enamine in situ
of DHP 15a was lower, in relation to the corresponding batch should improve the efficiency of the process and it was thought
process, the continuous flow process was a success. Further op- could lead to better transfer of reaction parameters between
timization, by lowering the flow rate and decreasing the reac- batch and flow platforms. The use of propynal 14c would
tion time (Table 2, entries 10 and 11), caused a small reduction further expand the scope of this reaction and establish if
in the yield of both DHP 15a and 15b, which was improved 3-substituted propargyl aldehydes would undergo Hantzsch
little by increasing the flow rate and thus decreasing the resi- DHP 15c synthesis or participate instead in a tandem Michael
dence time (Table 2, entry 12). However, returning to the orig- addition–cyclodehydration reaction, in accordance with the
inal conditions (Table 2, entry 13) delivered a good yield of original Bohlmann–Rahtz report (which had used propynal), to
1963

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
Scheme 5: Three- or four-component synthesis of Hantzsch DHP 15c,d.
give trisubstituted pyridines 16 [49]. Returning to the pyridine synthesis and no 2,3,4-trisubstituted pyridine 16 was
microwave batch reactor, a solution of phenylpropargyl alde- formed (Scheme 5). This supported earlier findings [49] by
hyde (14c) and enamine 11 (2 equiv) in PhMe–AcOH (Table 3, Bohlmann and Rahtz and highlights a reactivity trend of
entry 1) or EtOH–AcOH (5:1) was irradiated at 100 °C for 3-substituted propargyl aldehydes in reaction with enamines. A
1 min, cooled and then extracted and purified as before to give comparable process in EtOH in the absence of AcOH failed to
DHP 15c in a remarkable 98 or >98% yield, respectively. provide complete conversion (Table 3, entry 3), whereas the
Clearly, using stoichiometry appropriate for Hantzsch DHP syn- reagents were only poorly soluble in AcOH alone and so the
thesis, this process was totally selective over Bohlmann–Rahtz effect of change in solvent was not pursued further. To try and
Table 3: Synthesis of Hantzsch DHP 15c,d from propargyl aldehydes 14c,d in batch and flow.
Entry
Process Heating
Reagents and conditionsa
15
Yieldb
1
2
3
4
5
6
7
8
9
Batch
Batch
Batch
Batch
Batch
Batch
Flowe
Flowe
Flowe
Microwavesc 14c (1 equiv), 11 (2 equiv), PhMe–AcOH, 100 °C, 1 min
15c 98%
15c >98%
15c –d
Microwavesc 14c (1 equiv), 11 (2 equiv), EtOH–AcOH, 100 °C, 1 min
Microwavesc 14c (1 equiv), 11 (2 equiv), EtOH, 120 °C, 15 min
Microwavesc 14c (1 equiv), 13 (2 equiv), NH4OAc (3 equiv), EtOH–AcOH, 120 °C, 5 min
Microwavesc 14d (1 equiv), 11 (2 equiv), EtOH–AcOH, 100 °C, 1 min
15c 96%
15d 82%
15d 84%
15d –f
Microwavesc 14d (1 equiv), 13 (2 equiv), NH4OAc (3 equiv), EtOH–AcOH, 120 °C, 5 min
Microwavesc 14d (1 equiv), 13 (2 equiv), NH4OAc (3 equiv), PhMe–AcOH, 120 °C, 5 min
Microwavesc 14c (1 equiv), 13 (2 equiv), NH4OAc (3 equiv), EtOH–AcOH, 120 °C, 5 min
Microwavesc 14c (1 equiv), 13 (2 equiv), NH4OAc (3 equiv), EtOH–AcOH, 120 °C, 5 min
15c 70%
15c 85%g
aTemperature refers to vessel temperature, maintained by moderation of the initial microwave power, as measured by the in-built IR sensor; bisolated
yield of DHP 15 after quenching in H2O and extraction (entries 1–8); ccarried out using a commercial CEM single-mode instrument at an initial power
of 70 W (entries 1–3 and 5), 90 W (entries 4 and 6), 200 W (entry 7) or 100 W (entries 8 and 9); dunreacted starting materials were present; ecarried
out using the microwave flow reactor (10 mL) filled with sand at a flow rate of 0.6 mL min−1; fheterogeneity in the solvent system caused pump failure;
gisolated yield after quenching in aqueous NaHCO3 solution and filtering the precipitated solid.
1964

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
identify which component, aldehyde or acetoacetate, had been microwave irradiation [10] and under continuous flow
responsible for the dramatic improvement in yield, a 4-compo- processing, observed by ourselves and others [73,74], this tech-
nent Hantzsch reaction was also investigated (Table 3, entry 4). nology stands out as the heating method of choice for the
Irradiating a solution of propargyl aldehyde 14c, acetoacetate preparation of 1,4-DHP derivatives.
13 (2 equiv) and NH4OAc (3 equiv) in EtOH–AcOH (5:1) at
120 °C for 5 min gave DHP 15c in 96% isolated yield. Investi- Conclusion
gating an alternative propargyl aldehyde, the 3- or 4-compo- These studies have demonstrated that a microwave flow reactor
nent batch syntheses of DHP 15d using 3-(trimethyl- can be used for the one-step preparation of pyridines
silyl)propynal (14d), similarly, gave excellent yields of the pro- and dihydropyridines using the Bohlmann–Rahtz reaction
duct under microwave irradiation (Table 3, entries 5 and 6). or Hantzsch multicomponent reaction, respectively.
Thus, it was concluded that 3-substituted propargyl aldehydes Bohlmann–Rahtz pyridine synthesis under continuous flow
are highly reactive and useful substrates for Hantzsch DHP syn- processing in the presence of a Brønsted acid catalyst allows
thesis and give little or no competing formation of the corres- Michael addition and cyclodehydration to be carried out in one
ponding Bohlmann–Rahtz pyridine 16 under conditions that step without the isolation of intermediates to give a trisubsti-
nominally can promote both processes.
tuted pyridine as a single regioisomer. Furthermore, the use of
microwave heating for facilitating this two-step-in-one transfor-
With the batch methods established, a 4-component reaction mation is well justified, compares favourably with the tradi-
using a propargyl aldehyde was transferred to the microwave tional two-step procedure and, using these protocols, delivers
flow reactor with minimal change in reaction parameters. The Bohlmann–Rahtz pyridines quickly and efficiently. In batch
flow cell was primed with the solvent of choice and heated mode using a single-mode instrument this process is highly
under microwave irradiation; once the temperature of the predictable and is most reliably scaled up using continuous flow
reactor stabilized, the reaction mixture was introduced. Using processing, either on a conductive heating platform or using a
3-(trimethylsilyl)propynal (14d) in PhMe–AcOH resulted in microwave flow reactor in favour over a multimode batch
pump failure, due to the heterogeneity of the reagent flow in reactor. On the other hand, the scale up of a microwave-assisted
this reaction solvent (Table 3, entry 7). Switching to the use of Hantzsch DHP synthesis under open-vessel conditions as
phenylpropargyl aldehyde (14c) and changing the solvent described by Leadbeater [10] outperforms even the small-scale
system to EtOH–AcOH produced a homogeneous reagent flow microwave-assisted batch reaction, but the use of continuous
and allowed the reaction mixture to be processed at 120 °C at a flow processing in a microwave reactor as shown by ourselves
continuous flow rate of 0.5 mL min−1 through the microwave and others [74] can deliver the target heterocycle in excellent
reactor. After passing through the back-pressure regulator, the yield. For both Hantzsch and Bohlmann–Rahtz reactions, para-
outflow was quenched in H2O and extracted (Table 3, entry 8) meters transferred very well from high temperature batch condi-
or quenched in aqueous NaHCO3 solution and filtered (Table 3, tions in a sealed vessel to continuous flow processing through a
entry 9) to give the 4-(phenylethynyl)-DHP 15c in 70 or 85% microwave flow cell in a single-mode cavity. In some cases, it
yield, respectively. Although the yields of both flow reactions was possible to further transfer parameters between conductive
were slightly lower than their batch mode counterparts, (96% heating and microwave heated flow platforms, with only minor
batch yield vs 85% yield under flow processing for the syn- variations in yield. Furthermore, it has been affirmed that
thesis of 15c) the continuous processing of Hantzsch DHPs had 3-substituted propargyl aldehydes are not suitable substrates for
been realized.
the Bohlmann–Rahtz reaction and instead undergo Hantzsch
dihydropyridine synthesis in very high yield in a process that is
Reviewing all of our methods for the microwave-assisted readily transferred to continuous flow processing in a
preparation of DHP derivatives, the isolated yield for the batch microwave flow cell. Although this sets a new challenge on
synthesis of Hantzsch DHP 15c (96%) compares very how to access 2,3,4-trisubstituted pyridines using
favourably to other microwave-assisted 4-component Hantzsch Bohlmann–Rahtz methods, a transformation which currently
reactions (cf. 81% yield of a DHP under flow processing [74], cannot be realized, it does provide a useful substrate for 3- or
51–92% yield [67] or 84–99% yield [72] of a range of deriva- 4-component Hantzsch DHP synthesis that undergoes cyclocon-
tives in batch using a single-mode instrument, and 96% yield of densation with high efficiency. To conclude, continuous flow
15a under open vessel batch conditions on 0.5 mol scale [10]) microwave-assisted reactions represent a reliable method to
and transfers well to flow processing giving 85% yield under scale up the production of pyridine derivatives and, for the
microwave irradiation (cf. 81% [74]). Given the excellent Bohlmann–Rahtz pyridine synthesis, give improved perfor-
performance of microwave dielectric heating in promoting the mance over a comparable large scale multimode batch experi-
4-component Hantzsch reaction with direct scalability under ment. This expands the growing set of heterocyclic targets that
1965

Beilstein J. Org. Chem. 2013, 9, 1957–1968.
have been accessed by the reactions of ethynyl ketones under (2 × 15 mL) and the organic extracts were combined, washed
continuous flow processing and sets the stage for their future with brine (15 mL), dried (NaSO4) and evaporated in vacuo to
incorporation into automated multistep processes.
give the title compound (0.16 g, 84%) as a pale yellow solid,
with identical physical and spectroscopic properties.
Experimental
Diethyl 4-(trimethylsilylethynyl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (15d)
Supporting Information
Supporting information contains experimental procedures
for the synthesis of known compounds.
Supporting Information File 1
General experimental methods and detailed procedures for
the synthesis of propynone 12b, Bohlmann–Rahtz pyridine
2b and Hantzsch dihydropyridines 15a, 15b and 15c.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-232-S1.pdf]
3-Component Hantzsch DHP synthesis in a single-mode
microwave batch reactor (Table 3, entry 5). A mixture of
3-(trimethylsilyl)propynal (14d, 50 mg, 0.53 mmol) and ethyl
β-aminocrotonate (11, 0.14 g, 1.1 mmol) in PhMe–glacial acetic Acknowledgements
acid (5:1, 2 mL) was irradiated at 100 °C for 1 min in a sealed We thank the EPSRC (GR/S41463 and GR/S25456; awards to
tube using a CEM Discover microwave synthesizer at an initial MCB, MCL and VF), and the R M Phillips Trust (award to
power of 70 W. The reaction mixture was cooled in a stream of MCB) for support of our work, Otman Benali (Uniqsis), Laura
compressed air and partitioned between saturated aqueous Favretto (Milestone), Matthew Burwood (a1-envirotech) and
NaHCO3 solution (25 mL) and EtOAc (25 mL). The aqueous Robin Wood (AstraZeneca) for valuable assistance, CEM
layer was further extracted with EtOAc (2 × 15 mL) and the (Microwave Technology) Ltd, Milestone S.r.I. and Uniqsis Ltd
combined organic extracts were washed with brine (15 mL), for permitting us to test their apparatus in our laboratories, and
dried (NaSO4) and evaporated in vacuo to give the title com- the EPSRC Mass Spectrometry Service at the University of
pound (0.15 g, 82%) as a yellow solid, mp 137–138 °C (aq Wales, Swansea UK for mass spectra.
EtOH); (Found: [M + H]+, 350.1783. C18H27NO4Si, [M + H]
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