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

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

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

Flow

Microwavesc

Conductivee

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, 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

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

1962

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

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

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

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

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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