A High Mobility Reactor Unit for R&D Continuous ... - ACS Publications

Subscriber access provided by University of Newcastle, Australia

Full Paper

A High Mobility Reactor Unit for R&D Continuous Flow Transfer Hydrogenations Rasmus K Jensen, Nikolaj Thykier, Martin V. Enevoldsen, and Anders T. Lindhardt Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00441 • Publication Date (Web): 08 Feb 2017 Downloaded from http://pubs.acs.org on February 9, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

A High Mobility Reactor Unit for R&D Continuous Flow Transfer Hydrogenations Rasmus K. Jensen,‡ Nikolaj Thykier,‡ Martin V. Enevoldsen, Anders T. Lindhardt* Aarhus University, Department of Engineering, Section of Biological and Chemical Engineering. Hangøvej 2, 8200 Aarhus C, Denmark.

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 21

TOC Graphic Con$nuous Flow Hydrogen Transfer

O NO 2

MeO HO O

O OMe

Ph

MeO

NHCbz

Mobile Reactor Unit

MeO

CH 3

NH 2

HO O Ph

O OMe

NH 2

MeO


2

Page 3 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


KEYWORDS: Flow Chemistry, Packed Bed Reactor, Palladium Catalysis, Transfer Hydrogenation, Mobile Reactor Unit.

ABSTRACT: A suitcase sized mobile reactor unit (MRU) weighing in at less than 10 kg was designed for laboratory scale transfer hydrogenations in continuous flow. Simple cyclohexene and a co-solvent in combination with a palladium-on-charcoal packed bed reactor provided a setup with isolation of nearly all products without the need for further purification. Several functional groups including olefins, triple bonds, nitro-groups, carbonyls, etc. were effectively reduced with retention times as low as 2 minutes. Additionally, standard protection groups such as Cbz, benzyl and allyl ether or esters were removed in high yields. To prove the flexibility of the setup an example of the Mizoroki-Heck reaction was also performed on the MRU. Finally, two scale-up transfer hydrogenation experiments were performed affording isolation of the desired target compounds in 0.5 and 0.8 mol scales with less than 4 hours of continuous operation on the MRU.

INTRODUCTION The advantages of applying continuous flow setups in research and development (R&D) laboratories have become obvious during the last decade.1 The ability to perform chemistry under conditions that extend beyond the round-bottomed flask combined with precise control of nearly all reaction parameters has attained significant research interest. Especially, reactions requiring high-pressure or high temperatures have enjoyed the adaptation to continuous flow mode, while simultaneously improving the operator safety.2 Even high-energy intermediates can now be handled safely in telescoped flow reactions, as these reagents are produced and


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 21

transformed continuously with no hold-up or storage.3 Numerous other examples have been published proving that continuous flow protocols holds the ability to enhance selectivity, shortened reaction time (ultrafast), enhanced heat and mass transport, etc.4 In addition, once a reaction has been developed in continuous flow its scale-up to produce large amounts of material has proven more straightforward.1a,d,2b,5 Despite, all these arguments speaking in favor of the installation of flow chemistry equipment in any R&D laboratory, there are drawbacks towards application of these methods, the major one being practicality. Constructing a specific flow-setup with all needed pumping equipment, mixers, flow-reactors, backpressure regulation and connecting everything with tubing is inherently time-consuming. So any advantages gained from continuous flow might be eliminated by time concerns leading to classical round bottom flask synthesis, especially, if only one or few reactions are to be performed. Alternatively, a given flow-setup or commercial flow-unit could be permanently installed in a designated fume hood, however, not all laboratories hold the luxury of being sub-populated given that laboratory space is costly. Hence, the need to develop complete flow reactor setups that are widely applicable and mobile would be of great interest. Such mobile systems would allow the R&D chemist to rapidly move the flow-reactor system into the fume-hood and initiate the desired reaction. Furthermore, if the flow-setup would cover a series of different reactions types, its applicability would increase significantly.

In this manuscript, we wish to report on the development of a Mobile Reactor Unit (MRU) towards transfer hydrogenation in continuous flow. The concept behind the MRU is a robust, yet simple design based on HPLC parts for all tubing, packed bed reactor and fittings. Standard


4

Page 5 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


palladium on charcoal (Pd/C) in combination with cyclohexene served as the hydrogen source allowing reaction work-up to be fast and simple. The fully constructed MRU was fitted inside an alumina suitcase (dimensions 46 cm x 33 cm x 15 cm) and weighed in below 10 kilograms! Several common functional groups underwent successful hydrogen transfer reduction with flow reactor residence times between 2.5 minutes and 40 minutes. Other transformations based on the inherent reactivity of the palladium catalyst were investigated including Tjusi Trost type deprotection of allylic ethers or esters and Mizoroki-Heck reactions. Finally, fume hood scale-up hydrogen transfer reduction on the MRU was performed affording 137.7 g and 82.6 g isolation of reduced eugenol and ethyl 4-nitrobenzoate, respectively. The latter of these scale-up studies was also applied to gain insight to potential catalyst leaching and/or deactivation of the packed bed reactor.

Results and Discussion During the construction of the Mobile Reactor Unit for transfer hydrogenation the following considerations were taken into account. Although, hydrogen gas is the most atom- and cost efficient reagent used in reductions, the handling of this gaseous molecule has some drawbacks.6,7 Hydrogen is typically stored and transported in pressurized cylinders compromising the desired simplicity of the MRU. Online production of hydrogen could also be facilitated by smart systems such as the H-cube.6a,8

Figure 1. Schematic Representation and Suitcase Installed Transfer Hydrogenation MRU.


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Sample Loop

MeO HO

Page 6 of 21

1

Hydrogen Solvent Donor

MeOH or EtOAc

Packed Bed Reactor Palladium on Charcoal

HPLC Pump

MeO

BPR

HO

H H 2

However, the use of hydrogen will always result in two-phase systems due to the low solubility of this gaseous reagent in common laboratory solvents.9 We therefore decided to apply a transfer hydrogenation approach, as this would allow the hydrogen source, typically salts or liquids, to be part of the reaction mixture.10 Palladium on charcoal (Pd/C) was chosen as the catalyst as this material often already is present in chemical laboratories or readily available through several chemical vendors.6,9,10c,11 The Pd/C catalyst was loaded into an empty HPLC column, as a packed bed reactor, thereby allowing the reaction mixture to pass the catalyst without the need for subsequent removal by filtration.12 An additional advantage to the application of the packed bed reactor approach is the presence of super-stoichiometric amounts of catalyst, resulting in a significant reduction in the required residence time. Despite this super stoichiometric amount of Pd/C experienced by the limiting substrate, at any given time, in the reactor the overall flow-


6

Page 7 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


system will become catalytic upon prolonged operation. As all reactants are mixed prior to entering the packed bed reactor a one-pump setup could be designed, and the reaction mixture would either be pumped continuously by feeding on a stock reservoir (for large-scale applications) or loaded by injection into a loop (10 mL) positioned between the pump and packed bed reactor (See figure 1). As the heating source, a heating mantle, connected to a PID temperature controller, was placed around the packed bed reactor. The mantle was heated using cartridge heaters and isolated with vermiculite for safety reasons and to minimize heat exchange with the surroundings. The heating mantle allows the packed bed reactor to reach the desired reaction temperature in few minutes. Finally, the flow-setup was fitted with a backpressure regulator set to 1000 psi, permitting reaction temperature settings above solvent boiling points. During this study two different packed bed reactor designs were tested, differing in the method of packaging and the amount of Pd/C catalyst loaded. Pd/C was mixed with silica in order to reduce the pressure drop over the packed bed reactor. Finally, both ends of the HPLC column were sealed with additional silica and cotton plugs to prevent small particles of Pd/C from exiting the reactor.

Scheme 1. MRU Transfer Hydrogenation of Eugenol. Sample Loop MeO HO

γ-Terpinene 3.0 M

1 - 0.5 M

HPLC Pump

Entry

MeO

Palladium on Charcoal

EtOAc

Flowrate

HO

140 °C Residence

2

Yielda


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

[ml/min]

time

Page 8 of 21

[%]

[min] 1

1

15 min

(100)b

2

10

90 sec

91

3c

8

113 sec

86.3 (137.7 grams)

a

Isolated yield. b Conversion based on 1H-NMR analysis of crude reaction mixture. c Large scale experiment – See supporting information for reaction setup.

The void volume of the packed bed reactor was determined by the weight difference of the dry and ethyl acetate loaded column at room temperature correlated to the density of the liquid. Besides the heating mantle, all parts for the MRU design was constructed from commercially available HPLC parts (See the Supporting Information for a full description of the MRU setup). The reduction of eugenol was used as test system applying γ-terpinene as the hydrogen donor (See Scheme 1). Eugenol (1) (0.5 M) and γ-terpinene (3.0 M) dissolved in ethyl acetate was loaded onto the sample loop (10 mL – 5 mmol reaction scale) and then pumped through the packed bed reactor set at 140 °C. Operating the system at a flow rate of 1 mL/min, corresponding to a residence time of 15 minutes, resulted in full conversion of eugenol to 2-methoxy-4propylphenol (2) as determined by 1H-NMR analysis. Interestingly, increasing the flowrate in a stepwise manner all the way to the maximum HPLC pump-capacity of 10 mL/min (residence time = 1.5 min) still afforded the fully reduced compound (2) in an isolated yield of 91%. Next, a large-scale reduction of eugenol was initiated. An ethyl acetate stock solution of 1 mol of eugenol and γ-terpinene, in the same ratios as above, was pumped through the packed bed reactor at 8 mL/min (residence time = 1 min 53 sec). Collection of material was initiated after clearing two reactor volumes assuming that flow reactor operation had reached steady state.


8

Page 9 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Collection was continued for 4 hours, corresponding to processing 0.96 mol of eugenol. The reaction progress was followed by 1H NMR and showed full consumption of 1 throughout the entire process. 2 was isolated by basic washing of the crude reaction mixture followed by acidification and extraction of the aqueous phase. This resulted in the isolation of 2 in 86.3 % (137.7 grams) corresponding to a catalytic palladium loading of 0.054 mol % (TON = 1851). We then turned our attention to other hydrogen transfer reagents to substitute the γ-terpinene. Although, γ-terpinene worked well in the reduction of eugenol, its removal from the crude reaction mixture is complicated by high boiling points of this compound and its fully oxidized counterpart (182 °C and 177 °C, respectively). A brief look in the literature provides numerous alternatives including, formic acid,14 ammonium formate,15 1,3- or 1,4-cyclohexadienes,16 silane derivatives,11a, 17 cyclohexene,10, 18 etc.10,19 After testing several combinations, the most reliable system for the reduction was found to be: eugenol (0.1 M) dissolved in a 1:1 solvent:cyclohexene mixture passed through the packed bed reactor set at 120 °C with a residence time of 10 minutes (Tabel 1 – entry 1). Cyclohexene (bp = 83 °C) proved highly useful as this hydrogen donor and its oxidation products 1,3-cyclohexadiene, 1,4-cyclohexadiene or benzene (bp = 80 °C, 88 °C and 80 °C, respectively) all could be removed by simple rotary evaporation, hence eliminating the need to perform workup on the crude reaction mixture.18a Benzene, which is most likely formed during transfer hydrogenation, is a toxic substance and a known carcinogenic. If benzene is to be completely avoided in the obtained products, 1-, or 4-methylcyclohexene could possibly be used to substitute cyclohexene, leading to the formation of more benign toluene instead.20 With this setup in hand, we set out to test the utility of the transfer hydrogenation MRU, the results of which are shown in Table 1. All entries are batch-flow experiments and were


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 21

optimized for individual required residence times tested at 0-10 min, 20, 30 or 40 minutes (See Supporting Information). The reactor output was collected for 2.5 x residence times followed by removal of all volatiles under reduced pressure, and apart from a few examples, no further product purification was required. Simple reduction of eugenol (1) afforded 2 in a similar 93% isolated yield (entry 1). Subjection of the alkyne derivative (3) to the conditions afforded the fully reduced methyl 3phenylpropanoate (4) in a good 94% isolated yield (entry 2). Next, two nitro-functionalized analogues (5 and 7) and one 4-azido substituted acetophenone (9) were tested all affording the target anilines in yields ranging from 87-99% with residence times as low as 2 minutes (entries 3-5). Reduction of ketones and aldehydes also proved possible applying trifluoroacetic acid as a reaction additive affording 11 and 15 in 95% and 88% isolated yields (entries 6 and 8).21 Interestingly, benzonitrile (12) did not undergo reduction using the current setup (entry 7). Attention was then turned towards application of the flow setup as a tool for the removal of classical oxygen and nitrogen protection groups. Cbz-protected 4-methoxyaniline (16) and 2phenylethanamine (18) both afforded their corresponding free amines in 99% and 85% isolated yield with a retention time of 20 minutes (Entries 9 and 10).16 Hydrogenolysis of benzylethers (20 and 21) and benzyl ester (23) was accomplished in near quantitative isolated yields applying retention times of 20-40 minutes (entries 11, 12 and 13).16 Successful dechlorination of 25 required the addition of triethylamine, to remove the in situ formed HCl, and an isolated yield of 95% with a retention time of 20 minutes was obtained.22 Reductive cleavage of the azoderivative 27 afforded 4-methoxyaniline (17) and 4-aminophenol (28) in a combined yield of 95% for the two compounds.23


10

Page 11 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Transfer Hydrogenation Reaction Scopea Reactant (0.05-0.5 M) cyclohexene:solvent (1:1) Palladium on Charcoal

EtOAc

Product

120 °C

Entry

Concentration [M] / Solvent / additive

Substrate

Time [Min]

Yieldb [%]

Product MeO

MeO

1

1

[0.1] / MeOH

OMe

[0.1] / EtOAc

HO

10

2

HO

O

2

3

Ph

20

O Ph

4 OMe

[0.1] / EtOAc

5

4

NH 2

NO 2 EtO

7

[0.5] / EtOAc

2

EtO

8

NH 2

N3

5

[0.1] / EtOAc

9

2.5

O

6

[0.05] / MeOH TFA (2 equiv)

10

Ph

Ph

CN 12 O MeO HO

6

87

11

95

O

O

7

H 14

[0.05] / MeOH

20

[0.05] / MeOH TFA [0.1]

40

[0.05] / MeOH

20

NH 2

16

MeO

NHCbz 18

Ph

MeO 15

HO

OMe

11 12

20

Ph

OBn OBn 21

NH 2 17

MeO

[0.05] / MeOH TFA [0.1] [0.05] / MeOH TFA [0.1] [0.05] / MeOH TFA [0.1]

ND

13

NHCbz

9 10

99

O

O

8

93

6 O

O

4

94

NH 2

NO 2

3

93

20

Ph

30

2

40

Ph

NH 2 19

88 99 95

OMe OH OH 22

99 96


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

OMe O

13

MeO

[0.05] / MeOH

OBn

OMe O

20

MeO

23

25

TsO

[0.05] / MeOH TEA [0.06]

20

15 MeO

N

[0.05] /MeOH

20

27

93

26 TsO

OH N

99

OH 24

Cl

14

Page 12 of 21

NH 2 MeO

17 H 2N

OH 28

95c

OMe 0.05 / MeOH 30 99 2 29 NO Cyclehexene O OH O 31 O 30 0.05 / MeOH 17 20 95 Ph OH Ph O NO Cyclehexene a See general methods for reaction conditions. All reactions performed on reactor design 2 and solvents were chosen to ensure a homogeneous reaction mixture. b Isolated yields. c Combined yield of 17 and 28. OMe

16

Deallylation of compounds 29 and 30 proved possible with retention times of 30 and 20 minutes, respectively. Importantly, applying methanol as the solvent and transfer allylation acceptor, deallylation was performed in the absence of the hydrogen donor and 2 and 31 were obtained in 95% and 92% isolated yields (entries 16 and 17).24 Importantly, due to the absence of a hydrogen donor, deprotection of 30 was possible without concurrent reduction of the α,β-unsaturation in the formed cinnamic acid. Adaptation of the Pd/C packed bed reactor to other reaction types would extend the applicability of the MRU flow setup considerably and an example of the Mizoroki-Heck reaction was attempted (Scheme 2).25 After some experimentation it was found that passing a mixture of 4-iodobenzonitrile (0.33 M), butyl acrylate (1.3 M) and triethyl amine (0.49M) dissolved in MeCN through the MRU flow-reactor set at 150 °C with a retention time of only 10 minutes afforded the desired cinnamic acid derivative 32 in an good 80% isolated yield after column chromatography. Compound 32 was then passed through the packed bed reactor again, but this time subjected to the transfer hydrogenation conditions developed above, affording the reduced


12

Page 13 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


butyl 3-(4-cyanophenyl)propanoate (33) in an excellent 93% isolated yield, again with no sign of concurrent cyano-group reduction (Scheme 2).

Scheme 2. Mizoroki-Heck coupling followed by transfer hydrogenation.

I O

NC (0.33 M)

TEA (0.49 M) Dissolved in MeCN

O

O-nBu

MRU Pd/C

150 °C

O-nBu 80% - 32

NC

(1.3 M) : EtOAc O O-nBu NC

93% - 33

MRU

1

:

1

Pd/C

120 °C Rt = 30 min

As the final part of this study, it was decided to address the question regarding lifetime of the packed reactor bed. Besides catalyst deactivation, palladium leaching was considered to be most significant problem effectively leading to required reactor reloading. However, from the initial large scale study seen in Scheme 1 a high turnover number of 1851 was observed without reactor failure indicating good reactor stability. It was then speculated that the reduction of eugenol probably did not serve as the correct experiment to test the reactor bed stability, as its reduced counterpart (2) does not contain functionalities that would coordinate Pd(0) strongly. Instead, the experiment on the reduction of 4-ethyl nitrobenzoate (7 – Table 1 entry 4) was revisited, expecting that the formed aniline would perform better as a ligand to palladium potentially causing a higher degree of catalyst leaching. Hence, 7 (195,17 g, 1 mol, 0.5 M) dissolved in cyclohexene: EtOAc 1:1 was pumped directly onto a freshly packed bed reactor (reactor design 2) set at standard operating temperature of 120 °C. The reduction was performed with a retention


13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 21

time of 2 minutes corresponding to 3.5 mmol/min conversion of 7. Collection of the reduced aniline (8) was initiated after clearing two reactor volumes thereby ensuring the reactor was operating at steady state. A batch was collected every 30 minutes and analyzed for conversion determined by 1H NMR analysis of the crude reaction mixture. The results of this study are shown in scheme 3.

Scheme 3. Scale-out experiment to test reactor stability.

NO 2 EtO 7

Palladium on Charcoal

: EtOAc

120 °C

O

NH 2 EtO O

82,6 grams (0.5 mol)

Residence =me = 2 min

1:1

8

Conversion / %

Entry

Time (minutes)

Conversion

1

30

100

100

2

60

100

80

3

90

100

60

4

120

98

5

150

93

6

180

69

7

210

45

Conversion of 7 over ,me

40 20

Time/Min

0 0

30

60

90

120

150

180

210

240

From the data seen in scheme 3, full conversion was retained for the first 90 minutes of operation. Batch 4 begins to show traces of unconverted starting material and in batch number 5 the average conversion had dropped 93%. After this point (batches 6 and 7) catalyst activity drops dramatically and the experiment was stopped.26 Batches 4 and 5 were recrystallized and combined with batches 1-3 to afford a combined yield of 82.6 grams (0.5 mol) of analytically pure 8. 1.5 grams of Pd/C (10% w/w) was loaded into the packed bed reactor correlating to a


14

Page 15 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TON of 355 of 7 to 8. Still, the presented design allows for the conversion of >0.5 mol of material before repacking of the reactor bed would be required.27 This in turn corresponds to running hundreds of 1-2 mmol scale transfer hydrogenations on the MRU before maintenance would be needed thereby emphasizing the high durability and usability of this flow setup for laboratory scale synthesis.

In conclusion, a mobile reactor unit (MRU) was designed for laboratory scale transfer hydrogenations. The entire flow setup was fitted inside a 46 cm x 33 cm x 15 cm alumina suitcase weighing in at less than 10 kilograms. General catalytic conditions were developed using a 1:1 mixture of cyclohexene with a co-solvent, typically methanol or ethyl acetate, as the hydrogen donor. These conditions were chosen in order to minimize workup as all regents and products thereof are removable by simple evaporation. Reductions of standard functional groups, including double bonds, triple bonds, nitro group, ketones and aldehydes was carried out on the MRU applying retention times between 2-40 minutes operating the Pd/C packed bed reactor at 120 °C. Furthermore, Cbz and benzyl ether protection groups were effectively removed in high yields. Examples of allyl-ether and allyl esters protection groups were effectively removed on the same catalyst bed, in the absence of hydrogen donor, by the use of methanol as solvent. Performing a Mizoroki-Heck coupling proved additional flexibility of the MRU, affording a cinnamic ester derivative, which was subsequently reduced under the developed transfer hydrogenation conditions. Finally, two different scale-up experiments were performed, providing the desired target compounds in >0.5 mol scale. The latter experiment was conducted in order to study potential catalyst leaching or deactivation of the reactor bed, indicating that hundreds of 12 mmol scale reactions can be performed on the MRU before maintenance would be required.


15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 21

ASSOCIATED CONTENT Supporting Information. A detailed description of the mobile reactor unit, general procedure, experimental details including 1H NMR, 13C NMR spectra for all reported compounds. The following file are available free of charge. Supporting Information (PDF) AUTHOR INFORMATION Corresponding Author Tel.: (+45 23823086). E-mail: [email protected] ORCID ID: Anders T Lindhardt:0000-0001-8941-4899 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors are deeply appreciative of generous financial support of the Carlsberg Foundation, Danish Counsel of Independent Research – Technology and Production (Grant number 414800031) and Aarhus University.


16

Page 17 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


REFERENCES

1

For reviews on chemistry in continuous flow, see: (a) McQuade, D. T:; Seeberger, P. H. J.

Org. Chem. 2013, 78, 6384. (b) Malet-Sanz, L.; Susanne, F. J. Med. Chem. 2012, 55, 4062. (c) Hartman, R. L.; McMullen, J. P.; Jensen, K. V. Angew. Chem. Int. Ed. 2011, 50, 7502. (d) Calabrese, G. S.; Pissavini, S. AIChE J. 2011, 57, 828. (e) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47, 4583. (f) Yoshida, J-I.; Kim, H.; Nagaki, A. ChemSusChem. 2011, 4, 331. (g) Jas, G.; Kirschning, A. Chem. Eur. J. 2003, 9, 5708. (h) Baxendale, I. R. J. Chem. Technol. Biotechnol. 2013, 88, 519. (i) Baxendale, I. R.; Brocken, L.; Mallia, C. J. Green Process Synth. 2013, 2, 211. 2

(a) Razzaq, T.; Kappe, C. O. Chem. Asian. J. 2010, 5, 1274. (b) Gutmann, B.; Cantillo, D.;

Kappe, C. O. Angew. Chem. Int. Ed. 2015, 54, 6688. (c) Hartwig, J.; Ceylan, S.; Kupracz, L.; Coutable, L.; Kirschning, A. Angew. Chem. Int. Ed. 2013, 52, 9813. (d) Bogdan, A. R.; Charaschanya, M.; Dombrowski, A. W.; Wang, Y.; Djuric, S. W. Org. Lett. 2016, 18, 1732. 3

(a) Broek, S. A. M. W.; Leliveld, J. R.; Becker, R.; Delville, M. M. E.; Nieuwland, P. J.;

Koch, K.; Rutjes, F. P. J. T. Org. Process. Res. Dev. 2012, 16, 934. (b) Chernyak, N.; Buchwald, S. L. J. Org. Chem. 2012, 134, 12466. (c) Mastronardi, F.; Gutmann, B.; Kappe, C. O. Org. Lett. 2013, 15, 5590. (d) Hutchings, M.; With, T. J. Flow Chem. 2016, 6, 202.(e) Yu, Z.; Tong, G.; Xie, X.; Zhou, P.; Lv. Y.; Su, W. Org. Process. Res. Dev. 2015, 19, 892. (f) Teci, M.; Tilley, M.; McGuire, M. A.; Organ, M. G. Org. Precess. Res. Dev. 2016, 20, 1967. 4

For selected examples, see: (a) Webb, D.; Jamison, T. F. Org. Lett. 2012, 14, 568. (b) Snead,

D. R.; Jaminson, T. F. Angew. Chem. Int. Ed. 2015, 54, 983. (c) Noël, T.; Maimone, T. J.;


17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 21

Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 8900. (d) Yoshida, J-I.; Takahashi, Y.; Nagaki, A. Chem. Commun. 2013, 49, 9896. (e) Hafner, A.; Meisenbach, M.; Sedelmeier, J. Org. Lett. 2016, 18, 3630. (f) Wirth, T. Angew. Chem. Int. Ed. 2016 ASAP. 5

(a) Sedelmeier, J.; Lima, F.; Litzler, A.; Martin, B.; Venturoni, F. Org. Lett. 2013, 15, 5546.

(b) Baxendale, I. Chem. Eng. Technol. 2015, 38, 1713. (c) Müller, S. T. R.; Murat, A.; Wirth, T. Org. Process. Res. Dev. 2016, 20, 495. (d) Hartman, R. L.; McMullen, J. P.; Jensen. K. F. Angew. Chem. Int. Ed. 2011, 50, 7502. 6

(a) Irfan, M.; Glasnov, T. N.; Kappa, C. O. ChemSusChem. 2011, 4, 300. (b) Roberge, D. M.;

Noti, C.; Irle, E.; Eyholzer, M.; Rittiner, B.; Penn, G.; Sedelmeier, G.; Schenkel, B. J. Flow. Chem. 2014, 4, 26. 7

For a examples on hydrogenation using a tube-in-tube system, see: (a) Mercadante, M. A.;

Kelly, C. B.; Lee, C.; Leadbeater, N. E. Org. Process. Res. Dev. 2012, 16, 1064. (b) O´Brien, M.; Taylor, N:, Polyzos, A.; Baxendale, I. R.; Ley, S. V. Chem. Sci. 2011, 2, 1250. (c) Mallia, C. J.; Baxendale, I. R. Org. Process. Res. Dev. 2016, 20, 327. 8

(a) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem. Commun. 2005, 2909. (b)

Winterbottom, J. M.; Khan, Z.; Boyes, A. P.; Raymahasay, S. Catal. Today 1999, 48, 221. (c) Knudsen, K. R.; Holden, J.; Ley, S. V.; Ladlow, M. Adv. Synth. Catal. 2007, 349, 535. 9

(a) Elamin, B.; Park, J.-W.; Means, G. E. Tetrahedron Lett. 1988, 29, 5599. (b) Haywood, T.;

Miller, P. W. ChemCatChem 2014, 6, 1199.


18

Page 19 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


10

(a) Johnstone, R. A. W.; Wilby, A. H. Chem. Rev. 1985, 85, 129. (b) Brieger, G.; Nestrick,

T. J. Chem. Rev. 1974, 74, 567. (c) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621. 11

For examples on hydrogen transfer protocols in continuous flow, see: (a) Hutchings, M.;

Wirth, T. Synlett 2016, 27, 1832. (b) Neumann, K.; Klimczyk, S.; Burhardt, M. N.; BangAndersen, B.; Skrydstrup, T.; Lindhardt, A. T. ACS Catal. 2016, 6, 4710. (c) Rojo, M .V.; Guetzoyan, L.; Baxendale, I. R. Org. Biomol. Chem. 2015, 13, 1768. (d) Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org. Lett. 2013, 15, 2278. 12

For an excellent review on solid supported reagents, see: Ley, S. V.; Baxendale, I. R. Nat.

Rev. Drug Discovery 2002, 1, 573. 14

Selected examples: (a) Boudjouk, P.; Han, B.-H. J. Catal. 1983, 79, 489. (b) Gowda, D. C.;

Gowda, S. Indian J. Chem. B 2000, 39, 709. (c) Prasad, K.; Jiang, X.; Slade, J. S.; Clemens, J.; Repic, O.; Blacklock, T. J. Adv. Synth. Catal. 2005, 347, 1769. (d) Weir, J. D.; Patel, B. A.; Heck, R. F. J. Org. Chem. 1980, 45, 4926. 15

Selected examples: (a) Bieg, T.; Szeja, W. Synthesis 1985, 76. (b) Jnaneshwara, G. K.;

Sudalai, A.; Deshpande, V. H. J. Chem. Res. (S) 1998, 160. (c) Anwer, M. K.; Spatola, A. F. Tetrahedron Lett. 1985, 26, 1381. 16

Selected examples: (a) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;

Meienhofer, J. J. Org. Chem. 1978, 43, 4194. (b) Quinn, J. F.; Razzano, D. A.; Golden, K. C.; Gregg, B. T. Tetrahedron Lett. 2008, 49, 6137.


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

17

Page 20 of 21

Selected example: Maddani, M. R.; Moorthy, S. K.; Prabhu, K. R. Tetrahedron, 2010, 66,

329. 18

Selected examples: (a) Carrá, S.; Beltrame, P.; Ragaini, V. J. Catal. 1964, 3, 353. (b)

Nishiguchi, T.; Imai, H.; Hirose, Y.; Fukuzumi, K. J. Catal. 1976, 41, 249. (c) Anantharamaiah, G. M.; Sivanandaiah, K .M. J. Chem. Soc., Perkin Trans. 1 1977, 490. (d) Rampulla, R. A.; Russel, R. K. Synthetic Commun. 1896, 16, 1229. 19

For examples on diimide as the hydrogen donor in flow see: (a) Pieber, B.; Martinez, S. T.;

Cantillo, D.; Kappe, C. O. Angew. Chem. Int. Ed. 2013, 52, 10241. (b) Kleinke, A. S.; Jamison, T. F. Org. Lett. 2013, 15, 710. 20

For an example og the use of methylcyclohexenes in transfer hydrogenations, see:

Chapman, N.; Conway, B.; O´Grady, F.; Wall, M. D. Synlett, 2006, 7, 1043. 21

(a) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1988, 29, 3741. (b) Brieger, G.; Nestrick, T. J.; Fu,

T-H. J. Org. Chem. 1979, 44, 1876. 22

23

Imai, H.; Nishiguchi, T.; Tanaka, M.; Fukuzumi, K. J. Org. Chem. 1977, 42, 2309.

Compounds 17 and 28 were separated by column chromatography to ensure their correct

identification. See supporting information. 24

Deallylation of compounds 29 and 30 is believed to occur through a Tsuji Trost type

mechanism. See reference 22. 25

Carxola, C.; Billamboz, M.; Bricout, H.; Monflier, E.; Len, C. Eur. J. Chem. 2016, ASAP.


20

Page 21 of 21

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


26

The mode of catalyst deactivation, i.e. leaching or poisoning, was not determined.

27

Additionally, almost 1 mol of eugenol was reduced under similar conditions without signs of

catalyst deactivation. See Scheme 1.


21

A High Mobility Reactor Unit for R&D Continuous ... - ACS Publications

Recommend Documents