Ruthenium-catalyzed ester reductions applied to pharmaceutical intermediates

Youssef Shaalan, Lee Boulton,* and Craig Jamieson

Article

Ruthenium-Catalyzed Ester Reductions Applied to Pharmaceutical

Intermediates

Cite This: https://dx.doi.org/10.1021/acs.oprd.0c00410

Read Online

ACCESS

Metrics & More

Article Recommendations

sı Supporting Information

ABSTRACT: Ruthenium pincer complexes were synthesized and used for catalytic ester reductions under mild conditions (∼5 bar

of hydrogen). An experimental design approach was used to optimize the conditions for yield, purity, and robustness. Evidence for

the catalytically active ruthenium dihydride species is presented. Observed intermediates and side products, as well as time-course

data, were used to build mechanistic insight. The optimized procedure was further demonstrated through scaled-up reductions of

two pharmaceutically relevant esters, both in batch and continuous ﬂow.

KEYWORDS: ester reduction, ruthenium catalysis, hydrogenation, CSTR ﬂow, batch scale-up, mechanistic insight

INTRODUCTION

Ester reductions are staple functional group interconversions

These catalysts typically exploit “metal−ligand cooperation”

■

as a means of heterolytically cleaving molecular hydrogen to

achieve the desired reactivity. A simpliﬁed mechanistic cycle

encountered throughout organic syntheses. For the purpose

of small-scale syntheses, these are typically achieved using

nucleophilic hydride reagents such as lithium aluminum

is illustrated below (Figure 2). For more in-depth mechanistic

25,26

discussions, see studies by Dub

and Schaub.

hydride. While these reagents are reliable, the process of

handling and quenching these reagents is hazardous, and they

generate signiﬁcant waste streams often requiring specialist

disposal, making them nonpreferred for larger-scale applica-

tions. As such, this makes catalytic alternatives an attractive

prospect. Catalytic homogeneous ester reductions have gained

increased attention over the past two decades. These have the

advantages of being operable under milder conditions

compared to those required by heterogeneous reductions

and exhibit higher selectivity toward esters in the presence of

other functional groups, including alkenes and aromatic

heterocycles.

−10

Numerous reviews on this topic have been published.

Pioneering work in this ﬁeld was done by Grey, Teunissen

and Elsevier, as well as Milstein and co-workers (Figure 1 ).

Figure 2. General catalytic cycle for ester hydrogenation.

Adoption of this technology within the pharmaceutical

industry in contrast has been signiﬁcantly slower, and metal

hydride reagents are more typically employed. The primary

Figure 1. Catalysts for hydrogenation of esters.

concerns are the high pressures of hydrogen required for these

catalysts to operate eﬃciently, as well as the limited functional

Since these ﬁndings, signiﬁcant eﬀorts within academia have

been directed toward designing a wealth of catalyst systems

Received: September 15, 2020

based on ruthenium, iridium, osmium, ₁and rhenium and

7,18

19,20

increasingly base metals including iron,

manganese,

and cobalt. Extensive work has also been done within the

fragrance and ﬂavor industry, with Geisser, Kuriyama, and

Saudan having reported their own catalysts, these typically

being ruthenium pincer complexes bearing an NH group.

XXXX American Chemical Society

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

group tolerance. The reduction of 2,2-diﬂuoro-2-phenylacetate,

an intermediate en route to a β-2-adrenergic receptor agonist,

has previously been achieved using Ru-MACHO under 20 bar

Table 1. Comparison of the Catalytic Activity with Respect

to Reduction of Methyl 2-Naphthoate

of hydrogen enabled by the use of a continuous ﬂow reactor.

The issue of high-pressure reductions has been addressed in a

recent publication wherein a ruthenium pincer complex

bearing a carbene ligand (I) was shown to reduce esters

catalyst

I Ru(PNP)

IIa Ru(diEtSNS)

IIb Ru(din-BuSNS)

IIc Ru(diPhSNS)

yield (%)

under particularly mild conditions.

Herein, eﬀorts toward understanding the applicability of this

area of catalysis toward reduction of pharmaceutically relevant

ester-containing substrates are made. Mechanistic factors are

discussed, and the formation of side products is ultimately

suppressed using an experimental design approach. Finally, the

reduction of two pharmaceutically relevant esters is demon-

strated on large scale in batch and continuous ﬂow.

Reaction conversion assessed by high-performance liquid chroma-

tography (HPLC) at 220 nm.

process-friendly alternative to tetrahydrofuran (THF) (see the

RESULTS AND DISCUSSION

A variety of ruthenium catalysts were synthesized following

SI for details). KOt-Bu and KOMe were both found to

eﬃciently promote the reaction, while sodium and lithium

alkoxide bases, as well as organic bases, did not (see the SI for

details).

■

modiﬁcation of a procedure reported by Ogata, Kayaki, and co-

workers (Scheme 1). Reaction of commercially available

The model substrate, methyl 2-naphthoate, was seen to

reduce most cleanly with Ru(PNP) (I). Furthermore,

examination of the gas-uptake curves revealed Ru(PNP) (I)

to reduce the ester at the fastest rate. The Ru(SNS) complexes

also had signiﬁcantly longer induction periods. Accordingly,

Ru(PNP) (I) was used for the remainder of this study.

To get a better understanding of how the robustness of the

reaction outcome is aﬀected by the continuous variables, an

experimental design was conducted. A two-level, full-factorial

design with four center points was run, wherein base loading,

pressure, temperature, and concentration were the parameters

investigated (Table 2).

Scheme 1. Synthesis of Ruthenium Pincer Complexes

Table 2. Parameters for Experimental Design

[

Ru(p-cymene)Cl ] with silver carbene transfer reagent (1)

aﬀorded ruthenium carbene complex (2) in good yield.

Substitution of the p-cymene ligand with a variety of tridentate

ligands was achieved by heating these with complex 2 in

ethanol. This allowed the formation of the reported Ru(PNP)

complex (I) as well as three Ru(SNS) complexes. Ru(SNS)

parameter

investigation range

base

10−20 mol %

2−8 bar

0.25−1.00 mol/L

30−60 °C

hydrogen pressure

concentration

reaction temperature

complexes bearing a PPh ligand have been previously shown

to possess high activity by Gusev and co-workers.

Ru(SNS) complexes IIa, IIb, and IIc have not previously

been reported, though a procedure for in situ generation of a

Ru(SNS) complex bearing a carbene ligand has previously

been suggested. The meridional geometry of the ligand on

Ru(diEtSNS) (IIa) was conﬁrmed with a crystal structure.

While the catalysts are air-sensitive in the solution state, they

are stable to ambient conditions when dry.

All reactions reached completion within 8 h or less, and

good reproducibility was seen for the center-point conditions

(full details in the SI ). The temperature primarily aﬀected the

rate of reaction, with certain reactions going to completion in

under an hour. Increased hydrogen pressure was beneﬁcial, as

this resulted in cleaner reaction proﬁles. Less starting material

was observed, and formation of side products, such as those

formed through transesteriﬁcation, were disfavored. The

concentration and quantity of the base were also found to

aﬀect the extent of hydrolysis that took place (Figure 3). In

particular, addition of less base and running reactions more

concentrated diminished its formation. This is consistent with

the inherent residual moisture content present within both the

base and the solvent on this scale.

Formation of the active dihydride complex was achieved by

subjecting Ru(PNP) (I) to a base and hydrogen in an NMR

tube. A single new compound was observed by P NMR with

two hydride signals in the H NMR [δ = −7.33 (td, J = 21.0,

.5 Hz), −7.71 (td, J = 21.0, 9.5 Hz)], with chemical shifts and

coupling constants comparable to those previously reported on

related ruthenium complexes (full details in the Supporting

Information (SI)).

Low pressures of hydrogen (5 bar) were employed when

comparing the catalytic performance of the complexes as a

means of making the conditions more accessible to hydro-

genation vessels typically used within the pharmaceutical

industry (Table 1). 2-MeTHF was employed as a more

Following this, a number of diﬀerent substrates were

investigated to give a variety of pharmaceutically relevant

34−39

primary alcohols (Table 3).

1) and C−Br (entry 4) bonds were shown to be preserved.

Potentially labile C−I (entry

Certain heterocycles containing esters, including pyridyl esters

Organic Process Research & Development

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

formation of tert -butyl benzoate (Figure 5 ).

Article

Figure 4. Isolated intermediates and side products.

Intrigued by these observations, we were interested in

establishing what other side products are formed in this

reaction. Monitoring the reduction of methyl benzoate by

React IR revealed that before hydrogen is applied, a pre-

equilibrium exists between the ester and the base, resulting in

Figure 3. Surface response for hydrolysis side product.

Table 3. Substrates Investigated^a^,^b^,^c

Figure 5. Formation of tert-butyl ester observed by IR.

In addition to this, irreversible hydrolysis also takes place

Figure 6 ). During the reduction of methyl benzoate,

Reaction conversion assessed by HPLC at 220 nm. Isolated by ﬂash

chromatography. Isolated by vacuum distillation.

Figure 6. React IR time-course reduction of methyl benzoate.

(

entries 5 and 6), were tolerated. Other heterocycles, including

thiazoles, isoxazoles, and imidazoles, in contrast, remained

unreactive. Nitro- and nitrile-containing compounds were also

shown to preclude reactivity, even when higher catalyst

loadings were employed (see the SI for a full list of substrates).

Based on these ﬁndings, we envisage this transformation being

most applicable to less functionally rich substrates.

benzaldehyde was not directly observed. This suggests for

this particular substrate that benzaldehyde was only formed

either transiently or masked as a hemiacetal or indeed in its

hydrated form. Benzyl benzoate, while known to form under

these conditions, could not be diﬀerentiated from starting

material by React IR.

In addition, a temperature-dependent induction was

observable, whereby the end of the induction period also

coincided with formation of the hydrolysis product plateauing.

This strongly suggests the induction period to be directly

linked with the consumption of adventitious water. Water has

indeed previously been shown to inhibit activity in related

Interestingly, the anilino ester (entry 2) reduced particularly

slowly, likely due to the reduced electrophilicity of the ester. In

addition to the product alcohol, other intermediates including

aldehyde were isolated from the reaction mixture (Figure 4),

providing evidence that at least in certain cases, aldehydes (or

masked forms thereof) may be formed before reduction to the

alcohol.

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

catalytic systems. Addition of 20 mol % of potassium

benzoate showed no deleterious eﬀect on conversion.

No issues with exotherms or formation of emulsions took place

during the workup while achieving a similar Process Mass

Based on the previous observations, the following scheme

depicts the proposed fate of the ester substrate (Scheme 2).

Intensity (PMI). Furthermore, the composition of the

resulting waste streams was more favorable. In addition to

the desired product, hydrolysis side product (3) and desbromo

side product (4) were observed by HPLC as low-level

impurities (Scheme 4).

Scheme 2. Fate of Ester

Scheme 4. Isolated Side Products from Reduction of Methyl

-Bromo-2-naphthoate

The hydrolysis side product (3) formed while aﬀecting the

yield was readily removed by performing a basic wash. The

desbromo side product (4), thought to form as a result of trace

palladium present in the vessel, was not readily purged.

Following on from this, we investigated transferring the

hydrogenation of methyl 6-bromo-2-naphthoate to a con-

tinuous ﬂow reactor. The potential beneﬁts of this would be to

allow access to higher temperatures/pressures in a safer

manner, should this be necessary as a means of intensifying the

process. The key challenge to overcome based on previous

batch observations was the issue of solids being generated over

the course of the reaction, which would likely block

conventional tubing or capillaries. As such, a bespoke CSTR

ﬂow reactor available from Autichem Ltd. was examined with

the following setup (Figure 7).

The two inputs into the reactor are hydrogen gas and the

reaction mixture consisting of methyl 6-bromo-2-naphthoate,

KOt-Bu, Ru(PNP) (I), and 2-MeTHF, which were made up in

a feed tank. As the liquid phase enters the reactor, the rotating

agitator ensured eﬃcient gas−liquid contact. The rate at which

the mixture was pumped gave control over the residence time.

In addition to giving a plug-ﬂow-like behavior, this setup has

the added beneﬁt of having a greater tolerance for solids as the

agitator helped mobilize slurries. Initial runs resulted in no

conversion, as KOt-Bu had settled within the feed tank in

which the reaction mixture was made up and thus did not enter

the reactor. This issue was resolved by replacing solid KOt-Bu

with KOt-Bu as a solution in THF to give a homogeneous feed

solution. The results from the runs following this are

summarized below (Table 4).

During the induction period, hydrolysis and transesteriﬁcation

with the base take place. Upon formation of the active catalytic

species, reduction of either ester takes place. This initially

forms an aldehyde, possibly as a short-lived intermediate or

masked as a hemiacetal or hydrate, and then is further reduced

to the product alcohol. The product may then undergo

transesteriﬁcation with the starting material to give a

homocoupled ester; this too, given enough time may reduce

to the product alcohol. With the exception of the hydrolysis

side product, all other substrates eventually react to give the

product.

With this knowledge in hand, two of the previously

identiﬁed pharmaceutically relevant intermediates were con-

sidered for further examination. First, the reduction of methyl

-bromo-2-naphthoate was performed on a 10 g scale

(Scheme 3).

Scheme 3. Reduction of Methyl 6-bromo-2-naphthaote

The setup was operationally straightforward and worked

with minimal complications to aﬀord a suspension of the

product. Long residence times were required to achieve high

conversions. The longest residence time (54 min) would allow

0 g of substrate to be reduced in ∼17 h. While the reactor

The reaction was run in a 500 mL glass-jacketed vessel.

Solids were observed to precipitate out of the solution as the

reaction proceeded, presumably due to the product alcohol

being less soluble in the reaction solvent, 2-MeTHF, than the

starting material. The reaction was left overnight, after which

the rate of gas consumption had plateaued. At this stage, the

reaction mixture was sampled, and complete consumption of

starting material was indicated. Isolation of the product was

performed by aqueous extraction, followed by a put-and-take

distillation with addition of isooctane. Compared to the

existing process in which the reduction was performed with

DIBAL-H, the isolation procedure was signiﬁcantly simpliﬁed.

itself was rated to higher temperatures and pressures, other

components in this particular setup were rated to a maximum

of 7 bar of pressure. Throughput could in principle be

increased by applying higher temperatures and pressures.

Furthermore, larger variants of these reactors are commercially

available.

Following on from this, we focused our attention on the

large-scale reduction of methyl 6-methylnicotinate, another

pharmaceutically relevant intermediate (Scheme 5). The

reaction was performed in a 5 L Hastelloy pressure reactor

equipped with a gas entrainment impeller. A lower catalyst

loading (0.1 mol %) was used without loss of activity.

Organic Process Research & Development

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Article

Figure 7. Schematic of CSTR ﬂow setup.

Table 4. Results from CSTR Flow Reactor

CONCLUSIONS

■

In summary, the catalytic reduction of pharmaceutically

relevant esters using low hydrogen pressures has been

demonstrated. Both batch and continuous ﬂow setups have

been utilized, the former beneﬁtting from being amenable for

transfer into multipurpose hydrogenation vessels and the latter

beneﬁtting from the potential for higher throughput. The

workup procedures and isolations were simpliﬁed compared to

corresponding metal hydride-mediated reductions, and aque-

ous aluminum-containing waste streams were avoided. In the

case of the reduction of methyl 6-methylnicotinate, a

signiﬁcantly improved PMI was also obtained. Work is ongoing

in assessing other pharmaceutically relevant substrates, as well

as transferring hydrogenations to a high-pressure segmented

ﬂow reactor.

residence time (min)

conversion (%)

Reaction conversion assessed by HPLC at 220 nm.

Scheme 5. Scaled-Up Reduction of Methyl 6-

Methylnicotinate

EXPERIMENTAL SECTION

■

Large-Scale Batch Reduction of Methyl 6-Bromo-2-

naphthoate. To a 500 mL Ecoclave equipped with a gas

entrainment impeller was added methyl 6-bromo-2-naphthoate

(

10 g, 38 mmol, 1.0 equiv) and Ru(PNP) (I) (268 mg, 0.377

After an initial induction period of about 15 min, the

reaction proceeded very quickly, and of the 50 L of hydrogen

gas-uptake measure in total, 47 L was consumed within the

ﬁrst 1.5 h. During this time, the highest recorded temperature

was 53 °C, 3 °C above the jacket temperature. This reﬂected

insigniﬁcant exothermic activity, and no additional restrictions

on the feed rate of hydrogen gas were deemed necessary at this

scale. Once the reaction had reached completion, the solvent

was distilled oﬀ and the product was isolated by vacuum

distillation using a wiped ﬁlm evaporator. In addition to

eﬀectively purging the less volatile hydrolysis product, 6-

methylnicotinic acid, this also reduced the level of residual

mmol, 0.01 equiv). The vessel was left to purge with nitrogen

for 5 min before adding 2-MeTHF (100 mL) and potassium

tert-butoxide (847 mg, 7.54 mmol, 0.20 equiv). The vessel was

sealed, and the impeller was set to stir at 300 rpm. The vessel

was pressurized with nitrogen (3.5 bar), then vented (×3), and

then pressurized with hydrogen (3.5 bar), then vented. The

vessel was then pressurized and maintained with hydrogen (4.0

bar). The jacket of the vessel was heated to 45 °C, the impeller

was set to 700 rpm, and the mixture was left in this state for 4

h. Analysis by HPLC indicated >99% conversion. 1 M aqueous

hydrochloric acid (100 mL) was added, and the mixture was

stirred at 1000 rpm for 10 min. The organic phase was

separated and passed through a silica plug (16 g, 2.5 cm). The

solvent was removed by distillation while continually adding

isooctane (90 mL). Following this, the mixture was cooled in

an ice bath. The precipitated solids were collected by ﬁltration

and dried under reduced pressure to obtain the product as a

ruthenium to 10 ppm. Compared to an existing LiAlH

process, a signiﬁcantly improved PMI was achieved (20 vs

90) and may be further improved by reducing the mechanical

losses that occurred during the isolation process. This

improved PMI is both a reﬂection of employing a catalytic

rather than a stoichiometric method, as well as less solvent

being required for the quench and workup of the reaction.

Further to this, the waste stream consisted of residues enriched

in ruthenium, which could be sent directly for metal recovery.

pale yellow powder (7.3 g, 31 mmol, 82%). H NMR (400

MHz, CDCl ): δ 8.00 (d, 1H, J = 1.5 Hz, ArH), 7.79 (s, 1H,

ArH), 7.75 (d, 1H, J = 8.5 Hz), 7.71 (d, 1H, J = 8.5 Hz), 7.56

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

dd, 1H, J = 8.5, 2.0 Hz, ArH), 7.51 (dd, 1H, J = 8.5, 1.5 Hz,

Complete contact information is available at:

Article

(

Craig Jamieson − Department of Pure and Applied Chemistry,

University of Strathclyde, Glasgow G1 1XL, United

Kingdom; orcid.org/0000-0002-6567-8272

ArH), 4.86 (s, 2H, CH O), 1.80 (br. s, 1H, OH); C NMR

(

101 MHz, CDCl ): δ 139.0, 134.1, 132.0, 129.9, 129.74,

29.68, 127.6, 126.3, 125.4, 120.0, 65.4.

Large-Scale Reduction of Methyl 6-Bromo-2-naph-

https://pubs.acs.org/10.1021/acs.oprd.0c00410

thoate in Continuous Flow. A stirred feed-tank was charged

with Ru(PNP) (I) (668 mg, 0.941 mmol, 0.005 equiv), methyl

Author Contributions

-bromo-2-naphthoate (50 g, 189 mmol, 1 equiv), potassium

Experimental work was performed by Y.S. The manuscript was

written through the contributions of all authors. All authors

have given approval to the ﬁnal version of the manuscript.

tert-butoxide (38 mL, 38 mmol, 1 M in THF), and 2-MeTHF

(

500 mL) while maintaining a nitrogen atmosphere.

Through an Autichem CSTR ﬂow reactor was pumped the

Notes

reaction mixture while also being supplied with hydrogen gas

5 bar). The jacket of the reactor was set to 65 °C, and the

(

The authors declare no competing ﬁnancial interest.

agitator was set to 219 rpm. The residence time of the reaction

mixture was varied by altering the rate at which the mixture

was pumped (54, 23, and 12 min). The reaction was left to

reach a steady state before directly sampling the resulting

reaction mixture for analysis.

ACKNOWLEDGMENTS

■

We thank GlaxoSmithKline and the University of Strathclyde

for a Ph.D. studentship. Special thanks also go to the EPSRC

for funding via Prosperity Partnership EP/S035990/1. The

authors also acknowledge the contributions of G. Williams, L.

Edwards, A.-S. Bretonnet and S. Bate (GSK), and A. Kennedy

Large-Scale Batch Reduction of Methyl 6-Methylni-

cotinate. To a 5 L Bu

entrainment impeller was added methyl 6-methylnicotinate

200 g, 1.32 mol, 1.0 equiv), Ru(PNP) (I) (937 mg, 1.32

chi Kiloclave equipped with a gas

(

UoS).

(

mmol, 0.0010 equiv), potassium tert-butoxide (29.7 g, 265

mmol, 0.20 equiv), and 2-MeTHF (2.5 L). The vessel was

sealed and purged with nitrogen (3 × 3 bar), then hydrogen (3

REFERENCES

■

(1) Seyden-Penne, J. Reductions by the Alumino-and Borohydrides in

Organic Synthesis; John Wiley & Sons, 1997.

(2) Magano, J.; Dunetz, J. R. Large-Scale Carbonyl Reductions in the

Pharmaceutical Industry. Org. Process Res. Dev. 2012 , 16 , 1156 −1184.

3) Walker, E. R. H. The functional group selectivity of complex

hydride reducing agents. Chem. Soc. Rev. 1976, 5, 23−50.

4) Kuriyama, W.; Matsumoto, T.; Ogata, O.; Ino, Y.; Aoki, K.;

2.5 bar), before being ﬁlled and maintained with hydrogen

(

2.8 bar). The jacket temperature was set to 50 °C, and the

impeller was set to 750 rpm. After 1.5 h, the hydrogen pressure

was increased (5 bar) and left to stir overnight. The jacket

temperature was set to 20 °C, the hydrogen was released, and

the vessel was purged with nitrogen (3 × 5 bar). HPLC

analysis indicated >98% conversion. Saturated ammonium

chloride solution (30 mL) was added, and the solvent was

distilled oﬀ under reduced pressure. The product was then

isolated by vacuum distillation (100 °C, 0.7 mbar) to obtain

Tanaka, S.; Ishida, K.; Kobayashi, T.; Sayo, N.; Saito, T. Catalytic

Hydrogenation of Esters. Development of an Efficient Catalyst and

Processes for Synthesising (R)-1,2-Propanediol and 2-(l-Menthoxy)-

ethanol. Org. Process Res. Dev. 2012, 16, 166−171.

(5) Zhou, Y.; Khan, R.; Fan, B.; Xu, L. Ruthenium-Catalyzed

Selective Reduction of Carboxylic Esters and Carboxamides. Synthesis

2019, 51, 2491−2505.

the ﬁnal product as a yellow solid (118 g, 955 mmol, 72%). H

NMR (400 MHz, CDCl ): δ 8.34 (s, 1H, NCH), 7.59 (dd, 1H,

6) Clarke, M. L. Recent developments in the homogeneous

J = 8.0, 2.0 Hz, NCCHCH), 7.12 (d, 1H, J = 8.0 Hz, NCCH).

hydrogenation of carboxylic acid esters. Catal. Sci. Technol. 2012, 2,

2418−2423.

7) Dub, P. A.; Ikariya, T. Catalytic Reductive Transformations of

.64 (s, 2H, CH ), 3.77 (br. s, 1H, OH), 2.50 (s, 3H, CH );

C NMR (101 MHz, CDCl ): δ 157.5, 147.8, 136.7, 133.8,

Carboxylic and Carbonic Acid Derivatives Using Molecular Hydro-

23.3, 62.4, 24.0.

gen. ACS Catal. 2012, 2, 1718−1741.

ASSOCIATED CONTENT

8) Werkmeister, S.; Junge, K.; Beller, M. Catalytic Hydrogenation

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.oprd.0c00410.

of Carboxylic Acid Esters, Amides, and Nitriles with Homogeneous

Catalysts. Org. Process Res. Dev. 2014, 18, 289−302.

(9) Pritchard, J.; Filonenko, G. A.; van Putten, R.; Hensen, E. J. M.;

Pidko, E. A. Heterogeneous and homogeneous catalysis for the

hydrogenation of carboxylic acid derivatives: history, advances and

future directions. Chem. Soc. Rev. 2015, 44, 3808−3833.

Experimental procedures; characterization of com-

pounds; PMI calculations; and further details of DoE

studies (PDF)

10) Hey, D. A.; Reich, R. M.; Baratta, W.; Kuhn, F. E. Current

advances on ruthenium(II) N-heterocyclic carbenes in hydrogenation

reactions. Coord. Chem. Rev. 2018, 374, 114 −132.

AUTHOR INFORMATION

11) Grey, R. A.; Pez, G. P.; Wallo, A. Anionic metal hydride

■

catalysts. 2. Application to the hydrogenation of ketones, aldehydes,

carboxylic acid esters, and nitriles. J. Am. Chem. Soc. 1981, 103, 7536−

Corresponding Author

Lee Boulton − Chemical Development, GlaxoSmithKline

Medicines Research Centre, Stevenage SG1 2NY, United

Kingdom; orcid.org/0000-0002-3749-5524;

Email: lee.t.boulton@gsk.com

542.

12) Teunissen, H. T.; Elsevier, C. J. Homogeneous ruthenium

catalyzed hydrogenation of esters to alcohols. Chem. Commun. 1998,

367−1368.

13) Zhang, J.; Leitus, G.; Ben-David, Y.; Milstein, D. Efficient

(14) Yan, X.; Yang, X. Mechanistic insights into the iridium

Authors

homogeneous catalytic hydrogenation of esters to alcohols. Angew.

Chem., Int. Ed. 2006, 45, 1113 −1115.

Youssef Shaalan − Chemical Development, GlaxoSmithKline

Medicines Research Centre, Stevenage SG1 2NY, United

Kingdom; Department of Pure and Applied Chemistry,

University of Strathclyde, Glasgow G1 1XL, United Kingdom

catalysed hydrogenation of ethyl acetate to ethanol: a DFT study.

Dalton Trans. 2018, 47, 10172−10178.

Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

15) Spasyuk, D.; Smith, S.; Gusev, D. G. From esters to alcohols

and back with ruthenium and osmium catalysts. Angew. Chem., Int. Ed.

012, 51, 2772−2775.

16) Naruto, M.; Agrawal, S.; Toda, K.; Saito, S. Catalytic

(34) Budzik, B.; Li, P.; Pero, J. E.; Griﬃths-Jones, C. M.; Heightman,

T. D.; Willems, D. M. G.; Weelford, A. J. 3-Carboxylic Acid Pyrroles

as NRF2 Regulators. WO Patent WO2018/109641, 2018.

(35) Halbert, S. M.; Thompson, S. K.; Veber, D. F. Protease

Inhibitors. US Patent US1999/5998470, 1999.

transformation of functionalized carboxylic acids using multifunc-

tional rhenium complexes. Sci. Rep. 2017, 7, No. 3425.

(36) Siesel, D. Processes for Producing Cycloalkylcarboxamido-

pyridine Benzoic Acids. WO Patent WO2010/1384842010.

(37) Pu, Y.-M.; Ku, Y.-Y.; Grieme, T.; Black, L. A.; Bhatia, A. V.;

Cowart, M. An Expedient and Multikilogram Synthesis of a

Naphthalenoid H3Antagonist. Org. Process Res. Dev. 2007, 11,

1004−1009.

(38) Sisko, J.; Mans, D.; Yin, H. Process for Preparing Pyrano-[2,3-

C]pyridine Derivatives. WO Patent WO2012/012391, 2012.

(39) Davidson, A. H.; Moﬀat, D. F. C.; Day, F. A.; Donald, A. D. G.

HDAC inhibitors. WO Patent WO2008/040934, 2008.

(17) Alberico, E.; Sponholz, P.; Cordes, C.; Nielsen, M.; Drexler, H.

J.; Baumann, W.; Junge, H.; Beller, M. Selective hydrogen production

from methanol with a defined iron pincer catalyst under mild

conditions. Angew. Chem., Int. Ed. 2013, 52, 14162−14166.

(18) Fairweather, N. T.; Gibson, M. S.; Guan, H. Homogeneous

Hydrogenation of Fatty Acid Methyl Esters and Natural Oils under

Neat Conditions. Organometallics 2015, 34, 335 −339.

19) Widegren, M. B.; Clarke, M. L. Manganese Catalyzed

Hydrogenation of Enantiomerically Pure Esters. Org. Lett. 2018, 20,

654−2658.

20) Widegren, M. B.; Harkness, G. J.; Slawin, A. M. Z.; Cordes, D.

(

B.; Clarke, M. L. A Highly Active Manganese Catalyst for

Enantioselective Ketone and Ester Hydrogenation. Angew. Chem.,

Int. Ed. 2017, 56, 5825−5828.

(21) Junge, K.; Wendt, B.; Cingolani, A.; Spannenberg, A.; Wei, Z.;

Jiao, H.; Beller, M. Cobalt Pincer Complexes for Catalytic Reduction

of Carboxylic Acid Esters. Chem. - Eur. J. 2018, 24, 1046−1052.

(22) Geisser, R. W.; Oetiker, J. D.; Schroder, F. Improvements in or

Relating to Organic Compounds. WO Patent WO2015/110515,

015.

23) Saudan, L. A.; Saudan, C. M.; Debieux, C.; Wyss, P.

Dihydrogen reduction of carboxylic esters to alcohols under the

catalysis of homogeneous ruthenium complexes: high efficiency and

unprecedented chemoselectivity. Angew. Chem., Int. Ed. 2007, 46,

(

473−7476.

24) Khusnutdinova, J. R.; Milstein, D. Metal-ligand cooperation.

Angew. Chem., Int. Ed. 2015, 54, 12236−12273.

25) Dub, P. A.; Batrice, R. J.; Gordon, J. C.; Scott, B. L.; Minko, Y.;

(

Schmidt, J. G.; Williams, R. F. Engineering Catalysts for Selective

Ester Hydrogenation. Org. Process Res. Dev. 2020 , 24 , 415 −442.

(26) Dub, P. A.; Gordon, J. C. Metal −Ligand Bifunctional Catalysis:

The “Accepted ” Mechanism, the Issue of Concertedness, and the

Function of the Ligand in Catalytic Cycles Involving Hydrogen

Atoms. ACS Catal. 2017, 7, 6635−6655.

(27) Tindall, D. J.; Menche, M.; Schelwies, M.; Paciello, R. A.;

Schafer, A.; Comba, P.; Rominger, F.; Hashmi, A. S. K.; Schaub, T.

Ru(0) or Ru(II): A Study on Stabilizing the ″Activated ″ Form of Ru-

PNP Complexes with Additional Phosphine Ligands in Alcohol

Dehydrogenation and Ester Hydrogenation. Inorg. Chem. 2020, 59,

(

099−5115.

28) Prieschl, M.; García-Lacuna, J.; Munday, R.; Leslie, K.;

O ʼ Kearney-McMullan, A.; Hone, C. A.; Kappe, C. O. Optimization

and sustainability assessment of a continuous flow Ru-catalyzed ester

hydrogenation for an important precursor of a β 2-adrenergic receptor

agonist. Green Chem. 2020, 22, 5762−5770.

(29) Ogata, O.; Nakayama, Y.; Nara, H.; Fujiwhara, M.; Kayaki, Y.

Atmospheric Hydrogenation of Esters Catalyzed by PNP-Ruthenium

Complexes with an N-Heterocyclic Carbene Ligand. Org. Lett. 2016,

30) Spasyuk, D.; Smith, S.; Gusev, D. G. Replacing phosphorus

8, 3894−3897.

with sulfur for the efficient hydrogenation of esters. Angew. Chem., Int.

Ed. 2013, 52, 2538−2542.

31) Schorgenhumer, J.; Zimmermann, A.; Waser, M. SNS-Ligands

for Ru-Catalyzed Homogeneous Hydrogenation and Dehydrogen-

ation Reactions. Org. Process Res. Dev. 2018, 22, 862−870.

(32) Nguyen, D. H.; Trivelli, X.; Capet, F.; Swesi, Y.; Favre-

Reguillon, A.; Vanoye, L.; Dumeignil, F.; Gauvin, R. M. Deeper

Mechanistic Insight into Ru Pincer-Mediated Acceptorless Dehydro-

genative Coupling of Alcohols: Exchanges, Intermediates, and

Deactivation Species. ACS Catal. 2018 , 8 , 4719 −4734.

(33) Aycock, D. F. Solvent Applications of 2-Methyltetrahydrofuran

in Organometallic and Biphasic Reactions. Org. Process Res. Dev. 2007,

11, 156−159.