Continuous Flow Chiral Amine Racemization Applied to Continuously Recirculating Dynamic Diastereomeric Crystallizations

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Continuous Flow Chiral Amine Racemization Applied to

Continuously Recirculating Dynamic Diastereomeric Crystallizations

Maria H. T. Kwan, Jessica Breen, Martin Bowden, Louis Conway, Ben Crossley, Martin F. Jones,

Rachel Munday, Nisha P. B. Pokar, Thomas Screen, and A. John Blacker *

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ABSTRACT: A new, dynamic diastereomeric crystallization method has

been developed, in which the mother liquors are continuously separated,

racemized over a ﬁxed-bed catalyst, and recirculated to the crystallizer in a

resolution−racemization−recycle (R³) process. Separating the racemization

from crystallization overcomes problems of using catalysts in situ, that suﬀer

conﬂicting sets of conditions, inhibition, and separation. Continuous

racemization has been achieved through the covalent attachment of

[IrCp*I₂]₂SCRAM catalyst to Wang resin solid support to give a ﬁxed-bed catalyst. One tertiary and a variety of secondary

optically enriched amines have been racemized eﬃciently, with residence times compatible with the crystallization (2.25−30 min).

The catalyst demonstrates lower turnover (TOF) than the homogeneous analogue but with reuse shows a long lifetime (e.g., 40

recycles, 190 h) giving acceptable turnover number (TON) (up to 4907). The slow release of methylamine during racemization of

N-methyl amines was found to inactivate the catalyst, which could be partially reactivated using hydroiodic acid. Dynamic

crystallization is achieved in the R³process through the continual removal of the more soluble diastereomer and supply of the less

soluble one. The solubility of the diastereomers was determined, and the diﬀerence correlates to the rate of resolution but is also

aﬀected by the rates of racemization, crystal growth, and dissolution. A variety of cyclic and acyclic amine salts were resolved using

mandelic acid (MA) and ditoluoyl tartaric acid (DTTA) with higher resolvability (S = yield × d.e.) than the simple diastereomeric

crystallization alone. Comparing resolvabilities, resolutions were 1.6−44 times more eﬀective with the R³process than batch, though

one case was worse. Further investigation of this revealed an unusual thermodynamic switching behavior: rac-N-methylphenethyl-

amine was initially resolved as an (S,S)-bis-alkylammonium tartrate crystal but over time became the equivalent (R,S) salt. Thermal,

mixing, concentration, stoichiometry, and seeding conditions were all found to aﬀect the onset of the switching behavior which is

only associated with difunctional resolving reagents.

DKR employs enzymes to react selectively with one

enantiomer while racemizing the other in situ, Figure 1. The

technique requires an enantioselective enzyme and substrate

that racemizes under the same reaction conditions. The

requirement for solvents, reactants, temperatures, and

concentrations that are compatible with both catalysts

compromises the optimal activity of each and reduces the

overall DKR performance. CIAT works for compounds that

form conglomerate crystals. The entropic barrier of going from

a racemate to a single enantiomer can be overcome by adding

seeds and mechanically grinding to make smaller particles,

causing secondary nucleation, supersaturation, and re-

growth.^17,18Despite its elegance, the method is limited in

scope because too few chiral compounds crystallize with the

INTRODUCTION

■

When racemization is used in combination with chiral

resolution, it is a powerful alternative to the asymmetric

synthesis of chiral amines. These intermediates are used widely

in the pharmaceutical and ﬁne chemical industries but are

often diﬃcult to make in large quantities and as a result can be

costly.¹⁻⁴While catalytic asymmetric synthesis has largely

superseded ineﬃcient stoichiometric methods, both chemo-

and biocatalysts often perform poorly with highly function-

alized compounds with issues of regio- and enantioselectivity,

competing ligands, solubility, and product separation.⁵

Racemic starting materials are commonly resolved using

enantioselective enzymes⁶or by forming and breaking

diastereomeric salts.⁷These processes are used frequently in

industry, as they are simple and reliable, but they suﬀer low

yields and high wastes. Improvements employ in situ

racemization of the unwanted isomer, with the techniques

known as dynamic kinetic resolution (DKR), crystallization-

induced asymmetric transformation (CIAT), and crystalliza-

tion-induced diastereomeric transformation (CIDT), Figure

1.⁸⁻¹⁶

Received: November 3, 2020

Published: January 22, 2021

American Chemical Society

https://dx.doi.org/10.1021/acs.joc.0c02617

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Figure 1. Dynamic techniques used in chiral amine resolution, each involving a racemization catalyst.

Scheme 1. Preparation of the Immobilized Racemization Catalyst, SCRAM, 1

26

̈

required space group and have easily racemizable chiral

centers.¹⁹⁻²¹CIDT involves establishing a dynamic thermody-

namic equilibrium between the salts epimerizing in solution

and crystallization of the less soluble diastereomer. The

equilibrium adjusts by dissolution of the more soluble

diastereomer and results in a higher yield of the resolved

solid, Figure 1.²²Each of these techniques requires compounds

that racemize easily under resolution conditions, relying on

substrates with an acidic or enolizable chiral proton. However,

racemization and resolution processes compete, with the

former being faster at higher temperatures while the latter

operated preferably under ambient conditions. This limitation

can be overcome by continuously ﬂowing the soluble reactants

across a solid supported, heated, racemization catalyst and

cooling back for the resolution. Furthermore, when kept

separate, interference between the resolution and racemization

is avoided, and the product is more easily separated from the

catalyst.

A way to increase the scope of amine racemizations beyond

those that rely on acidic, tautomerizable chiral centers is to

employ hydrogen transfer catalysts which are able to

dehydrogenate unactivated amines. Heterogenous amine

racemization catalysts such as Pd/C or Pd/BaSO₄lend

themselves well to this but can suﬀer poor activity and

selectivity.^23,24A variety of homogeneous catalysts are known

to borrow and replace the proton at the chiral center of

secondary alcohols; however, few have been identiﬁed that

perform a similar hydrogen transfer reaction with chiral

amines.²⁵Catalysts that have proven eﬀective in this regard

are the ruthenium based Shvo and analogues and iodo-

iridium, SCRAM.¹⁶The former is better able to racemize

primary amines, and the latter, secondary and tertiary chiral

amines. This is because the iridium center coordinates and

activates primary imines toward N-alkylation, resulting in

dimerization.²⁷Both of these homogeneous catalysts have been

used in enzymatic DKR of amines but not in CIDT.²⁸⁻³⁰

A

̈

silica-supported Shvo catalyst has been reported recently for

the transfer hydrogenation of levulinic acid³¹but is not

reported for racemization. Similarly, a polymer supported

chloro-iridium catalyst, tethered by a functionalized Cp*

ligand, is reported for the reduction of benzaldehyde and

repeated reuse.³²The same supported metal, modiﬁed with

chiral ligand, has shown a long lifetime in the continuous ﬂow

asymmetric transfer hydrogenation of ketones.³³

There are several ways in which a combined resolution and

racemization can be conﬁgured. A DKR example reported by

Falus et al. uses solid supported subtilisin enzyme to resolve an

amine by esterifying selectively one enantiomer.³⁴The mixture,

containing the remaining alcohol enantiomer, is ﬂowed across

a ﬁxed-bed racemization catalyst and the sequence repeated

across 10 columns to give the amide in 98% e.e. and 79% yield

with productivity of 8 g/L/h running over a week. In another

example, de Miranda et al. packed into one column layers of

solid-supported CalB lipase (to resolve phenethyl alcohol) and

VOSO₄(to racemize the unreacted alcohol enantiomer) using

toluene at 70 °C.³⁵Four resolution and three racemizing layers

were enough to generate the product in 90% e.e. and 82%

yield. To avoid sequential columns, each separately supported

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Figure 2. Scheme and setup for continuous ﬂow racemization of amines 6−12.

Table 1. Continuous Flow Racemization of Chiral Amines

b

c

Ir loading

(mol %)

temp

(°C)

racemization at steady state

t_Res

(min)

TOF

a

entry

amine [mM]

solvent(s) (ratio)

(e.e. min⁻¹

)

(h⁻¹

)

d

e

1

2

(S)-6 [100]

toluene/DTBP (1:1)

5

105

80

73

80

60

50

80

0.4

16

15

12

30

2.25

6

0.25

34.8

14.4

2.80

2.20

227

25.8

0

158

252

f

(S)-7 [100]

(R)-8 [50]

(S)-9 [50]

(S)-10 [62]

(R/S)-10-(S)-MA [64]

(S)-11 [80]

(S)-11 [100]

ⁱPrOAc

2.87

3

4

5

EtOAc/MeOH (4:1)

5

1.17

0.47

0.37

37.8

g

EtOCOⁱBu

10

5

ⁱPrOAc/ⁱPrOH (7:3)

EtOAc/MeOH (7:1)

MTBE/ⁱPrOH (95:5)

ⁱPrOAc

6

7

8

9

h

ij

4.3 ^,

0

4.5

6

5

13.17

i

10

(1S,4S)-12 [500]

toluene

1

4.2

15

a

Synthesis and characterization described in the Experimental Section and Supporting Information. Bracketed values are feed concentrations.

b

c

d

Relative to the total amount of amine pumped across the catalyst. Average taken over 2−3 RV. Deﬁned in the Supporting Information. 2,4-

e

f

g

Dimethylpentan-3-ol. While racemizing, most of the amine decomposed to other species. The initial e.e. of (S)-7 was 86%. Ethyl iso-butyrate.

h

i

j

Mandelic acid. D.e. The initial d.e. was 38%.

catalyst can be intimately mixed; however, thermal control of

each is then lost. Nevertheless, Farkas et al. achieved high e.e.’s

and conversion in the DKR of benzylic primary amines using a

supported CalB lipase and palladium-based hydrogen transfer

catalyst.³⁶Another operational mode is to continuously

recirculate the solution between resolution and racemization,

though this appears not to have been evaluated for dynamic

crystallizations. This involves separating crystals from mother

liquors and racemizing and recirculating them. The work

described here starts by preparing an immobilized iodo-iridium

racemization catalyst 1, exploring its use in continuous ﬂow

racemization, and then integrating this with diastereomeric

crystallization to give the resolution−racemization−recycle R³

process.

Scheme 1. After thorough washing of the beads, the amount of

iridium supported on the resin was found by ICP to equate to

0.39 mmol of Ir/g.

To integrate the racemization and resolution processes, it is

necessary to have a common solvent. It was found that the

immobilized catalyst 1 is active in most solvents, except dipolar

aprotics that may coordinate to the metal. This is convenient,

because the selection of crystallization solvent is critical to the

eﬃciency of the diastereomeric resolution. Solvents that are

preferred for both steps maximize the diﬀerence in solubility

between the diastereomeric salts and have a high enough

boiling point to increase the racemization rate, but below 120

°C, the point at which the polymer support breaks down. It

was shown that alcoholic solvents, that act as hydrogen donors,

are useful cosolvents, as they can increase the rate of

racemization by enhancing imine reduction and reduce side-

reactions.³⁷Racemization in continuous ﬂow was tested with

optically pure amines 6−12, Figure 2.

RESULTS AND DISCUSSION

■

Continuous Flow Racemization. The immobilized

SCRAM catalyst, 1, was prepared as described previously,³²

by reacting the homogeneous chloro-iridium Cp*C₅OH

complex 3 ﬁrst with excess sodium iodide to exchange the

halide for an iodo-ligand, 4, and then activating the alcohol by

triﬂation to make 5, which was reacted in situ with Wang resin,

A mass of immobilized catalyst 1, suﬃcient to give 5−10

mol % iridium loading, was mixed with washed sand, to

manage swelling and compaction, and packed into an empty 4

mL, 23 cm HPLC column. The reactor’s ﬂuid volume was

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Figure 3. Gradual deactivation of catalyst 1 during 10 days of intermittent ﬂow of amine (S)-7.

measured by solvent mass diﬀerence as 1.5 mL. The column

was placed in an electrically heated aluminum block, and amine

solution was pumped at a temperature and ﬂow rate enough to

cause a signiﬁcant amount of racemization in a short residence

time. Table 1 shows the results of continuous ﬂow

racemization of optically pure amines 6−12 at steady state

(Supporting Information section 7), measured as the fall in e.e.

per minute and converted to turnover frequency (TOF) per

hour.

acid (0.1 M) for 2 h recovered about 25% of the activity. More

concentrated acid or extended exposure led to cleavage of the

catalyst from the resin. Unfortunately, this reactivation

procedure is tedious and requires extensive washing to remove

the acid. As it was only partially successful, emptying and

repacking the ﬁxed bed using fresh catalyst was adopted

instead.

Salsolidine (S)-10 was racemized at 37.8% e.e./min, so a

residence time (t_res) of 2.25 min gave a fall of 85% e.e., entry 6.

The same packed column of catalyst was reused in diﬀerent

experiments 130 times, giving a total TON of 1105. The

mother liquor solution derived from the diastereomeric

crystallization of 10 with (S)-mandelic acid ((S)-MA) gave a

reduced TOF of 25.8 h⁻¹; nevertheless, in a single pass, or 1

reactor volume, the catalyst was able to epimerize the

diastereomer by 26% d.e., indicating that continuous

racemization of crystallization mother liquor (ML) would be

feasible, entry 7. The possibility that the epimerization was

caused by racemization of (S)-MA, or the mandelate anion,

rather than the amine, was tested by stirring (S)-MA or its

mandelate salt with catalyst 1 in batch under the same

conditions as entry 7. Neither of them showed any

racemization. However, after 12 h, 3.5% phenylglyoxalate was

formed from the mandelate salt by dehydrogenation of the

alcohol group. Since epimerization of the diastereomeric salt

involves only the amine, the process is hereinafter described as

racemization. Surprisingly, the racemization of heterocyclic

amine (S)-11 failed when methyl tert-butyl ether (MTBE) and

iso-propyl alcohol were used, entry 8. However, iso-propyl

acetate solvent worked well, giving a racemization rate of

13.2% e.e./min with a catalyst TOF of 158 h⁻¹, entry 9. The

continuous ﬂow epimerization of sertraline (1S,4S)-12 in

toluene at 80 °C was successful with a catalyst TOF of 252 h⁻¹,

though over 9 reaction volumes the activity fell by half. As with

amine 7, a linear deactivation of the catalyst was found with 12,

at a rate of 14% d.e./h which is also caused by methylamine.³⁸

Development of a Resolution−Racemization−Re-

cycle Process. With a continuous ﬂow racemization method

in hand, we sought to integrate this with the diastereomeric

The primary amine (S)-6 is racemized slowly, entry 1, the

reason being that side-reactions associated with the inter-

mediate imine cause liberation of ammonia that deactivates the

catalyst. An attempt to suppress the side reactions by adding

the hindered hydrogen donor 2,4-dimethylpentanol 50% (v/v)

was of limited success.³⁰Benzylic amines (S)-7 to (S)-9

racemized with rates of 0.37−2.87% e.e./min at steady state.

With ﬂow rates adjusted to give residence times of 12−30 min,

racemizations of 43, 14, and 11% ee for (S)-7, (S)-8, and (S)-

9, respectively, were achieved in one pass, entries 2, 4, and 5.

The TOFs of 1 are signiﬁcantly less than the homogeneous

catalyst [IrCp*I₂]₂used with these substrates in batch

(Supporting Information section 7); however, this is

compensated using 5−10 mol % of 1. A 10-day continuous

ﬂow racemization was performed on (S)-7 to determine the

impact of catalyst deactivation on extended use, Figure 3.

On day 1, the e.e. reached steady state after two to three

vials, falling from 98% (stock solution) to 12.5% ee. Thereafter,

the activity of the catalyst fell almost linearly at 2.8% e.e./h,

until after 10 days the amine was only racemized by 13% e.e,

with a TON of 30 compared with 187 at the start.

Nevertheless, the cumulative TON was 4907, showing an

eﬀective catalyst use of 0.02 mol %. The cause of deactivation

has been determined as methylamine coordination to the

iridium which arises from hydrolysis of the imine inter-

mediate.³⁸Reducing the moisture content or adding iso-

propanol hydrogen donor reduces but does not eliminate the

catalyst deactivation. The addition of potassium iodide at day 9

had little eﬀect on reversing the inhibition; however, it was

found that treating the spent catalyst with dilute hydroiodic

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crystallization. Direct addition of the homogeneous SCRAM

catalyst to the crystallization was unsuccessful because the

racemization rates were too low at ambient temperature.

Furthermore, the homogeneous catalyst interfered with the

crystallization (the crystals formed were dark rather than white

solids) and made puriﬁcation of the product more diﬃcult.

This provided the rationale for the recycle system using

immobilized catalyst 1. An important consideration was the

acidity of the system, as carboxylic acids are known to retard

hydrogen transfer by reacting with the iridium hydride

intermediate to form dihydrogen (hence the use of

triethylammonium formate as hydrogen donor rather than

formic acid³⁹). It was already shown that 1 was active in

racemizing the diastereomeric salt, Table 1, entry 7, and that

(S)-MA salt was insensitive to racemization. To ensure a

neutral or basic solution, a slight under-charge of the resolving

acid was used at the start of the work; however, it was later

shown as unnecessary and a 1:1 stoichiometry was satisfactory.

The equipment used to integrate the resolution, racemization,

and recycle steps is shown in Figure 4.

Scheme 2. Proposed Mechanism for the Formation of the

Predominant Diastereomer

soluble amine (and derived impurities) from the initial amount

using calibrated GC. The d.e. was measured from a sample of

the solid, dried, and dissolved in solvent for analysis by chiral

1

HPLC, H NMR, or GC to determine the e.e. of the free

amine generated from the salt. The solubility of each pure

diastereomer was measured by analyzing its saturated solution

in the corresponding solvent. It is useful to compare the

performance of the batch and R³processes; however, yield and

d.e. can be competing functions and determining optimum

conditions can be time-consuming. Resolvability, S, is the

product of both variables and can be useful to compare

outcomes. In a perfect batch resolution, S_max= 1.0, i.e., 2 ×

50% yield × 100% d.e., and in a dynamic system, S_max= 2.0.⁴⁰

The resolvability of 7-(S)-MA was found to be the same in

batch diastereomeric crystallization as the R³process, S = 0.36,

Table 2, entries 1 and 2; however, the solid yield is 30% with

60% d.e. in the R³process but 49% yield with 37% d.e. in

batch. Acetophenone, formed by hydrolysis of the intermediate

imine, was seen to accumulate slowly over 190 h to about 10%

of the reaction mass. Since methylamine is a potent catalyst

inhibitor, catalyst activity was assayed at the end of the

experiment and was 42% less active than at the start.

Nevertheless, this does not explain the low solid yield in the

R³process; rather, this indicates a change in crystallinity,

perhaps because of the impurities or crystal growth inhibition.

A diﬀerent resolving reagent gave better results, entries 11 and

12, but also exposed some unusual behaviors that are discussed

later.

There is a large diﬀerence in the solubilities of the 8-(S)-MA

diastereomers, which provides a good driving force for the

dynamic resolution, Table 2, entries 3 and 4. The R³process

was run at a ﬂow rate of 0.1 mL/min, giving a recycle time of

4.75 h. The d.e. steadily increased to 89% after 30 recycles with

an isolated solid yield of 62%, Figure 5.

The concentration and e.e. of amine 8 in the mother liquors

(MLs) fell gradually over the course of the experiment.

However, the rate of fall does not correlate with the solid,

indicating that the rate-limiting step may be the growth or

dissolution of the solid, not racemization. It would be

interesting to determine these parameters, as the eﬀect of

constant supersaturation of one diastereomer and subsatura-

tion of the other may be diﬀerent from those in the batch

diastereomeric crystallization. The resolvability of amine 8 was

improved to S = 1.1, compared with the batch diastereomeric

crystallization S = 0.67. Based on the measured solubilities, the

Figure 4. Schematic of the R³process, with solid retained in the

crystallizer by an in-line ﬁlter (photograph). The enantiomerically

enriched solution is pumped across the heated ﬁxed bed of iodo-

iridium racemization catalyst, and the racemized solution is

recirculated back to the crystallizer where more of the less soluble

diastereomer can form.

A temperature-controlled crystallizer with gas-tight PTFE

lid, drilled with holes to support the in- and outﬂow tubes, is

gently stirred with a magnetic stirrer bar, and the system is a

closed loop. Solutions of the acid and amine were introduced

in a solvent at a concentration enough to cause precipitation of

solid. The solubility of each diastereomer was measured to

facilitate selection of the optimal concentration. The mother

liquors, that are enriched with the more soluble diastereomer,

were separated from the solid using a sintered glass in-line ﬁlter

that pumped the saturated solution into the electrically heated

racemization column. The hot outﬂow is now enriched in the

less soluble diastereomer and subsaturated in the more soluble

one. As the solution is returned to the crystallizer, it becomes

supersaturated in the less soluble diastereomer which further

crystallizes. This happens as the more soluble diastereomer

dissolves, thus providing a dynamic equilibrium, Scheme 2.

The scope of the system was tested with (S)-MA salts of

amines 7−11, Table 2, entries 1−10. The poor results with

amines 7 and 9 prompted us to use (S,S)-ditoluoyl tartaric acid

((S,S)-DTTA) instead, entries 11−14.

The solvent and substrate concentrations were selected from

those that gave a substantial amount of solid in batch at

ambient temperature. The yield of solid produced during the

reaction was inferred by subtracting the concentration of

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Table 2. Comparison of the Resolvability of Four Amine Salts in Batch with the R³Process

a

b

c

a

solubility

(mg/mL)

resolvability in

batch

no. of recycles

(h)

yield

d.e.

resolvability R³

entry

product

solvent

ⁱPrOAc

(%)

process

d

1

(S)-7-(S)-MA

25.2

3.6

0.36

40 (190)

30

60

0.36

2

(R)-7-(S)-MA

ⁱPrOAc

e

f

3

4

5

(S)-8-(S)-MA

(R)-8-(S)-MA

(S)-9-(S)-MA

EtOCOⁱBu

ⁱPrOAc

145

0.3

>43

3.0

0.67

30 (142)

N/A

62

89

1.10

N/A

6

(R)-9-(S)-MA

ⁱPrOAc

g

h

7

8

9

(S)-10-(S)-MA

(R)-10-(S)-MA

(S)-11-(S)-MA

(R)-11-(S)-MA

[(S)-7]₂-(S,S)-DTTA

[(R)-7]₂-(S,S)-DTTA

[(S)-9]-(S,S)-DTTA

[(R)-9]-(S,S)-DTTA

EtOAc/ⁱPrOH

ⁱPrOAc

EtOAc/ⁱPrOH

0.11

8 (6.7)

16 (30)

65

52

96

89

1.25

0.93

0.7

7.5

i

0.11

10

11

12

13

14

2.4

g

j

0.2

0.03

35 (166)

17 (242)

78

17

86

77

1.34

0.26

0.9

9.5

k

l

EtOAc/EtOH

0.49

k

44.1

a

b

c

Resolvability, S = 2 × yield × d.e. Isolated molar yield of diastereomeric solid based on 100% amine. D.e. determined by ¹H NMR (in CDCl₃),

d

e

f

g

h

i

chiral HPLC, or chiral GC (on the free amine). 49% yield, 37% d.e. Ethyl iso-butyrate. 48% yield, 70% d.e. 7:1 (v/v). 80% yield, 7% d.e. 53%

yield, 20% d.e. 84% yield, 2% d.e.; measured at 6 h. 7:3 (v/v). 42% yield, 59% d.e.

j

k

l

Figure 5. Resolution of racemic amine 8 with (S)-MA using the R³

process.

Figure 6. Resolution of racemic amine 10 with (S)-MA and

continuous racemization of the mother liquors showing initial

formation of solid and its gradual increase in d.e. with recycle.

predicted yield is 80%, while the isolated yield was 62%; the

diﬀerence is due mainly to formation of acetophenone

(16.7%).

Resolution of amine 9 using (S)-MA failed, as the

diastereomeric salts failed to crystallize in any of the solvents

tested; in iso-propyl acetate, the solubility at ambient

temperature exceeded 43 mg/mL, entries 5 and 6. Instead,

the diacid resolving reagent (S,S)-DTTA was tried with results

discussed later, entries 13 and 14.

Racemic 1-methyl tetrahydro-iso-quinoline 10 forms diaster-

eomeric salts easily with (S)-MA, and a solvent composition of

ethyl acetate and iso-propanol (7:1 v/v) was found to give a

high d.e. solid at ambient temperature, Table 2, entries 7 and 8.

The batch diastereomeric crystallization gave 80% yield and

7% d.e., S = 0.11; however, the R³process gave a resolvability

of S = 1.25. Figure 6 shows the reaction proﬁle with change in

solid yield, d.e., and impurities over 30 recycles; each recycle

was 48 min, at a ﬂow rate of 0.5 mL/min.

After one recycle, 83% of the amine forms a solid and this

remains relatively constant; however, the initial 44% d.e. drops

to 17% after one racemization recycle and then slowly rises

over the next 30 recycles (24 h) to ﬁnish at 96% d.e. The

improved performance of R³was encouraging, but a limitation

identiﬁed was that the yield of the solid is determined by the

solubility of the least soluble diastereomer. The solubility of

both diastereomers was measured as 3.0 and 0.7 mg/mL. This

4.3-fold diﬀerence explains the driving force on the dynamic

equilibrium but also that 9% of the mass remains in solution,

giving a theory maximum yield of 91%, versus the 86% yield

observed. The remaining mass is the side-reaction impurities

dihydro- and iso-quinoline resulting from transfer dehydrogen-

ation. However, they remained at low levels using iso-propanol

as a hydrogen donor which serves to reduce them back into 10.

When (S)-MA was added to racemic amine 11 in batch, 53%

solid of 20% d.e. formed immediately, Table 2, entries 9 and

10. Applying these conditions to the R³process, a ﬂow rate of

0.25 mL/min gave a recycle time of 114 min and racemization

residence time of 6 min at 80 °C. The resolvability in the R³

process was S = 0.93 compared to S = 0.11 in batch, with the

solid d.e. improved from 20 to 89% but little change in yield.

The solubility of both diastereomers was determined as 7.5 and

2.4 mg/mL, giving a theoretical yield of 61% solid versus 52%

isolated. A yellow colored impurity formed during racemiza-

tion was tentatively assigned by MS as a trimeric species.⁴¹

A

similar trend was observed with d.e. increasing with time,

reaching 89% after 16 recycles (30 h), Figure 7.

The e.e. and concentration of the amine in the mother

liquors fell gradually, though at a higher rate than the solid,

perhaps indicating crystal growth or dissolution as rate

limiting. The activity of the catalyst was determined at the

end of the experiment and had the same TOF as at the start,

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pH.⁴²The unusual switch in solid form was investigated

further, Figure 9.

Figure 9a shows that the higher the temperature, the more

rapid the switch from [(S)-7]₂-(S,S)-DTTA to [(S)-7][(R)-7]-

(S,S)-DTTA, which may be related to increased mass transfer

and nucleation rate. Figure 9b shows that a 2:1 stoichiometry

of the amine and diacid is required, and with only a quarter

equivalent of (S,S)-DTTA to (S)-7, the [(S)-7]₂-(S,S)-DTTA

diastereomeric salt remains stable over 36 h. Figure 9c

illustrates that higher concentrations of (S)-7 cause a faster

rate of switching at the same 2:1 amine/acid stoichiometry,

presumably because of an increased nucleation rate. Similarly,

higher rates of mixing cause more crystal attrition and are likely

to increase the [(S)-7][(R)-7]-(S,S)-DTTA nucleation rate,

Figure 9d. This is conﬁrmed when seeds of [(S)-7][(R)-7]-

(S,S)-DTTA are added to the system and the more stable

diastereomer is formed more rapidly over 5 h, whereas the

seeds of [(S)-7]₂-(S,S)-DTTA have no eﬀect on the switching

time compared to the control, Figure 9e. In the R³process of

amine 7, 0.25 equiv of (S,S)-DTTA was ﬁrst added to form

solely the less soluble (S)-7-(S,S)-DTTA-(S)-7 ﬁrst. The

remaining 0.25 equiv of (S,S)-DTTA was added slowly to

allow enough time for (R)-7 to racemize to (S)-7 so as to

lower the concentration of (R)-7 in the system, hence avoiding

the switching to (S)-7-(S,S)-DTTA-(R)-7, Table 2, entries 11

and 12. A resolvability of 1.34 was achieved, a 44-fold

improvement compared to diastereomeric resolution alone. It

is interesting to speculate whether other diastereomeric

crystallizations that employ diacids might be susceptible to

this eﬀect: initially, the diastereomer is formed under kinetic

control, giving a metastable product, and with time, a more

stable crystal morphology is formed. When resolving reagents

and conditions are screened, samples are rarely taken over

time, so a low d.e. will be dismissed as a failure. Though of

little practical use, as no resolution is achieved, the

thermodynamic phenomenon appears to be the opposite of

CIAT that is under kinetic control.

Figure 7. Resolution of racemic amine 11 with (S)-MA and

continuous racemization of the mother liquors.

though after two further runs of similar duration it was found

to have lost half of its activity.

To improve the resolution of amine 7, a half mole equivalent

of chiral acid, (S,S)-DTTA, was tested, Table 2, entries 11 and

12. Using ethyl acetate with 20% (v/v) iso-propanol, an

insoluble precipitate was isolated after 6 h in 84% yield.

Analysis indicated a 2:1 amine:acid salt of only 2% d.e. The

diastereomeric crystallization was carried out in the presence of

homogeneous SCRAM catalyst in a one-pot recycle system.

The concentration of amine 7 in solution and d.e. of the solid

remained at 66 and 75%, respectively, for about 25 h.

Surprisingly, a sample taken after 30 h revealed a signiﬁcant

drop of concentration of 7 in solution to <40% and the d.e. of

1

the solid decreased to about 6%. H NMR analysis of the

DTTA showed no epimerization, and the 2:1 stoichiometry of

the salt was the same. The same system was tested in batch

without racemization and was sampled with time. It was found

that the initial d.e. of the solid formed was 70% but fell to 6%

over 6−12 h, Figure 8.

Crystals taken at the start and end of the experiment were

analyzed by powder and single crystal X-ray diﬀraction, Figure

8. It was found that a switch in amine enantiomers within the

solid phase had occurred, going from the [(S)-7]₂-(S,S)-DTTA

diastereomer to a, presumably more stable, meso-like form

[(S)-7][(R)-7]-(S,S)-DTTA containing a racemate of both

amine enantiomers, hence the observed fall in d.e. The

experiment was repeated twice with similar results. Ferreira et

al. have observed this behavior previously with rac-6-(S,S)-

DTTA, and they developed a model to explain the diﬀerent

solid forms that were related to solubility, acid:amine ratio, and

Unlike amine 7, the N,N-dimethyl analogue 9 forms a 1:1

rather than 2:1 salt with (S,S)-DTTA, using either 0.5 or 1

equiv of the diacid. A solvent screen was carried out and ethyl

acetate−ethanol (7:3) gave the best yield (42%) and d.e.

(59%) with S = 0.49, Table 2, entries 13 and 14. Since the

racemization of 9 was found to be slow, a residence time of 2.5

h was selected as well as a whole process recirculation time of

14.3 h. At the start, a gradual increase in d.e. of the solid was

Figure 8. Left: X-ray crystal structures of (a) [(S)-7]₂-(S,S)-DTTA, (b) [(R)-7]₂-(S,S)-DTTA, and (c) [(S)-7][(R)-7]-(S,S)-DTTA. The

hydrogen atoms are omitted for clarity. The nitrogen and oxygen atoms are highlighted in blue and red, respectively. Right: Diastereomeric

resolution of 7 with (S,S)-DTTA at 25 °C, 400 rpm stirring, without racemization catalysts.

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Figure 9. Eﬀect of (a) temperature, (b) stoichiometry, (c) concentration, (d) stirring rate, and (e) seeding on the d.e. of initially formed [(S)-7]₂-

(S,S)-DTTA with time. The fall in d.e. in each case is due to thermodynamic switching to a meso-like [(S)-7][(R)-7]-(S,S)-DTTA solid form.

observed; however, its yield decreased as the solution

concentration of 9 increased, concurrent with its racemization.

The reaction was run over 242 h, with a ﬁnal yield of 17% solid

with 77% d.e., S = 0.26, worse than that in batch. The apparent

change in diastereomer solubility was shown not to be

epimerization of (S,S)-DTTA, so a hypothesis that the less

soluble (S)-9-(S,S)-DTTA crystallizes more slowly than

dissolution of the more soluble (R)-9-(S,S)-DTTA diaster-

eomer was tested. Both diastereomers are less soluble in iso-

propanol:iso-propyl acetate (3:7); however, running the R³

process showed no improvement in either the yield or d.e. of

(S)-9-(S,S)-DTTA; instead, all of the crystals dissolved after

15 recycles. The cause of this is not clear, but an explanation

might be the iminium−enamine intermediates, that occur

during racemization, inhibit crystal nucleation/growth.

5−10 mol %, the racemization rate gives suitable residence

times; extended use gives eﬀective loadings that depend on the

duration of the experiment (tested up to 190 h continuous or

10 days intermittent ﬂow). A variety of benzylic and cyclic

secondary amines have been racemized with steady-state TOFs

of 2.8−252 h⁻¹and a tertiary amine with 2.2 h⁻¹in solvents

that are compatible with diastereomeric crystallization. Primary

amines are unsuitable for the iodo-iridium catalyst as the

intermediate imine is too reactive, forming ammonia that

rapidly inactivates the catalyst. In this case, the addition of iso-

propanol hydrogen donor failed to suppress the side-reactions.

It was found that racemization of N-methylamines causes slow

catalyst deactivation as a result of the hydrolysis of the imine

intermediate and subsequent release of methylamine.³⁸

Reducing the moisture content of the system and using iso-

propanol as a cosolvent and hydrogen donor suppressed this

side-reaction. A partial catalyst reactivation was identiﬁed using

hydroiodic acid, but a lengthy washing procedure precluded its

further use.

CONCLUSIONS

■

An immobilized iodo-iridium racemization catalyst has been

prepared, characterized, and used in ﬁxed-bed continuous ﬂow.

Though its activity is around 10 times lower than its

homogeneous counterpart. When used in the ﬁxed bed at

The continuous racemization was applied in a new

resolution−racemization−recycle (R³) process in which tubing

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connected the racemization catalyst to the crystallizer, allowing

continuous recirculation of the mother liquors. This allowed

both reactions to be operated separately at diﬀerent temper-

atures. The resolvability of amines 8−11 (S)-MA salts was

improved using the R₃process by 1.6−11 times over batch.

The exception was amine 7, but its resolution was more

successful using the diacid (S,S)-DTTA. In this case, a

surprising eﬀect was observed, when, instead of harvesting the

solid soon after it was formed, it was left until the next day, the

d.e. dropped from >70% to almost zero. Investigation of the

crystal structures showed a change in molecular structure,

producing a more stable meso-like or “neutral” form in which

the chiralities of both N-methylphenethylammonium mole-

cules were (R) and (S) rather than being both (S) as they were

at the start.⁴²The racemization of DTTA was eliminated. The

switch in structure appeared to be stochastic and aﬀected by

temperature, mixing, concentration, stoichiometry, and seed-

ing. These parameters are those that aﬀect secondary

nucleation rates, like those seen in CIAT and in polymorph

switches. By slow addition of the diacid with (fast)

racemization of (R)-7, the switch to the meso-like form can

be avoided, giving a 44-fold improvement in resolvability over

the control diastereomeric crystallization, achieving 78% yield

and 86% d.e. The diﬃculty this exposes is that a good or bad

resolution with a diacid depends on when the sample is taken;

a low d.e. might be dismissed as a failed set of conditions,

whereas a sample taken with high d.e. might cause problems

later on when the crystallization is held. A diﬀerent explanation

is needed for the failure to resolve N,N-dimethylphenethyl-

amine 9 which forms a 1:1 salt with (S,S)-DTTA. In this case,

racemization and recirculation cause dissolution of the solid

which might be accumulation of impurities that slow crystal

nucleation and growth but not dissolution. Further work is

required to conﬁrm this.

As with other CIDT processes, the increased optical purity is

likely to occur through dissolution of the more soluble

diastereomer, and crystallization of the less soluble one, and is

driven by the diﬀerence in concentration between the raﬃnate

and racemized feed. As material of low d.e. is returned to the

crystallizer, it is enriched in the less soluble diastereomer and

causes its supersaturation, while the dynamic equilibrium is

maintained by dissolution of the more soluble one. Since the

dynamic system in the R³process in most cases allows

formation of the most thermodynamically stable diastereomer,

the yield and d.e. are both determined by the diastereomer

solubilities and the resolution rates by the racemization, crystal

growth, and dissolution. More work is required to quantify and

model these. Prior determination of these parameters in

diﬀerent solvents might overcome the usual need for careful

solvent, temperature, and chiral acid screening to ﬁnd the

optimal resolution conditions.

EXPERIMENTAL SECTION

■

General Information. Unless otherwise stated, all chemicals were

obtained from Sigma-Aldrich, Fisher Scientiﬁc, Alfa Aesar, or

Fluorochem and were used without further puriﬁcation. All solvents

used were HPLC grade. The syringe pumps used were Harvard

Apparatus Model 11 from Scientiﬁc Support. Column chromato-

graphic puriﬁcations were performed using Biotage (Isolera Spektra

One, silica column = RediSepR_f). Nuclear magnetic resonance

(NMR) spectra were recorded on a Bruker 500 UltraShield

Spectrometer operating at 500 MHz (¹H NMR) and 126 MHz

(¹³C NMR). Liquid chromatography−mass spectrometry (LCMS)

was performed on an Agilent Technologies 1200 Series LC system

with a C18 column (Phenomenex Luna 5u C18(2), 50 mm × 2 mm

× 5 μm) eluted with an acetonitrile/water gradient (15−95%

acetonitrile, 0.1% formic acid over 3 min) and a Bruker Daltonics

HCTUltra system equipped with an ion trap MS detector, or a

Thermo Ultimate 3000 UHPLC system with a C18 column

(Phenomenex Kinetex, 50 mm × 2.1 mm × 2.6 μm) eluted with an

acetonitrile/water gradient (2−95% acetonitrile, 0.1% formic acid

over 1 min) and a Bruker Amazon Speed ion trap mass spectrometer.

High resolution mass spectrometry (HRMS) was performed on a

Bruker Maxis Impact Electron Spray Ionization (ESI) spectrometer

with a qTOF mass analyzer. For clarity in the assignment of MS peaks

of the amine salts, the cationic and anionic fragments were assigned as

X and Y, respectively. Melting points were recorded using a Stuart

Scientiﬁc SMP3 melting point apparatus. FT-IR was recorded using a

Bruker Platinum-ATR spectrometer. Optical rotations ([α]_D) were

measured using a Polartronic H532 at 589 nm. Achiral and chiral gas

chromatography (GC) were used to determine the conversion and

enantiomeric excess (ee) of the substrates (7, 8, 10, 11, and 12),

respectively. They were performed using a HP6890 series GC system,

Agilent Technologies 7683 series injector, and HP7683 series

autosampler. The e.e. of 10 and diastereomeric excess (d.e.) of

mandelate salts were analyzed by chiral high performance liquid

chromatography (HPLC) using an Agilent Technologies 1290 Inﬁnity

system, while the e.e. of (S)-MA was analyzed by chiral HPLC using

an Agilent 1100 Series system. The calculations of resolvability, yield,

residence time, and total process time are given in Supporting

Information section 1. The supported SCRAM catalyst 1 was

prepared as previously reported.³²

Optical rotations ([α]_D) were measured using a Polartronic H532

at 589 nm and were calculated as

rotation × 100

[α]^T_D

=

(1.1)

c × l

where T = temperature; c = concentration of sample in g/100 mL;

and l = path length, which is the length of the cell in dm (the cell used

was 1 dm).

Achiral and chiral gas chromatography (GC) were used to

determine the conversion and enantiomeric excess (ee) of the

substrates (7, 8, and 11), respectively. They were performed using a

HP6890 series GC system, Agilent Technologies 7683 series injector,

and HP7683 series autosampler. The ee of 10 and diastereomeric

excess (de) of the MA salts of 10 were analyzed by chiral high

performance liquid chromatography (HPLC) using an Agilent

Technologies 1290 Inﬁnity system, while the ee of MA was analyzed

by chiral HPLC using an Agilent 1100 Series system.

In all resolution and R³processes, the resolvability of the system S

was calculated as

The R³process provides a simple, reproducible, low cost,

and low waste method of producing chiral amines. If the

catalyst activity could be increased further, the process might

be amenable for use in chiral amine manufacture and studies

on this are in progress. Continuous ﬂow racemization might

also be applied to CIAT, enzyme DKR, and chiral chromato-

graphic resolution processes. Potential applications are in the

end-of-pipe resolution processes to recover waste amine, for

example, in chromatographic, enzymatic, or crystal resolution

processes.

S = 2 × yield × d.e.

(1.2)

where yield is a function of the quantity of amines in the system

irrespective of the amount of chiral acids charged, assuming the

stoichiometry of the amine and acid in the salts remain constant

under the conditions employed, and was calculated as

m_crystals

yield =

× 100%

n_amine

× M_salt

(

)

(1.3)

r

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where m_crystalsis the mass of crystals obtained from the resolution;

126.4, 39.5, 15.1. The spectral data correspond to those reported in

the literature.⁴³ν_max/cm⁻¹: 1634, 1578, 1493, 1445, 1396, 1365, 1284.

Racemic N-Methyl-α-methylbenzylamine, 7.

n

_amineis the number of moles of amine in the system; r is the ratio of

amine:acid in the salt; and M_saltis the molar mass of the salt formed.

For all ﬂow processes, residence time was calculated as

RV

flow rate

T =

r

(1.4)

where RV is the volume of the reactor.

N -Methyl-α -methylbenzylimine (12.4 g, 93.1 mmol) was dissolved

into methanol (200 mL). The mixture was cooled to <0 °C. Sodium

borohydride (18.3 g, 484.5 mmol) was added slowly in portions over

2 h to maintain the temperature at <10 °C. After the addition was

complete, the reaction mixture was warmed to room temperature.

After 24 h of stirring, the reaction was cooled to 0 −5 °C and was

acidi ﬁ ed by aqueous hydrochloric acid (2 M, 250 mL). The mixture

was concentrated in vacuo to give a white solid which was basi ﬁ ed by

aqueous sodium hydroxide (3 M, 200 mL). Dichloromethane (100

mL) was added, and the mixture was separated. The aqueous layer

was further extracted with dichloromethane (2 × 100 mL). The

combined organic layer was dried by anhydrous MgSO₄and ﬁ ltered,

and the solvent was removed in vacuo to give a yellow oil (9.3 g). The

crude product was puri ﬁ ed by column chromatography using Biotage

(ethyl acetate/triethylamine gradient, 95 −96.5% ethyl acetate); TLC:

silica plate, ethyl acetate/triethylamine 95:5, visualization by UV (254

nm; R_fof product = 0.33) to yield rac -7 as a pale yellow oil (7.9 g,

overall yield from acetophenone = 70%). ¹H NMR (500 MHz,

CDCl₃) δ 7.36 −7.26 (m, 4H), 7.29 −7.24 (m, 1H), 3.64 (q, J = 6.5

Hz, 1H), 2.31 (s, 3H), 1.45 (br s, 1H), 1.35 (d, J = 6.5 Hz, 3H);

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 145.4, 128.4, 126.9, 126.6, 60.3,

34.5, 23.9. The spectral data correspond to those reported in the

literature.⁴³ν_max/cm⁻¹: 3284, 3025, 2787, 1603, 1493, 1475, 1449,

1281, 1222. HRMS (ESI) m/z: [M + H]⁺Calcd for C₉H₁₄N⁺

136.1126; Found 136.47 by LCMS, +ESI-MS [M + H]⁺{lit.⁴³

HRMS (ESI) [M + H]⁺: 136.1120}.

The total process time of the R³process was calculated as the

product of residence time τ_rand number of cycles (eq S1.5).

total process time = T × number of cycles

(1.5)

r

Stock solutions of known concentrations of 7, 8, 10, 11, 6,7-

dimethoxy-1-methyl-3,4-dihydroisoquinoline, acetophenone, and the

internal standards were prepared (Table S2.1). For each calibration

sample, a known volume of the stock solution and internal standard

(50 mM, 20 μL) were diluted into ethyl acetate to make up 1 mL.

The samples were analyzed by achiral GC. The calibration curves

were produced by plotting the peak area ratio of the compounds to

the internal standard against the concentration of the compound

(Figures S2.1 −S2.7).

General Procedure for Continuous Flow Racemization. All

of the racemic and optically active amines used in the study are

known, and methods for their synthesis, along with characterization

data, are described below. Fresh catalyst 1 (ICP 6.3%, 0.32 g, 0.11

mmol of Ir) was used to racemize each optically active amine using

the equipment shown in Supporting Information section 8. The

catalyst was mixed with sand and loaded into an empty stainless

HPLC column (4 mL). The column was placed inside an aluminum

block which was connected to an electrical heater and equilibrated

with the selected solvent. The liquid volume was determined by mass

diﬀerence. A solution of amine (2.1 mmol) in solvent (20 mL) at

room temperature was pumped from a syringe through the heated

column at a speciﬁc ﬂow rate. The eluent was collected from the

second reactor volume onward. When all of the reaction mixture was

pumped, the column was washed with the reaction solvent or iso-

propyl alcohol while cooling to room temperature. Each collected

fraction was sampled and analyzed to determine its e.e. Detail

procedures of sampling and analysis were shown in Supporting

Information section 7. The e.e. at steady state was calculated as the

average from reactor volumes 2−5.

Racemic N-Isopropyl-α-methylbenzylamine, 8.

Synthesis of Catalysts. Catalysts and intermediates 1−5 were

prepared using published procedures.³³

Acetone (250 mL) was added to racemic 1-phenylethylamine (10.0 g,

82.5 mmol), and the mixture was heated to re ﬂ ux using a heating

mantle. After 24 h, the reaction was cooled to room temperature and

the solvent was removed in vacuo to give a yellow oil. Methanol (200

mL) was added, and the solution was cooled on ice. Sodium

borohydride (5.6 g, 148.0 mmol) was added, and the mixture was

stirred on ice for 1.5 h and for a further 2.5 h at room temperature.

The mixture was acidi ﬁ ed by aqueous hydrochloric acid (2 M), and

the solvent was removed in vacuo to give a white solid. Water and

dichloromethane were added, and the mixture was basi ﬁ ed with

aqueous sodium hydroxide (1 M). The layers were separated. The

organic layer was washed with brine and dried with anhydrous

MgSO₄, and the solvent was removed in vacuo to give a yellow oil (8.5

g). The crude product was puri ﬁ ed by column chromatography using

Biotage (ethyl acetate/triethylamine gradient, 96.3 −98.5% ethyl

acetate); TLC: silica plate, ethyl acetate/triethylamine 95:5, visual-

ization by UV (254 nm; R_fof product = 0.49) to yield a pale yellow

oil (7.4 g, 55%). ¹H NMR (500 MHz, CDCl₃) δ 7.34 −7.30 (m, 4H),

7.22 (tt, J = 1.8, 7 Hz, 1H), 3.88 (q, J = 6.5 Hz, 1H), 2.62 (hept, J =

6.2 Hz, 1H), 1.33 (d, J = 6.5 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H), 0.99

(d, J = 6.2 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 146.2,

128.4, 126.7, 126.5, 55.1, 45.5, 24.9, 24.1, 22.2. The spectral data

correspond to those reported in the literature.⁴⁴ν_max/cm⁻¹: 2960,

1602, 1492, 1465, 1451, 1367, 1336. HRMS (ESI) m/z: [M + H]⁺

Calcd for C₁₁H₁₈N⁺[M + H]⁺: 164.1439; Found 164.41 by LCMS,

+ESI-MS [M + H]⁺{lit.⁴⁴HRMS (ESI) [M + H]⁺: 164.1434}.

Synthesis of Amines. Racemic α-methylbenzylamine 6, (S)-α-

methylbenzylamine (S)-6, racemic N,N-dimethyl-α-methylbenzyl-

amine 9, (S)-N,N-dimethyl-α-methylbenzylamine (S)-9, (R)-N,N-

dimethyl-α-methylbenzylamine (R)-9, racemic 2-methylpiperidine 11,

and (S)-2-Methylpiperidine (S)-11 were bought from Sigma-Aldrich

Ltd. (1S,4S)-N-Methyl-4-(3,4-dichloro)phenyl-1-amino-1,2,3,4-tetra-

hydronaphthalene 12 was received as a gift from S.Amit and Co. India

Ltd.

N-Methyl-α-methylbenzylimine.

Acetophenone (10 g, 83.2 mmol) and degassed ethanol (40 mL) were

added to a round-bottom ﬂ ask containing molecular sieves (3 Å, 16 g)

which was purged with nitrogen, followed by the addition of

methylamine solution in ethanol (33% wt, 22 mL). The mixture was

stirred at room temperature for 48 h. The reaction was then ﬁ ltered

through Celite and was washed with dichloromethane. The solvent

was removed in vacuo to give a yellow oil (12.5 g) which contained

1

about 10% acetophenone (by H NMR). The E /Z isomeric ratio of

crude imine was not determined and was used directly in the next step

without further puri ﬁ cation. ¹H NMR (500 MHz, CDCl₃) δ 7.74 (dd,

J = 6.5 and 3.0 Hz, 2H), 7.39 −7.34 (m, 3H), 3.34 (s, 3H), 2.22 (s,

3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 167.1, 141.2, 129.4, 128.2,

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(R)-N-Isopropyl-α-methylbenzylamine, (R)-8.

content was warmed to room temperature and stirred overnight. The

reaction mixture was basi ﬁ ed by aqueous sodium hydroxide (5 M)

and extracted with dichloromethane (4 × 50 mL). The combined

organic layer was dried over anhydrous MgSO₄and ﬁ ltered, and the

solvent was removed in vacuo to yield 6,7-dimethoxy-1-methyl-3,4-

dihydroisoquinoline as an orange solid (5.4 g, 97%). The product was

used in the next step without puri ﬁ cation. Mp = 103 −105 °C {lit.⁴⁶

mp 108−109 °C}; ¹H NMR (500 MHz, CDCl₃) δ 6.99 (s, 1H), 6.69

(s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.63 (dt, J = 7.5 and 1.4 Hz, 2H),

2.64 (t, J = 7.5, 2H), 2.36 (t, J = 1.4 Hz, 3H); ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 163.1, 150.4, 147.0, 130.7, 122.0, 109.8, 108.6, 55.8,

55.5, 46.6, 25.3, 22.9. ν_max/cm⁻¹: 2941, 2924, 2837, 1625, 1603, 1571,

1512, 1286, 1272, 1211. The spectral data correspond to those

reported in the literature.⁴⁶HRMS (ESI) m/z: [M + H]⁺Calcd for

The same procedures as the synthesis of rac -8 were applied to

synthesize (R )-8 using (R )-1-phenylethylamine (2 g, 16.5 mmol).

Yield = 1.8 g (68%); ee = 100% (by chiral GC after derivatization

with tri ﬂ uoroacetic anhydride). [α ]_D²³= +56.1° (c 0.52, chloroform);

the ¹H and ¹³C NMR, IR, and MS data correspond to those reported

for the racemate.

(S)-N-Isopropyl-α-methylbenzylamine, (S)-8.

+

C₁₂H₁₆NO₂206.1181; Found 206.0 by LCMS, ESI-MS [M + H]⁺

{lit.⁴⁶HRMS [M⁺]: 205.1102}.

Racemic 6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquino-

line, 10.⁴⁶

The same procedures as the synthesis of rac -8 were applied to

synthesize (S )-8 using (S )-1-phenylethylamine (1 g, 8.3 mmol). Yield

= 0.64 g (48%); ee = 98% (by chiral GC after derivatization with

6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline (4.3 g, 21.0 mmol)

was dissolved into methanol (70 mL) and was cooled to 0 °C.

Sodium borohydride (4.0 g, 105.5 mmol) was added slowly in

portions over 20 min. The reaction mixture was stirred at room

temperature overnight. The reaction mixture was acidi ﬁ ed by aqueous

hydrochloric acid (1 M) and then concentrated in vacuo . The white

solid obtained was basi ﬁ ed with aqueous sodium hydroxide (1 M)

and extracted with dichloromethane (3 × 100 mL). The combined

organic layer was washed with brine (1 × 50 mL), dried over

anhydrous MgSO₄, and ﬁ ltered, and the solvent was removed in vacuo

to yield a light brown oil. The crude product was puri ﬁ ed by column

chromatography using Biotage (ethyl acetate/triethylamine gradient,

95 −96.5% ethyl acetate); TLC: silica plate, ethyl acetate/triethyl-

amine 95:5, visualization by UV (254 nm; R_fof product = 0.15) to

yield rac -10 as a pale yellow oil. O ﬀ -white solid was formed overnight

(3.7 g, 84%). Mp = 35 −38 °C {lit.⁴⁶mp 48−49 °C}; ¹H NMR (500

MHz, CDCl₃) δ 6.63 (s, 1H), 6.57 (s, 1H), 4.05 (q, J = 6.7 Hz, 1H),

3.85 (s, 3H), 3.84 (s, 3H), 3.25 (dt, J = 13.0 and 5.2 Hz, 1H), 3.00

(ddd, J = 13.0, 8.8, and 4.9 Hz, 1H), 2.79 (ddd, J = 15.9, 8.8, and 5.2

Hz, 1H), 2.65 (dt, J = 15.9 and 4.9 Hz, 1H), 1.82, (br s, 1H), 1.44 (d,

J = 6.7 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 147.3, 147.2,

23

tri ﬂ uoroacetic anhydride). [α ]_D= −61.9 ° (c 0.40, chloroform); the

¹H and ¹³C NMR, IR, and MS data correspond to those reported for

the racemate.

N-(3,4-Dimethoxyphenethyl)acetamide.⁴⁵

3,4-Dimethoxyphenethylamine (97%, 9.9 g, 53.1 mmol) was charged

to a mixture of dichloromethane (50 mL) and triethylamine (12 mL,

86.3 mmol), and the mixture was cooled to 0 °C. With stirring, acetyl

chloride (5 mL, 70.3 mmol) was charged dropwise to the reaction

mixture over 0.5 h. The pH was checked to ensure the reaction

mixture stayed basic. The reaction mixture was warmed to room

temperature and stirred overnight. The content was then poured into

ice-cold water and was acidi ﬁ ed by aqueous hydrochloric acid (1 M).

The organic and aqueous layers were separated, and the aqueous layer

was further extracted with dichloromethane (3 × 50 mL). The

combined organic layer was washed with water (100 mL), dried by

anhydrous MgSO₄, and ﬁ ltered. The solvent was removed in vacuo to

yield a pale yellow solid (12.1 g). The product was recrystallized in

hexane/ethyl acetate 1:1 to yield the acetamide product as o ﬀ -white

crystals (9.2 g, 78%). Mp 98 −100 °C {lit.⁴⁵100−101 °C}; ¹H NMR

(500 MHz, CDCl₃) δ 6.82 (d, J = 8.0 Hz, 1H), 6.74−6.71 (m, 2H),

5.43 (br s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.50 (q, J = 7.0 Hz, 2H),

2.76 (t, J = 7.0 Hz, 2H), 1.95 (s, 3H); ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 170.0, 149.1, 147.8, 131.4, 120.6, 111.9, 111.4, 56.0, 55.9,

40.8, 35.2, 23.4. ν_max/cm⁻¹: 3249, 3078, 2992, 2928, 2839, 1632,

1563, 1515, 1471, 1261, 1233. The spectral data correspond to those

reported in the literature.^45,46HRMS (ESI) m/z: [M + H]⁺Calcd for

132.6, 126.9, 111.8, 109.1, 56.0, 55.9, 51.3, 41.9, 29.6, 22.9. ν_max

/

cm⁻¹: 3311, 2931, 2831, 1609, 1509, 1462, 1404, 1253, 1220. The

spectral data correspond to those reported in the literature.⁴⁸HRMS

(ESI) m/z: [M + H]⁺Calcd for C₁₂H₁₈NO₂⁺208.1338; Found 208.0

by LCMS, +ESI-MS [M + H]⁺{lit.⁴⁸HRMS [M⁺]: 207.1258}.

(S)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline, (S)-

10.⁴⁹

+

C₁₂H₁₈NO₃224.1287; Found 224.0 by LCMS, +ESI-MS [M + H]⁺

{lit.⁴⁵+ESI-MS [M + H]⁺: 224.37}.

Formic acid (7.2 mL) was added to acetonitrile (20 mL) under

nitrogen and stirred at 0 °C. Triethylamine (10.6 mL) was added

slowly to maintain the temperature at below 10 °C. After the addition

was complete, the reaction mixture was warmed to room temperature.

Ru(p -cymene)(R ,R -TsDPEN) (0.2 g, 0.3 mmol) was dissolved in

acetonitrile (25 mL) and added to the formic acid −triethylamine

mixture. The content was stirred for 15 min. A solution of 6,7-

dimethoxy-1-methyl-3,4-dihydroisoquinoline (6.2 g, 30.3 mmol) in

acetonitrile (35 mL) was charged to the reaction mixture and was

warmed to 30 °C using a heating mantle. The reaction was stirred

overnight. After the reaction was complete, the reaction mixture was

cooled to room temperature and concentrated in vacuo . The residue

was acidi ﬁ ed with aqueous hydrochloric acid (2 M) and washed with

toluene (2 × 20 mL). The aqueous layer was basi ﬁ ed with aqueous

sodium hydroxide (5 M) and was extracted with dichloromethane (3

6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline.⁴⁷

The acetamide from stage 1 (6.0 g, 27.0 mmol) was added to toluene

(30 mL, dried over 4 Å molecular sieve, 1 −2 mm beads) in a round-

bottom ﬂ ask ﬁ tted with an air condenser and calcium chloride drying

tube. The mixture was warmed to 40 °C using a heating mantle.

Phosphoryl chloride (6 mL, 64.4 mmol) was charged dropwise into

the mixture over 20 min. When the addition was complete, the

mixture was heated to re ﬂ ux for 3 h using a heating mantle. The

reaction mixture was then cooled to 0 °C for 2 h. The mixture was

decanted, and water was charged to the remaining solid at 0 °C. The

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× 50 mL). The combined organic layer was dried with anhydrous

MgSO₄and ﬁ ltered, and the solvent was removed in vacuo to give a

dark brown oil (ee = 100% by chiral HPLC). The crude product was

puri ﬁ ed by column chromatography using Biotage (ethyl acetate/

triethylamine gradient, 95 −96.5% ethyl acetate); TLC: silica plate,

ethyl acetate/triethylamine 95:5, visualization by UV (254 nm; R_fof

product = 0.15) to yield (S )-10 as a pale brown oil (5.4 g, 88%).

(S)-N-Methyl-α-methylbenzylammonium Di-p-toluoyl-^D-tar-

trate, [(S)-7]₂-(S,S)-DTTA.

[α ]_D= −54.4 ° (c 1.10, ethanol) {lit.⁴⁸[α]_D= −41.3° (c 1.10,

ethanol)}. The spectral and MS data correspond to those reported for

rac-10 and in the literature.^48,50

23

20

to prepare [(S )-7 ]₂-(S ,S )-DTTA . Using (S )-7 (50.2 mg, 0.37 mmol),

a white solid was obtained (0.1 g, 80%) with 100% d.e. (by ¹H NMR

in d₆-DMSO, 500 MHz). Mp = 179−182 °C; [α ]_D²⁰= +69.3° (c 0.12,

MeOH); ¹H NMR (500 MHz, d₆-DMSO) δ 7.90 (d, J = 8.5 Hz, 4H),

7.41 (dd, J = 7.0 and 1.5 Hz, 4H), 7.32 (m, 10H), 5.66 (s, 2H), 3.99

(q, J = 6.8 Hz, 2H), 2.38 (s, 6H), 2.20 (s, 6H), 1.38 (d, J = 6.8 Hz,

6H); ¹³C{¹H} NMR (126 MHz, d₆-DMSO) δ 169.1, 165.0, 143.2,

139.6, 129.3, 129.0, 128.6, 128.0, 127.6, 127.3, 73.6, 58.0, 31.0, 21.1,

20.5. ν_max/cm⁻¹: 3017, 2870, 1712, 1637, 1612, 1594, 1455, 1371,

1337, 1268. HRMS (ESI) m /z : [M + Y ]⁺Calcd for C₉H₁₄N⁺

136.1126; Found 136.1118; HRMS (ESI) m /z : [M − 2 X + H]⁻

(R)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline, (R)-

10.

10 with Ru(p -cymene)(S ,S -TsDPEN). Toluene was used instead of

dichloromethane in the extraction of product from the aqueous layer

during workup. A pale brown oil (5.7 g, 94%) was obtained with an ee

−

of 96% (by chiral HPLC). [α ]_D= +52.3° (c 1.13, ethanol) {lit.⁴⁸

23

Calcd for C₂₀H₁₇O₈385.0923; Found 385.0919.

20

(R)-N-Methyl-α-methylbenzylammonium-(S)-mandelate, (R)-7-

(S)-MA.

[α]_D= +59.7° (c 1.10, ethanol)}. The spectral and MS data

correspond to those reported for rac-10.

(R)-2-Methylpiperidine, (R)-11.

(R )-11-(S )-MA (0.25 g, 0.99 mmol) was dissolved into aqueous

ammonia solution (10%, 10 mL) and was extracted with dichloro-

methane (20 mL). The mixture was separated, and the aqueous layer

was further extracted with dichloromethane (2 × 10 mL). The

combined organic layer was dried with anhydrous MgSO₄and ﬁ ltered,

and the solvent was removed in vacuo to yield a pale yellow oil (0.063

g, 63%) with an ee of 100% (by chiral GC after derivatization with

(S )-MA (0.11 g, 0.74 mmol) was dissolved into ethyl isobutyrate (2

mL), and the solution was added to (R )-7 (0.10 g, 0.74 mmol). The

slurry was heated to re ﬂ ux until all solid dissolved. The mixture was

cooled to room temperature with reduced stirring and was ﬁ ltered to

give a white solid which was dried in air overnight (0.17 g, 82%) with

d.e. = 100% (by ¹H NMR in CDCl₃₁, 500 MHz). Mp = 109−111 °C;

51

20

22

acetic anhydride). [α ]_D= −3.65 ° (c 2.0, methanol) {lit. [α]_D

=

23

[α ]_D= +62.3° (c 0.49, MeOH); H NMR (500 MHz, CDCl₃) δ

−8.5° (c 0.5, methanol)}; ¹H NMR (500 MHz, CDCl₃) δ 3.09−3.01

(m, 1H), 2.64 (td, J = 11.8 and 3.0 Hz, 1H), 2.61−2.55 (m, 1H),

1.80−1.72 (m, 1H), 1.62−1.52 (m, 3H), 1.44−1.28 (m, 2H), 1.12−

0.99 (m, 4H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 52.3, 47.1, 34.6,

26.1, 24.3, 23.0. The spectral data correspond to those reported in the

literature for rac-11. ν_max/cm⁻¹: 3270, 2925, 2854, 2795, 1441, 1375,

1325, 1306. HRMS (ESI) m/z: [M + H]⁺Calcd for C₆H₁₄N⁺

100.1126; Found 100.58 by LCMS, +ESI-MS/MS [M + H]⁺{lit.⁵²

LCMS [M + H]⁺: 100.1}.

7.48 (d, J = 7.5 Hz, 2H), 7.32 (m, 5H), 7.24 (m, 3H), 4.91 (s, 1H),

3.68 (q, J = 6.9 Hz, 1H), 1.99 (s, 3H), 1.46 (d, J = 6.9 Hz, 3H);

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 178.5, 142.6, 136.3, 129.2,

129.1, 128.1, 127.6, 127.3, 126.8, 74.6, 59.1, 30.2, 19.5. ν_max/cm⁻¹:

3029, 2698, 2460, 1622, 1556, 1509, 1491, 1453, 1363, 1330, 1302,

1273. HRMS (ESI) m /z : [M − Y ]⁺Calcd for C₉H₁₄N⁺136.1126;

Found 136.1118. HRMS (ESI) m /z : [M − X ]⁻Calcd for C₈H₇O₃

151.0395; Found 151.0397.

(S)-N-Methyl-α-methylbenzylammonium-(S)-mandelate, (S)-7-

(S)-MA.

Synthesis of Diastereomeric Salts. (R)-N-Methyl-α-methyl-

benzylammonium Di-p-toluoyl-^D-tartrate, [(R)-7]₂-(S,S)-DTTA.

(S )-MA (0.11 g, 0.74 mmol) was dissolved into ethyl isobutyrate (1

mL), and the solution was added to (S )-7 (0.10 g, 0.74 mmol). The

mixture was stirred overnight at room temperature for solid to

precipitate, which was then heated to re ﬂ ux. After all solid dissolved,

the mixture was cooled to room temperature with reduced stirring

overnight. The slurry was ﬁ ltered, and the solid collected was dried in

air overnight (0.14 g, 67%) with d.e. = 100% (by ¹H NMR in CDCl₃,

500 MHz). Mp = 93 −94 °C; [α ]_D= +37.5° (c 0.50, MeOH); H

NMR (500 MHz, CDCl₃) δ 7.44 (m, 2H), 7.36 (m, 3H), 7.27 (m,

5H), 4.89 (s, 1H), 3.42 (q, J = 6.8 Hz, 1H), 2.00 (s, 3H), 1.37 (d, J =

6.8 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 178.5, 142.5,

136.5, 129.2, 129.1, 128.1, 127.6, 127.2, 126.8, 74.6, 59.0, 30.3, 19.9.

ν_max/cm⁻¹: 3301, 2706, 2465, 1623, 1578, 1451, 1380, 1359, 1330,

1314, 1279, 1220. HRMS (ESI) m /z : [M − Y ]⁺Calcd for C₉H₁₄N⁺

136.1126; Found 136.1114. HRMS (ESI) m /z : [M − X ]⁻Calcd for

C₈H₇O₃151.0395; Found 151.0398.

(S ,S )-DTTA (72.5 mg, 0.19 mmol) was dissolved into ethyl acetate/

methanol 10:1 (2.9 mL) and was added to (R )-7 (50.7 mg, 0.38

mmol). The mixture was stirred at room temperature for 1 h and then

ﬁ ltered. The solid was dried in air to obtain a white solid (0.1 g, 80%)

1

with 100% d.e. (by H NMR in d₆-DMSO, 500 MHz). Mp = 160−

163 °C; [α ]_D²⁰= +102.2° (c 0.11, MeOH); ¹H NMR (500 MHz, d₆-

DMSO) δ 7.86 (d, J = 8.0 Hz, 4H), 7.35 (m, 14H), 5.63 (s, 2H), 3.95

(q, J = 6.8 Hz, 2H), 2.37 (s, 6H), 2.23 (s, 6H), 1.35 (d, J = 6.8 Hz,

6H); ¹³C{¹H} NMR (126 MHz, d₆-DMSO) δ 169.6, 165.1, 143.1,

139.1, 129.3, 129.0, 128.6, 128.1, 127.8, 127.4, 74.3, 57.9, 30.7, 21.1,

20.1. ν_max/cm⁻¹: 3016, 2878, 1714, 1633, 1611, 1566, 1455, 1371,

1329, 1265. HRMS (ESI) m /z : [M + Y ]⁺Calcd for C₉H₁₄N⁺

136.1126; Found 136.1117. HRMS (ESI) m /z : [M − X − Y ]⁻

23

1

−

Calcd for C₂₀H₁₇O₈385.0923; Found 385.0913.

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(R)-N-Isopropyl-1-phenylethylammonium-(S)-mandelate, (R)-8-

(S)-MA.

(1 mL). The organic layer was dried with anhydrous MgSO₄and

ﬁ ltered through a plug of Celite. A solution of (S )-MA in methanol

(21 mg mL⁻¹, 100 μ L) was added, and the mixture was sonicated and

then dried in vacuo . The residue was analyzed by ¹H NMR (500 MHz,

d₆-DMSO) δ 7.83 (d, J = 8.0 Hz, 4H), 7.45 −7.39 (m, 2H), 7.39 −7.34

(m, 3H), 7.31 (d, J = 8.0 Hz, 4H), 5.67 (s, 2H), 4.10 (br d, J = 7.3 Hz,

1H), 2.44 (s, 6H), 2.35 (s, 6H), 1.45 (d, J = 7.3 Hz, 3H); ¹³C{¹H}

NMR (75 MHz, d₆-DMSO) δ 168.1, 164.8, 143.8, 136.7, 129.3,

129.3, 129.1, 128.8, 128.7, 128.5, 126.7, 72.0, 64.4, 21.2, 16.8. ν_max

/

(S )-MA (0.094 g, 0.62 mmol) and (R )-8 (0.1 g, 0.62 mmol) were

dissolved in isopropyl acetate (1.5 and 0.5 mL, respectively). The two

solutions were mixed, and more isopropyl acetate (8 mL) was added.

The mixture was heated to re ﬂ ux using a heating mantle. Isopropanol

was added until all solid dissolved. The mixture was then cooled to

room temperature with reduced stirring and was ﬁ ltered to give a

white ﬂ u ﬀ y solid (0.14 g, 74%) with 100% d.e. (by ¹H NMR in

cm⁻¹: 2984, 2731, 1719, 1680, 1610, 1456, 1406, 1388, 1338, 1265,

1252, 1232. HRMS (ESI) m /z : [M − Y ]⁺Calcd for C₁₀H₁₅N⁺

150.1283; Found 150.1249. HRMS (ESI) m /z : [M − X ]⁻Calcd for

−

C₂₀H₁₇O₈385.0923; Found 385.0828.

(S)-N,N-Dimethyl-α-methylbenzylammonium Di-p-toluoyl-^D-tar-

trate, [(S)-9]-(S,S)-DTTA.

23

CDCl₃, 500 MHz). Mp = 169−174 °C; [α ]_D= +61.5° (c 0.39,

methanol); ¹H NMR (500 MHz, CDCl₃) δ 7.52 (d, J = 7.5 Hz, 2H),

7.32 (m, 7H), 7.22 (t, J = 7.5 Hz, 1H), 4.94 (s, 1H), 3.99 (q, J = 6.7

Hz, 1H), 2.72 (hept, J = 6.4 Hz, 1H), 1.46 (d, J = 6.5 Hz, 3H), 1.12

(d, J = 6.5 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H); ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 177.2, 142.4, 136.9, 129.1, 128.8, 128.0, 127.7, 127.1,

126.7, 74.7, 55.5, 47.2, 20.6, 19.9, 17.6. ν_max/cm⁻¹: 3040, 2866, 2679,

2461, 1617, 1568, 1518, 1490, 1446, 1364, 1329, 1265, 1217. HRMS

(ESI) m /z : [M + Y ]⁺Calcd for C₁₁H₁₈N⁺164.1439; Found

DTTA . After more isopropyl acetate was added to the hot solution of

(S )-9 /(S ,S )-DTTA , isopropyl alcohol (8 mL) was added for the

complete dissolution of the precipitate. (S )-9 -(S ,S)-DTTA was

isolated as a white crystalline solid (0.26 g, 73%) with d.e. = 100%

(determined as the ee of 9 ). Mp = 140 −141 °C; [α ]_D²⁰= +200.2° (c

−

164.1429; HRMS (ESI) m /z : [M − X ]⁻Calcd for C₈H₇O₃

151.0395; Found 151.0391.

(S)-N-Isopropyl-1-phenylethylammonium-(S)-mandelate, (S)-8-

(S)-MA.

1

0.5, methanol); H NMR (500 MHz, d₆-DMSO) δ 7.84 (d, J = 8.0

Hz, 4H), 7.45 −7.39 (m, 2H), 7.35 (t, J = 3.3 Hz, 3H), 7.31 (d, J = 8.0

Hz, 4H), 5.68 (s, 2H), 4.13 (q, J = 6.7 Hz, 1H), 2.43 (s, 6H), 2.36 (s,

6H), 1.47 (d, J = 6.7 Hz, 3H); ¹³C{¹H} NMR (75 MHz, d₆-DMSO) δ

168.0, 164.8, 143.8, 136.8, 129.3, 129.2, 129.1, 128.8, 128.6, 128.5,

126.7, 71.9, 64.3, 21.2, 16.8. ν_max/cm⁻¹: 2955, 2701, 1719, 1681,

1611, 1458, 1408, 1325, 1251. HRMS (ESI) m /z : [M − Y ]⁺Calcd for

C₁₀H₁₅N⁺150.1283; Found 150.1248. HRMS (ESI) m /z : [M − X ]⁻

(S )-MA (0.093 g, 0.61 mmol) and (S )-8 (0.1 g, 0.61 mmol) were

dissolved in isopropyl acetate (1.5 and 0.5 mL, respectively) at room

temperature. The two solutions were mixed and the solvent

evaporated in vacuo to give a thick oil which solidi ﬁ ed upon standing

−

Calcd for C₂₀H₁₇O₈385.0923; Found 385.0818.

(R)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolinium-

(S)-mandelate, (R)-10-(S)-MA.

1

(0.17 g, 90%); 100% d.e. (by H NMR in CDCl₃, 500 MHz). Mp =

23

97 −102 °C; [α ]_D= +36.2° (c 0.51, methanol); ¹H NMR (500

MHz, CDCl₃) δ 7.47 (d, J = 6.9 Hz, 2H), 7.40 (m, 5H), 7.27 (m,

3H), 4.97 (s, 1H), 3.70 (q, J = 6.8 Hz, 1H), 2.69 (m, 1H), 1.33 (d, J =

6.5 Hz, 3H), 1.09 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H);

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 177.3, 141.9, 136.8, 129.2,

128.9, 128.0, 127.6, 127.3, 126.7, 74.4, 55.4, 47.3, 20.7, 19.7, 17.7.

ν_max/cm⁻¹: 3385, 2985, 2716, 2514, 1709, 1625, 1596, 1454, 1390,

1357, 1276, 1214. HRMS (ESI) m /z : [M − Y ]⁺Calcd for C₁₁H₁₈N⁺

164.1439; Found 164.1429; HRMS (ESI) m /z : [M − X ]⁻Calcd for

A solution of (S )-MA (0.3 g, 1.9 mmol) in ethyl acetate/methanol 7:1

(2 mL) was added to a solution of (R )-10 (0.4 g, 1.9 mmol) in ethyl

acetate/methanol 7:1 (2 mL). The mixture was heated to re ﬂ ux using

a heating mantle. More ethyl acetate/methanol 7:1 was added until all

of the solids dissolved. The stirring was stopped and the heat switched

o ﬀ , allowing the mixture to cool to room temperature. The slurry was

ﬁ ltered to give an o ﬀ -white crystalline solid (0.4 g, 47%) with 100%

−

C₈H₇O₃151.0395; Found 151.0395.

(R)-N,N-Dimethyl-α-methylbenzylammonium Di-p-toluoyl-^D-

tartrate, [(R)-9]-(S,S)-DTTA.

1

d.e. (by H NMR in CDCl₃, 500 MHz). The resolution results are

shown in Supporting Information Table S7.1. Mp = 172−174 °C;

[α]_D²³= +66.3° (c 1.10, chloroform); ¹H NMR (500 MHz, CDCl₃) δ

7.31−7.23 (m, 2H), 7.20−7.15 (m, 3H), 6.55 (s, 1H), 6.48 (s, 1H),

4.74 (s, 1H), 4.17 (q, J = 6.6 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H),

3.24−3.13 (m, 1H), 2.95−2.84 (m, 2H), 2.79−2.68 (m, 1H), 1.41 (d,

J = 6.6 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 178.8, 148.6,

148.3, 142.1, 127.9, 127.0, 126.4, 125.7, 123.6, 111.3, 108.7, 74.4,

56.1, 56.0, 50.3, 38.9, 25.3, 19.6. ν_max/cm⁻¹: 3188, 3061, 2832, 2757,

2656, 2573, 2525, 2493, 1582, 1518, 1366, 1244, 1211. HRMS (ESI)

(S ,S )-DTTA (0.26 g, 0.67 mmol) and (R )-9 (99.7 mg, 0.67 mmol)

were dissolved into isopropyl acetate (3 and 2 mL, respectively). The

two solutions were mixed, stirred, and heated to re ﬂ ux using a heating

mantle. More isopropyl acetate (9 mL) was added until all solid

dissolved. Stirring was stopped. The reaction mixture was cooled to

room temperature and ﬁ ltered to give a white crystalline solid (0.24 g,

67%). A small amount of crystals was dissolved into aqueous sodium

carbonate solution (10% w/v, 1 mL) and extracted with ethyl acetate

+

m/z: [M − Y]⁺Calcd for C₁₂H₁₈NO₂208.1337; Found 208.53 by

LCMS, ESI-MS/MS. HRMS (ESI) m/z: [M − X]⁻Calcd for

−

C₈H₇O₃151.0395; Found 150.87 by LCMS, ESI-MS/MS.

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1

(S)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolinium-

(S)-mandelate, (S)-10-(S)-MA.

CHCl₃); H NMR (500 MHz, CDCl₃) δ 7.46 (d, J = 7.6 Hz, 2H),

7.28 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 4.87 (s, 1H), 3.05

(d, J = 12.5 Hz, 1H), 2.50 (td, J = 12.5 and 3 Hz, 1H), 2.44 −2.34 (m,

1H), 1.66 (d, J = 10.5 Hz, 1H), 1.58 (d, J = 14.5 Hz, 1H), 1.51 (d, J =

14.0 Hz, 1H), 1.39 −1.16 (m, 3H), 1.04 (d, J = 6.5 Hz, 3H); ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 178.3, 142.6, 128.0, 127.0, 126.6, 74.4,

52.1, 44.0, 30.4, 22.5, 21.7, 19.1. ν_max/cm⁻¹: 3184, 2695, 2582, 2541,

1627, 1574, 1497, 1449, 1382, 1337, 1213. HRMS (ESI) m /z : [M −

Y ]⁺Calcd for C₆H₁₄N⁺100.1126; Found 100.27 by LCMS, ESI-MS/

MA . Ethyl acetate/methanol 15:1 was used as the solvent mixture.

(S )-10 -(S )-MA was isolated as an o ﬀ -white crystalline solid (0.2 g,

32%) with 100% d.e. (by ¹H NMR in CDCl₃, 500 MHz). Mp = 163−

−

MS. HRMS (ESI) m /z : [M − X ]⁻Calcd for C₈H₇O₃151.0395;

Found 150.97 by LCMS, ESI-MS/MS.

Triethylammonium (S)-Mandelate.

23

1

166 °C; [α ]_D= +39.6° (c 1.10, chloroform); H NMR (500 MHz,

CDCl₃) δ 7.31 (d, J = 7.0 Hz, 2H), 7.24 −7.14 (m, 3H), 6.53 (s, 1H),

6.47 (s, 1H), 4.77 (s, 1H), 3.98 (q, J = 6.6 Hz, 1H), 3.87 (s, 3H), 3.86

(s, 3H), 3.16 (dt, J = 12.5 and 5.5 Hz, 1H), 2.98 (ddd, J = 12.5, 8.0,

and 5.5 Hz, 1H), 2.85 −2.76 (m, 1H), 2.72 (dt, J = 17.0 and 5.5 Hz,

1H), 1.45 (d, J = 6.6 Hz, 3H); ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

178.8, 148.6, 148.3, 142.2, 128.0, 127.0, 126.5, 125.6, 123.6, 111.3,

108.7, 74.4, 56.1, 55.9, 50.3, 39.0, 25.2, 19.8. ν_max/cm⁻¹: 3410, 3001,

2836, 2580, 2533, 2410, 1577, 1512, 1360, 1257, 1218. HRMS (ESI)

(S )-MA (0.3 g, 2.0 mmol) was dissolved in ethyl acetate (5 mL) and

was added to a solution of triethylamine (0.7 mL, 5.0 mmol) in ethyl

acetate (5 mL). The mixture was stirred at room temperature for 3 h.

The solvent was removed in vacuo to yield the crude product as a

colorless oil (0.47 g, 94%) which was used without further

+

m /z : [M − Y ]⁺Calcd for C₁₂H₁₈NO₂208.1338; Found 208.06 by

LCMS, ESI-MS/MS. HRMS (ESI) m /z : [M − X ]⁻Calcd for

20

puri ﬁ cation. [α ]_D= +62.1° (c 1.0, methanol); ¹H NMR (500

−

C₈H₇O₃151.0395; Found 151.03 by LCMS, ESI-MS/MS.

MHz, d₆-DMSO) δ 7.39 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.3 Hz, 2H),

7.22 (t, J = 7.3 Hz, 1H), 4.71 (s, 1H), 2.93 (q, J = 7.3 Hz, 4H), 1.10

(t, J = 7.3 Hz, 6H); ¹³C{¹H} NMR (126 MHz, d₆-DMSO) δ 174.7,

142.5, 127.6, 126.5, 126.4, 73.1, 45.1, 8.8. ν_max/cm⁻¹: 3324, 2984,

2431, 1732, 1599, 1494, 1478, 1452, 1339. HRMS (ESI) m /z : [M −

Y ]⁺Calcd for C₆H₁₆N⁺102.1283; Found 102.63 by LCMS, ESI-MS/

(R)-2-Methylpiperidinium-(S)-mandelate, (R)-11-(S)-MA.

−

MS. HRMS (ESI) m /z : [M − X ]⁻Calcd for C₈H₇O₃151.0395;

Found 150.84 by LCMS, ESI-MS/MS.

Triethylammonium Phenylglyoxylate.

(S )-MA (2.3 g, 15.1 mmol) was added to a solution of rac-11 (1.5 g,

15.1 mmol) in tert -butyl methyl ether/methanol 24:1 (20 mL). The

mixture was heated to re ﬂ ux using a heating mantle. More of the tert -

butyl methyl ether/methanol mixture was added until all solid

dissolved. The mixture was cooled to room temperature and stirred

overnight. The slurry was ﬁ ltered to yield a white solid which was

recrystallized from the same solvent mixture to give a white crystalline

solid (0.7 g, 19%) with 100% d.e. (by ¹H NMR in CDCl₃, 500 MHz).

Phenylglyoxylic acid (0.15 g, 1.0 mmol) was dissolved in ethyl acetate

(3 mL) and was added to a solution of trimethylamine (0.35 mL, 2.5

mmol) in ethyl acetate (2 mL). The pale yellow mixture was stirred at

room temperature overnight. The solvent was removed in vacuo to

Mp = 119 −122 °C {lit.⁵³mp 119 °C}; [α]_D= +76.3° (c 1.0,

20

chloroform) {lit.⁵³[α]_D= +78.0° (c 1.0, chloroform)}; H NMR

(500 MHz, CDCl₃) δ 7.46 (d, J = 7.3 Hz, 2H), 7.28 (t, J = 7.3 Hz,

2H), 7.21 (t, J = 7.3 Hz, 1H), 4.86 (s, 1H), 2.98 (d, J = 12.5 Hz, 1H),

2.70−2.64 (m, 1H), 2.25−2.20 (m, 1H), 1.69 (d, J = 13.5 Hz, 1H),

1.57−1.51 (m, 3H), 1.29−1.19 (m, 1H), 1.16−1.09 (m, 4H);

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 178.3, 142.6, 128.0, 127.0,

126.6, 74.5, 52.3, 43.8, 30.2, 22.5, 21.8, 19.1. ν_max/cm⁻¹: 3153, 2696,

2590, 2544, 1593, 1491, 1477, 1444, 1381, 1267. The spectral data

correspond to those reported in the literature.⁵³HRMS (ESI) m/z:

[M − Y]⁺Calcd for C₆H₁₄N⁺100.112624; Found 100.27 by LCMS,

ESI-MS/MS; {lit.⁵³HRMS [M − Y]⁺: 100.1125}; HRMS (ESI) m/z:

22

1

yield the crude product as a thick pale yellow oil (0.24 g, 95%). H

NMR (500 MHz, d₆-DMSO) δ 7.95 −4.85 (m, 2H), 7.62 (tt, J = 7.3

and 1.5 Hz, 1H), 7.58 −7.46 (m, 2H), 3.10 (q, J = 7.4 Hz, 6H), 1.21

(t, J = 7.4 Hz, 9H); ¹³C{¹H} NMR (126 MHz, d₆-DMSO) δ 195.1,

169.6, 134.1, 133.0, 128.9, 128.5, 45.4, 8.5. ν_max/cm⁻¹: 2987, 2639,

2489, 1676, 1594, 1475, 1450, 1398, 1311, 1224. HRMS (ESI) m /z :

[M − Y ]⁺Calcd for C₆H₁₆N⁺102.1283; Found 102.35 by LCMS,

ESI-MS/MS. HRMS (ESI) m /z : [M − X ]⁻Calcd for C₈H₅O₃

−

149.0239; Found 148.92 by LCMS, ESI-MS/MS.

Resolution−Racemization−Recycle Process. The experimen-

tal setup is shown in Supporting Information Figures S8.1 and S8.2.

The 50 mL magnetically stirred crystallizer, used at ambient

temperature, was ﬁtted with an in-line sintered glass ﬁlter, suitable

to retain the crystals and allow the separation from the mother

liquors. A PTFE lid with inlet and outlet tubes was tightly ﬁtted to

prevent solvent evaporation. The mother liquors were pumped

through the heated racemization column using a Jasco pump and

recirculated back to the crystallizer. The parameters used for each of

the R³processes are shown in Supporting Information Tables S8.1 −

S8.12. The diastereomeric salts were made by dissolving the racemic

amine and resolving acid in the chosen solvent at a supersaturating

concentration to cause precipitation. Otherwise, reactions were

seeded with the pure diastereomeric salt (5% w/w). An initial sample

was taken (150 μL) and prepared for analysis by ﬁltering the mother

liquor and diluting in ethyl acetate (2850 μL) and basiﬁed by aqueous

Na₂CO₃(10% w/w, 3 mL); the organic layer was dried with MgSO₄

and ﬁltered through a plug of Celite. The crystals collected from each

−

[M − X]⁻Calcd for C₈H₇O₃151.0395; Found 151.02 by LCMS,

ESI-MS/MS.

(S)-2-Methylpiperidinium-(S)-mandelate, (S)-11-(S)-MA.

Solutions of (S )-11 (0.50 g, 5.0 mmol) in tert -butyl methyl ether (10

mL) and (S )-MA (0.77 g, 5.0 mmol) in the same solvent (10 mL)

were mixed, and the slurry was heated to re ﬂ ux using a heating

mantle. More tert -butyl methyl ether was added (20 mL) followed by

methanol until all solid dissolved. The reaction was cooled to room

temperature with reduced stirring. After 2 h, the mixture was ﬁ ltered

1

to give a white ﬂ u ﬀ y solid (1.0 g, 81%) with 100% d.e. (by H NMR

20

in CDCl₃, 500 MHz). Mp = 92−95 °C; [α ]_D= +63.9° (c 1.0,

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sample were dissolved in dichloromethane, dried in vacuo, and

analyzed by ¹H NMR (CDCl₃, 500 MHz). The pump was started, and

samples were taken as described after each complete recirculation of

the system volume, for the designated number of cycles. The activity

of the catalyst was determined at the end of the reaction by pumping

the optically active amine through the heated ﬁxed bed for 3−4

reactor volumes (i.e., steady state) (Supporting Information section

9).

ACKNOWLEDGMENTS

■

We gratefully acknowledge AstraZeneca and EPSRC for the

ﬁnancial support of M.H.T.K. and N.P.B.P. through CASE

awards EP/L50550X/1 and NP EP/R51200X1, respectively.

J.B. thanks Innovate UK, EPSRC, AstraZeneca, Syngenta,

Pﬁzer, Dr Reddys, and ApexMolecular for support and

collaboration under grant EP/K504154/1.

ASSOCIATED CONTENT

DEDICATION

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.0c02617.

This paper is dedicated to the memory of Prof. Takao Ikariya.

REFERENCES

■

(1) Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M.; Bruggink, A.;

Zwanenburg, B. Controlled racemization of optically active organic

compounds: Prospects for asymmetric transformation. Tetrahedron

1997, 53 (28), 9417−9476.

(2) Nugent, T. C. Chiral amine synthesis: methods, developments and

applications; Wiley-VCH: Weinheim, Germany, 2010.

(3) Li, W.; Zhang, X. Stereoselective formation of amines. Springer-

Verlag: Berlin, Heidelberg, 2014.

(4) Guo, F.; Berglund, P. Transaminase biocatalysis: optimization

and application. Green Chem. 2017, 19 (2), 333−360.

(5) Heller, D.; De Vries, A. H. M.; De Vries, J. G. Catalyst Inhibition

and Deactivation in Homogeneous Hydrogenation. The Handbook of

Homogeneous Hydrogenation; De Vries, J. G., Elsevier, C. J., Eds.;

WILEY-VCH Verlag GmbH & Co KGaA, 2007.

(6) Sheldon, R. A.; Brady, D. The limits to biocatalysis: pushing the

envelope. Chem. Commun. 2018, 54 (48), 6088−6104.

(7) Wang, Y.; Chen, A. Crystallization-Based Separation of

Enantiomers. Stereoselective Synthesis of Drugs and Natural Products

2013, 1−20.

(8) Parvulescu, A.; Janssens, J.; Vanderleyden, J.; Vos, D.

Heterogeneous Catalysts for Racemization and Dynamic Kinetic

Resolution of Amines and Secondary Alcohols. Top. Catal. 2010, 53

(13−14), 931−941.

(9) Verho, O.; Backvall, J.-E. Chemoenzymatic dynamic kinetic

resolution: a powerful tool for the preparation of enantiomerically

pure alcohols and amines. J. Am. Chem. Soc. 2015, 137 (12), 3996−

4009.

(10) Havinga, E. Spontaneous formation of optically active

substances. Biochim. Biophys. Acta 1954, 13, 171−174.

(11) Viedma, C. Chiral Symmetry Breaking During Crystallization:

Complete Chiral Purity Induced by Nonlinear Autocatalysis and

Recycling. Phys. Rev. Lett. 2005, 94 (6), No. 065504.

(12) Black, S. N.; Williams, L. J.; Davey, R. J.; Moffatt, F.; Jones, R.

V. H.; McEwan, D. M.; Sadler, D. E. The preparation of enantiomers

of paclobutrazol: A crystal chemistry approach. Tetrahedron 1989, 45

(9), 2677−2682.

Analytical data; synthesis and characterization of other

compounds; solubility measurements; details of race-

mizations; diastereomeric resolutions; and catalyst

activity assay (PDF)

Accession Codes

CCDC 2041125, 2041131, and 2041218 contain the

supplementary crystallographic data for this paper. These

data can be obtained free of charge via www.ccdc.cam.ac.uk/

data_request/cif, or by emailing data_request@ccdc.cam.ac.

uk, or by contacting The Cambridge Crystallographic Data

Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44

1223 336033.

AUTHOR INFORMATION

■

Corresponding Author

A. John Blacker − School of Chemistry and School of

Chemical and Process Engineering. Institute of Process

Research and Development, University of Leeds, Leeds LS2

9JT, U.K.; orcid.org/0000-0003-4898-2712;

Email: j.blacker@leeds.ac.uk

Authors

Maria H. T. Kwan − School of Chemistry and School of

Chemical and Process Engineering. Institute of Process

Research and Development, University of Leeds, Leeds LS2

9JT, U.K.

Jessica Breen − School of Chemistry and School of Chemical

and Process Engineering. Institute of Process Research and

Development, University of Leeds, Leeds LS2 9JT, U.K.

Martin Bowden − Syngenta, Bracknell RG42 6EY, U.K.

Louis Conway − Syngenta, Bracknell RG42 6EY, U.K.

Ben Crossley − ApexMolecular, Alderley Park SK10 4TG,

U.K.

Martin F. Jones − Pharmaceutical Technology and

Development, AstraZeneca, Macclesﬁeld SK10 2NA, U.K.

Rachel Munday − Pharmaceutical Technology and

Development, AstraZeneca, Macclesﬁeld SK10 2NA, U.K.

Nisha P. B. Pokar − School of Chemistry and School of

Chemical and Process Engineering. Institute of Process

Research and Development, University of Leeds, Leeds LS2

9JT, U.K.

(13) Noorduin, W. L.; Izumi, T.; Millemaggi, A.; Leeman, M.;

Meekes, H.; Van Enckevort, W. J. P.; Kellogg, R. M.; Kaptein, B.;

Vlieg, E.; Blackmond, D. G. Emergence of a Single Solid Chiral State

from a Nearly Racemic Amino Acid Derivative. J. Am. Chem. Soc.

2008, 130 (4), 1158−1159.

(14) Brands, K. M. J.; Davies, A. J. Crystallization-Induced

Diastereomer Transformations. Chem. Rev. 2006, 106 (7), 2711−

2733.

(15) Palmans, A. R. A. Deracemisations under kinetic and

thermodynamic control. Molecular Systems Design & Engineering

2017, 2 (1), 34−46.

Thomas Screen − ApexMolecular, Alderley Park SK10 4TG,

U.K.

(16) Blacker, A. J.; Stirling, M. J.; Page, M. I. Catalytic racemisation

of chiral amines and application in dynamic kinetic resolution. Org.

Process Res. Dev. 2007, 11 (3), 642−648.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c02617

(17) Anderson, N. G. Developing Processes for Crystallization-

Induced Asymmetric Transformation. Org. Process Res. Dev. 2005, 9

(6), 800−813.

Notes

(18) Hein, J. E.; Huynh Cao, B.; Viedma, C.; Kellogg, R. M.;

Blackmond, D. G. Pasteur ’s Tweezers Revisited: On the Mechanism

The authors declare no competing ﬁnancial interest.

2472

https://dx.doi.org/10.1021/acs.joc.0c02617

J. Org. Chem. 2021, 86, 2458−2473

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

́

̈

of Attrition-Enhanced Deracemization and Resolution of Chiral

Conglomerate Solids. J. Am. Chem. Soc. 2012, 134 (30), 12629−

12636.

(19) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, racemates, and

resolutions; Wiley: 1981.

(20) Brock, C. P.; Schweizer, W. B.; Dunitz, J. D. On the validity of

Wallach ’s rule: on the density and stability of racemic crystals

compared with their chiral counterparts. J. Am. Chem. Soc. 1991, 113

(26), 9811−9820.

(21) Otero-de-la-Roza, A.; Hein, J. E.; Johnson, E. R. Reevaluating

the Stability and Prevalence of Conglomerates: Implications for

Preferential Crystallization. Cryst. Growth Des. 2016, 16 (10), 6055−

6059.

(37) Pamies, O.; Ell, A. H.; Samec, J. S. M.; Hermanns, N.; Backvall,

J.-E. An efficient and mild ruthenium-catalyzed racemization of

amines: application to the synthesis of enantiomerically pure amines.

Tetrahedron Lett. 2002, 43, 4699−4702.

(38) Kwan, M. H. T.; Pokar, N. P. B.; Good, C.; Jones, M. F.;

Munday, R.; Screen, T.; Blacker, A. J. Deactivation Mechanisms of

Iodo-Iridium Catalysts in Chiral Amine Racemization. Tetrahedron

2020, 131823.

(39) Wu, X.; Li, X.; King, F.; Xiao, J. Insight into and Practical

Application of pH-Controlled Asymmetric Transfer Hydrogenation of

Aromatic Ketones in Water. Angew. Chem., Int. Ed. 2005, 44 (22),

3407−3411.

(40) Resolution by Formation and Fractional Crystallization of

Diastereomeric Salts. CRC Handbook of Optical Resolutions via

Diastereomeric Salt Formation; Kozma, D., Ed.; CRC Press: 2001.

(41) Gomm, A.; Lewis, W.; Green, A. P.; O’Reilly, E. A New

Generation of Smart Amine Donors for Transaminase-Mediated

Biotransformations. Chem. - Eur. J. 2016, 22 (36), 12692−12695.

(42) Ferreira, F. C.; Ghazali, N. F.; Cocchini, U.; Livingston, A. G.

Rational approach to the selection of conditions for diastereomeric

resolution of chiral amines by diacid resolving agents. Tetrahedron:

Asymmetry 2006, 17 (9), 1337−1348.

(43) Wakchaure, V. N.; Kaib, P. S. J.; Leutzsch, M.; List, B.

Disulfonimide-catalysed asymmetric reduction of N-alkyl imines.

Angew. Chem., Int. Ed. 2015, 54, 11852−11856.

(44) Ezawa, M.; Moriyama, K.; Togo, H. Transformation of N,N-

diisopropylarylmethylamines into N-isopropylarylmethylamines with

molecular iodine. Tetrahedron Lett. 2015, 56, 6689−6692.

(45) Johannes, M.; Altmann, K.-H. A Ring-Closing Metathesis-

Based Approach to the Synthesis of (+)-Tetrabenazine. Org. Lett.

2012, 14, 3752−3755.

(22) Lee, W. K.; Park, Y. S.; Beak, P. Dynamic Thermodynamic

Resolution: Advantage by Separation of Equilibration and Resolution.

Acc. Chem. Res. 2009, 42 (2), 224−234.

(23) Reetz, M. T.; Schimossek, K. Lipase-Catalyzed Dynamic

Kinetic Resolution of Chiral Amines: Use of Palladium as the

Racemization Catalyst. Chimia 1996, 50 (12), 668−669.

(24) Parvulescu, A. N.; Jacobs, P. A.; De Vos, D. E. Palladium

Catalysts on Alkaline-Earth Supports for Racemization and Dynamic

Kinetic Resolution of Benzylic Amines. Chem. - Eur. J. 2007, 13 (7),

2034−2043.

(25) Jiang, C.-j.; Cheng, G.-I. Racemization of Amines and Related

Derivatives Leading to Their Dynamic Kinetic Resolution. Curr. Org.

Chem. 2013, 17 (11), 1225−1234.

̈

(26) Samec, J. S. M.; Backvall, J.-E. Ruthenium-Catalyzed Transfer

Hydrogenation of Imines by Propan-2-ol in Benzene. Chem. - Eur. J.

2002, 8 (13), 2955−2961.

(27) Stirling, M. J.; Mwansa, J. M.; Sweeney, G.; Blacker, A. J.; Page,

M. I. The kinetics and mechanism of the organo-iridium catalysed

racemisation of amines. Org. Biomol. Chem. 2016, 14 (29), 7092−

7098.

(46) Zhu, R.; Xu, Z.; Ding, W.; Liu, S.; Shi, X.; Lu, X. Efficient and

Practical Syntheses of Enantiomerically Pure (S)-(−)-Norcryptosty-

line I, (S)-(−)-Norcryptostyline II, (R)-(+)-Salsolidine and (S)-

(−)-Norlaudanosine via a Resolution-Racemization Method. Chin. J.

Chem. 2014, 32, 1039−1048.

(28) Stirling, M.; Blacker, A. J.; Page, M. I. Chemoenzymatic

dynamic kinetic resolution of secondary amines. Tetrahedron Lett.

2007, 48, 1247−1250.

(47) Brossi, A.; Dolan, L. A.; Teitel, S. Organic Syntheses Collective,

Vol. 6; Wiley: 1988.

(29) Pamies, O.; Ell, A. H.; Samec, J. S. M.; Hermanns, N.; Backvall,

J.-E. An efficient and mild ruthenium-catalyzed racemization of

amines: application to the synthesis of enantiomerically pure amines.

Tetrahedron Lett. 2002, 43 (26), 4699−4702.

(48) Zhu, R.; Xu, Z.; Ding, W.; Liu, S.; Shi, X.; Lu, X. Wei Ding,

Shiling Liu, Xiaoxin Shi, Xia Lu, Efficient and practical syntheses of

enantiomerically pure (S )-(−)-Norcryptostyline I, (S )-(−)-Norcryp-

tostyline II, (R )-(+)-Salsolidine and (S )-(−)-Norlaudansosine via a

resolution-racemisation method. Chin. J. Chem. 2014, 32, 1039−1048.

(49) Prech, J.; Vaclavik, J.; Pechacek, J.; Vilhanova, B.; Januscak, J.;

Syslova, K.; Pazout, R.; Maixner, J.; Zapal, J.; Kuzma, M.; Kacer, P.

Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines

using Ru(II) diamine catalysts. Catal. Commun. 2013, 36, 67−70.

(50) Li, Z.-W.; Wang, T.-L.; He, Y.-M.; Wang, Z.-J.; Fan, Q.-H.; Pan,

J.; Xu, L.-J. Air-Stable and Phosphine-Free Iridium Catalysts for

Highly Enantioselective Hydrogenation of Quinoline Derivatives. Org.

Lett. 2008, 10 (22), 5265−5268.

(51) Al-Sehemi, A. G.; Atkinson, R. S.; Fawcett, J. Kinetic resolution

of amines with enantiopure 3-N,Ndiacylaminoquinazolin-4(3H)-ones.

J. Chem. Soc., Perkin Trans. 1 2002, 257−274.

(52) Metkar, P. S.; Scialdone, M. A.; Moloy, K. G. Lysinol: a

renewably resourced alternative to petrochemical polyamines and

aminoalcohols. Green Chem. 2014, 16, 4575−4586.

(30) Thalen, L. K.; Backvall, J.-E. Development of dynamic kinetic

resolution on large scale for ( )-1-phenylethylamine. Beilstein J. Org.

Chem. 2010, 6, 823−9.

́

(31) He, D.; Horvath, I. T. Application of silica-supported Shvo ’s

catalysts for transfer hydrogenation of levulinic acid with formic acid.

J. Organomet. Chem. 2017, 847, 263−269.

(32) Lucas, S. J.; Crossley, B. D.; Pettman, A. J.; Vassileiou, A. D.;

Screen, T. E. O.; Blacker, A. J.; McGowan, P. C. A robust method to

heterogenise and recycle group 9 catalysts. Chem. Commun. 2013, 49

(49), 5562−5564.

(33) Kawakami, Y.; Borissova, A.; Chapman, M. R.; Goltz, G.;

Koltsova, E.; Mitrichev, I.; Blacker, A. J. Continuous Flow

Asymmetric Transfer Hydrogenation with Long Catalyst Lifetime

and Low Metal Leaching. Eur. J. Org. Chem. 2019, 2019 (45), 7499−

7505.

́

(34) Falus, P.; Cerioli, L.; Bajnoczi, G.; Boros, Z.; Weiser, D.; Nagy,

J.; Tessaro, D.; Servi, S.; Poppe, L. A Continuous-Flow Cascade

Reactor System for Subtilisin A- Catalyzed Dynamic Kinetic

Resolution of N-tert-Butyloxycarbonylphenylalanine Ethyl Thioester

with Benzylamine. Adv. Synth. Catal. 2016, 358 (10), 1608−1617.

(35) de Miranda, A. S.; de M. Silva, M. V.; Dias, F. C.; de Souza, S.

P.; Leao, R. A. C.; de Souza, R. O. M. A. Continuous flow dynamic

kinetic resolution of rac-1-phenylethanol using a single packed-bed

containing immobilized CAL-B lipase and VOSO4 as racemization

catalysts. Reaction Chemistry & Engineering 2017, 2 (3), 375−381.

(53) Vu, V. H.; Jouanno, L.-A.; Cheignon, A.; Roisnel, T.; Dorcet,

V.; Sinbandhit, S.; Hurvois, J.-P. Modified Fry Cyanation of a Chiral

Pyridinium Salt: Asymmetric Syntheses of (−)-Coniine and

(−)-Solenopsin. A Eur. J. Org. Chem. 2013, 2013, 5464−5474.

́

̈

(36) Farkas, E.; Olah, M.; Foldi, A.; Koti, J.; Eles, J.; Nagy, J.; Gal, C.

́

A.; Paizs, C.; Hornyanszky, G.; Poppe, L. Chemoenzymatic Dynamic

Kinetic Resolution of Amines in Fully Continuous-Flow Mode. Org.

Lett. 2018, 20 (24), 8052−8056.

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https://dx.doi.org/10.1021/acs.joc.0c02617

J. Org. Chem. 2021, 86, 2458−2473

Article Doi

Continuous Flow Chiral Amine Racemization Applied to Continuously Recirculating Dynamic Diastereomeric Crystallizations

DOI: 10.1021/acs.joc.0c02617

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Article abstract of DOI:10.1021/acs.joc.0c02617

Full text of DOI:10.1021/acs.joc.0c02617

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