A General and Direct Reductive Amination of Aldehydes and Ketones with Electron-Deficient Anilines

SYNTHESIS

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2016, 48, A–Q

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J. Pletz et al.

Feature

Synthesis

A General and Direct Reductive Amination of Aldehydes and

Ketones with Electron-Deficient Anilines

Jakob Pletz

EWG

H

hydride reductant

activating agent

NH₂

O

R¹

N

R¹

Bernhard Berg

Rolf Breinbauer*

+

R²

29 examples

R²

Institute of Organic Chemistry, Graz University of Technology,

Stremayrgasse 9, 8010 Graz, Austria

breinbauer@tugraz.at

up to 99% yield

3 methods:

A) BH₃•THF, AcOH, CH₂Cl₂, 0–20 °C

B) BH₃•THF, TMSCl, DMF, 0 °C

C) NaBH₄, TMSCl, DMF, 0 °C

12 anilines

14 ketones

3 aldehydes

In memoriam Philipp Köck

Received: 01.12.2015

Accepted after revision: 20.01.2016

Published online: 01.03.2016

Our first goal was the design and synthesis of analogues

of intermediates in the transformation catalyzed by the

protein PhzA/B. According to Wulf’s proposal,¹this enzyme

was expected to catalyze the imine formation between the

putative aminoketone B, resulting from the transformation

of PhzF with dihydrohydroxyanthranilic acid (DHHA; A),

with itself, thereby establishing the tricyclic skeleton C,

from which after a series of oxidation reactions phenazine-

carboxylic acid E will be formed (Scheme 1). In my group

the project was pursued by two talented students: Almut

Graebsch synthesized in her diploma thesis the first li-

gands, which could be shown, by isothermal calorimetry

DOI: 10.1055/s-0035-1561384; Art ID: ss-2015-t0688-fa

Abstract In our ongoing efforts in preparing tool compounds for in-

vestigating and controlling the biosynthesis of phenazines, we recog-

nized the limitations of existing protocols for C–N bond formation of

electron-deficient anilines when using reductive amination. After ex-

tensive optimization, we have established three robust and scalable

protocols for the reductive amination of ketones with electron-defi-

cient anilines, by using either BH₃·THF/AcOH/CH₂Cl₂(method A), with

reaction times of several hours, or the more powerful combinations

BH₃·THF/TMSCl/DMF (method B) and NaBH₄/TMSCl/DMF (method C),

which give full conversions for most substrates within 10 to 25 minutes.

The scope and limitations of these reactions have been defined for 12

anilines and 14 ketones.

CO₂H

O

Key words amines, anilines, borane, hydride, reductive amination,

ketones, process chemistry, sodium borohydride

NH₂

O

NH₂

OH

PhzF

+

H₂N

H

CO₂H

A

Introduction

B

DHHA

PhzA/B

– 2 H₂O

In 2005 I saw at a conference in London a poster by the

structural biologist and enzymologist Wulf Blankenfeldt,

who presented his progress on the investigation of the bio-

synthesis of phenazines, a class of bacterial natural prod-

ucts among which the virulence factor pyocyanine is proba-

bly its most prominent member.¹He had already solved the

structure of several enzymes along this biosynthetic path-

way, but there were several open mechanistic questions, for

which it would be important to have substrate analogues

binding to these proteins. These probes would ideally serve

also as inhibitors of these enzymes, potentially allowing the

chemical control of the biosynthesis pathway – an attrac-

tive goal and formidable challenge for a synthetic organic

chemist and the starting point of a fruitful collaboration be-

tween our two groups.

HO₂C

PhzE

PhzD

N

chorismic acid

CO₂H

PhzA/B

C

HO₂C

H

N

PhzG

+ O₂

N

– CO₂

– H₂O₂

N

CO₂H

E

D

Scheme 1 Biosynthesis of phenazines

B

J. Pletz et al.

Feature

Synthesis

(ITC) and X-ray crystallography of the protein ligand com-

plex, to bind to PhzA/B. This work was continued by Matthias

Mentel, who, after the move of our laboratory to the Univer-

sity of Leipzig, used information gained from X-ray crystal-

lography and ITC to design even more potent molecules, ul-

timately leading to two important ligands, which we named

‘Phenazistatin’ (F) and ‘Maverick’ (G) (Figure 1). Phenazista-

tin, which binds to PhzA/B with a K_d= 51 nM, is a strongly

affine ligand, mimicking the intermediate after the first

imine formation catalyzed by PhzA/B. The X-ray crystal

structure of the protein-ligand complex of PhzA/B·F proved

important for the unambiguous assignment of the biologi-

cal purpose and mechanistic details of PhzA/B function.²

Compound G was isolated in 1% yield, as Matthias noticed it

as a minor byproduct in the Ullmann–Goldberg reaction of

2-bromobenzoic acid with 3-aminopiperidine, where

waste products of the Ullmann–Goldberg reaction led to ra-

cemic G by bromination of the main product. When sub-

jecting it to ITC and X-ray crystal structure analysis, we

made the completely unexpected and stunning observation

that for racemic G both enantiomers were found in the

binding pocket of PhzA/B simultaneously. We have carefully

investigated this case, which is the first example in which

the textbook notion of eutomer vs. distomer behavior of ra-

cemic drugs is not valid, since each enantiomer of Maverick

(G) binds more strongly to the protein than its racemate.³

After the move of our laboratory to Graz, Jakob Pletz

continued the work of Matthias Mentel, and tried to pre-

pare even more affine ligands of PhzA/B and analogues of

Maverick, exploring if other molecules would also exhibit

the amazing phenotype of simultaneous binding of racemic

Biographical sketches

Jakob Pletz was born in Ober-

pullendorf (Austria) in 1987. He

obtained his B.Sc. in chemistry

and his M.Sc. in technical chem-

istry from the Graz University of

Technology and the University

of Graz. After an Erasmus ex-

change stay in the laboratory of

Professor John K. Gallos at the

Aristotle University of Thessa-

loniki (Greece), he carried out

his Diploma thesis project un-

der the guidance of Professor

Rolf Breinbauer. Since 2012 he

has been working on his Ph.D.

thesis on the synthesis and bio-

logical characterization of ana-

logues of amine-containing

natural products under the

guidance of Professor Rolf

Breinbauer at the Graz Universi-

ty of Technology (Austria).

Bernhard Berg was born in

San Francisco (USA) in 1990. He

finished his primary education

(elementary and high school) in

Linz (Austria) and began study-

ing chemistry at the Graz Uni-

versity of Technology in 2011,

accomplishing his B.Sc. thesis

under the supervision of Prof.

Rolf Breinbauer in early 2015. In

the summer 2015 he worked in

the laboratory of Nancy I. Totah,

in the Department of Chemistry

at Syracuse University (USA).

Since 2015 he has been pursu-

ing his Master studies in techni-

cal chemistry at the Graz

University

(Austria).

of

Technology

Rolf Breinbauer was born in

Schärding (Austria) in 1970. He

studied chemistry at the Vienna

University of Technology and

the University of Heidelberg,

carrying out his Diploma thesis

project under the guidance of

Professor Günter Helmchen.

From 1995 to 1998, he worked

as a Ph.D. student under the

guidance of Professor Manfred

T. Reetz at the Max-Planck-Insti-

tut für Kohlenforschung in Mül-

heim/Ruhr (Germany). After

working as a postdoctoral re-

searcher with an Erwin-

Schrödinger fellowship in the

laboratory of Professor Eric N.

Jacobsen (Harvard University,

USA), he moved in 2000 to

of Dortmund. From 2005 to

2007 he was a professor of or-

ganic chemistry at the Universi-

ty of Leipzig. Since 2007, he has

been a full professor of organic

chemistry at the Graz University

of Technology in Graz (Austria).

His research interests encom-

pass the design and synthesis of

tool compounds for chemical

biology and the development of

new synthetic methods.

Dortmund (Germany) as

a

group leader at the Max-Planck

Institute of Molecular Physiolo-

gy (department head: Professor

Herbert Waldmann) and as a ju-

nior professor at the University

C

J. Pletz et al.

Feature

Synthesis

more available than the alicyclic amines necessary for the

Ullmann–Goldberg route (Figure 2). The lack of control of

the resulting stereogenic center should not bother us at this

early stage of biological testing with PhzA/B, because we

have learned from the studies with Maverick (G) that race-

mic ligands could offer interesting surprises with this par-

ticular protein. First we had to develop more efficient pro-

tocols for reductive aminations, as we soon noticed that all

established protocols proved to be inefficient for our elec-

tron-deficient aniline substrates. In this article we want to

report three methods, which proved to be very valuable for

this type of substrates.

CO₂H

H

N

Br

N

Br

H

CO₂H

Maverick

Phenazistatin

G

F

Figure 1 Structures of Phenazistatin (F) and Maverick (G)

molecules in a single binding pocket. Jakob soon recognized

that a major limitation in his work was the inefficiency of

the Ullmann–Goldberg reaction for the C–N bond forma-

tion.⁴Despite considerable efforts and some success in im-

proving the yields for some substrates by optimizing the re-

action conditions, no reliable protocol could be found

which was suitable for the diverse and highly functional-

ized substrates of our ligands. Jakob suggested a different

route in which the C–N bond is formed with the alkyl car-

bon by using reductive amination as the strategic transfor-

mation, which should lead to higher yields and have the ad-

ditional advantage that the required ketone substrates are

Ullmann–Goldberg

amination

reductive

amination

EWG

H

N

R¹

R²

Figure 2 Strategic disconnections for the synthesis of PhzA ligands

Table 1 Screening of Reductive Amination Methods

CO₂Me

H

CO₂Me

NH₂

O

reductive

amination

N

+

Br

CN

Entry

1

Conditions

Ref.

14

Product formation

–

1. toluene, 4 Å MS, reflux, Dean–Stark, 4 d

2. NaBH₄(3 equiv), MeOH, N₂, 20 °C, 6 h

–

2

1. PTSA, toluene, reflux, Dean–Stark, 2 d

2. NaBH₄(3 equiv), MeOH, N₂, 20 °C, 6 h

–

3

4

TiCl₄(0.5 equiv), Et₃N (2.0 equiv), CH₂Cl₂, 20 °C, 4 d

15

16

–

1. Ti(OⁱPr)₄, neat, 20 °C, 1 h

2. NaCNBH₃(0.55 equiv), EtOH, 20 °C, 3 d

5

6

1. Ti(OⁱPr)₄(1.25 equiv), neat, 40 °C, 16 h

2. NaBH₄(2 equiv), 0–20 °C, EtOH, 6 h

17

18

–

1. Ti(OⁱPr)₄(1.25 equiv), neat, 40 °C, 16 h

2. PMHS (2 equiv), 0–20 °C, THF, 6 h

9

NaBH(OAc)₃(2 equiv), HC(OEt)₃–CH₂Cl₂, 1:1, 20 °C, 23 h

19

20

–

0

10

1. Na₂SO₄(10 equiv), AcOH, 20 °C, 40 min

2. NaBH(OAc)₃(3 equiv), 20 °C, 24 h

11

12

13

14

NaBH(OAc)₃(2 equiv), AcOH (1 equiv), toluene, 20 °C, 6 d

NaBH(OAc)₃(2.8 equiv), AcOH (5 equiv), DCE, 20 °C, 30 h^b

21

0

5b

+

Hantzsch ester (1.5 equiv), thiourea (0.1 equiv), 4 Å MS, toluene, 50 °C, 20 h

1.5 equiv BH₃·THF, CH₂Cl₂–AcOH, 2:1, 20 °C, 3 d

7b

9b

+

++

^aKey: – no conversion, 0 moderate conversion, + good conversion, ++ full conversion.

^bMethyl 3-oxocyclohexane-1-carboxylate was used as the ketone.

D

J. Pletz et al.

Feature

Synthesis

Results and Discussion

strates, optimized method A (1.5 equiv carbonyl substrate,

3 equiv BH₃·THF) proved to be a reliable and versatile meth-

od for the reductive amination of a wide range of electron-

deficient amines (entry 3). The detailed substrate scope

will be described in the following sections.

Reductive amination is one of the most frequently used

synthetic reactions for the production of secondary (and

tertiary) amines.^5–9The advantages over other transforma-

tions are the ready accessibility of the starting materials

and its selectivity avoiding overalkylation. A comprehen-

sive review has been published in 2002,¹⁰in which the re-

action with sterically congested ketone substrates and the

reductive amination with electron-deficient amine nucleo-

philes have been defined as the remaining challenges in

this field. The problematic step is often the initial imine for-

mation due to the unreactive nature of either the carbonyl

or amine component. Specific examples which have been

described as test cases are the reaction of 2,6-disubstituted

anilines with aldehydes¹¹and aliphatic or alicyclic ke-

tones,^5bof camphor with benzylamine,^5band the reaction of

a β-keto ester with 2-fluoroaniline¹²(modest yield). Several

methods which perform well specifically for the reductive

amination of electron-deficient amines have been pub-

lished.^{5b,c,e–g,13}We tested several of these methods for the

reductive amination of methyl 2-amino-5-bromobenzoate

and 3-oxocyclohexane-1-carbonitrile as model substrates

(Table 1).^{5b,7b,9b,14–21}Most reactions failed or gave only low

conversions of the starting materials due to the unreactive

nature of the aromatic amine.

The methods which worked best for the synthesis of the

phenazistatin A derivative in these initial screenings (Table

1) were investigated in detail. For further optimization the

model reaction was simplified to methyl anthranilate and

cyclohexanone (commercially available) and the reactions

were repeated using the same procedures as described in

Table 1 (entries 12–14). The results are listed in Table 2 (vi-

de infra). The well-established NaBH(OAc)₃(STAB) method

by Abdel-Magid,^5bled to incomplete conversion of methyl

anthranilate to the product 4 even after one week of reac-

tion time (Table 2, entry 1). The transfer hydrogenation ap-

proach by Menche using the Hantzsch ester as hydride

source and a thiourea organocatalyst,^7bresulted in full con-

version after six days at 50 °C (entry 2). The third method

was the reductive amination using BH₃·THF^9b(or

BH₃·SMe₂)^9cin CH₂Cl₂/AcOH at room temperature, which

has been described to enable the reaction of the very elec-

tron-deficient 2-nitroaniline with acetone (3 equiv) in ex-

cellent yields within 16–20 hours. However, our attempts to

apply the non-optimized method for our model reaction

led only to incomplete conversion. We observed that pro-

longed reaction time and increased carbonyl loading did

not improve conversion, but increasing the amount of re-

ductant ultimately led to full conversion. In our experience,

a minimum of three equivalents of BH₃·THF is needed to

ensure full conversion for most substrates. When exploring

the scope of this useful transformation with other sub-

Table 2 Comparison of the Reported Reductive Amination Methods

with Established Protocols

CO₂Me

NH₂

CO₂Me

reductive

amination

O

H

N

+

4

Entry Method

Temp

Time

Conversion Yield

(%)

(%)^a

1

2

3

4

5

NaBH(OAc)₃

20 °C

50 °C

0 °C

7 d

6 d

3 h

77^c

73

91

80

97

99

b

Hantzsch ester^d

100

A^e

B^f

0 °C

15 min

C^g

0 °C

^aIsolated yield.

^bAccording to Abdel-Magid et al.:^5baniline (1.0 equiv), ketone (2.0 equiv),

AcOH (5 equiv), NaBH(OAc)₃(2.8 equiv), DCE, 20 °C.

^cn-Nonane was used as an internal standard.

^dAccording to Menche et al.:^7baniline (1.0 equiv), cyclohexanone (1.5

equiv), Hantzsch ester (1.5 equiv), thiourea (0.1 equiv), 5 Å MS, toluene, 50 °C.

^eMethod A: amine (1.00 mmol), cyclohexanone (1.50 mmol), BH₃·THF (3.0

mmol, 3.0 equiv), CH₂Cl₂–AcOH, 2:1, 0–20 °C.

^fMethod B: amine (300 μmol, 1.0 equiv), cyclohexanone (330 μmol, 1.1

equiv), TMSCl (750 μmol, 2.5 equiv), BH₃·THF (300 μmol, 1.0 equiv), DMF, 0 °C.

^gMethod C: amine (300 μmol, 1.0 equiv), cyclohexanone (330 μmol, 1.1

equiv), TMSCl (750 μmol, 2.5 equiv), NaBH₄(300 μmol, 1.0 equiv), DMF, 0 °C.

When applying method A for the synthesis of various

Phenazistatin derivatives using substituted arylamines and

cyclohexanones, we sometimes obtained lower yields and

noticed the formation of two byproducts, namely N-acetyl-

ated and N-ethylated aniline substrate (Scheme 2). Such by-

products have been previously reported for the NaBH(OAc)₃

method by Abdel-Magid^5bwhen AcOH was used as Lewis

acid. In fact, protocols for the N-ethylation of amines using

NaBH₄in neat carboxylic acid have been reported in the lit-

erature.^22–24It is suggested that the product originates from

a stepwise process in which acetic acid is reduced to acetal-

dehyde (or an acetaldehyde equivalent), which reacts with

the amine to form an iminium ion. Reduction of this imine

results in the ethylamine product.²²Marchini could isolate

the N-acetylated product by heating the NaBH₄-carboxylic

acid mixture before addition of the amine.²⁴During the

synthesis of Phenazistatin derivative 1, we observed the

formation of these byproducts (2 and 3), which accounted

for considerable consumption of the substrate arylamine

(Scheme 2).

E

J. Pletz et al.

Feature

Synthesis

°C, but loses hydride activity when kept at room tempera-

ture, creating a stability and safety concern.^27,28While

BH₃·THF can be conveniently handled in a research labora-

tory, it would be desirable to substitute BH₃·THF by a more

inexpensive and inherently safer reducing agent for large-

scale applications.^28d,eWe conducted a screening of com-

monly employed hydride sources in combination with

TMSCl as activating agent (Table 3).

CO₂Me

H

N

Br

CO₂Me

NH₂

1, 79%

cis/trans = 53:47

CO₂Me

H

N

Br

BH₃•THF (4 equiv)

+

CH₂Cl₂/AcOH (2:1)

0–20 °C, 4 d

O

Br

Table 3 Test Reaction with Different Hydride Sources

2, 19%

CO₂Me

NH₂

CO₂Me

reducing agent

(1.0 equiv)

CO₂Me

O

H

CO₂Me

(1.3 equiv)

H

N

+

TMSCl (2.5 equiv)

DMF, 0–20 °C, 24 h

Br

4

3, 2%

Entry

Reducing agent

Conversion (%)^aYield (%)^bPrice [€/mol H]^c

Scheme 2 Observed byproduct formation in the synthesis of a

Phenazistatin derivative (percentages refer to GC-MS peak areas)

1

2

3

4

5

6

7

8

9

PMHS

0

–

14

108

218

6

Et₃SiH

–

We reasoned that by using a different acid additive we

might suppress these side reactions and increase the yields.

Full conversion was obtained with the acids (9 equiv each)

TFA (12 h), MeSO₃H (3 d), malonic acid (13 h), and phenyl-

phosphonic acid (13 h) and the activating agent TMSCl (12

h) for the reaction of 2-aminobenzonitrile and 4-tert-butyl-

cyclohexanone in rates similar to AcOH (12 h). Among these

reagents, TMSCl proved to be the most attractive substitute

for AcOH due to its availability, low molecular weight, low

price, and, most importantly, by its lack of the formation of

the common byproducts mentioned above for AcOH. TMSCl

has been used extensively in combination with boranes for

the reduction of carbonyl substrates, along with borohy-

drides mainly for the in situ generation of borane.²⁵Black-

lock had used TMSCl as an additive for the reductive alkyla-

tion of ureas, thioureas, and carbamates (with benzalde-

hydes, NaBH₄in AcOH).²⁶By screening different solvents we

observed that DMF increases the reaction rate significantly

and lowers the extent of carbonyl reduction. Optimization

of the reaction parameters resulted in optimized method B

(1.1 equiv carbonyl substrate, 2.5 equiv TMSCl, 1.0 equiv

BH₃·THF), which gave 97% yield in 15 minutes at 0 °C for the

model reaction (Table 2, entry 4). It is noteworthy that the

reaction proceeds to completion within minutes at 0 °C. An

amount of 1.0 equiv of BH₃·THF sufficed for all tested reac-

tions, but full conversion was detected for the reaction of 2-

aminobenzonitrile with cyclohexanone even when only 0.5

equiv BH₃·THF was used. The reductive amination was car-

ried out at high concentrations of the arylamine in DMF

(1.5 M) but was found to perform equally well in higher di-

lutions (0.5 M). We kept the solvent volume at a minimum

to facilitate the removal of DMF during workup.

PhSiH₃

100

92

84

88

66

90

91

81

73

NaBH₄

NaBH(OAc)₃

BH₃·THF^d

pinacolborane

9-BBN^e

207

64

100

88

350

496

727

catecholborane

77

^a1,2-DME was used as an internal standard.

^bIsolated yield.

^cPrices from Sigma-Aldrich catalog November 2015.

^d1.0 M solution in THF.

^e0.5 M solution in THF.

PMHS and Et₃SiH did not react under the reaction con-

ditions of method B (Table 3, entries 1 and 2), while PhSiH₃

and the boron-based reductants resulted in good to high

conversions and yields (entries 3–9). To our delight, NaBH₄

performed equally well compared to BH₃·THF in the reduc-

tive amination (entries 4 and 6), allowing us to define the

cost-efficient method C (TMSCl, NaBH₄, DMF, 0 °C), as the

price per hydride equivalent of NaBH₄is significantly lower

than for any other active reductant, with BH₃·THF the sec-

ond least expensive one. In order to explore the substrate

scope, we conducted a series of experiments using method

C. The results are summarized in the following section. In

Table 2 we have compared the performance of the best es-

tablished procedures in the literature with our new meth-

ods A–C for the same test substrate. Methods A–C deliver

product 4 in much shorter reaction times and lower reac-

tion temperatures.

So far, all reported reactions have been performed in an

anhydrous solvent under inert conditions. To test the sensi-

tivity of method C towards moisture and air, we performed

the reaction of methyl anthranilate with cyclohexanone in

an open flask using synthesis-grade (99.8%) DMF. We were

One parameter which requires special attention is the

reducing agent borane–tetrahydrofuran complex. BH₃·THF

is commonly used as a 1.0 M solution in THF (stabilized

with NaBH₄),²⁷which is stable when stored and used at 0

F

J. Pletz et al.

Feature

Synthesis

pleased to find that the same yield as for the inert condi-

tions was isolated after 15 minutes reaction time at 0 °C

(see below, Table 4, entry 7C*).

reactivity and reaction rate, we observed that the selectivi-

ty and tolerance for functional groups seem to be con-

served in most cases.

On the basis of previous studies by Abdel-Magid,^5a

Borch,^29aRoth,^6eand Schellenberg,^29bwe propose a possible

mechanism outlined in Scheme 3, suggesting a dual role of

TMSCl. First, TMSCl activates the carbonyl substrate for nu-

cleophilic attack by the amine. Second, it shifts the equilib-

rium to the imine by serving as a dehydrating agent,^25g

which also provides the acid required for the formation of

the iminium ion, which is the ultimate substrate for hy-

dride attack (Scheme 3).

Table 4 Investigation of the Aniline Substrate Scope for Reductive

Amination by Methods A, B, and C

R

H

R

NH₂

O

N

method A/B/C

+

method A: amine (1 equiv), ketone (1.5 equiv),

BH₃•THF (3 equiv), CH₂Cl₂/AcOH^a

method B: amine (1 equiv), ketone (1.1 equiv),

TMSCl (2.5 equiv), BH₃⋅THF (1 equiv), DMF^b

method C: amine (1 equiv), ketone (1.1 equiv),

TMSCl (2.5 equiv), NaBH₄(1 equiv), DMF^c

TMSCl

TMS

R'

TMS

R'

O

Cl

R

R'

R

Amine

Product Entry

Method^a–cTime

Yield

(%)^d

TMSCl

OMe

TMS

R'' NH₂

HO

O

1A

1B

1C

A

B

C

21 h

15 min

81

85

90

NH₂

5

HCl

TMS

hydride

reductant

ⁱPr

R''

R'

R''

O

HN

R

HN

R

2B

2B*

2C

B

140 min

230 min

15 min

0

66^g

0

R''

Cl

R'

Cl

B^e,f

C

R

R'

6

7

N

H₂

ⁱPr

Scheme 3 Proposed mechanism of the reductive amination process

NH₂

3A

3B

3C

A

B

C

19 h

15 min

77

70

Reductive Amination with Weakly Nucleophilic

Amines

OEt

EtO

P

O

The described methods are very efficient in reductive

amination reactions with weakly basic and nonbasic

amines. The results in Table 4 show that a wide range of

arylamines can successfully react in the reductive amina-

tion with cyclohexanone. The reductive amination follow-

ing the BH₃·THF/AcOH/CH₂Cl₂method (Table 4, method A)

with reaction times from 3–41 hours is generally slower

than the BH₃·THF/TMSCl/DMF method (Table 4, method B)

and the NaBH₄/TMSCl/DMF method (Table 4, method C),

which typically require 10–230 minutes. It is noteworthy

that method B and method C proceed at 0 °C within min-

utes while method A and other described methods for elec-

tron-deficient aromatic amines require room or even high-

er temperatures and reaction times of hours to days. We

found that method B (BH₃·THF/DMF) and method C

(NaBH₄/DMF) yielded comparable results for most of the ar-

omatic amines tested; however, method B (BH₃·THF/DMF)

was chosen for the study of reactive carbonyl groups in the

next section (see below, Table 5), as the handling of the liq-

uid BH₃·THF solution was more suitable for parallel opera-

tions on a small scale. While there is a significant difference

between method A and method B/method C in matters of

4A

4B

A

B

3 h

10 min

89

72

8

9

NH₂

Cl

5A

5B

5C

A

B^f

C

6 d

18 min

15 min

(18^h)

90

87

NH₂

Cl

CO₂H

NH₂

6B

6C

B

C

10 min

15 min

91

10

4

CO₂Me

NH₂

7A

7B

7C

7C*

A

B

3 h

80

97

99

15 min

C

Cⁱ

NH₂

8A

8B

A

B

21 h

15 min

29

79

11

O

G

J. Pletz et al.

Feature

Synthesis

Table 4 (continued)

Amine

90% and 87% yield (entries 5B and 5C), respectively. The

most sterically hindered aniline used, 2,6-diisopropylani-

line, failed to undergo reaction with cyclohexanone by both

methods B and C (entries 2B and 2C). However, the reactivi-

ty of method B could be enhanced by the use of TMSOTf in-

stead of TMSCl (entry 2B*). The reaction proceeded very

slowly (230 min) but gave the product 6 in 66% yield.

The very electron-deficient 2-nitroaniline gave product

14 in 94% yield after 30 min at 0 °C by method B (Table 4,

entry 11B). Abdel-Magid^5bcould only obtain 30% conver-

sion to the desired product after 6 days at room tempera-

ture when using the optimized NaBH(OAc)₃conditions. An-

thranilic acid reacted well by methods A and B to give prod-

uct 10 in 91% yield (entries 6B and 6C). Interestingly, the

heterocyclic arylamine 3-aminopyridine reacted to form

the reductive amination product 15 in 84% yield by method

B (entry 12B).

Product Entry

Method^a–cTime

Yield

(%)^d

F

NH₂

9A

9B

9C

A

B

C

3 h

10 min

15 min

72

68

67

12

13

CF₃

CN

10A

10B

10C

A

B

C

15 h

18 min

15 min

94

91

NH₂

NO₂

NH₂

11A

11B

11C

A

B

C

21 h

30 min

74

94

78

14

15

NH₂

Reductive Amination of Aldehydes and Ketones

12B

B

11 min

84

N

The results in Table 5 show that the reductive amination

of a variety of aromatic aldehydes as well as cyclic and acy-

clic ketones with the electron-deficient anilines H and I was

successfully accomplished under the standard conditions

(methods A and B) and furnished the products in moderate

to excellent yields. The scope of the reaction includes differ-

ent aromatic aldehydes (entries 1A, 1B, and 2B), cinnamic

aldehyde (entry 3B), alicyclic ketones (entries 5A, 8A, 9A,

and 4B–9B), 2-adamantanone (entries 9A and 9B), saturat-

ed acyclic ketones (entries 10A, 11A, 11B, 12B, and 13B*),

methyl 3-oxobutanoate (entry 12B), acetophenone (entries

16A and 16B*) and 1,1-diethoxycyclohexane (entry 18B).

For the same primary aromatic amine the rate of the reac-

tion was dependent on the steric and electronic factors as-

sociated with the carbonyl substrates as well as with the re-

ductive amination protocol used. The substrates reacted

consistently more sluggishly when using the BH₃·THF in

CH₂Cl₂/AcOH system (method A) as compared to the

BH₃·THF/TMSCl/DMF system (method B).

Aldehydes and ketones are known to be reduced by

BH₃·THF³⁰and NaBH₄,³¹and thus carbonyl reduction could

be expected to compete with the reductive amination pro-

cess.^5bHowever, the chosen reaction conditions were so se-

lective that the reductive amination with aldehydes and ke-

tones worked efficiently and resulted in clean reactions in

most cases. Cases in which carbonyl reduction was detected

involved the sterically hindered 2-tert-butylcyclohexan-1-

one in both methods A and B (Table 5, entries 14A, 14B, and

14B*), 2,6-diisopropylaniline in the modified method B (Ta-

ble 4, entry 2B*), and acetophenone when using the modi-

fied method B (Table 5, entry 16B*).

^aMethod A: amine (1.00 mmol), cyclohexanone (1.50 mmol), BH₃·THF (3.0

mmol, 3.0 equiv), CH₂Cl₂–AcOH, 2:1, 0–20 °C.

^bMethod B: amine (300 μmol, 1.0 equiv), cyclohexanone (330 μmol, 1.1

equiv), TMSCl (750 μmol, 2.5 equiv), BH₃·THF (300 μmol, 1.0 equiv), DMF, 0

°C.

^cMethod C: amine (300 μmol, 1.0 equiv), cyclohexanone (330 μmol, 1.1

equiv), TMSCl (750 μmol, 2.5 equiv), NaBH₄(300 μmol, 1.0 equiv), DMF, 0

°C.

^dIsolated yield.

^eTMSOTf was used instead of TMSCl.

^fCyclohexanone (1.5 equiv) was used.

^gCarbonyl reduction was observed.

^hConversion of the starting material (n-nonane used as internal standard).

ⁱPerformed in an open flask using synthesis-grade DMF (99.8%).

One case in which the selectivity differs between meth-

od A and method B is found in the reductive amination of 4-

acetylaniline. Method A gives the product 11 in low yields

(Table 4, entry 8A), due to a large amount of self-condensa-

tion of the aromatic ketone with the aniline, whereas with

method B the aromatic ketone moiety remains untouched

and the product 11 is obtained in good yield (entry 8B).

The described methods give good yields for electron-

rich primary anilines and a wide range of electron-deficient

primary aromatic amines. The reactions are convenient and

simple and show a high degree of tolerance for a variety of

functional groups including acetyl, alkoxycarbonyl, car-

boxy, cyano, diethylphosphonyl, halo, and nitro groups.

Substitution at the ortho position of aromatic amines

did not seem to have any detrimental effect on the reaction

rate, and high to excellent yields were obtained (Table 4). As

mentioned above, the reductive amination of 2,6-disubsti-

tuted anilines has been described in the literature as a chal-

lenging substrate combination.^5b,10The sterically hindered

2,6-dichloroaniline reacted very slowly by method A (entry

5A, 18% conversion after 6 d), but to our delight reacted

smoothly by method B and method C, giving product 9 in

Of all the carbonyl substrates used in this study, the ali-

cyclic ketones were the most reactive and gave very good to

excellent yields (Table 5, entries 5A–9A and 4B–9B). Alde-

hydes gave somewhat lower yields with comparable reac-

H

J. Pletz et al.

Feature

Synthesis

Table 5 (continued)

Carbonyl reagent

tion times (entries 1A and 1B–3B), but, in contrast to estab-

lished silane-based methods, we did not observe any over-

alkylated products. trans-Cinnamaldehyde reacted smooth-

ly with methyl anthranilate providing 19 in 81% yield with

no trace of C=C reduction product (entry 3B), which is a

common side reaction with borane reagents. Saturated acy-

clic ketones reacted more sluggishly and gave lower yields

(entries 10A, 11A, 11B, and 13B*). The β-keto ester methyl

3-oxobutanoate (entry 12B) reacted slowly and gave prod-

uct 29 in 67% yield. The acid-labile ketone 1-Boc-3-piperi-

done reacted well with methyl anthranilate by method A,

producing 23 (66%) (entry 8A), whereas method C yielded a

complex mixture. Method A might be the better method for

the coupling of more acid-sensitive carbonyl and arylamine

substrates.

Entry Amine Method^a,bTime

Product Yield (%)^c

O

8A

H

A

44 h

23

66

N

Boc

O

9A

9B

I

H

A

B

41 h

24 min 25

24

80

94

O

10A

I

A

39 h

26

80

11A

11B

I

H

A

B

39 h

23 h

27

28

69

43

Table 5 Investigation of the Carbonyl Substrate Scope for Reductive

Amination by Methods A and B

O

OMe

12B

H

B

6 h

29

67

O

R¹

R²

H

O

method A/B

NH₂

N

R²

+

R³

13B

13B*

H

B

17 h

20 h

–

30

0

50

R³

H: R = CO₂Me

I: R = CN

B^d,e

method A: amine (1 equiv), ketone (1.5 equiv),

BH₃•THF (3 equiv), CH₂Cl₂/AcOH^a

O

14A

14B

14B*

I

H

A

24 h

17 h

18 h

–

0^f

B

0^f

method B: amine (1 equiv), ketone (1.1 equiv),

B^d,e

traces^f,g

^tBu

O

TMSCl (2.5 equiv), BH₃⋅THF (1 equiv), DMF^b

15A

15B

15B*

I

H

A

41 h

23 h

18 h

–

0

Carbonyl reagent

Entry Amine Method^a,bTime

Product Yield (%)^c

B

B^d,e

traces^g

I

H

1A

1B

A

B

15 h

20 min 17

16

80

85

O

16A

16B

16B*

I

H

A

39 h

23 h

31

–

32

70

0

B

O

N

B^d,e

87^f

2B

H

B

10 min 18

84

O

17A

17B

17B*

I

H

A

4 d

17 h

20 h

–

0

3B

4B

H

B

10 min 19

15 min 20

81

96

O

B

B^d,e

traces^g

EtO

O

18B

H

B

19 min

4

71^h

5A

5B

I

H

A

B

15 h

15 min

13

4

94

97

^aMethod A: amine (1.0 mmol), cyclohexanone (1.5 mmol), BH₃·THF (3.0

mmol, 3.0 equiv), CH₂Cl₂–AcOH, 2:1, 0–20 °C.

^bMethod B: amine (300 μmol, 1.0 equiv), cyclohexanone (330 μmol, 1.1

equiv), TMSCl (750 μmol, 2.5 equiv), BH₃·THF (300 μmol, 1.0 equiv), DMF, 0

°C.

6B

7B

H

B

15 min 21

15 min 22

91

96

^cIsolated yield.

O

N

O

^dTMSOTf was used instead of TMSCl.

^eCyclohexanone (1.5 equiv) was used.

^fCarbonyl reduction was observed.

OEt

^gProduct mass was identified by GC-MS (<5%).

^hMethyl 2-(cyclohexylamino)benzoate was obtained as the product.

I

J. Pletz et al.

Feature

Synthesis

Reductive Amination of Aromatic and Sterically Hin-

dered Ketones

(BH₃·THF/AcOH/CH₂Cl₂) is distinguished by inexpensive re-

agents and simple workup, but requires longer reaction

times and gives rise to acetylated byproducts for substrate

combinations with slow imine formation. For these sub-

strates, the more reactive activating agent TMSCl is recom-

mended, and both method B (BH₃·THF/TMSCl/DMF) as well

as method C (NaBH₄/TMSCl/DMF) offer powerful reagent

combinations, which result in full conversions for most

substrates within 10–25 minutes. In case these methods

fail, the use of TMSOTf offers an additional possibility to

make sterically more congested substrates accessible. To-

gether, these methods have expanded the scope of the re-

ductive amination reaction, which will become an even

more powerful tool for the organic synthesis of substituted

amines.

The least reactive ketones were aromatic and sterically

hindered alicyclic and aliphatic ketones. It is noteworthy

that acetophenone reacted smoothly by method A to give

the desired product 31 in good yield, whereas the unmodi-

fied method B failed (Table 5, entries 16A and 16B). For oth-

er unreactive carbonyl substrates, the arylamine substrate

was quantitatively acetylated to the byproduct N-(2-cyano-

phenyl)acetamide, as judged by GC-MS (entries 14A, 15A,

and 17A). The formation of small amounts of these byprod-

ucts was also described for some slow reactions when us-

ing the established NaBH(OAc)₃-protocol.^5bBenzophenone,

2-(tert-butyl)cyclohexan-1-one, and (+)-camphor failed to

react with 2-aminobenzonitrile by method A (entries 14A,

15A, and 17A). These substrates as well as acetophenone

and benzophenone could also not be converted in the reac-

tion with methyl anthranilate by method B (entries 13B,

14B, 15B, 16B, and 17B).

However, the reactivity could be enhanced by using the

more reactive TMSOTf instead of TMSCl as demonstrated

for the reaction with pinacolone and acetophenone giving

the products 30 and 32 in good yields (entries 13B* and

16B*) after reaction times of 20 and 23 hours, respectively.

However, even with the TMSOTf-modified method B, the

other challenging ketones hardly reacted with methyl an-

thranilate, and only traces (<5%) of the desired products

were detected by GC-MS (entries 14B*, 15B*, and 17B*) af-

ter 18–23 hours. Interestingly, method B can also be used

for the reductive amination with ketals, as exemplified for

1,1-diethoxycyclohexane as a substrate (entry 18B).

TMSCl (98%) and BH₃·THF (1.0 M solution in THF) were purchased

from Sigma Aldrich and anhyd DMF was purchased from Alfa Aesar

and stored over 3 Å molecular sieves in an amber 1000 mL Schlenk

bottle. All experiments were carried out by using established Schlenk

techniques. Analytical TLC was carried out on Merck TLC silica gel 60

F254 aluminum sheets and spots were visualized by UV light (λ = 254

and/or 366 nm) or by staining with cerium ammonium molybdate

[CAM; 2.0 g Ce(SO₄)₂, 50.0 g (NH₄)₆Mo₇O₂₄, and 50 mL concd H₂SO₄in

400 mL H₂O] or potassium permanganate (0.3 g KMnO₄, 20 g K₂CO₃,

and 5 mL 5% aq NaOH in 300 mL H₂O). Flash column chromatography

was performed using silica gel 0.035–0.070 mm, 60 Å (Acros Organ-

ics). ATR-IR spectra were recorded using an ALPHA FT-IR spectrome-

ter (Bruker; Billerica, MA, USA). ¹H and ¹³C NMR spectra were record-

ed on a Bruker AVANCE III 300 spectrometer (¹H: 300.36 MHz; ¹³C:

75.53 MHz) and ¹⁹F (282.47 MHz) and ³¹P (121.58 MHz) NMR spectra

were recorded on a Varian INOVA 300 spectrometer and referenced

versus TMS using the internal ²H-lock signal of the solvent.

To demonstrate the scalability of method B, the gram-

scale synthesis of the Phenazistatin derivatives 33 and 34

(Figure 3) was performed, which delivered 33 and 34 in 96%

and 97% yield, respectively, in the short reaction times ob-

served for the model reactions.

Method A: Reductive Amination of Arylamines and Aldehydes/

Ketones with BH₃·THF in CH₂Cl₂/AcOH; General Procedure A

A dry 20 mL Schlenk tube with magnetic stirring bar was charged

consecutively with arylamine (1.0 mmol, 1.0 equiv), carbonyl sub-

strate (1.5 mmol, 1.5 equiv), anhyd CH₂Cl₂(2.0 mL), and glacial AcOH

(1.0 mL) in a N₂counter-stream. The reaction mixture was cooled to 0

°C, the glass stopper was replaced by a rubber septum, and a 1.0 M

solution of BH₃·THF in THF (3.0 mL, 3.0 mmol, 3 equiv) was added

slowly by syringe over a period of 10–20 min. The flask was sealed

with a glass stopper and the mixture was kept stirring in the thawing

ice bath until full conversion was detected by TLC. The vigorously

stirred mixture was cooled to 0 °C again and sat. NaHCO₃(5 mL) was

added carefully (CO₂evolution!) followed by EtOAc (10 mL). The two-

phase mixture was kept stirring until the gas evolution had ceased

(typically 20–60 min). The phases were separated and the aqueous

layer was extracted with EtOAc (5 × 10 mL). The combined organic

layers were dried over Na₂SO₄, the drying agent was removed by fil-

tration, and the solvents were removed under reduced pressure. The

crude product (adsorbed onto Celite) was purified by chromatogra-

phy (silica gel, cyclohexane–EtOAc, gradient).

MeO

O

MeO

O

H

N

H

N

Br

I

33

34

O

OMe

O

OMe

2.70 g, 48 min

96%

8.61 g, 30 min

97%

Figure 3 Gram-scale synthesis of Phenazistatin derivatives using

method B

Summary and Conclusions

In conclusion, we have established three new methods

which have proven useful for the reductive amination of

electron-deficient anilines with ketones. Method

A

J

J. Pletz et al.

Feature

Synthesis

Method B: Reductive Amination of Arylamines and Aldehydes/

Ketones with BH₃·THF and TMSCl in DMF; General Procedure B

Prepared according to general procedure C from methyl anthranilate

(39.2 μL, 300 μmol); 15 min reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 200:1, 150:1, size: 7.5 × 2.2 cm);

yield: 69.1 mg (296 μmol, 99%); light-yellow, viscous liquid.

A dry 20 mL Schlenk tube with magnetic stirring bar was charged

consecutively with arylamine (300 μmol, 1.0 equiv), carbonyl sub-

strate (330 μmol, 1.1 equiv), anhyd DMF (200 μL), and TMSCl (96.8 μL,

750 μmol, 2.5 equiv) in a N₂counter-stream. The reaction mixture

was cooled to 0 °C, the glass stopper was replaced by a rubber sep-

tum, and a 1.0 M solution of BH₃·THF in THF (300 μL, 300 μmol, 1.0

equiv) was added slowly with a syringe over a period of 10–20 min.

The flask was sealed with a glass stopper and the reaction mixture

was kept stirring at 0 °C until full conversion was detected by TLC.

The vigorously stirred reaction mixture was treated with H₂O (3 mL)

and the mixture was stirred for 20 min. EtOAc (5 mL) was added fol-

lowed by sat. Na₂CO₃solution (2.5 mL) (CO₂evolution!). The two-

phase mixture was kept stirring until the gas evolution had ceased

(typically 20–60 min). In case the aqueous phase was turbid, small

amounts of H₂O were added to provide a clear aqueous phase. The

phases were separated and the aqueous layer was extracted with EtOAc

(5 × 8 mL). The combined organic layers were dried over Na₂SO₄, the

drying agent was removed by filtration, and the solvents were re-

moved under vacuum. The crude product (adsorbed onto Celite) was

purified by chromatography (silica gel, cyclohexane–EtOAc, gradient).

R_f= 0.67 (cyclohexane–EtOAc, 8:1) (254 nm, 366 nm, CAM: orange).

IR (ATR): 3346, 2928, 2852, 1680, 1606, 1579, 1516, 1436, 1328, 1249,

1223, 1187, 1161, 1137, 1107, 1075, 1045, 745, 702, 565, 525 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.93–7.84 (m, 1 H, ArH), 7.82–7.69 (m,

1 H, NH), 7.36–7.21 (m, 1 H, ArH), 6.74–6.63 (m, 1 H, ArH), 6.56–6.45

(m, 1 H, ArH), 3.84 (s, 3 H, CH₃), 3.47–3.30 (m, 1 H, CH), 2.10–1.94 (m,

2 H, CH₂), 1.84–1.69 (m, 2 H, CH₂), 1.67–1.53 (m, 1 H, CH₂), 1.49–1.20

(m, 5 H, CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.3 (C_q), 150.5 (C_q), 134.6, 132.0,

114.0, 111.8, 109.6 (C_q), 51.5, 50.6, 33.0, 26.0, 24.8.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₄H₁₉NO₂: 233.1416; found:

233.1424.

N-Cyclohexyl-2-methoxyaniline (5)

Prepared according to general procedure A from 2-methoxyaniline

(114 μL, 1.00 mmol); 21 h reaction time; purified by column chroma-

tography (cyclohexane–EtOAc, 40:1, size: 11 × 2.8 cm); yield: 166 mg

(810 μmol, 81%); amorphous, colorless solid.

Method C: Reductive Amination of Arylamines and Aldehydes/

Ketones with NaBH₄and TMSCl in DMF; General Procedure C

Prepared according to general procedure B from 2-methoxyaniline

(34.2 μL, 300 μmol); 15 min reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 100:1, size: 14 × 0.8 cm); yield:

52.6 mg (256 μmol, 85%); amorphous, colorless solid.

A dry 20 mL Schlenk tube with magnetic stirring bar was charged

consecutively with arylamine (1.0 mmol, 1.0 equiv), carbonyl sub-

strate (1.1 mmol, 1.1 equiv), anhyd DMF (670 μL), and TMSCl (323 μL,

2.5 mmol, 2.5 equiv) in a N₂counter-stream. The reaction mixture

was cooled to 0 °C and NaBH₄(39.0 mg, 1.0 μmol, 1.0 equiv) was add-

ed in one portion. The flask was sealed with a glass stopper and the

reaction mixture was kept stirring at 0 °C until full conversion was

detected by TLC. The vigorously stirred reaction mixture was treated

with sat. NaHCO₃solution (5 mL) (CO₂evolution!) followed by EtOAc

(5 mL). The two-phase mixture was kept stirring until the gas evolu-

tion had ceased (typically 20–60 min). In case the aqueous phase was

turbid, small amounts of H₂O were added to provide a clear aqueous

phase. The phases were separated and the aqueous layer was extract-

ed with EtOAc (5 × 10 mL). The combined organic layers were dried

over Na₂SO₄, the drying agent was removed by filtration, and the sol-

vents were removed by using a rotary evaporator. The solvents were

removed under vacuum and the crude product (adsorbed onto Celite)

was purified by chromatography (silica gel, cyclohexane–EtOAc, gra-

dient).

Prepared according to general procedure C from 2-methoxyaniline

(114 μL, 1.00 mmol); 15 min reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 100:1, 50:1, size: 20 × 1.4 cm);

yield: 184 mg (902 μmol, 90%); amorphous, colorless solid; mp 32 °C;

R_f= 0.31 (cyclohexane–EtOAc, 3:1) (254 nm, 366 nm, CAM: purple).

IR (ATR): 3422, 2919, 2849, 1600, 1507, 1449, 1252, 1234, 1219, 1125,

1026, 738 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 6.87 (td, ³J_HH= 7.8 Hz, ⁴J_HH= 1.3 Hz, 1 H,

ArH), 6.78 (dd, ³J_HH= 8.1 Hz, ⁴J_HH= 1.0 Hz, 1 H, ArH), 6.70–6.58 (m, 2 H,

2 × ArH), 4.16 (s, 1 H, NH), 3.86 (s, 3 H, CH₃), 3.35–3.20 (m, 1 H, CH),

2.17–2.00 (m, 2 H, CH₂), 1.87–1.60 (m, 3 H, CH₂), 1.50–1.12 (m, 5 H,

CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 146.8 (C_q), 137.4 (C_q), 121.4, 115.9,

110.3, 109.7, 55.5, 51.5, 33.6, 26.1, 25.2.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₃H₁₉NO: 205.1467; found:

205.1471.

Methyl 2-(Cyclohexylamino)benzoate (4)

N-Cyclohexyl-2,6-diisopropylaniline (6)

Prepared according to general procedure A from methyl anthranilate

(131 μL, 1.0 mmol); 3 h reaction time; purified by column chromatog-

raphy (cyclohexane–EtOAc, 150:1, size: 11 × 2.8 cm); yield: 186 mg

(797 μmol, 80%); light-yellow, viscous liquid.

Prepared according to general procedure B from 2,6-diisopropylani-

line (62.9 μL, 300 μmol) using TMSOTf (139 μL, 750 μmol) instead of

TMSCl; 230 min reaction time; purified by column chromatography

(cyclohexane–EtOAc, 100:1, size: 8 × 0.8 cm); yield: 51.6 mg (199

μmol, 66%); colorless, viscous liquid; R_f= 0.76 (cyclohexane–EtOAc,

9:1) (254 nm, KMnO₄: yellow).

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol); 15 min reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 200:1, 150:1, size: 7.5 × 2.2 cm);

yield: 68.2 mg (292 μmol, 97%); light-yellow, viscous liquid.

The spectra (see SI) were in accordance with the previously reported

data.³²

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and 1,1-diethoxycyclohexane (64.5 μL, 330

μmol); 19 min reaction time; purified by column chromatography

(cyclohexane–EtOAc, 150:1, size: 8 × 0.8 cm); yield: 49.4 mg (212

μmol, 71%); light-yellow, viscous liquid.

N-Cyclohexylaniline (7)

Prepared according to general procedure A from aniline (92.0 μL, 1.00

mmol); 19 h reaction time; purified by column chromatography (cy-

clohexane–EtOAc, 45:1, size: 11 × 2.8 cm); yield: 134 mg (765 μmol,

77%); light-yellow, viscous liquid.

K

J. Pletz et al.

Feature

Synthesis

Prepared according to general procedure B from aniline (27.7 μL, 300

μmol); 15 min reaction time; purified by column chromatography

(cyclohexane–EtOAc, 150:1, 80:1, size: 14 × 0.8 cm); yield: 40.4 mg

(230 μmol, 77%); light-yellow, viscous liquid.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₂H₁₅Cl₂N: 243.0582; found:

243.0582.

2-(Cyclohexylamino)benzoic Acid (10)

Prepared according to general procedure C from aniline (92.0 μL, 1.00

mmol); 15 min reaction time; purified by column chromatography

(cyclohexane–EtOAc, 45:1, size: 15.5 × 3.5 cm); yield: 123 mg (702

μmol, 70%); light-yellow, viscous liquid.

Prepared according to general procedure B from anthranilic acid (42.0

mg, 300 μmol); 10 min reaction time; purified by column chromatog-

raphy (cyclohexane–EtOAc–AcOH, 100:10:1, size: 15 × 0.8 cm); yield:

59.9 mg (273 μmol, 91%); light-yellow solid.

R_f= 0.79 (cyclohexane–EtOAc, 3:1) (254 nm, CAM: carnate).

Prepared according to general procedure C from anthranilic acid (140

mg, 1.00 mmol); 15 min reaction time; purified by column chroma-

tography (cyclohexane–EtOAc–AcOH, 100:10:1, size: 15 × 3.5 cm);

yield: 200 mg (912 μmol, 91%); light-yellow solid.

The spectra (see SI) were in accordance with the previously reported

data.³³

Mp 116 °C, R_f= 0.18 (cyclohexane–EtOAc–AcOH, 100:10:1) (254 nm,

Diethyl [2-(Cyclohexylamino)phenyl]phosphonate (8)

366 nm, CAM: orange-green).

Prepared according to general procedure A from diethyl (2-amino-

phenyl)phosphonate³⁴(229 mg, 1.00 mmol); 3 h reaction time; puri-

fied by column chromatography (cyclohexane–EtOAc, 5:1, size: 11 ×

2.8 cm); yield: 276 mg (886 μmol, 89%); light-yellow, viscous liquid.

The spectra (see SI) were in accordance with the previously reported

data.³⁵

1-[4-(Cyclohexylamino)phenyl]ethan-1-one (11)

Prepared according to general procedure B from diethyl (2-amino-

phenyl)phosphonate³⁴(68.8 mg, 300 μmol); 10 min reaction time;

purified by column chromatography (cyclohexane–EtOAc, 5:1, size:

15 × 0.8 cm); yield: 67.6 mg (217 μmol, 72%); light-yellow, viscous

liquid.

Prepared according to general procedure A from 4-aminoacetophe-

none (138 mg, 1.00 mmol); 21 h reaction time, purified by column

chromatography (cyclohexane–EtOAc, 40:1, size: 13 × 2.8 cm), yield:

62.5 mg (288 μmol, 29%); light-orange, sticky solid.

R_f= 0.24 (cyclohexane–EtOAc, 5:1) (254 nm, 366 nm, CAM: blue).

Prepared according to general procedure B from 4-aminoacetophe-

none (41.4 mg, 300 μmol); 15 min reaction time; purified by column

chromatography (cyclohexane–EtOAc, 9:1, size: 15 × 0.8 cm), yield:

51.5 mg (237 μmol, 79%); light-yellow solid.

IR (ATR): 3314, 2981, 2853, 1598, 1582, 1523, 1456, 1325, 1220, 1046,

1017, 955, 747, 559, 532, 513 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.51–7.38 (m, 1 H, ArH), 7.36–7.24 (m,

1 H, ArH), 6.69–6.44 (m, 3 H, 2 × ArH, NH), 4.20–3.94 (m, 4 H, 2 × CH₂),

3.40–3.25 (m, 1 H, CH), 2.05–1.92 (m, 2 H, CH₂), 1.84–1.68 (m, 2 H,

CH₂), 1.65–1.53 (m, 1 H, CH₂), 1.47–1.19 (m, 11 H, CH₂, 2 × CH₃).

Mp 115–117 °C; R_f= 0.43 (cyclohexane–EtOAc, 3:1) (254 nm).

IR (ATR): 3324, 2924, 2914, 2852, 1648, 1584, 1569, 1451, 1431, 1359,

1339, 1279, 1257, 1170, 1147, 1106, 1069, 953, 823, 611, 568, 498,

468 cm^–1

.

2

¹³C NMR (75.53 MHz, CDCl₃): δ = 151.2 (d, J_CP= 9.0 Hz, C_q, Ar-N),

134.2 (d, ⁴J_CP= 2.1 Hz, CH_arom), 134.0 (d, ²J_CP= 7.3 Hz, CH_arom), 114.8 (d,

¹H NMR (300 MHz, CDCl₃): δ = 7.79 (d, ³J_HH= 8.7 Hz, 2 H, ArH), 6.52 (d,

³J_HH= 8.7 Hz, 2 H, ArH), 4.47–3.85 (m, 1 H, NH), 3.42–3.24 (m,1 H, CH),

2.48 (s, 3 H, CH₃), 2.12–1.96 (m, 2 H, CH₂), 1.86–1.58 (m, 3 H, CH₂),

1.49–1.07 (m, 5 H, CH₂).

³J_CP= 14.2 Hz, CH_arom), 111.5 (d, ³J_CP= 12.2 Hz, CH_arom), 107.5 (d, ¹J_CP

=

2

182.6 Hz, C_q, Ar-P), 62.0 (d, J_CP= 4.9 Hz, CH₂), 50.8 (s, CH), 32.8 (s,

CH₂), 26.0 (s, CH₂), 24.7 (s, CH₂), 16.4 (d, ³J_CP= 6.7 Hz, CH₃).

³¹P NMR (122 MHz, CDCl₃): δ = 22.06 (s).

¹³C NMR (75.53 MHz, CDCl₃): δ = 196.3 (C_q), 151.5 (C_q), 131.0, 126.3

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₆H₂₆NO₃P: 311.1650; found:

(C_q), 111.6, 51.4, 33.2, 26.0, 25.8, 24.9.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₄H₁₉NO: 217.1467; found:

311.1669.

217.1470.

2,6-Dichloro-N-cyclohexylaniline (9)

N-Cyclohexyl-2-fluoro-5-(trifluoromethyl)aniline (12)

Prepared according to general procedure B from 2,6-dichloroaniline

(49.6 mg, 300 μmol) and cyclohexanone (47.2 μL, 450 μmol); 18 min

reaction time; purified by column chromatography (cyclohexane–

EtOAc, 400:1, size: 14 × 0.8 cm); yield: 66.0 mg (270 μmol, 90%); col-

orless, viscous liquid.

Prepared according to general procedure A from 2-fluoro-5-(trifluo-

romethyl)aniline (134 μL, 1.00 mmol); 3 h reaction time; purified by

column chromatography (cyclohexane, size: 9.5 × 3.6 cm); yield: 187

mg (717 μmol, 72%); colorless, viscous liquid.

Prepared according to general procedure C from 2,6-dichloroaniline

(165 mg, 1.00 mmol); 15 min reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 300:1, 150:1, size: 8 × 2.7 cm);

yield: 213 mg (872 μmol, 87%); light-yellow, viscous liquid.

Prepared according to general procedure B from 2-fluoro-5-(trifluo-

romethyl)aniline (40.2 μL, 300 μmol); 10 min reaction time; purified

by column chromatography (cyclohexane–EtOAc, 300:1, size: 15 × 0.8

cm); yield: 53.2 mg (204 μmol, 68%); colorless, viscous liquid.

R_f= 0.84 (cyclohexane–EtOAc, 9:1) (254 nm)

Prepared according to general procedure C from 2-fluoro-5-(trifluo-

romethyl)aniline (134 μL, 1.00 mmol); 15 min reaction time; purified

by column chromatography (cyclohexane, size: 15.5 × 3.0 cm); yield:

174 mg (666 μmol, 67%); light-yellow, viscous liquid.

IR (ATR): 3355, 2926, 2851, 1580, 1493, 1447, 1421, 1249, 1139, 1081,

889, 836, 805, 762, 723, 623, 528 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.22 (d, ³J_HH= 8.0 Hz, 2 H, ArH), 6.75 (t,

³J_HH= 8.0 Hz, 1 H, ArH), 3.98–3.37 (m, 2 H, NH, CH), 2.03–1.88 (m, 2 H,

CH₂), 1.82–1.68 (m, 2 H, CH₂), 1.67–1.53 (m, 1 H, CH₂), 1.40–1.08 (m, 5

H, CH₂).

R_f= 0.85 (cyclohexane–EtOAc, 3:1) (254 nm, KMnO₄: yellow).

IR (ATR): 3435, 2932, 2857, 1624, 1534, 1444, 1351, 1322, 1302, 1283,

1259, 1240, 1195, 1161, 1091, 1066, 934, 853, 805, 658, 625, 610 cm^–1

.

¹³C NMR (75.53 MHz, CDCl₃): δ = 142.1 (C_q), 128.8, 126.7 (C_q), 121.5,

55.4, 34.5, 25.9, 25.2.

L

J. Pletz et al.

Feature

Synthesis

¹H NMR (300 MHz, CDCl₃): δ = 7.07–6.94 (m, 1 H, ArH), 6.91–6.78 (m,

2 H, ArH), 3.95 (br s, 1 H, NH), 3.41–3.19 (m, 1 H, CH), 2.13–1.93 (m, 2

H, CH₂), 1.87–1.57 (m, 3 H, CH₂), 1.51–1.10 (m, 6 H, CH₂).

2-(Benzylamino)benzonitrile (16)

Prepared according to general procedure A from 2-aminobenzonitrile

(121 mg, 1.00 mmol) and benzaldehyde (155 μL, 1.5 mmol); 15 h re-

action time; purified by column chromatography (cyclohexane–EtOAc,

30:1, size: 11 × 2.6 cm); yield: 167 mg (803 μmol, 80%); colorless sol-

id; mp 110–112 °C; R_f= 0.15 (cyclohexane–EtOAc, 30:1) (254 nm, 366

nm, CAM: violet-grey).

1

¹³C NMR (75.53 MHz, CDCl₃): δ = 153.0 (d, J_CF= 243.1 Hz, C_q, Ar-F),

136.4 (d, ²J_CF= 12.3 Hz, C_q, Ar-N), 127.3 (dd, ²J_CF= 32.1 Hz, ⁴J_CF= 3.2 Hz,

1

2

C_q, Ar-CF₃), 124.4 (d, J_CF= 271.9 Hz, CF₃), 114.7 (d, J_CF= 20.3 Hz,

CH_arom), 113.3–112.7 (m, CH_arom), 109.0–108.7 (m, CH_arom), 51.4 (s,

CH), 33.3, 25.9, 25.0.

The spectra (see SI) were in accordance with the previously reported

data.³⁹

¹⁹F NMR (282 MHz, CDCl₃): δ = –62.07, –132.19.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₃H₁₅F₄N: 261.1141; found:

261.1145.

Methyl 2-(Benzylamino)benzoate (17)

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and benzaldehyde (33.9 μL, 330 μmol); 20 min

reaction time; purified by column chromatography (cyclohexane–

EtOAc, 100:1, 70:1, size: 12 × 2.4 cm); yield: 61.6 mg (255 μmol, 85%);

light-yellow, very viscous liquid; R_f= 0.72 (cyclohexane–EtOAc, 4:1)

(254 nm, 366 nm).

2-(Cyclohexylamino)benzonitrile (13)

Prepared according to general procedure A from 2-aminobenzonitrile

(121 mg, 1.00 mmol); 15 h reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 50:1, size: 11 × 2.6 cm); yield: 188

mg (938 μmol, 94%); colorless solid.

IR (ATR): 3380, 2945, 1672, 1601, 1576, 1516, 1494, 1453, 1434, 1323,

1287, 1225, 1187, 1166, 1147, 1102, 1077, 753, 728, 703, 693, 595,

Prepared according to general procedure B from 2-aminobenzonitrile

(36.2 mg, 300 μmol); 18 min reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 100:1, size: 16 × 0.8 cm); yield:

56.2 mg (281 μmol, 94%); colorless solid.

566, 527, 458 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 8.09 (br s, 1 H, NH), 7.84 (dd, ³J_HH= 8.0

4

Hz, J_HH= 1.3 Hz, 1 H, ArH), 7.36–7.12 (m, 6 H, ArH), 6.63–6.45 (m, 2

Prepared according to general procedure C from 2-aminobenzonitrile

(121 mg, 1.00 mmol); 15 min reaction time; purified by column chro-

matography (cyclohexane–EtOAc, 70:1, size: 7 × 2.7 cm); yield: 182

mg (910 μmol, 91%); light-yellow solid.

H, ArH), 4.37 (s, 2 H, CH₂), 3.78 (s, 3 H, CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.2 (C_q), 151.1 (C_q), 139.0 (C_q),

134.7, 131.8, 128.8, 127.3, 127.2, 115.0, 111.8, 110.4 (C_q), 51.6, 47.2.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₅H₁₅NO₂: 241.1103; found:

Mp 61–62 °C; R_f= 0.32 (cyclohexane–EtOAc, 30:1) (254 nm, 366 nm,

241.1108.

CAM: orange).

The spectra (see SI) were in accordance with the previously reported

data.³⁶

Methyl 2-[(Pyridin-3-ylmethyl)amino]benzoate (18)

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and 3-pyridinecarboxaldehyde (31.6 μL, 330

μmol); 10 min reaction time; purified by column chromatography

(cyclohexane–EtOAc, 3:1, 2:1, size: 15 × 0.8 cm); yield: 61.1 mg (252

μmol, 84%); light-yellow, viscous liquid; Rf = 0.16 (cyclohexane–EtOAc,

2:1) (254 nm, 366 nm).

N-Cyclohexyl-2-nitroaniline (14)

Prepared according to general procedure A from 2-nitroaniline (141

mg, 1.00 mmol); 21 h reaction time; purified by column chromatog-

raphy (cyclohexane–EtOAc, 50:1, size: 11 × 2.8 cm); yield: 162 mg

(735 μmol, 74%); bright-orange solid.

IR (ATR): 3473, 3365, 2950, 2846, 1680, 1607, 1586, 1516, 1487, 1452,

Prepared according to general procedure B from 2-nitroaniline (42.3

mg, 300 μmol); 30 min reaction time; purified by column chromatog-

raphy (cyclohexane–EtOAc, 80:1, size: 7.5 × 2.2 cm); yield: 62.1 mg

(282 μmol, 94%); bright-orange solid.

1297, 1238, 1188, 1161, 1094, 1024, 962, 748, 699, 665, 526, 499 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 8.70–8.62 (m, 1 H, ArH), 8.55 (d, ³J_HH

=

3.9 Hz, 1 H, ArH), 8.23 (br s, 1 H, NH), 7.96 (dd, ³J_HH= 8.0 Hz, ⁴J_HH= 1.2

Hz, 1 H, ArH), 7.70 (d, ³J_HH= 7.8 Hz, 1 H, ArH), 7.39–7.23 (m, 2 H, ArH),

6.71–6.58 (m, 2 H, ArH), 4.50 (d, ³J_HH= 5.5 Hz, 2 H, CH₂), 3.89 (s, 3 H,

CH₃).

Prepared according to general procedure C from 2-nitroaniline (42.3

mg, 300 μmol); 30 min reaction time; purified by column chromatog-

raphy (cyclohexane–EtOAc, 80:1, size: 7.5 × 2.2 cm); yield: 51.5 mg

(234 μmol, 78%); bright-orange solid.

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.2 (C_q), 150.6 (C_q), 149.1, 148.8,

134.9, 134.8, 134.5 (C_q), 131.9, 123.7, 115.5, 111.6, 110.71 (C_q), 51.7,

44.7.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₄H₁₄N₂O₂: 242.1055; found:

242.1058.

Mp 101–103 °C, R_f= 0.70 (cyclohexane–EtOAc, 2:1) (254 nm, VIS: or-

ange).

The spectra (see SI) were in accordance with the previously reported

data.³⁷

Methyl 2-(Cinnamylamino)benzoate (19)

N-Cyclohexylpyridin-3-amine (15)

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and cinnamic aldehyde (42.4 mg, 330 μmol); 10

min reaction time; purified by column chromatography (cyclohex-

ane–EtOAc, 50:1, size: 15 × 0.8 cm); yield: 65.0 mg (243 μmol, 81%);

yellow-orange, amorphous solid; mp 33–35 °C; R_f= 0.88 (cyclohex-

ane–EtOAc, 3:1) (254 nm, 366 nm, CAM: yellow).

Prepared according to general procedure B from 3-aminopyridine

(28.5 mg, 300 μmol); 11 min reaction time; purified by column chro-

matography (CH₂Cl₂–MeOH, 80:1, size: 13 × 1 cm); yield: 44.2 mg

(251 μmol, 84%); light-beige solid; mp 86–89 °C; R_f= 0.20 (CH₂Cl₂–

MeOH, 80:1) (254 nm, 366 nm, KMnO₄: yellow).

The spectra (see SI) were in accordance with the previously reported

data.³⁸

IR (ATR): 3386, 3362, 3023, 3003, 2947, 2844, 1675, 1605, 1575, 1513,

1436, 1318, 1278, 1254, 1219, 1191, 1163, 1149, 1096, 1081, 1048,

963, 743, 730, 691, 664, 528 cm^–1

.

M

J. Pletz et al.

Feature

Synthesis

¹H NMR (300 MHz, CDCl₃): δ = 8.10–7.75 (m, 2 H, NH, ArH), 7.41–7.14

CH₂), 3.82 (s, 3 H, CH₃), 3.65–3.49 (m, 1 H, CH), 3.22–3.00 (m, 2 H,

3

(m, 6 H, ArH), 6.71 (d, J_HH= 8.5 Hz, 1 H), 6.66–6.53 (m, 2 H), 6.37–

CH₂), 2.10–1.89 (m, 2 H, CH₂), 1.62–1.39 (m, 2 H, CH₂), 1.25 (t, J_HH

=

6.22 (m, 1 H), 4.05 (d, ³J_HH= 11.5 Hz, 2 H, CH₂), 3.85 (s, 3 H, CH₃).

7.0 Hz, 3 H, CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.2 (C_q), 151.1 (C_q), 137.0 (C_q),

134.7, 131.8, 131.6, 128.7, 127.6, 126.51, 126.47, 115.0, 111.8, 110.4

(C_q), 51.6, 45.1.

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.1 (C_q), 155.6 (C_q), 149.9 (C_q),

134.6, 132.0, 114.7, 111.5, 110.1 (C_q), 61.4, 51.5, 48.5, 42.2, 31.7, 14.7.

HR-MS: m/z [M]⁺calcd for C₁₆H₂₂N₂O₄: 306.1580; found: 306.1595.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₇H₁₇NO₂: 267.1259; found:

267.1273.

tert-Butyl 3-{[2-(Methoxycarbonyl)phenyl]amino}piperidine-1-

carboxylate (23)

Methyl 2-(Cyclopentylamino)benzoate (20)

Prepared according to general procedure A from methyl anthranilate

(131 μL, 1.00 mmol) and 1-Boc-3-piperidone (305 mg, 1.50 mmol);

44 h reaction time; purified by column chromatography (cyclohex-

ane–EtOAc, 20:1, size: 20 × 1.2 cm); yield: 220 mg (657 μmol, 66%);

light-yellow, very viscous liquid; R_f= 0.49 (cyclohexane–EtOAc, 3:1)

(254 nm, 366 nm, CAM: crimson).

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and cyclopentanone (29.5 μL, 330 μmol); 15 min

reaction time; purified by column chromatography (cyclohexane–

EtOAc, 250:1, size: 8 × 0.8 cm); yield: 63.0 mg (287 μmol, 96%); color-

less liquid; R_f= 0.20 (cyclohexane–EtOAc, 200:1) (254 nm, 366 nm,

CAM: orange-green).

IR (ATR): 3342, 2974, 2935, 2857, 1681, 1606, 1581, 1517, 1457, 1421,

IR (ATR): 3353, 2950, 2869, 1680, 1606, 1579, 1514, 1457, 1435, 1331,

1365, 1331, 1255, 1237, 1141, 1076, 973, 867, 747, 704, 526 cm^–1

.

1256, 1231, 1184, 1161, 1138, 1086, 1077, 1046, 745, 702, 526 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.97–7.70 (m, 2 H, NH, ArH), 7.34 (dd,

¹H NMR (300 MHz, CDCl₃): δ = 7.98–7.65 (m, 2 H, NH, ArH), 7.40–7.28

(m, 1 H, ArH), 6.72 (d, ³J_HH= 8.5 Hz, 1 H, ArH), 6.55 (t, ³J_HH= 7.5 Hz, 1

H, ArH), 3.95–3.75 (m, 4 H, CH, CH₃), 2.14–1.93 (m, 2 H, CH₂), 1.88–

1.49 (m, 6 H, CH₂).

³J_HH= 11.3 Hz, ⁴J_HH= 4.2 Hz, 1 H, ArH), 6.80 (d, ³J_HH= 8.2 Hz, 1 H, ArH),

3

6.59 (t, J_HH= 7.5 Hz, 1 H, ArH), 4.41–3.61 (m, 5 H, CH₃, CH₂), 3.54–

3.37 (m, 1 H, CH), 3.26–2.56 (m, 2 H, CH₂), 2.18–1.95 (m, 1 H, CH₂),

1.89–1.27 (m, 12 H, CH₂, 3 × CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.3 (C_q), 150.9 (C_q), 134.6, 131.8,

114.2, 112.2, 109.8 (C_q), 53.8, 51.5, 33.6, 24.2.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₃H₁₇NO₂: 219.1259; found:

219.1260.

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.2 (C_q), 154.8 (C_q), 150.0 (C_q),

134.8, 131.9, 115.0, 111.8, 110.3 (C_q), 79.7 (C_q), 51.6, 48.8, 48.4, 44.1,

31.0, 28.5, 23.8.

HR-MS (DI-EI): m/z [M]⁺calcd for C₁₈H₂₆N₂O₄: 334.1893; found

334.1894.

Methyl 2-(Cycloheptylamino)benzoate (21)

2-(Adamantan-2-ylamino)benzonitrile (24)

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and cycloheptanone (39.3 μL, 330 μmol); 15 min

reaction time; purified by column chromatography (cyclohexane–

EtOAc, 200:1, size: 8 × 0.8 cm); yield: 67.5 mg (273 μmol, 91%); color-

less, very viscous liquid; R_f= 0.23 (cyclohexane–EtOAc, 200:1) (254

nm, 366 nm, CAM: orange-green).

Prepared according to general procedure A from 2-aminobenzonitrile

(121 mg, 1.00 mmol) and 2-adamantanone (228 mg, 1.50 mmol); 41

h reaction time; purified by column chromatography (cyclohexane–

EtOAc, 50:1, size: 12 × 2.7 cm); yield: 203 mg (803 μmol, 80%); color-

less solid; mp 96–100 °C; R_f= 0.30 (cyclohexane–EtOAc, 50:1) (254

nm, 366 nm, CAM: light-violet).

IR (ATR): 3349, 2923, 2853, 1681, 1606, 1579, 1515, 1457, 1436, 1328,

1227, 1187, 1161, 1142, 1087, 1046, 841, 745, 702, 569, 525 cm^–1

.

IR (ATR): 3379, 3368, 3074, 2901, 2888, 2845, 2215, 1603, 1573, 1513,

1463, 1449, 1322, 1285, 1164, 1129, 1064, 1026, 810, 799, 740, 503

¹H NMR (300 MHz, CDCl₃): δ = 8.12–7.67 (m, 2 H, NH, ArH), 7.39–7.28

(m, 1 H, ArH), 6.73–6.46 (m, 2 H, ArH), 3.85 (s, 3 H, CH₃), 3.66–3.47

(m, 1 H, CH), 2.09–1.89 (m, 2 H, CH₂), 1.78–1.43 (m, 10 H, CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.3 (C_q), 150.2 (C_q), 134.6, 132.0,

114.1, 112.1, 109.9 (C_q), 52.9, 51.5, 34.7, 28.4, 24.4

cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.42–7.27 (m, 2 H, ArH), 6.71–6.49 (m,

2 H, ArH), 5.02–4.79 (m, 1 H, NH), 3.69–3.54 (m, 1 H, CH), 2.09–1.55

(m, 14 H, CH, CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 149.5 (C_q), 134.2, 132.9, 118.2 (C_q),

116.0, 111.2, 95.8 (C_q), 56.5, 37.6, 37.3, 31.6, 31.5, 27.4, 27.2.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₅H₂₁NO₂: 247.1572; found:

247.1589.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₇H₂₀N₂: 252.1626; found:

252.1627.

Ethyl 4-{[2-(Methoxycarbonyl)phenyl]amino}piperidine-1-car-

boxylate (22)

Methyl 2-(Adamantan-2-ylamino)benzoate (25)

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and ethyl 4-oxopiperidine-1-carboxylate (50.7 μL,

330 μmol); 15 min reaction time; purified by column chromatogra-

phy (cyclohexane–EtOAc, 7:1, 6:1, size: 6 × 2.2 cm); yield: 88.3 mg

(288 μmol, 96%); light-yellow, viscous liquid; R_f= 0.30 (cyclohexane–

EtOAc, 3:1) (254 nm, 366 nm, CAM: orange-green).

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and 2-adamantanone (50.1 mg, 330 μmol); 24

min reaction time; purified by column chromatography (cyclohex-

ane–EtOAc, 150:1, 120:1, size: 4 × 2.2 cm); yield: 80.8 mg (283 μmol,

94%); light-yellow, waxy solid; mp 98–100 °C; R_f= 0.73 (cyclohexane–

EtOAc, 9:1) (254 nm, 366 nm, CAM: crimson).

IR (ATR): 3342, 2981, 2948, 2856, 1680, 1605, 1581, 1517, 1455, 1431,

1379, 1330, 1238, 1220, 1192, 1155, 1128, 1096, 1075, 1032, 974,

IR (ATR): 3360, 2961, 2905, 2853, 1681, 1604, 1579, 1516, 1456, 1433,

1328, 1254, 1227, 1162, 1076, 1062, 796, 746, 701, 583, 551, 526, 497

848, 747, 703, 559 cm^–1

.

cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.99–7.69 (m, 2 H, ArH, NH), 7.31 (t,

³J_HH= 7.8 Hz, 1 H, ArH), 6.67 (d, ³J_HH= 8.5 Hz, 1 H, ArH), 6.56 (t, ³J_HH

7.5 Hz, 1 H, ArH), 4.12 (q, ³J_HH= 7.0 Hz, 2 H, CH₂-O), 4.04–3.87 (m, 2 H,

=

N

J. Pletz et al.

Feature

Synthesis

¹H NMR (300 MHz, CDCl₃): δ = 8.21 (br s, 1 H, NH), 7.83 (d, ³J_HH= 8.0

Hz, 1 H, ArH), 7.23 (t, ³J_HH= 7.8 Hz, 1 H, ArH), 6.59 (d, ³J_HH= 8.6 Hz, 1

H, ArH), 6.44 (t, J_HH= 7.5 Hz, 1 H, ArH), 3.79 (s, 3 H, CH₃), 3.66–3.52

(m, 1 H, CH), 2.06–1.45 (m, 14 H, CH₂, CH).

¹³C NMR (75.53 MHz, CDCl₃): δ = 168.3 (C_q), 149.3 (C_q), 133.5, 130.9,

¹H NMR (300 MHz, CDCl₃): δ = 7.89 (d, ³J_HH= 8.0 Hz, 1 H, ArH), 7.66 (br

s, 1 H, NH), 7.33 (t, ³J_HH= 7.8 Hz, 1 H, ArH), 6.70 (d, ³J_HH= 8.5 Hz, 1 H,

ArH), 6.53 (t, ³J_HH= 7.5 Hz, 1 H, ArH), 3.85 (s, 3 H, CH₃), 3.71–3.55 (m,

1 H, CH-N), 1.87–1.70 (m, 1 H, CH), 1.65–1.50 (m, 1 H, CH₂), 1.44–1.15

(m, 4 H, CH₃, CH₂), 1.03–0.80 (m, 6 H, 2 × CH₃).

3

112.8, 110.6, 108.5 (C_q), 55.0, 50.4, 36.7, 36.3, 30.8, 30.6, 26.4, 26.3.

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.3 (C_q), 150.8 (C_q), 134.7, 132.0,

114.0, 111.6, 109.7 (C_q), 51.5, 46.7, 45.8, 25.2, 22.9, 21.1.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₄H₂₁NO₂: 235.1572; found:

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₈H₂₃NO₂: 285.1729; found:

285.1740.

235.1585.

2-(Pentan-2-ylamino)benzonitrile (26)

Methyl 2-[(4-Methoxy-4-oxobutan-2-yl)amino]benzoate (29)

Prepared according to general procedure A from 2-aminobenzonitrile

(121 mg, 1.00 mmol) and 2-pentanone (164 μL, 1.5 mmol); 39 h reac-

tion time; purified by column chromatography (cyclohexane–EtOAc,

50:1, size: 11 × 2.6 cm); yield: 150 mg (795 μmol, 80%); light-yellow,

sticky solid; R_f= 0.31 (cyclohexane–EtOAc, 30:1) (254 nm, 366 nm,

CAM: yellow).

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and methyl acetoacetate (36.0 μL, 330 μmol); 6 h

reaction time; purified by column chromatography (cyclohexane–

EtOAc, 17:1, size: 8 × 0.8 cm); yield: 50.8 mg (202 μmol, 67%); color-

less, viscous liquid; R_f= 0.55 (cyclohexane–EtOAc, 3:1) (254 nm, 366

nm, CAM: orange-green).

IR (ATR): 3407, 3363, 2960, 2931, 2872, 2210, 1604, 1575, 1512, 1461,

1380, 1324, 1289, 1167, 1042, 744, 568, 495 cm^–1

.

IR (ATR): 3341, 2952, 1735, 1682, 1605, 1581, 1516, 1457, 1435, 1323,

1299, 1239, 1190, 1162, 1130, 1077, 1047, 1005, 748, 703, 527 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.41–7.29 (m, 2 H, ArH), 6.70–6.55 (m,

2 H, ArH), 4.34 (br s, 1 H, NH), 3.64–3.47 (m, 1 H, CH), 1.67–1.31 (m, 4

H, 2 × CH₂), 1.22 (d, ³J_HH= 6.3 Hz, 3 H, CH₃), 0.94 (t, ³J_HH= 7.1 Hz, 3 H,

CH₃).

¹³C NMR (76 MHz, CDCl₃): δ = 149.9 (C_q), 134.3, 133.0, 118.2 (C_q),

116.0, 111.0, 95.7 (C_q), 48.3, 39.2, 20.7, 19.4, 14.1.

¹H NMR (300 MHz, CDCl₃): δ = 8.00–7.65 (m, 2 H, NH, ArH), 7.41–7.30

(m, 1 H, ArH), 6.75 (d, ³J_HH= 8.5 Hz, 1 H, ArH), 6.59 (t, ³J_HH= 7.3 Hz, 1

H, ArH), 4.16–3.99 (m, 1 H. CH), 3.85 (s, 3 H, CH₃), 3.69 (s, 3 H, CH₃),

2

3

2

2.73 (dd, J_HH= 15.1 Hz, J_HH= 5.0 Hz, 1 H, CH₂), 2.43 (dd, J_HH= 15.1

Hz, ³J_HH= 7.8 Hz, 1 H, CH₂), 1.33 (d, ³J_HH= 6.4 Hz, 3 H, CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 172.1 (C_q, C-12), 169.1 (C_q, C-2),

149.8 (C_q, C-8), 134.8 (CH_arom), 132.0 (CH_arom), 115.0 (CH_arom), 111.8

(CH_arom), 110.4 (C_q, C-3), 51.8 (CH₃), 51.6 (CH₃), 45.1 (C-10), 41.2 (C-

11), 20.8 (C-9).

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₂H₁₆N₂: 188.1313; found:

188.1315.

2-[(4-Methylpentan-2-yl)amino]benzonitrile (27)

HR-MS: m/z [M]⁺calcd for C₁₃H₁₇NO₄: 251.1158; found: 251.1172.

Prepared according to general procedure A from 2-aminobenzonitrile

(121 mg, 1.00 mmol) and 4-methylpentan-2-one (191 μL, 1.5 mmol);

39 h reaction time; purified by column chromatography (cyclohex-

ane–EtOAc, 50:1, size: 11 × 2.6 cm); yield: 139 mg (685 μmol, 69%);

colorless, amorphous solid; mp 30–32 °C; Rf = 0.34 (cyclohexane–EtOAc,

30:1) (254 nm, 366 nm, CAM: yellow).

Methyl 2-[(3,3-Dimethylbutan-2-yl)amino]benzoate (30)

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol), pinacolone (57.4 μL, 450 μmol) and TMSOTf (139

μL, 750 μmol, instead of TMSCl); left stirring in the thawing ice bath;

20 h reaction time; purified by column chromatography (cyclohex-

ane–EtOAc, 1:0, 120:1, size: 14 × 2.5 cm); yield: 35.2 mg (150 μmol,

50%); yellow, viscous liquid; R_f= 0.23 (cyclohexane–EtOAc, 120:1)

(254 nm, 366 nm, CAM: orange-yellow).

IR (ATR): 3356, 2959, 2918, 2863, 2839, 2214, 1604, 1574, 1516, 1464,

1432, 1366, 1324, 1292, 1268, 1165, 1035, 742, 567, 523, 489, 430

cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 7.43–7.28 (m, 2 H, ArH), 6.72–6.54 (2

IR (ATR): 3345, 2955, 2871, 1680, 1606, 1580, 1518, 1457, 1435, 1370,

1350, 1321, 1254, 1232, 1189, 1161, 1119, 1080, 1046, 745, 702, 520

H, ArH), 4.30 (br s, 1 H, NH), 3.70–3.50 (m, 1 H, CH-N), 1.84–1.66 (m, 1

H, CH), 1.58–1.41 (m, 1 H, CH₂), 1.40–1.27 (m, 1 H, CH₂), 1.19 (d, ³J_HH

=

cm^–1

.

6.9 Hz, 3 H, CH₃), 1.02–0.80 (m, 6 H, 2 × CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 149.9 (C_q), 134.3, 133.3, 118.2 (C_q),

116.0, 110.9, 95.7 (C_q), 46.6, 46.5, 25.1, 22.8, 22.7, 21.0.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₃H₁₈N₂: 202.1470; found:

¹H NMR (300 MHz, CDCl₃): δ = 8.17–7.81 (m, 2 H, NH, ArH), 7.37–7.27

(m, 1 H, ArH), 6.73 (d, ³J_HH= 8.6 Hz, 1 H, ArH), 6.51 (t, ³J_HH= 7.4 Hz, 1

3

H, ArH), 3.85 (s, 3 H, CH₃), 3.45–3.30 (m, 1 H, CH), 1.14 (d, J_HH= 6.5

Hz, 3 H, CH₃), 1.02 (s, 9 H, 3 × CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.5 (C_q), 151.3 (C_q), 134.7, 132.0,

202.1484.

113.8, 111.6, 109.5 (C_q), 56.6, 51.6, 35.0 (C_q), 26.7, 15.7.

HR-MS: m/z [M]⁺calcd for C₁₄H₂₁NO₂: 235.1572; found: 235.1602.

Methyl 2-[(4-Methylpentan-2-yl)amino]benzoate (28)

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol) and 4-methylpentan-2-one (42.2 μL, 330 μmol);

left stirring in the thawing ice bath; 23 h reaction time; purified by

column chromatography (cyclohexane–EtOAc, 150:1, 120:1, size: 12

× 2.4 cm); yield: 30.6 mg (130 μmol, 43%); light-yellow, viscous liq-

uid; R_f= 0.77 (cyclohexane–EtOAc, 9:1) (254 nm, 366 nm, CAM: yel-

low).

2-[(1-Phenylethyl)amino]benzonitrile (31)

Prepared according to general procedure A from 2-aminobenzonitrile

(121 mg, 1.00 mmol) and acetophenone (178 μL, 1.5 mmol); 39 h re-

action time; purified by column chromatography (cyclohexane–EtOAc,

50:1, size: 11 × 2.6 cm); yield: 156 mg (701 μmol, 70%); colorless,

crystalline solid; mp 84 °C; R_f= 0.27 (cyclohexane–EtOAc, 30:1) (254

nm, 366 nm, CAM: red-grey).

IR (ATR): 3346, 2955, 2927, 2870, 1682, 1606, 1579, 1516, 1458, 1435,

1325, 1249, 1224, 1189, 1163, 1132, 1083, 1047, 746, 703, 527 cm^–1

.

O

J. Pletz et al.

Feature

Synthesis

IR (ATR): 3361, 3024, 2973, 2930, 2866, 2213, 1603, 1577, 1517, 1491,

1470, 1448, 1342, 1330, 1316, 1291, 1261, 1167, 1147, 1095, 1023,

¹H NMR (300 MHz, CDCl₃): δ = 7.99 (d, ⁴J_HH= 2.3 Hz, 1 H, ArH), 7.71 (d,

³J_HH= 7.2 Hz, 1 H, NH), 7.37 (dd, ³J_HH= 9.0 Hz, ⁴J_HH= 2.2 Hz, 1 H, ArH),

6.58 (d, J_HH= 9.1 Hz, 1 H, ArH), 3.84 (s, 3 H, CH₃), 3.66 (s, 3 H, CH₃),

3

947, 759, 741, 700, 608, 565, 541, 484, 445 cm^–1

.

3.44–3.25 (m, 1 H, CH), 2.51–2.30 (m, 2 H, CH, CH₂), 2.19–1.84 (m, 3

H, CH₂), 1.52–1.12 (m, 4 H, CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 175.3 (C_q), 168.1 (C_q), 149.1 (C_q),

137.2 (CH_arom), 134.2 (CH_arom), 113.6 (CH_arom), 111.4 (C_q), 105.6 (C_q),

51.84, 51.81, 50.7, 42.5, 35.3, 32.6, 28.5, 24.4.

¹H NMR (300 MHz, CDCl₃): δ = 7.41–7.14 (m, 7 H, ArH), 6.60 (t, ³J_HH

=

7.5 Hz, 1 H, ArH), 6.41 (d, ³J_HH= 8.5 Hz, 1 H, ArH), 4.89 (br s, 1 H, NH),

4.62–4.47 (m, 1 H, CH), 1.57 (d, ³J_HH= 6.7 Hz, 1 H, CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 149.4 (C_q), 143.8 (C_q), 134.2, 132.7,

129.0, 127.4, 125.7, 118.1 (C_q), 116.8, 112.1, 96.0 (C_q), 53.4, 25.0

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₅H₁₄N₂: 222.1157; found:

222.1167.

(1S*,3S*)-33

R_f= 0.47 (cyclohexane–EtOAc, 5:1) (254 nm, 366 nm, CAM: orange).

IR (ATR): 3344, 2936, 2860, 1730, 1683, 1575, 1502, 1435, 1314, 1215,

Methyl 2-[(1-Phenylethyl)amino]benzoate (32)

1188, 1113, 1079, 1042, 967, 883, 808, 788, 706 644, 564, 521 cm^–1

.

Prepared according to general procedure B from methyl anthranilate

(39.2 μL, 300 μmol), acetophenone (53.5 μL, 450 μmol) and TMSOTf

(139 μL, 750 μmol, instead of TMSCl); left stirring in the thawing ice

bath; 23 h reaction time; purified by column chromatography (cyclo-

hexane–EtOAc, 80:1, size: 8 × 0.8 cm); yield: 66.3 mg (260 μmol,

87%); colorless, viscous liquid; R_f= 0.14 (cyclohexane–EtOAc, 120:1)

(254 nm, 366 nm, CAM: orange-red).

¹H NMR (300 MHz, CDCl₃): δ = 7.99 (d, ⁴J_HH= 2.3 Hz, 1 H, ArH), 7.90 (d,

³J_HH= 6.8 Hz, 1 H, NH), 7.39 (dd, ⁴J_HH= 9.0, ³J_HH= 2.2 Hz, 1 H, ArH), 6.67

(d, ³J_HH= 9.1 Hz, 1 H, ArH), 3.92–3.62 (m, 7 H, CH, 2 × CH₃), 2.77–2.63

(m, 1 H, CH), 2.14–1.96 (m, 1 H, CH₂), 1.89–1.49 (m, 7 H, CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 175.9 (C_q), 168.3 (C_q), 149.2 (C_q),

137.4 (CH_arom), 134.1 (CH_arom), 113.7 (CH_arom), 111.3 (C_q), 105.6 (C_q),

51.8, 47.0, 38.7, 32.6, 31.1, 28.1, 21.2.

IR (ATR): 3352, 3026, 2965, 2950, 2869, 1681, 1605, 1580, 1514, 1451,

1436, 1324, 1241, 1202, 1163, 1124, 1080, 1046, 1017, 747, 698, 557,

522 cm^–1

.

Methyl 5-Iodo-2-{[3-(methoxycarbonyl)cyclohexyl]amino}benzo-

ate (34)

¹H NMR (300 MHz, CDCl₃): δ = 8.13 (br s, 1 H, NH), 7.82 (dd, ³J_HH= 8.0

Hz, ⁴J_HH= 1.2 Hz, 1 H, ArH), 7.33–7.03 (m, 6 H, ArH), 6.45 (t, ³J_HH= 7.6

Hz, 1 H, ArH), 6.36 (d, ³J_HH= 8.5 Hz, 1 H, ArH), 4.57–4.41 (m, 1 H, CH),

3.81 (s, 3 H, O-CH₃), 1.51 (d, ³J_HH= 6.7 Hz, 3 H, CH₃).

¹³C NMR (75.53 MHz, CDCl₃): δ = 169.4 (C_q), 150.3 (C_q), 145.0 (C_q),

134.6, 131.6, 128.8, 127.0, 125.9, 114.9, 112.9, 110.2 (C_q), 53.0, 51.6,

25.2.

A dry 100 mL Schlenk flask with magnetic stirring bar was charged

with methyl 2-amino-5-iodobenzoate hydrochloride (6.69 g, 21.3

mmol, 1.0 equiv) and the solid was dried under an oil-pump vacuum

for 10 min. To the Schlenk flask were added anhyd DMF (40 mL) fol-

lowed by methyl 3-oxocyclohexane-1-carboxylate⁴⁰(3.50 g, 22.4

mmol, 1.05 equiv) and TMSCl (8.30 mL, 64.0 mmol, 3.0 equiv). The

glass stopper was replaced by a rubber septum, the flesh-colored,

two-phase mixture was cooled with an ice bath, and BH₃·THF (23.0

mL, 23.0 mmol, 1.08 equiv) was added over a period of 60 min. The

flask was sealed and the mixture was left stirring at 0 °C until full

conversion of the starting material was detected by TLC (30 min). The

light-yellow solution was carefully treated with H₂O (20 mL), fol-

lowed by neutralization with 25% NH₄OH. The solvents were removed

under vacuum and the residue was adsorbed on Celite (24 g, suspend-

ed in MeOH) and purified by column chromatography (cyclohexane–

EtOAc, 15:1, 10:1, 8:1, 6:1, 300 g silica gel, size: 13 × 7.5 cm); yield:

8.61 g (20.6 mmol, 97%); yellow, very viscous liquid.

HR-MS (GC-EI): m/z [M]⁺calcd for C₁₆H₁₇NO₂: 255.1259; found:

255.1267.

Methyl 5-Bromo-2-{[3-(methoxycarbonyl)cyclohexyl]amino}ben-

zoate (33)

A dry 100 mL Schlenk flask with magnetic stirring bar was charged

with methyl 2-amino-5-bromobenzoate hydrobromide (2.37 g, 7.62

mmol, 1.0 equiv) and the solid was dried under an oil-pump vacuum

for 10 min. To the Schlenk flask were added anhyd DMF (5 mL), meth-

yl 3-oxocyclohexane-1-carboxylate⁴⁰(1.25 g, 8.00 mmol, 1.05 equiv),

and TMSCl (2.95 mL, 22.9 mmol, 3.0 equiv) at r.t. The glass stopper

was replaced by a rubber septum, the yellow two-phase mixture was

cooled to 0 °C, and BH₃·THF (7.60 mL, 7.60 mol, 1.0 equiv) was added

by syringe over a period of 42 min. The flask with the colorless solu-

tion with colorless precipitate was sealed and was left stirring for 48

min at 0 °C, when full conversion was detected by TLC. H₂O (10 mL)

was added carefully, followed by neutralization with 25% NH₄OH. The

solvents were removed under vacuum and the residue was adsorbed

on Celite (7 g, suspending in MeOH) and purified by column chroma-

tography (cyclohexane–EtOAc, 20:1, 15:1, 12:1, 80 g silica gel, size: 18

× 3.5 cm); yield: 2.70 g (7.30 μmol, 96%); light-yellow, very viscous

liquid.

HR-MS (DI-EI): m/z [M]⁺calcd for C₁₆H₂₀INO₄: 417.0437; found:

417.0443.

(1S*,3R*)-34

R_f= 0.46 (cyclohexane–EtOAc, 4:1) (254 nm, 366 nm, CAM: yellow).

IR (ATR): 3338, 2937, 2859, 1732, 1682, 1591, 1571, 1500, 1435, 1403,

1320, 1308, 1247, 1201, 1127, 1106, 1075, 1015, 965, 899, 806, 788,

758, 697, 637, 572, 518 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 8.15 (d, ⁴J_HH= 2.1 Hz, 1 H, ArH), 7.73 (d,

³J_HH= 7.2 Hz, 1 H, NH), 7.51 (dd, ³J_HH= 8.9 Hz, ⁴J_HH= 1.9 Hz, 1 H, ArH),

3

6.48 (d, J_HH= 9.0 Hz, 1 H, ArH), 3.83 (s, 3 H, CH₃), 3.66 (s, 3 H, CH₃),

HR-MS (DI-EI): m/z [M]⁺calcd for C₁₆H₂₀BrNO₄: 369.0576; found:

369.0580.

3.41–3.25 (m, 1 H, CH), 2.52–2.28 (m, 2 H, CH, CH₂), 2.17–1.82 (m, 3

H, CH₂), 1.52–1.11 (m, 4 H, CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 175.3 (C_q), 168.0 (C_q), 149.5 (C_q),

142.7 (CH_arom), 140.2 (CH_arom), 114.1 (CH_arom), 112.2 (C_q), 73.9 (C_q),

51.84, 51.79, 50.6, 42.4, 35.3, 32.6, 28.4, 24.4.

(1S*,3R*)-33

R_f= 0.40 (cyclohexane–EtOAc, 5:1) (254 nm, 366 nm, CAM: orange).

IR (ATR): 3339, 2946, 2859, 1733, 1685, 1598, 1574, 1502, 1435, 1407,

1308, 1245, 1201, 1127, 1108, 1074, 1015, 966, 898, 807, 787, 706,

(1S*,3S*)-34

644, 569, 519 cm^–1

.

R_f= 0.51 (cyclohexane–EtOAc, 4:1) (254 nm, 366 nm, CAM: yellow).

P

J. Pletz et al.

Feature

Synthesis

IR (ATR): 3342, 2946, 2859, 1730, 1681, 1591, 1571, 1499, 1435, 1404,

1314, 1215, 1188, 1140, 1111, 1081, 1042, 807, 788, 697, 644, 562,

A.; Kahlcke, N.; Feurer, M.; Roth, S. Chem. Eur. J. 2011, 17, 12203.

(f) Matsumura, T.; Nakada, M. Tetrahedron Lett. 2014, 55, 1829.

With PMHS, see: (g) Chandrasekhar, S.; Reddy, C. R.; Ahmed, M.

Synlett 2000, 1655. (h) Patel, J. P.; Li, A.-H.; Dong, H.; Korlipara,

V. L.; Mulvihill, M. J. Tetrahedron Lett. 2009, 50, 5975. (i) Kumar,

V.; Sharma, S.; Sharma, U.; Singh, B.; Kumar, N. Green Chem.

2012, 14, 3410. (j) Nayal, O. S.; Bhatt, V.; Sharma, S.; Kumar, N.

J. Org. Chem. 2015, 80, 5912. With PhSiH₃, see: (k) Apodaca, R.;

Xiao, W. Org. Lett. 2001, 3, 1745. (l) Smith, C. A.; Cross, L. E.;

Hughes, K.; Davis, R. E.; Judd, D. B.; Merritt, A. T. Tetrahedron

Lett. 2009, 50, 4906.

520 cm^–1

.

¹H NMR (300 MHz, CDCl₃): δ = 8.16 (d, ⁴J_HH= 2.0 Hz, 1 H, ArH), 7.93 (d,

³J_HH= 7.0 Hz, 1 H, NH), 7.53 (dd, ³J_HH= 8.9 Hz, ⁴J_HH= 1.6 Hz, 1 H, ArH),

6.57 (d, ³J_HH= 9.0 Hz, 1 H, ArH), 3.94–3.62 (m, 7 H, 2 × CH₃, CH), 2.78–

2.62 (m, 1 H, CH), 2.13–1.92 (m, 1 H, CH₂), 1.90–1.51 (m, 7 H, CH₂).

¹³C NMR (75.53 MHz, CDCl₃): δ = 175.9 (C_q), 168.2 (C_q), 149.6 (C_q),

142.8 (CH_arom), 140.1 (CH_arom), 114.3 (CH_arom), 112.1 (C_q), 73.9 (C_q),

51.8 (2 × CH₃), 46.9, 38.7, 32.5, 31.0, 28.1, 21.2.

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6605. (g) Lei, Q.; Wei, Y.; Talwar, D.; Wang, C.; Xue, D.; Xiao, J.

Chem. Eur. J. 2013, 19, 4021. (h) Talwar, D.; Salguero, N. P.;

Robertson, C. M.; Xiao, J. Chem. Eur. J. 2014, 20, 245.

(i) Gülcemal, D.; Gülcemal, S.; Robertson, C. M.; Xiao, J. Organo-

metallics 2015, 34, 4394.

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Fujihara, S.; Yamamoto, T.; Ohta, T.; Ito, Y. Tetrahedron 2005, 61,

6988. (b) Li, C.; Villa-Marcos, B.; Xiao, J. J. Am. Chem. Soc. 2009,

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Chem. Int. Ed. 2014, 53, 5199. (h) Kolesnikov, P. N.; Yagafarov, N.

Z.; Usanov, D. L.; Maleev, V. I.; Chusov, D. Org. Lett. 2015, 17,

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M.; Vaccaro, L. Org. Lett. 2015, 17, 3990.

Acknowledgment

Financial support by the Austrian Science Fund FWF (Project I-668)

and NAWI Graz is gratefully acknowledged. We thank Prof. Wulf

Blankenfeldt (Helmholtz-Zentrum für Infektionsforschung, Braun-

schweig/D) for our continuous collaboration in the development of

inhibitors of the phenazine biosynthesis pathway, Prof. Hansjörg

Weber for NMR measurements, and Mario Mugitsch, Manuel

Köckinger, and Minh-Hao Hoang for skillful assistance in the lab.

Supporting Information

Supporting information for this article is available online at

http://dx.doi.org/10.1055/s-0035-1561384.

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A General and Direct Reductive Amination of Aldehydes and Ketones with Electron-Deficient Anilines

DOI: 10.1055/s-0035-1561384

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