Hydrogen-Borrowing Amination of Secondary Alcohols Promoted by a (Cyclopentadienone)iron Complex

DOI: 10.1055/s-0039-1690101

Source and publish data:

Synthesis p. 3545 - 3555 (2019)

Update date:2022-08-02

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Authors:

Aiolfi, Francesco

Bai, Xishan

Cettolin, Mattia

Dal Corso, Alberto

Gennari, Cesare

Piarulli, Umberto

Pignataro, Luca

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Article abstract of DOI:10.1055/s-0039-1690101

Thanks to a highly active catalyst, the scope of the (cyclopentadienone)iron complex-promoted 'hydrogen-borrowing' (HB) amination has been expanded to secondary alcohols, which had previously been reported to react only in the presence of large amounts of co-catalysts. A range of cyclic and acyclic secondary alcohols were reacted with aromatic and aliphatic amines giving fair to excellent yields of the substitution products. The catalyst was also able to promote the cyclization of diols bearing a secondary alcohol group with primary amines to generate saturated N-heterocycles.

Full text of DOI:10.1055/s-0039-1690101

SYNTHESIS

2019, 51, A–K

paper

X. Bai et al.

Paper

Synthesis

Hydrogen-Borrowing Amination of Secondary Alcohols Promoted

by a (Cyclopentadienone)iron Complex

Xishan Bai^a

Francesco Aiolfi^a

Mattia Cettolin^a

Umberto Piarulli^b

Alberto Dal Corso^a

Luca Pignataro*^a

Cesare Gennari*^a

0-0

2-6

0-0

7-8

0-0

2-7

0-9

00-0

2-7

^aUniversità degli Studi di Milano, Dipartimento di

Chimica, Via C. Golgi 19, 20133 Milano, Italy

^bUniversità degli Studi dell’Insubria, Dipartimento di

Scienza e Alta Tecnologia, Via Valleggio 11, 22100

Como, Italy

luca.pignataro@unimi.it

cesare.gennari@unimi.it

Received: 18.04.2019

Accepted after revision: 27.05.2019

Published online: 26.06.2019

cent years, when catalytic methodologies relying on base

metals have been increasingly studied.^3aIn this context, Fe-

ringa, Barta et al. reported in 2014 the first application of a

well-defined homogeneous iron catalyst for the HB amina-

tion of alcohols: the ‘Knölker complex’ 1a (Figure 1) was

shown to promote the amination of several primary alco-

hols and diols.^10c

DOI: 10.1055/s-0039-1690101; Art ID: ss-2019-t0234-op

Abstract Thanks to a highly active catalyst, the scope of the (cyclo-

pentadienone)iron complex-promoted ‘hydrogen-borrowing’ (HB) ami-

nation has been expanded to secondary alcohols, which had previously

been reported to react only in the presence of large amounts of co-cat-

alysts. A range of cyclic and acyclic secondary alcohols were reacted

with aromatic and aliphatic amines giving fair to excellent yields of the

substitution products. The catalyst was also able to promote the cy-

clization of diols bearing a secondary alcohol group with primary

amines to generate saturated N-heterocycles.

R³

Overall transformation

R²

R¹

R²

Key words hydrogen borrowing, iron, amination, alcohols, (cyclopenta-

dienone)iron complexes

Cat.

Cat.-H₂

Alcohol amination is an attractive and atom-economic

reaction which provides access to amines – a valuable class

of fine chemicals¹– generating H₂O as the only by-product.

As OH^–is a poor leaving group, this transformation cannot

occur via the S_N2 mechanism and, on the other hand, its

acid-promoted version requires harsh conditions.²Catalytic

processes involving the ‘hydrogen-borrowing’ (HB) mecha-

nism (also known as ‘hydrogen autotransfer’)³are the most

effective way to perform alcohol amination. In these reac-

tions, an alcohol dehydrogenation/imine formation/imine

hydrogenation sequence takes place (Scheme 1 A), with no

net consumption or release of hydrogen. The catalyst has

the role to temporarily store a H₂molecule taken from the

substrate and then transfer it to the imine intermediate,

thus forming the amine product. Rhodium, ruthenium, and

iridium complexes were initially used to catalyze HB ami-

nations⁴and, after remarkable progress in the area,³most

recent studies have focused on the latter two noble met-

als.^5,6Cheaper metals such as copper,⁷cobalt⁸and iron⁹

have been much less exploited for HB amination until re-

R³

R²

R¹

R²

R¹

R³NH₂

H₂O

R¹

R²

Me₃NO

base

H₂O

R¹

or hν

Precatalyst 1

2 (Cat.-H₂)

act-1 (Cat.)

Scheme 1 A: general mechanism of HB amination of alcohols. B: for-

mation of HB amination catalysts (act-1 and 2) from (cyclopentadien-

one)iron complexes 1

This methodology had the advantage of using a highly

stable and easy-to-handle pre-catalyst, which can be readi-

ly activated in situ (see Scheme 1 B). The main limitation

was that the substrate scope is restricted to primary alco-

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

X. Bai et al.

Paper

Synthesis

hols. Further reports on the use of (cyclopentadienone)iron

complexes 1¹¹in HB amination by Feringa/Barta,^10a,bPoat-

er/Renaud,¹²and Morrill^13a(Figure 1) did not expand the

scope to the more challenging secondary alcohols.¹³To this

end, Wills and co-workers (Figure 1) showed that pre-cata-

lysts 1c–h can promote the amination of a few cycloal-

kanols.¹⁴Zhao et al. reported that the isolated catalyst 2a, in

the presence AgF (40 mol%) as co-catalyst, is able to pro-

mote the HB amination of secondary alcohols in fair to good

yields.¹⁵

However, the latter methodology suffers from serious

limitations such as high catalyst loading (10 mol%) and sen-

sitivity of the isolated complex 2a, which cannot be han-

dled in the air. Most importantly, the necessity of large

amounts of a semi-precious metal co-catalyst (AgF) offsets

the economic and environmental advantages of using an

iron catalyst.

This paper accounts for the effort taken by our research

group – building on its expertise in this area¹⁶– to extend

the use of (cyclopentadienone)iron complexes to the HB

amination of secondary alcohols. To this end, we exploited

our previously reported pre-catalyst 1i (Figure 1).^16dThis

complex showed superior activity compared to other (cy-

clopentadienone)iron complexes, such as the ‘Knölker com-

plex’ 1a, in the catalytic transfer hydrogenation (CTH) of ke-

timines and in the CTH-based reductive amination of ke-

tones.^16b,cAs these reactions share the same elementary

steps of the HB amination, we expected 1i to display suffi-

cient activity to promote the amination of secondary alco-

hols.

A preliminary test in the HB amination of a primary al-

cohol [1-octanol (4a)] with p-anisidine (3a) showed that 1i

is indeed more active than 1a, giving >95% (Table 1, entry 1)

versus 69% yield (reported by Barta, Feringa et al. using

1a).¹⁷Thus, we tested pre-catalyst 1i in the reaction of 3a

with 1-phenylethanol (4b) under the same conditions used

with 1-octanol, and observed a poor conversion to the de-

sired product P2 (entry 2). The presence of 3Å molecular

sieves in the reaction environment positively affected the

conversion (entry 3 vs 2), possibly accelerating the imine

formation step (see Scheme 1). Varying the reaction stoichi-

ometry was found to remarkably affect the conversion (en-

tries 4–10), the best result (76%) being obtained with 4:1

alcohol/amine ratio (entry 5). The addition of a Brønsted

acid to the reaction environment – expected to accelerate

the imine formation step – did not significantly impact on

the conversion (entries 11, 12). Next, the amination of 4b

was carried out in several different aprotic solvents (entries

13–17), but lower conversions than in toluene were ob-

served. To conclude the optimization, the reaction tempera-

ture was increased from 130 to 150 °C (entry 18 vs 5),

which allowed to increase the conversion to 89%.

With the optimized conditions in hand, a number of

secondary alcohols were screened in the reaction with p-

anisidine (3a). To our delight, good to excellent yields were

achieved in several cases (Table 2), thus demonstrating the

synthetic value of our 1i-based catalytic methodology.

A careful examination of the data allows to recognize

the following general trends:

1) Yields roughly decreased with the increasing steric

bulk surrounding the OH group, that is, along the series 4b

→ 4c → 4l → 4m → 4n for benzylic alcohols (Table 2, entries

1, 2, 11–13), 4d → 4e → 4g → 4h → 4f for aliphatic alcohols

(entries 3–7), and 4i → 4k → 4j for allylic alcohols (entries

8–10).

2) Extending the reaction time to 72 hours allowed to

significantly improve the yield of the reactions, which were

incomplete after 24 hours (Table 2, entries 2, 5, 7–9, 11–13).

Hence, it is evident that the catalytic complex undergoes no

or slow decomposition under the reaction conditions, and

thus remains active for a long time.

Feringa, Barta et al.¹⁰

Morrill et al.^12a

Poater, Renaud et al.¹³

Morrill et al.^12a

Wills et al.¹⁴

Zhao et al.¹⁵

This work

TMS

1d Ar = Ph

1e Ar = 4-MeOC₆H₄

1f Ar = 3,4,5-(MeO)₃-C₆H₂

1g Ar = 4-ClC₆H₄

AgF (40 mol%)

1h Ar = 4-(F₃CC)-C₆H₄

primary alcohols/diols

primary alcohols

- primary alcohols/diols

- cycloalkanols

- primary alcohols

- secondary alcohols

- primary alcohols/diols

- secondary alcohols/diols

Figure 1 Previous applications of (cyclopentadienone)iron complexes in HB amination

X. Bai et al.

Paper

Synthesis

Table 1 HB Amination of Alcohols with p-Anisidine Promoted by Precatalyst 1i – Optimization^a

1i (5 mol%)

Me₃NO (10 mol%)

NH₂

PMP

R²

additive(s)

R¹

solvent, 130 °C

24 h

4a (R¹= C₇H₁₅, R²= H)

4b (R¹= Ph, R²= Me)

P1 (R¹= C₇H₁₅, R²= H)

P2 (R¹= Ph, R²= Me)

MeO

Entry

Solvent

Alcohol

Alcohol/3a

1.5:1

Additive(s)

Conv. (%)^b

toluene

–

95^c

1.5:1

3:1

–

3Å MS (400 mg)

4:1

6:1

10:1

1:1

1:1.5

1:4

4:1

3Å MS (400 mg)

TFA (1 mol%)

toluene

4:1

3Å MS (400 mg)

AcOH (1 mol%)

18^e

CPME^d

1,4-dioxane

DMF

4:1

3Å MS (400 mg)

DME

DCE

toluene

^aReaction conditions: 3a/1i/Me₃NO = 100:5:10. Catalyst activation: solvent, Me₃NO, r.t., 15 min, C_0,cat.= 0.1 M; HB amination: solvent, C_0,sub.= 0.25 M (0.5

mmol), 130 °C, 24 h.

^bDetermined by ¹H NMR analysis of the reaction crude.

^cIsolated yield.

^dCPME: Cyclopentyl methyl ether.

^eReaction run at 150 °C.

The latter finding is in agreement with the kinetic stud-

ies previously reported by our group for the catalytic hy-

drogenation of ketones, showing that 1i retains its activity

for a longer period than 1a.^16dSuch remarkable stability is

possibly due to the presence of bulky cyclooctane rings

fused to the cyclopentadienone and may explain the higher

observed activity of complex 1i compared to other mem-

bers of its family.^16b,cConsistent with this interpretation,

when the HB amination of cyclohexanol 4h (Table 2, entry

7, pre-catalyst 1i) was repeated using pre-catalyst 1a under

the same conditions, a much lower yield of product P8 was

obtained (32% at 24 h and 63% at 72 h).

The 1i-catalyzed synthesis of amine P7 was uneventful-

ly repeated on gram-scale (Table 2, entry 6). Interestingly,

the amination of allylic alcohols took place along with par-

tial (entry 10) or complete (entries 8 and 9) reduction of the

C=C bond. This outcome is due to the presence of excess al-

cohol which acts as terminal reducing agent. After the ini-

tial dehydrogenation step, generating the ,-unsaturated

ketone 5, three possible pathways may be conceived

(Scheme 2). Path 1, involving two C=N 1,2-reduction steps,

was ruled out on the basis of a control experiment showing

that allylic amine 6, prepared according to known proce-

dures,¹⁸is unreactive at 150 °C in the presence of catalyst 1i

and alcohol 4i (see the Supporting Information). Path 2 and

Path 3, involving a 1,4-reduction¹⁹followed by a C=N 1,2-re-

duction, are both viable and probably operating.

We screened also other functionalized alcohols and

achieved a good result with alcohol 4o, possessing a tertiary

amino group, which gave the corresponding secondary

amine P15 in good yields (Table 2, entry 14). -Hydroxy-

esters (e.g., methyl lactate, methyl mandelate, ethyl malate)

were also tested but failed to afford the desired amination

products.

X. Bai et al.

Paper

Synthesis

Path 1

NH₂

act-1i/2i

PMP

MeO

– act-1i

6 (R = Me)

7a (R = Me)

7b (R = Me)

act-1i

Path 2

– act-1i

act-1i

H₂N

OMe

– act-1i

– 2i

PMP

Path 3

– act-1i

NH₂

PMP

MeO

– act-1i

Scheme 2 Possible pathways for the amination of allylic alcohols with concomitant C=C bond reduction

Table 2 Screening of Alcohol Substrates in the HB Amination with p-Anisidine Promoted by Precatalyst 1i^a

1i (5 mol%)

Me₃NO (10 mol%)

NH₂

PMP

3 Å MS

R¹

R²

toluene, 150 °C

R²

MeO

Entry

Alcohol

Product

Yield (%)^b

t = 24 h

t = 72 h

PMP

99 (99)^c

X. Bai et al.

Paper

Synthesis

Table 2 (continued)

Entry

Alcohol

Product

Yield (%)^b

t = 24 h

t = 72 h

PMP

P10

PMP

40 (1:1)^d

49 (1:1)^d

P11

PMP

P12

PMP

TMS

P13

PMP

P14

PMP

MeN

P15

^aReaction conditions: alcohol/3a/1i/Me₃NO = 400:100:5:10. Catalyst activation: toluene, Me₃NO, r.t., 15 min, C_0,cat.= 0.1 M; HB amination: toluene, C_0,sub.= 0.25

M(0.5 mmol), 150 °C.

^bIsolated yield after column chromatography.

^cYield of gram-scale experiment.

^dRatio P8:P11.

Next, a series of different amine nucleophiles were

screened in the HB amination of 1-phenylethanol 4b (Table

3).

was limited to substrates bearing primary alcohol groups.²⁰

Thus, we tested pre-catalyst 1i in the cyclization of 2,5-hex-

anediol (8) with several primary amines (Table 4).

Analogously to what we observed in the alcohol screen-

ing (Table 2), increasing the steric bulk of the nucleophile

decreased the yields: N-methylbenzylamine (3f) gave lower

yields than benzylamine (3e) (Table 3, entry 6 vs 5) and 2,4-

dimethoxyaniline (3b) was found less reactive than p-anisi-

dine (3a), yet giving useful yields (entry 2 vs 1). Aliphatic

3c,d and benzylic amines 3e,f showed lower reactivity than

anilines 3a,b (entries 3–6 vs 1, 2), although also in this case

extended reaction times (72 vs 24 h) allowed to remarkably

improve the yields.

Delightfully, 2,5-dimethylpyrrolidine products were ob-

tained in good yields from aniline 3a and the benzylic

amines 3e, 3g, and 3h; while in the former case a long reac-

tion time positively affected the yield (Table 4, entry 1),

with benzylic amines a reaction time of 24 hours led to

similar (entry 3) or even higher yields (entries 2 and 4) than

an extended one (72 h). 2,5-Dimethylpyrrolidines P21–P24

were obtained as cis/trans-diastereoisomer mixtures, as de-

termined by ¹H NMR analysis,²¹and the cis-product was the

most abundant in all cases.

(Cyclopentadienone)iron complexes have been reported

to promote the reaction of diols with primary amines to

yield saturated N-heterocycles,^10b,c,14abut so far the scope

In conclusion, in this paper the scope of the HB amina-

tion of alcohols promoted by (cyclopentadienone)iron-

complexes has been remarkably expanded, thanks to the

X. Bai et al.

Paper

Synthesis

high activity of pre-catalyst 1i.^16b–dIn the presence of 5

mol% 1i and Me₃NO, a range of cyclic and acyclic secondary

alcohols were aminated in good yields without need of ex-

pensive co-catalysts such AgF.¹⁵Notably, this reaction has

been extended for the first time to a secondary diol [2,5-

hexanediol (8)], which afforded the corresponding 2,5-di-

methylpyrrolidine products in good yields. We believe that

these achievements represent an important step towards

the replacement of precious metal catalysts with cheap and

environmentally friendly base metal complexes in a very

important and atom-economic transformation such as the

HB amination of alcohols.

60 F254 pre-coated glass plates (0.25 mm thickness). Visualization

was accomplished by irradiation with a UV lamp and/or staining with

an alkaline KMnO₄solution or with a ninhydrin solution. Flash col-

umn chromatography was performed using silica gel (60 Å, particle

size 40–64 m) as stationary phase, following the procedure by Still

and co-workers.^{22 1}H NMR spectra were recorded on a spectrometer

operating at 400.13 MHz. Proton chemical shifts are reported in ppm

() with the solvent reference relative to TMS as the internal standard

(CDCl₃,  = 7.26; CD₂Cl₂ = 5.32). Standard abbreviations are used to

describe spin multiplicity. ¹³C NMR spectra were recorded on a 400

MHz spectrometer operating at 100 MHz, with complete proton de-

coupling. Carbon chemical shifts are reported in ppm () relative to

TMS with the respective solvent resonance as the internal standard

(CDCl₃ = 77.16; CD₂Cl₂ = 54.00). The coupling constant values are

given in hertz (Hz). ¹⁹F NMR spectra were recorded on a 300 MHz

spectrometer operating at 282 MHz, with complete proton decou-

pling. Fluorine chemical shifts are reported in ppm () relative to ex-

ternal CFCl₃at 0 ppm (positive values downfield). IR spectra were re-

corded on a standard FT/IR spectrophotometer. High-resolution mass

All reactions were carried out in flame-dried glassware with magnet-

ic stirring under inert atmosphere (N₂or argon), unless otherwise

stated. The reactions were monitored by analytical TLC using silica gel

Table 3 Screening of Amine Nucleophiles in the HB Amination of 1-Phenylethanol Promoted by Precatalyst 1i^a

1i (5 mol%)

Me₃NO (10 mol%)

R²

R¹

3 Å MS

R¹

R²

toluene, 150 °C

Entry

Amine

Product

Yield (%)^b

t = 24 h

t = 72 h

PMP

NH₂

MeO

OMe

NH₂

MeO

OMe

P16

P17

P18

P19

P20

NH₂

^aReaction conditions: 4b/amine/1i/Me₃NO = 400:100:5:10. Catalyst activation: toluene, Me₃NO, r.t., 15 min, C_0,cat.= 0.1 M; HB amination: toluene, C_0,sub.= 0.25

M (0.5 mmol), 150 °C.

^bIsolated yield after column chromatography.

X. Bai et al.

Paper

Synthesis

Table 4 Amination of Primary Amines with 2,5-Hexanediol Promoted by Precatalyst 1i^a

1i (5 mol%)

Me₃NO (10 mol%)

3 Å MS

RNH₂

toluene, 150 °C

Entry

Amine

Product

Yield (%)^b

t = 24 h

t = 72 h

NH₂

MeO

25 (57:43)^c

66 (79:21)^c

71 (58:42)^c

43 (79:21)^c

MeO

P21

NH₂

P22

NH₂

55 (76:24)^c

72 (73:27)^c

60 (79:21)^c

66 (76:24)^c

P23

CF₃

NH₂

CF₃

P24

^aReaction conditions: 8/amine/1i/Me₃NO = 400:100:5:10. Catalyst activation: toluene, Me₃NO, r.t., 15 min, C_0,cat.= 0.1 M; HB amination: toluene, C_0,sub.= 0.25 M

(0.5 mmol), 150 °C.

^bIsolated yield after column chromatography.

^ccis/trans Ratio determined by ¹H NMR of the reaction crude.²¹

spectra (HRMS) were performed on a ESI QTof SYNAPT G2 Si mass

spectrometer (Waters), available at the UNITECH-COSPECT laborato-

ries (Università degli Studi di Milano).

filtered through Celite (rinsing several times with EtOAc), and then

the solvent was removed with a rotavapor. The product was purified

by flash chromatography.

Toluene was distilled from Na/benzophenone before use, and trans-

ferred under N₂. Alcohols and amines used in the substrate screening

were purchased from commercial suppliers (TCI Chemicals, ACROS,

Sigma Aldrich). The liquid amines were distilled before use, whereas

the other reagents were used as received. Pre-catalyst 1i was pre-

pared as previously described by our group.^16d3Å MS were dried un-

der high vacuum at 200 °C and then stored in an oven at 110 °C.

4-N-Octylamino-1-methoxybenzene (P1)^10c

Reaction time: 24 h; yield: 111.8 mg (95%); yellow oil; R_f= 0.24 (95:5

hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.78 (d, J = 8.9 Hz, 2 H), 6.58 (d, J = 8.9

Hz, 2 H), 3.75 (s, 3 H), 3.06 (t, J = 7.1 Hz, 2 H), 1.62–1.56 (m, 2 H),

1.41–1.26 (m, 10 H), 0.88 (t, J = 6.7 Hz, 3 H).

HB Amination of Alcohols; General Procedure

4-Methoxy-N-(1-phenylethyl)aniline (P2)²³

Toluene (0.25 mL) was added to a mixture of pre-catalyst 1i (9.6 mg,

0.025 mmol, 0.05 equiv) and Me₃NO (3.8 mg, 0.050 mmol, 0.010

equiv) under argon in a Schlenk vessel fitted with a Teflon screw cap.

The resulting solution, which gradually turned from yellow to dark

red, was stirred for 20 minutes at r.t. The amine substrate 3 (0.5

mmol, 1 equiv) was added, followed by 3Å MS (beads, 400 mg), the

respective alcohol (2.0 mmol, 4.0 equiv), and additional toluene (1.75

mL). The reaction vessel was sealed and stirred in a pre-heated oil

bath at 150 °C for 24 h or 72 h. After cooling down, the mixture was

Reaction time: 72 h; yield: 108.0 mg (95%); yellow oil; R_f= 0.23 (98:2

hexane/EtOAc + 0.1% Et₃N).

¹H NMR (400 MHz, CDCl₃):  = 7.42–7.34 (m, 4 H), 7.28–7.24 (m, 1 H),

6.74 (d, J = 8.8 Hz, 2 H), 6.52 (d, J = 8.8 Hz, 2 H), 4.45 (q, J = 6.8 Hz, 1 H),

3.73 (s, 3 H), 1.53 (d, J = 6.8 Hz, 3 H).

4-Methoxy-N-[1-(naphthalen-2-yl)ethyl]aniline (P3)²⁴

Reaction time: 72 h; yield: 89.0 mg (64%); pale yellow solid; mp 97–

99 °C (Lit.²⁵mp 98–100 °C); R_f= 0.28 (95:5 hexane/EtOAc).

X. Bai et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 7.83–7.79 (m, 4 H), 7.52 (dd, J = 8.4, 1.6

Hz, 1 H), 7.48–7.41 (m, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 6.55 (d, J = 9.0 Hz,

2 H), 4.58 (q, J = 6.8 Hz, 1 H), 3.68 (s, 3 H), 1.60 (d, J = 6.8 Hz, 3 H).

¹H NMR (400 MHz, CDCl₃):  = 6.79 (d, J = 8.9 Hz, 2 H), 6.61 (d, J = 8.8

Hz, 2 H), 5.86–5.74 (m, 2 H), 3.92 (br s, 1 H), 3.77 (s, 3 H), 2.11–2.03

(m, 2 H), 1.94–1.87 (m, 1 H), 1.76–1.55 (m, 3 H).

4-(Isopropylamino)anisole (P4)^10c

N-(1,3-Diphenylprop-2-yn-1-yl)-4-methoxyaniline (P12)³¹

Reaction time: 24 h; yield: 79.0 mg (95%); yellow oil; R_f= 0.30 (95:5

Reaction time: 72 h; yield: 42.3 mg (27%); yellow oil; R_f= 0.20 (95:5

hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.80 (d, J = 8.8 Hz, 2 H), 6.62 (d, J = 8.8

Hz, 2 H), 3.77 (s, 3 H), 3.57 (m, 1 H), 1.20 (d, J = 6.6 Hz, 6 H).

¹H NMR (400 MHz, CDCl₃):  = 7.67–7.65 (m, 2 H), 7.42–7.38 (m, 4 H),

7.36–7.27 (m, 4 H), 6.82–6.75 (m, 4 H), 5.41 (s, 1 H), 3.88 (br s, 1 H),

3.76 (s, 3 H).

4-Methoxy-N-(octan-2-yl)aniline (P5)²⁶

(Z)-3-(4-Methoxyphenylamino)-1-phenylprop-2-en-1-one (P13)³²

Reaction time: 24 h; yield: 117.0 mg (99%); yellow oil; R_f= 0.28 (99:1

hexane/EtOAc).

Reaction time: 72 h; yield: 34.5 mg (29%); colorless oil; R_f= 0.26 (98:2

hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.77 (d, J = 9.0 Hz, 2 H), 6.62–6.59 (m, 2

H), 3.75 (s, 3 H), 3.36 (q, J = 6.0 Hz, 1 H), 1.43–1.27 (m, 10 H), 1.16 (d,

J = 6.0 Hz, 3 H), 0.88 (t, J = 6.9 Hz, 3 H).

¹H NMR (400 MHz, CDCl₃):  = 12.12 (d, J = 12.2 Hz, 1 H), 7.90–7.82 (d,

J = 6.5 Hz, 2 H), 7.51–7.42 (m, 4 H), 6.99 (d, J = 8.9 Hz, 2 H), 6.83 (d, J =

8.9 Hz, 2 H), 5.91 (d, J = 7.7 Hz, 1 H), 3.74 (s, 3 H).

4-Methoxy-N-(3-pentyl)aniline (P6)²⁷

N-Benzhydryl-4-methoxyaniline (P14)³³

Reaction time: 72 h; yield: 51.2 mg (53%); light orange oil; R_f= 0.26

(99:1 hexane/EtOAc).

Reaction time: 72 h: yield 43.4 mg (30%); yellow solid; mp 78–80 °C

(Lit.³⁴mp 81 °C); R_f= 0.29 (95:5 hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.83–6.75 (d, J = 8.9 Hz, 2 H), 6.61–6.55

(d, J = 8.9 Hz, 2 H), 3.77 (s, 3 H), 3.17 (pent, J = 5.9 Hz, 1 H), 1.61–1.42

(m, 4 H), 0.95 (t, J = 7.4 Hz, 6 H).

¹H NMR (400 MHz, CD₂Cl₂):  = 7.39–7.30 (m, 8 H), 7.27–7.23 (m, 2

H), 6.68 (d, J = 8.8 Hz, 2 H), 6.50 (d, J = 8.8 Hz, 2 H), 5.44 (s, 1 H), 4.12

(br s, 1 H), 3.67 (s, 3 H).

N-Cyclopentyl-4-methoxyaniline (P7)²⁸

N-(4-Methoxyphenyl)-1-methylpiperidin-4-amine (P15)³⁵

Reaction time: 24 h; yield: 94.7 mg (99%). Gram-scale experiment;

yield: 1.51 g (99%) using 0.995 g (8.0 mmol) of p-anisidine; pale yel-

low oil; R_f= 0.30 (95:5 hexane/EtOAc).

Reaction time: 24 h; yield: 92.5 mg (84%); yellow oil; R_f= 0.21 (9:1

DCM/MeOH + 0.5% Et₃N).

¹H NMR (400 MHz, CDCl₃):  = 6.80 (d, J = 8.9 Hz, 2 H), 6.60 (d, J = 8.9

Hz, 2 H), 3.77 (s, 3 H), 3.75 (m, 1 H), 2.02 (m, 2 H), 1.75 (m, 2 H), 1.63

(m, 2 H), 1.54–1.40 (m, 2 H).

¹H NMR (400 MHz, CDCl₃):  = 6.77 (d, J = 8.9 Hz, 2 H), 6.58 (d, J = 8.9

Hz, 2 H), 3.74 (s, 3 H), 3.24–3.17 (m, 1 H), 2.85–2.82 (m, 2 H), 2.31 (s, 3

H), 2.17–2.03 (m, 4 H), 1.53–1.44 (m, 2 H).

N-Cyclohexyl-4-methoxyaniline (P8)^10c

2,4-Dimethoxy-N-(1-phenylethyl)aniline (P16)³⁶

Reaction time: 72 h; yield: 97.5 mg (95%); white solid; mp 43–44 °C

Reaction time: 72 h; yield: 91.4 mg (71%); white solid; mp 77–78 °C

(Lit.²⁸mp 45–46 °C); R_f= 0.42 (9:1 hexane/EtOAc).

(Lit.³⁶mp 78 °C); R_f= 0.20 (95:5 hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.77 (d, J = 8.8 Hz, 2 H), 6.59 (d, J = 8.8

Hz, 2 H), 3.74 (s, 3 H), 3.20–3.14 (m, 1 H), 2.08–2.02 (m, 2 H), 1.79–

1.76 (m, 2 H), 1.67–1.61 (m, 1 H), 1.40–1.11 (m, 5 H).

¹H NMR (400 MHz, CDCl₃):  = 7.37–7.29 (m, 4 H), 7.23–7.19 (m, 1 H),

6.44 (t, J = 1.4 Hz, 1 H), 6.24–6.23 (m, 2 H), 4.40 (q, J = 6.7 Hz, 1 H),

4.29 (br s, 1 H), 3.86 (s, 3 H), 3.69 (s, 3 H), 1.53 (d, J = 6.7 Hz, 3 H).

N-(sec-Butyl)-4-methoxyaniline (P9)²⁹

1-(1-Phenylethyl)pyrrolidine (P17)³⁷

Reaction time: 72 h; yield: 27.8 mg (31%); light brown oil; R_f= 0.32

Reaction time: 72 h; yield: 65.7 mg (75%); colorless oil; R_f= 0.22 (8:2

(95:5 hexane/EtOAc).

hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.80 (d, J = 8.9 Hz, 2 H), 6.64 (d, J = 8.9

Hz, 2 H), 3.77 (s, 3 H), 3.38–3.28 (m, 1 H), 1.70–1.57 (m, 1 H), 1.53–

1.41 (m, 1 H), 1.18 (d, J = 6.3 Hz, 3 H), 0.97 (t, J = 7.4 Hz, 3 H).

¹H NMR (400 MHz, CDCl₃):  = 7.38–7.22 (m, 5 H), 3.21 (q, J = 6.6 Hz, 1

H), 2.58 (m, 2 H), 2.44–2.34 (m, 2 H), 1.82–1.75 (m, 4 H), 1.43 (d, J =

6.6 Hz, 3 H).

4-Methoxy-N-(pentan-2-yl)aniline (P10)²⁸

4-(1-Phenylethyl)morpholine (P18)³⁸

Reaction time: 72 h; yield: 27.1 mg (28%); yellow oil; R_f= 0.28 (95:5

Reaction time: 72 h; yield: 52.0 mg (54%); colorless oil; R_f= 0.14 (8:2

hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.80 (d, J = 8.9 Hz, 2 H), 6.61 (d, J = 8.9

Hz, 2 H), 3.77 (s, 3 H), 3.41 (m, 1 H), 1.63–1.53 (m, 1 H), 1.48–1.37 (m,

3 H), 1.18 (d, J = 6.3 Hz, 3 H), 0.95 (t, J = 7.1 Hz, 3 H).

¹H NMR (400 MHz, CDCl₃):  = 7.34 (m, 4 H), 7.30–7.23 (m, 1 H), 3.71

(t, J = 4.7 Hz, 4 H), 3.32 (q, J = 6.7 Hz, 1 H), 2.56–2.47 (m, 2 H), 2.42–

2.32 (m, 2 H), 1.38 (d, J = 6.7 Hz, 3 H).

N-(Cyclohex-2-en-1-yl)-4-methoxyaniline (P11)³⁰

N-Benzyl-1-phenylethylamine (P19)³⁹

Reaction time: 72 h; yield: 25.4 mg (25%); yellow oil; R_f= 0.27 (98:2

Reaction time: 72 h; yield 82.4 mg (78%); yellow oil; R_f= 0.21 (95:5

hexane/EtOAc).

X. Bai et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 7.36–7.24 (m, 10 H), 3.82 (q, J = 6.8 Hz,

1 H), 3.67 (d, J = 13.1 Hz, 1 H), 3.60 (d, J = 13.1 Hz, 1 H), 1.37 (d, J = 6.4

Hz, 3 H).

HRMS (ESI+): m/z [M + H]⁺calcd for C₁₃H₁₉FN: 208.1502; found:

208.1501.

2,5-Dimethyl-1-(3-(trifluoromethyl)benzyl)pyrrolidine (P24, mix-

ture of diastereomers)

N-Benzyl-N-methyl-1-phenylethylamine (P20)⁴⁰

Reaction time: 72 h; yield: 48.4 mg (43%); yellow oil; R_f= 0.35 (95:5

Reaction time: 24 h; yield: 92.6 mg (72%); yellow oil; R_f= 0.24 (97:3

hexane/EtOAc).

hexane/EtOAc 85:15 + 0.1% Et₃N).

¹H NMR (400 MHz, CDCl₃):  = 7.46–7.20 (m, 10 H), 3.67 (q, J = 6.8 Hz,

1 H), 3.61 (d, J = 13.3 Hz, 1 H), 3.33 (d, J = 13.3 Hz, 1 H), 2.16 (s, 3 H),

1.45 (d, J = 6.8 Hz, 3 H).

IR (film): 2964.05, 2928.38, 2871.49, 2803.03, 2611.14, 1676.80,

1615.09, 1597.73, 1491.67, 1451.17, 1374.03, 1329.68, 1256.40,

1199.51, 1163.83, 1126.22, 1091.51, 1073.19, 948.81, 920.84, 889.99,

799.35, 750.17, 702.93, 660.50 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 7.64 (s, 1 H, trans-isomer), 7.59 (s, 1 H,

cis-isomer), 7.56 (d, J = 7.6 Hz, 1 H, trans-isomer), 7.52 (d, J = 7.8 Hz, 1

H, cis-isomer), 7.47 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 3.85 (d,

J = 14.4 Hz, 1 H, trans-isomer), 3.75 (s, 2 H, cis-isomer), 3.60 (d, J =

14.4 Hz, 1 H, trans-isomer), 3.04–3.00 (m, 2 H, trans-isomer), 2.61–

2.56 (m, 2 H, cis-isomer), 2.04–1.98 (m, 2 H, trans-isomer), 1.85–1.79

(m, 2 H, cis-isomer), 1.43–1.35 (m, 2 H), 1.00 (d, J = 6.0 Hz, 6 H, cis-

isomer), 0.96 (d, J = 6.4 Hz, 6 H, trans-isomer).

¹³C NMR (100 MHz, CDCl₃):  = 142.2 (trans-isomer), 141.9 (cis-iso-

mer), 132.2 (q, J_C,F= 1.5 Hz, cis-isomer), 131.8 (q, J_C,F= 1.5 Hz, trans-

isomer), 130.5 (q, J_C,F= 31.7 Hz, trans-isomer), 130.4 (q, J_C,F= 31.7 Hz,

cis-isomer), 128.5 (trans-isomer), 128.4 (cis-isomer), 125.5 (q, J_C,F= 4

1-(4-Methoxyphenyl)-2,5-dimethylpyrrolidine (P21, mixture of

diastereomers)²¹

Reaction time: 72 h; yield: 72.9 mg (71%); yellow oil; R_f= 0.28 (99:1

hexane/EtOAc).

¹H NMR (400 MHz, CDCl₃):  = 6.86 (m, 2 H), 6.65 (d, J = 9.1 Hz, 2 H,

cis-isomer), 6.58 (d, J = 9.1 Hz, 2 H, trans-isomer), 4.01–3.93 (m, 2 H,

trans-isomer), 3.78 (s, 3 H), 3.71–3.62 (m, 2 H, cis-isomer), 2.37–2.15

(m, 2 H, trans-isomer), 2.07–1.99 (m, 2 H, cis-isomer), 1.77–1.67 (m, 2

H, cis-isomer), 1.67–1.59 (m, 2 H, trans-isomer), 1.27 (d, J = 6.2 Hz, 6

H, cis-isomer), 1.09 (d, J = 6.1 Hz, 6 H, trans-isomer).

1-Benzyl-2,5-dimethylpyrrolidine (P22, mixture of diastereo-

mers)²¹

Hz, cis-isomer), 125.1 (q, J_C,F= 4 Hz, trans-isomer), 124.5 (d, J_C,F

270.5 Hz, trans-isomer), 124.5 (d, J_C,F= 270.4 Hz, cis-isomer), 123.5 (q,

J_C,F= 4 Hz, cis- and trans-isomer), 60.9 (cis-isomer), 55.9 (cis-isomer),

55.1 (trans-isomer), 51.4 (trans-isomer), 31.5 (cis-isomer), 31.1

(trans-isomer), 21.0 (cis-isomer), 17.3 (trans-isomer).

¹⁹F NMR (282 MHz, CDCl₃):  = –62.46.

HRMS (ESI+): m/z [M + H]⁺calcd for C₁₄H₁₉F₃N: 258.1470; found:

Reaction time: 24 h; yield: 62.5 mg (66%); yellow oil; R_f= 0.50 (95:5

DCM/MeOH).

¹H NMR (400 MHz, CDCl₃):  = 7.38–7.25 (m, 4 H), 7.24–7.20 (m, 1 H),

3.83 (d, J = 13.6 Hz, 1 H, trans-isomer), 3.74 (s, 2 H, cis-isomer), 3.52

(d, J = 13.6 Hz, 1 H, trans-isomer), 3.04–3.00 (m, 2 H, trans-isomer),

2.60–2.55 (m, 2 H, cis-isomer), 2.05–1.97 (m, 2 H, trans-isomer),

1.81–1.75 (m, 2 H, cis-isomer), 1.40–1.34 (m, 2 H, cis- and trans-iso-

mer), 1.05 (d, J = 6.0 Hz, 6 H, cis-isomer), 0.97 (d, J = 6.0 Hz, 6 H, trans-

isomer).

258.1472.

Funding Information

1-(3-Fluorobenzyl)-2,5-dimethylpyrrolidine (P23, mixture of dias-

tereomers)

X. Bai thanks the China Scholarship Council for a Ph.D. fellowship

(CSC No. 201608410107). L. Pignataro thanks ‘Piano di Sostegno alla

Ricerca 2015–2017’ (Dipartimento di Chimica, Università degli Studi

di Milano) and PRIN 2017 – Progetto 20174SYJAF (MIUR) for financial

Reaction time: 72 h; yield: 62.2 mg (60%); light yellow oil; R_f= 0.21

(98:2 DCM/MeOH).

IR (film): 2962.13, 2927.41, 2870.52, 2802.06, 1616.06, 1590.99,

1485.88, 1450.21, 1373.07, 1350.89, 1328.71, 1254.47, 1203.36,

1130.08, 1073.19, 992.20, 944.95, 926.63, 871.67, 783.92, 745.35,

support.

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Supporting Information

¹H NMR (400 MHz, CD₂Cl₂):  = 7.27–7.22 (m, 1 H), 7.15–7.08 (m, 2

H), 6.92–6.87 (m, 1 H), 3.80 (d, J = 14.4 Hz, 1 H, trans-isomer), 3.67 (s,

2 H, cis-isomer), 3.56 (d, J = 14.4 Hz, 1 H, trans-isomer), 3.02–3.00 (m,

2 H, trans-isomer), 2.63–2.57 (m, 2 H, cis-isomer), 2.02–1.97 (m, 2 H,

trans-isomer), 1.83–1.78 (m, 2 H, cis-isomer), 1.38–1.35 (m, 2 H), 0.98

(d, J = 6.4 Hz, 6 H, cis-isomer), 0.95 (d, J = 6.4 Hz, 6 H, trans-isomer).

Supporting information for this article is available online at

https://doi.org/10.1055/s-0039-1690101.

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References

¹³C NMR (100 MHz, CD₂Cl₂):  = 163.6 (d, J_C,F= 242.4 Hz, trans-iso-

mer), 163.4 (d, J_C,F= 242.5 Hz, cis-isomer), 144.8 (d, J_C,F= 9.2 Hz), 130.0

(d, J_C,F= 9 Hz, trans-isomer), 129.8 (d, J_C,F= 8.3 Hz, cis-isomer), 124.8

(d, J_C,F= 2.6 Hz, cis-isomer), 124.5 (d, J_C,F= 2.6 Hz, trans-isomer), 116.0

(d, J = 21.1 Hz, cis-isomer), 115.6 (d, J = 21.2 Hz, trans-isomer), 113.7

(d, J_C,F= 21.1 Hz, trans-isomer), 113.7 (d, J = 21.1 Hz, cis-isomer), 61.6

(cis-isomer), 56.4 (cis-isomer), 55.6 (trans-isomer), 51.6 (trans-iso-

mer), 32.1 (cis-isomer), 31.6 (trans-isomer), 21.4 (cis-isomer), 17.5

(trans-isomer).

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